BIOLOGICAL PROPERTIES OF ADRIAMYCIN BOUND TO BIODEGRADABLE POLYMERIC CARRIERS

NARCIS (Netherlands)

HOES, CJT; GROOTOONK, J; DUNCAN, R; HUME, IC; BHAKOO, M; BOUMA, JMW; FEIJEN, J

Three different conjugates having adriamycin (ADR) bound to the side chain carboxyl groups of high-molecular weight poly(alpha-L-glutamic acid) (PGA) either directly or by interpolation of GlyGly and GlyGlyGlyLeu spacers, respectively, were compared with respect to immunogenicity and cytotoxicity in

Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction

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Chen, Shuyuan [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Chen, Jiaxi [The University of Texas Southwestern Medical Center at Dallas, Medical School, 5235 Harry Hine Blvd., Dallas, TX (United States); Huang, Pintong [Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province (China); Meng, Xing-Li; Clayton, Sandra; Shen, Jin-Song [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Grayburn, Paul A., E-mail: paulgr@baylorhealth.edu [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Department of Internal Medicine, Division of Cardiology, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall St, Suite H030, Dallas, TX (United States)

2015-03-20

Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. Methods and results: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. Conclusions: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. - Highlights: • The activation of nuclear FoxO1 in cardiac muscle cells associated with adriamycin cardiomyopathy. • Myocardial nuclear GLP-1 stimulates myocardial regeneration and reverses adriamycin cardiomyopathy. • The process of myocardial regeneration associated with dedifferentiation and proliferation.

Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction

International Nuclear Information System (INIS)

Chen, Shuyuan; Chen, Jiaxi; Huang, Pintong; Meng, Xing-Li; Clayton, Sandra; Shen, Jin-Song; Grayburn, Paul A.

2015-01-01

Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. Methods and results: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. Conclusions: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. - Highlights: • The activation of nuclear FoxO1 in cardiac muscle cells associated with adriamycin cardiomyopathy. • Myocardial nuclear GLP-1 stimulates myocardial regeneration and reverses adriamycin cardiomyopathy. • The process of myocardial regeneration associated with dedifferentiation and proliferation

Effect of eplerenone on serum TNF-α levels in adriamycin induced heart failure male rat models

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Xuan Nan; Song Liping; Xing Haiyan

2009-01-01

Objective: To investigate the effect of eplerenone on serum TNF-α levels in adriamycin induced heart failure male rat models. Methods: Forty male rat models of adriamycin-induced heart failure were prepared with weekly intraperitoneal injection of adriamycin (4/mg/kg) for six weeks. Twenty surviving models were randomly divided into two groups: (1)eplerenone-treated group, n=10, treated with garage of eplerenone 200mg/kg/d for 12 weeks (2) non-treated group n=10. All the surviving models (group (1) n=8, group (2) n=6) were sacrificed after 12 weeks with left ventricular hemodynamic function parameters tested and serum TNF-α levels measured. Ten male rats without adriamycin administration served as controls. Results: Left ventricular hemodynamic parameters in the non-treated group were significantly worse than those in controls (P<0.05). The parameters in the eplerenone treated group were significantly better than those in the non-treated group (P<0.05). The serum TNF-α levels in the non-treated group were significantly higher than those in controls (P<0.05). TNF-α levels in the eplerenone group were significantly lower than those in the non-treated group (P<0.05). Conclusion: Eplerenone could reduce the serum TNF-α levels in the rat models of heart failure. (authors)

Adriamycin-induced oxidative stress is prevented by mixed hydro-alcoholic extract of Nigella sativa and Curcuma longa in rat kidney.

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Mohebbati, Reza; Shafei, Mohammad Naser; Soukhtanloo, Mohammad; Mohammadian Roshan, Noema; Khajavi Rad, Abolfazl; Anaeigoudari, Akbar; Hosseinian, Sara; Karimi, Sareh; Beheshti, Farimah

2016-01-01

Inflammation and oxidative stress is considered to have a crucial role in induction of nephropathy. Curcuma longa (C. longa) and Nigella sativa (N. sativa) have anti-inflammatory and antioxidant effects. This study was designed to investigate the effect of mixed hydro-alcoholic extract of N.sativa and C. longa on the oxidative stress induced by Adriamycin (ADR) in rat kidney. The animals were divided into 6 groups: control (CO), ADR, Adriamycin+ Vitamin C (ADR+VIT C), C. longa extract+ Adriamycin (C.LE+ADR), N. sativa extract+ Adriamycin (N.SE+ADR) and C. longa extract+ N. sativa extract + Adriamycin (N.S+C.L+ADR). ADR (5mg/kg) was injected intravenously, whereas VITC (100mg/kg) and extract of C. longa (1000mg/kg) and N. sativa (200mg/kg) were administrated orally. Finally, the renal tissue, urine and blood samples were collected and submitted to measure of redox markers, osmolarity and renal index. The renal content of total thiol and superoxide dismutase (SOD) activity significantly decreased and Malondialdehyde (MDA) concentration increased in Adriamycin group compared to control group. The renal content of total thiol and SOD activity significantly enhanced and MDA concentration reduced in treated-mixed extract of C. longa and N. sativa along with ADR group compared to ADR group. The mixed extract did not restore increased renal index percentage induced by ADR. There also was no significant difference in urine and serum osmolarity between the groups. hydro-alcoholic extracts of N.sativa and C.longa led to an improvement in ADR-induced oxidative stress and mixed administration of the extracts enhanced the aforementioned therapeutic effect.

Studies on uptake and distribution of chemotherapeutic agents to malignant tumors of the head and neck in rabbits, 2. /sup 3/H-Adriamycin

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Yamada, R. (Gifu Univ. (Japan). Faculty of Medicine)

1981-09-01

Experiments were performed to investigate incorporation and distribution of chemotherapeutic agents into malignant tumors of the head and neck by microautoradiographic and electron microscopic-autoradiographic observations of VX2 carcinoma transplanted in the lower genial region of rabbits after injection of /sup 3/H-Adriamycin as a tracer. The following findings were obtained. 1. On microautoradiograms, /sup 3/H-Adriamycin was distributed predominantly in the nucleoplasm, rather than in the cytoplasm, of tumor tissues. 2. At the ultrastructural level, /sup 3/H-Adriamycin was localized in the nuclear membrane and nucleoli within the nucleoplasm and in the rough endoplasmic reticulum and secretory granules within the cytoplasm. 3. These findings seem to indicate that Adriamycin may inhibit the synthesis of DNA and RNA in the nucleoplasm.

Abnormal notochord branching is associated with foregut malformations in the adriamycin treated mouse model.

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Hajduk, Piotr; Sato, Hideaki; Puri, Prem; Murphy, Paula

2011-01-01

Oesophageal atresia (OA) and tracheooesophageal fistula (TOF) are relatively common human congenital malformations of the foregut where the oesophagus does not connect with the stomach and there is an abnormal connection between the stomach and the respiratory tract. They require immediate corrective surgery and have an impact on the future health of the individual. These abnormalities are mimicked by exposure of rat and mouse embryos in utero to the drug adriamycin. The causes of OA/TOF during human development are not known, however a number of mouse mutants where different signalling pathways are directly affected, show similar abnormalities, implicating multiple and complex signalling mechanisms. The similarities in developmental outcome seen in human infants and in the adriamycin treated mouse model underline the potential of this model to unravel the early embryological events and further our understanding of the processes disturbed, leading to such abnormalities. Here we report a systematic study of the foregut and adjacent tissues in embryos treated with adriamycin at E7 and E8 and analysed between E9 and E12, comparing morphology in 3D in 149 specimens. We describe a spectrum of 8 defects, the most common of which is ventral displacement and branching of the notochord (in 94% of embryos at E10) and a close spatial correspondence between the site of notochord branching and defects of the foregut. In addition gene expression analysis shows altered dorso-ventral foregut patterning in the vicinity of notochord branches. This study shows a number of features of the adriamycin mouse model not previously reported, implicates the notochord as a primary site of disturbance in such abnormalities and underlines the importance of the model to further address the mechanistic basis of foregut congenital abnormalities.

Inhibition of cyclooxygenase-2 reduces hypothalamic excitation in rats with adriamycin-induced heart failure.

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Min Zheng

Full Text Available BACKGROUND: The paraventricular nucleus (PVN of the hypothalamus plays an important role in the progression of heart failure (HF. We investigated whether cyclooxygenase-2 (COX-2 inhibition in the PVN attenuates the activities of sympathetic nervous system (SNS and renin-angiotensin system (RAS in rats with adriamycin-induced heart failure. METHODOLOGY/PRINCIPAL FINDING: Heart failure was induced by intraperitoneal injection of adriamycin over a period of 2 weeks (cumulative dose of 15 mg/kg. On day 19, rats received intragastric administration daily with either COX-2 inhibitor celecoxib (CLB or normal saline. Treatment with CLB reduced mortality and attenuated both myocardial atrophy and pulmonary congestion in HF rats. Compared with the HF rats, ventricle to body weight (VW/BW and lung to body weight (LW/BW ratios, heart rate (HR, left ventricular end-diastolic pressure (LVEDP, left ventricular peak systolic pressure (LVPSP and maximum rate of change in left ventricular pressure (LV±dp/dtmax were improved in HF+CLB rats. Angiotensin II (ANG II, norepinephrine (NE, COX-2 and glutamate (Glu in the PVN were increased in HF rats. HF rats had higher levels of ANG II and NE in plasma, higher level of ANG II in myocardium, and lower levels of ANP in plasma and myocardium. Treatment with CLB attenuated these HF-induced changes. HF rats had more COX-2-positive neurons and more corticotropin releasing hormone (CRH positive neurons in the PVN than did control rats. Treatment with CLB decreased COX-2-positive neurons and CRH positive neurons in the PVN of HF rats. CONCLUSIONS: These results suggest that PVN COX-2 may be an intermediary step for PVN neuronal activation and excitatory neurotransmitter release, which further contributes to sympathoexcitation and RAS activation in adriamycin-induced heart failure. Treatment with COX-2 inhibitor attenuates sympathoexcitation and RAS activation in adriamycin-induced heart failure.

A new class of free radical scavengers reducing adriamycin mitochondrial toxicity

NARCIS (Netherlands)

Praet, M.; Calderon, P. B.; Pollakis, G.; Roberfroid, M.; Ruysschaert, J. M.

1988-01-01

Beef heart mitochondria were incubated with ADM and NADH. An adriamycin semiquinone radical was detected using ESR spectroscopy. The semiquinone radical production rate is decreased upon addition of a scavenger (AD 20) in the reaction medium. NMRI mice were treated with AD 20 (70 mg/kg, i.p.) 15 min

Study of the effect of vitamins C and E on the radiation response of multicell spheroids treated with Adriamycin

International Nuclear Information System (INIS)

Sridhar, R.; Stroude, E.; Inch, W.R.

1979-01-01

Treatment with Adriamycin (0.6 μg/ml for 60 min) was not cytotoxic to multicell spheroids. At this concentration, the drug was not a sensitizer of hypoxic cells in V79 multicell spheroids, which were irradiated at 37 0 C in medium equilibrated with a mixture of 5% O 2 :3% CO 2 :92% N 2 . The addition of vitamins C and E did not increase the radiation sensitivity of Adriamycin-treated spheroids. In some experiments, catalase was included in the growth medium to overcome the toxic effect of hydrogen peroxide, which is known to be formed in solutions containing vitamin C and also in Adriamycin solutions treated with vitamin C or microsomal preparations. As a result of these experiments, it was found that catalase increased the radiation killing in multicell spheroids

Improved distribution and reduced toxicity of adriamycin bound to albumin-heparin microspheres

NARCIS (Netherlands)

Cremers, Harry; Cremers, H.F.M.; Bayon, L.G.; Verrijk, R.; Wesseling, M.M.; Wondergem, J.; Heuff, G.; Kwon, G.S.; Bae, Y.H.; Feijen, Jan; Kim, S.W.

1995-01-01

Adriamycin (ADR) was formulated in albumin-heparin conjugate microspheres (AHCMS) to improve site-specific delivery and to reduce the toxicity of the drug. The effect of formulating ADR in AHCMS was investigated upon intrahepatic administration to male Wag/Rij rats. After intraveno-portal (i.v.p.)

Effect of α-tocopherol on the cardiotoxicity of adriamycin in the rat

NARCIS (Netherlands)

Sonneveld, P.

1978-01-01

Adriamycin (ADR)-induced cardiomyopathy was studied in a rat model by means of electrocardiograms (ECGs), light microscopy, and determination of heart weight. Pretreatment with D-α-tocopherol (α-T) 24 hours prior to a high dose of ADR diminishes cardiotoxic effects, as judged by ECG changes,

Adriamycin continuous i.v. infusion for the treatment of childhood hepatic malignancies, toxicity and efficacy: a pilot study childrens cancer study group

International Nuclear Information System (INIS)

Ortega, J.A.; Feusner, J.; Reaman, G.; Woods, W.

1986-01-01

In an effort to increase the number of patients with hepatoblastoma and hepatocellular carcinoma receiving the benefits of complete surgical excision, a pilot study was undertaken at a few Childrens Cancer Study Group institutions. For this purpose, repeated courses of adriamycin administered as a continuous I.V. infusion either singly or in combination with c-platinum and radiation therapy treatment was selected. The patient population consisted of a total of eleven children with primary hepatic malignancies: six children had hepatoblastoma; all six were under two years of age at diagnosis. Five patients with hepatocellular carcinoma were entered to the study. Of the eleven patients, four had previously received adriamycin as an I.V. bolus. A table summarizes the patient's characteristics, the adriamycin dose they received and their responses to therapy

Effect of methanolic fraction of Kalanchoe crenata on metabolic parameters in adriamycin-induced renal impairment in rats.

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Kamgang, René; Foyet, Angèle F; Essame, Jean-Louis O; Ngogang, Jeanne Y

2012-01-01

To investigate the effect of Kalanchoe crenata methanolic fraction (MEKC) on proteinuria, glucosuria, and some other biochemical parameters in adriamycin-induced renal impairment in rats. Ether anesthetized rats received three intravenous injections (days 0, 14, and 28) of 2 mg/kg body weight of adriamycin. Repeated doses of the extract (0, 50, and 68 mg/kg b.w.) and losartan (10 mg/kg b.w.) were administered orally once daily, for 6 weeks, to these rats. Kidney functions were assessed through biochemical parameters. MEKC decreased proteinuria and also the urinary excretion of creatinine, glucose, and urea significantly in diseased rats. A decrease in serum levels of creatinine, urea, potassium, alkaline phosphatase, conjugate bilirubin, and alanine transaminase level was also recorded in nephropathic rats, but plasma levels of uric acid and glucose remained unchanged. Moreover, the plant extract markedly (P < 0.05) increased plasma sodium and decreased (P < 0.01) the urinary sodium and potassium levels. The results indicated that the treatment with the methanolic fraction of K. crenata may improve proteinuria and all other symptoms due to adriamycin-induced nephropathy and, more than losartan, could ameliorate kidney and liver functions. K. crenata could be a potential source of new oral antinephropathic drug.

The efficacy and safety of the targeted drug combined with adriamycin liposome solution for HER-2-positive breast cancer

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Zi-Ping Zhou

2017-05-01

Full Text Available Objective: To study the efficacy and safety of the targeted drug trastuzumab combined with adriamycin liposome solution for HER-2-positive breast cancer. Methods: A total of 112 patients with breast cancer who received chemotherapy in Department of Cardiothoracic Breast Surgery, Guangdong TongJiang Hospital between May 2014 and April 2016 were selected as the research subjects and divided into two groups by random number table, liposome group received trastuzumab + adriamycin liposome chemotherapy, and the control group received trastuzumab + adriamycin chemotherapy. Before chemotherapy as well as 4 weeks and 8 weeks after chemotherapy, serum levels of tumor markers, cytokines and myocardial injury indexes were detected, the electrocardiography was conducted and the degree of myocardial injury was determined. Results: 4 weeks and 8 weeks after chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF and MK levels of both groups were significantly lower than those before chemotherapy, serum CK-MB and cTnI levels were significantly higher than those before chemotherapy, limb leads QRS amplitudes and chest leads QRS amplitudes were significantly lower than those before chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF, MK, CK-MB and cTnI levels of liposome group were significantly lower than those of control group, and the limb leads QRS amplitudes and chest lead QRS amplitudes were significantly higher than those of control group. Conclusion: Targeted drug combined with adriamycin liposome therapy for HER-2-positive breast cancer can improve the curative effect and reduce the cardiotoxicity.

Adriamycin and derivatives interaction with the mitochondrial membrane: O2 consumption and free radicals formation

NARCIS (Netherlands)

Pollakis, G.; Goormaghtigh, E.; Delmelle, M.; Lion, Y.; Ruysschaert, J. M.

1984-01-01

Adriamycin induces the formation of semiquinone free radicals, O(2) and OH. species, in beef heart intact mitochondria, submitochondrial particles and complex I-III containing proteoliposomes. Free radicals were detected by the use of Electron Spin Resonance (ESR) spectroscopy with the spin trapping

Adriamycin activity's durational governance of different cell death types and zonality in rat liver acinus. Immunohistochemical studies

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Pedrycz Agnieszka

2014-03-01

Full Text Available The aim of this study was to develop and examine a model of apoptosis and necrosis of hepatocytes induced by a damaging factor - adriamycin, correlating time after its administration with cell death type, and to investigate the localisation within the liver acinus of hepatocytes dying in these two ways. The results obtained in the present and previous studies were compared in order to make a map of cell death localisation in the liver acinus, showing the effect of time in action and dose of adriamycin. The experiment was performed on 32 female Wistar rats, divided into four groups: I and II - experimental, and III and IV - control. Adriamycin (3 mg/kg b.w. was administered intraperitoneally to rats in groups I and II, and the rats were decapitated after four (group I and eight (group II weeks. Animals in control groups III and IV were given 0.5 mL of 0.9% NaCl solution, and decapitated after four and eight weeks respectively. Sections of the liver were examined with a three-stage immunohistochemical method. This method allowed to examine hepatocytes qualitatively and quantitatively for the presence of proteins involved in three types of apoptosis: induced by the mitochondrial pathway (caspase 3, 9, the intrinsic pathway related to endoplasmic reticulum stress (caspase 3, 12, and the extrinsic pathway (caspase 3, 8. One of the inflammatory markers, caspase 1, was also examined. The zonal localisation of all three types of apoptosis was assessed in the liver tissue. More oxidated hepatocytes indicated only signs of the internal mitochondrial pathway, whereas less oxidated hepatocytes induced the internal reticular pathway and the external apoptotic pathway. The period between adriamycin administration and hepatic cell investigation was a main factor of the process. A longer period post insult resulted in a more pronounced effect of the activation of apoptosis. Sections explored eight weeks after treatment with different doses of the drug (3 and 5

Studies on the effects of adriamycin-derivatives in combination with X-rays on MeWo- and Be11-cells

International Nuclear Information System (INIS)

Krueger, M.; Beuningen, D. van; Streffer, C.

1990-01-01

The survival rate of human melanoma cells after X-ray irradiation, treamtment with adriamycin derivatives and combined treatment with X-rays and adriamycin derivatives was measured by means of the colony formation test. After X-ray irradiation the melanoma cells showed a high resistance for cell survival. In all tests the Be11-cells were more resistant than MeWo-cells. On combined exposure especially with higher doses of adriamycin derivatives, both cell lines showed the interesting effect, that with increasing concentration the survival rate decreased whereas the D 0 increased. Aclacinomycin-A (ACM-A) and Pirarubicin reduced recovery processes after X-ray irradiation. Therefore Be11-cells showed a four times higher DMF (dosis modifying factor) after ACM-A-treatment than MeWo-cells. Low ACM-A-concentrations combined with low X-ray doses showed on both cell lines supraadditive effects. The effect of pirarubicin was in most of the tests only additive. Compared with ACM-A, pirarubicin was less cytotoxic, showed a larger therapeutic range, caused a smaller D 0 and D q and had a supraadditive effect in low concentrations on both cell lines. For clinical combined therapy with patients ACM-A is probably better suited than pirarubicin. (orig.) [de

SPIN1, negatively regulated by miR-148/152, enhances Adriamycin resistance via upregulating drug metabolizing enzymes and transporter in breast cancer.

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Chen, Xu; Wang, Ya-Wen; Gao, Peng

2018-05-09

Spindlin1 (SPIN1), a protein highly expressed in several human cancers, has been correlated with tumorigenesis and development. Alterations of drug metabolizing enzymes and drug transporters are major determinants of chemoresistance in tumor cells. However, whether the metabolizing enzymes and transporters are under the control of SPIN1 in breast cancer chemoresistance has not yet been defined. SPIN1 expression in breast cancer cells and tissues was detected by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Chemosensitivity assays in vitro and in vivo were performed to determine the effect of SPIN1 on Adriamycin resistance. Downstream effectors of SPIN1 were screened by microarray and confirmed by qRT-PCR and Western blot. Luciferase assay and Western blot were used to identify miRNAs regulating SPIN1. We showed that SPIN1 was significantly elevated in drug-resistant breast cancer cell lines and tissues, compared with the chemosensitive ones. SPIN1 enhanced Adriamycin resistance of breast cancer cells in vitro, and downregulation of SPIN1 by miRNA could decrease Adriamycin resistance in vivo. Mechanistically, drug metabolizing enzymes and transporter CYP2C8, UGT2B4, UGT2B17 and ABCB4 were proven to be downstream effectors of SPIN1. Notably, SPIN1 was identified as a direct target of the miR-148/152 family (miR-148a-3p, miR-148b-3p and miR-152-3p). As expected, miR-148a-3p, miR-148b-3p or miR-152-3p could increase Adriamycin sensitivity in breast cancer cells in vitro. Moreover, high expression of SPIN1 or low expression of the miR-148/152 family predicted poorer survival in breast cancer patients. Our results establish that SPIN1, negatively regulated by the miR-148/152 family, enhances Adriamycin resistance in breast cancer via upregulating the expression of drug metabolizing enzymes and drug transporter.

Reinduction therapy for adult acute leukemia with adriamycin, vincristine, and prednisone: a Southwest Oncology Group study.

Science.gov (United States)

Elias, L; Shaw, M T; Raab, S O

1979-08-01

In an attempt to improve remissions and survivals in previously treated patients with adult acute leukemia, we gave Adriamycin, vincristine, and prednisone for induction therapy, followed by 6-mercaptopurine and methotrexate for maintenance therapy to patients attaining complete remission (CR). The study group consisted of 18 patients with acute myeloblastic leukemia (AML), ten with acute lymphoblastic leukemia, and one with acute undifferentiated leukemia. Only one patient had previously received Adriamycin. Overall, there were ten CRs and two partial remissions. The five CRs and one partial remission in patients with AML occurred among those with one prior induction attempt; none of the eight AML patients with more than one prior induction attempt responded. The actuarial median duration of CR was 15 weeks and was similar for AML and acute lymphoblastic leukemia patients. Responders had a longer median survival (30 weeks) than nonresponders (9 weeks). Thus, although a reasonable number of responses in previously treated patients were obtained with this program, improvements in maintenance therapy are clearly needed.

Sequential radiotherapy and adriamycin in the management of bronchogenic carcinoma: the question of additive toxicity

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Ruckdeschel, J.C.; Baxter, D.H.; McKneally, M.F.; Killam, D.A.; Lunia, S.L.; Horton, J.

1979-08-01

Intrapleural immunotherapy, radiotherapy and chemotherapy were employed in that sequence in 22 patients with Stage III non-oat cell bronchogenic carcinoma confined to the thorax. Seven patients received intrapleural BCG in a pilot study and 15 were randomized between intrapleural BCG and intrapleural saline. Isoniazid was begun on day 14 and irradiation (3000 rad in 10 fractions) to the primary lesion, mediastinum and ipsilateral supraclavicular nodes was started on day 21. One to two weeks following irradiation, CAMP chemotherapy was initiated (Cyclophosphamide 300 mg/M/sup 2/ iv, d. 1,8; Adriamycin 20 mg/M/sup 2/ iv, d. 1,8; Methotrexate 15 mg/M/sup 2/ iv, d. 1,8 and Procarbazine 100 mg/M/sup 2/ p.o., d. 1 to 10). Chemotherapy was given for a total of six months. Two patients expired prior to radiotherapy (1 tumor progression, 1 myocardial infarction) and 2 patients were lost to follow-up. Nausea, vomiting, alopecia and fatigue were universal side effects of the chemotherapy. Esophagitis occurred in 9 patients, 7 prior to and 2 after initiation of Adriamycin. In only one case did Adriamycin exacerbate a previous radiation esophagitis. No patient developed clinical radiation pneumonitis, although all had eventual radiation fibrosis. Congestive heart failure occurred in 1 patient with known valvular heart disease and responded to diuretics. Three patients developed localized herpes zoster infections. One patient developed radiation myelitis one year after initiating therapy and six months after completing all chemotherapy. The major side effect was leukopenia with relative platelet sparing. Although significant morbidity was encountered in this primarily older patient population (mean age 64.8 years) recall reactions involving irradiated intrathoracic structures were not a significant clinical problem.

Effect of abnormal notochord delamination on hindgut development in the Adriamycin mouse model.

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Sato, Hideaki; Hajduk, Piotr; Furuta, Shigeyuki; Wakisaka, Munechika; Murphy, Paula; Puri, Prem; Kitagawa, Hiroaki

2013-11-01

Adriamycin mouse model (AMM) is a model of VACTERL anomalies. Sonic hedgehog (Shh) pathway, sourced by the notochord, is implicated of anorectal malformations. We hypothesized hindgut anomalies observed in the AMM are the result of abnormal effect of the notochord. Time-mated CBA/Ca mice received two intraperitoneal injections of Adriamycin (6 mg/kg) or saline as control on embryonic day (E) 7 and 8. Fetuses were harvested from E9 to E11, stained following whole mount in situ hybridization with labeled RNA probes to detect Shh and Fork head box F1(Foxf1) transcripts. Immunolocalization with endoderm marker Hnf3β was used to visualize morphology. Embryos were scanned by OPT to obtain 3D representations of expressions. In AMM, the notochord was abnormally displaced ventrally with attachment to the hindgut endoderm in 71 % of the specimens. In 32 % of the treated embryos abnormal hindgut ended blindly in a cystic structure, and both of types were remarked in 29 % of treated embryos. Endodermal Shh and mesenchymal Foxf1 genes expression were preserved around the hindgut cystic malformation. The delamination of the developing notochord in the AMM is disrupted, which may influence signaling mechanisms from the notochord to the hindgut resulting in abnormal patterning of the hindgut.

Adriamycin-radiation combinations: drug induced delayed gastrointestinal radiosensitivity

International Nuclear Information System (INIS)

Schenken, L.L.; Burholt, D.R.; Kovacs, C.J.

1979-01-01

The administration of Adriamycin (ADR) results in acute short-term reductions in cell production within the gastrointestinal mucosa. Interactions between ADR doses and radiation appear minimized as the inter-treatment time interval expands to five days. However, as the times between drug administration and abdominal radiation exposure are further lengthened (from 14 to 49 days), a progressively severe defect in post-irradiation mucosal cell production is noted. Although the mucosa appears abnormal histologically and crypt cell cellularity and cell production are normal, the proliferative response following radiation is reduced by as much as 50% if ADR is given 7 weeks prior to the radiation exposure. We postulate that this effect is a manifestation of latent damage to the stem cell compartment within the crypt or that secondary support systems such as mucosal vascularity have been compromised by ADR

Role of free radicals in an adriamycin-resistant human small cell lung cancer cell line

NARCIS (Netherlands)

Meijer, C.; Mulder, N H; Timmer-Bosscha, H; Zijlstra, J G; de Vries, E G

1987-01-01

In two Adriamycin (Adr) resistant sublines (GLC4-Adr1 and GLC4-Adr2) of a human small cell lung carcinoma cell line, GLC4, cross-resistance for radiation was found. GLC4-Adr1 has an acquired Adr resistance factor of 44 after culturing without Adr for 20 days and GLC4-Adr2, the same subline cultured

Lingzhilactones from Ganoderma lingzhi ameliorate adriamycin-induced nephropathy in mice.

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Yan, Yong-Ming; Wang, Xin-Long; Zhou, Li-Li; Zhou, Feng-Jiao; Li, Rong; Tian, Yuan; Zuo, Zhi-Li; Fang, Ping; Chung, Arthur C K; Hou, Fan-Fan; Cheng, Yong-Xian

2015-12-24

Several Ganoderma fungi are well-known for their medical uses to treat cancer, insomnia and kidney disease in East Asia. Triperpenoids and polysaccharides have been considered for a long time to be the major active components of the genus Ganoderma. The present study is to examine the effects of lingzhilactones from G. lingzhi on adriamycin-induced nephropathy in mice. A combination of various chromatography led to the isolation of lingzhilactones A-C, their structures were identified by spectroscopic and computational methods. The intracellular reactive oxygen species (ROS) was detected with the carboxymethyl-H2-dichlorofluorescein diacetate fluoroprobe. The fibrotic markers were analyzed by real-time RT-PCR and Western blot analyses. Detection of SEAP was conducted with the chemiluminescent. Urine albumin was measured using an ELISA assay. Histology and immunohistochemical staining was used to assess fibrotic lesions in mice. Three new lingzhilactones A-C (1-3) containing a fused lactone moiety were isolated from G. lingzhi. We found that 2 could inhibit ROS generation in a dose-dependent manner, inhibit mRNA expression of collagen IV, fibronectin, IL-6 and increase expression of Nrf2 in rat tubular epithelial cells. Furthermore, we found that 2 could reduce urinary albumin levels, abrogate myofibroblastic activation and inhibit the phosphorylation of Smad3 in adriamycin-induced mice. The in vitro and in vivo results suggested that lingzhilactone B could protect against renal injuries by increasing the activities of antioxidants and inhibiting inflammation. The inhibition of Smad3 phosphorylation suggested that this substance displays in vivo antifibrotic activity by a mechanism that is dependent on disruption of Smad3. These results promote understanding of the traditional usage of G. lingzhi and provide promising findings which may be beneficial for anti-kidney disease drug design. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A Prospective Comparative Study of the Toxicity Profile of 5-Flurouracil, Adriamycin, Cyclophosphamide Regime VS Adriamycin, Paclitaxel Regime in Patients with Locally Advanced Breast Carcinoma

Science.gov (United States)

Pillai, Pradeep Sadasivan; Jayakumar, Krishnan Nair Lalithamma

2015-01-01

Introduction A 5-flurouracil, Adriamycin, Cyclophosphamide (FAC) and Adriamycin, Paclitaxel (AT) are two popular chemotherapeutic regimens for treatment of breast carcinoma. The most time tested and popular regimen is FAC. It is extensively studied for efficacy and toxicity. But data regarding toxicity profile and efficacy of AT regimen is sparse. Aim To study the toxicity profile, severity of toxicities and clinical response rate of FAC and AT regimens in patients with locally advanced breast carcinoma. Materials and Methods A prospective observational study with 50 patients in each treatment arm. Study duration was 12 months from November 2012 to October 2013. Consecutive patients with locally advanced breast carcinoma receiving treatment with either FAC or AT regimen, satisfying inclusion criteria were enrolled into the study after getting informed written consent. Prior to initiation of treatment detailed medical history was taken from all patients. General clinical examination, examination of organ systems and local examination of breast lump were done. After each cycle of chemotherapy and after completion of treatment patients were interviewed and examined for clinical response and toxicities. Toxicities were graded with WHO toxicity grading criteria. All data were entered in a structured proforma. At least 50% reduction in tumour size was taken as adequate clinical response. Statistical Analysis Data was analysed using Chi-square test with help of Excel 2007 and SPSS-16 statistical software. Results Different pattern of toxicities were seen with FAC and AT regimens. Anaemia, thrombocytopenia, stomatitis, hyperpigmentation, photosensitivity and diarrhoea were more common with patients receiving FAC regimen. Leucopenia, peripheral neuropathy, myalgia, arthralgia, vomiting and injection site reactions were more common in AT regimen. Both FAC and AT regimens gave 100% clinical response. Conclusion FAC and AT regimens are equally efficacious but have different

[Antitumor effect of recombinant Xenopus laevis vascular endothelial growth factor (VEGF) as a vaccine combined with adriamycin on EL4 lymphoma in mice].

Science.gov (United States)

Niu, Ting; Liu, Ting; Jia, Yong-Qian; Liu, Ji-Yan; Wu, Yang; Hu, Bing; Tian, Ling; Yang, Li; Kan, Bing; Wei, Yu-Quan

2005-09-01

To explore the antitumor effect of immunotherapy with recombinant Xenopus laevis vascular endothelial growth factor (xVEGF) as a vaccine combined with adriamycin on lymphoma model in mice. EL4 lymphoma model was established in C57BL/6 mice. Mice were randomized into four groups: combination therapy, adriamycin alone, xVEGF alone and normal saline (NS) groups, and then were given relevant treatments. The growth of tumor, the survival rate of tumor-bearing mice, and the potential toxicity of regimens above were observed. Anti-VEGF antibody-producing B cells (APBCs) were detected by enzyme-linked immunospot (ELISPOT) assay. In addition, microvessel density (MVD) of tumor was detected by immunohistochemistry, and tumor cell apoptosis was also detected by TUNEL staining. The tumor volumes of mice were significantly smaller in combination group than those in other three groups (P < 0.05). Complete regression of tumor was observed in 3 of 10 mice in combination group. Forty-eight days after inoculation of tumor cells, the survival rate of mice was significantly higher in combination group than in NS group (P < 0.01). The anti-VEGF APBC count in combination group or xVEGF group was significantly higher, compared with that in adriamycin group or NS group (P < 0.01). MVD in tumor tissues was significantly lower in combination group than those in other three groups (P < 0.05). Moreover, tumor cell apoptosis was significantly higher in combination group than those in other three groups (P < 0.05). In this experimental study, the use of xVEGF vaccine and adriamycin as a combination of immunotherapy with chemotherapy has sucessfully produced synergistic antitumor effect on lymphoma in mice.

Effects of liposome-adriamycin (L-ADM) and thermotherapy on glioma cells: an experimental study

OpenAIRE

Zheng-hua SHI; Jian-ning ZHANG

2013-01-01

Objective 　To observe the effects of liposome-adriamycin (L-ADM) and thermotherapy on proliferation and apoptosis of SWO-38 glioma cells. Methods 　The SWO-38 glioma cells were cultivated in vitro. The effects of thermotherapy (43℃), ADM chemotherapy, L-ADM chemotherapy, thermotherapy + ADM chemotherapy, and thermotherapy + L-ADM chemotherapy on the cell proliferation and apoptosis were observed. The working concentration of ADM and L-ADM, and the cell proliferation rate were determined by MTT...

Solanine induced apoptosis and increased chemosensitivity to Adriamycin in T-cell acute lymphoblastic leukemia cells.

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Yi, Ying-Jie; Jia, Xiu-Hong; Wang, Jian-Yong; Chen, Jie-Ru; Wang, Hong; Li, You-Jie

2018-05-01

Solanine is an alkaloid and is the main extract of the traditional Chinese herb, Solanum nigrum Linn . It has been reported that Solanine has anti-inflammatory and antitumor properties. The present study aimed to investigate the antitumor effect of Solanine in Jurkat cells and demonstrate the molecular mechanism of antitumor activity of Solanine. A Cell Counting Kit-8 assay demonstrated that Solanine inhibited the proliferation of Jurkat cells in a dose-and time-dependent manner. Cell apoptosis was measured by flow cytometry. Flow cytometry revealed that Solanine induced apoptosis in a dose-dependent manner in Jurkat cells. Reverse transcription-quantitative polymerase chain reaction demonstrated that Solanine modulated the mRNA levels of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Additionally, Bcl-2 and Bax expression was measured using western blot analysis. Western blot analysis revealed a significant increase in the expression of Bax and decrease in the expression of Bcl-2. Solanine increased the chemosensitivity of Jurkat cells to Adriamycin. In summary, the present results indicated that the antitumor activity of Solanine was associated with inhibition of cell proliferation, induction of apoptosis and increasing cytotoxicity of Adriamycin. Therefore, Solanine may have potential as a novel agent for the treatment of acute lymphocytic leukemia.

Adriamycin resistance, heat resistance and radiation response in Chinese hamster fibroblasts

International Nuclear Information System (INIS)

Wallner, K.; Li, G.

1985-01-01

Previous investigators have demonstrated synergistic interaction between hyperthermia and radiation or Adriamycin (ADR), using cell lines that are sensitive to heat or ADR alone. The authors investigated the effect of heat, radiation or ADR on Chinese hamster fibroblasts (HA-1), their heat resistant variants and their ADR resistant variants. Heat for ADR resistance did not confer cross resistance to radiation. Cells resistant to heat did show cross resistance to ADR. While cells selected for ADR resistance were not cross resistant to heat, they did not exhibit drug potentiation by hyperthermia, characteristic of ADR sensitive cells. Cytofluorometric measurement showed decreased ADR uptake in both heat and ADR resistant cells. The possibility of cross resistance between heat and ADR should be considered when designing combined modality trials

Pharmacokinetics of adriamycin vaginal suppository on uterine cervical cancer

International Nuclear Information System (INIS)

Noda, Tsuneo; Kiyozuka, Yasuhiko; Katakami, Yoshiaki

1986-01-01

Vaginal suppositories of Adriamycin (ADM, 5 mg), for reducing the capacity for repair from sublethal damage of X-ray-irradiated cells, were prepared using Wipepsol S-55 as the vehicle, and were intravaginally administered to patients with advanced uterine cervical cancer, and their pharmacokinetics and clinical effects were studied. The ADM concentration in the uterine cervical cancer tissues indicated high levels (17 to 566 μg/g), and migration into the cardinal ligament and regional lymph nodes was noted. However, little ADM was detected in serum (0 to 0.14 μg/g), probably because of its molecular weight and excellent tissue absorbance, and no side effects, such as cardiotoxicity and myelosuppression due to consecutive administration were detected. Histologically, the effect obtained when administered alone was limited, administration in combination with radiotherapy being more effective. Accordingly, radiotherapy of advanced uterine cervical cancer with concomitant administration of ADM vaginal suppositories seems to bring about a more powerful antitumoral effect with fewer systemic side effects. (author)

Pharmacokinetics of adriamycin vaginal suppository on uterine cervical cancer

Energy Technology Data Exchange (ETDEWEB)

Noda, Tsuneo; Kiyozuka, Yasuhiko; Katakami, Yoshiaki

1986-03-01

Vaginal suppositories of Adriamycin (ADM, 5 mg), for reducing the capacity for repair from sublethal damage of X-ray-irradiated cells, were prepared using Wipepsol S-55 as the vehicle, and were intravaginally administered to patients with advanced uterine cervical cancer, and their pharmacokinetics and clinical effects were studied. The ADM concentration in the uterine cervical cancer tissues indicated high levels (17 to 566 ..mu..g/g), and migration into the cardinal ligament and regional lymph nodes was noted. However, little ADM was detected in serum (0 to 0.14 ..mu..g/g), probably because of its molecular weight and excellent tissue absorbance, and no side effects, such as cardiotoxicity and myelosuppression due to consecutive administration were detected. Histologically, the effect obtained when administered alone was limited, administration in combination with radiotherapy being more effective. Accordingly, radiotherapy of advanced uterine cervical cancer with concomitant administration of ADM vaginal suppositories seems to bring about a more powerful antitumoral effect with fewer systemic side effects.

The effect of adriamycin on dentinogenesis and 3H-thymidine incorporation into the enamel organ of the rat incisor

International Nuclear Information System (INIS)

Karim, A.C.

1990-01-01

The effect of adriamycin (5 mg/kg) on 3 H-thymidine incorporation and on dentin formation was studied in rat incisors. Male Sprague Dawley rats received an intravenous injection of adriamycin. Some of these also received a subcutaneous injection of 3 H-thymidine at a dose of 2 mCi/kg one day later. One group of control animals received an intravenous injection of a volume of physiological saline equal to that of the adriamycin dose. Another group received physiological saline, and one hour later was given an additional injection of 3 H-thymidine at a similar dose as above. All the animals were killed 1 h, 1 d, 4 d, 8 d, 16 d, 28 d, and 32 d after 3 H-thymidine treatment. Light microscopy revealed irregular dentin deposits between the mantle and circumpulpal layer of the labial dentin at 16 d. Within these deposits were trapped cells. The latter, through radioautographic labelling, appeared to be cells from the odontoblast layer. Also, the labelling pattern of the enamel organ in both the control and experimental groups indicated that the eruption rate of the tooth was not affected. Serial sectioning and examination of the lingual portion of the incisors at 28 d revealed a lack of dentin formation and a failure in the closure of the apical foramen. Electron microscopic observations showed an irregular and random arrangement of collagen fibers within the deposits of irregular dentin, and the presence of twisted odontoblastic processes. Examination of the lingual surface showed the presence of fibroblasts and collagen fibers bridging the gap that resulted from the failure in dentin formation. These cells, which were similar to periodontal ligament cells, appeared to have arisen from that area. (author)

Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time

NARCIS (Netherlands)

Kramer, Andrea B.; van Timmeren, Mirjan M.; Schuurs, Theo A.; Vaidya, Vishal S.; Bonventre, Joseph V.; van Goor, Harry; Navis, Gerjan

Kramer AB, van Timmeren MM, Schuurs TA, Vaidya VS, Bonventre JV, van Goor H, Navis G. Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time. Am J Physiol Renal Physiol 296: F1136-F1145, 2009. First published February

Sequence-dependent toxicity profile in modified FAMTX (fluorouracil-adriamycin-methotrexate) chemotherapy with lenograstim support for advanced gastric cancer: a feasibility study

NARCIS (Netherlands)

Westermann, A. M.; Taal, B. G.; Swart, M.; Boot, H.; Craanen, M.; Gerritsen, W. R.

2000-01-01

For advanced irresectible gastric cancer, sequential high-dose methotrexate and 5-fluorouracil (both on day 1) combined with adriamycin on day 15 (FAMTX regimen), cycled every 28 days, is a fairly effective but toxic treatment, with a high incidence of neutropenic fever, dose reductions and dose

Survival and kinetics of Chinese hamster ovary cell subpopulations induced by Adriamycin and radiation

International Nuclear Information System (INIS)

Schneiderman, M.H.

1979-01-01

Mitotic selection of Chinese hamster ovary (CHO) cells, at 10 min intervals after the initiation of Adriamycin and/or x-ray treatment was used to measure the kinetics and survival of cells which progressed without delay, the ''refractory'' cells, the cells that reached mitosis only after recovery from the treatment-induced delay, the ''recovered'' cells, and the survival of the cells remaining attached to the flask 5 h after treatment. The cell kinetics were determined from the rate at which cells entered mitosis, and the reproductive integrity from the survival of the selected refractory, recovered and remaining (unselected) cells

Evaluation of adriamycin nephropathy by an in vivo electron paramagnetic resonance

International Nuclear Information System (INIS)

Oteki, Takaaki; Nagase, Sohji; Yokoyama, Hidekatsu; Ohya, Hiroaki; Akatsuka, Takao; Tada, Mika; Ueda, Atsushi; Hirayama, Aki; koyama, Akio

2005-01-01

A rat model for human minimal change nephropathy was obtained by the intravenous injection of adriamycin (ADR) at 5 mg/kg. By using an in vivo electron paramagnetic resonance (EPR) spectrometer operating at 700 MHz, the temporal changes in signal intensities of a nitroxide radical, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), in the kidneys of rats with ADR nephropathy were investigated. The decay rate of the EPR signal intensity obtained in the kidney is indicative of the renal reducing ability. It was found that the reducing ability in the kidney declined on the 7th day after ADR administration and recovered after the 14th day. Impairment of the reducing ability occurred before the appearance of continuous urinary protein. The in vitro EPR study showed that this impairment of in vivo renal reducing ability is related to impairment of the reducing ability in the mitochondria

Peiminine serves as an adriamycin chemosensitizer in gastric cancer by modulating the EGFR/FAK pathway.

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Tang, Qianqian; Wang, Yunfei; Ma, Lanjing; Ding, Meiling; Li, Tingyu; Nie, Yongzhan; Gu, Zhengyi

2018-03-01

Gastric cancer (GC) is one of the most common malignancies of the digestive tract. Adriamycin (ADR) has been widely utilized in various chemotherapy regimens for treating GC, yet its long-term application may increase drug resistance resulting in treatment failure. Increasing evidence shows that bioactive natural products can be used as chemotherapeutic sensitizers that can significantly improve chemotherapy sensitivity. Peiminine (PMI) is a biologically active component extracted from Fritillaria walujewii Regel. Thus, in the present study, we aimed to investigate whether peiminine (PMI) alters the chemosensitivity of GC to adriamycin (ADR). GC cells were treated with ADR with or without PMI. MTT assay, flow cytometry and a nude mouse tumor xenograft model of SGC7901 cells were used to evaluate the chemosensitization activity of PMI combined with ADR. Western blotting was used to examine the expression of cyclin D1 and cleaved PARP. The RayBio® Human RTK phosphorylation antibody array kit was used to test the differential protein expression. Compared with the ADR group, PMI combined with ADR significantly suppressed cell proliferation and induced cell apoptosis in vitro. The growth curve and tumor weight of the tumor xenografts were significantly decreased in mice treated with the combination of PMI and ADR. However, the organs showed no obvious abnormality after treatment with PMI plus ADR. The expression of cyclin D1 was decreased and the level of cleaved PARP was increased after treatment with PMI and ADR. The expression of p-EGFR and p-FAK was downregulated in cells treated with PMI and ADR, and the validation of p-EGFR and p-FAK was in accordance with the result of the phosphorylation antibody array kit. PMI may serve as a new chemosensitizer by inhibiting the proliferation and inducing the apoptosis to enhance the chemotherapeutic drug sensitivity of ADR in GC.

Treatment of carcinoma of uterine cervix stage III by adriamycin, bleomycin and cisplatinum, neoadjuvant, modified radical hysterectomy and adjuvant chemotherapy

International Nuclear Information System (INIS)

Valle, J.C. do; Ribeiro, C.W.; Rezende, Magda C.; Figueiredo, E.; Chu, C.

1987-01-01

Forty-eight patients with untreated carcinoma of the cervix stage III A and IIIB, were submitted to 3 to 5 cycles of a combination of adriamycin (ADR), bleomycin (BLEO) and cisplatinum (CDDP), followed by modified radical hysterectomy and adjuvant chemotherapy, 6 cycles, of the same association. The surgical aspect is emphasized and the operative sequence is described. A comparative evaluation between the treatment presented and the radiotherapy is done. The survical rate is studied. (M.A.C.) [pt

Intravesical instillation of Adriamycin plus irradiation in the prophylactic treatment of recurring bladder tumors

International Nuclear Information System (INIS)

Yoneda, Fumio; Kan, Masaharu; Tsujimura, Haruhiro; Nakajima, Mikio

1989-01-01

The prevention of the recurrence of bladder tumors was attempted in 45 patients by intravesical instillation of Adriamycin plus irradiation (20 Gy). 30 ml saline solution containing ADM 30mg was instilled into the bladder and then irradiation was performed every day for 10 days. Patients' ages ranged from 36 to 84 years with a mean of 66.5 years; the sex ratio was 3(M) : 1(F). The recurrence rate following therapy was 8.1% after 1 year, 29.4% after 2 years and 29.4% after 3 years. The recurrence rate was low in patients with low grade tumors, those with single tumors and those who received this combination therapy after surgery. Only one patient was obliged to interrupt the therapy due to a bladder irritation. (author)

Mesenchymal stem cells attenuate adriamycin-induced nephropathy by diminishing oxidative stress and inflammation via downregulation of the NF-kB.

Science.gov (United States)

Song, In-Hwan; Jung, Kyong-Jin; Lee, Tae-Jin; Kim, Joo-Young; Sung, Eon-Gi; Bae, Young Chul; Park, Yong Hoon

2018-05-01

This study aimed to evaluate the molecular mechanism mitigating progress of chronic nephropathy by mesenchymal stem cells (MSCs). Rats were divided into normal control (Normal), adriamycin (ADR)+vehicle (CON), and ADR+MSC (MSC) groups. Nephropathy was induced by ADR (4 mg/kg) and MSCs (2 × 10 6 ) were injected. Rats were euthanized 1 or 6 weeks after ADR injection. NF-kB, MAPKs, inflammation, oxidative stress, profibrotic molecules, and nephrin expression were evaluated. Electron and light microscopy were used for structural analysis. MSCs were co-cultured with renal tubular epithelial cells or splenocytes to evaluate relation with oxidative stress and inflammatory molecules RESULTS: Adriamycin treatment upregulated inflammation, oxidative stress, and profibrotic molecules; this was mitigated by MSCs. Glomerulosclerosis and interstitial fibrosis were observed in ADR-treated groups, and were more prominent in the CON group than in the MSC group. Fusion of foot processes and loss of slit diaphragms were also more prominent in the CON group than in the MSC group. In vitro, MSCs reduced oxidative stress related molecules, inflammatory cytokines, and NF-kB transcription. MSC- or ADR-induced regulation of NF-kB transcriptional activity was confirmed by a luciferase reporter assay. Mesenchymal stem cells attenuate ADR-induced nephropathy by diminishing oxidative stress and inflammation via downregulation of NF-kB. © 2017 Asian Pacific Society of Nephrology.

Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222.

Science.gov (United States)

Yu, Dan-Dan; Wu, Ying; Zhang, Xiao-Hui; Lv, Meng-Meng; Chen, Wei-Xian; Chen, Xiu; Yang, Su-Jin; Shen, Hongyu; Zhong, Shan-Liang; Tang, Jin-Hai; Zhao, Jian-Hua

2016-03-01

Breast cancer (BCa) is one of the major deadly cancers in women. However, treatment of BCa is still hindered by the acquired-drug resistance. It is increasingly reported that exosomes take part in the development, metastasis, and drug resistance of BCa. However, the specific role of exosomes in drug resistance of BCa is poorly understood. In this study, we investigate whether exosomes transmit drug resistance through delivering miR-222. We established an adriamycin-resistant variant of Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line (MCF-7/Adr) from a drug-sensitive variant (MCF-7/S). Exosomes were isolated from cell supernatant by ultracentrifugation. Cell viability was assessed by MTT assay and apoptosis assay. Individual miR-222 molecules in BCa cells were detected by fluorescence in situ hybridization (FISH). Then, FISH was combined with locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH). Individual miR-222 could be detected as bright photostable fluorescent spots and then the quantity of miR-222 per cell could be counted. Stained exosomes were taken in by the receipt cells. MCF-7/S acquired drug resistance after co-culture with exosomes from MCF-7/Adr (A/exo) but did not after co-culture with exosomes from MCF-7/S (S/exo). The quantity of miR-222 in A/exo-treated MCF-7/S was significantly greater than in S/exo-treated MCF-7/S. MCF-7/S transfected with miR-222 mimics acquired adriamycin resistance while MCF-7/S transfected with miR-222 inhibitors lost resistance. In conclusion, exosomes are effective in transmitting drug resistance and the delivery of miR-222 via exosomes may be a mechanism.

shRNA-mediated EMMPRIN silencing inhibits human leukemic monocyte lymphoma U937 cell proliferation and increases chemosensitivity to adriamycin.

Science.gov (United States)

Gao, Hui; Jiang, Qixiao; Han, Yantao; Peng, Jianjun; Wang, Chunbo

2015-03-01

EMMPRIN is a widely distributed cell surface glycoprotein, which plays an important role in tumor progression and confers resistance to some chemotherapeutic drugs. Recent studies have shown that EMMPRIN overexpression indicates poor prognosis in acute myeloid leukemia (AML). However, little was known on the role of EMMPRIN in leukemia. Human leukemia cell line U937 was stably transfected with a EMMPRIN-targeted shRNA-containing vector to investigate the effect of EMMPRIN on cellular functions. EMMPRIN expression was monitored by qRT-PCR and Western blotting. Cell viability and proliferation were determined by trypan blue exclusion and BrdU labeling, respectively. Cell cycle and apoptosis were analyzed by flow cytometry. Cytotoxicity of chemotherapeutic agent adriamycin on cells was assessed by MTT assay. Knockdown of EMMPRIN gene significantly inhibited cell viability and decreased cell proliferation. Fluorescence-activated cell-sorting analysis revealed that the reduced EMMPRIN expression resulted in cell cycle arrest at G1 phase and induced apoptosis. Meanwhile, western blotting analysis showed that EMMPRIN knockdown was associated with downregulation of cell cycle- and apoptosis-related molecules including cyclin D1, cyclin E, as well as increase in cleavage of caspase-3 and PARP. This study also showed that silencing of EMMPRIN sensitized U937 cells to Adriamycin. EMMPRIN is involved in proliferation, growth, and chemosensitivity of human AML line U937, indicating that EMMPRIN may be a promising therapeutic target for AML.

Osteoclastome-like giant cell thyroid carcinoma controlled by intensive radiation and adriamycin, in a patient with meningioma and multiple myeloma treated by radiation and cytoxan

International Nuclear Information System (INIS)

Vizel-Schwartz, M.

1981-01-01

The eighth cases of osteoclastome-like giant cell carcinoma of the thyroid, and the first one to be treated with adriamycin in addition to surgery and radiation, is reported. This rare variant of anaplastic thyroid carcinoma appeared in a patient operated on for meningioma and treated for multiple myeloma with cranial radiation and chronic administration of cytoxan

LC-MS/MS method for simultaneous determination of thalidomide, lenalidomide, cyclophosphamide, bortezomib, dexamethasone and adriamycin in serum of multiple myeloma patients.

Science.gov (United States)

Shu, Chang; Zeng, Tianmei; Gao, Shouhong; Xia, Tianyi; Huang, Lifeng; Zhang, Feng; Chen, Wansheng

2016-08-15

Multiple myeloma (MM), a malignant neoplastic serum-cell disorder, has been a serious threat to human health. The determination of 6 commonly used drug concentrations, including thalidomide, lenalidomide, cyclophosphamide, bortezomib, dexamethasone and adriamycin, in MM patients was of great clinical interest. Herein, we reported a method for the rapid and simultaneous measurement of the above therapeutics by liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method with solid phase extraction. Analysis was performed on a Waters XBridge(®) BEH C18 column (2.5μm, 2.1 mm×50mm), with formic acid aqueous solution and acetonitrile as the mobile phase at flow rate 0.3mL/min. All analytes showed good correlation coefficients (r>0.996), and LLOQ of thalidomide, lenalidomide, cyclophosphamide, bortezomib, dexamethasone and adriamycin were 4, 2, 2, 2, 2 and 2ng/mL, respectively. The inter- and intra-day precisions and stability were expressed as variation coefficients within 15% and relative error less than 15%. Dilution effect, carryover and incurred sample reanalysis were investigated according to the 2015 edition Chinese Pharmacopoeia guidelines, as US FDA (2013, revision 1) required. The LC-MS/MS based assay described in this article may improve future clinical studies evaluating common therapeutics for MM treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Cobrotoxin from Naja naja atra Venom Ameliorates Adriamycin Nephropathy in Rats

Directory of Open Access Journals (Sweden)

Shu-Zhi Wang

2015-01-01

Full Text Available Chronic kidney disease (CKD becomes a global health problem with high morbidity and mortality. Adriamycin- (ADR- induced rodent chronic nephropathy is a classic experimental model of human minimal lesion nephrotic syndrome. The present study investigated the effect of cobrotoxin (CTX on ADR-induced nephropathy. Rats were given 6 mg/kg ADR once through the tail vein to replicate ADR nephropathy model. CTX was administered to rats daily by placing a fast dissolving CTX membrane strip under the tongue starting from 5 days prior to ADR administration until the end of experiment. The results showed that CTX ameliorated the symptoms of ADR nephropathy syndrome with reduced body weight loss, proteinuria, hypoalbuminemia, dyslipidemia, serum electrolyte imbalance, oxidative stress, renal function abnormities, and kidney pathological lesions. Anti-inflammatory cytokine IL-10 expression was elevated after CTX administration in ADR nephropathy model. CTX inhibited the phosphorylation of IκB-α and NF-κB p65 nuclear translocation. Meanwhile, CTX upregulated the protein level of podocyte-specific nephrin and downregulated the level of fibrosis-related TGF-β. These findings suggest that CTX may be a potential drug for chronic kidney diseases.

Pristimerin overcomes adriamycin resistance in breast cancer cells through suppressing Akt signaling

Science.gov (United States)

XIE, GUI'E; YU, XINPEI; LIANG, HUICHAO; CHEN, JINGSONG; TANG, XUEWEI; WU, SHAOQING; LIAO, CAN

2016-01-01

Breast cancer remains a major public health problem worldwide. Chemotherapy serves an important role in the treatment of breast cancer. However, resistance to chemotherapeutic agents, in particular, multi-drug resistance (MDR), is a major cause of treatment failure in cancer. Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. Pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, has been shown to possess antitumor, anti-inflammatory, antioxidant and insecticidal properties. The aim of the present study was to investigate whether pristimerin can override chemoresistance in MCF-7/adriamycin (ADR)-resistant human breast cancer cells. The results demonstrated that pristimerin indeed displayed potent cytocidal effect on multidrug-resistant MCF-7/ADR breast cancer cells, and that these effects occurred through the suppression of Akt signaling, which in turn led to the downregulation of antiapoptotic effectors and increased apoptosis. These findings indicate that use of pristimerin may represent a potentially promising approach for the treatment of ADR-resistant breast cancer. PMID:27123073

Kinetically directed combination therapy with adriamycin and x-irradiation in a mammary tumor model

International Nuclear Information System (INIS)

Braunschweiger, P.G.; Schenken, L.L.; Schiffer, L.M.

1981-01-01

In the present studies, the interaction of adriamycin (A) and x-irradiation (X) in T1699 mouse mammary tumors was evaluated. Mitotic indices and thymidine labeling indices were determined at various intervals after A or X alone, and after A + X given in combination. The results with A (1.0 mg/kg) and X(200 R) alone suggest that those quantities of each agent induce a G 2 progression delay of 9 to 12 h. The kinetic results after A + X in combination indicated increased S phase transit time and G 2 progression delay. Recovery kinetics after A + X were used to predict optimum sequence intervals for subsequent A + X fractions. Sequential A + X treatment schedules, up to 4 fractions, were designed and evaluated by regrowth delay measurements. The results indicated that the interaction was additive when A and X were given together in combination. Fractionation of A + X to minimize proliferative recovery between fractions resulted in an enhanced antitumor effect

[Effect of gross saponins of Tribulus terrestris on cardiocytes impaired by adriamycin].

Science.gov (United States)

Zhang, Shuang; Li, Hong; Xu, Hui; Yang, Shi-Jie

2010-01-01

This study is to observe the protection of gross saponins of Tribulus terrestris (GSTT) on cardiocytes impaired by adriamycin (ADR) and approach its mechanism of action. Cardiocytes of neonate rat were cultivated for 72 hours and divided into normal control group, model (ADR 2 mg x L(-1)) group, and GSTT (100, 30, and 10 mg x L(-1)) groups. MTT colorimetric method was deployed to detect cardiocyte survival rate, activities of CK, LDH, AST, SOD, MDA and NO were detected, and apoptosis was detected with flow cytometry. Effect of GSTT on caspase-3 was detected with Western blotting. Compared with control group, contents of CK, LDH, AST, MDA and NO were increased, and activity of SOD was reduced (P < 0.05, P < 0.01, P < 0.001) by ADR. Numbers of survival cells were increased (P < 0.05, P < 0.001), contents of CK, LDH, AST, MDA and NO were decreased, and activity of SOD was increased (P < 0.05, P < 0.01, P < 0.001) by GSTT (100 and 30 mg x L(-1)). Apoptosis of cardiocytes and concentration of caspase-3 can be reduced by GSTT (100 and 30 mg x L(-1)). GSTT can protect cardiocytes impaired by ADR, which are possible involved with its effect of resisting oxygen free radical.

Liposomal curcumin alters chemosensitivity of breast cancer cells to Adriamycin via regulating microRNA expression.

Science.gov (United States)

Zhou, Siying; Li, Jian; Xu, Hanzi; Zhang, Sijie; Chen, Xiu; Chen, Wei; Yang, Sujin; Zhong, Shanliang; Zhao, Jianhua; Tang, Jinhai

2017-07-30

Emerging evidence suggests that curcumin can overcome drug resistance to classical chemotherapies, but poor bioavailability and low absorption have limited its clinical use and the mechanisms remain unclear. Also, Adriamycin (Adr) is one of the most active cytotoxic agents in breast cancer; however, the high resistant rate of Adr leads to a poor prognosis. We utilized encapsulation in liposomes as a strategy to improve the bioavailability of curcumin and demonstrated that liposomal curcumin altered chemosensitivity of Adr-resistant MCF-7 human breast cancer (MCF-7/Adr) by MTT assay. The miRNA and mRNA expression profiles of MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr cells were analyzed by microarray and further confirmed by real-time PCR. We focused on differentially expressed miR-29b-1-5p to explore the involvement of miR-29b-1-5p in the resistance of Adr. Candidate genes of dysregulated miRNAs were identified by prediction algorithms based on gene expression profiles. Networks of KEGG pathways were organized by the selected dysregulated miRNAs. Moreover, protein-protein interaction (PPI) was utilized to map protein interaction networks of curcumin regulated proteins. We first demonstrated liposomal curcumin could rescue part of Adriamycin resistance in breast cancer and further identified 67 differentially expressed microRNAs among MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr. The results showed that lower expressed miR-29b-1-5p decreased the IC50 of MCF-7/Adr cells and higher expressed miR-29b-1-5p, weaken the effects of liposomal curcumin to Adr-resistance. Besides, we found that 20 target genes (mRNAs) of each dysregulated miRNA were not only predicted by prediction algorithms, but also differentially expressed in the microarray. The results showed that MAPK, mTOR, PI3K-Akt, AMPK, TNF, Ras signaling pathways and several target genes such as PPARG, RRM2, SRSF1and EPAS1, may associate with drug resistance of breast cancer cells to Adr. We determined

Interaction of radiation, Dihydroxyanthraquinone, and Adriamycin on the induction of acute lethality in mice

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Kimler, B.F.; Cox, G.G.; Reddy, E.K.

1984-01-01

The acute lethality induced by combinations of radiation, Dihydroxyanthraquinone (DHAQ), and Adriamycin (ADR) was investigated in mice. Whole-body irradiation produced acute lethality, with an LD-50/30 of approximately 6.5 Gy. ADR and DHAQ produced LD-50/30's of 14 and 4 mg/kg, respectively. When 10 mg/kg doses were fractionated into 5 x 2 mg/kg daily doses, both drugs were equally or more efficient at producing mortality, 90% by day 30. When 4 Gy radiation was combined with 5 mg/kg ADR or 5 mg/kg DHAQ, a response no greater than that produced by drug alone was obtained. However, when 5 mg/kg ADR was administered concomitantly with 5 mg/kg DHAQ, there was a less-than-additive induction of lethality, resulting in only 21% mortality by day 20. ADR and DHAQ (at doses of 5 mg/kg) were combined but with a 1 day interval between drugs, the protective effect was lost and animals died earlier than after either agent alone. At present, no definite explanation is available for this unusual protective effect of ADR against acute lethality induced by DHAQ

Combination chemotherapy with cyclophosphamide adriamycin and vincristine for small cell carcinoma of the lung

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Edralin, A.C.

1992-01-01

Between January, 1988 and January, 1991, 29 patients were treated with cyclophosphamide, adriamycin and vincristine (CAV) chemotherapy and were evaluable after a median follow-up of 7.5 months. Of the 29 patients, 25 had limited disease (LD) and 4 had extensive disease (ED). Three patients had a complete remission (CR), 19 had a partial remission (PR) and 7 were non-responders. All the complete responders are still alive at 8, 10 and 40.8 months. The median survival time (MST) of all the patients was 8.5 months. The patients with LD had an MST of 8.5 months while those with ED had an MST of 5.5 months. The chemotherapy regimen produced a total response rate and median survival comparable to those achieved with other regimens. The complete response rate, however, was low and needed to be improved with other approaches. In partial responders, continuation of chemotherapy beyond the 3 courses given for induction did not improve the CR rate. Drug resistance was a limiting factor to the efficacy of this CAV regimen. Prophylactic cranial irradiation is recommended. (auth.). 21 refs.; 2 figs.; 2 tabs

Therapeutic potential of regulatory macrophages generated from peritoneal dialysate in adriamycin nephropathy.

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Cao, Qi; Wang, Yiping; Wang, Changqi; Wang, Xin M; Lee, Vincent W S; Zheng, Guoping; Zhao, Ye; Alexander, Stephen I; Harris, David C H

2018-04-01

Cell therapy using macrophages requires large amounts of cells, which are difficult to collect from patients. Patients undergoing peritoneal dialysis (PD) discard huge numbers of peritoneal macrophages in dialysate daily. Macrophages can be modulated to become regulatory macrophages, which have shown great promise as a therapeutic strategy in experimental kidney disease and human kidney transplantation. This study aimed to examine the potential of using peritoneal macrophages (PMs) from peritoneal dialysate to treat kidney disease. Monocytes/macrophages accounted for >40% of total peritoneal leukocytes in both patients and mice undergoing PD. PMs from patients and mice undergoing PD were more mature than peripheral monocytes/macrophages, as shown by low expression of C-C motif chemokine receptor 2 (CCR2) and morphological changes during in vitro culture. PMs from patients and mice undergoing PD displayed normal macrophage function and could be modulated into a regulatory (M2) phenotype. In vivo, adoptive transfer of peritoneal M2 macrophages derived from PD mice effectively protected against kidney injury in mice with adriamycin nephropathy (AN). Importantly, the transfused peritoneal M2 macrophages maintained their M2 phenotype in kidney of AN mice. In conclusion, PMs derived from patients and mice undergoing PD exhibited conventional macrophage features. Peritoneal M2 macrophages derived from PD mice are able to reduce kidney injury in AN, suggesting that peritoneal macrophages from patients undergoing PD may have the potential for clinical therapeutic application.

[Combination of adriamycin and cis-diammine-dichloro-platinum (II) in the treatment of advanced, therapy-resistant, ovarian carcinoma (author's transl)].

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Cavalli, F; Stoller, U; Tschopp, L; Sonntag, R W; Brunner, K W

1978-06-02

Adriamycin (doxorubicin, Adriblastin) and cis-diammine-dichloro-platinum (II) (DDP, NSC 119 875) were used in the treatment of 18 patients with ovarian carcinoma, usually after intensive pre-treatment, both in a dosage of 50 mg/m2 once every 4 weeks. Forced diuresis was initiated at the same time. On average three such treatments were given. Six patients showed partial remission defined as decrease of tumour mass by more than 50% or as almost complete disappearance of ascites during more than two months without concomitant diuretic treatment. The remission time was 2+, 3, 3+, 3.5, 7+, and 9+ months. In all patients severe gastrointestinal toxicity occurred, however the myelosuppressive action was only moderate. Nephrotoxicity was negligible. Combined chemotherapy with Adriblastin and DDP thus seems effective even in intensively pretreated patients with ovarian carcinoma.

The growth of hemopoietic precursor cells (CFU-C) of adriamycin-treated or whole-body-irradiated dogs with or without bleomycin in vitro

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Volkamer, A.

1984-01-01

The effect of the cytostatic drug bleomycin (BLM) on the growth of canine hemopoietic stem-cells in vitro was tested in order to detect a stem-cell deficiency after in vivo-treatment with adriamycin (ADM) or whole-body-irradiation. Stem-cells damaged by irradiation or cytostatics are suppressed by bleomycin-induced strand-breaks in vitro. After stem-cell recovery the increased sensitivity towards bleomycin can no longer be detected. After whole-body-irradiation and cytostatical treatment the stem-cells who remained intact have to compensate the quantitative change of the stem-cells by increased proliferation. The proliferating cells show a particular bleomycin-sensitivity. Especially after irradiation a long persistence of the bleomycin-sensitivity can be reckoned on. (orig./MG) [de

[Improvement and the mechanism of cardiac function by knockdown of ADAM10 in adriamycin-induced cardiomyopathy rats].

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Li, Xiaoou; Xie, Lili; He, Bing; Huang, Wei

2018-01-01

Objective To study the role of a disintegrin and metalloproteinase10 (ADAM10) in shedding neural cadherin (N-cadherin) and develop an approach to interfere the process of ventricular remodeling in adriamycin-induced cardiomyopathy (ACM) rats. Methods In a rat model of ACM, the effects of intraperitoneal injection of the lentiviral RNAi vector of ADAM10 on the morphology of cardiomyocytes and contractile function were observed by HE staining and color Doppler echocardiography. The expressions of N-cadherin and C-terminal fragment 1 (CTF1) were detected by Western blotting and immunohistochemistry. Results In the in vivo experiment, a large amount of fluorescence was seen in the isolated primary cardiomyocytes, which indicated that the transfection in the rat model was successful. In the treatment group, the morphology of cardiomyocytes and function of the heart were evidently improved, N-cadherin protein expression was remarkably up-regulated and CTF1 protein was obviously down-regulated compared with the model group. Conclusion Knock-down of ADAM10 increases N-cadherin expression and decreases CTF1 expression, thus improves cardiac function in the rat model of ACM.

Exosomes decrease sensitivity of breast cancer cells to adriamycin by delivering microRNAs.

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Mao, Ling; Li, Jian; Chen, Wei-Xian; Cai, Yan-Qin; Yu, Dan-Dan; Zhong, Shan-Liang; Zhao, Jian-Hua; Zhou, Jian-Wei; Tang, Jin-Hai

2016-04-01

While adriamycin (adr) offers improvement in survival for breast cancer (BCa) patients, unfortunately, drug resistance is almost inevitable. Mounting evidence suggests that exosomes act as a vehicle for genetic cargo and constantly shuttle biologically active molecules including microRNAs (miRNAs) between heterogeneous populations of tumor cells, engendering a resistance-promoting niche for cancer progression. Our recent study showed that exosomes from docetaxel-resistance BCa cells could modulate chemosensitivity by delivering miRNAs. Herein, we expand on our previous finding and explore the relevance of exosome-mediated miRNA delivery in resistance transmission of adr-resistant BCa sublines. We now demonstrated the selective packing of miRNAs within the exosomes (A/exo) derived from adr-resistant BCa cells. The highly expressed miRNAs in A/exo were significantly increased in recipient fluorescent sensitive cells (GFP-S) after A/exo incorporation. Gene ontology analysis of predicted targets showed that the top 30 most abundant miRNAs in A/exo were involved in crucial biological processes. Moreover, A/exo not only loaded miRNAs for its production and release but also carried miRNAs associated with Wnt signaling pathway. Furthermore, A/exo co-culture assays indicated that miRNA-containing A/exo was able to increase the overall resistance of GFP-S to adr exposure and regulate gene levels in GFP-S. Our results reinforce our earlier reports that adr-resistant BCa cells could manipulate a more deleterious microenvironment and transmit resistance capacity through altering gene expressions in sensitive cells by transferring specific miRNAs contained within exosomes.

Acetylcholine-induced vasodilation in the uterine vascular bed of pregnant rats with adriamycin-induced nephrosis.

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Yousif, Mariam H; Adeagbo, Ayotunde S; Kadavil, Elizabeth A; Chandrasekhar, Bindu; Oriowo, Mabayoje A

2002-01-01

This project was designed to study endothelium-dependent vasodilation in the uterine vascular bed during experimentally induced preeclampsia in rats. Uterine vascular beds were isolated from non-pregnant and pregnant rats with or without treatment with adriamycin (ADR) and perfused with physiological solution. Thereafter, vasodilator responses to acetylcholine were recorded. RECORDS: Pregnant ADR-treated rats displayed symptoms of preeclampsia including hypertension and proteinuria. Blood pressure was 110.0 +/- 4.7 mm Hg (n = 5) in control pregnant rats and 136.0 +/- 5.3 mm Hg (n = 5) in ADR-treated pregnant rats, and urinary protein concentrations were 0.35 mg/ml (n = 5) and 13.2 +/- 3.6 mg/ml (n = 9), respectively. Both blood pressure and proteinuria values were significantly (p acetylcholine-induced dose-dependent vasodilator responses in the vascular beds were not significantly different between the pregnant and nonpregnant rats. Although acetylcholine-induced vasodilation was significantly reduced by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) in both groups, the residual response to acetylcholine was not affected by indomethacin, suggesting that prostanoids were not involved in this response. The L-NAME-resistant component, endothelium-derived hyperpolarizing factor (EDHF), was greater in ADR-treated uterine beds than in those of the controls, indicating a significant contribution from EDHF in these vessels. In the presence of an elevated external potassium ion concentration, acetylcholine produced similar vasodilator responses, indicating that the release of nitric oxide was not impaired. These results indicate that endothelium-dependent vasodilation was not impaired in this model of preeclampsia.

Therapeutic efficacy of interleukin-2 activated killer cells against adriamycin resistant mouse B16-BL6 melanoma.

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Gautam, S C; Chikkala, N F; Lewis, I; Grabowski, D R; Finke, J H; Ganapathi, R

1992-01-01

Development of multidrug-resistance (MDR) remains a major cause of failure in the treatment of cancer with chemotherapeutic agents. In our efforts to explore alternative treatment regimens for multidrug-resistant tumors we have examined the sensitivity of MDR tumor cell lines to lymphokine activated killer (LAK) cells. Adriamycin (ADM) resistant B16-BL6 melanoma, L1210 and P388 leukemic cell lines were tested for sensitivity to lysis by LAK cells in vitro. While ADM-resistant B16-BL6 and L1210 sublines were found to exhibit at least 2-fold greater susceptibility to lysis by LAK cells, sensitivity of ADM-resistant P388 cell was similar to that of parental cells. Since ADM-resistant B16-BL6 cells were efficiently lysed by LAK cells in vitro, the efficacy of therapy with LAK cells against the ADM-resistant B16-BL6 subline in vivo was evaluated. Compared to mice bearing parental B16-BL6 tumor cells, the adoptive transfer of LAK cells and rIL2 significantly reduced formation of experimental metastases (P less than 0.009) and extended median survival time (P less than 0.001) of mice bearing ADM-resistant B16-BL6 tumor cells. Results suggest that immunotherapy with LAK cells and rIL2 may be a useful modality in the treatment of cancers with the MDR phenotype.

Combined modality therapy of diffuse histology non-Hodgkin's lymphoma with cyclophosphamide, adriamycin, vincristine, prednisone (CHOP) and total body irradiation

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Weick, J.K.; Antunez, A.; Kraus, T.A.; Fabian, C.J.; Dixon, D.

1983-01-01

The combination of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) alternating with total body irradiation (TBI) has been shown earlier to be effective therapy in patients with malignant lymphoma who have received prior chemotherapy and/or radiation therapy. A limited institutional pilot study was therefore done by the Southwest Oncology Group between October 1977, and November 1978 to test the benefit of this program in previously untreated persons with Stages 3 and 4 diffuse histology non-Hodgkin's lymphoma. Eleven evaluable patients with the following histologies were treated: 7 poorly differentiated, 2 with histiocytic, 1 with mixed lymphoma and 1 with well-differentiated morphology. Responses were seen in 8/11 patients (6 CR and 2 PR); 5 persons are currently alive and 6 are dead. The median duration of remission is 15 months and the median survival for all patients is 48 months. The therapy was well tolerated with a mean nadir leukocyte count of 3020 x 10 9 /μl (range 1.2 to 5.5) and a mean nadir platelet count of 188 x 10 9 /μl (range 016 to 270). As delivered, this program is capable of producing durable remissions and needs to be verified in a larger series of patients

Pathologic Response Rates of Gemcitabine/Cisplatin versus Methotrexate/Vinblastine/Adriamycin/Cisplatin Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Bladder Cancer

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Franklin C. Lee

2013-01-01

Full Text Available Objectives. To compare pathologic outcomes after treatment with gemcitabine and cisplatin (GC versus methotrexate, vinblastine, adriamycin, and cisplatin (MVAC in the neoadjuvant setting. Methods. Data was retrospectively collected on 178 patients with T2-T4 bladder cancer who underwent radical cystectomy between 2003 and 2011. Outcomes of interest included those with complete response (pT0 and any response (≤pT1. Odds ratios were calculated using multivariate logistic regression. Results. Compared to those who did not receive neoadjuvant chemotherapy, there were more patients with complete response (28% versus 9%, OR 3.11 (95% CI: 1.45–6.64, P=0.03 and any response (52% versus 25%, OR 3.23 (95% CI: 1.21–8.64, P=0.01. Seventy-two patients received GC (n=41 or MVAC (n=31. CR was achieved in 29% and 22% of GC and MVAC patients, respectively (multivariate OR 0.39, 95% CI 0.10–1.58. Any response (≤pT1 was achieved in 56% of GC and 45% of MVAC patients (multivariate OR 0.45, 95% CI 0.12–1.71. Conclusions. We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of patients with muscle invasive urothelial cancer (MIBC. Our findings support the use of GC as an alternative regimen in the neoadjuvant setting.

Timed sequential chemotherapy of cytoxan-refractory multiple myeloma with cytoxan and adriamycin based on induced tumor proliferation.

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Karp, J E; Humphrey, R L; Burke, P J

1981-03-01

Malignant plasma cell proliferation and induced humoral stimulatory activity (HSA) occur in vivo at a predictable time following drug administration. Sequential sera from 11 patients with poor-risk multiple myeloma (MM) undergoing treatment with Cytoxan (CY) 2400 mq/sq m were assayed for their in vitro effects on malignant bone marrow plasma cell tritiated thymidine (3HTdR) incorporation. Peak HSA was detected day 9 following CY. Sequential changes in marrow malignant plasma cell 3HTdR-labeling indices (LI) paralleled changes in serum activity, with peak LI occurring at the time of peak HS. An in vitro model of chemotherapy demonstrated that malignant plasma cell proliferation was enhanced by HSA, as determined by 3HTdR incorporation assay, 3HTdR LI, and tumor cells counts, and that stimulated plasma cells were more sensitive to cytotoxic effects of adriamycin (ADR) than were cells cultured in autologous pretreatment serum. Based on these studies, we designed a clinical trial to treat 12 CY-refractory poor-risk patients with MM in which ADR (60 mg/sq m) was administered at the time of peak HSA and residual tumor cell LI (day 9) following initial CY, 2400 mg/m (CY1ADR9). Eight of 12 (67%) responded to timed sequential chemotherapy with a greater than 50% decrement in monoclonal protein marker and a median survival projected to be greater than 8 mo duration (range 4-21+ mo). These clinical results using timed sequential CY1ADR9 compare favorably with results obtained using ADR in nonsequential chemotherapeutic regimens.

Effect and mechanism of Qishen Yiqi Pills on adriamycin- induced cardiomyopathy in mice.

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Tong, Jia-Yi; Xu, Yan-Juan; Bian, Ye-Ping; Shen, Xiang-Bo; Yan, Lei; Zhu, Xin-Yi

2013-09-01

To study the effect and probable mechanism of Qishen Yiqi Pills on adriamycin (ADR)-induced cardiomyopathy in mice. Sixty-four mice were randomly divided into (1) the ADR group: saline (1 mL/100 g) administered every day by intragavage, ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks; (2) the ADR + Qishen Yiqi Pills I group: ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks, and at the beginning of the third week Qishen Yiqi Pills (3.5 mg/100 g) administered by intragavage every day for four weeks; (3) the ADR + Qishen Yiqi Pills II group: ADR (4 mg·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks, and at the same time Qishen Yiqi Pills (3.5 mg/100 g) administered by intragavage every day for four weeks; (4) the control group: saline (1 mL/100 g) administered every day by intragavage, saline (1 mL·kg(-1)) administered to each mouse by intraperitoneal injection twice a week for four weeks. Six weeks later, cardiac function, myocardial pathology, and expression of Bcl-2 and Bax were evaluated. 1. The left ventricular diastolic diameter and the left ventricular systolic diameter were significantly increased (P Pills I group and the ADR + Qishen Yiqi Pills II group improved. 2. Myocardial morphologic observation showed that the myocardial fibers were disordered, there was cell edema, and gap widening in the ADR group. The degree of myocardial cell injury was reduced in the ADR + Qishen Yiqi Pills I group and ADR + Qishen Yiqi Pills II group compared with the ADR group. 3. The expression of Bax in the ADR group was significantly up-regulated, and the expression of Bcl-2 was significantly downregulated in the ADR group compared with the ADR + Qishen Yiqi Pills I group, the ADR + Qishen Yiqi Pills II group, and the control group (P Pills can effectively improve the cardiac function of ADR-induced cardiomyopathy, and the

Distribution of Interstitial Cells of Cajal in the Esophagus of Fetal Rats with Esophageal Atresia

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Caner Isbir

2016-04-01

Full Text Available Aim: Scarcity of the interstitial cells of Cajal (ICC is related to motility disorders. In the study, we aimed to evaluate the number and density of ICCs in the fetal rat esophagus in the adriamycin - esophageal atresia (EA model. Material and Method: Rat fetuses were divided into three groups as a control, adriamycin group without EA and adriamycin group with EA. Four doses of adriamycin, 2 mg/kg each, were injected intraperitoneally to the adriamycin group rats between on 6 and 9 days of gestation. The presence of ICCs in the esophagus of the rat fetuses was determined by using an immunohistochemistry technique (c-kit, CD117. The average numbers of ICCs were calculated with microscopic evaluation by using a visual scoring system (range1 to 3. Results: Seven fetuses were included in each group. The ICCs score 3 distributions of fetuses were 5 (72% fetuses in the control group, 3 (43% fetuses in the adriamycin group without EA, 1 (14% fetus in the adriamycin group with EA. It have been found that there was a marked reduction of ICCs distribution in the adriamycin group with EA compared to control group (p 0.05. Discussion: ICCs density was significantly decreased in the rat fetuses with EA compared to the fetuses without EA. These findings support the idea that ICCs density may be congenitally abnormal in EA. This may be led to dismotility seen in the operated esophagus due to EA.

Characterization in vitro and in vivo of progressively adriamycin-resistant B16-BL6 mouse melanoma cells.

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Ganapathi, R; Grabowski, D; Schmidt, H; Bell, D; Melia, M

1987-07-01

Adriamycin (ADR)-resistant sublines of B16-BL6 mouse melanoma selected by exposure to increasing concentrations of ADR were characterized in vitro for growth properties and in vivo for tumorigenicity and pulmonary metastases. The progressively resistant sublines adapted to grow in the presence of 0.025, 0.05, 0.1, and 0.25 microgram/ml ADR in monolayer culture were found to be 5-, 10-, 20-, and 40-fold ADR-resistant, respectively, compared to the parental sensitive cells, using a soft-agar colony assay and continuous ADR treatment for 7 days. The doubling time in monolayer culture of the parent sensitive and progressively ADR-resistant sublines of B16-BL6 melanoma cells was approximately 16-18 h. Although the colony-forming efficiency in soft agar of parental sensitive cells was only 0.5-4%, the 5-, 10-, 20-, and 40-fold ADR-resistant sublines had colony-forming efficiencies of 15, 20, 30, and 77%, respectively. Tumorigenicity in C57BL/6 mice of progressively ADR-resistant sublines was similar to parental sensitive cells following s.c. and i.p. implantation of 10(5)-10(6) tumor cells. Experimental pulmonary metastases were significantly lower in ADR-resistant sublines with progressive resistance. Additionally, unlike the parental sensitive and 5-fold ADR-resistant B16-BL6 cells, the 10-, 20-, and 40-fold ADR-resistant sublines were spontaneously nonmetastatic. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunochemical detection of P-glycoprotein revealed the presence of a Mr 170,000 plasma membrane glycoprotein in the 40-fold ADR-resistant subline and its counterpart maintained for 1 year in ADR-free medium. Results from this study suggest that progressively ADR-resistant B16-BL6 mouse melanoma cells selected in vitro demonstrate a marked increase in colony formation in soft agar and a decrease in the ability to produce pulmonary metastases, without alterations in tumorigenicity.

Functionalized graphene oxide mediated adriamycin delivery and miR-21 gene silencing to overcome tumor multidrug resistance in vitro.

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Feng Zhi

Full Text Available Multidrug resistance (MDR is a major impediment to successful cancer chemotherapy. Co-delivery of novel MDR-reversing agents and anticancer drugs to cancer cells holds great promise for cancer treatment. MicroRNA-21 (miR-21 overexpression is associated with the development and progression of MDR in breast cancer, and it is emerging as a novel and promising MDR-reversing target. In this study, a multifunctional nanocomplex, composed of polyethylenimine (PEI/poly(sodium 4-styrenesulfonates (PSS/graphene oxide (GO and termed PPG, was prepared using the layer-by-layer assembly method to evaluate the reversal effects of PPG as a carrier for adriamycin (ADR along with miR-21 targeted siRNA (anti-miR-21 in cancer drug resistance. ADR was firstly loaded onto the PPG surface (PPGADR by physical mixing and anti-miR-21 was sequentially loaded onto PPGADR through electric absorption to form (anti-miR-21PPGADR. Cell experiments showed that PPG significantly enhanced the accumulation of ADR in MCF-7/ADR cells (an ADR resistant breast cancer cell line and exhibited much higher cytotoxicity than free ADR, suggesting that PPG could effectively reverse ADR resistance of MCF-7/ADR. Furthermore, the enhanced therapeutic efficacy of PPG could be correlated with effective silencing of miR-21 and with increased accumulation of ADR in drug-resistant tumor cells. The endocytosis study confirmed that PPG could effectively carry drug molecules into cells via the caveolae and clathrin-mediated endocytosis pathways. These results suggest that this PPG could be a potential and efficient non-viral vector for reversing MDR, and the strategy of combining anticancer drugs with miRNA therapy to overcome MDR could be an attractive approach in cancer treatment.

Renal F4/80+ CD11c+ mononuclear phagocytes display phenotypic and functional characteristics of macrophages in health and in adriamycin nephropathy.

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Cao, Qi; Wang, Yiping; Wang, Xin Maggie; Lu, Junyu; Lee, Vincent W S; Ye, Qianling; Nguyen, Hanh; Zheng, Guoping; Zhao, Ye; Alexander, Stephen I; Harris, David C H

2015-02-01

Conventional markers of macrophages (Mфs) and dendritic cells (DCs) lack specificity and often overlap, leading to confusion and controversy regarding the precise function of these cells in kidney and other diseases. This study aimed to identify the phenotype and function of renal mononuclear phagocytes (rMPs) expressing key markers of both Mфs and DCs. F4/80(+)CD11c(+) cells accounted for 45% of total rMPs in normal kidneys and in those from mice with Adriamycin nephropathy (AN). Despite expression of the DC marker CD11c, these double-positive rMPs displayed the features of Mфs, including Mф-like morphology, high expression of CD68, CD204, and CD206, and high phagocytic ability but low antigen-presenting ability. F4/80(+)CD11c(+) cells were found in the cortex but not in the medulla of the kidney. In AN, F4/80(+)CD11c(+) cells displayed an M1 Mф phenotype with high expression of inflammatory mediators and costimulatory factors. Adoptive transfer of F4/80(+)CD11c(+) cells separated from diseased kidney aggravated renal injury in AN mice. Furthermore, adoptive transfer of common progenitors revealed that kidney F4/80(+)CD11c(+) cells were derived predominantly from monocytes, but not from pre-DCs. In conclusion, renal F4/80(+)CD11c(+) cells are a major subset of rMPs and display Mф-like phenotypic and functional characteristics in health and in AN. Copyright © 2015 by the American Society of Nephrology.

A decrease in cyclin B1 levels leads to polyploidization in DNA damage-induced senescence.

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Kikuchi, Ikue; Nakayama, Yuji; Morinaga, Takao; Fukumoto, Yasunori; Yamaguchi, Naoto

2010-05-04

Adriamycin, an anthracycline antibiotic, has been used for the treatment of various types of tumours. Adriamycin induces at least two distinct types of growth repression, such as senescence and apoptosis, in a concentration-dependent manner. Cellular senescence is a condition in which cells are unable to proliferate further, and senescent cells frequently show polyploidy. Although abrogation of cell division is thought to correlate with polyploidization, the mechanisms underlying induction of polyploidization in senescent cells are largely unclear. We wished, therefore, to explore the role of cyclin B1 level in polyploidization of Adriamycin-induced senescent cells. A subcytotoxic concentration of Adriamycin induced polyploid cells having the features of senescence, such as flattened and enlarged cell shape and activated beta-galactosidase activity. In DNA damage-induced senescent cells, the levels of cyclin B1 were transiently increased and subsequently decreased. The decrease in cyclin B1 levels occurred in G2 cells during polyploidization upon treatment with a subcytotoxic concentration of Adriamycin. In contrast, neither polyploidy nor a decrease in cyclin B1 levels was induced by treatment with a cytotoxic concentration of Adriamycin. These results suggest that a decrease in cyclin B1 levels is induced by DNA damage, resulting in polyploidization in DNA damage-induced senescence.

Studies on uptake and distribution of chemotherapeutic agents to malignant tumors of the head and neck in rabbits, 2

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Yamada, Ryuichi

1981-01-01

Experiments were performed to investigate incorporation and distribution of chemotherapeutic agents into malignant tumors of the head and neck by microautoradiographic and electron microscopic-autoradiographic observations of VX2 carcinoma transplanted in the lower genial region of rabbits after injection of 3 H-Adriamycin as a tracer. The following findings were obtained. 1. On microautoradiograms, 3 H-Adriamycin was distributed predominantly in the nucleoplasm, rather than in the cytoplasm, of tumor tissues. 2. At the ultrastructural level, 3 H-Adriamycin was localized in the nuclear membrane and nucleoli within the nucleoplasm and in the rough endoplasmic reticulum and secretory granules within the cytoplasm. 3. These findings seem to indicate that Adriamycin may inhibit the synthesis of DNA and RNA in the nucleoplasm. (author)

Randomized trial comparing adriamycin vincristine (av) cyclophosphamide methotrexate 5-Fluorouracil prednisone (cmfp) hybrid versus av-cmfp monthly alternated in metastatic breast-cancer.

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Vallejo, C; Bianco, A; Perez, J; Machiavelli, M; Leone, B; Romero, A; Rabinovich, M; Alvarez, L; Rodriguez, R; Cuevas, M; Hannois, A; Lacava, J

1993-03-01

194 metastatic breast cancer patients with no prior chemotherapy for advanced disease were randomized to one of two alternating schedules, fulfilling the requisites of Goldie and Coldman's hypothesis to evaluate if the earlier alternation of two non-cross resistant regimens is superior in terms of response (R), duration of R (DR), and survival (SV). arm A: Adriamycin (A) 60 mg/m2 IV day (d) 1 and vincristine (V) 1.4 mg/m2 IV d 1 and 8 monthly alternated with cyclophosphamide (C) 100 mg/m2 p.o. d 1-14; methotrexate (M) 30 mg/m2 IV d 1 and 8; 5-fluorouracil (F) 600 mg/m2 IV d 1 and 8 and prednisone (Pr) 40 mg/m2 p.o. d 1-14. Arm B (hybrid): A 60 mg/m2 IV d 1; V 1.4 mg/m2 IV d 1; C 100 mg/m2 p.o. d 8-14; M 30 mg/m2 IV d 8; F 600 mg/m2 IV d 8 and Pr 40 mg/m2 p.o. d 8-14. 87 and 89 patients are evaluable for R. Arm A: R= 59% (51/87); median DR= 13 months (m); median SV= 25 m. Arm B: R= 69% (61/89); median DR= 15 m.; median SV= 29 m. Myelosuppression was slightly more marked in arm B. Three patients had toxic-related deaths (arm A: 1; arm B: 2). a trend favoring an earlier alternation and higher dose intensity (DI) was found regarding to R, DR and SV. However, differences were not statistically significant.

Global DNA hypermethylation-associated cancer chemotherapy resistance and its reversion with the demethylating agent hydralazine

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Benitez-Bribiesca Luis

2006-08-01

Full Text Available Abstract Background The development of resistance to cytotoxic chemotherapy continues to be a major obstacle for successful anticancer therapy. It has been shown that cells exposed to toxic concentrations of commonly used cancer chemotherapy agents develop DNA hypermetylation. Hence, demethylating agents could play a role in overcoming drug resistance. Methods MCF-7 cells were rendered adriamycin-resistant by weekly treatment with adriamycin. Wild-type and the resulting MCF-7/Adr cells were analyzed for global DNA methylation. DNA methyltransferase activity and DNA methyltransferase (dnmt gene expression were also determined. MCF-7/Adr cells were then subjected to antisense targeting of dnmt1, -3a, and -b genes and to treatment with the DNA methylation inhibitor hydralazine to investigate whether DNA demethylation restores sensitivity to adriamycin. Results MCF-7/Adr cells exhibited the multi-drug resistant phenotype as demonstrated by adriamycin resistance, mdr1 gene over-expression, decreased intracellular accumulation of adriamycin, and cross-resistance to paclitaxel. The mdr phenotype was accompanied by global DNA hypermetylation, over-expression of dnmt genes, and increased DNA methyltransferase activity as compared with wild-type MCF-7 cells. DNA demethylation through antisense targeting of dnmts or hydralazine restored adriamycin sensitivity of MCF-7/Adr cells to a greater extent than verapamil, a known inhibitor of mdr protein, suggesting that DNA demethylation interferes with the epigenetic reprogramming that participates in the drug-resistant phenotype. Conclusion We provide evidence that DNA hypermethylation is at least partly responsible for development of the multidrug-resistant phenotype in the MCF-7/Adr model and that hydralazine, a known DNA demethylating agent, can revert the resistant phenotype.

Co-administration of dexamethasone increases severity and accelerates onset day of neutropenia in bladder cancer patients on methotrexate, vinblastine, adriamycin and cisplatin chemotherapy: a retrospective cohort study.

Science.gov (United States)

Itai, Shingo; Suga, Yukio; Hara, Yusuke; Izumi, Kouji; Maeda, Yuji; Kitagawa, Yasuhide; Ishizaki, Junko; Shimada, Tsutomu; Mizokami, Atsushi; Sai, Yoshimichi

2017-01-01

Bladder cancer patients receiving methotrexate, vinblastine, adriamycin and cisplatin (MVAC) chemotherapy are co-administered with dexamethasone as an anti-emetic. We examined whether or not dexamethasone affects the severity and onset day of MVAC-induced severe neutropenia. This was a retrospective study of bladder cancer patients treated with MVAC chemotherapy with or without dexamethasone as an antiemetic at Kanazawa University Hospital during January 2005 - December 2009. Patients were categorized into three groups; no dexamethasone use (Dex (-)), dexamethasone on day 2 (Dex 1 day), and dexamethasone on days 2, 3 and 4 (Dex multiday). We evaluated the incidence of grade 3/4 neutropenia and the day of onset of first severe neutropenic episode during the first course of MVAC chemotherapy. Logistic regression was used to investigate whether co-administration of dexamethasone was a risk factor for severe neutropenia. Episodes of grade 3/4 neutropenia occurred in 3 out of 6 (50.0%), 11 out of 12 (91.7%) and 6 out of 6 (100%) patients in the Dex (-), Dex 1 day, and Dex multiday groups, respectively. The appearance day of first severe neutropenia in the Dex multiday group (13.2 ± 1.0) was significantly accelerated compared to the Dex (-) group (17.7 ± 2.1). Univariate logistic regression analysis revealed that dexamethasone is a risk factor for severe neutropenia (OR 17.0; 95%CI: 1.3-223.1). Co-administration of dexamethasone for anti-emesis brings forward the first appearance of neutropenia, and increases the severity of neutropenia, in bladder cancer patients receiving MVAC chemotherapy.

Evaluation of the secondary cardiotoxicity to use adriamycin in patients with breast cancer with nuclear medicine studies

International Nuclear Information System (INIS)

Garcia P, S.

2003-01-01

The number of surviving of cancer is increased highly with the current regimes of chemotherapy. For the year 2010 in U.S. it is considered that one of each 250 adults can be a survivor of wicked illness and many of these survivors will have been exposed to regimes with anthracycline. The anthracyclines concern to the group of antibiotics and they are effective point for hematological neoplasms as solid tumors. Although the relationship dose answer, among the regimes with anthracycline as well as the remission and the period free of illness is very established one, the latent risk of cardiotoxicity limits the use of these agents. Results: 30 patients were recruited with diagnostic of invader breast cancer tried with chemotherapy to base anthracycline in the understood period of may to december of the 2000. The medium of age it was of 48 years with a range of 27-80 years. The clinical stage that prevailed it was the EC IIB that represents a 36% in second place the EC IIIA with a 20%, EC IIA with 16% the EC IIIB and the unclassifiable ones represented 10% with 3 patients and finally the clinical stage IV with 8%, the most frequent localization was the left side.The received chemotherapy outline it was with the base of doxorubicin in its modality neo or patient adjutant, 5 patients also received taxanes like treatment adjutant. Prevailed the continuous infusion in 24 hours in 50%. The medium of accumulated dose of adriamycin was 274 mg/m 2 . With a left ventricular ejection fraction LVEF pretreatment of 62% (medium) determined by VRI and a medium of 69% by SPECT. The LVEF pos treatment had one medium of 57% for VRI and by SPECT a medium of 60%. They received concomitant radiotherapy with chemotherapy in modality pre operation 53.3% (16 patients), and 40% radiotherapy post operation, 2 patients didn't receive radiotherapy. In relation to the heart toxicity any patient present electrocardiographic alterations, neither arrhythmias neither clinical data of heart congestive

Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin-cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study.

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Thamlikitkul, Lucksamon; Srimuninnimit, Vichien; Akewanlop, Charuwan; Ithimakin, Suthinee; Techawathanawanna, Sirisopa; Korphaisarn, Krittiya; Chantharasamee, Jomjit; Danchaivijitr, Pongwut; Soparattanapaisarn, Nopadol

2017-02-01

The purpose of this study is to determine the efficacy of ginger for reducing chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients receiving adriamycin and cyclophosphamide (AC) regimens. We enrolled breast cancer patients receiving AC who experienced moderate to severe nausea or vomiting during the first chemotherapy cycle. Subjects were randomized to receive a 500-mg ginger capsule or placebo twice a day for 5 days starting on the first day of the second AC cycle and were switched to the other treatment in the third cycle. All participants also received ondansetron and dexamethasone for CINV prophylaxis. Nausea severity was recorded once a day during the first 5 days of each cycle. The primary outcome was reduction in nausea score. Thirty-four subjects (68 cycles of AC) were enrolled. Mean (range) maximum nausea score in the first AC cycle was 58 (40-90). Thirty-three subjects (97 %) received the same AC doses in the second as in the third cycle. Mean (±standard error) maximum nausea scores in patients receiving ginger and placebo were 35.36 (±4.43) and 32.17 (±3.71), respectively. The difference in mean maximum nausea scores was 3 (95 % confidence interval, -3 to 9; P = 0.3). There were no significant differences between ginger and placebo in terms of vomiting incidence and severity, rescue medication use, chemotherapy compliance, and adverse events. Ginger (500 mg) twice daily was safe, but conferred no additional benefit in terms of reducing nausea severity in breast cancer patients receiving AC and ondansetron and dexamethasone for CINV prophylaxis.

Cardiotoxicity of combined administration of adriamycin and granulocyte colony-stimulating factor (G-CSF) in rats. With special reference to 125I-MIBG cardioautoradiography and histopathological findings

International Nuclear Information System (INIS)

Niitsu, Nozomi; Yamazaki, Junichi; Serizawa, Isao; Misaizu, Tadashi; Sato, Masanori.

1995-01-01

We studied whether adriamycin (ADM)-induced myocardial damage in rats is advanced when recombinant human granulocyte colony-stimulating factor (G-CSF) is administered. Rats were divided into three groups: ADM group, ADM+G-CSF group and vehicle-treated control group. ADM (2 mg/kg, i.p.) was administered for the first 2 days in each cycle and 10 days administration of G-CSF (50lμg/kg, s.c.) was started two days after the second administration of ADM in each cycle. The administration cycle was repeated 3 times. One day after the last administration, following parameters were analyzed: hematological examination including peripheral blood and bone marrow cells, electrocardiogram (ECG) and histopathological findings. At 4 hr after an intravenous administration of 125 I-metaiodobenzylguanidine ( 125 I-MIBG), accumulation of 125 I-MIBG in some organs and findings of autoradiography (ARG) of the heart was examined. ECG revealed an extended ventricular activation (VAT) time in the ADM and ADM+G-CSF groups. In the histopathological analysis, vacuolar degeneration of the myocardium was observed in both the ADM and ADM+G-CSF groups. The severity of the change was equivalent in those groups. The accumulation of 125 I-MIBG in the heart was lower in both the ADM and ADM+G-CSF groups than in the control group. The same tendency was observed in ARG, but the difference between the ADM group and the ADM+G-CSF group was not significant. These results suggest that administration of G-CSF in the standard clinical dosage does not aggravate ADM-induced myocardial damage. However, because this disorder may be more clearly manifested by treatment with higher doses of ADM, it is necessary to conduct further studies on the methods of administration. (author)

骨肉腫における化学療法の有効性の指標としての腫瘍細胞の核面積の検討

OpenAIRE

滝沢, 隆史; Takizawa, Takashi

1990-01-01

Nuclear sizes of tumor cells in preoperative biopsy specimens and in resected materials, response to administration of adriamycin and methotrexate, and survival rates were compared in nineteen patients of osteosarcomas in the period from 1974 through 1988. Ten patients were treated with adriamycin and nine patients with methotrexate. Thirteen patients were classified into non-effective group which were designated as grade I or II by Rosen’s classification as to effectiveness of chemotherapy a...

The suppression effect of the intrahepatic recurrence of transcatheter arterial chemoembolization with cisplatin in the hepatocellular carcinoma patients

International Nuclear Information System (INIS)

Moon, Tae Yong; Lee, Suck Hong; Kim, Byung Soo; Kim, Yong Woo

1997-01-01

To compare the suppressive effects in hepatocellular carcinoma patients of transhepatic arterial chemoembolization by the infusion of adriamycin-lipiodol emulsion and of this plus 10ml of cisplatin solution. In a total of 151 cases, the frequency of intrahepatic recurrence was compared with follow-up angiographic findings after the first and second transhepatic arterial chemoembolization with adriamycin-lipiodol emulsion and adriamycin-lipiodol emulsion plus 10ml of cisplatin solution, respectively. Among 46 patients whose first single infusion was after mean 119 days, the recurrence rate was 22% ; for 42 who were given their first multiple infusion after mean 76 days this rate was 5% ; for 35 whose second single infusion was administered after mean 147 days, the rate was 34%, and among 28 whose second multiple infusion was after mean 110 days, the rate was 43%. During the first trial of transcatheter arterial chemoembolization with adriamycinlipiodol plus cisplatin solution, hepatocellular carcinoma recurred much less frequently, but during the second trial with cisplatin, recurrence was not suppresed

Optical coherence tomography (OCT) of a murine model of chronic kidney disease

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Wang, Hsing-Wen; Guo, Hengchang; Andrews, Peter M.; Anderson, Erik; Chen, Y.

2015-03-01

Chronic Kidney Disease (CKD) is characterized by a progressive loss in renal function over time. Pathology can provide valuable insights into the progression of CKD by analyzing the status of glomeruli and the uriniferous tubules over time. Optical coherence tomography (OCT) is a new procedure that can analyze the microscopic structure of the kidney in a non-invasive manner. This is especially important because there are significant artifacts associated with excision biopsies and immersion fixation procedures. Recently, we have shown that OCT can provide real time images of kidney microstructure and Doppler OCT (DOCT) can image glomerular renal blood flow in vivo without administrating exogenous contrast agents. In this study, we used OCT to evaluate CKD in a model induced by intravenous Adriamycin injection into Munich-Wistar rats. We evaluated tubular density and tubular diameter from OCT images at several post- Adriamycin induction time points and compared them with conventional light microscopic histological imaging. Proteinurea and serum creatinine were used as physiological markers of the extent of CKD. Preliminary OCT results revealed changes in tubular density due to tubular necrosis and interstitial fibrosis within the first 4 weeks following Adriamycin injection. From week 4 to 8 after Adriamycin induction, changes in tubular density and diameter occurred due to both tubular loss and tubular dilation. The results suggest OCT can provide additional information about kidney histopathology in CKD. DOCT revealed reduced blood flow in some glomeruli probably as a consequence of focal glomerularsclerosis.

Endothelial progenitors encapsulated in bioartificial niches are insulated from systemic cytotoxicity and are angiogenesis competent.

Science.gov (United States)

Ratliff, B B; Ghaly, T; Brudnicki, P; Yasuda, K; Rajdev, M; Bank, M; Mares, J; Hatzopoulos, A K; Goligorsky, M S

2010-07-01

Intrinsic stem cells (SC) participate in tissue remodeling and regeneration in various diseases and following toxic insults. Failure of tissue regeneration is in part attributed to lack of SC protection from toxic stress of noxious stimuli, thus prompting intense research efforts to develop strategies for SC protection and functional preservation for in vivo delivery. One strategy is creation of artificial SC niches in an attempt to mimic the requirements of endogenous SC niches by generating scaffolds with properties of extracellular matrix. Here, we investigated the use of hyaluronic acid (HA) hydrogels as an artificial SC niche and examined regenerative capabilities of encapsulated embryonic endothelial progenitor cells (eEPC) in three different in vivo models. Hydrogel-encapsulated eEPC demonstrated improved resistance to toxic insult (adriamycin) in vitro, thus prompting in vivo studies. Implantation of HA hydrogels containing eEPC to mice with adriamycin nephropathy or renal ischemia resulted in eEPC mobilization to injured kidneys (and to a lesser extent to the spleen) and improvement of renal function, which was equal or superior to adoptively transferred EPC by intravenous infusion. In mice with hindlimb ischemia, EPC encapsulated in HA hydrogels dramatically accelerated the recovery of collateral circulation with the efficacy superior to intravenous infusion of EPC. In conclusion, HA hydrogels protect eEPC against adriamycin cytotoxicity and implantation of eEPC encapsulated in HA hydrogels supports renal regeneration in ischemic and cytotoxic (adriamycin) nephropathy and neovascularization of ischemic hindlimb, thus establishing their functional competence and superior capabilities to deliver stem cells stored in and released from this bioartificial niche.

The synthesis and characterization of polypeptide-adriamycin conjugates and its complexes with adriamycin. Part I

NARCIS (Netherlands)

Heeswijk, W.A.R.; Hoes, C.J.T.; Stoffer, T.; Eenink, M.J.D.; Potman, W.; Feijen, Jan

1985-01-01

Poly(α-l-glutamic acid) (PGA) was grafted with amino acid and oligopeptide spacers up to 5 amino acids with the use of N,N'-carbonyldiimidazole and 2,3-dihydro-1,2-benz-isothiazole-3-on-1, 1-dioxide (saccharin) as an additive, and these polypeptides were characterized. The antitumor antibiotic

[Combination chemotherapy of experimental leukemia].

Science.gov (United States)

Emanuel', N M; Konovalova, N P; D'iachkovskaia, R F

1977-01-01

In the present work an attempt was made to gain greater therapeutic effect of diazane coupled with adriamycin and sarcolysin. Leucemias L-1210 and La served as a model. In leucosis La diazane was injected once in 5 days. Either an additional injection of adriamycin two days prior to diazane injection or sarcolysin injected simultaneously with diazane enabled the authors to obtain a distinct synergestic effect. In leucemia L-1210 a simultaneous administration of diazane and sarcolysin also contributes to considerably longer survival of leucemic animals. Such combinations are likely to be promising in their clinical use.

Photostabilization of doxorubicin hydrochloride with radioprotective and photoprotective agents: Potential mechanism for enhancing chemotherapy during radiotherapy

International Nuclear Information System (INIS)

Habib, M.J.; Asker, A.F.

1989-01-01

p-Aminobenzoic acid (PABA), urocanic acid, and sodium urate were found to significantly enhance the photostability of doxorubicin hydrochloride [adriamycin, (ADR)]. d1-Methionine, thiourea, and glycine also increased the photostability of this drug, but to a lesser degree. Sodium thiosulfate on the other hand, was found to be detrimental to the photostability of ADR. The photostabilizing effect of PABA was found to increase with increase of its concentration and was influenced by the pH and the buffer species of the vehicle. The findings would have an impact on the enhancement of therapeutic efficacy of adriamycin when administered during radiation therapy

Study of multidrug resistance and radioresistance

International Nuclear Information System (INIS)

Kang, Yoon Koo; Yoo, Young Do

1999-04-01

We investigated the mechanism of 5-FU, adriamycin, radiation resistance in Korean gastric cancer cells. First we investigated the relation between Rb and multidrug resistance. Rb stable transfectants exhibited 5- to 10- fold more resistance to adriamycin than the control cells. These Rb transfectants showed increased MDR1 expression. We also investigated up-regulation in radiation-resistant tumor tissues. HSP27, MRP-8, GST, and NKEF-B were up-regulated in radiation resistant tumor. Expression of NKEF-B was also increased by radiation exposure in Head and Neck cells. These results demonstrated that NKEF-B is a stress response protein and it may have an important role in radiation resistance

Postirradiation soft tissue sarcoma occurring in breast cancer patients: report of seven cases and results of combination chemotherapy

International Nuclear Information System (INIS)

Kuten, A.; Sapir, D.; Cohen, Y.; Haim, N.; Borovik, R.; Robinson, E.

1985-01-01

Seven cases of soft tissue sarcoma developing after primary or postoperative radiotherapy for breast carcinoma are reported. The sarcomas occurred within the irradiated volume, after a latent period of 4-26 years. These cases conform well to established criteria for the diagnosis of radiation-induced sarcoma. Chemotherapy, consisting of the four-drug combination CYVADIC (cyclophosphamide, vincristine, adriamycin, DTIC) was employed in six of the seven patients. Only two of them achieved partial remission, lasting only 2 and 3 months, respectively. The effectiveness of adriamycin-containing chemotherapy regimens in soft tissue sarcomas as well as the remote hazard of radiation-related sarcoma in primary or postoperative breast irradiation are discussed

Nkx2.5 enhances the efficacy of mesenchymal stem cells transplantation in treatment heart failure in rats.

Science.gov (United States)

Deng, Bo; Wang, Jin Xin; Hu, Xing Xing; Duan, Peng; Wang, Lin; Li, Yang; Zhu, Qing Lei

2017-08-01

The aim of this study is to determine whether Nkx2.5 transfection of transplanted bone marrow mesenchymal stem cells (MSCs) improves the efficacy of treatment of adriamycin-induced heart failure in a rat model. Nkx2.5 was transfected in MSCs by lentiviral vector transduction. The expressions of Nkx2.5 and cardiac specific genes in MSCs and Nkx2.5 transfected mesenchymal stem cells (MSCs-Nkx2.5) were analyzed with quantitative real-time PCR and Western blot in vitro. Heart failure models of rats were induced by adriamycin and were then randomly divided into 3 groups: injected saline, MSCs or MSCs-Nkx2.5 via the femoral vein respectively. Four weeks after injection, the cardiac function, expressions of cardiac specific gene, fibrosis formation and collagen volume fraction in the myocardium as well as the expressions of GATA4 and MEF2 in rats were analyzed with echocardiography, immunohistochemistry, Masson staining, quantitative real-time PCR and Western blot, respectively. Nkx2.5 enhanced cardiac specific gene expressions including α-MHC, TNI, CKMB, connexin-43 in MSCs-Nkx2.5 in vitro. Both MSCs and MSCs-Nkx2.5 improved cardiac function, promoted the differentiation of transplanted MSCs into cardiomyocyte-like cells, decreased fibrosis formation and collagen volume fraction in the myocardium, as well as increased the expressions of GATA4 and MEF2 in adriamycin-induced rat heart failure models. Moreover, the effect was much more remarkable in MSCs-Nkx2.5 than in MSCs group. This study has found that Nkx2.5 enhances the efficacy of MSCs transplantation in treatment adriamycin-induced heart failure in rats. Nkx2.5 transfected to transplanted MSCs provides a potential effective approach to heart failure. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis and evaluation of novel N-substituted-6-methoxynaphthalene-2-carboxamides as potential chemosensitizing agents for cancer.

Science.gov (United States)

Lokhande, Tushar Narendra; Viswanathan, Chelakara Lakshmann; Juvekar, Aarti Shashikant

2008-07-01

A novel class of molecules with structure N-[3-(heteroaryl)propyl]-6-methoxynaphthalene-2-carboxamides 8-13 were synthesized by condensing 6-methoxy-2-naphthoyl chloride 1 with 3-(heteroaryl)propyl amines 2-7. Compounds 8-12 were evaluated in vitro, in P388 murine lymphocytic leukemia cell line (P388) using SRB assay for cytotoxicity and in adriamycin resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Compounds 8-12 were non-toxic at lower dose of 20 microg/ml, and effectively reversed adriamycin resistance. However, at higher doses (40, 80 microg/ml) they showed significant cytotxicity and hence reversal potency was not determined at these concentrations.

Blocking CHK1 Expression Induces Apoptosis and Abrogates the G2 Checkpoint Mechanism

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Yan Luo

2001-01-01

Full Text Available Checkpoint kinase 1 (Chki is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates the Cdc2 activating phosphatase Cdc25C. This in turn inactivates Cdc2, which leads to G2/M arrest. We report that blocking Chki expression by antisense or ribozymes in mammalian cells induces apoptosis and interferes with the G2/M arrest induced by adriamycin. The Chki inhibitor UCN-01 also blocks the G2 arrest after DNA damage and renders cells more susceptible to adriamycin. These results indicate that Chki is an essential gene for the checkpoint mechanism during normal cell proliferation as well as in the DNA damage response.

Cardiotoxicity of copper-based antineoplastic drugs casiopeinas is related to inhibition of energy metabolism

International Nuclear Information System (INIS)

Hernandez-Esquivel, Luz; Marin-Hernandez, Alvaro; Pavon, Natalia; Carvajal, Karla; Moreno-Sanchez, Rafael

2006-01-01

Isolated rat hearts were perfused with glucose, octanoate or glucose + octanoate and different concentrations of the copper-based antineoplastic drugs casiopeina II-gly (CSII) or casiopeina III-i-a (CSIII). In isolated perfused hearts with glucose + octanoate, both casiopeinas induced diminution in cardiac work and O 2 consumption with half-maximal inhibitory concentrations (IC 5 ) of 4 (CSII) and 4.6 (CSIII) μM, after 1 h of perfusion. Strong inhibition of the pyruvate and 2-oxoglutarate dehydrogenases as well as total creatine kinase by casiopeinas suggested that ATP generation by oxidative phosphorylation and its transfer towards myofibrils were targets for these drugs. In consequence, the cellular contents of ATP and phosphocreatine were also lowered by casiopeinas. Remarkably, casiopeinas were less toxic than adriamycin (IC 5 = 2.6 μM), a well-known potent cardiotoxic and antineoplastic drug, which has a wide clinical use. In an open-chest animal, which is a more physiological model than the isolated heart, femoral administration of 1 μM drug revealed that CSII was innocuous very likely due to strong binding to serum albumin, whereas adriamycin induced again a potent cardiotoxic effect (diminution in heart rate and severe depression of systolic blood pressure). Thus, it seems that casiopeinas are a group of new antineoplastic drugs with milder secondary toxic effects than proven drugs such as adriamycin

Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials

International Nuclear Information System (INIS)

Schuck, Andreas; Ahrens, Susanne; Paulussen, Michael; Kuhlen, Michaela; Koenemann, Stefan; Ruebe, Christian; Winkelmann, Winfried; Kotz, Rainer; Dunst, Juergen; Willich, Normann; Juergens, Heribert

2003-01-01

Purpose: The impact of different local therapy approaches on local control, event-free survival, and secondary malignancies in the CESS 81, CESS 86, and EICESS 92 trials was investigated. Methods and Materials: The data of 1058 patients with localized Ewing tumors were analyzed. Wherever feasible, a surgical local therapy approach was used. In patients with a poor histologic response or with intralesional and marginal resections, this was to be followed by radiotherapy (RT). In EICESS 92, preoperative RT was introduced for patients with expected close resection margins. Definitive RT was used in cases in which surgical resection seemed impossible. In CESS 81, vincristine, adriamycin, cyclophosphamide, and actinomycin D was used. In CESS 86, vincristine, adriamycin, ifosfamide, and actinomycin D was introduced for patients with central tumors or primaries >100 cm 3 . In CESS 92, etoposide, vincristine, adriamycin, ifosfamide, and actinomycin D was randomized against vincristine, adriamycin, ifosfamide, and actinomycin D in patients with primaries >100 cm 3 . Results: The rate of local failure was 7.5% after surgery with or without postoperative RT, and was 5.3% after preoperative and 26.3% after definitive RT (p=0.001). Event-free survival was reduced after definitive RT (p=0.0001). Irradiated patients represented a negatively selected population with unfavorable tumor sites. Definitive RT showed comparable local control to that of postoperative RT after intralesional resections. Patients with postoperative RT had improved local control after intralesional resections and in tumors with wide resection and poor histologic response compared with patients receiving surgery alone. Patients with marginal resections with or without postoperative radiotherapy showed comparable local control, yet the number of patients with good histologic response was higher in the latter treatment group (72.2% vs. 38.5%). Conclusion: Patients with resectable tumors after initial

Kaposi's sarcoma: Good outcome with doxorubicin, bleomycin and ...

African Journals Online (AJOL)

KS) in children in low-income countries. We prospectively treated 12 patients with an institutional review board-approved protocol consisting of four monthly courses of doxorubicin (Adriamycin), bleomycin and vincristine sulphate (ABV), with ...

Clinical study on external carotid artery infusion (trans-femoral) treatment of recurrent nasopharyngeal carcinoma

International Nuclear Information System (INIS)

Zhou Zejian; Li Chong; Luo Pengfei; Shao Peijian; Zhang Liangming; Li Weike; Li Yong; Xu Rongde; Zhuang Wenxing; Zhang Hua

2002-01-01

Objective: To evaluate the effect and safety of external carotid artery infusion treatment of recurrent nasopharyngeal carcinoma (NPC). Methods: 20 cases of recurrent NPC (13 male and 7 female, age 36-65 years, mean 50 years) diagnosed by clinical examination (including nasopharyngoscope), serology (VCA-IgA) and imaging (CT, MR) and treated by external carotid artery infusion (trans-femoral) with adriamycin (or epi-adriamycin), cisplatin (or carboplatin), Pingyangmycin and 5-Fluorouracil. Results: Of all the patients, 8 cases (40%) had a complete response (CR), 7 cases (35%) had a partial response (PR). The overall response rate (CR + PR) was 75%. Cumulative survival rates at 1, 3 years were 90% (18/20), 50%(10/20) respectively. No severe side-effects and complications found. Conclusion: External carotid artery infusion (trans-femoral) should be effective and safe in the treatment of recurrent NPC

Role of proteinuria in the regulation of renal renin-angiotensin system components in unilateral proteinuric rats

NARCIS (Netherlands)

Deelman, LE; Navis, G; Wietses, M; de Zeeuw, D; Henning, RH

Renin-angiotensin system (RAS) overactivity has been implied in progressive renal function loss. We investigated whether changes in the renal expression of RAS components are specifically associated with the proteinuric kidney. Unilateral adriamycin-induced proteinuria was obtained by clamping the

Chemotherapy of gastric cancer - a radiological control

International Nuclear Information System (INIS)

Theobaldy, S.; Hofmann-Preiss, K.; Walter, M.

1987-01-01

In most cases of metastatic gastric cancer, treatment with cytostatic drugs seems to be justified. Responsiveness to chemotherapy, according to the MAF-schedule (Methotrexat, Adriamycin, 5-Fluorouracil) was reported to be successful in 50% of this cancer type. (orig.) [de

Four cycles of adriamycin and cyclophosphamide followed by four cycles of docetaxel (NSABP-B27 with concomitant trastuzumab as neoadjuvant therapy for high-risk, early-stage, HER2-positive breast cancer patients

Directory of Open Access Journals (Sweden)

Abdel-Razeq H

2018-04-01

Full Text Available Hikmat Abdel-Razeq,1,2 Salwa S Saadeh,1 Mahmoud Abu-Nasser,1 Hazem Abdulelah,1 Lina Marie,1 Murad Salam,1 Basel Al-Haj Ali,1 Mohammad Ibrahim,1 Dalia Rimawi3 1Department of Internal Medicine, Section of Hematology and Medical Oncology, King Hussein Cancer Center, Amman, Jordan; 2School of Medicine, University of Jordan, Amman, Jordan; 3Office of Scientific Affairs and Research, King Hussein Cancer Center, Amman, Jordan Background: The majority of breast cancer patients in Jordan are diagnosed at a young age and present with metastatic or locally advanced disease. The National Surgical Adjuvant Breast and Bowel Project Protocol B27 (NSABP-B27 (four cycles of adriamycin and cyclophosphamide [AC] followed by four cycles of docetaxel is a standard neoadjuvant regimen in our institution. In this study, we report the efficacy of adding trastuzumab to docetaxel in this regimen for high-risk human epidermal growth factor receptor 2 (HER2-positive early-stage disease. Patients and methods: Consecutive HER2-positive breast cancer patients treated with this regimen were included. Treatment was given at standard doses and schedules as reported in NSABP-B27. Trastuzumab was given with docetaxel and then continued for 1 year. Results: A total of 121 patients (mean age 45.4 years were included. The majority had high-risk features including large tumor size, positive axillary lymph nodes, and grade III disease. Three patients did not complete the planned cycles of AC due to a lack of response. Eight (6.6% patients missed at least one cycle of docetaxel. Following neoadjuvant therapy, 119 patients underwent surgery, of whom 59 (49.6% patients achieved pathological complete response. The response was higher in node-negative patients (64.0 vs 45.7%; P=0.03 and in hormone receptor-negative disease patients (69.7 vs 41.9%; P=0.018. Breast-conserving surgery was performed in 21.5% of the patients. The median disease-free survival (DFS for the whole group was not

EBV-positive immunodeficiency lymphoma after alemtuzumab-CHOP therapy for peripheral T-cell lymphoma

NARCIS (Netherlands)

Kluin-Nelemans, Hanneke C.; Coenen, Jules L.; Boers, James E.; van Imhoff, Gustaaf W.; Rosati, Stefano

2008-01-01

Chemotherapy with alemtuzumab and the combination of cyclophosphamide, adriamycin, oncovin, and prednisone (CHOP) has become experimental trial therapy for aggressive T-cell lymphoma. Several multicenter phase 3 trials; will incorporate this scheme. As part of an ongoing phase 2 trial in which we

Case report

African Journals Online (AJOL)

abp

2017-09-07

Sep 7, 2017 ... protocol) and radiotherapy with a favorable follow up. Pan African Medical ... liver and kidney functions tests were normal. The tuberculin skin ... Chemotherapy was indicated, the patient received ABVD protocol. (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) followed by radiotherapy. The clinical and ...

Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial

DEFF Research Database (Denmark)

Oakman, C; Francis, P A; Crown, J

2013-01-01

Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease...

Role of radiation therapy in the treatment of pediatric non-Hodgkin's lymphomas. [Complications of local irradiation and chemotherapy

Energy Technology Data Exchange (ETDEWEB)

Carabell, S.C.; Cassady, J.R.; Weinstein, H.J.; Jaff, N.

1978-11-01

Between 1971 and 1976, 64 patients less than 18 years of age with non-Hodgkin's lymphoma were treated at Boston's Children's Hospital Medical Center-Joint Center for Radiation Therapy. A multimodality approach was used, consisting of radiation therapy (3500 to 4500 rad), surgery, and chemotherapy. Since 1973, all patients have received a regimen initially comprising Adriamycin, Prednisone, 6-Mercaptopurine, Vincristine, and L-Asparaginase. Methotrexate was substituted for Adriamycin following a cumulative total dose of 450 mg/m/sup 2/. The 5-year actuarial survival for all patients was 61%, while relapse-free survival was 54%. The actuarial and relapse-free survival for patients presenting with localized disease was 75% and 72%, respectively. Median follow-up was 40 months and all relapses occurred within 24 months of initial therapy. A multidisciplinary approach, such as the current regimen, offers a good prognosis for this disease.

Comparison of survival rates among different treatment methods of transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma

Energy Technology Data Exchange (ETDEWEB)

Shim, Yong Woon; Lee, Jong Tae; Yoo, Hyung Sik; Lee, Do Yun; Jun, Pyoung Jun; Chang, So Yong [Yonsei Univ. College of Medicine, Seoul (Korea, Republic of)

1996-06-01

To compare the survival rates of patients with hepatoma using different methods of transcatheter arterial chemoemblization(THAE). Four hundred and eighty three patients with hepatoma diagnosed by biopsy, serum alpha-fetoprotein, abdominal CT scan, abdominal ultrasonography or hepatic angiography were included, but not all had received surgical treatment. They were divided onto two groups according to Child's classification and into subgroups according to different methods of THAE. Five-tear survival rates among these groups were retrospectively compared. The patients were aged between 24 and 85(mean, 58) ; male to female ratio was 324 : 61 for those who received THAE (369 : 87 when only hepatic angiography was considered.). In the group with more than a single episode of chemoembolization, regardless of Child's classification, a better survival rate compared to the other groups with or without concommitant radiotherapy or without chemoembolization was noted. There was no difference in the survival rate of patients with multiple chemoembolization. moreover, no difference in this rate was observed no matter what chemotherapeutic agents, including Adriamycin, Cis-Diaminedichloroplatinum of I-131-Lipiodol, were used. Amortization by gelfoam in conjuction with Adriamycin resulted in no difference in survival rate regardless of frequency of chemoembolization. An improved survival rate was seen when multiple episodes of chemoembolization were applied, but no difference was seen when there was concomitant application of either gelfoam or radiotherapy. Two different chemotherapeutic agents, Adriamycin and Cis-Diaminedichloroplatinum, were used, but there was no difference between them in their effect on survival rates.

Radiation dose and long term risk of cardiac pathology following radiotherapy and anthracyclin for a childhood cancer

International Nuclear Information System (INIS)

Guldner, Laurence; Haddy, Nadia; Pein, Francois; Diallo, Ibrahima; Shamsaldin, Akthar; Dahan, Michel; Lebidois, Jerome; Merlet, Pascal; Villain, Elisabeth; Sidi, Daniel; Sakiroglu, Olivia; Hartmann, Olivier; Leftakopoulos, Dimitri; Vathaire, Florent de

2006-01-01

Purpose: To determine the cardiac status in children 15 years (yrs) or more after a solid tumour treatment. Patients and Methods: Of the 447 patients, 229 were fully studied and 218 were not. The following cardiac evaluation was proposed to all the 447 consecutive patients: (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-h holter ECG; (3) 131 I-mIBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO 2 max measurement. The radiation dose delivered to 7 points in the heart was estimated for all patients who had received radiotherapy. Results: Cardiac disorder was diagnosed in 89 evaluated patients (39%) including 24 heart failures and 65 other asymptomatic cardiac diseases. When adjusting on potential confounders, cardiac disorder and cardiac failure risks were respectively linear (ERR at 1 Gy: 26%) and linear-quadratic (ERR at 1 Gy: 19%) functions of the average radiation dose received to the heart. No interaction between cumulative dose of adriamycin and average radiation dose was evidenced for cardiac disorders, but the ERR/Gy of cardiac failure was higher for patients receiving less than 350 mg/m 2 of Adriamycin. Conclusion: Long term heart pathologies are probably one of the major iatrogenic risks encored by patients who survived a childhood cancer. This study strongly emphasizes the need to limit the heart irradiation during radiotherapy, particularly, for patients who also received or were susceptible to later received adriamycin

Chen et al., Afr J Tradit Complement Altern Med. (2011) 8(4):467-476

African Journals Online (AJOL)

AJTCAM

Keywords: Shen-qi-di-huang decoction, proteinuria, nephrin, adriamycin nephropathy. Introduction. Proteinuria is a clinical signature of podocyte injury resulting in many renal diseases. The slit diaphragm (SD) which connects neighboring foot processes of podocytes represents a critical structure of protein filtration (Tarabra ...

Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma.

NARCIS (Netherlands)

Lokhorst, H.M.; Schmidt-Wolf, I.; Sonneveld, P.; Holt, B. van der; Martin, H.; Barge, R.; Bertsch, U.; Schlenzka, J.; Bos, G.M.; Croockewit, S.; Zweegman, S.; Breitkreutz, I.; Joosten, P.; Scheid, C.; Marwijk-Kooy, M. van; Salwender, H.J.; Oers, M.H. van; Schaafsma, R.; Naumann, R.; Sinnige, H.A.M.; Blau, I.; Delforge, M.; Weerdt, O. de; Wijermans, P.W.; Wittebol, S.; Duersen, U.; Vellenga, E.; Goldschmidt, H.

2008-01-01

In the prospective phase 3 HOVON-50/GMMG-HD3 trial, patients randomized to TAD (thalidomide, doxorubicin, dexamethasone) had a significantly higher response rate (at least PR) after induction compared with patients randomized to VAD (vincristine, adriamycin, dexamethasone, 72% vs. 54%, p<0.001).

Albumin-heparin microspheres as carriers for cytostatic agents

NARCIS (Netherlands)

Cremers, Harry; Feijen, Jan; Kwon, G.; Bae, Y.H.; Kim, S.W.; Noteborn, H.P.J.M.; Mcvie, J.G.

1990-01-01

Much work has been done on adriamycin-loaded albumin microspheres (Alb-MS) for chemoembolization [1–4], the rationale being that site-specific drug delivery may increase the therapeutic efficacy of the drug. Alb-Ms are being investigated because of their biocompatibility and because the degradation

Rare case of left adrenal cortical carcinoma with level 3 inferior vena ...

African Journals Online (AJOL)

K. Jain

2017-05-02

May 2, 2017 ... carcinoma with no renal parenchymal invasion and the immuno-histochemistry showing it to be positive for synaptophysin, inhibin and KI-67 (15%) while negative for chromogranin, pan cytokeratin and CD-10 receptors. Patient then received 3 weekly 6 cycles of adriamycin and cisplatin chemotherapy.

Radiation recall and radiosensitisation with alkylating agents

Energy Technology Data Exchange (ETDEWEB)

Kellie, S.J.; Plowman, P.N.; Malpas, J.S.

1987-05-16

This brief note records the results of experiments with Adriamycin, 1,2:5,6 dianhydrodulcit and hydroxyurea combined with an endogenous substance inhibiting myeloid proliferation selectively against target cells taken from normal rat, mouse or human haemopoietic lines, spontaneous human leukaemias and the HL-60 established promyelocytic cell line.

Characteristics and overcome of the resistance to chemotherapeutic agents

International Nuclear Information System (INIS)

Hong, Weon Seon; Im, Young Hyuck; Kim, Young Sun

1993-01-01

Although the clinical use of colony-stimulating factor (CSF) improves the therapeutic results, there have been a lot of evidences that CSF may stimulate the growth of cancer cells. This study was conducted to investigate the effects of granulocytemacrophage(GM)-CSF and granulocyte(G)-CSF on the colony formations in eight human cancer cell lines. The stimulatory effects of GM-CSF and G-CSF on the colony formation were evaluated in human tumor colony assay against four human cancer cell lines, four sublines resistant to adriamycin or cisplatin : PC-9 and PC-14 (pulmonary adenoca), MKN-45 and KATO III (gastric adenoca), PC/ADM and PC/CDDP (sublines of PC-14 resistant to adriamycin and cisplatin, respectively), MKN/ADM and MKN/CDDP (sublines of MKN-45 resistant to adriamycin and cisplatin, respectively). Cancer cells were plated at concentrations of 1x10 3 and 1x10 5 cells/well in the upper layer. Two kinds of GM-CSF (LBD-005 and CSF 39-300) and two kinds of G-CSF (Grasin and Neutrogin) were tested by the addition of final concentrations of GM-CSF and G-CSF (0.01, 0.1 and 1.0 μg/ml) to the lower layer to allow continuous exposure for 14 days. The colony formations (%) of eight cell lines tested were 85-113% and 92-106% in wells plated at the concentrations (/well) of 1x10 3 and 1x10 5 plated, respectively, in all cell lines compared to those of control wells. These results suggest that GM-CSF and G-CSF dose not directly stimulate the growth of cancer cells in all cell lines tested. (Author)

Proteomic Analysis Reveals a Role for Bcl2-associated Athanogene 3 and Major Vault Protein in Resistance to Apoptosis in Senescent Cells by Regulating ERK1/2 Activation*

Science.gov (United States)

Pasillas, Martina P.; Shields, Sarah; Reilly, Rebecca; Strnadel, Jan; Behl, Christian; Park, Robin; Yates, John R.; Klemke, Richard; Gonias, Steven L.; Coppinger, Judith A.

2015-01-01

Senescence is a prominent solid tumor response to therapy in which cells avoid apoptosis and instead enter into prolonged cell cycle arrest. We applied a quantitative proteomics screen to identify signals that lead to therapy-induced senescence and discovered that Bcl2-associated athanogene 3 (Bag3) is up-regulated after adriamycin treatment in MCF7 cells. Bag3 is a member of the BAG family of co-chaperones that interacts with Hsp70. Bag3 also regulates major cell-signaling pathways. Mass spectrometry analysis of the Bag3 Complex revealed a novel interaction between Bag3 and Major Vault Protein (MVP). Silencing of Bag3 or MVP shifts the cellular response to adriamycin to favor apoptosis. We demonstrate that Bag3 and MVP contribute to apoptosis resistance in therapy-induced senescence by increasing the level of activation of extracellular signal-regulated kinase1/2 (ERK1/2). Silencing of either Bag3 or MVP decreased ERK1/2 activation and promoted apoptosis in adriamycin-treated cells. An increase in nuclear accumulation of MVP is observed during therapy-induced senescence and the shift in MVP subcellular localization is Bag3-dependent. We propose a model in which Bag3 binds to MVP and facilitates MVP accumulation in the nucleus, which sustains ERK1/2 activation. We confirmed that silencing of Bag3 or MVP shifts the response toward apoptosis and regulates ERK1/2 activation in a panel of diverse breast cancer cell lines. This study highlights Bag3-MVP as an important complex that regulates a potent prosurvival signaling pathway and contributes to chemotherapy resistance in breast cancer. PMID:24997994

Adjuvant chemotherapy for osteosarcoma.

Science.gov (United States)

Eilber, F R; Rosen, G

1989-08-01

From this review of chemotherapy trials, several observations can be made. Osteosarcoma is a complex disease involving multiple histologies, each with a different prognosis. Prognostic factors that have been shown to be important include anatomic location of the primary tumor, stage at presentation (patients with metastatic or local recurrent disease fair far worse than those with primary disease), age at onset (children fair worse than the teenager with osteosarcoma), and location within the extremity (patients with more distal tumors fairing better than patients with more proximal tumors). There is convincing evidence for the efficacy of chemotherapeutic agents such as methotrexate in high doses (at least 8 g/m2 for adults, 12 g/m2 for children), Adriamycin, and cisplatin. The combination of Adriamycin and cisplatin appears to be more beneficial relative to either one of these agents alone. The efficacy of the combination of BCD as a triple-drug regimen, although useful in several different trials, has not been convincingly shown. Finally, from several of the recent randomized trials, it appears, that chemotherapeutic regimens containing an Adriamycin and cisplatin combination appear to be superior to those that do not include this combination. However, these observations are made from a historical perspective and have not been conclusively proven by randomized prospective investigations. The observations concerning the natural history of the disease and the activity of various chemotherapeutic agents suggest certain clinical practice algorithms. Essential staging procedures would include a bone scan looking for multifocal or metastatic disease, and CT scans of the chest looking for metastases to the lung. From all studies, it is apparent that surgery is mandatory for the primary tumor and should be an integral portion of all treatment methods. Chemotherapy should be considered for all patients with osteosarcoma, and the essential drugs in the regimen appear at

Ameliorative effect of Draba nemorosa extract on chronic heart ...

African Journals Online (AJOL)

Purpose: To evaluate the effect of Draba nemorosa extract (DNE) on oxidative stress and hemodynamics in rats with chronic congestive heart failure (CHF). Methods: Adriamycin was used to establish CHF in Sprague Dawley (SD) rat model. Six groups of SD rats were used in this study: control group, CHF group, captopril ...

A novel fluoride anion modified gelatin nanogel system for ultrasound-triggered drug release.

Science.gov (United States)

Wu, Daocheng; Wan, Mingxi

2008-01-01

Controlled drug release, especially tumor-targeted drug release, remains a great challenge. Here, we prepare a novel fluoride anion-modified gelatin nanogel system and investigate its characteristics of ultrasound-triggered drug release. Adriamycin gelatin nanogel modified with fluoride anion (ADM-GNMF) was prepared by a modified co-precipitation method with fluoride anion and sodium sulfate. The loading and encapsulation efficiency of the anti-neoplastic agent adriamycin (ADM) were measured by high performance liquid chromatography (HPLC). The size and shape of ADM-GNMF were determined by electron microscopy and photo-correlation spectroscopy. The size distribution and drug release efficiency of ADM-GNMF, before and after sonication, were measured by two designed measuring devices that consisted of either a submicron particle size analyzer and an ultrasound generator as well as an ultrasound generator, automatic sampler, and HPLC. The ADM-GNMF was stable in solution with an average diameter of 46+/-12 nm; the encapsulation and loading efficiency of adriamycin were 87.2% and 6.38%, respectively. The ultrasound-triggered drug release and size change were most efficient at a frequency of 20 kHz, power density of 0.4w/cm2, and a 1~2 min duration. Under this ultrasound-triggered condition, 51.5% of drug in ADM-GNMF was released within 1~2 min, while the size of ADM-GNMF changed from 46 +/- 12 nm to 1212 +/- 35 nm within 1~2 min of sonication and restored to its previous size in 2~3 min after the ultrasound stopped. In contrast, 8.2% of drug in ADM-GNMF was released within 2~3 min without sonication, and only negligible size changes were found. The ADM-GNMF system efficiently released the encompassed drug in response to ultrasound, offering a novel and promising controlled drug release system for targeted therapy for cancer or other diseases.

Proteomic analysis reveals a role for Bcl2-associated athanogene 3 and major vault protein in resistance to apoptosis in senescent cells by regulating ERK1/2 activation.

Science.gov (United States)

Pasillas, Martina P; Shields, Sarah; Reilly, Rebecca; Strnadel, Jan; Behl, Christian; Park, Robin; Yates, John R; Klemke, Richard; Gonias, Steven L; Coppinger, Judith A

2015-01-01

Senescence is a prominent solid tumor response to therapy in which cells avoid apoptosis and instead enter into prolonged cell cycle arrest. We applied a quantitative proteomics screen to identify signals that lead to therapy-induced senescence and discovered that Bcl2-associated athanogene 3 (Bag3) is up-regulated after adriamycin treatment in MCF7 cells. Bag3 is a member of the BAG family of co-chaperones that interacts with Hsp70. Bag3 also regulates major cell-signaling pathways. Mass spectrometry analysis of the Bag3 Complex revealed a novel interaction between Bag3 and Major Vault Protein (MVP). Silencing of Bag3 or MVP shifts the cellular response to adriamycin to favor apoptosis. We demonstrate that Bag3 and MVP contribute to apoptosis resistance in therapy-induced senescence by increasing the level of activation of extracellular signal-regulated kinase1/2 (ERK1/2). Silencing of either Bag3 or MVP decreased ERK1/2 activation and promoted apoptosis in adriamycin-treated cells. An increase in nuclear accumulation of MVP is observed during therapy-induced senescence and the shift in MVP subcellular localization is Bag3-dependent. We propose a model in which Bag3 binds to MVP and facilitates MVP accumulation in the nucleus, which sustains ERK1/2 activation. We confirmed that silencing of Bag3 or MVP shifts the response toward apoptosis and regulates ERK1/2 activation in a panel of diverse breast cancer cell lines. This study highlights Bag3-MVP as an important complex that regulates a potent prosurvival signaling pathway and contributes to chemotherapy resistance in breast cancer. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Cellular recovery kinetic studies relevant to combined-modality research and therapy

International Nuclear Information System (INIS)

Dethlefsen, L.A.

1979-01-01

The relevance of cellular recovery kinetics to combined-modality therapy is evaluated within the framework of an idealized experimental flow chart and published adriamycin data. Within this context, limitations for both experimental design and data interpretations are discussed. The effects of adriamycin have been documented extensively at the molecular and cellular level and its interactions with x-irradiation have been studied, both in vitro and in vivo. The limited in vivo results suggest that the end results of a given protocol correlate with cellular recovery kinetics; however, definitive experiments simply have not been done. For example, no one has used single-dose drug and irradiation data to predict the outcome and then confirm or refute the prediction even in a relatively simple 2-dose drug + 2-dose drug + 2-dose x-ray protocol. Thus, at this time, the extent of the correlations between cellular recovery kinetics and clinical response for either normal or malignant tissues is not known and the possible relevance of such studies cannot be discounted

Chemical constituents of Hericium erinaceum associated with the inhibitory activity against cellular senescence in human umbilical vascular endothelial cells.

Science.gov (United States)

Noh, Hyung Jun; Yang, Hyo Hyun; Kim, Geum Soog; Lee, Seung Eun; Lee, Dae Young; Choi, Je Hun; Kim, Seung Yu; Lee, Eun Suk; Ji, Seung Heon; Kang, Ki Sung; Park, Hye-Jin; Kim, Jae-Ryong; Kim, Ki Hyun

2015-12-01

Hericium erinaceum is an edible and medicinal mushroom widely used in Korea, Japan, and China. On the search for biologically active compounds supporting the medicinal usage, the MeOH extract of the fruiting bodies of H. erinaceum was investigated for its chemical constituents. Six compounds were isolated and identified as hericenone D (1), (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3β-ol (2), erinacerin B (3), hericenone E (4), hericenone F (5) and isohericerin (6) by comparing their spectroscopic data with previously reported values. The inhibitory effects on adriamycin-induced cellular senescence in human dermal fibroblasts (HDFs) and human umbilical vein endothelial cells (HUVECs) of the isolates (1-6) were studied. Among the isolated compounds, ergosterol peroxide (2) reduced senescence associated β-galactosidase (SA-β-gal) activity increased in HUVECs treated with adriamycin. According to experimental data obtained, the active compound may inspire the development of a new pharmacologically useful substance to be used in the treatment and prevention of age-related diseases.

Urinary collagen degradation products as early markers of progressive renal fibrosis

DEFF Research Database (Denmark)

Hijmans, Ryanne S.; Rasmussen, Daniel Guldager Kring; Yazdani, Saleh

2017-01-01

-fibrotic S1P-receptor modulator FTY720 treatment. Methods: Proteinuria was induced in male Wistar rats by Adriamycin (ADR) injection (n = 16). Healthy rats served as controls (n = 12). Six weeks post-injection, all underwent renal biopsy, and FTY720-treatment started in ADR-rats (n = 8) and controls (n = 6...... controls, P ADR-rats versus controls...

Serial assessment of doxorubicin cardiomyopathy with the computerized scintillation probe

International Nuclear Information System (INIS)

Strashun, A.; Goldsmith, S.J.; Horowitz, S.F.

1982-01-01

Cardiac function was serially monitored in 55 patients receiving adriamycin chemotherapy over 18 months with quantitative radionuclide assessment by both a nonimaging computerized scintillation probe and gamma camera-computer imaging. Interval ejection fraction change was comparable with both techniques and predicted incipient cardiotoxicity. Probe data revealed ejection fraction decline was antedated by decline left ventricular emptying and filling rates

Inhibitory effect of sequential combined chemotherapy and radiotherapy on growth of implanted tumor in mice

International Nuclear Information System (INIS)

Okada, Kouji

1983-01-01

Sequential chemotherapy using FT-207, adriamycin and mitomycin C followed by radiotherapy was attempted to achieve effective inhibition against implanted tumor in C57BL/6 black mice bearing YM-12 tumors. Sequential combined chemotherapy was more effective than single drug chemotherapy or combined chemotherapy of other drugs. Addition of radiotherapy to the sequential combined chemotherapy was successful for enhancing therapeutic effect. (author)

Prognostic value of lymphoma-specific S-phase fraction compared with that of other cell proliferation markers

Energy Technology Data Exchange (ETDEWEB)

Holte, H.; Kvaloey, S. [Dept. of Oncology, Univ. of Oslo (Norway); Suo Zhenhe; Langholm, R. [Dept. of Pathology, Univ. of Oslo (Norway); Smeland, E.B. [Dept. of Immunology, Univ. of Oslo (Norway); Stokke, T. [Dept. of Biophysics, Univ. of Oslo (Norway)

1999-11-01

The proliferation-associated antigens Ki67 (immunohistochemistry) and proliferative cell nuclear antigen (PCNA) (immunohistochemistry and immunoblotting) were analysed together with DNA synthesis ({sup 3}H-thymidine incorporation) and cell-cycle distribution (tumour-specific S-phase fraction determined by flow cytometry) in lymph node suspensions from 63 patients with newly diagnosed B-Cell non-Hodgkin`s lymphomas. Details of clinical parameters, treatment and patient outcome were available for all patients, and retrospectively analysed. Of the proliferation-associated parameters, only high S-phase fraction (p < 0.00001) and high PCNA expression by immunoblotting (p=0.012) were predictive of a poor prognosis. Of the conventional parameters, high-grade malignancy, high International Prognostic Index (IPI) score, bulky disease and presence of B symptoms predicted a patient for poor survival. High S-phase fraction was predictive of a short survival for the low-grade lymphomas analyses separately (p < 0.00001), as well as for patients treated with an Adriamycin- and a non-Adriamycin-containing regimen (p < 0.005 for both groups). In a multivariate analysis, S-phase fraction (p=0.00006), IPI score (p=0.015) and B symptoms (p=0.017) had independent prognostic values, but not histological grade. (orig.)

Prognostic value of lymphoma-specific S-phase fraction compared with that of other cell proliferation markers

International Nuclear Information System (INIS)

Holte, H.; Kvaloey, S.; Suo Zhenhe; Langholm, R.; Smeland, E.B.; Stokke, T.

1999-01-01

The proliferation-associated antigens Ki67 (immunohistochemistry) and proliferative cell nuclear antigen (PCNA) (immunohistochemistry and immunoblotting) were analysed together with DNA synthesis ( 3 H-thymidine incorporation) and cell-cycle distribution (tumour-specific S-phase fraction determined by flow cytometry) in lymph node suspensions from 63 patients with newly diagnosed B-Cell non-Hodgkin's lymphomas. Details of clinical parameters, treatment and patient outcome were available for all patients, and retrospectively analysed. Of the proliferation-associated parameters, only high S-phase fraction (p < 0.00001) and high PCNA expression by immunoblotting (p=0.012) were predictive of a poor prognosis. Of the conventional parameters, high-grade malignancy, high International Prognostic Index (IPI) score, bulky disease and presence of B symptoms predicted a patient for poor survival. High S-phase fraction was predictive of a short survival for the low-grade lymphomas analyses separately (p < 0.00001), as well as for patients treated with an Adriamycin- and a non-Adriamycin-containing regimen (p < 0.005 for both groups). In a multivariate analysis, S-phase fraction (p=0.00006), IPI score (p=0.015) and B symptoms (p=0.017) had independent prognostic values, but not histological grade. (orig.)

The sensitivity testing of Wilms' tumors to cytostatic agents with an autoradiographic in vitro short-term test

International Nuclear Information System (INIS)

Willnow, U.

1984-01-01

Sensitivity of 15 Wilms' tumors in children was tested towards cytostatic agents in vitro by means of an autoradiographic short-term test. Sensitivity was measured as the magnitude of the inhibition of 3 H-thymidine or 3 H-uridine incorporation. The test was performed with Adriamycin, Actinomycin D, Daunomycin, Bleomycin, Cyclophosphamide, Ifosfamide, Trenimon, and Arabinosylcytosine. None of the tumors is resistant to all substances, they are responsive against 2 or more drugs. The most effective drugs tested are Adriamycin, Actinomycin D and Cyclophosphamide. The tumors show a marked individual sensitivity pattern. This behavior is explained mainly by the usually high proliferative activity of Wilms' tumors. The possibilities and limits of long-term and short-term methods for sensitivity testing are discussed critically. For the evaluation of the results of in vitro testing and in vivo effectiveness the close correlation should be considered between the type of cytostatic agent and proliferation kinetics of the tumor, cytostatic agent and effect on tumor metabolism as well as the effect of the cytostatics and the nucleic acid precursors used for the short-term test. Despite the methodological limitations preclinical testing should be preferred to unselected chemotherapy. (author)

Clinical and laboratory assessment of a combination of drugs with radiation. Coordinated programme on improvement in radiotherapy of cancer using modifiers of radiosensitivity of cells

International Nuclear Information System (INIS)

Bleehen, N.

1982-01-01

Applications were clinically studied of misonidazole (MISO) as a hypoxic cell radiosensitizer with pharmacokinetic studies. Work with desmethylmisonidazole was focused on its penetration into the CNS because its low lipophilicity would predict poorer access than MISO. Laboratory work was focused on the interaction of hyperthermia with drugs. Cytotoxicity of MISO induced by hyperthermia was studied. Heat response following hypoxic pretreatment with MISO of EMT6 spheroids showed marked enhancement of subsequent heat killing dependent on the duration of the hypoxic pretreatment. The effect was studied in vitro of preheat temperature at modest temperatures (39 to 43 0 C) on thermal tolerance and subsequent hyperthermic (43 to 44 0 C) interaction with bleomycin, adriamycin and BCNU. Interaction between several cytotoxic drugs and two potentially critical normal tissues, skin and bone marrow was studied in the mouse. No increase in the heat reaction in the skin of the mouse foot was observed following single injections of adriamycin, bleomycin or 5 daily doses of bleomycin together with a single heat treatment. Single doses of BCNU and CTX increased the heat reaction. The radioprotector WR2721 failed to protect against either the heat or heat drug reactions from CTX and BCNU

The Endocannabinoid System as a Target for Treatment of Breast Cancer

Science.gov (United States)

2011-08-01

cannabinoids with radiation in MCF-7, MDA-MB-231, and 4T1 breast tumor cell lines. Interestingly, the high efficacy synthetic cannabinoid agonist...tumorgenesis in FAAH (-/-) mice vs. wild type mice; and 2) the synthetic cannabinoid receptor agonist WIN55,212-2 in combination with radiation or adriamycin...THC (the primary active psychoactive constituent present in marijuana ), cannabidiol (CBD: a marijuana -derived cannabinoid that lacks psychomimetic

Hazards of combined chemotherapy and radiotherapy in rhabdomyosarcoma of the mediastinum. A case report

Energy Technology Data Exchange (ETDEWEB)

De Moor, N G; Levy, J I; Katz, G [University of the Witwatersrand, Johannesburg (South Africa)

1977-02-05

A total tumour irradiation dose of 2900 rad and a dose of 2500 rad to a metastasis, as well as the administration of 330mg/m/sup 2/ adriamycin, successfully eradicated all traces of malignant disease after partial surgical excision in a 12-year-old Black boy with a rhabdomyosarcoma of the mediastinum. The treatment, however, damaged the heart and caused the death of the patient.

The hazards of combined chemotherapy and radiotherapy in rhabdomyosarcoma of the mediastinum: a case report.

Science.gov (United States)

de Moor, N G; Levy, J I; Katz, G

1977-02-05

A total tumour irradiation dose of 2900 rad and a dose of 2500 rad to a metastasis, as well as the administration of 330 mg/m2 adriamycin, successfully eradicated all traces of malignant disease after partial surgical excision in a 12-year-old Black boy with a rhabdomyosarcoma of the mediastinum. The treatment, however, damaged the heart and caused the death of the patient.

The hazards of combined chemotherapy and radiotherapy in rhabdomyosarcoma of the mediastinum

International Nuclear Information System (INIS)

De Moor, N.G.; Levy, J.I.; Katz, G.

1977-01-01

A total tumour irradiation dose of 2900 rad and a dose of 2500 rad to a metastasis, as well as the administration of 330mg/m 2 adriamycin, successfully eradicated all traces of malignant disease after partial surgical excision in a 12-year-old Black boy with a rhabdomyosarcoma of the mediastinum. The treatment, however, damaged the heart and caused the death of the patient

The combination of radiotherapy and chemotherapy in the treatment of malignant tumours: indications and dangers

International Nuclear Information System (INIS)

Bartelink, H.; Somers, R.

1980-01-01

The combination of radiotherapy and chemotherapy has improved the results of treatment of certain malignant tumours. However, during both experimental investigations and clinical treatment, a number of severe side effects have been observed, during as well as some time after the administration, especially with use of actinomycin and adriamycin. Also the possibility exists that more secondary tumours are induced as the consequence of combination therapy. (Auth.)

Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study

International Nuclear Information System (INIS)

Hoppe, Bradford S.; Flampouri, Stella; Zaiden, Robert; Slayton, William; Sandler, Eric; Ozdemir, Savas; Dang, Nam H.; Lynch, James W.; Li, Zuofeng; Morris, Christopher G.; Mendenhall, Nancy P.

2014-01-01

Purpose: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. Methods and Materials: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on 18 F-Fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. Results: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. Conclusions: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes were similar

Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study

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Hoppe, Bradford S., E-mail: bhoppe@floridaproton.org [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States); Flampouri, Stella [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States); Zaiden, Robert [Department of Medicine, Division of Hematology and Oncology, University of Florida College of Medicine, Jacksonville, Florida (United States); Slayton, William [Department of Pediatrics, Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville, Florida (United States); Sandler, Eric [Department of Pediatrics, Division of Hematology/Oncology Nemours Children' s Clinic, Jacksonville, Florida (United States); Ozdemir, Savas [Department of Radiology, Division of Functional and Molecular Imaging, University of Florida College of Medicine, Jacksonville, Florida (United States); Dang, Nam H.; Lynch, James W. [Department of Medicine, Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville, Florida (United States); Li, Zuofeng; Morris, Christopher G.; Mendenhall, Nancy P. [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States)

2014-08-01

Purpose: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. Methods and Materials: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on {sup 18}F-Fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. Results: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. Conclusions: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes

Interactions of adriamycin and X-rays in Chinese hamster cells

International Nuclear Information System (INIS)

Meder, G.

1982-01-01

The effect of a combined ADM-and-radiation treatment of varying intervals was investigated in vitro. ADM sensitized the cells for the subsequent irradiation. This action was noticeable after 7h as a synergystic and after 2 and 3d as an additive effect of the combination treatment. Obviously, the ADM damage was inherited by the following cell generations. After 7d the sensitization of the cells could no longer be proved. From these results and those of other authors some general conclusions can be drawn. Different cell types react differently to the same kind of treatment. All forms of interaction are noticeable. Moreover, the ADM damage is obviously inherited. It must be assumed that this variability of the phenomena observed in vitro is also found in the human organism. (orig.) [de

Evaluation of the secondary cardiotoxicity to use adriamycin in patients with breast cancer with nuclear medicine studies; Evaluacion de la cardiotoxicidad secundaria al empleo de adriamicina en pacientes con cancer de mama con estudios de medicina nuclear

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Garcia P, S

2003-07-01

The number of surviving of cancer is increased highly with the current regimes of chemotherapy. For the year 2010 in U.S. it is considered that one of each 250 adults can be a survivor of wicked illness and many of these survivors will have been exposed to regimes with anthracycline. The anthracyclines concern to the group of antibiotics and they are effective point for hematological neoplasms as solid tumors. Although the relationship dose answer, among the regimes with anthracycline as well as the remission and the period free of illness is very established one, the latent risk of cardiotoxicity limits the use of these agents. Results: 30 patients were recruited with diagnostic of invader breast cancer tried with chemotherapy to base anthracycline in the understood period of may to december of the 2000. The medium of age it was of 48 years with a range of 27-80 years. The clinical stage that prevailed it was the EC IIB that represents a 36% in second place the EC IIIA with a 20%, EC IIA with 16% the EC IIIB and the unclassifiable ones represented 10% with 3 patients and finally the clinical stage IV with 8%, the most frequent localization was the left side.The received chemotherapy outline it was with the base of doxorubicin in its modality neo or patient adjutant, 5 patients also received taxanes like treatment adjutant. Prevailed the continuous infusion in 24 hours in 50%. The medium of accumulated dose of adriamycin was 274 mg/m{sup 2}. With a left ventricular ejection fraction LVEF pretreatment of 62% (medium) determined by VRI and a medium of 69% by SPECT. The LVEF pos treatment had one medium of 57% for VRI and by SPECT a medium of 60%. They received concomitant radiotherapy with chemotherapy in modality pre operation 53.3% (16 patients), and 40% radiotherapy post operation, 2 patients didn't receive radiotherapy. In relation to the heart toxicity any patient present electrocardiographic alterations, neither arrhythmias neither clinical data of heart

COPBLAM: infusion chemotherapy for large cell lymphoma

International Nuclear Information System (INIS)

Coleman, M.; Bernhardt, B.; Boyd, D.B.; Gerstein, G.

1986-01-01

This chapter describes a new combination chemotherapy program that was initiated at the New York Hospital-Cornell Medical Center for large cell lymphoma (LCL). The program, known as COPBLAM (Cyclophosphamide, Oncovin, Prednisone, Bleomycin, Adriamycin, Matulane) was an intensive multidrug regimen designed to maximize tumor cell kill. Some of the novel concepts and features are described. The treatment was fully successful in 60% of the 48 patients studied that were undergoing radiation therapy

Effects of Single and Combined Losartan and Tempol Treatments on Oxidative Stress, Kidney Structure and Function in Spontaneously Hypertensive Rats with Early Course of Proteinuric Nephropathy.

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Danijela Karanovic

Full Text Available Oxidative stress has been widely implicated in both hypertension and chronic kidney disease (CKD. Hypertension is a major risk factor for CKD progression. In the present study we have investigated the effects of chronic single tempol (membrane-permeable radical scavenger or losartan (angiotensin II type 1 receptor blocker treatment, and their combination on systemic oxidative status (plasma thiobarbituric acid-reactive substances (pTBARS production, plasma antioxidant capacity (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid, pABTS, erythrocyte antioxidant enzymes activities and kidney oxidative stress (kTBARS, kABTS, kidney antioxidant enzymes activities, kidney function and structure in spontaneously hypertensive rats (SHR with the early course of adriamycin-induced nephropathy. Adult SHR were divided into five groups. The control group received vehicle, while the other groups received adriamycin (2 mg/kg, i.v. twice in a 21-day interval, followed by vehicle, losartan (L,10 mg/kg/day, tempol (T,100 mg/kg/day or combined T+L treatment (by gavage during a six-week period. Adriamycin significantly increased proteinuria, plasma lipid peroxidation, kidney protein oxidation, nitrite excretion, matrix metalloproteinase-1 (MMP-1 protein expression and nestin immunostaining in the kidney. Also, it decreased kidney antioxidant defense, kidney NADPH oxidase 4 (kNox4 protein expression and abolished anti-inflammatory response due to significant reduction of kidney NADPH oxidase 2 (kNox2 protein expression in SHR. All treatments reduced protein-to-creatinine ratio (marker of proteinuria, pTBARS production, kidney protein carbonylation, nitrite excretion, increased antioxidant capacity and restored kidney nestin expression similar to control. Both single treatments significantly improved systemic and kidney antioxidant defense, bioavailability of renal nitric oxide, reduced kMMP-1 protein expression and renal injury, thus retarded CKD progression

Vitamin D3 regulates cell viability in gastric cancer and cholangiocarcinoma

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Baek, Sungmin; Lee, Young-Suk; Shim, Hye-Eun; Yoon, Sik; Baek, Sun-Yong; Kim, Bong-Seon; Oh, Sae-Ock

2011-01-01

A low serum level of vitamin D has been associated with an increased incidence of gastrointestinal tract cancers. However, the effects of vitamin D3 have not been investigated in gastric cancer and cholangiocarcinoma. In the present study, we found that vitamin D3 treatment significantly suppressed the viability of gastric cancer and cholangiocarcinoma cells. Moreover, vitamin D3 had a synergistic effect with other anti-cancer drugs, such as paclitaxel, adriamycin, and vinblastine, for suppre...

Flow cytometric applications of tumor biology: prospects and pitfalls

International Nuclear Information System (INIS)

Raju, M.R.; Johnson, T.S.; Tokita, N.; Gillette, E.L.

1979-01-01

A brief review of cytometry instrumentation and its potential applications in tumor biology is presented using our recent data. Age-distribution measurements of cells from spontaneous dog tumors and cultured cells after exposure to x rays, alpha particles, or adriamycin are shown. The data show that DNA fluorescence measurements have application in the study of cell kinetics after either radiation or drug treatment. Extensive and careful experimentation is needed to utilize the sophisticated developments in flow cytometry instrumentation

Flow cytometric applications to tumour biology: prospects and pitfalls

International Nuclear Information System (INIS)

Raju, M.R.; Johnson, T.S.; Tokita, N.; Gillette, E.L.

1980-01-01

A brief review of cytometry instrumentation and its potential applications in tumour biology is presented. DNA distribution measurements of cells from spontaneous dog tumours and cultured cells after exposure to X-rays, alpha particles or adriamycin are shown. The data show that DNA fluorescence measurements have application in the study of cell kinetics after either radiation or drug treatment. Extensive and careful experimentation is needed, however, to utilize the sophisticated developments in flow cytometry instrumentation. (author)

Reversal of multidrug resistance by surfactants.

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Woodcock, D. M.; Linsenmeyer, M. E.; Chojnowski, G.; Kriegler, A. B.; Nink, V.; Webster, L. K.; Sawyer, W. H.

1992-01-01

Cremophor EL, a pharmacologically inactive solubilising agent, has been shown to reverse multidrug resistance (MDR). Using flow cytometric evaluation of equilibrium intracellular levels of daunorubicin (DNR), we found that eight other surface active agents will also reverse MDR. All the active detergents contain polyethoxylated moieties but have no similarities in their hydrophobic components. The properties of three polyethoxylated surfactants that showed the lowest toxicities, Cremophor, Tween 80 and Solutol HS15, were examined in more detail. The concentrations of Tween 80 and Solutol required to reverse DNR exclusion were 10-fold lower than for Cremophor. However while concentrations greater than or equal to 1:10(2) of the former two surfactants resulted in breakdown of cells, even 1:10 of Cremophor did not lyse cells. Studies of the effects of Cremophor on the uptake and efflux of DNR in normal and MDR cell types showed that Cremophor increases intracellular DNR primarily by locking the rapid efflux from the cells. This blockage of drug efflux may be mediated by a substantial alteration in the fluidity of cell membranes induced by Cremophor, as shown by decreased fluorescence anisotropy of a membrane probe. Consistent with these data, coinjection of adriamycin plus Cremophor into mice carrying a multidrug resistant P388 transplantable tumour significantly increased the survival time of the mice compared with adriamycin treatment alone. PMID:1637678

Characterization of the evolution of the nutritional condition of patients with breast cancer on chemotherapy

International Nuclear Information System (INIS)

Lancheros, L; Gamba M; Gonzalez H; Sanchez R

2004-01-01

Introduction: breast cancer is common in women, and it is usually treated with chemotherapy. It has been asserted that this treatment affects nutritional condition because it produces a gastrointestinal symptomatology and modifies food consumption. Objective: characterize the nutritional condition in women with breast cancer treated with adriamycin and cyclophosphamide (AC). Materials and methods: this study used a prospective, longitudinal design with 25 patients during three continuous cycles of chemotherapy. Food intake and anthropometrical indicators of nutritional status were measured before the treatment and at the beginning of each cycle, and gastrointestinal effects were evaluated weekly. Results: during chemotherapy the consumption of meats, desserts, and bakery products diminished, and piece size and consumption of cheese, fruits, and rice decreased. 40% of women had a nor- mal weight and 40% were overweight before and during treatment. The most frequent gastrointestinal effects were xerostomia (61%) and nausea (55%) 56% of patients presented changes in smell and 47% in taste. the rejected foods were beef, fish, milk, and yogurt. there was a statistically significant association between alterations in smell and taste and food aversion but there was no association between aversions and decreased food intake. Conclusions: the short-term treatment with adriamycin and cyclophosphamide did not produce changes in body weight during chemotherapy and, despite gastrointestinal effects; food intake was not affected in a significant way

Isolation and partial characterisation of a mammalian cell mutant hypersensitive to topoisomerase II inhibitors and X-rays

International Nuclear Information System (INIS)

Davies, S.M.; Davies, S.L.; Hickson, I.D.; Hall, A.G.

1990-01-01

The authors have isolated, following one-step mutagenesis, a Chinese hamster ovary cell mutant hypersensitive to the intercalating agent, adriamycin. This agent exerts at least part of its cytotoxic action via inhibition of the nuclear enzyme, topoisomerase II. The mutant, designated ADR-3, showed hypersensitivity to all classes of topoisomerase II inhibitors, inlcuding actinomycin D, amsacrine (m-AMSA), etoposide (VP16) and mitoxantrone. ADR-3 cells also showed cross-sensitivity to ionizing radiation, but not no UV light. Topoisomerase II activity was elevated to a small but significant degree in ADR-3 cells, and this was reflected in a 1.5-fold higher level of topoisomerase II protein in ADR-3 than in CHO-K1 cells, as judged by Western blotting. ADR-3 cells were hypersensitive to cumene hydroperoxide but cross-resistant to hydrogen peroxide, suggesting possible abnormality in the detoxification of peroxides by glutathione peroxidase or catalase. Glutathione peroxidase activity against hydroperoxide was elevated to a small but significant extent in mutant cells. Catalase levels were not significantly different in ADR-3 and CHO-K1 cells. ADR-3 cells were recessive in hybrids with parental CHO-K1 cells with respect to sensitivity to topoisomerase II inhibitors and X-rays, and represent a different genetic complementation group from the previously reported adriamycin-sensitive mutant, ADR-1. (author). 34 refs.; 5 figs.; 3 tabs

Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment

International Nuclear Information System (INIS)

Hopwood, L.E.; Davies, B.M.; Moulder, J.E.

1990-01-01

RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance

DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury.

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Eun Lee, Jee; Kim, Jung Eun; Lee, Mi Hwa; Song, Hye Kyoung; Ghee, Jung Yeon; Kang, Young Sun; Min, Hye Sook; Kim, Hyun Wook; Cha, Jin Joo; Han, Jee Young; Han, Sang Youb; Cha, Dae Ryong

2016-05-01

Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.

Effect of quercetin on apoptosis of PANC-1 cells.

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Lee, Joo Hyun; Lee, Han-Beom; Jung, Gum O; Oh, Jung Taek; Park, Dong Eun; Chae, Kwon Mook

2013-12-01

To investigate the chemotherapeutic effect of quercetin against cancer cells, signaling pathway of apoptosis was explored in human pancreatic cells. Various anticancer drugs including adriamycin, cisplatin, 5-fluorouracil (5-FU) and gemcitabine were used. Cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphe-nyltetra zolium bromide assay. Apoptosis was determined by 4'-6-diamidino-2-phenylindole nuclei staining and flow cytometry in PANC-1 cells treated with 50 µg/mL quercetin for 24 hours. Expression of endoplas mic reticulum (ER) stress mediators including, Grp78/Bip, p-PERK, PERK, ATF4, ATF6 and GADD153/CHOP proteins were measured by Western blot analysis. Mitochondrial membrane potential was measured by fluorescence staining with JC-1, rhodamine 123. Quercetin induced the apoptosis of PANC-1, which was characterized as nucleic acid and genomic DNA fragmentation, chromatin condensation, and sub-G0/G1 fraction of cell cycle increase. But not adriamycin, cisplatin, gemcitabine, and 5-FU. PANC-1 cells were markedly sensitive to quercetin. Treatment with quercetin resulted in the increased accumulation of intracellular Ca(2+) ion. Treatment with quercetin also increased the expression of Grp78/Bip and GADD153/CHOP protein and induced mitochondrial dysfunction. Quercetin exerted cytotoxicity against human pancreatic cancer cells via ER stress-mediated apoptotic signaling including reactive oxygen species production and mitochondrial dysfunction. These data suggest that quercetin may be an important modulator of chemosensitivity of cancer cells against anticancer chemotherapeutic agents.

Low temperature protects mammalian cells from apoptosis initiated by various stimuli in vitro

International Nuclear Information System (INIS)

Sakurai, Toshiharu; Itoh, Katsuhiko; Liu Yu; Higashitsuji, Hiroaki; Sumitomo, Yasuhiko; Sakamaki, Kazuhiro; Fujita, Jun

2005-01-01

Mild hypothermia shows protective effects on patients with brain damage and cardiac arrest. To elucidate the molecular mechanisms underlying these effects, we examined the effects of low temperature (32 deg. C) on cells exposed to a variety of stress in vitro. We found that 32 deg. C suppressed induction of apoptosis by cytotoxic stimuli such as adriamycin, etoposide, thapsigargin, NaCl, H 2 O 2 , and anti-Fas antibody. In adriamycin-treated BALB/3T3 cells, the down-shift in temperature from 37 deg. C to 32 deg. C increased the Bcl-xL protein level and decreased the mRNA level of Puma and mitochondrial translocation of Bax, suppressing caspase-9-mediated apoptosis. Furthermore, the protein level and stability of p53 were decreased, and its nuclear export was increased concomitant with Mdm2 mRNA upregulation. The low temperature effect was not observed in p53 -/- /Mdm2 -/- mouse embryonic fibroblasts, suggesting that the effect is mediated by suppression of the p53 pathway. In contrast, while thapsigargin-induced apoptosis was suppressed by the low temperature, no effect on the p53 protein level was observed. Furthermore, the survival rate of p53 -/- /Mdm2 -/- cells exposed to thapsigargin was increased when cultured at 32 deg. C compared with 37 deg. C. In conclusion, mild hypothermia protects cells from a variety of stress by p53-dependent and p53-independent mechanisms

UCH-L1-containing exosomes mediate chemotherapeutic resistance transfer in breast cancer.

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Ning, Kuan; Wang, Teng; Sun, Xu; Zhang, Pengfei; Chen, Yun; Jin, Jian; Hua, Dong

2017-06-01

Chemotherapy resistance has become a serious challenge in the treatment of breast cancer. Previous studies showed cells can transfer proteins, including those responsible for drug resistance to adjacent cells via exosomes. The switches of drug resistance via exosomes transfer were assessed by CellTiter-Blue Viability assay, flow cytometry, and immunostaining analysis. Relative protein levels of Ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1), P-glycoprotein (P-gp), extracellular-signal regulated protein kinase1/2 (ERK1/2), and phospho-extracellular-signal regulated protein kinase1/2 (p-ERK1/2) were measured by Western blot. Immunohistochemistry was performed on 93 breast cancer samples to assess the associations of UCH-L1 levels with immunofluorescence value of UCH-L1 in circulating exosomes. The Adriamycin-resistant human breast cancer cells (MCF7/ADM) secreted exosomes carrying UCH-L1 and P-gp proteins into the extracellular microenvironment then integrated into Adriamycin-sensitive human breast cancer cells (MCF7/WT) in a time-dependent manner, transferring the chemoresistance phenotype. Notably, in blood samples from patients with breast cancer, the level of exosomes carrying UCH-L1 before chemotherapy was significantly negatively correlated with prognosis. Our study demonstrated that UCH-L1-containing exosomes can transfer chemoresistance to recipient cells and these exosomes may be useful as non-invasive diagnostic biomarkers for detection of chemoresitance in breast cancer patients, achieving more effective and individualized chemotherapy. © 2017 Wiley Periodicals, Inc.

Any value of podocyte B7-1 as a biomarker in human MCD and FSGS?

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Novelli, Rubina; Gagliardini, Elena; Ruggiero, Barbara; Benigni, Ariela; Remuzzi, Giuseppe

2016-03-01

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most common causes of nephrotic syndrome in children and in young adults. Relapsing MCD carries the risk of severe complications and prolonged immunosuppression, whereas FSGS remains largely untreatable and urgently needs more effective treatments. Recently, induction of B7-1 (CD80), an immune-related protein expressed by antigen-presenting cells, was observed in podocytes of MCD and FSGS patients, suggesting that B7-1 plays a role in the pathogenesis of these diseases, and hence that abatacept, a B7-1 inhibitor, could be a possible treatment. Since previous studies raised serious concerns regarding the reliability of immunohistochemical assays for B7-1 detection and the efficacy of B7-1 inhibitory treatment, we investigated B7-1 podocyte expression in MCD and FSGS patients. Using different primary antibodies and immunohistochemical assays, no significant upregulation of podocyte B7-1 was detected in patients' biopsies compared with controls. To further confirm our findings, we analyzed mice with adriamycin-induced nephropathy, a model of human FSGS, and mice injected with LPS as additional control. Podocyte B7-1 was not observed in mice injected with adriamycin or LPS either. In conclusion, since B7-1 is not induced in podocyte of MCD and FSGS patients, the antiproteinuric action of abatacept, if confirmed, may not be the result of an effect on podocyte B7-1. Copyright © 2016 the American Physiological Society.

The Role of Doppler Ultrasound in Assessing the Therapeutic Response in Advanced Breast Cancer

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Jamal Eyvazi-Ziaei

2018-01-01

Full Text Available Background and Objectives: Breast cancer is one of the most common cancers in Iran, which neo-adjuvant chemotherapy used to treat in advanced types to reduce tumor burden. The aim of this study was to evaluate the ultrasound scales of patients with advanced disease, using two common treatment methods include TACs (Taxotere, Adriamycin, and Cyclophosphamide and AC (Adriamycin, Cyclophosphamide. Material and Methods: Clinical examination and Doppler ultrasound were performed before and after treatment. Before and after the treatment, the size of the primary tumor and tumor vascularization, and the ultrasound Resistivity Index (RI, Pulsality Index (PI, Peak Systolic Velocity (PSV and the condition of the anterior lymph nodes, and the effect of two different therapies were investigated in response to treatment. The SPSS statistical software 17.0 was used to evaluate the relationship between the variables with 95% confidence interval, and P≤ 0.05. Results: The mean age of the patients was 48.90 (±10.58 SD years. From these, 8 were postmenopausal and 9 were menopausal, and in 3 cases the situation was unknown. There was significant difference between the PSV levels of the main breast mass, pre and post chemotherapy (P=0.004. Changes in other indexes of breast mass and axillary mass were not statistical significant. Conclusion: Color Doppler ultrasonography seems to be a promising alternative as an independent and complementary tool, to assess the response to treatment of breast masses to primary medical treatment in advanced breast cancers.

Annual Progress Report (FY-80) Department of Clinical Investigation.

Science.gov (United States)

1980-09-30

in patients with more depressed PHA responses; and was abrogated by removal of ad- herent cells from the culture system. ". "I . . , . ,. /-- Date...None C: 7 Qcr’ber_!9 n ! -- C " i’. 4139 Is.’.I’. . .,:r i ’i X ’ O " "A Randomized Comparison of Ne.phalan, 5FU , and .!E.gace Versus Adriamycin...Cytoxan, 5FU , and ?egace in thr4 Treatment of Patients with Primary Stage III, or IV Recurrent or Residual Endometrial Carcinoma (Phase II!)" COG 1! 28

Nephroprotective effect of heparanase in experimental nephrotic syndrome.

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Suheir Assady

Full Text Available Heparanase, an endoglycosidase that cleaves heparan sulfate (HS, is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS in a mouse model.BALB/c wild-type (wt mice and heparanase overexpressing transgenic mice (hpa-TG were tail-vein injected with either Adriamycin (ADR, 10 mg/kg or vehicle. Albuminuria was investigated at days 0, 7, and 14 thereafter. Mice were sacrificed at day 15, and kidneys were harvested for various analyses: structure and ultrastructure alterations, podocyte proteins expression, and heparanase enzymatic activity.ADR-injected wt mice developed severe albuminuria, while ADR-hpa-TG mice showed only a mild elevation in urinary albumin excretion. In parallel, light microscopy of stained cross sections of kidneys from ADR-injected wt mice, but not hpa-TG mice, showed mild to severe glomerular and tubular damage. Western blot and immunofluorescence analyses revealed significant reduction in nephrin and podocin protein expression in ADR-wt mice, but not in ADR-hpa-TG mice. These results were substantiated by electron-microscopy findings showing massive foot process effacement in injected ADR-wt mice, in contrast to largely preserved integrity of podocyte architecture in ADR-hpa-TG mice.Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation. Moreover, hpa-TG mice comprise an invaluable in vivo platform to investigate the interplay between heparanase and glomerular injury.

The roots of modern oncology: from discovery of new antitumor anthracyclines to their clinical use.

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Cassinelli, Giuseppe

2016-06-02

In May 1960, the Farmitalia CEO Dr. Bertini and the director of the Istituto Nazionale dei Tumori of Milan Prof. Bucalossi (talent scout and city's Mayor) signed a research agreement for the discovery and development up to clinical trials of new natural antitumor agents. This agreement can be considered as a pioneering and fruitful example of a translational discovery program with relevant transatlantic connections. Owing to an eclectic Streptomyces, found near Castel del Monte (Apulia), and to the skilled and motivated participants of both institutions, a new natural antitumor drug, daunomycin, was ready for clinical trials within 3 years. Patent interference by the Farmitalia French partner was overcome by the good quality of the Italian drug and by the cooperation between Prof. Di Marco, director of the Istituto Ricerche Farmitalia Research Laboratories for Microbiology and Chemotherapy, and Prof. Karnofsky, head of the Sloan-Kettering Cancer Institute of New York, leading to the first transatlantic clinical trials. The search for daunomycin's sister anthracyclines led to the discovery and development of adriamycin, one of the best drugs born in Milan. This was the second act prologue of the history of Italian antitumor discovery and clinical oncology, which started in July 1969 when Prof. Di Marco sent Prof. Bonadonna the first vials of adriamycin (doxorubicin) to be tested in clinical trials. This article reviews the Milan scene in the 1960s, a city admired and noted for the outstanding scientific achievements of its private and public institutions in drugs and industrial product discovery.

[Benefits of cisplatin-based polychemotherapy in non-small cell bronchogenic carcinoma. Kyushu Lung Cancer Chemotherapy Study Group].

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Ohta, M; Hara, N; Ichikawa, Y; Kanda, T; Shima, K; Tamura, K; Hokama, M

1988-06-01

We studied the efficacy of cisplatin-based polychemotherapy for non-small-cell lung cancer. One hundred nineteen patients with adenocarcinoma or large cell carcinoma were randomized to receive cyclophosphamide, adriamycin, cisplatin and mitomycin C (CAPM) or mitomycin C, cytosine arabinoside and tegafur (MCT), and 48 patients with squamous cell carcinoma were randomized to receive cisplatin, adriamycin and peplomycin (PAP) or mitomycin C, cyclophosphamide, tespamine, toyomycin and tegafur (MCTTT). Radiation was given to the chest in patients with stage I-III disease. The response rates were CAPM, 34.5%; MCT, 13.1% (p less than 0.01) and PAP, 63.3%; MCTTT, 42.3%. A significant difference in response rate between the CAPM and MCT regimens was observed only in stage IV patients and not in stage I-III patients. The median survival was 9.5 months in the CAPM arm vs. 6.5 months in the MCT arm (p less than 0.007), and 8.5 months in the PAP arm vs. 6.5 months in the MCTTT arm. Improved median survival for the CAPM regimen was noted only in stage IV patients and not in stage I-III patients when compared to patients given the MCT regimen, respectively. Nausea and vomiting were significantly increased in patients with cisplatin-based polychemotherapy. Myelosuppression was more severe with the CAPM regimen than with the other chemotherapy regimens. We concluded that cisplatin-based polychemotherapy, CAPM and PAP therapy were of more benefit to patients with disseminated non-small-cell lung cancer than MCT and MCTTT therapy.

The impact of cofactors and inhibitors on DNA repair synthesis after γ-irradiation in semi-permeable Escherichia coli cells

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Gaertner, C.

1981-01-01

The DNA-repair synthesis in tuluol-permeable E. coli cells after γ-irradiation has been investigated in dependence on the co-facotrs. ATB and NAD by means of enzyme kinetics. A partly repair-deficient mutants were taken into consideration which are well characterized in view of molecular biology; they showed which enzyme functions participate in the γ-induced DNA repair synthesis. The inhibition of the DNA-repair synthesis by the intercalary substances Adriamycin and Proflavin has been described and compared with the survival rates after irradiation and after combined treatment by irradiation and intercalary agents. (orig./AJ) [de

Primary Adrenal Lymphoma Infiltrating in to Pancreas: A Rare Cause of Adrenomegaly

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Lovelesh Kumar Nigam

2017-03-01

Full Text Available Primary adrenal lymphoma is a rare entity and may be suspected in patients having bilateral adrenal masses, with/without lymphadenopathy, and with/without adrenal insufficiency. We report a rare case of a 45-year-old man who presented with pain in the abdomen, with no signs of adrenal insufficiency and bilateral adrenal masses on imaging. Light microscopy findings with immunohistochemistry and flow cytometry confirmed the diagnosis of diffuse large B-cell lymphoma. The patient was offered cyclophosphamide, adriamycin, vincristine, and prednisolone chemotherapy regimen and doing well till the last follow-up. [J Interdiscip Histopathol 2017; 5(1.000: 25-28

Pediatric Hodgkin Lymphoma Treated at Cancer Institute, Chennai, India: Long-Term Outcome

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Dhanushkodi, Manikandan; Ganesan, Trivadi S.; Ganesan, Prasanth; Sundersingh, Shirley; Selvaluxmy, Ganesarajah; Swaminathan, Rajaraman; Rama, Ranganathan; Sagar, Tenali Gnana

2017-01-01

Purpose Pediatric Hodgkin lymphoma (HL) is a highly curable malignancy. Outcomes for pediatric HL may vary between developed and developing countries for multiple reasons. This study was conducted to ascertain the outcomes of children with HL at our center and to identify risk factors for recurrent disease. Methods We analyzed the outcomes of 172 consecutive, previously untreated patients with pediatric HL presenting at our center from 2001 to 2010. Patients were treated with either adriamycin, bleomycin, vinblastine, and dacarbazine or adriamycin, bleomycin, vinblastine, cyclophosphamide, vincristine, prednisone, and procarbazine chemotherapy initially, and radiation to bulky sites or a single site of residual disease when appropriate. Results The median duration of follow-up was 77 months. The median age of the patients was 10 years; 127 (74%) of the 172 patients were male. The extent of disease was stage I and II in 59% of the patients. B symptoms were present in 32% of the patients, and 27% had bulky disease. The most common histologic subtype was mixed cellularity (45%). The 5-year overall survival (OS) and progression-free survival (PFS) of the entire cohort were 92.9% and 83.1%, respectively. The 5-year OS rates for patients with stage I, II, III, and IV were 96%, 94.7%, 84%, and 69.8%, respectively. On univariate analysis, advanced stage, response on interim radiologic assessment, and presence of B symptoms significantly predicted inferior PFS and OS. On multivariate analysis, only interim radiologic response significantly predicted PFS (P < .001) and OS (P < .001). Conclusion Overall, the outcomes of patients treated at our center are comparable to those observed in other centers in India and globally. PMID:29094094

Pediatric Hodgkin Lymphoma Treated at Cancer Institute, Chennai, India: Long-Term Outcome

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Venkatraman Radhakrishnan

2017-10-01

Full Text Available Purpose: Pediatric Hodgkin lymphoma (HL is a highly curable malignancy. Outcomes for pediatric HL may vary between developed and developing countries for multiple reasons. This study was conducted to ascertain the outcomes of children with HL at our center and to identify risk factors for recurrent disease. Methods: We analyzed the outcomes of 172 consecutive, previously untreated patients with pediatric HL presenting at our center from 2001 to 2010. Patients were treated with either adriamycin, bleomycin, vinblastine, and dacarbazine or adriamycin, bleomycin, vinblastine, cyclophosphamide, vincristine, prednisone, and procarbazine chemotherapy initially, and radiation to bulky sites or a single site of residual disease when appropriate. Results: The median duration of follow-up was 77 months. The median age of the patients was 10 years; 127 (74% of the 172 patients were male. The extent of disease was stage I and II in 59% of the patients. B symptoms were present in 32% of the patients, and 27% had bulky disease. The most common histologic subtype was mixed cellularity (45%. The 5-year overall survival (OS and progression-free survival (PFS of the entire cohort were 92.9% and 83.1%, respectively. The 5-year OS rates for patients with stage I, II, III, and IV were 96%, 94.7%, 84%, and 69.8%, respectively. On univariate analysis, advanced stage, response on interim radiologic assessment, and presence of B symptoms significantly predicted inferior PFS and OS. On multivariate analysis, only interim radiologic response significantly predicted PFS (P < .001 and OS (P < .001. Conclusion: Overall, the outcomes of patients treated at our center are comparable to those observed in other centers in India and globally.

Interactions of black cohosh, a traditional herbal medicine, with therapy for breast cancer

International Nuclear Information System (INIS)

Rockwell, S.; Liu, Y.; Higgins, S.A.

2003-01-01

Herbal medicines based on extracts of Cimicifuga racemosa (black cohosh) are widely used by breast cancer patients, but the effects of these extracts have not been rigorously studied. We examined the effects of standardized commercial extracts of black cohosh on the cytotoxicity of radiation, Adriamycin, Taxotere, and Cisplatin to breast cancer cells in vitro. Exponentially growing cultures of EMT6 mouse mammary tumor cells were exposed to black cohosh extracts continuously for 24 h, beginning 4 hours before irradiation or the 2 h drug treatment. Full dose-response curves were determined for radiation and for each drug under three conditions: alone, in combination with black cohosh extract, and in combination with the vehicle used to prepare the extract. Cell survival was assayed using a colony formation assay. The herbal extracts alone had no significant effect on the growth or viability of these breast cancer cells. The effects of the extracts on the outcome of treatment varied with the treatment agent. Black cohosh protected cells slightly from Cisplatin, had no effect on the dose-response curve for radiation, and sensitized cells to Adriamycin and Taxotere. The vehicle had no discernable effect. These findings show that black cohosh extracts are not simply 'harmless herbs' that can be ignored by physicians treating cancer patients, but instead contain active agents which can modulate the effects of therapy with conventional therapeutic agents. Further cell culture studies are needed to determine the mechanism underlying this effect. Studies with tumors and normal tissues in mice are needed to assess whether black cohosh extracts alter the effectiveness of radiation and drugs in treating breast cancer or alter the toxicities of these therapies

Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells.

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Payne, Kyle K; Keim, Rebecca C; Graham, Laura; Idowu, Michael O; Wan, Wen; Wang, Xiang-Yang; Toor, Amir A; Bear, Harry D; Manjili, Masoud H

2016-09-01

Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25(+) NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25(+) NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy. © The Author(s).

Gynecologic cancer

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Uehara, Takashi; Katsumata, Noriyuki

2008-01-01

Surgery and radiation therapy have been the main types of treatment for gynecologic cancer. However, chemotherapy in gynecologic oncology has recently made dramatic progress and presently is becoming the most widespread treatment. After the discovery of cisplatin in the field of chemotherapy for epithelial ovarian cancer, it has now become the leading treatment modality. According to the result of several important phase III randomized control trials (RCTs), the platinum-taxane combined therapy has now become the standard treatment regimen. Regarding endometrial cancer, Cisplatin-Adriamycin-Cyclophosphamide (CAP) therapy has been used as an effective adjuvant chemotherapy in Japan. The adjuvant chemotherapy (Adriamycin-Cisplatin therapy) for the endometrial cancer has now been recognized worldwide as the standard therapy based on the findings of a phase III RCT. Concurrent chemoradiotherapy for cervical cancer has also been recommended as the standard therapy in Japan since 1999 based on the successful results of numerous RCTs which proved its efficacy. The chemotherapy for gynecologic cancers has been investigated and standardized based on the results of numerous clinical trials. These trials have been conducted by many clinical trial groups, such as the Gynecologic Oncology Group (GOG), Southwest Oncology Group (SWOG), and the European Organization for Research and Treatment of Cancer (EORTC) throughout the world, in addition to the Japan Clinical Oncology Group (JCOG) and the Japanese Gynecologic Oncology Group (JGOG) in Japan. The valuable contributions of these clinical trials are helping in the development of new drug therapies, thus leading to such treatment regimens playing increasingly important and wider roles in the field of gynecologic oncology treatment in the future. (author)

Influence of docosahexaenoic acid in vitro on intracellular adriamycin concentration in lymphocytes and human adriamycin-sensitive and -resistant small-cell lung cancer cell lines, and on cytotoxicity in the tumor cell lines

NARCIS (Netherlands)

Zijlstra, J G; de Vries, E G; Muskiet, F A; Martini, I A; Timmer-Bosscha, H; Mulder, N H

1987-01-01

An increase in the therapeutic effects of cancer chemotherapeutic agents and circumvention of drug resistance in cancer cells might result from an increase in the intracellular drug level. Alteration of the lipid domain of the cell membrane can result in a higher intracellular drug level. This

Study of tea polyphenol as a reversal agent for carcinoma cell lines' multidrug resistance (study of TP as a MDR reversal agent)

International Nuclear Information System (INIS)

Zhu Aizhi; Wang Xiangyun; Guo Zhenquan

2001-01-01

The aim of this study was to examine MDR1 expression product P-glycoprotein (Pgp) and study the effect and mechanism of tea polyphenol (TP) in reversion of multidrug resistance (MDR) in carcinoma cell lines. Immunocytochemical method was used for qualitative detection of Pgp. A comparative study of cytotoxicity and multidrug resistance reversion effect was made by MTT assay for tea polyphenol and quinidine in MCF-7 and MCF-7/Adr cell lines. The multidrug resistance reversion effect and mechanism were studied by measuring the uptake of 99m Tc-tetrofosmin in the carcinoma cell lines. (1) The Pgp overexpression in MCF-7/Adr cells was found to be strong positive, while the Pgp expression of MCF-7 was negative. (2) Although both tea polyphenol and quinidine could not remarkably change the toxicity of adriamycin to MCF-7, they could improve the sensitivity of MCF-7/Adr to adriamycin. The reversion index of tea polyphenol and quinidine was 3 and 10 respectively. (3) The cellular uptake of 99m Tc-tetrofosmin was remarkably lower in MCF-7/Adr than in MCF-7. The uptake of 99m Tc-tetrofosmin in MCF-7/Adr exhibited a 4, 13, 16 fold increase in the presence of 200, 400 and 500 μg/ml of tea polyphenol respectively. The uptake of 99m Tc-tetrofosmin in MCF-7/Adr exhibited only a 4-fold increase in the presence of 200 μM of quinidine. Immunocytochemistry can detect P-glycoprotein expression level qualitatively. Tea polyphenol is not only an anti-tumor agent, but also a multidrug resistant modulator similar to quinidine. The multidrug resistance reversion mechanism of tea polyphenol seems to be its inhibition of the activity of P-glycoprotein. Tea polyphenol has the advantage of very low toxicity in tumor treatment

Eight-MHz RF-hyperthermia for advanced urological malignancies

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Hisazumi, Haruo; Nakajima, Kazuyoshi

1986-01-01

Eight-MHz radiofrequency hyperthermia (H) using a Thermotron-RF Model 8, and its combination with irradiation (RH), anticancer drugs (CH) or anticancer drugs plus irradiation (CRH), were carried out for a total of 48 urological malignancies: 10 cases of renal cancer, 1 of renal pelvic cancer, 2 of uretetral cancer, 19 of bladder cancer, 5 of prostatic cancer, 9 of metastatic lesion of urological cancers and 2 of other urological cancers. All had failed in previous treatments, or had not undergone surgery because of their poor general condition. Four cases, including 2 of bladder cancer, 1 of prostatic cancer and 1 of metastatic lesion of bladder cancer, were treated with H. Twenty-five cases, including 3 renal cancer cases, were treated with RH. Seven of the 10 cases of renal cancer were treated with mitomycin C-microcapsule embolization prior to RH (CRH). Twelve of the 23 cases with urothelial cancer or its metastasis, including 1 of renal pelvic cancer, 10 of bladder cancer and 1 of metastatic lesion of bladder cancer, received combined treatment of THP-adriamycin, one of the derivatives of adriamycin, by i.v. and RF-heating (CH). Hyperthermia was given twice a week, totalling 10 sessions in 5 weeks. Intratumoral temperature was kept above 42.5 deg C for 30 to 40 minutes during one-hour heating. Complete tumor disappearance was obtained in the 5 bladder cancer cases. Partial tumor regression, defined as a regression of 50 % or more, was obtained in 11 cases. As side effects, mild skin burns and anorexia were observed in approximately 30 to 40 % of cases. Seven obese cases, who had subcutaneous tissue 15 mm thick or more, developed fat tissue induration after treatment. (author)

Effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy: a pharmacogenetic study.

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Daniela Caronia

Full Text Available Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response.In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs and 2 Copy Number Variants (CNVs in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1×10⁻⁵, and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9×10⁻⁵, rs1128503 and rs10276036 (r² = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value = 7.9×10⁻⁵. Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values [permutation test] ≤ 0.03.Our findings suggest that these polymorphisms may affect osteosarcoma treatment efficacy. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of osteosarcoma, helping in the design of individualized therapy.

Case report: value of gene expression profiling in the diagnosis of atypical neuroblastoma.

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Harttrampf, Anne C; Chen, Qingrong; Jüttner, Eva; Geiger, Julia; Vansant, Gordon; Khan, Javed; Kontny, Udo

2017-08-17

Nephroblastoma and neuroblastoma belong to the most common abdominal malignancies in childhood. Similarities in the initial presentation may provide difficulties in distinguishing between these two entities, especially if unusual variations to prevalent patterns of disease manifestation occur. Because of the risk of tumor rupture, European protocols do not require biopsy for diagnosis, which leads to misdiagnosis in some cases. We report on a 4½-year-old girl with a renal tumor displaying radiological and laboratory characteristics supporting the diagnosis of nephroblastoma. Imaging studies showed tumor extension into the inferior vena cava and bilateral lung metastases while urine catecholamines and MIBG-scintigraphy were negative. Preoperative chemotherapy with vincristine, actinomycine D and adriamycin according to the SIOP2001/GPOH protocol for the treatment of nephroblastoma was initiated and followed by surgical tumor resection. Histopathology revealed an undifferentiated tumor with expression of neuronal markers, suggestive of neuroblastoma. MYCN amplification could not be detected. DNA-microarray analysis was performed using Affymetrix genechip human genome U133 plus 2.0 and artificial neural network analysis. Results were confirmed by multiplex RT-PCR. Principal component analysis using 84 genes showed that the patient sample was clearly clustering with neuroblastoma tumors. This was confirmed by hierarchical clustering of the multiplex RT-PCR data. The patient underwent treatment for high-risk neuroblastoma comprising chemotherapy including cisplatin, etoposide, vindesine, dacarbacine, ifosfamide, vincristine, adriamycine and autologous stem cell transplantation followed by maintenance therapy with 13-cis retinoic acid (GPOH NB2004 High Risk Trial Protocol) and is in complete long-term remission. The use of gene expression profiling in an individual patient strongly contributed to clarification in a diagnostic dilemma which finally led to a change of

Relation between number of hemopoietic stem cells in newborn mice and their radiosensitivity

International Nuclear Information System (INIS)

Sutter, T.; Maes, J.; Gerber, G.B.; Leonard, A.

1985-01-01

Fractionation of a radiation exposure causes greater damage in newborn mice than a single application since it induces radioresistant foetal hemopoietic stem cells to differentiate prematurely to more radiosensitive adult ones. In the present investigation, it was studied whether other agents that give rise to extensive stem cell destruction also lead to such a change in radiosensitivity. Indeed, treatment with cytostatic drugs which reduces the number of spleen colony forming units (CFU-s) and total cells also diminished the D 0 value of the surviving cells 3 days later. Adriamycin was most effective in causing damage to hemopoietic stem cells and in inducing micronuclei in bone marrow; it also had the most marked action on the D 0 of the surviving stem cells. (orig.)

Hyperthermia and chemotherapy agent

International Nuclear Information System (INIS)

Roizin-Towle, L.; Hall, E.J.

1981-01-01

The use of chemotherapeutic agents for the treatment of cancer dates back to the late 19th century, but the modern era of chemotherapy drugs was ushered in during the 1940's with the development of the polyfunctional alkylating agent. Since then, numerous classes of drugs have evolved and the combined use of antineoplastic agents with other treatment modalities such as radiation or heat, remains a large relatively unexplored area. This approach, combining local hyperthermia with chemotherapy agents affords a measure of targeting and selective toxicity not previously available for drugs. In this paper, the effects of adriamycin, bleomycin and cis-platinum are examined. The adjuvant use of heat may also reverse the resistance of hypoxic cells noted for some chemotherapy agents

Enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer

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Einhorn, L.; Krause, M.; Hornback, N.; Furnas, B.

1976-01-01

In a recently completed study, combination chemotherapy consisting of bleomycin, adriamycin, cyclophosphamide, and vincristine was given to 29 patients with oat cell lung cancer. There were no cases of pulmonary fibrosis in these 29 patients. Although several of these patients had prior radiotherapy, none had concomitant radiotherapy and chemotherapy. This same four-drug chemotherapy regimen was combined with concomitant radiotherapy in 13 patients with oat cell lung cancer. There were three cases of fatal pulmonary fibrosis and two other cases of clinically significant pulmonary fibrosis. All five cases of pulmonary fibrosis occurred several weeks after completion of a six-week course of bleomycin (total dosage 90 units). It is concluded that bleomycin cannot be safely administered while patients are receiving radiotherapy of the lung

Effects of microirradiation of heart cells in culture at the mitochondrial level

International Nuclear Information System (INIS)

Salet, Christian; Moreno, Giuliana; Lampidis, T.J.

1980-01-01

The technique of micro-irradiation has been applied in irradiating the nucleus or the mitochondria of heart cells in tissue culture. Using classical or stimulated (laser) sources, variations in the beating rate have been utilized as an endpoint in assaying effects of micro-irradiation on the function of cardiac cells. The most important target for the stimulation of the beating rate of heart cells in vitro is the mitochondrion. When the mitochondrial oxidative system is perturbed with either KCN, ATP or adriamycin this stimulating effect is inhibited. Consequently, this combination of micro-irradiation and beating heart cells in culture is a powerful tool in determining the localization and investigating the mechanism of action of various drugs at the mitochondrial level

Renal endothelial function and blood flow predict the individual susceptibility to adriamycin-induced renal damage

NARCIS (Netherlands)

Ochodnicky, Peter; Henning, Robert H.; Buikema, Hendrik; Kluppel, Alex C. A.; van Wattum, Marjolein; de Zeeuw, Dick; van Dokkum, Richard P. E.

Background. Susceptibility to renal injury varies among individuals. Previously, we found that individual endothelial function of healthy renal arteries in vitro predicted severity of renal damage after 5/6 nephrectomy. Here we hypothesized that individual differences in endothelial function in

Renal endothelial function and blood flow predict the individual susceptibility to adriamycin-induced renal damage

NARCIS (Netherlands)

Ochodnicky, Peter; Henning, Robert H.; Buikema, Hendrik; Kluppel, Alex C. A.; van Wattum, Marjolein; de Zeeuw, Dick; van Dokkum, Richard P. E.

2009-01-01

Susceptibility to renal injury varies among individuals. Previously, we found that individual endothelial function of healthy renal arteries in vitro predicted severity of renal damage after 5/6 nephrectomy. Here we hypothesized that individual differences in endothelial function in vitro and renal

An ultrasensitive electrochemical DNA biosensor based on a copper oxide nanowires/single-walled carbon nanotubes nanocomposite

International Nuclear Information System (INIS)

Chen, Mei; Hou, Changjun; Huo, Danqun; Yang, Mei; Fa, Huanbao

2016-01-01

Graphical abstract: A novel and sensitive electrochemical biosensor based on hybrid nanocomposite consisting of copper oxide nanowires (CuO NWs) and carboxyl-functionalized single-walled carbon nanotubes (SWCNTs-COOH) was first developed for the detection of the specific-sequence target DNA. This schematic represents the fabrication procedure of our DNA biosensor. - Highlights: • An ultrasensitive DNA electrochemical biosensor was developed. • CuO NWs entangled with the SWCNTs formed a mesh structure with good conductivity. • It is the first time use of CuONWs-SWCNTs hybrid nanocomposite for DNA detection. • The biosensor is simple, selective, stable, and sensitive. • The biosensor has great potential for use in analysis of real samples. - Abstract: Here, we developed a novel and sensitive electrochemical biosensor to detect specific-sequence target DNA. The biosensor was based on a hybrid nanocomposite consisting of copper oxide nanowires (CuO NWs) and carboxyl-functionalized single-walled carbon nanotubes (SWCNTs-COOH). The resulting CuO NWs/SWCNTs layers exhibited a good differential pulse voltammetry (DPV) current response for the target DNA sequences, which we attributed to the properties of CuO NWs and SWCNTs. CuO NWs and SWCNTs hybrid composites with highly conductive and biocompatible nanostructure were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and cyclic voltammetry (CV). Immobilization of the probe DNA on the electrode surface was largely improved due to the unique synergetic effect of CuO NWs and SWCNTs. DPV was applied to monitor the DNA hybridization event, using adriamycin as an electrochemical indicator. Under optimal conditions, the peak currents of adriamycin were linear with the logarithm of target DNA concentrations (ranging from 1.0 × 10"−"1"4 to 1.0 × 10"−"8 M), with a detection limit of 3.5 × 10"−"1"5 M (signal/noise ratio of 3). The biosensor also showed high selectivity to

An ultrasensitive electrochemical DNA biosensor based on a copper oxide nanowires/single-walled carbon nanotubes nanocomposite

Energy Technology Data Exchange (ETDEWEB)

Chen, Mei [Key Laboratory of Biorheology Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China); Hou, Changjun, E-mail: houcj@cqu.edu.cn [Key Laboratory of Biorheology Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China); National Key Laboratory of Fundamental Science of Micro/Nano-Device and System Technology, Chongqing University, Chongqing 400044 (China); Huo, Danqun [Key Laboratory of Biorheology Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China); National Key Laboratory of Fundamental Science of Micro/Nano-Device and System Technology, Chongqing University, Chongqing 400044 (China); Yang, Mei [Key Laboratory of Biorheology Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044 (China); Fa, Huanbao [College of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044 (China)

2016-02-28

Graphical abstract: A novel and sensitive electrochemical biosensor based on hybrid nanocomposite consisting of copper oxide nanowires (CuO NWs) and carboxyl-functionalized single-walled carbon nanotubes (SWCNTs-COOH) was first developed for the detection of the specific-sequence target DNA. This schematic represents the fabrication procedure of our DNA biosensor. - Highlights: • An ultrasensitive DNA electrochemical biosensor was developed. • CuO NWs entangled with the SWCNTs formed a mesh structure with good conductivity. • It is the first time use of CuONWs-SWCNTs hybrid nanocomposite for DNA detection. • The biosensor is simple, selective, stable, and sensitive. • The biosensor has great potential for use in analysis of real samples. - Abstract: Here, we developed a novel and sensitive electrochemical biosensor to detect specific-sequence target DNA. The biosensor was based on a hybrid nanocomposite consisting of copper oxide nanowires (CuO NWs) and carboxyl-functionalized single-walled carbon nanotubes (SWCNTs-COOH). The resulting CuO NWs/SWCNTs layers exhibited a good differential pulse voltammetry (DPV) current response for the target DNA sequences, which we attributed to the properties of CuO NWs and SWCNTs. CuO NWs and SWCNTs hybrid composites with highly conductive and biocompatible nanostructure were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and cyclic voltammetry (CV). Immobilization of the probe DNA on the electrode surface was largely improved due to the unique synergetic effect of CuO NWs and SWCNTs. DPV was applied to monitor the DNA hybridization event, using adriamycin as an electrochemical indicator. Under optimal conditions, the peak currents of adriamycin were linear with the logarithm of target DNA concentrations (ranging from 1.0 × 10{sup −14} to 1.0 × 10{sup −8} M), with a detection limit of 3.5 × 10{sup −15} M (signal/noise ratio of 3). The biosensor also showed high

SKP2 siRNA inhibits the degradation of P27kip1 and down-regulates the expression of MRP in HL-60/A cells.

Science.gov (United States)

Xiao, Jie; Yin, Songmei; Li, Yiqing; Xie, Shuangfeng; Nie, Danian; Ma, Liping; Wang, Xiuju; Wu, Yudan; Feng, Jianhong

2009-08-01

S-phase kinase-associated protein 2 (SKP2) gene is a tumor suppressor gene, and is involved in the ubiquitin-mediated degradation of P27kip1. SKP2 and P27kip1 affect the proceeding and prognosis of leukemia through regulating the proliferation, apoptosis and differentiation of leukemia cells. In this study, we explored the mechanism of reversing of HL-60/A drug resistance through SKP2 down-regulation. HL-60/A cells were nucleofected by Amaxa Nucleofector System with SKP2 siRNA. The gene and protein expression levels of Skp2, P27kip1, and multi-drug resistance associated protein (MRP) were determined by reverse transcription-polymerase chain reaction and western blot analysis, respectively. The cell cycle was analyzed by flow cytometry. The 50% inhibitory concentration value was calculated using cytotoxic analysis according to the death rate of these two kinds of cells under different concentrations of chemotherapeutics to compare the sensitivity of the cells. HL-60/A cells showed multi-drug resistance phenotype characteristic by cross-resistance to adriamycin, daunorubicin, and arabinosylcytosine, due to the expression of MRP. We found that the expression of SKP2 was higher in HL-60/A cells than in HL-60 cells, but the expression of P27kip1 was lower. The expression of SKP2 in HL-60/A cells nucleofected by SKP2 siRNA was down-regulated whereas the protein level of P27kip1 was up-regulated. Compared with the MRP expression level in the control group (nucleofected by control siRNA), the mRNA and protein expression levels of MRP in HL-60/A cells nucleofected by SKP2 siRNA were lower, and the latter cells were more sensitive to adriamycin, daunorubicin, and arabinosylcytosine. Down-regulating the SKP2 expression and arresting cells in the G0/G1 phase improve drug sensitivity of leukemia cells with down-regulated MRP expression.

Radiation response of drug-resistant variants of a human breast cancer cell line

International Nuclear Information System (INIS)

Lehnert, S.; Greene, D.; Batist, G.

1989-01-01

The radiation response of drug-resistant variants of the human tumor breast cancer cell line MCF-7 has been investigated. Two sublines, one resistant to adriamycin (ADRR) and the other to melphalan (MLNR), have been selected by exposure to stepwise increasing concentrations of the respective drugs. ADRR cells are 200-fold resistant to adriamycin and cross-resistant to a number of other drugs and are characterized by the presence of elevated levels of selenium-dependent glutathione peroxidase and glutathione-S-transferase. MLNR cells are fourfold resistant to melphalan and cross-resistant to some other drugs. The only mechanism of drug resistance established for MLNR cells to date is an enhancement of DNA excision repair processes. While the spectrum of drug resistance and the underlying mechanisms differ for the two sublines, their response to radiation is qualitatively similar. Radiation survival curves for ADRR and MLNR cells differ from that for wild-type cells in a complex manner with, for the linear-quadratic model, a decrease in the size of alpha and an increase in the size of beta. There is a concomitant decrease in the size of the alpha/beta ratio which is greater for ADRR cells than for MLNR cells. Analysis of results using the multitarget model gave values of D0 of 1.48, 1.43, and 1.67 Gy for MCF-7 cells are not a consequence of cell kinetic differences between these sublines. Results of split-dose experiments indicated that for both drug-resistant sublines the extent of sublethal damage repair reflected the width of the shoulder on the single-dose survival curve. For MCF-7 cells in the stationary phase of growth, the drug-resistant sublines did not show cross-resistance to radiation; however, delayed subculture following irradiation of stationary-phase cultures increased survival to a greater extent for ADRR and MLNR cells than for wild-type cells

Molecular biological studies on the human radioresistance and drug resistance

International Nuclear Information System (INIS)

Kim, Chang Min; Hong, Weon Seon

1992-04-01

We irradiated the MKN45 and PC14 cell lines with 500 rads and also established the adriamycin-resistant and cis-platinum resistant cell line. The genomic DNA and total RNA were extracted and subjected to the Southern and Northern analysis using various probes including heat shock protein 70, MDR1, fos, TGFb etc. The mRNA transcript was increased 1 hour after the irradiation and sustained during the 48 hours and returned to the level of pre-irradiation. No significant change was observed with the drug resistant cell lines at the level of gene dosage. We suggest that the marked increase of the hsp70 transcript is very important finding and is believed to be a good candidate for the modulation of the cellular response to irradiation and the radioresistance. (Author)

Peripheral blood stem cell harvest in patients with limited stage small-cell lung cancer

Energy Technology Data Exchange (ETDEWEB)

Katakami, Nobuyuki; Takakura, Shunji; Fujii, Hiroshi; Nishimura, Takashi; Umeda, Bunichi [Kobe City General Hospital (Japan)

2000-06-01

Chemotherapy plus granulocyte colony-stimulating factor (G-CSF) induced mobilization of peripheral blood stem cells (PBSC) was performed in patients with limited stage small-cell lung cancer. Chemotherapy consisted of cisplatin/etoposide or cisplatin/adriamycin/etoposide. The amounts of CD34 positive cells and granulocyte-macrophage colony forming units (CFU-GM) collected during 2-3 courses of apheresis were 3.1{+-}2.9 x 10{sup 6}/kg (n=10) and 3.1{+-}1.5 x 10{sup 5}/kg (n=8) , respectively. Adequate amounts of PBSC were also harvested even in patients treated with concurrent chemoradiotherapy. Eight patients were successfully treated with high-dose chemotherapy consisting of ifosfamide, carboplatin and etoposide with PBSC transfusion. The patients'-bone marrow reconstruction was rapid and no treatment-related death was observed. (author)

Effect of intra-hepatic arterial infusion chemotherapy for patients with liver metastasis from breast cancer

International Nuclear Information System (INIS)

Liu Dezhong; Li Huai; Zeng Huiying; Yang Ling

2001-01-01

Objective: To evaluate the efficacy of intra-hepatic arterial infusion chemotherapy for patients with liver metastasis from breast cancer. Methods: 1993-1998 years, Thirty four patients with liver metastasis from breast cancer had received epi-adriamycin, cisplatin, mitomycin and 5-fluorouracil by intrahepatic arterial infusion chemotherapy. Twelve patients had received embolization. Results: Six patients (17.65%) had a complete response, 12 patients (35.29%) had a partial response. The overall response rate was 52.94%. Cumulative survival rates at 1, 2, 3 and 4 years were 56.90%, 25.00%, 5.00% and 5.00% respectively (Kaplan-Meier method). The median overall survival time was 11.5 months. Conclusion: Intra-hepatic arterial infusion chemotherapy is safe and effective for liver metastasis from breast cancer and should be the first choice of treatment for these patients

Induction of C-Mip by IL-17 Plays an Important Role in Adriamycin-Induced Podocyte Damage

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Yanbo Liu

2015-07-01

Full Text Available Background/Aims: Although the disturbance of T lymphocyte and glomerular podocyte exerts a crucial function in the pathogenesis of proteinuria, the potential link is still unclear. Methods: The balance of Treg and Th17 cells, and the expression of IL-17/IL-17R and c-mip were investigated in adrimycin-induced nephropathy (AN mice. The effect and mechanism of IL-17 on podocyte were explored in cultured podocytes. Results: The proportion of Th17 cells in peripheral blood mononuclear cells, the amount of IL-17 in serum and kidney cortical homogenates, and the expression of IL-17R and c-mip in glomerular podocyte were increased obviously in AN mice. In cultured podocytes, recombinant IL-17 led to an induction of apoptosis and cytoskeletal disorganization, an overproduction of c-mip while down-regulation of phosphor-nephrin, and an increased binding of c-mip to NF-κB/RelA. Silence of c-mip prevented podocyte apoptosis and reduction of phosphor-nephrin by prompting nuclear translocation of NF-κB/RelA in IL-17 treated cells. Persistent activation of NF-κB up-regulated pro-survival protein Bcl-2 and decreased podocyte apoptosis, but had no effect on phosphor-nephrin level. Conclusion: These findings demonstrated that induction of IL-17 released by Th17 cells plays a key role in podocytopathy most likely through down-regulation of phosphor-nephrin and Bcl-2 level via overproduction of c-mip.

Biophysical aspects of the integrated combination of cytostatic drugs with radiotherapy. Pt. 2

International Nuclear Information System (INIS)

Ulmer, W.

1991-01-01

Dose-effect relations have been evaluated by the treatment of cell cultures (9L glioma cells of rat as monolayers and tumor spheroids, L 1210 cells of mice) with activated isophosphamide, adriamycin, epirubicin and 6 MeV electrons. The magnitude of synergistic effects obtained by combined treatment modalities is strictly pH-dependent, but even for tumor spheroids it appears that thers exists an optimum time-interval between drug administration and consecutive irradiation. The determination of the intracellular pH value with the help of pH sensor microelectrodes and 31 P NMR spectroscopy indicates that 31 P spectroscopy only provides the global pH of the complete culture (average value), whereas the local pH can only be determined by sensors. The ATP-concentration before and after irradiation depends significantly on the glucose supply of culture medium. (orig.) [de

Prognostic factors in transcatheter arterial chemoembolization of hepatocellular carcinoma : analysis of more than 3 year survivors

International Nuclear Information System (INIS)

Seo, Heung Suk

1999-01-01

To determine which prognostic factors contribute to long-term survival after transcatheter arterial chemoembolization(TACE) of hepatocellular carcinoma. In 100 patients who expired within one year and 84 who survived or have survived for more than 3 years after TACE, prognostic factors were retrospectively evaluated. TACE was accomplished by hepatic arterial infusion of a suspension of Lipiodol and anticancer drugs(Mitomycin-C and Adriamycin), either alone or followed by gelfoam embolization. Fisher's exact test of probability was used to determine which prognostic factors were statistically significant. Statistically significant prognostic factors were as follows : Child classification(p 0.05). The prognosis of patients with hepatocellular carcinoma treated by TACE was affected favorably by good liver function(Child classification A), low alpha-fetoprotein value, nodular or massive-type tumor, patent main and first-order portal vein, and hypervascular tumor

Ultra-thin layer chromatography with integrated silver colloid-based SERS detection.

Science.gov (United States)

Wallace, Ryan A; Lavrik, Nickolay V; Sepaniak, Michael J

2017-01-01

Simplified lab-on-a-chip techniques are desirable for quick and efficient detection of analytes of interest in the field. The following work involves the use of deterministic pillar arrays on the micro-scale as a platform to separate compounds, and the use of Ag colloid within the arrays as a source of increased signal via surface enhanced Raman spectroscopy (SERS). One problem traditionally seen with SERS surfaces containing Ag colloid is oxidation; however, our platforms are superhydrophobic, reducing the amount of oxidation taking place on the surface of the Ag colloid. This work includes the successful separation and SERS detection of a fluorescent dye compounds (resorufin and sulforhodamine 640), fluorescent anti-tumor drugs (Adriamycin and Daunomycin), and purine and pyrimidine bases (adenine, cytosine, guanine, hypoxanthine, and thymine). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Clinical impact of FDG-PET/CT in the planning of radiotherapy for early-stage Hodgkin lymphoma

DEFF Research Database (Denmark)

Hutchings, Martin; Loft, Annika; Hansen, Mads

2007-01-01

BACKGROUND: Early-stage Hodgkin lymphoma (HL) has excellent survival rates but carries a high risk of late treatment-related adverse effects. Modern, individualised therapeutic strategies require an accurate determination of the extent of the disease. This study investigated the potential impact...... of 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography/computerised tomogrpahy (FDG-PET/CT) in the planning of involved field radiotherapy (IFRT). PATIENTS AND METHODS: Thirty patients received staging FDG-PET/CT before therapy, and IFRT after a short course of ABVD (adriamycin, bleomycin......, vinblastine, dacarbazine) chemotherapy. IFRT planning was performed using only the CT data from the FDG-PET/CT scan. Later, the IFRT planning was performed anew using the FDG-PET/CT data as basis for contouring. RESULTS: In 20 out of 30 patients, the radiotherapy (RT) course was unaffected by the addition...

Caso para diagnóstico Case for diagnosis

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Cristina Paula Salaro

2011-08-01

Full Text Available Paciente do sexo masculino de 55 anos com placas e nódulos infiltrados exuberantes em membro inferior esquerdo há seis meses. Cardiopatia, nefropatia e endocrinopatia associadas. O exame histopatológico, acrescido da imunoistoquímica, confirma linfoma cutâneo difuso de células B. Marcadores CD-20, CD-79a e Ki-67 foram positivos. A quimioterapia com ciclofosfamida, adriamicina e vincristina promoveu remissão parcialA fifty-five year old Caucasian male presented with infiltrated plaques and nodules on the left leg. The lesions had been present for 6 months. He presented associated cardiopathy, nephropathy and endocrinopathy. Histopathological and immunohistochemical examinations confirmed the diagnosis of cutaneous diffuse B cell lymphoma. CD 20, CD 79a and Ki-67 were positive. Chemotherapy with cyclophosphamide, adriamycin and vincristine promoted partial remission

Primary Pulmonary Synovial Sarcoma: A Case with Unique and Impressive Computed Tomography Findings

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Jaspreet S Kambo

2015-01-01

Full Text Available Primary pulmonary synovial sarcoma (PPSS is a rare malignancy. Its etiology, imaging features and optimal treatment are not well understood. Pulmonary pseudoaneurysms and lymphadenopathy are rare complications of synovial sarcomas. A 40-year-old woman with mild hemoptysis and thoracic back pain underwent a computed tomography scan that revealed multiple pulmonary lesions, paraesophageal lymphadenopathy and incidental bilateral pulmonary emboli. A diagnosis of PPSS was made through the identification of an SS18 translocation by fluorescence in situ hybridization. She was started on adriamycin, ifosfamide and mesna chemotherapy. Over the subsequent two months, she developed three pulmonary artery pseudoaneurysms, ultimately requiring endovascular coiling. Seven months after starting treatment, the patient was asymptomatic. The lesions and lymphadenopathy decreased in size. The present case highlights complications of a rare malignancy and demonstrates positive response to ifosfamide-based chemotherapy in the setting of PPSS.

Microencapsulation of chemotherapeutic agents

International Nuclear Information System (INIS)

Byun, Hong Sik

1993-01-01

Mixing various amounts of chemotherapeutic agents such as cisplatinum, 5-fluorouracil, mitomycin-C, and adriamycin with polymers such as poly-d, 1-lactide, ethylhydroxyethylcellulose, and polycaprolactone, several kinds of microcapsules were made. Among them, microcapsule made from ethylhydroxyethylcellulose showed best yield. Under light microscopy, the capsules were observed as particles with refractive properties. For the basic toxicity test, intraarterial administration of cisplatinum was done in 6 adult mongrel dogs. Follow-up angiography was accomplished in 2 wk intervals for 6 wks. Despite no significant difference in the histopathological examination between the embolized and normal kidneys, follow-up angiogram showed atrophy of renal cortex and diminished numbers of arterial branches in the embolized kidneys. In order to identify the structural properties of microcapsules, and to determine the drug content and the rate of release, further experiment is thought to be necessary. (Author)

Radiation and concurrent chemotherapy for the treatment of Lewis lung tumor and B16 melanoma tumor in C57/BL mice

International Nuclear Information System (INIS)

Pedersen, J.E.; Barron, G.

1984-01-01

C57/BL mice bearing either Lewis lung tumor or B16 melanoma tumor were treated with radiation and concurrent chemotherapy. The treatment results were determined in vivo by tumor regrowth delay assay. When continuous infusion of either Cyclophosphamide (CYCLO) or 5-Fluorouracil (5-FU) or Adriamycin (ADRIA) or Mitomycin-C (MITO-C) was used in combination with continuous radiation at 1 cGy/min, no increase in tumor regrowth delay was observed over that of radiation alone. When multiple drug chemotherapy, FAM (5-FU, ADRIA, MITO-C) was administered in combination with radiation at 80 cGy/min, no increase in tumor regrowth delay was observed over that of radiation alone. In these two murine tumor models, when clinically relevant concentrations of commonly used chemotherapy agents were combined with radiation, no therapeutic advantage was observed

Primary cardiac lymphoma: diagnostic tools and treatment challenges.

LENUS (Irish Health Repository)

Bambury, R

2011-03-01

Primary cardiac lymphoma (PCL) is a rare malignancy and the optimal treatment strategy remains uncertain. It appears to respond much better to systemic chemotherapy than to surgery and it should be considered in the differential diagnosis of all cardiac tumours before definitive management is undertaken. We report a case of this rare disorder treated successfully with a combination of rituximab and cyclophosphamide, adriamycin, vincristine and prednisolone. The patient developed recurrent unstable ventricular tachycardia (VT) post-chemotherapy secondary to extensive scarring at the tumour site. The tumour as well as the post-treatment scarring is well illustrated by cardiac magnetic resonance imaging highlighting its usefulness in this setting. An implantable cardioverter defibrillator (ICD) was placed. This is only the second case in the literature of PCL to have an ICD placed for recurrent VT. A brief literature review is included.

Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial.

Science.gov (United States)

van den Berg, Henk; Paulussen, Michael; Le Teuff, Gwénaël; Judson, Ian; Gelderblom, Hans; Dirksen, Uta; Brennan, Bernadette; Whelan, Jeremy; Ladenstein, Ruth Lydia; Marec-Berard, Perrine; Kruseova, Jarmila; Hjorth, Lars; Kühne, Thomas; Brichard, Benedicte; Wheatley, Keith; Craft, Alan; Juergens, Heribert; Gaspar, Nathalie; Le Deley, Marie-Cécile

2015-11-01

Based on the randomised Euro-EWING99-R1 trial, vincristine, adriamycin, cyclophosphamide (VAC) may be able to replace vincristine, adriamycin, ifosfamide (VAI) in the treatment of standard-risk Ewing sarcoma. However some heterogeneity of treatment effect by gender was observed. The current exploratory study aimed at investigating the influence of gender on treatment efficacy and acute toxicity. Impact of gender on event-free survival (EFS), acute toxicity by course, switches between treatment arms and cumulative dose of alkylating agents was evaluated in multivariable models adjusted for age including terms to test for heterogeneity of treatment effect by gender. The analysis of the EFS was performed on the intention-to-treat population. EFS did not significantly differ between the 509 males and 347 females (p=0.33), but an interaction in terms of efficacy was suspected between treatment and gender (p=0.058): VAC was associated with poorer EFS than VAI in males, hazard ratio (HR) (VAC/VAI)=1.37 [95% confidence interval (CI), 0.98-1.90], contrasting with HR=0.81 [95%CI, 0.53-1.24] in females. Severe toxicity was more frequent in females, whatever the toxicity type. Thirty patients switched from VAI to VAC (9/251 males, 4%, and 21/174 females, 12%) mostly due to renal toxicity, and three from VAC to VAI (2/258 males, 0.8%, and 1/173 females, 0.6%). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% versus 9%, p=0.005), with no major difference between VAC and VAI (10% versus 13%, p=0.15). Differences of acute toxicity rate and cumulative doses of alkylating agents could not explain the marginal interaction observed in the Euro-EWING99-R1 trial data. Effects of gender-dependent polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide versus cyclophosphamide should be explored. External data are required to further evaluate whether there is heterogeneity of alkylating agent effect by gender. NCT00987636 and

Second malignancies after treatment for Ewing's sarcoma

International Nuclear Information System (INIS)

Ahrens, Susanne; Dunst, Juergen; Ruebe, Christian; Paulussen, Michael; Hoffmann, Christine; Juergens, Herbert

1997-01-01

Background: Some former retrospective studies have suggested that patients with Ewing's sarcoma might have a very high risk for developing secondary sarcomas if treated with radiotherapy. We have evaluated the risk of second malignancies (SM) in patients treated in the German Cooperative Ewing's Sarcoma Studies CESS 81 and CESS 86. Materials and methods: From January 1981 through June 1991, a total number of 674 patients was registered in the two multicentric Ewing's sarcoma trials CESS 81 (1981 through 1985) and CESS 86 (1986 through June 1991). The systemic treatment consisted in both studies of a four-drug-chemotherapy (VACA= vincristine, actinomycin D, cyclophosphamide and adriamycin; or VAIA= vincristine, actinomycin D, ifosfamide and adriamycin) and a total number of four courses, each lasting nine weeks, was recommended by the protocol. Local therapy was either complete surgery or surgery plus postoperative radiotherapy with 36-46Gy or definitive radiotherapy with 46 to 60Gy. The median follow-up at the time of this analysis was 7 years, the maximum follow-up 16 years. Results: Eight patients developed a SM, 4 were acute myelogenic leucemias, three sarcomas and one benign neurinoma. One of the sarcomas was considered as radiation-induced because of its location in the former radiation field. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17 to 78 months for the four AMLs and 82 to 136 months for the three sarcomas. All solid second tumors occurred in irradiated patients. The cumulative risk of a SM is given in table 1. Three patients (all with AML) died of their SM, the other five were salvage by subsequent treatment and are in clinical remission with a median follow-up of 1 to 10 years. Conclusions: The risk of leukemia after treatment for Ewing's sarcoma is probably low in the range of 1-2% or less and accounts for about 1% of all deaths. There was no risk of solid tumors in surgically treated patients. Irradiated

Second malignancies after treatment for Ewing's sarcoma

Energy Technology Data Exchange (ETDEWEB)

Ahrens, Susanne; Dunst, Juergen; Ruebe, Christian; Paulussen, Michael; Hoffmann, Christine; Juergens, Herbert

1997-07-01

Background: Some former retrospective studies have suggested that patients with Ewing's sarcoma might have a very high risk for developing secondary sarcomas if treated with radiotherapy. We have evaluated the risk of second malignancies (SM) in patients treated in the German Cooperative Ewing's Sarcoma Studies CESS 81 and CESS 86. Materials and methods: From January 1981 through June 1991, a total number of 674 patients was registered in the two multicentric Ewing's sarcoma trials CESS 81 (1981 through 1985) and CESS 86 (1986 through June 1991). The systemic treatment consisted in both studies of a four-drug-chemotherapy (VACA= vincristine, actinomycin D, cyclophosphamide and adriamycin; or VAIA= vincristine, actinomycin D, ifosfamide and adriamycin) and a total number of four courses, each lasting nine weeks, was recommended by the protocol. Local therapy was either complete surgery or surgery plus postoperative radiotherapy with 36-46Gy or definitive radiotherapy with 46 to 60Gy. The median follow-up at the time of this analysis was 7 years, the maximum follow-up 16 years. Results: Eight patients developed a SM, 4 were acute myelogenic leucemias, three sarcomas and one benign neurinoma. One of the sarcomas was considered as radiation-induced because of its location in the former radiation field. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17 to 78 months for the four AMLs and 82 to 136 months for the three sarcomas. All solid second tumors occurred in irradiated patients. The cumulative risk of a SM is given in table 1. Three patients (all with AML) died of their SM, the other five were salvage by subsequent treatment and are in clinical remission with a median follow-up of 1 to 10 years. Conclusions: The risk of leukemia after treatment for Ewing's sarcoma is probably low in the range of 1-2% or less and accounts for about 1% of all deaths. There was no risk of solid tumors in surgically treated patients. Irradiated

Assessment of pulmonary toxicities in breast cancer patients undergoing treatment with anthracycline and taxane based chemotherapy and radiotherapy- a prospective study

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Aramita Saha

2013-12-01

Full Text Available Background: Anthracycline based regiments and/or taxanes and adjuvant radiotherapy; the main modalities of treatment for breast cancers are associated with deterioration of pulmonary functions and progressive pulmonary toxicities. Aim: Assessment of pulmonary toxicities and impact on pulmonary functions mainly in terms of decline of forced vital capacity (FVC and the ratio of forced expiratory volume (FEV in 1 Second and FEV1/FVC ratio with different treatment times and follow ups in carcinoma breast patients receiving anthracycline and/or taxane based chemotherapy and radiotherapy. Materials and methods: A prospective single institutional cohort study was performed with 58 breast cancer patients between January 2011 to July 2012 who received either anthracycline based (37 patients received 6 cycles FAC= 5 FU, Adriamycin, Cyclophosphamide regime and radiotherapy or anthracycline and taxane based chemotherapy (21 patients received 4cycles AC= Adriamycin, Cyclophosphamide; followed by 4 cycles of T=Taxane and radiotherapy. Assessment of pulmonary symptoms and signs, chest x-ray and pulmonary function tests were performed at baseline, midcycle, at end of chemotherapy, at end radiotherapy, at 1 and 6 months follow ups and compared. By means of a two-way analysis of variance (ANOVA model, the course of lung parameters across the time points was compared. Results and Conclusion: Analysis of mean forced vital capacities at different points of study times showed definitive declining pattern, which is at statistically significant level at the end of 6th month of follow up (p=0.032 .The FEV1/FVC ratio (in percentage also revealed a definite decreasing pattern over different treatment times and at statistically significant level at 6th month follow up with p value 0.003. Separate analysis of mean FEV1/FVC ratios over time in anthracycline based chemotherapy and radiotherapy group as well as anthracycline and taxane based chemotherapy and radiotherapy group

Hodgkin's lymphoma-related vanishing bile duct syndrome: A case report and literature review

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Kiong-Ming Wong

2013-11-01

Full Text Available We report the case of a 38-year-old man who developed vanishing bile duct syndrome in association with Hodgkin's lymphoma. He was noted to have cervical lymphadenopathy and marked elevation of total serum bilirubin at diagnosis. He achieved complete remission with normalization of serum bilirubin after eight courses of Adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed with autologous hematopoietic cell transplantation. Consecutive liver biopsies performed at diagnosis and at the stage of complete remission revealed the disappearance and regeneration of interlobular bile ducts, respectively. Our case provides pathological evidence that Hodgkin's lymphoma-related vanishing bile duct syndrome is a reversible bile duct injury disease. Bilirubin is a reliable serum marker to monitor the treatment response of these cases. The mechanism to develop hyperbilirubinemia with vanishing bile duct in such a case of Hodgkin's lymphoma remains to be studied. A literature review was carried out.

Comparison of the oncogenic potential of several chemotherapeutic agents

International Nuclear Information System (INIS)

Miller, R.C.; Hall, E.J.; Osmak, R.S.

1981-01-01

Several chemotherapeutic drugs that have been routinely used in cancer treatment were tested for their carcinogenic potential. Two antitumor antibiotics (adriamycin and vincristine), an alkalating agent (melphalan), 5-azacytidine and the bifunctional agent cis-platinum that mimics alkylating agents and/or binds Oxygen-6 or Nitrogen-7 atoms of quanine were tested. Cell killing and cancer induction was assessed using in vitro transformation system. C3H/10T 1/2 cells, while normally exhibiting contact inhibition, can undergo transformation from normal contact inhibited cells to tumorgenic cells when exposed to chemical carcinogens. These cells have been used in the past by this laboratory to study oncogenic transformation of cells exposed to ionizing radiation and electron affinic compounds that sensitize hypoxic cells to x-rays. The endpoints of cell killing and oncogenic transformation presented here give an estimate of the carcinogenic potential of these agents

Regional immunotherapy has a detrimental effect on the response to combined irradiation and chemotherapy in locally advanced non-small cell bronchognic carcinoma

International Nuclear Information System (INIS)

Ruckdeschel, J.C.; De Vore, C.; Caradonna, R.; Horton, J.; McKneally, M.F.; Kellar, S.; McIlduff, J.B.; Baxter, D.H.; Killam, D.; Sedransk, N.

1981-01-01

Twenty-one patients with stage III M 0 non-oat cell bronchogenic carcinoma confined to the thorax were randomized to receive either intrapleural BCG (10 7 cfu, Tice strain) or intrapleural saline 3 weeks prior to beginning combined irradiation and chemotherapy. Radiation to the primary tumor and regional nodes was given at a dose of 3,000 rad in ten sessions and was followed in 7-14 days by CAMP chemotherapy (cyclophosphamide, adriamycin, methotrexate, and procarbazine) for a planned duration of 6 months. Isoniazid, 300 mg/day, was given to all patients for 3 months starting 1 week after intrapleural therapy. There were no significant differences in pretreatment prognostic factors or in response to radiation therapy. The patients receiving intrapleural BCG in addition to radiation and chemotherapy had a median survival of 18 weeks, significantly shorter than that for the patients receiving intrapleural saline (54 weeks, P=0.017). (orig.)

Treatment of hepatocellular carcinoma by transarterial injection of anticancer agents in iodized oil suspension or of radioactive iodized oil solution

International Nuclear Information System (INIS)

Kobayashi, H.; Hidaka, H.; Kajiya, Y.; Tanoue, P.; Inoue, H.; Ikeda, K.; Nakajo, M.; Shinohara, S.

1986-01-01

Transarterial injection of modified iodized oil was performed in 48 patients with hepatoma. In 41 cases an adriamycin and/or mitomycin C-iodized oil suspension was administered into the proper hepatic artery or peripheral hepatic branches. A reduction in tumor size of over 50% was obtained in 14 of the 33 patients in whom CT examination was performed before and after treatment. Serum alpha-fetoprotein levels decreased in 20 of 21 cases within the first month after injection. The one-year survival rate was estimated at 55% in advanced hepatoma. In 7 patients, transarterial internal irradiation using radioactive iodized oil was carried out. A decrease in tumor size was observed in all cases and in alpha-fetoprotein levels in 6 cases. One patient with severe liver cirrhosis died in hepatorenal failure. No severe complications or other adverse reactions were encountered with either of the methods. (orig.)

Three-drug chemotherapy combined with radiation therapy in small cell carcinoma of the lung

International Nuclear Information System (INIS)

Sibille, Y.; Steyaert, J.; Francis, C.; Bosly, A.; Prignot, J.

1983-01-01

In 43 cases of small cell carcinoma of the lung, a combined treatment has been initiated with three drugs (cyclophosphamide 750 mg/m 2 , adriamycin 50 mg/m 2 and vincristine sulphate 1 or 2 mg total dosis), split-course-radiation therapy on the primary tumour (3500 rads) and prophylactic irradiation of the brain (2000 rads). The median survival of the 34 cases evaluable at day 50 attains 253 days. A more favourable evolution is observed for patients with a good response after therapy (median survival: 315 days) and for cases with limited disease (321 days) than for non-responders (median survival: 157 days) and for cases with extensive disease (median survival: 214 days). In spite of tumour site irradiation, prophylactic irradiation of CNS and chemotherapy, there were six local relapses, two CNS extensions and six metastatic relapses and only two autopsied cases without macroscopic evidence of relapse. (author)

Determination of somatic mutations in human erythrocytes by cytometry

International Nuclear Information System (INIS)

Jensen, R.H.; Langlois, R.G.; Bigbee, W.L.

1985-01-01

Flow cytometric assays of human erythrocytes labeled with monoclonal antibodies specific for glycophorin A were used to enumerate variant cells that appear in peripheral blood as a result of somatic gene-loss mutations in erythrocyte precursor cells. The assay was performed on erythrocytes from 10 oncology patients who had received at least one treatment from radiation or mutagenic chemotherapy at least 3 weeks before being assayed. The patients were suffering from many different malignancies (e.g., breast, renal, bone, colon and lung), and were treated with several different mutagenic therapeutics (e.g., cisplatinum, adriamycin, daunomycin, or cyclophosphamide). The frequency of these variant cells is an indication of the amount of mutagenic damage accumulated in the individual's erythropoietic cell population. Comparing these results to HPRT clonogenic assays, we find similar baseline frequencies of somatic mutation as well as similar correlation with mutagenic exposures. 9 refs., 3 figs., 1 tab

Determination of somatic mutations in human erythrocytes by cytometry

Energy Technology Data Exchange (ETDEWEB)

Jensen, R.H.; Langlois, R.G.; Bigbee, W.L.

1985-06-21

Flow cytometric assays of human erythrocytes labeled with monoclonal antibodies specific for glycophorin A were used to enumerate variant cells that appear in peripheral blood as a result of somatic gene-loss mutations in erythrocyte precursor cells. The assay was performed on erythrocytes from 10 oncology patients who had received at least one treatment from radiation or mutagenic chemotherapy at least 3 weeks before being assayed. The patients were suffering from many different malignancies (e.g., breast, renal, bone, colon and lung), and were treated with several different mutagenic therapeutics (e.g., cisplatinum, adriamycin, daunomycin, or cyclophosphamide). The frequency of these variant cells is an indication of the amount of mutagenic damage accumulated in the individual's erythropoietic cell population. Comparing these results to HPRT clonogenic assays, we find similar baseline frequencies of somatic mutation as well as similar correlation with mutagenic exposures. 9 refs., 3 figs., 1 tab.

[Metastatic lung cancer origin from osteosarcoma of mandible invading tracheal lumen].

Science.gov (United States)

Taguchi, K; Noriyuki, T; Furonaka, O; Kuroda, Y; Akimoto, E; Kuranishi, F; Nakahara, M; Fukuda, T; Ishizaki, Y; Okuda, H; Hashimoto, M; Yonehara, S

2009-07-01

A 52-year-old woman underwent the surgical treatment for osteosarcoma of the left mandible in 2003 and was followed up afterward. She suffered from dry cough and bloody sputum, and was admitted to our hospital in April 2007. Computed tomography (CT) revealed several nodules in bilateral lung, and bronchofiberscopy showed the endobronchial tumor obstructing in the right main bronchus. The metastatic tumor progressed in the right main bronchus from the right S6 lung segment. The tumor rapidly progressed in the right bronchus in comparison with the CT findings in about 2 weeks, and the possibility of the tracheal obstruction was considered. She underwent the right middle and lower lobectomy, and the endobronchial tumor was pulled through the right main bronchus. The postoperative course was uneventful, the patient was discharged on 14th postoperative day, and the chemotherapy using cisplatin (CDDP) and adriamycin (ADR) is on-going.

Biophysical aspects of the integrated combination of cytostatic drugs with radiotherapy. Pt. 3

International Nuclear Information System (INIS)

Ulmer, W.

1991-01-01

Radiobiological data referring to in vitro cell cultures proved to be adequate for the determination of an optimum sequence between drug incubation and consecutive, irradiation, if the intracellular pH was subjected to accurate controls. An extension of the comparative study to the in vivo model of murine C3H mammary adenocarcinoma yielded synergistic effects, if the animals were treated with 10 MeV electrons and one of the drugs: Cis-platinum, adriamycin, epirubicin, activated cyclophosphamide, activated isophosphamide. For comparative purpose the survey of the therapeutic results during and after finishing of the schedules was performed with 31 P-NMR spectroscopy, radiometry ( 3 H-thymidine) and a scanning system using 100 pH sensor microelectrodes. Although most extensive with regard to measurement technique, the latter method provided an accurate local pH distribution of a tumor tissue, while 31 P only yielded the global pH-value (average). (orig.) [de

Studies on the antimutagenic activities of garlic extract

International Nuclear Information System (INIS)

Knasmueller, S.; Szakmary, A.; Domjan, G.; de Martin, R.

1989-01-01

Experiments with Salmonella tester strains indicated that aqueous garlic extract possesses antimutagenic properties toward ionizing radiation, peroxides, adriamycin, and N-methyl-N'-nitro-nitrosoguanidine. The assumption that radical scavenging garlic constituents, i.e., molecules with sulfur moieties, might be responsible for the inhibitory effect of aqueous extract toward mutagenesis induced by radiation and radiomimetic compounds was confirmed by the results of subsequent experiments; (1) garlic extract attenuated the lethal effects of γ-rays on repair-deficient E. coli strains; (2) the garlic constituent allicin (thio-2-propene-1-sulfinic acid S-allyl ester) is partly responsible for the reduced radiation-induced mutagenesis in Salmonella typhimurium TA 102. No such inhibitory effects were detected with alliin (S-allyl-L-cysteine sulfoxide) or cysteine; (3) aqueous garlic extract inhibited hydrogen-peroxide-induced lipid peroxidation. Results obtained in preliminary experiments with Chinese hamster ovary cells suggest that the antimutagenic properties of garlic extract are not restricted to procaryotic cells

Malignant Ewing-Like Neoplasm With an EWSR1-KLF15 Fusion: At the Crossroads of a Myoepithelial Carcinoma and a Ewing-Like Sarcoma. A Case Report With Treatment Options.

Science.gov (United States)

Stevens, Todd M; Qarmali, Morad; Morlote, Diana; Mikhail, Fady M; Swensen, Jeffrey; Gatalica, Zoran; Siegal, Gene P; Conry, Robert M

2018-01-01

We present a case of a malignant Ewing-like neoplasm of the parotid gland in a 20-year-old woman with an EWSR1-KLF15 gene fusion that presented with pulmonary metastasis. Despite the fact that the tumor was essentially immunohistochemically negative for keratins, p63, and p40, we interpret this neoplasm as an unusual form of a high-grade myoepithelial carcinoma based on its focal plasmacytoid cytology, chondromyxoid matrix, SOX10, S100 protein, and calponin expression, and the knowledge that the EWSR1-KLF15 gene fusion has, to date, only been identified in 2 tumors, both myoepithelial carcinomas of the kidney. We also present a cytogenetic analysis of this unusual tumor. This "Ewing-like myoepithelial carcinoma" initially did not respond to 2 cycles of ifosfamide and etoposide alternated with a cycle of cytoxan, adriamycin, and vincristine, a standard regimen for Ewing sarcoma. Subsequent oral pazopanib therapy did result in a reduction of the patient's pulmonary and nodal disease.

Laser scanning cytometry (LCS) allows detailed analysis of the cell cycle in PI stained human fibroblasts (TIG-7).

Science.gov (United States)

Kawasaki, M; Sasaki, K; Satoh, T; Kurose, A; Kamada, T; Furuya, T; Murakami, T; Todoroki, T

1997-01-01

We have demonstrated a method for the in situ determination of the cell cycle phases of TIG-7 fibroblasts using a laser scanning cytometer (LSC) which has not only a function equivalent to flow cytometry (FCM) but also has a capability unique in itself. LSC allows a more detailed analysis of the cell cycle in cells stained with propidium iodide (PI) than FCM. With LSC it is possible to discriminate between mitotic cells and G2 cells, between post-mitotic cells and G1 cells, and between quiescent cells and cycling cells in a PI fluorescence peak (chromatin condensation) vs. fluorescence value (DNA content) cytogram for cells stained with PI. These were amply confirmed by experiments using colcemid and adriamycin. We were able to identify at least six cell subpopulations for PI stained cells using LSC; namely G1, S, G2, M, postmitotic and quiescent cell populations. LSC analysis facilitates the monitoring of effects of drugs on the cell cycle.

20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs.

Science.gov (United States)

Liu, Junhua; Wang, Xu; Liu, Peng; Deng, Rongxin; Lei, Min; Chen, Wantao; Hu, Lihong

2013-07-15

Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Wilms tumor in adult: case report; Tumor de Wilms em adulto: relato de caso

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Albuquerque, Mauro Guimaraes; Vieira, Sabas Carlos; Rego, Cristiane Fortes Napoleao do [Universidade Estadual do Piaui (UESPI), Teresina, PI (Brazil); Fortes, Emanuel Augusto de C.; Santana, Gerusia Ibiapina [Hospital Sao Marcos, Teresina, PI (Brazil)]. E-mail: sabasvieira@uol.com.br

2004-07-01

Wilms' tumor is the renal tumor with the higher incidence on the childhood, however it rarely occurs in adults.The incidence in this group is estimated at about 1% of all the cases and they have an obscure prognosis. In this report is related a new case in a 52 years old man presenting intensive abdominal pain associated by weightiness. Abdominal ultrasound revealed expansive and complex lesion with indefinite contour in the left flank. Computed tomography of abdomen demonstrated solid lesion on antero-superior pole of the left kidney invading para-vertebral musculature, peri and para-renal spaces. Total nephrectomy and the histopathologic analysis were realized. A nephroblastoma (Wilms' tumor) in stage II without anaplasia was diagnosed by the anatomopathological studies.Local radiotherapy was applied. Thereafter was diagnosed pulmonary and hepatic metastasis, and then initiated the chemotherapy with adriamycin, actinomycin and vincristine. The prognosis of Wilms' tumor is worse in adult and it requires an aggressive therapeutic and follow up. (author)

Wilms tumor in adult: case report

International Nuclear Information System (INIS)

Albuquerque, Mauro Guimaraes; Vieira, Sabas Carlos; Rego, Cristiane Fortes Napoleao do; Fortes, Emanuel Augusto de C.; Santana, Gerusia Ibiapina

2004-01-01

Wilms' tumor is the renal tumor with the higher incidence on the childhood, however it rarely occurs in adults.The incidence in this group is estimated at about 1% of all the cases and they have an obscure prognosis. In this report is related a new case in a 52 years old man presenting intensive abdominal pain associated by weightiness. Abdominal ultrasound revealed expansive and complex lesion with indefinite contour in the left flank. Computed tomography of abdomen demonstrated solid lesion on antero-superior pole of the left kidney invading para-vertebral musculature, peri and para-renal spaces. Total nephrectomy and the histopathologic analysis were realized. A nephroblastoma (Wilms' tumor) in stage II without anaplasia was diagnosed by the anatomopathological studies.Local radiotherapy was applied. Thereafter was diagnosed pulmonary and hepatic metastasis, and then initiated the chemotherapy with adriamycin, actinomycin and vincristine. The prognosis of Wilms' tumor is worse in adult and it requires an aggressive therapeutic and follow up. (author)

Human C6orf211 Encodes Armt1, a Protein Carboxyl Methyltransferase that Targets PCNA and Is Linked to the DNA Damage Response

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J. Jefferson P. Perry

2015-03-01

Full Text Available Recent evidence supports the presence of an L-glutamyl methyltransferase(s in eukaryotic cells, but this enzyme class has been defined only in certain prokaryotic species. Here, we characterize the human C6orf211 gene product as “acidic residue methyltransferase-1” (Armt1, an enzyme that specifically targets proliferating cell nuclear antigen (PCNA in breast cancer cells, predominately methylating glutamate side chains. Armt1 homologs share structural similarities with the SAM-dependent methyltransferases, and negative regulation of activity by automethylation indicates a means for cellular control. Notably, shRNA-based knockdown of Armt1 expression in two breast cancer cell lines altered survival in response to genotoxic stress. Increased sensitivity to UV, adriamycin, and MMS was observed in SK-Br-3 cells, while in contrast, increased resistance to these agents was observed in MCF7 cells. Together, these results lay the foundation for defining the mechanism by which this post-translational modification operates in the DNA damage response (DDR.

Establishment and characterization of a hypocatalasemic mouse cell strain

International Nuclear Information System (INIS)

Utsumi, Hiroshi; Tano, Keizo; Hashimoto, Mitsumasa W.; Kodama, Seiji; Watanabe, Hiromitsu

1998-01-01

Contact-inhibited catalase-deficient fibroblast cell strain has been established from the homozygous hypocatalasemic C3H/Cs b mutant mouse. This cell strain has low level of catalase enzyme activity and has normal level of enzyme activities of both glutathione peroxidase and superoxide dismutase. Catalase-deficient C3H/Cs b mutant cell strain is markedly more sensitive to the toxicity of hydrogen peroxide compared to wild-type C3H/Cs a cell strain. In addition, mutant cell strain is sensitive to X-rays and near-UV compared to wild-type cell strain, but shows the same sensitivities to topoisomerase II inhibitors, adriamycin and 4'-(9-acridinylamino) methanesulfon-m-anisidide (m-AMSA), and the DNA cross-linking agents, cis-diamminedichloroplatinum (II) (cis-Pt) and trans-diamminedichloroplatinum (II) (trans-Pt). These cell strains will be of use in the study of the roles which catalase plays in the intracellular prevention of DNA damage induced by oxidative stress. (author)

Doxorubicin-anti-carcinoembryonic antigen immunoconjugate activity in vitro.

Science.gov (United States)

Richardson, V J; Ford, C H; Tsaltas, G; Gallant, M E

1989-04-01

An in vitro model consisting of a series of 11 human cancer cell lines with varying density of expression of membrane carcinoembryonic antigen (CEA) has been used to evaluate conjugates of doxorubicin (Adriamycin) covalently linked by a carbodiimide method to goat polyclonal antibodies and mouse monoclonal antibodies to CEA. Conjugates were produced which retained both antigen binding and drug cytotoxicity. IC50 values were determined for free drug, free drug mixed with unconjugated antibodies and for the immunoconjugates. Cell lines that were very sensitive to free drug (IC50 less than 100 ng/ml) were also found to be highly sensitive to conjugated drug and similarly cell lines resistant to drug (IC50 greater than 1,000 ng/ml) were also resistant to conjugated drug. Although there was no correlation between CEA expression and conjugates efficacy, competitive inhibition studies using autologous antibody to block conjugate binding to cells indicated immunoconjugates specificity for the CEA target.

Probe for intracellular concentrations of drugs: delayed fluorescence from acridine orange

International Nuclear Information System (INIS)

Wardman, P.; Dennis, M.F.; White, J.

1989-01-01

The aim of this work is to develop fluorescent probes that will indicate effective concentrations of therapeutic agents, or endogenous protectors, at important cellular sites. Acridine orange associates with nucleic acids and emits a 'delayed' fluorescence signal. This signal is quenched by oxidants such as oxygen, nitroaryl radiosensitizers, adriamycin and mitomycin-c, and reductants such as thiols, ascorbate and other radioprotectors. The quenching of the acridine orange delayed fluorescence reflects the effective concentration of these therapeutically-important oxidants and reductants near DNA. The relative concentration of basic radiosensitizers such as pimonidazole (Ro 03-8799) near the DNA is greater than that of misonidazole. Thiols quench the delayed fluorescence signal according to the degree of ionization of the thiol function; this may model the reactivity of thiols with guanine radical sites in DNA. Ascorbate and aminopyrine do not quench the delayed fluorescence from cells stained with acridine orange as these compounds are taken up by cells very inefficiently

Primary Synovial Sarcoma of Kidney: A Rare Differential Diagnosis of Renomegaly

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Gaurang Modi

2014-01-01

Full Text Available Synovial sarcomas (SS are classified as subgroup of soft tissue sarcomas affecting mainly extremities of young adults. Primary SS of kidney are very rare tumours with poor prognosis. Though they have characteristic histology and immunohistochemistry (IHC due to rarity of incidence it is difficult to diagnose them. Sometimes chromosomal rearrangement studies are required to confirm the diagnosis. We are presenting a case of 41-year-old male who was referred to our cancer centre for evaluation of left renal mass. CT scan of abdomen revealed a large left renal mass encasing the aorta. Biopsy of renal mass revealed poorly differentiated sarcoma and IHC was positive for vimentin, CD99, and BCL2 and negative for AE1, epithelial membrane antigen, and leukocyte common antigen. The patient was clinically inoperable as renal mass was encasing the aorta. So he was subsequently offered palliative chemotherapy in form of ifosfamide and adriamycin. CT abdomen shows partial response after 3 cycles of chemotherapy according to RECIST criteria.

Chemoembolization through intercostal arteries in hepatocellular carcinoma: Report of a case of transient spinal cord injury

International Nuclear Information System (INIS)

Moon, Tae Yong; Hwang, In Tae; Kim, Byung Soo; Ko, Hyun Yoon; Yang, Ung Suk; Kim, Hak Jin

1994-01-01

Liver has a dual blood supply from portal vein and hepatic artery. Hepatocellular carcinoma receive their blood supply almost exclusively from hepatic artery. Thus, the concept of treating hepatocellular carcinoma by chemoembolization through these arteries is very effective . However, there may be several collateral or parasitic vessels feeding them in case of huge tumor or previous chemoembolization. We experienced a case of huge tumor involving right upper posterior portion of liver fed by 9th, 10th, 11th right posterior intercostal arteries and an anomalous hepatic artery. We tried chemoembolization with Adriamycin-Lipiodol suspension and Gelfoam material through the right posterior intercostal arteries to treat the lesion. After the procedure, the patient(55 years old female) became paraplegic with voiding and defecation difficulty which could be due to spinal cord infarction by anterior spinal arterial occlusion caused by embolic material through the artery of Adamkiewicz from a posterior intercostal artery. She recovered completely after 20 days of treatment

Hemangiopericytoma of the spleen.

Science.gov (United States)

Illuminati, Giulio; Pizzardi, Giulia; Calio, Francesco; Pacilè, Maria A; Carboni, Fabio; Palumbo, Piergaspare; Vietri, Francesco

2015-03-01

Hemangiopericytoma of the spleen is a very rare tumor, with 14 isolated reports. It was our aim to review our experience and compare it with all the reported cases in an attempt to standardize surgical treatment, adjuvant treatment and follow-up protocol of this infrequent condition. A consecutive case series study, with a mean follow-up of 44 months. Five patients (mean age, 49 years) underwent simple splenectomy for hemangiopericytoma limited to the spleen followed by adriamycin-based chemotherapy in one patient. All the patients are alive and free from disease. For tumors confined to the spleen, simple splenectomy can be considered curative, without any need for further adjuvant treatment. On review of the medical literature, cure can still be achieved with complete resection of recurrences, when feasible, with adjuvant chemotherapy being also indicated. The slow-growing pattern of the tumor suggests a 10-year follow-up. Copyright © 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Effect of dihydroxyanthraquinone (DHAQ) and radiation on the survival of cultured Chinese hamster ovary cells

International Nuclear Information System (INIS)

Kimler, B.F.

1983-01-01

Dihydroxyanthraquinone (DHAQ) is currently being tested as a cancer chemotherapeutic agent because of its structural similarity to Adriamycin (ADR) and other DNA-intercalating antibiotics. The interaction of DHAQ and ionizing radiation on the induction of cell lethality was investigated in Chinese hamster ovary cells in culture. In asynchronous populations of cells, DHAQ produced a slight enhancement of radiation-induced cell lethality as evidenced by changes in both shoulder and slope of the radiation dose-survival curves. However, DHAQ had no effect on either the extent or time course of recovery from sublethal radiation damage. In synchronous populations of cells treated at various times before or after selection in mitosis, the combination of DHAQ and radiation produced greater cell killing than that predicted based on simple additivity of effect, with a decided enhancement for cells treated during S phase. These results indicate that DHAQ is similar to other DNA-intercalating antibiotics in regard to the interaction with ionizing radiation to produce cell lethality

Langerhan’s cell sarcoma: two case reports

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Tasneem A. Kaleem

2016-04-01

Full Text Available Langerhan’s cell sarcoma (LCS is a rare neoplasm with a poor prognosis. To our knowledge, only sixty-six cases have been published. We discuss two patients who presented very differently with LCS, as well as a recently published review of all sixty-six cases. Our first case had a complicated history of metastatic, high-grade myxofibrosarcomas and presented with a single skin lesion of LCS which was treated with resection to a positive margin and adjuvant radiotherapy. The LCS recurred locoregionally and was again resected. The patient is alive two years after initial diagnosis. The second case presented with bone marrow and splenic involvement, leukocytosis, and thrombocytopenia. This patient had an excellent response to etoposide, prednisone, oncovorin, cyclophosphamide, and adriamycin, with normalization of the complete blood count, negative bone marrow biopsy at follow up, and splenectomy without viable neoplasm. This patient is alive without signs of disease at 16 months after initial diagnosis.

Interaction of nogalamycin and analogs with DNA and other biopolymers

Energy Technology Data Exchange (ETDEWEB)

Krueger, W C [Univ. of Minnesota, Minneapolis; Pschigoda, L M; Schpok, S L.F.; Moscowitz, A.; McGovren, J P; Neta, P; Merritt, M V; Li, L H

1981-01-01

The interaction with calf thymus DNA of the anthracycline antibiotics, nogalamycin and its analogs, was studied by electronic absorption, circular dichroism (CD), thermal denaturation, solvent partition and pulse radiolysis techniques. The Scatchard, thermal denaturation (..delta..T/sub m/), difference circular dichroism (..delta..CD) and solvent partition binding parameters gave the same order of relative binding on a given lot of DNA, but some parameters were DNA-lot-dependent. In general, molecules containing the sugar moiety nogalose at C-7 or those having the natural or dis stereochemistry of nogalamycin at C-7 bound more strongly to DNA than did the molecules lacking nogalose or those with the opposite configuration at C-7 (con stereochemistry). This stereochemical-binding correlation differs from that found for adriamycin which has the con stereochemistry, but which binds strongly to DNA. Scatchard binding parameters could not be obtained from the pulse radiolysis or solvent partition techniques because of solubility difficulties.

Radiotherapy to the surviving kidney after unilateral nephrectomy in bilateral Wilms' tumour

International Nuclear Information System (INIS)

Kirkbride, P.; Plowman, P.N.

1992-01-01

Four out of seven patients with bilateral tumours died in the period from 1952 to 1960 and five out of eight in the period from 1971 to 1989, at St Bartholomew's Hospital and the Hospital for Sick Children. More aggressive chemotherapy with both adriamycin and actinomycin D and concern over young age being predisposed to late radiation morbidity kept radiotherapy dose prescriptions to the surviving kidney below the quoted renal radiation tolerance dose equivalent. In three long-term survivors treated with daily fractions up to 167 cGy and total doses of 1000-1200 cGy, renal function and growth was within the ''normal'' range at follow-up and the patients normotensive 6-8 years later. As four of the eight patients reported here died from local disease progression within the kidney (albeit despite slightly larger dose prescriptions), the authors discuss the potential for larger total doses to be delivered in this situation. (author)

Multispectral and phase-contrast diffuse optical tomography of breast cancer during neoadjuvant chemotherapy: a case study

Science.gov (United States)

Liang, Xiaoping; Zhang, Qizhi; Staal, Stephen; Grobmyer, Stephen; Jiang, Huabei

2009-02-01

Multispectral and phase-contrast diffuse optical tomography are used to track treatment progress in a patient with locally advanced invasive carcinoma of the breast cancer during neoadjuvant chemotherapy. Two types of chemotherapy treatment including four cycles of Adriamycin/Cytoxin (AC cycles) and twelve cycles of Taxol/Herceptin (TH cycles) were applied to patient. A total of eight optical exams were performed before and within the chemotherapy. Images of tissue refractive index, and absorption and scattering coefficients, as well as oxy-hemoglobin and deoxy-hemoglobin concentrations along with scattering particle volume fraction and mean diameter of cellular components were all obtained. The tumor was identified through absorption and scattering images. Tumor shrinkage was observed during the course of chemotherapy from all the optical images. Our results show that oxy-hemoglobin, deoxy-hemoglobin and total hemoglobin in tumor decreased after chemotherapy compared to that of before chemotherapy. Significant changes in tumor refractive index along with tumor cellular morphology during the entire chemotherapy are also observed.

Ovarian carcinoma: Role of radiation therapy versus chemotherapy

International Nuclear Information System (INIS)

Shehata, W.M.; Meyer, R.L.; Cormier, W.J.; Jazy, F.K.

1986-01-01

The authors evaluated 83 patients with ovarian cancer who were irradiated or treated by a combination of cytoxan, adriamycin, and cisplatin. According to FIGO stage, eight patients had stage I disease, 12 had stage II disease, 61 had stage II disease and two has stage IV disease. Fifty patients had bulky disease and 33 had minimal disease of 2 cm or less. Sixty patients were irradiated to an open abdominopelvic field (30 Gy delivered over 4 weeks), with or without a pelvic boost. Fifty-five patients received combination chemotherapy and 30 received a single agent as initial therapy. The patients were divided into three groups. The 26 patients in group I received primary radiation therapy with or with out adjuvant single-agent chemotherapy, then combination chemotherapy to salvage. The 34 patients in group II were irradiated after chemotherapy, mainly combination chemotherapy, failed. The 23 patients in group III received, mainly combination chemotherapy with second-line drugs for salvage

Primary lymphoma of the liver treated by extended hepatectomy and chemotherapy: a case report Linfoma primário do fígado tratado por hepatectomia ampliada e quimioterapia: relato de caso

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Eleazar Chaib

2002-09-01

Full Text Available Primary lymphoma of the liver is an extremely rare entity. A case of anaplastic large B-cell (both CD-20 and lambda positive non-Hodgkin's lymphoma that was confined to the liver in a 33-year-old man is reported. The patient was treated with an extended right hepatectomy and combination chemotherapy: cyclophosphamide, adriamycin, vincristine, and prednisone. The patient was disease free 24 months after the procedure.O linfoma primário do fígado é uma entidade extremamente rara. Os autores relatam um caso de linfoma não-Hodgkin de células B grandes anaplásicas (positivo para CD-20 e Lambda em um paciente do sexo masculino de 33 anos. O tumor estava localizado no lobo hepático direito e foi tratado por hepatectomia direita ampliada e quimioterapia pós-operatória com ciclofosfamida, adriamicina, vincristina e prednisone. Vinte quatro meses de seguimento o paciente encontra-se sem recidiva tumoral.

The Management of Classical Hodgkin's Lymphoma: Past, Present, and Future.

Science.gov (United States)

Richardson, S E; McNamara, C

2011-01-01

The management of classical Hodgkin's lymphoma (CHL) is a success story of modern multi-agent haemato-oncology. Prior to the middle of the twentieth century CHL was fatal in the majority of cases. Introduction of single agent radiotherapy (RT) demonstrated for the first time that these patients could be cured. Developments in chemotherapy including the mechlorethamine, vincristine, procarbazine and prednisolone (MOPP) and Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) regimens have resulted in cure rates of over 80%. Even in relapse, CHL patients can be salvaged with high dose chemotherapy and autologous haematopoietic stem cell transplantation (ASCT). Challenges remain, however, in finding new strategies to manage the small number of patients who continue to relapse or progress. In addition, the young age of many Hodgkin's patients forces difficult decisions in balancing the benefit of early disease control against the survival disadvantage of late toxicity. In this article we aim to summarise past trials, define the current standard of care and appraise future developments in the management of CHL.

Clinical study on the adriamycin induced cardiomyopathy using the cardiac magnetic resonance imaging. Total dose and cardiac dysfunction

International Nuclear Information System (INIS)

Yamaguchi, Kyoko; Teraoka, Kunihiko; Hirano, Masaharu

2001-01-01

We studied cardiac functional disorders caused by Adoriamycin using gadolinium (Gd) contrast cine MRI. Forty-eight patients were given ACT (31 men and 17 women; mean age, 52±15 years). First, the relationship between dose and the left ventricular volume, cardiac function, left ventricular cardiac mass and localized wall motion were examined in all patients. Patients given a total dose of 300 mg/m 2 or higher were assigned to the high dose group and those given doses under 300 mg/m 2 to the low dose group. The same parameters were studied in both groups and compared. A 1.5-Tesla superconductive MRI was used for all studies. Cine images of the long and short axes at the papillary muscle level were obtained by ECG R-wave synchronized Gd contrast cine MRI. Left ventricular volume and cardiac function were analyzed using the long-axis cine images and the wall thickness in diastole and systole was measured at each site using the short-axis cine images. The percentage of wall thickness was calculated at each site. The mean ACT dose was 273.3±218.2 mg/m 2 . In all patients the total dose directly correlated with ESVI and inversely correlated with the ejection fraction (EF). In the high dose group, the total dose and EF were inversely correlated, but no significant differences were observed in the low dose group. In the high dose group, the ESVI was significantly greater and the SVI and EF were more significantly reduced than in the low dose group. In the high dose group, the thickness of the anterior, lateral and posterior walls, excluding the septum, was significantly lower than in the low dose group. However, changes in wall thickness were not significantly different between the groups. Gd contrast cine MRI was useful in examining cardiac functional disorders caused by anthracyclines. The total dose of anthracycline correlated directly with the ESVI, and inversely with the EF. A total dose of 300 mg/m 2 appeared to be the borderline dose beyond which there were significant cardiac functional disorders. (author)

Clinical study on the adriamycin induced cardiomyopathy using the cardiac magnetic resonance imaging. Total dose and cardiac dysfunction

Energy Technology Data Exchange (ETDEWEB)

Yamaguchi, Kyoko; Teraoka, Kunihiko; Hirano, Masaharu [Tokyo Medical Coll. (Japan)

2001-05-01

We studied cardiac functional disorders caused by Adoriamycin using gadolinium (Gd) contrast cine MRI. Forty-eight patients were given ACT (31 men and 17 women; mean age, 52{+-}15 years). First, the relationship between dose and the left ventricular volume, cardiac function, left ventricular cardiac mass and localized wall motion were examined in all patients. Patients given a total dose of 300 mg/m{sup 2} or higher were assigned to the high dose group and those given doses under 300 mg/m{sup 2} to the low dose group. The same parameters were studied in both groups and compared. A 1.5-Tesla superconductive MRI was used for all studies. Cine images of the long and short axes at the papillary muscle level were obtained by ECG R-wave synchronized Gd contrast cine MRI. Left ventricular volume and cardiac function were analyzed using the long-axis cine images and the wall thickness in diastole and systole was measured at each site using the short-axis cine images. The percentage of wall thickness was calculated at each site. The mean ACT dose was 273.3{+-}218.2 mg/m{sup 2}. In all patients the total dose directly correlated with ESVI and inversely correlated with the ejection fraction (EF). In the high dose group, the total dose and EF were inversely correlated, but no significant differences were observed in the low dose group. In the high dose group, the ESVI was significantly greater and the SVI and EF were more significantly reduced than in the low dose group. In the high dose group, the thickness of the anterior, lateral and posterior walls, excluding the septum, was significantly lower than in the low dose group. However, changes in wall thickness were not significantly different between the groups. Gd contrast cine MRI was useful in examining cardiac functional disorders caused by anthracyclines. The total dose of anthracycline correlated directly with the ESVI, and inversely with the EF. A total dose of 300 mg/m{sup 2} appeared to be the borderline dose beyond which there were significant cardiac functional disorders. (author)

Preparation and characteristics of lipid nanoemulsion formulations loaded with doxorubicin

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Jiang SP

2013-08-01

. Analysis results of in-vitro and in-vivo antitumor activities reveal that doxorubicin-loaded LNE exerts a therapeutic effect similar to that of the commercial Adriamycin. Moreover, the toxicity of doxorubicin, particularly its cardiac toxicity, is reduced. Conclusion: The present LNE formulation of doxorubicin can effectively suppress tumor growth and improve the safety of Adriamycin. Keywords: PEGylation, stability, antitumor activity

The sensitivity of radiation and its combined effect with anticancer drugs on cultured human lung cancer cells

International Nuclear Information System (INIS)

Okada, Shinichiro

1986-01-01

The cultured lung tumor cells were irradiated with 60 Co γ-rays, with and without combinations of adriamycin (ADR) and 5-Fluorouracil (5-FU). Cell survival was assayed by colony formation in vitro in soft agar and in plate. Most of small cell lung carcinoma cells used here were radiosensitive, while one of them showed radioresistent comparable to non-small cell lung tumors and other tumor cells. In the treatment with drugs (ADR or 5-FJ) following 60 Co γ-irradiation (postirradiation treatment), it proved to be twice as effective as drug treatment preceding irradiation (preirradiation treatment). Preirradiation treatment demonstrated that 5-FU treated cell were more radiosensitive than ADR treated ones. In the preirradiation treatment, the most enhanced killing effect was observed when cells were irradiated twenty four hours after 5-FU treatment, on the other hand, in the ADR treatment, treatment interval showed no differrece. In the postirradiation treatment, the greatest enhancement was observed when cells were irradiated twenty hours after ADR exposure, while most effective forty eight hours after 5-FU treatment. (author)

Primitive neuroectodermal tumor of adrenal: Clinical presentation and outcomes

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Deep Dutta

2013-01-01

Full Text Available Primitive neuroectodermal tumor (PNET of adrenal is an extremely rare tumor of neural crest origin. A nonfunctional left adrenal mass (14.6 × 10.5 × 10.0 cm on computed tomography (CT was detected in a 40-year-old lady with abdominal pain, swelling, and left pleural effusion. She underwent left adrenalectomy and left nephrectomy with retroperitoneal resection. Histopathology revealed sheets and nest of oval tumor cells with hyperchromatic nuclei, prominent nucleoli, scanty cytoplasm, brisk mitotic activity, necrosis, lymphovascular invasion, capsular invasion, and extension to the surrounding muscles; staining positive for Mic-2 (CD-99 antigen, vimentin, synaptophysin, and Melan-A. Thoracocentesis, pleural fluid study, and pleural biopsy did not show metastasis. She responded well to vincristine, adriamycin, and cyclophosphamide followed by ifosfamide and etoposide (IE. This is the first report of adrenal peripheral PNET (pPNET from India. This report intends to highlight that pPNET should be suspected in a patient presenting with huge nonfunctional adrenal mass which may be confused with adrenocortical carcinoma.

Transformation of Nonfunctioning Pancreatic Neuroendocrine Carcinoma Cells into Insulin Producing Cells after Treatment with Sunitinib

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Jung Hun Ohn

2013-06-01

Full Text Available We report a rare case of severe hypoglycemia after sunitinib treatment for pancreatic neuroendocrine carcinoma. We describe the initial clinical presentation, laboratory results, pathologic findings, and managment in a patient with a nonfunctioning pancreatic neuroendocrine carcinoma with liver metastases who developed life threatening hypoglycemia after 2 months of sunitinib therapy. A 46-year-old woman presented to the emergency department with loss of consciousness from hypoglycemia. Serum C-peptide and insulin levels at fasting state revealed that the hypoglycemia resulted from endogenous hyperinsulinemia. She had been diagnosed with nonfunctioning pancreatic neuroendocrine carcinoma based on a biopsy of metastatic cervical lymph node and was being treated with sunitinib, a small molecule tyrosine kinase inhibitor. Immunohistochemical stain of the metastatic liver mass demonstrated that the initially nonfunctioning neuroendocrine carcinoma cells had changed into insulin-producing cells after sunitinib therapy. Transarterial chemoembolization of the liver masses and systemic chemotherapy with streptozotocin/adriamycin relieved the hypoglycemia. A nonfunctioning pancreatic neuroendocrine carcinoma was transformed into an insulin-producing tumor after treatment with sunitinib, causing endogenous hyperinsulinemia and severe hypoglycemia.

Prognostic factors in transcatheter arterial chemoembolization of hepatocellular carcinoma : analysis of more than 3 year survivors

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Seo, Heung Suk [Hanyang Univ. College of Medicine, Seoul (Korea, Republic of)

1999-06-01

To determine which prognostic factors contribute to long-term survival after transcatheter arterial chemoembolization(TACE) of hepatocellular carcinoma. In 100 patients who expired within one year and 84 who survived or have survived for more than 3 years after TACE, prognostic factors were retrospectively evaluated. TACE was accomplished by hepatic arterial infusion of a suspension of Lipiodol and anticancer drugs(Mitomycin-C and Adriamycin), either alone or followed by gelfoam embolization. Fisher's exact test of probability was used to determine which prognostic factors were statistically significant. Statistically significant prognostic factors were as follows : Child classification(p<0.01), alpha-fetoprotein value(p<0.05), type of tumor(p<0.01), portal vein status(p<0.01), and vascularity of the tumor(p<0.05). HBsAg, tumor size, and method of chemoembolization were not statistically significant(p>0.05). The prognosis of patients with hepatocellular carcinoma treated by TACE was affected favorably by good liver function(Child classification A), low alpha-fetoprotein value, nodular or massive-type tumor, patent main and first-order portal vein, and hypervascular tumor.

Ewing’s sarcoma: an uncommon breast tumor

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Sawsen Meddeb

2014-10-01

Full Text Available Ewing’s sarcoma/primitive neuroectodermal tumors (EWS/PNET are rare malignant and aggressive tumors, usually seen in the trunk and lower limbs of children and young adults. They are uncommon in the breast. We report a case of a 43-year-old woman who developed a painless breast mass. An initial core needle biopsy concluded to a fibrocystic dystrophy contrasting with a rapidly growing mass; thus a large lumpectomy was done. Diagnosis of primary PNET of the breast was established, based on both histopathological examination and immunohistochemical findings. Surgical margins were positive, therefore, left modified radical mastectomy with axillary lymph nodes dissection was performed. The patient was given 6 cycles of adjuvant chemotherapy containing cyclophosphamide, adriamycin and vincristine. Twenty months later, she is in life without recurrence or metastasis. EWS/PNET may impose a diagnostic challenge. Indeed, mammography and ultrasonography features are non specific. The histopathological pattern is variable depending on the degree of neuroectodermal differentiation. Immuno-phenotyping is necessary and genetic study is the only confirmatory tool of diagnosis showing a characteristic cytogenetic anomaly; t (11; 22 translocation.

Fertility concerns and preservation in younger women with breast cancer.

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Anchan, Raymond Manohar; Ginsburg, Elizabeth Sarah

2010-06-01

Nearly 30% of breast cancer cases present in women younger than 50 years old. While newer treatment regimens employed are less gonadotoxic, regimens still consist of combination medications that include cyclophosphamide, known to deplete the number of primordial follicles, thereby potentially leading to infertility. For common regimens such as adriamycin/cytoxan (AC), the risk of premature ovarian failure was thought to be largely dependent on patient age, with the risk of complete ovarian failure women women >40 (Hortobagyi et al. (1986) [1]); however recent studies indicate that AC is considered to have intermediate risk for gonadotoxicity in women >40 years age. This review examines major strides in the field of reproductive medicine over the past 20 years including the use of leuprolide acetate, embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking. We also discuss the role of gestational carriers and adoption in establishing families as a viable option for many of these cancer patients who may be unable to avail themselves of other alternatives to fertility preservation. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1.

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Zhu, Yinghua; Liu, Yujie; Zhang, Chao; Chu, Junjun; Wu, Yanqing; Li, Yudong; Liu, Jieqiong; Li, Qian; Li, Shunying; Shi, Qianfeng; Jin, Liang; Zhao, Jianli; Yin, Dong; Efroni, Sol; Su, Fengxi; Yao, Herui; Song, Erwei; Liu, Qiang

2018-04-23

Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients.

Design, synthesis and biological evaluation of LBM-A5 derivatives as potent P-glycoprotein-mediated multidrug resistance inhibitors.

Science.gov (United States)

Wu, Yuxiang; Pan, Miaobo; Dai, Yuxuan; Liu, Baomin; Cui, Jian; Shi, Wei; Qiu, Qianqian; Huang, Wenlong; Qian, Hai

2016-05-15

A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC50>100μM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemotherapy response as a prognosticator for survival in patients with limited squamous cell lung cancer treated with combined chemotherapy and radiotherapy

International Nuclear Information System (INIS)

Eagan, R.T.; Fleming, T.R.; Lee, R.E.; Ingle, J.N.; Frytak, S.; Creagan, E.T.

1980-01-01

Twenty-two patients with limited unresectable squamous cell lung cancer were treated with 6 courses of combination chemotherapy consisting of cyclophosphamide, adriamycin, cisplatin, and bleomycin (CAP-Bleo) and short-course thoracic irradiation started after the first 4 weeks of chemotherapy. Of 20 patients with visible tumor who were treated with 4 weeks of chemotherapy alone, 10 (50%) had a tumor regression in that 4 week period and 10 did not. Those patients with tumor regression had significantly better progression free and overall survivals than did patients with no chemotherapy regressions (medians of 258 days vs. 136 days and 356 days vs. 150 days respectively). The original bleomycin dose had to be reduced by 50% primarily because of excessive radiation esophagitis that has not been reported with use of either the CAP regimen or bleomycin along in conjunction with thoracic irradiation. An initial chemotherapy regression seems to be a good prognosticator for progression-free and overall survival in patients with limited squamous cell lung cancer treated with combined chemotherapy and radiotherapy

Clinical experience with RF thermotherapy for nonresectable primary and secondary liver tumors

International Nuclear Information System (INIS)

Yonemura, Yutaka; Fujimura, Takashi; Takegawa, Shigeru; Miyata, Ryuwa; Kamata, Toru; Miyazaki, Itsuo; Nakajima, Kazuyoshi; Hisazumi, Haruo; Saito, Yasuo

1987-01-01

Twenty two patients with primary or secondary liver tumors were treated by radiofrequency hyperthermia (8 MHz) combined with radiation or chemotherapy. Hyperthermia was administered twice a week for 40 - 60 minutes per session up to a total of 5 - 48 sessions. Five fractions per week of irradiation (10 MV X ray) at 180 - 200 cGy or intraarterial chemotherapy using mitomycin C, cis-diamminedichroloplatinum or adriamycine were carried out. Intratumor temperature over 42.5 deg C were obtained in 9 of 17 patients. Of the 22 patients treated, 2 (9 %) showed complete response, 8 (36 %) partial response, 3 (14 %) minor response, 7 (32 %) no change and 2 (9 %) progressive disease. 7 out of 14 tumors, heated over 42.5 deg C showed complete or partial response but only 1 out of 5 tumors, heated under 42.5 deg C was responder. Complication observed were thrombocytopenia and leukopenia in 30 % of cases. These results showed that combined treatment of hyperthermia radiation and chemotherapy appear to be useful from of therapy for the patients with liver tumor. (author)

The Management of Classical Hodgkin's Lymphoma: Past, Present, and Future

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S. E. Richardson

2011-01-01

Full Text Available The management of classical Hodgkin's lymphoma (CHL is a success story of modern multi-agent haemato-oncology. Prior to the middle of the twentieth century CHL was fatal in the majority of cases. Introduction of single agent radiotherapy (RT demonstrated for the first time that these patients could be cured. Developments in chemotherapy including the mechlorethamine, vincristine, procarbazine and prednisolone (MOPP and Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD regimens have resulted in cure rates of over 80%. Even in relapse, CHL patients can be salvaged with high dose chemotherapy and autologous haematopoietic stem cell transplantation (ASCT. Challenges remain, however, in finding new strategies to manage the small number of patients who continue to relapse or progress. In addition, the young age of many Hodgkin's patients forces difficult decisions in balancing the benefit of early disease control against the survival disadvantage of late toxicity. In this article we aim to summarise past trials, define the current standard of care and appraise future developments in the management of CHL.

Alveolar rhabdomyosarcoma: origin and prognostic implications of molecular findings.

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Eguía-Aguilar, Pilar; López-Martínez, Briceida; Retana-Contreras, Carmen; Perezpeña-Diazconti, Mario

We present the case of a 2-year-old male patient with a facial tumor partially treated with chemotherapy before his admission to our institution. The tumor involved from the frontal region to the maxillary floor, the orbit, and the maxillary and sphenoid sinuses. The histopathological diagnosis revealed a stage IV alveolar rhabdomyosarcoma with infiltration to bone marrow and cerebrospinal fluid. He was managed with four cycles of adriamycin, actinomycin, cyclophosphamide and vincristine; cisplatin and irinotecan were added to the last cycle. The tumor had a 50% size reduction, but the patient died after a neutropenia and fever episode. The aggressive behavior of alveolar rhabdomyosarcoma has been associated with the expression of oncogenic fusion proteins resulting from chromosomal translocations, particularly t(2;13) (q35;q14) PAX3/FOXO1, and t(1;13) (p36;q14) PAX7/FOXO1 which were present in this patient. Copyright © 2016 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

RNA binding protein RNPC1 inhibits breast cancer cells metastasis via activating STARD13-correlated ceRNA network.

Science.gov (United States)

Zhang, Zhiting; Guo, Qianqian; Zhang, Shufang; Xiang, Chenxi; Guo, Xinwei; Zhang, Feng; Gao, Lanlan; Ni, Haiwei; Xi, Tao; Zheng, Lufeng

2018-05-07

RNA binding proteins (RBPs) are pivotal post-transcriptional regulators. RNPC1, an RBP, acts as a tumor suppressor through binding and regulating the expression of target genes in cancer cells. This study disclosed that RNPC1 expression was positively correlated with breast cancer patients' relapse free and overall survival, and RNPC1suppressed breast cancer cells metastasis. Mechanistically, RNPC1 promoting a competing endogenous network (ceRNA) crosstalk between STARD13, CDH5, HOXD10, and HOXD1 (STARD13-correlated ceRNA network) that we previously confirmed in breast cancer cells through stabilizing the transcripts and thus facilitating the expression of these four genes in breast cancer cells. Furthermore, RNPC1 overexpression restrained the promotion of STARD13, CDH5, HOXD10, and HOXD1 knockdown on cell metastasis. Notably, RNPC1 expression was positively correlated with CDH5, HOXD1 and HOXD10 expression in breast cancer tissues, and attenuated adriamycin resistance. Taken together, these results identified that RNPC1 could inhibit breast cancer cells metastasis via promoting STARD13-correlated ceRNA network.

Phenotypic stability of B16-BL6 melanoma exposed to low levels of tyrosine and phenylalanine.

Science.gov (United States)

Elstad, C A; Meadows, G G

1990-01-01

We previously demonstrated that tyrosine (Tyr) and phenylalanine (Phe) restriction suppresses metastatic heterogeneity of B16-BL6 (BL6) melanoma and selects for tumor variants with decreased metastatic potential. In this study, we investigate stability of this Tyr- and Phe-modulated tumor phenotype by sequentially transplanting BL6 in vivo into mice fed Low Tyr and Phe Diet. Metastatic potential of BL6 is suppressed after one subcutaneous passage. Suppression is unlikely to result from inhibition of tumor growth, since growth in vitro is significantly increased. The metastatic potential of the Tyr- and Phe-modulated tumor is unstable after in vivo passage, and lung colonizing ability is regenerated after ten in vivo passages. Conversely, the antimetastatic effect of Tyr and Phe restriction is stable after prolonged in vitro passage. The metastatic potential of tumors from mice fed Normal Diet is unstable after long-term in vitro culture. Sensitivity to adriamycin of BL6 from mice fed Low Tyr and Phe Diet is increased and is not altered by change in metastatic potential.

Arsenic trioxide synergistically enhances radiation response in human cervical cancer cells through ROS-dependent p38 MAPK and JNK signalling pathway

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Kang, Young-Hee; Park, Seung-Moo; Kim, Min-Jeong [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)] (and others)

2006-07-01

Many factors affect susceptibility of tumor cells to ionizing radiation. Among them intrinsic apoptosis sensitivity or resistancy seems to play an important role. The use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic efficacy by overcoming a high apoptotic threshold. Several recent studies demonstrated additive effects of As{sub 2}O{sub 3} with conventional chemotherapeutic agents such as cisplatin, adriamycin, and etoposide, but no synergism. Previously, we have shown for the first time that As{sub 2}O{sub 3} sensitize human cervical cancer cells to ionizing radiation. Treatment of As{sub 2}O{sub 3} in combination of ionizing radiation has synergistic effects in decreasing clonogenic survival and in the regression of tumor growth in xenografts. We also have shown that the combination treatment enhanced apoptotic cell death through a reactive oxygen species-dependent pathway in human cervical cancer cells. In this study, we investigated the regulatory mechanism of ROS-mediated mitochondrial apoptotic cell death induced by combination treatment with As{sub 2}O{sub 3} and ionizing radiation in human cervical cancer cells.

Acute and late effects of multimodal therapy on normal tissues

International Nuclear Information System (INIS)

Phillips, T.L.; Fu, K.K.

1977-01-01

The increasing use of combined radiation, chemotherapy, and surgery has led to an increased incidence of acute and late complications. The complications are, in general, similar to those seen with each modality alone, but occur with increased incidence. Enhanced effects of combined radiation and surgery are modest in number and consist primarily of problems with wound healing and fibrosis, as well as late gastrointestinal damage. Combinations of radiotherapy and chemotherapy have shown a greater degree of enhanced acute and late reactions. Drugs, such as actinomycin-D and Adriamycin, are particularly dangerous if the marked enhancement of radiation effects caused by the drugs in almost all organs is not appreciated and the radiation dose not adjusted accordingly. Proper selection of drugs can lead to enhanced local control by radiotherapy and/or surgery, as well as eradication of microscopic distant metastases, without increased normal tissue injury. Late induction of malignancy can occur with either radiation or chemotherapy alone and, in some cases, this appears to be enhanced when they are combined

Full dose CHOP chemotherapy

International Nuclear Information System (INIS)

Tominaga, Shinichi; Kondo, Makoto; Ando, Yutaka; Yamashita, Shoji; Uematsu, Minoru; Shigematsu, Naoyuki; Nishiguchi, Iku; Hashimoto, Shozo

1985-01-01

Since 1982, we have performed 125 courses of CHOP chemotherapy for 27 patients of malignancy, adhering to the original regimen as strictly as possible. CHOP chemotherapy consisted of Cyclophosphamide 750 mg/m 2 , iv, on day 1; Adriamycin 50 mg/m 2 , iv, on day 1; Vincristine 1.4 mg/m 2 , iv, on day 1 (maximum single dose 2.0 mg) and Prednisolone 50 mg/m 2 , po, day 1 through 5. The cycle was repeated every 21 days. As side effects, myelosuppression, hair loss, fever, nausea, vomiting, liver dysfunction, stomatitis, neuropathy, herpes zoster, arrhythmia and hemorrhagic cystitis were seen. Due to myelosuppression, twenty patients experienced febrile episodes at each nadir of WBC counts on 40 courses. However, any febrile patient did not have life threatening infection. Other side effects were also reversible. The radiotherapy of most patients was carried out as initially scheduled, except for 3 patients in whom irradiation was interrupted due to severe stomatitis or herpes zoster. We consider that CHOP chemotherapy is excellent in feasibility even when combined with radiotherapy. (author)

Preclinical screening for drugs effective against 5-fluorouracil-resistant cells with a murine L5178Y cell line in vitro

International Nuclear Information System (INIS)

Hill, B.T.

1983-01-01

A subline of L5178Y cells has been established in vitro that exhibits a fiftyfold order of resistance to 5-fluorouracil (FUra) as compared to that of the parent line. The cytotoxic effects of 24-hour exposures to 23 antitumor drugs and to radiation were compared in the two cell lines. Four patterns of response were identified: 1) Only two drugs, mitomycin C and adriamycin, proved significantly more cytotoxic to FUra-resistant cells. 2) Four other drugs--anguidine, 4'-(9-acridinylamino)-methanesulfon-m-anisidide, melphalan, and quelamycin--showed marginal superiority against resistant cells. 3) X-radiation and the majority of drugs tested--including 5-azacytidine, 1,3-bis(2-chloroethyl)-1-nitrosourea, cisplatin, bleomycin, dibromodulcitol, razoxane, hydroxyurea, methotrexate, teniposide, etoposide, and three experimental agents, metoprine, spirogermanium HCl, and ellipticinum--proved equally cytotoxic to both cell lines. 4) Cross-resistance with FUra was exhibited with vincristine, vindesine, pyrazofurin, and indicine-N-oxide. This experimental system provides a simple method of testing agents for activity against FUra-resistant cells before phase 1 clinical studies

Protective, elective lung irradiation in non-metastatic Ewing's sarcoma

International Nuclear Information System (INIS)

Marinova, L.; Hristozova, I.; Mihaylova, I.; Perenovska, P.

2015-01-01

Ewing's sarcoma in childhood is a disease from family of the peripheral primitive neuroectodermal tumours. For a period of 16 y (1984-2000), 34 children with Ewing's sarcoma were treated and followed in our department. Twenty-seven of these patients were without distant metastases. Complex treatment was applied to all these patients-chemotherapy VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin), local radiotherapy to a total dose of 50-56 Gy ± surgery. After, a local tumour control was achieved in 11 children with non-metastatic Ewing's sarcoma, elective whole lung irradiation to a total dose of 12-15 Gy was applied. Our experience in these 11 patients with non-metastatic Ewing's sarcoma, in whom elective lung irradiation was applied, showed significant reduction in the lung metastases, improved free of disease survival and overall survival. The achieved good treatment results necessitate extending this treatment approach through defining the risk groups of patients, suitable for elective lung radiotherapy combined with chemotherapy in non-metastatic Ewing's sarcoma. (authors)

Protective, elective lung irradiation in non-metastatic Ewing's sarcoma.

Science.gov (United States)

Marinova, L; Hristozova, I; Mihaylova, I; Perenovska, P

2015-07-01

Ewing's sarcoma in childhood is a disease from family of the peripheral primitive neuroectodermal tumours. For a period of 16 y (1984-2000), 34 children with Ewing's sarcoma were treated and followed in our department. Twenty-seven of these patients were without distant metastases. Complex treatment was applied to all these patients-chemotherapy VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin), local radiotherapy to a total dose of 50-56 Gy +/- surgery. After, a local tumour control was achieved in 11 children with non-metastatic Ewing's sarcoma, elective whole lung irradiation to a total dose of 12-15 Gy was applied. Our experience in these 11 patients with non-metastatic Ewing's sarcoma, in whom elective lung irradiation was applied, showed significant reduction in the lung metastases, improved free of disease survival and overall survival. The achieved good treatment results necessitate extending this treatment approach through defining the risk groups of patients, suitable for elective lung radiotherapy combined with chemotherapy in non-metastatic Ewing's sarcoma. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma

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Paulino, Arnold C.; Simon, James H.; Zhen Weining; Wen, B.-C.

2000-01-01

Purpose: To examine the long-term effects of treatment in children receiving radiotherapy for head and neck rhabdomyosarcoma. Methods: From 1967 to 1994, a total of 30 children with head and neck rhabdomyosarcoma received megavoltage radiotherapy at one institution. Seventeen patients (57%) have survived and have at least a 5-year follow-up. There were 11 males and 6 females, with a median age of 5.7 years (range 2.2-11.6) at the time of radiotherapy. Tumor location was orbit in 6 patients, infratemporal fossa in 4, paranasal sinuses in 2, and supraglottic larynx in 2; the nasopharynx, pterygopalatine fossa, and parotid gland were sites for the remaining children. All but 2 patients had tumors of embryonal histology. The Intergroup Rhabdomyosarcoma Study (IRS) Group was I in 2, II in 3, and III in 11 children; 1 patient had a recurrent tumor after surgery alone. Radiotherapy volume was the primary tumor or tumor bed in 13, tumor and whole brain in 3, and tumor and craniospinal axis in 1. Median radiotherapy dose to the primary site was 5,040 cGy (range 4,140-6,500) and to the whole brain was 3,000 cGy. All but 1 were treated with 150-200-cGy fractions; 1 patient received 250-cGy fractions for a tumor in the larynx. Chemotherapy was vincristine (V), actinomycin-D (A), and cyclophosphamide (C) in 10 patients, VAC + adriamycin in 2, VA in 1, VA + ifosfamide in 1, VC + adriamycin in 1, and none in 2. One patient had salvage chemotherapy consisting of cisplatin and etoposide. Median follow-up time was 20 years (range 7.5-33). Results: Late effects of treatment were seen in all patients and included facial growth retardation in 11, neuroendocrine dysfunction in 9, visual/orbital problems in 9, dental abnormalities in 7, hearing loss in 6, and hypothyroidism in 3. Intellectual and academic delays were documented in 3 patients who had received whole brain radiotherapy. While neuroendocrine, thyroid, dental, and cognitive sequelae were primarily attributed to radiotherapy

Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial

International Nuclear Information System (INIS)

Dunst, Juergen; Juergens, Herbert; Sauer, Rolf; Pape, Hildegard; Paulussen, Michael; Winkelmann, Winfried; Ruebe, Christian

1995-01-01

Purpose: We present an update analysis of the multiinstitutional Ewing's sarcoma study CESS 86. Methods and Materials: From January 1986 through June 1991, 177 patients with localized Ewing's sarcoma of bone, aged 25 years or less, were recruited. Chemotherapy consisted of four 9-week courses of vincristine, actinomycin D, cyclophosphamide, and adriamycin (VACA) in low-risk tumors (extremity tumors 3 ), or vincristine, actinomycin D, ifosfamide, and adriamycin (VAIA) in high-risk tumors (central tumors and extremity tumors ≥ 100 cm 3 ). Local therapy was an individual decision in each patient and was either radical surgery (amputation, wide resection) or resection plus postoperative irradiation with 45 Gy or definitive radiotherapy with 60 Gy (45 Gy plus boost). Irradiated patients were randomized concerning the type of fractionation in either conventional fractionation (once daily 1.8-2.0 Gy, break of chemotherapy) or hyperfractionated split-course irradiation simultaneously with the VACA/VAIA chemotherapy (twice daily 1.6 Gy, break of 12 days after 22.4 Gy and 44.8 Gy, total dose and treatment time as for conventional fractionation). For quality assurance in radiotherapy, a central treatment planning program was part of the protocol. Results: Forty-four patients (25%) received definitive radiotherapy; 39 (22%) had surgery, and 93 (53%) had resection plus postoperative irradiation. The overall 5-year survival was 69%. Thirty-one percent of the patients relapsed, 30% after radiotherapy, 26% after radical surgery, and 34% after combined local treatment. The better local control after radical surgery (100%) and resection plus radiotherapy (95%) as compared to definitive radiotherapy (86%) was not associated with an improvement in relapse-free or overall survival because of a higher frequency of distant metastases after surgery (26% vs. 29% vs. 16%). In irradiated patients, hyperfractionated split-course irradiation and conventional fractionation yielded the same

High dose rate brachytherapy for the treatment of soft tissue sarcoma of the extremity

International Nuclear Information System (INIS)

Speight, J.L.; Streeter, O.E.; Chawla, S.; Menendez, L.E.

1996-01-01

Purpose: we examined the role of preoperative neoadjuvant chemoradiation and adjuvant high-dose rate brachytherapy on the management of prognostically unfavorable soft tissue sarcomas of the extremities. Our goal was to examine the effect of high dose rate interstitial brachytherapy (HDR IBT) on reducing the risk of local recurrence following limb-sparing resection, as well as shortening treatment duration. Materials and methods: eleven patients, ranging in age from 31 to 73 years old, with soft tissue sarcoma of the extremity were treated at USC/Norris Comprehensive Cancer Center during 1994 and 1995. All patients had biopsy proven soft tissue sarcoma, and all were suitable candidates for limb-sparing surgery. All lesions were greater than 5cm in size and were primarily high grade. Tumor histologies included malignant fibrous histiocytoma (45%), liposarcoma (18%) and leiomyosarcoma, synovial cell sarcoma and spindle cell sarcoma (36%). Sites of tumor origin were the lower extremity (55%), upper extremity (18%) and buttock (9%), 1 patient (9%) had lesions in both the upper and lower extremity. Patients received HDR IBT following combined chemotherapy and external beam irradiation (EBRT) and en bloc resection of the sarcoma. Neoadjuvant chemotherapy consisted of three to four cycles of either Ifosfamide/Mesna with or without Adriamycin, or Mesna, Adriamycin, Ifosfamide and Dacarbazine. One patient received Cis-platin in addition to Ifos/Adr. A minimum of two cycles of chemotherapy were administered prior to EBRT. Additional cycles of chemotherapy were completed concurrently with EBRT but prior to HDR IBT. Preoperative EBRT doses ranging from 40 to 59.4 Gy were given in daily fractions of 180 to 200cGy. Following en bloc resection, HDR IBT was administered using the Omnitron tm 2000 remote afterloading system. Doses ranging from 13 to 30 Gy were delivered to the surgical tumor bed at depths of 0.5mm to 0.75mm from the radioactive source. Results: median follow-up was

Effects of anti-proteinuric therapy with angiotensin-converting-enzyme inhibition on renal protein catabolism in the adriamycin-induced nephrotic rat

NARCIS (Netherlands)

Haas, M; de Jong, PE; Moolenaar, F; Meijer, DKF; de Zeeuw, D

A direct consequence of glomerular protein leakage is an increased exposure of proximal tubular cells to proteins. The aim of the present study was to examine whether chronic proteinuria affects the tubular handling of proteins and whether anti-proteinuric therapy by angiotensin-converting-enzyme

Response of intestinal cells of differing topographical and hierarchical status to ten cytotoxic drugs and five sources of radiation

International Nuclear Information System (INIS)

Ijiri, K.; Potter, C.S.

1983-01-01

The spatial distribution of cell death among the epithelial cells lining the adult mouse small intestinal mucosa at various times after a range of doses of 10 different drugs as well as after internal or external irradiation (#betta# particles from tritium, #betta#- and X-rays and neutrons) has been recorded. Cell death, expressed as pycnosis or apoptosis, has been recorded for each cell position up the side of the crypts of the small intestine. Adriamycin and the various forms of radiation tend to kill cells preferentially at cell position 4-5 i.e. on cells very early in the lineage, probably stem cells. Isopropyl-methane-sulphonate, nitrogen mustard and possibly Actinomycin-D act on cell position 6-7, while 5-fluorouracil, Myleran, cyclophosphamide, and cycloheximide tend to kill cells at cell position 7-9. Vincristine and hydroxyurea are the 2 agents that exhibit a specificity for cells highest up the crypt, i.e. latest in transit population of the cell lineage by acting on cell positions 10 or 11. The data also suggest that normal healthy cells continue to migrate up the crypt and onto the villus in spite of considerable cell death and reduced cell production. (author)

Enhanced killing of mammalian cells by radiation combined with m-AMSA

International Nuclear Information System (INIS)

Roberts, P.B.; Millar, B.C.

1980-01-01

m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected. m-AMSA increased radiation lethality throughout the cell cycle, but a contribution to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended. (author)

Intensive combined modality therapy of small round cell and undifferentiated sarcomas in children and young adults

International Nuclear Information System (INIS)

Bader, J.L.; Dewan, R.; Watkins, E.; Kinsella, T.J.; Glatstein, E.; STeinberg, S.M.

1989-01-01

Seventy-five patients (ages 4-35 years) with the following small round cell tumors and undifferentiated sarcoma were treated at the National Cancer Institute: Ewing's sarcome (n=32), peripheral neuroepithelioma (n=14), rhabdomyosarcoma (n=24), undifferentiated sarcoma (n=5). Most patients had poor prognostic features including 36 (48%) with metastatic disease, and 42 (56%) with central (truncal) tumors (22 in the pelvis). Treatment included 5 cycles of intensive induction chemotherapy with vincristine, cyclophosphamide and adriamycin, plus aggressive local radiation therapy using simulation and computerized treatment planning for all patients. Thereafter, complete clinical responses were consolidated with intensive chemotherapy, total body irradiation and autologous bone marrow transplantation. There were three local only failures, 10 local plus distant failures, 36 distant only failures, 3 treatment-related deaths, and one intercurrent death. Overall actuarial survival and event-free survival at 4 years are 49 and 29%, respectively. Actuarial freedom from local progression was seen in 74% of patients at 4 years, quite remarkable considering the bulk and location of most of these tumors. Without aggressive surgery, many of these high risk patients had satisfactory outcomes, but better systemic treatments are still needed.(author). 44 refs.; 8 figs.; 6 tabs

Toward the virtual screening of potential drugs in the homology modeled NAD+ dependent DNA ligase from Mycobacterium tuberculosis.

Science.gov (United States)

Singh, Vijai; Somvanshi, Pallavi

2010-02-01

DNA ligase is an important enzyme and it plays vital role in the replication and repair; also catalyzes nick joining between adjacent bases of DNA. The NAD(+) dependent DNA ligase is selectively present in eubacteria and few viruses; but missing in humans. Homology modeling was used to generate 3-D structure of NAD(+) dependent DNA ligase (LigA) of Mycobacterium tuberculosis using the known template (PDB: 2OWO). Furthermore, the stereochemical quality and torsion angle of 3-D structure was validated. Numerous effective drugs were selected and the active amino acid residue in LigA was targeted and virtual screening through molecular docking was done. In this analysis, four drugs Chloroquine, Hydroxychloroquine, Putrienscine and Adriamycin were found more potent in inhibition of M. tuberculosis through the robust binding affinity between protein-drug interactions in comparison with the other studied drugs. A phylogenetic tree was constructed and it was observed that homology of LigA in M. tuberculosis resembled with other Mycobacterium species. The conserved active amino acids of LigA may be useful to target these drugs. These findings could be used as the starting point of a rational design of novel antibacterial drugs and its analogs.

Hyperthermic radiosensitization of hypoxic cells with chlorpromazine

International Nuclear Information System (INIS)

Brown, D.M.; Herman, T.S.; Bump, E.A.; Hahn, G.M.; Calderwood, S.K.

1987-01-01

Many chemical compounds of diverse structures, properties and biological activities have been found to have a profound effect on the survival of mammalian cells in vitro and in more limited studies on murine tumors in vivo when they were administered with hyperthermia (42-44 0 C). These compounds include some of the conventional antitumor chemotherapeutics such as alkylating agents, cisplatinum, adriamycin, bleomcyin and the nitrosoureas. Furthermore, compounds have been identified that are without antitumor activity or cytotoxicity at 37 0 C, but in the presence of elevated temperature, the cytotoxicity is greatly enhanced. These compounds include: aliphatic alcohols; aminothiols such as cysteamine; The polyene antifungal agent Amphotericin B; The local anesthetic procaine; and polycations such as spermine and DEAE-dextran. It is the purpose of this program to extend these initial observations into a dedicated, systematic study that will develop chemical agents in vitro and in vivo to enhance the effectiveness of clinical hyperthermia. Compounds will also be identified that will sensitize tumor cells in vitro and in vivo to suboptimal treatment temperatures (40-42 0 C) and to sensitize thermotolerant cells and tumors to subsequent heat treatments. Data is presented from the authors' initial in vitro evaluation

Case of acute myelogenous leukemia following aplastic anemia after radiotherapy and chemotherapy for breast cancer

Energy Technology Data Exchange (ETDEWEB)

Takano, Y; Chinen, T; Ogawa, M; Kato, Y; Kitagawa, T [Japanese Foundation for Cancer Research, Tokyo. Hospital

1980-12-01

A 53 years old mastectomized woman for breast cancer treated with radiotherapy (total doses 12,600 rad) and with long term oral administration of cyclophosphamide (CPM) and ftorafur (FT), developed aplastic anemia and thereafter acute myelogenous leukemia. About six months after discontinuation of the above therapies, she developed anemia and leukopenia and was referred to our clinic. Hematological improvement was obtained by the administration of anabolic hormone, however, two months later she became pancytopenic again. At that time, quite atypical myeloblasts contained peroxidase positive granules, were found 39% in the peripheral blood and 89.4% in the bone marrow, respectively. Leukemic hiatus was present. A bone marrow biopsy revealed coexistence of leukemic cells and breast cancer cells. A diagnosis of breast cancer complicated with acute myelogenous leukemia was made. A combined therapy of adriamycin, CPM and FT was ineffective. OAP regimen of vincristine, cytosine arabinoside and predonisolone revealed transient hematologic improvement. Finally, the patient died of septicemia due to klebsiella. Autopsy revealed wide spread coexistence of leukemia and cancer in the bone marrow, liver, and thyroid. The authors discuss some possible explanations for development of acute leukemia after radiotherapy and chemotherapy.

Enhanced killing of mammalian cells by radiation combined with m-AMSA

Energy Technology Data Exchange (ETDEWEB)

Roberts, P B; Millar, B C [Institute of Cancer Research, Sutton (UK). Surrey Branch

1980-11-01

m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30 min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected. m-AMSA increased radiation lethality throughout the cell cycle, but a contribution to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended.

Chemistry and Selective Tumor Cell Growth Inhibitory Activity of Polyketides from the South China Sea Sponge Plakortis sp.

Science.gov (United States)

Li, Jiao; Li, Cui; Riccio, Raffaele; Lauro, Gianluigi; Bifulco, Giuseppe; Li, Tie-Jun; Tang, Hua; Zhuang, Chun-Lin; Ma, Hao; Sun, Peng; Zhang, Wen

2017-05-03

Simplextone E ( 1 ), a new metabolite of polyketide origin, was isolated with eight known analogues ( 2 - 9 ) from the South China Sea sponge Plakortis sp. The relative configuration of the new compound was elucidated by a detailed analysis of the spectroscopic data and quantum mechanical calculation of NMR chemical shifts, aided by the newly reported DP4+ approach. Its absolute configuration was determined by the TDDFT/ECD calculation. Simplextone E ( 1 ) is proven to be one of the isomers of simplextone D. The absolute configuration at C-8 in alkyl chain of plakortone Q ( 2 ) was also assigned based on the NMR calculation. In the preliminary in vitro bioassay, compounds 6 and 7 showed a selective growth inhibitory activity against HCT-116 human colon cancer cells with IC 50 values of 8.3 ± 2.4 and 8.4 ± 2.3 μM, corresponding to that of the positive control, adriamycin (IC 50 4.1 μM). The two compounds also showed selective activities towards MCF-7 human breast cancer and K562 human erythroleukemia cells while compound 3 only displayed weak activity against K562 cells.

Appearance of febrile neutropenia episodes after cytostatic therapy on oncology patients

International Nuclear Information System (INIS)

Lami Casaus, Leonardo; Arbesu Michelena, Maria Antonieta; Sarmiento, Sofia Alsina; Brito Iglesia, Rosario

2009-01-01

Treatment of oncology patient using cytotoxic drugs has the neutropenia and its infectious complications as the commonest dose-limiting toxicity. Its appearance provokes dose delays and reduction during post-chemotherapy cycles, as well as the quality of life deterioration of patients. Oncology Medicine Group including the Pharmacy Service carried out a study to analyze the appearance of febrile neutropenia after cytotoxic therapy administration, and the presence of other factors that may to increase the risk to these reactions. A total of 42 patients were studied admitted with febrile neutropenia after above therapy from February to August, 2007. Biomedical variables from included patient group were achieved and the previously applied cytostatic therapy. The prevalent age-group was those patients aged over 50 and predominance of male sex and advanced stages with associated affections. The more frequent tumor locations were in breast, lung, and non-Hodgkin lymphoma. The cytostatic agent more used in cases of febrile neutropenia was Adriamycin (71.4 %) followed by Cyclophosphamide (52.4 %). The factors more associated with febrile neutropenia appearance were: Anthracycline chemotherapy, age over 50, advanced stages, and presence of associated diseases

Radiation induction of drug resistance in RIF-1: Correlation of tumor and cell culture results

International Nuclear Information System (INIS)

Moulder, J.E.; Hopwood, L.E.; Volk, D.M.; Davies, B.M.

1991-01-01

The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual.We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors

Cell structure and function and response to chemotherapy in tumors heterotransplanted into the subrenal capsule of mice and rats.

Science.gov (United States)

Stenbäck, F; Kangas, L; Wasenius, V M

1985-12-01

Specimens from 16 freshly biopsied human tumors, two mammary adenocarcinomas, ten ovarian adenocarcinomas, two squamous cell carcinomas, one malignant histiocytoma and one chondrosarcoma of the bone, two human ovarian adenocarcinomas established by transplantation into nude mice and two adenocarcinomas induced in rat mammary gland were transplanted under the renal capsule of 510 normal immunocompetent mice and 180 rats and the effects of chemotherapy were evaluated. The results showed successful transplantation of all types of tumors in both animal species. Morphological analysis revealed preserved glandular structures with surface microvilli, mucin and CEA production and partially preserved basement membranes. Treatment with cyclophosphamide, vinblastine, adriamycin and cisplatin caused cell shrinkage, degradation and partial or total disappearance of the tumor cells. Vascularization was distinct in all specimens. A cellular infiltrate was found frequently but not consistently. A common end stage was a fibrotic scar with no cellular activity, occasionally giving a misleading impression of a growing tumor on gross observation. The results were obtained rapidly and suggest that the subrenal capsule assay would be useful for evaluating the sensitivity of human tumors to therapeutic manipulation, but needs supplementary histological examination.

Novel function of N,N-bis(2-chloroethyl)docos-13-enamide for reversal of multidrug resistance in tongue cancer.

Science.gov (United States)

Qin, Qing; Ma, Peng-Fei; Kuang, Xiao-Cong; Gao, Ming-Xing; Mo, De-Huan; Xia, Shuang; Jin, Ning; Xia, Jun-Jie; Qi, Zhong-Quan; Lin, Cui-Wu

2013-12-05

Multidrug resistance (MDR) is a key element in the failure of chemotherapies, and development of agents to overcome MDR is crucial to improving cancer treatments. The overexpression of glutathione-S-transferases (GSTs) is one of the major mechanisms of MDR. Because some agents used in traditional Chinese medicine have strong antitumor effects coupled with low toxicity; we investigated the ability of N,N-bis(2-chloroethyl)docos-13-enamide (compound J), the synthesized analog of a highly unsaturated fatty acid from Isatis tinctoria L., to reverse the MDR induced by adriamycin (ADM) in TCA8113/ADM cells. We found that compound J significantly increased the cytotoxicity of ADM in TCA8113/ADM cells, with a reversal fold of 2.461. Analysis of the mechanisms through which compound J reversed MDR indicated that compound J significantly decreased the activity of GSTs and enhanced the depletion of GSH in TCA8113/ADM cells, but did not affect the P-glycoprotein (P-gp) efflux. Taken together, our data suggested that compound J was an excellent candidate for reversing MDR in cancer therapy. © 2013 Published by Elsevier B.V.

Radiation and chemically induced potentially lethal lesions in noncycling mammalian cells: recovery analysis in terms of x-ray- and ultraviolet-like-systems

International Nuclear Information System (INIS)

Hahn, G.M.

1975-01-01

Recovery from and fixation of potentially lethal damage after exposure of Chinese hamster cells to uv and to x irradiation were investigated, as was recovery after exposure to chemotherapeutic agents. Recovery after uv radiation has a T/sub 1 / 2 / of about 20 hr; the fraction of cells able to undergo recovery depends upon nutritional factors both before and after exposure. After x irradiation, recovery proceeds with a T/sub 1 / 2 / of approximately 2 hr and is much less influenced by nutritional factors. Fixation after serum stimulation has a T/sub 1 / 2 / of 3 to 4 hr in uv-irradiated cells, a T/sub 1 / 2 / of 30 min in x-irradiated cells. Recovery kinetics after nitrogen mustard and bleomycin exposures mimic those for x-ray exposure; after methyl methane sulfonate the kinetics are mainly uv-like, though with an x-ray-like component. Recovery by cells with BUdR-substituted DNA and irradiated with visible light is primarily x-ray-like, though with a uv-like component. There is no recovery by cells exposed to adriamycin or to 1,3-bis(2-chloroethyl)-1-nitrosourea

Response of intestinal cells of differing topographical and hierarchical status to ten cytotoxic drugs and five sources of radiation

Energy Technology Data Exchange (ETDEWEB)

Ijiri, K; Potter, C S [Christie Hospital and Holt Radium Inst., Manchester (UK). Paterson Labs.

1983-02-01

The spatial distribution of cell death among the epithelial cells lining the adult mouse small intestinal mucosa at various times after a range of doses of 10 different drugs as well as after internal or external irradiation (..beta.. particles from tritium, ..gamma..- and X-rays and neutrons) has been recorded. Cell death, expressed as pycnosis or apoptosis, has been recorded for each cell position up the side of the crypts of the small intestine. Adriamycin and the various forms of radiation tend to kill cells preferentially at cell position 4-5 i.e. on cells very early in the lineage, probably stem cells. Isopropyl-methane-sulphonate, nitrogen mustard and possibly Actinomycin-D act on cell position 6-7, while 5-fluorouracil, Myleran, cyclophosphamide, and cycloheximide tend to kill cells at cell position 7-9. Vincristine and hydroxyurea are the 2 agents that exhibit a specificity for cells highest up the crypt, i.e. latest in transit population of the cell lineage by acting on cell positions 10 or 11. The data also suggest that normal healthy cells continue to migrate up the crypt and onto the villus in spite of considerable cell death and reduced cell production.

Optical coherence tomography and computer-aided diagnosis of a murine model of chronic kidney disease

Science.gov (United States)

Wang, Bohan; Wang, Hsing-Wen; Guo, Hengchang; Anderson, Erik; Tang, Qinggong; Wu, Tongtong; Falola, Reuben; Smith, Tikina; Andrews, Peter M.; Chen, Yu

2017-12-01

Chronic kidney disease (CKD) is characterized by a progressive loss of renal function over time. Histopathological analysis of the condition of glomeruli and the proximal convolutional tubules over time can provide valuable insights into the progression of CKD. Optical coherence tomography (OCT) is a technology that can analyze the microscopic structures of a kidney in a nondestructive manner. Recently, we have shown that OCT can provide real-time imaging of kidney microstructures in vivo without administering exogenous contrast agents. A murine model of CKD induced by intravenous Adriamycin (ADR) injection is evaluated by OCT. OCT images of the rat kidneys have been captured every week up to eight weeks. Tubular diameter and hypertrophic tubule population of the kidneys at multiple time points after ADR injection have been evaluated through a fully automated computer-vision system. Results revealed that mean tubular diameter and hypertrophic tubule population increase with time in post-ADR injection period. The results suggest that OCT images of the kidney contain abundant information about kidney histopathology. Fully automated computer-aided diagnosis based on OCT has the potential for clinical evaluation of CKD conditions.

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

Science.gov (United States)

Woolf, N; Pearson, B E; Bondzie, P A; Meyer, R D; Lavaei, M; Belkina, A C; Chitalia, V; Rahimi, N

2017-09-18

Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

Clinical applications of continuous infusion chemotherapy ahd concomitant radiation therapy

International Nuclear Information System (INIS)

Rosenthal, C.J.; Rotman, M.

1986-01-01

This book presents information on the following topics: theoretical basis and clinical applications of 5-FU as a radiosensitizer; treatment of hepatic metastases from gastro intestingal primaries with split course radiation therapy; combined modality therapy with 5-FU, Mitomycin-C and radiation therapy for sqamous cell cancers; treatment of bladder carcinoma with concomitant infusion chemotherapy and irradiation; a treatment of invasiv bladder cancer by the XRT/5FU protocol; concomitant radiation therapy and doxorubicin by continuous infusion in advanced malignancies; cis platin by continuous infusion with concurrent radiation therapy in malignant tumors; combination of radiation with concomitant continuous adriamycin infusion in a patient with partially excised pleomorphic soft tissue sarcoma of the lower extremeity; treatment of recurrent carcinoma of the paranasal sinuses using concomitant infusion cis-platinum and radiation therapy; hepatic artery infusion for hepatic metastases in combination with hepatic resection and hepatic radiation; study of simultaneous radiation therapy, continuous infusion, 5FU and bolus mitomycin-C; cancer of the esophagus; continuous infusion VP-16, bolus cis-platinum and simultaneous radiation therapy as salvage therapy in small cell bronchogenic carcinoma; and concomitant radiation, mitomycin-C and 5-FU infusion in gastro intestinal cancer

Hyaluronan and calcium carbonate hybrid nanoparticles for colorectal cancer chemotherapy

Science.gov (United States)

Bai, Jinghui; Xu, Jian; Zhao, Jian; Zhang, Rui

2017-09-01

A hybrid drug delivery system (DDS) composed of hyaluronan and calcium carbonate (CC) was developed. By taking advantage of the tumor-targeting ability of hyaluronan and the drug-loading property of CC, the well-formed hyaluronan-CC nanoparticles were able to serve as a DDS targeting colorectal cancer with a decent drug loading content, which is beneficial in the chemotherapy of colorectal cancer. In this study, hyaluronan-CC nanoparticles smaller than 100 nm were successfully developed to load the wide-range anti-cancer drug adriamycin (Adr) to construct hyaluronan-CC/Adr nanoparticles. On the other hand, we also found that hyaluronan-CC/Adr nanoparticles can possibly increase the uptake ratio of Adr into HT29 colorectal cancer cells when compared with hyaluronan-free nanoparticles (CC/Adr) via the CD44 receptor-mediated endocytosis via competitive uptake and in vivo imaging assays. Note that both in vitro (CCK-8 assay on HT29 cells) and in vivo (anti-cancer assay on HT-29 tumor-bearing nude mice model) experiments revealed that hyaluronan-CC/Adr nanoparticles exhibited stronger anti-cancer activity than free Adr or CC/Adr nanoparticles with minimized toxic side effects and preferable cancer-suppression potential.

Experimental studies on interactions of radiation and cancer chemotherapeutic drugs in normal tissues and a solid tumour

International Nuclear Information System (INIS)

Maase, H. van der

1986-01-01

The interactions of radiation and seven cancer chemotherapeutic drugs have been investigated in four normal tissues and in a solid C 3 H mouse mammary carcinoma in vivo. The investigated drugs were adriamycin (ADM), bleomycin (BLM), cyclophosphamide (CTX), 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin C (MM-C) and cis-diamminedichloroplatinum(II) (cis-DDP). The drugs enhanced the radiation response in most cases. However, signs of radioprotection was observed for CTX in skin and for MTX in haemopoietic tissue. The interval and the sequence of the two treatment modalities were of utmost importance for the normal tissue reactions. In general, the most serious interactions occurred when drugs were administered simultaneously with or a few hours before radiation. The radiation-modifying effect of the drugs deviated from this pattern in the haemopoietic tissue as the radiation response was most enhanced on drug administration 1-3 days after radiation. Enhancement of the radiation response was generally less pronounced in the tumour model than in the normal tissues. The combined drug-radiation effect was apparently less time-dependent in the tumour than in the normal tissues. (Auth.)

Investigating the pharmacodynamic and magnetic properties of pyrophosphate-bridged coordination complexes

Science.gov (United States)

Ikotun, Oluwatayo (Tayo) F.

The multidentate nature of pyrophosphate makes it an attractive ligand for complexation of metal cations. The participation of pyrophosphate in a variety of biological pathways and its metal catalyzed hydrolysis has driven our investigation into its coordination chemistry. We have successfully synthesized a library of binuclear pyrophosphate bridge coordination complexes. The problem of pyrophosphate hydrolysis to phosphate in the presence of divalent metal ions was overcome by incorporating capping ligands such as 1,10-phenanthroline and 2,2'-bipyridine prior to the addition of the pyrophosphate. The magnetic properties of these complexes was investigated and magneto-structural analysis was conducted. The biological abundance of pyrophosphate and the success of metal based drugs such as cisplatin, prompted our investigation of the cytotoxic properties of M(II) pyrophosphate dimeric complexes (where M(II) is CoII, CuII, and NiII) in adriamycin resistant human ovarian cancer cells. Thess compounds were found to exhibit toxicity in the nanomolar to picomolar range. We conducted in vitro stability studies and the mechanism of cytoxicity was elucidated by performing DNA mobility and binding assays, enzyme inhibition assays, and in vitro oxidative stress studies.

Effects of antineoplastic agents and ionizing irradiation on a human testicular cancer xenograft

International Nuclear Information System (INIS)

Osieka, R.; Pfeiffer, R.; Glatte, P.; Schmidt, C.G.; Bamberg, M.; Scherer, E.

1985-01-01

Chemotherapy has afforded a high percentage of definitive cures in advanced testicular cancer. Nevertheless some patients with large tumor burden still succumb to chemorefractory disease. Therefore preclinical and clinical evaluation of new drugs and agents not primarily used against this type of disease are still mandatory. For preclinical drug screening purposes heterotransplantation of specific human tumors yields a model with high validity for tumor markers and drug response. Heterotransplantation of a human embryonal testicular cancer was used for simultaneous testing of established agents such as cisplatin, melphalan, bleomycin, vinblastine, etoposide and adriamycin and some newer derivatives such as PHM or mafosfamide. Furthermore agents such as procarbazine, dacarbazine and methyl-CCNU that cross the blood-brain-barrier displayed some interesting activity. The results hint at a unique chemosensitivity pattern of the xenograft line, with some accordance between clinical response to vinblastine and bleomycin and good response of the xenografts to bleomycin but not to vinblastine. Radiotherapy was also effective against this tumor line, but there was not much difference in response when the schedule of fractionation was changed. It is concluded that a combined modality approach might salvage patients with residual, chemorefractory disease. (orig.) [de

Radiotherapy, chemotherapy, and growth-hormone deficiency

Energy Technology Data Exchange (ETDEWEB)

Schiliro, G; Russo, A; Sciotto, A; Distefano, G; Vigo, R [Catania Univ. (Italy). 1. and 2. Paediatric Clinics

1976-11-06

Measurements have been made of the growth hormone (GH) responses of nine children with acute lymphoblastic leukaemia to the insulin and arginine tolerance tests. All the patients had received induction treatment with prednisone, vincristine and doxorubicin ('Adriamycin') for 4 weeks followed by 2400 rad of orthovoltage cranial irradiation plus five intrathecal injections of methotrexate. During the study all the children were in complete remission, which had been maintained with 6-mercaptopurine and methotrexate for 4 to 26 months. No pulses of steroids were used in remission. Five patients in early remission did not respond to either stimulation test, three having longer remissions showed a late and low response to the insulin test and the one patient with the longest remission (26 months) had a normal GH response. Heights and bone ages were normal. These results, which suggest the possibility of a gradual recovery after the end of CNS treatment including orthovoltage cranial irradiation, are contrasted with those for megavoltage treatment reported by Shalet et al. (Shalet, S.M., Beardwell, C.G., Morris-Jones, P.H., Pearson, D., Archs. Dis. Childh., 1976, vol. 51, 489).

Late effects after treatment of twenty children with soft tissue sarcomas of the head and neck. Experience at a single institution with a review of the literature

International Nuclear Information System (INIS)

Fromm, M.; Littman, P.; Raney, R.B.; Nelson, L.; Handler, S.; Diamond, G.; Stanley, C.

1986-01-01

Twenty children with soft tissue sarcomas of the head and neck, treated at the Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania from 1972 to 1981, were evaluated for the late deleterious effects of treatment. All patients received radiation therapy and combination chemotherapy with vincristine, dactinomycin, and cyclophosphamide; certain patients also received Adriamycin (doxorubicin). All had ophthalmologic, otologic, growth, and cosmetic evaluations; 15 also had dental and maxillofacial examinations. The median age at diagnosis was 6 years (range, 7 months-13 years). Median follow-up from time of diagnosis was 5.5 years with a minimum of 3 years in all but four patients. The major problems encountered were related to the eyes (xerophthalmia and cataracts), ears (hearing loss), teeth (maleruption and caries), glandular structures (xerostomia, hypopituitarism), and development (craniofacial deformity). It is concluded that children treated for soft tissue sarcomas of the head and neck with combined modality therapy, including radiation enhancers, may show a variety of late treatment-related adversities. These children require close multidisciplinary follow-up for detection of late effects in order that appropriate prophylactic or symptomatic treatment can be instituted to minimize their consequences

Classification of malignant lymphomas

International Nuclear Information System (INIS)

Schneider, M.; Thyss, A.

1986-01-01

Malignant lymphomas, primary tumors of the lymphoid tissues, were first described in 1832 by Thomas Hodgkin. The histological characteristics were later defined by Sternberg and Reed, and Virchow introduced the concept of lymphosarcoma in 1863. Today, these pathologies are grouped together under the synonymous terms hematosarcoma or malignant lymphoma, which are in turn divided into Hodgkin's disease (HD) and non-Hodgkin's malignant lymphomas (NHL). The therapy of lymphomas is controversial. The validity of treatment for asymptomatic patients is questioned, owing to the indolent course of many lymphomas. Results for histologically unfavorable forms are highly disparate. Exclusive radiotherapy has occasionally produced up to 78% disease-free survival at 5 years for truly localized stages. Today, however, use of chemotherapy/radiotherapy combinations is almost universal, with chemotherapy occasionally being used alone and providing 90% disease-free survival at 5 years. Chemotherapy is the main treatment for disseminated forms; the major associations include doxorubicin hydrochloride (Adriamycin), cyclophosphamide, vincristine sulfate, methotrexate, and prednisone. Radiotherapy is used more for adjuvant purposes. Synthesis of recent studies allows us to reasonably expect 40% relapse-free survival at 10 years and the establishment of a cure plateau in the near future

[Antitumor effects of matrix protein of vesicular stomatic virus on EL4 lymphoma mice].

Science.gov (United States)

Lin, Shi-jia; Yu, Qin-mei; Meng, Wen-tong; Wen, Yan-jun; Chen, Li-juan; Niu, Ting

2011-03-01

To explore antitumor effects of plasmid pcDNA3. 1-MP encoding matrix protein of vesicular stomatitis virus (VSV) complexed with cationic liposome (DOTAP:CHOL) in mice with EL4 lymphoma. C57BL/6 mouse model with EL4 lymphoma was established. Sixty mice bearing EL4 lymphoma were divided randomly into five groups including Lip-MP, Lip-pVAX, Lip, ADM and NS groups, which were intravenously injected with liposome-pcDNA 3. 1-MP complex, liposome-pVAX complex, empty liposome, Adriamycin and normal saline respectively every three days. Tumor volumes and survival time were monitored. Microvessel density and tumor proliferative index in tumor tissues were determined by CD31, Ki-67 immunohistochemistry staining, meanwhile the tumor apoptosis index was measured by TUNEL method. From 6 days after treatments on, the tumor volume in Lip-MP group was much smaller than that in Lip-pVAX, Lip and NS group (P EL4 tumor cells in vivo (P EL4 lymphoma, which may be related to the induction of tumor cell apoptosis, inhibition of tumor angiogenesis, and suppression of tumor cell proliferation.

Sodium intake modifies the negative prognostic value of renal damage prior to treatment with ACE inhibitors on proteinuria induced by adriamycin

NARCIS (Netherlands)

Kramer, Andrea B.; Bos, Hendrik; van Goor, Harry; Navis, Gerjan J.

2006-01-01

Background: Antiproteinuric treatment by ACE inhibition (ACEi) provides renoprotection. However, resistance to antiproteinuric intervention occurs frequently, resulting in progressive renal damage. The extent of renal damage prior to treatment with ACEi reversely correlates with the antiproteinuric

Current status, opportunities and problems in clinical combined chemoradiotherapy

International Nuclear Information System (INIS)

Phillips, T.L.

1979-01-01

The clinical experience with combined radiation and chemotherapy has been positive in a number of situations. The enhanced local tumor control and patient cure due to the sterilization of distant metastases have been observed. More widespread clinical applications have been limited by the enhanced effects in normal tissues, necessitating radiation dose reduction which in some situations may be counterproductive. The limitations have been caused by the lack of a wide range of active anti-tumor compounds, particularly for most common solid tumors. The very active combinations of cyclophosphamide and adriamycin or cyclophosphamide and cis-Pt, as well as of the 3 agents, caused the response of a number of the solid tumors previously found to be drug resistant. The introduction of these compounds and a number of others active in slowly proliferating solid tumors will allow new look for improved survival in the tumors not yet amenable to combined radiation and chemotherapy. The experiments designed to elucidate the nature of the interaction of radiation and chemotherapy and in particular the nature of normal tissue response should allow for the safer employment of 2 modalities and should help in the design of prospective clinical trials on a more rational basis. (Yamashita, S.)

Preformulation Studies on Piperlongumine.

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Alhassan Aodah

Full Text Available Piperlongumine is a natural alkaloid extracted from piper plants which has been used traditionally for the treatment of certain diseases. This compound shows interesting in vitro pharmacological activity such as selective anticancer activity and higher cytotoxicity than methotrexate, cyclophosphamide and adriamycin on breast, colon, and osteosarcoma cancers, respectively. However, the physicochemical properties for this compound have not been well characterized. In this research, preformulation studies for piperlongumine have been performed to determine factors which influence solubility and stability which, in turn, can be used to assist future formulation development. The solubility of piperlongumine in water was found to be approximately 26 μg/ml. Using 10% polysorbate 80 as a surfactant resulted in a 27 fold increase in solubility. Cosolvents and cyclodextrins afforded concentrations of 1 mg/ml and higher. The pH degradation rate profile for piperlongumine at various temperatures shows significant instability of the drug at pH values ≥ 7 and 3, and maximum stability around pH 4. It was estimated that it would take approximately 17 weeks for piperlongumine to degrade by 10% at 25°C, pH 4. Additionally, piperlongumine showed marked photo-degradation upon exposure to an ultraviolet light source, especially in aqueous media.

In Silico Screening, Synthesis and In Vitro Evaluation of Some Quinazolinone and Pyridine Derivatives as Dihydrofolate Reductase Inhibitors for Anticancer Activity

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A. G. Nerkar

2009-01-01

Full Text Available Dihydrofolate reductase (DHFR is the important target for anticancer drugs belonging to the class of antimetabolites as the enzyme plays important role in the de novo purine synthesis. We here report the in silico screening to obtain best fit molecules as DHFR inhibitors, synthesis of some ʻbest fitʼ quinazolinone from 2-phenyl-3-(substituted-benzilidine-amino quinazolinones (Quinazolinone Shiff's bases QSB1-5 and pyridine-4-carbohydrazide Shiff's bases (ISB1-5 derivatives and their in vitro anticancer assay. Synthesis of the molecules was performed using microwave assisted synthesis. The structures of these molecules were elucidated by IR and 1H-NMR. These compounds were then subjected for in vitro anticancer evaluation against five human cancer cell-lines for anticancer cyto-toxicity assay. Methotrexate (MTX was used as standard for this evaluation to give a comparable inhibition of the cell proliferation by DHFR inhibition. Placlitaxel, adriamycin and 5-fluoro-uracil were also used as standard to give a comparable activity of these compounds with other mechanism of anticancer activity. ISB3 (4-(N, N-dimethyl-amino-phenyl Schiff''s base derivative of pyridine carbohydrazide showed equipotent activity with the standards used in in vitro anticancer assay as per the NCI (National Cancer Institute guidelines.

Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma

International Nuclear Information System (INIS)

Barrington, Sally F.; Somer, Edward J.; O'Doherty, Michael J.; Qian, Wendi; Franceschetto, Antonella; Bagni, Bruno; Brun, Eva; Almquist, Helen; Loft, Annika; Hoejgaard, Liselotte; Federico, Massimo; Gallamini, Andrea; Smith, Paul; Johnson, Peter; Radford, John

2010-01-01

To determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between 'core' laboratories operating in different countries. Four centres reported scans from 50 patients with stage II-IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using 'normal' mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading). There was agreement that the response scan was 'positive' or 'negative' for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74-0.96) for conservative reading and 0.79 (95% CI 0.67-0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively. The criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting. (orig.)

Quantitative evaluation of thallium-201 uptake in predicting chemotherapeutic response of osteosarcoma

International Nuclear Information System (INIS)

Lin, J.; Leung Waitong; Ho, S.K.W.; Ho, K.C.; Kumta, S.M.; Metreweli, C.; Johnson, P.J.

1995-01-01

This study attempts to quantitate changes in tumour to normal tissue ratio following chemotherapy. Eight consecutive patients with classical osteosarcoma received standard preoperative chemotherapy with a combination of cisplatin, adriamycin and high-dose methotrexate. 201 Tl gamma scintigraphic images were obtained both before and after chemotherapy. The average counts taken over the tumour divided by that from the contralateral normal tissue area yielded a tumour-to-normal tissue (T/N) ratio. The percentage change in the T/N ratio before and after preoperative chemotherapy was correlated with the percentage of tumour necrosis from pathological section. The median post-chemotherapy T/N ratio was 1.85 (range 0.5-7.7). The median percentage change in T/N ratio after chemotherapy was -58% (range +26% to -83%). The median percentage of necrosis from pathological section was 80% (range 0%-95%). There was a good correlation between the percentage of tumour necrosis and the percentage change in T/N ratio (rank correlation coefficient r=0.84, P=0.0085). Quantitative assessment of changes in 201 Tl uptake by osteosarcoma correlates well with tumour necrosis after preoperative chemotherapy. This method may be used to predict response to chemotherapy at an earlier stage, enabling the clinician to consider alternative chemotherapeutic regimens or salvage surgery. (orig.)

Intra-arterial chemotherapy combined with irradiation for invasive bladder cancer

International Nuclear Information System (INIS)

Fujimoto, Naohiro; Sato, Hideki; Harada, Shuji; Matsumoto, Tetsuro; Ikuyama, Toshihiro

2004-01-01

Total cystectomy and urinary diversion are the standard treatments for invasive bladder cancer. However, total cystectomy is not possible in some patients due to advanced age, a poor general condition, or refusal to undergo cystectomy. In such cases, intra-arterial chemotherapy (IAC) and/or radiotherapy are the alternative treatments. We performed IAC with cisplatin and adriamycin in 9 patients with invasive bladder cancer and obtained complete response (CR) in 5 out of the 9 patients (55.6%). However, 3 of these 5 CR patients developed local recurrence within 1 year. In an effort to improve the efficacy, we performed combination therapy comprising IAC plus radiotherapy in 12 patients with invasive bladder cancer. CR was obtained in 58.3% and the bladder was preserved in 91.7% with this combination therapy. However, distant metastases developed in 33.3% after the combined treatment of IAC plus radiation therapy. These findings suggest that the combination of radiotherapy and IAC is useful for local control of invasive bladder cancer. Data from more cases and results from a longer follow-up are needed to fully confirm the efficacy of this type of treatment. In addition, therapeutic modalities to prevent distant metastasis need to be considered. (author)

Technetium-99m sestamibi uptake in human breast carcinoma cell lines displaying glutathione-associated drug-resistance

International Nuclear Information System (INIS)

Kabasakal, L.; Oezker, K.; Hayward, M.; Akansel, G.; Griffith, O.; Isitman, A.T.; Hellman, R.; Collier, D.

1996-01-01

An in vitro study was designed to evaluate the uptake of sestamibi (MIBI) in P-glycoprotein (Pgp) and glutathione-associated (GSH) multidrug-resistant (MDR) cell lines. MIBI uptake was studied in various human breast carcinoma cell lines, i.e. in wild-type (MCF7/wt) cells, in adriamycin-resistant (MCF7/adr) cells which express Pgp and in melphalan-resistant (MCF7/mph) cells with increased levels of GSH. The effects of buthiomine sulphoximine (BSO) and verapamil on MIBI uptake were also studied in the MCF7/mph and MCF7/adr cells respectively. The cells were incubated for 1 h with a dose of 0.1 MBq thallium-201 and technetium-99m MIBI. Both BIBI and 201 Tl uptakes were higher for MCF7/mph cells than for the other cells studied. The mean MIBI uptake in MCF7/adr cells was significantly lower than that in MCF7/wt cells (1.9%±0.5% vs 3.1%.0.6%; P 0.1). This study suggests that the uptake of MIBI is not diminished by glutathione-associated drug resistance and that MIBI uptake in a tumour sample does not necessarly indicate that a cancer is sensitive to drugs. (orig.)

Semiconservative and unscheduled DNA-synthesis of rat thymocytes under the influence of some radioprotecting and radiosensitizing agents

Energy Technology Data Exchange (ETDEWEB)

Tempel, K.; Wulffius-Kock, M.; Winkle, J.; Schmerold, I.

1982-02-01

The effects of aminoethylisothiuroniumbromide (AET), cysteamine (CY-A), cysteine (CY-E), glutathione (GLU), mercaptoethanol (MA), mercaptopropionylglycine (MPG), N-ethylmaleimide (NEM), metronidazole (MNA), nitroacetophenone (NAP), nitrofurazone (NFA), arabinofuranosylcytosine (araC), fluorouracil (FU), adriamycin (AM), ethidiumbromide (E), bleomycin (BM), and diethyldithiocarbamate (DDC) on the semiconservative and unscheduled incorporation of /sup 3/H-thymidine into the DNA were tested on rat thymocytes in vitro. DNA damage has been measured using the hydroxylapatite system. Unscheduled DNA synthesis was induced by UV-light and/or X-irradiation. The semiconservative DNA synthesis was inhibited by the above substances-with exception of MA and MPG. Aminothioles, NAP, NFA, and BM enhanced, araC, FU, AM, E, and DDC diminished unscheduled DNA synthesis. After alkaline unwinding, the duplex form of DNA decreased under the influence of CY-A, CY-E, GLU, MPG, NEM, NAP, NFA, araC, FU, AM, E, and BM. It is suggested that stimulation of unscheduled DNA synthesis combined with a transient decrease of semiconservative DNA synthesis will amplify the DNA repair capacity of thymocytes, whereas radiation damage may be intensified by araC, FU, AM,E, and DDC - at least partly, through inhibition of unscheduled DNA synthesis. With respect to the action of NAP, NFA, and BM, DNA repair may be concerned in a more indirect manner.

Effects of cancer, radiotherapy and cytotoxic drugs on intestinal structure and function

Energy Technology Data Exchange (ETDEWEB)

Shaw, M T; Spector, M H; Ladman, A J [New Mexico Univ., Albuquerque (USA)

1979-09-01

Intestinal malabsorption and the structural changes in the small intestine in relation to cancer, radiotherapy and cytotoxic drugs are reviewed. Primary intestinal malignancies are often associated with malabsorption; further studies have shown that tumours outside the gastrointestinal tract may also be accompanied by changes in intestinal structure resulting in malabsorption. Abdominal radiotherapy of cancer patients has been shown to result in ultrastructural changes in the small intestine, a decrease in intestinal enzyme activity and malabsorption of nutrients. The effects of cytotoxic drugs on the small intestinal structure and function are reviewed in more detail. The drugs discussed include the alkylating agents such as nitrogen mustard, cyclophosphamide, iphosphamide, 1,3-bis (2-chloroethyl)-1-nitrosourea and 1(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea. The effects of antimetabolites such as aminopterin, methotrexate, 5-fluoracil, cytosine arabinoside and 6-mercaptorpurine are also reviewed. Other drugs discussed were adriamycin, vincrinstine sulfate, vinblastine and hydroxyurea. Studies of the effects of combination chemotherapy on small intestinal structure and function are also described. It is concluded that chemotherapeutic drugs and radiation therapy may aggravate a malabsorptive state in view of their toxicity to the small intestinal cell, or may by themselves be responsible for malabsorption with resultant increase in cachexia and weight loss.

Effects of cancer, radiotherapy and cytotoxic drugs on intestinal structure and function

International Nuclear Information System (INIS)

Shaw, M.T.; Spector, M.H.; Ladman, A.J.

1979-01-01

Intestinal malabsorption and the structural changes in the small intestine in relation to cancer, radiotherapy and cytotoxic drugs are reviewed. Primary intestinal malignancies are often associated with malabsorption; further studies have shown that tumours outside the gastrointestinal tract may also be accompanied by changes in intestinal structure resulting in malabsorption. Abdominal radiotherapy of cancer patients has been shown to result in ultrastructural changes in the small intestine, a decrease in intestinal enzyme activity and malabsorption of nutrients. The effects of cytotoxic drugs on the small intestinal structure and function are reviewed in more detail. The drugs discussed include the alkylating agents such as nitrogen mustard, cyclophosphamide, iphosphamide, 1,3-bis (2-chloroethyl)-1-nitrosourea and 1(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea. The effects of antimetabolites such as aminopterin, methotrexate, 5-fluoracil, cytosine arabinoside and 6-mercaptorpurine are also reviewed. Other drugs discussed were adriamycin, vincrinstine sulfate, vinblastine and hydroxyurea. Studies of the effects of combination chemotherapy on small intestinal structure and function are also described. It is concluded that chemotherapeutic drugs and radiation therapy may aggravate a malabsorptive state in view of their toxicity to the small intestinal cell, or may by themselves be responsible for malabsorption with resultant increase in cachexia and weight loss. (UK)

Semiconservative and unscheduled DNA-synthesis of rat thymocytes under the influence of some radioprotecting and radiosensitizing agents

International Nuclear Information System (INIS)

Tempel, K.; Wulffius-Kock, M.; Winkle, J.; Schmerold, I.

1982-01-01

The effects of aminoethylisothiuroniumbromide (AET), cysteamine (CY-A), cysteine (CY-E), glutathione (GLU), mercaptoethanol (MA), mercaptopropionylglycine (MPG), N-ethylmaleimide (NEM), metronidazole (MNA), nitroacetophenone (NAP), nitrofurazone (NFA), arabinofuranosylcytosine (araC), fluorouracil (FU), adriamycin (AM), ethidiumbromide (E), bleomycin (BM), and diethyldithiocarbamate (DDC) on the semiconservative and unscheduled incorporation of 3 H-thymidine into the DNA were tested on rat thymocytes in vitro. DNA damage has been measured using the hydroxylapatite system. Unscheduled DNA synthesis was induced by UV-light and/or X-irradiation. The semiconservative DNA synthesis was inhibited by the above subtrances-with exception of MA and MPG. Aminothioles, NAP, NFA, and BM enhanced, araC, FU, AM, E, and DDC diminished unscheduled DNA synthesis. After alkaline unwinding, the duplex form of DNA decreased under the influence of CY-A, CY-E, GLU, MPG, NEM, NAP, NFA, araC, FU, AM, E, and BM. It is suggested that stimulation of unscheduled DNA synthesis combined with a transient decrease of semiconservative DNA synthesis will amplify the DNA repair capacity of thymocytes, whereas radiation damage may be intensified by araC, FU, AM,E, and DDC - at least partly, through inhibition of unscheduled DNA synthesis. With respect to the action of NAP, NFA, and BM, DNA repair may be concerned in a more indirect manner. (orig.) [de

Diffuse large B-cell lymphoma chemotherapy reveals a combined immunodeficiency syndrome in cartilage hair hypoplasia.

Science.gov (United States)

Nguyen, Alexandre; Martin Silva, Nicolas; de Boysson, Hubert; Damaj, Gandhi; Aouba, Achille

2018-04-24

Cartilage hair hypoplasia (CHH) is a rare autosomal recessive ribosomopathy characterised by skeletal and integumentary system manifestations. It may also present with varied forms and intensities of haematopoietic and/or immune disorders. We report a 27-year-old female who presented a picture of combined immunodeficiency after receiving an adriamycin-based chemotherapy regimen followed by autologous stem cell transplantation. Her medical history indicated neonatal dwarfism, recurrent ear, nose and throat and respiratory infections, and hypogammaglobulinaemia, which were suggestive of a primary minor B-cell immune deficiency. Taken together, the diagnosis of cartilage hair hypoplasia was suspected and confirmed by means of molecular biological analysis. Here, we discuss the causal relationship and molecular mechanisms existing between both primary immunodeficiency and lymphoma conditions and between chemotherapy cytotoxicity and aggravation of the immune system and associated hematopoietic dysfunction, considering the role of all these components in light of the initially undiagnosed cartilage hair hypoplasia. Finally, this case highlights the importance of screening for primary immunodeficiencies in the setting of a diagnosis of lymphoma and/or dwarfism; moreover, CHH must be distinguished from other causes of small size; its diagnosis and complete check-up must include the molecular characterisation, and its management must be global in collaboration with haematologists, immunologists and internists.

Interventional radiology in the cancer patient

International Nuclear Information System (INIS)

Wallace, S.; Charnsangavej, C.

1987-01-01

The contributions of the interventional radiologist in the diagnosis and management of the cancer patient include angiography and intraarterial CT-angiography, intraarterial infusion therapy, embolization, chemoembolization, biopsy and drainage procedures, central venous catheter reposition and retrieval, and stent dilation of stenotic tubular structures in the following organ systems: (1) Kidney. Arterial embolization, therapeutic delay, enphrectomy, and medroxyprogesterone yield a response rate of 28% in patients with renal cell carcinoma and pulmonary parenchymal metastases. (2) Liver. The carcinoid syndrome secondary to hepatic metastases can be controlled by embolization in 87% of patients. Islet cell carcinoma of the pancreas with hepatic metastases is successfully managed in 75% of patients. Chemoembolization (Ivalon and cisplatin) has been effective in 60% of patients with hepatic metastases from ocular melanoma. (3) Bone. A 73% 3-year survival rate is now possible with the inraarterial infusion of cisplatin, while Adriamycin is given intravenously in patients with osteosarcoma. Limb salvage is now possible in 80% of cases. Cancers of the vulva, vagina, urethra, and penis have been successfully treated with intraarterial infusion of chemotherapy followed by radiation therapy. (5) An expansile metallic stent is available to alleviate obstructions of the vena cava, the aorta and its major branches, the tracheobronchial tree, and the common duct. These techniques are demonstrated and results discussed

Total Body Irradiation for Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia

Energy Technology Data Exchange (ETDEWEB)

Chung, Su Mi; Choi, Ihl Bohng; Kang, Ki Mun; Kim, In Ah; Shinn, Kyung Sub; Kim, Choon Choo; Kim, Dong Jip [Catholic University College of Medicine, Seoul (Korea, Republic of)

1994-06-15

Between July 1987 and December 1992, we treated 22 patients with chromic myelogenous leukemia; 14 in the chronic phase and 8 with more advanced disease. All were received with allogeneic bone marrow transplantation from HLA-identical sibling donors after a total body irradiation (TBI) cyclophosphamide conditioning regimen. Patients were non-randomly assigned to either 1200 cGy/6 fractions/3 days (6 patients) or 1320 cGy/8 fractions/4 days (16 patients) by dose of TBI. Of the 22 patients, 8 were prepared with cyclophosphamide alone, 14 were conditioned with additional adriamycin or daunorubicin. To prevent graft versus host disease, cyclosporine was given either alone or in conjunction with methotrexate. The actuarial survival and leukemic-free survival at four years were 58.5% and 41.2%, respectively, and the relapse rate was 36% among 22 patients. There was a statistically significant difference in survival between the patients in chronic phase and more advanced phase (76% vs 33%, p=0.05). The relapse rate of patients receiving splenectomy was higher than that of patients receiving splenic irradiation (50% vs 0%, p=0.04). We conclude that the probability of cure is highest if transplantation is performed while the patient remains in the chronic phase.

Total Body Irradiation for Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia

International Nuclear Information System (INIS)

Chung, Su Mi; Choi, Ihl Bohng; Kang, Ki Mun; Kim, In Ah; Shinn, Kyung Sub; Kim, Choon Choo; Kim, Dong Jip

1994-01-01

Between July 1987 and December 1992, we treated 22 patients with chromic myelogenous leukemia; 14 in the chronic phase and 8 with more advanced disease. All were received with allogeneic bone marrow transplantation from HLA-identical sibling donors after a total body irradiation (TBI) cyclophosphamide conditioning regimen. Patients were non-randomly assigned to either 1200 cGy/6 fractions/3 days (6 patients) or 1320 cGy/8 fractions/4 days (16 patients) by dose of TBI. Of the 22 patients, 8 were prepared with cyclophosphamide alone, 14 were conditioned with additional adriamycin or daunorubicin. To prevent graft versus host disease, cyclosporine was given either alone or in conjunction with methotrexate. The actuarial survival and leukemic-free survival at four years were 58.5% and 41.2%, respectively, and the relapse rate was 36% among 22 patients. There was a statistically significant difference in survival between the patients in chronic phase and more advanced phase (76% vs 33%, p=0.05). The relapse rate of patients receiving splenectomy was higher than that of patients receiving splenic irradiation (50% vs 0%, p=0.04). We conclude that the probability of cure is highest if transplantation is performed while the patient remains in the chronic phase

Effect of sulfhydryls on potentiation of radiation-induced cell lethality by substituted anthraquinones

International Nuclear Information System (INIS)

Kimler, B.F.

1984-01-01

The effects of various substituted anthraquinones (SAQ's) and Adriamycin (ADR) were investigated in cultured Chinese hamster V79 cells. These drugs cause a potentiation of radiation-induced cell lethality, albeit by different mechanisms. One possibility is that these components operate through the production of free radicals which then produce DNA strand breaks and crosslinks. If so, then one should be able to change the degree of cell kill by modifying sulfhydryl (SH) levels such that free radical processes are altered. Diamide, buthionine-S, R-sulfoximine, and N-ethylmaleimide (NEM) were used to reduce intracellular SH levels. Cysteamine and dithiotheitol were used to increase SH levels. In general, altered SH levels did not affect SAQ-induced cytotoxicity at low drug concentrations. When drug-tested cells were also irradiated, survival levels were generally those predicted from assuming purely additive interactions. On the other hand, survival after treatment with high concentrations of ADR and one other SAQ were decreased by concomitant treatment with NEM. Since altered SH levels do not produce changes in the potentiation of radiation-induced cell lethality by SAQs, it is concluded that free radicals are not involved in this potentiation. A free radical-mediated process may be involved in the cytotoxicity induced by ADR and other SAQs; however, it is not a simple process

[Nephroblastoma and xeroderma pigmentosum: A rare association].

Science.gov (United States)

Lahlimi, F; Harif, M; Elhoudzi, J

2016-01-01

Xeroderma pigmentosum (XP) is a rare, genetically heterogeneous, autosomal recessive disorder, more common in cases of consanguinity. The basic defect underlying the clinical manifestations is a nucleotide excision repair defect leading to the defective repair of DNA damaged by ultraviolet (UV) radiation. XP is characterized by a high incidence of skin cancer on exposed regions. We report the case of a 5-year-old boy, followed for xeroderma pigmentosum since the age of 4 years. His sister also has the same anomaly. He presented an abdominal mass revealed by abdominal pain and vomiting. Radiological examinations revealed a nephroblastoma with lung metastases. He received primary chemotherapy for six cycles (vincristine, and actinomycin-d adriamycin), then surgery with ureteronephrectomy. Pathological examination of the nephrectomy specimen confirmed the diagnosis of Wilms tumor with a diffuse anaplastic component reaching 50%. The patient was treated according to the GFAOP stage III protocol, with high histological risk. The outcome was favorable but complicated by renal failure due to the toxicity of the treatment. He is currently in complete remission at 1 year from the end of treatment. The association of xeroderma pigmentosum and nephroblastoma is a rare combination. This case illustrates the problem of management of both severe and difficult conditions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Enhancement of tumor radioresponse by combined chemotherapy in murine hepatocarcinoma

International Nuclear Information System (INIS)

Seong, Jin Sil; Kim, Sung Hee; Suh, Chang Ok

2000-01-01

The purpose of this study was to identify drugs that can enhance radioresponse of murine hepatocarcinoma. C3H/HeJ mice bearing 8 mm tumors of murine hepatocarcinoma, HCa-l, were treated with 25 Gy radiation and one of the following drugs: 5-Fu, 150 mg/kg; adriamycin, 8 mg/kg; cisplatin, 6 mg/kg; paclitaxel, 40 mg/kg; and gemcitabine, 50 mg/kg. Tumor response to the treatment was determined by tumor growth delay assay and by enhancement factor. Apoptotic level was assessed in tissue sections. Expression of regulating molecules was analyzed by western blotting for p53, 8c1-2, Sax, Bel-XL, Bd-XS, and p21 WAF1/CIP1 . Among the drugs tested, only gemcitabine enhanced the antitumor effect of radiation, with enhancement factor of 1.6. Induction of apoptosis by a combination of gerncitabine and radiation was shown as only additive level. In analysis of radiation-induced expression of regulating molecules, the most significant change by combining gemcitabine was activation of p21 WAF1/CIP1 . Gemcitabine is the first drug showing an enhancement of radioresponse in murine hepatocarcinoma, when combined with radiation. The key element of enhancement is thought to be p21 WAF1/CIP1

Enhancement of tumor radioresponse by combined chemotherapy in murine hepatocarcinoma

Energy Technology Data Exchange (ETDEWEB)

Seong, Jin Sil; Kim, Sung Hee; Suh, Chang Ok [College of Medicine, Yonsei Univ., Seoul (Korea, Republic of)

2000-12-01

The purpose of this study was to identify drugs that can enhance radioresponse of murine hepatocarcinoma. C3H/HeJ mice bearing 8 mm tumors of murine hepatocarcinoma, HCa-l, were treated with 25 Gy radiation and one of the following drugs: 5-Fu, 150 mg/kg; adriamycin, 8 mg/kg; cisplatin, 6 mg/kg; paclitaxel, 40 mg/kg; and gemcitabine, 50 mg/kg. Tumor response to the treatment was determined by tumor growth delay assay and by enhancement factor. Apoptotic level was assessed in tissue sections. Expression of regulating molecules was analyzed by western blotting for p53, 8c1-2, Sax, Bel-XL, Bd-XS, and p21{sup WAF1/CIP1}. Among the drugs tested, only gemcitabine enhanced the antitumor effect of radiation, with enhancement factor of 1.6. Induction of apoptosis by a combination of gerncitabine and radiation was shown as only additive level. In analysis of radiation-induced expression of regulating molecules, the most significant change by combining gemcitabine was activation of p21 {sup WAF1/CIP1}. Gemcitabine is the first drug showing an enhancement of radioresponse in murine hepatocarcinoma, when combined with radiation. The key element of enhancement is thought to be p21{sup WAF1/CIP1}.

Second malignancies after treatment for Ewing's sarcoma: a report of the CESS-studies

International Nuclear Information System (INIS)

Dunst, Juergen; Ahrens, Susanne; Paulussen, Michael; Ruebe, Christian; Winkelmann, Wilfried; Zoubek, Andreas; Harms, Dieter; Juergens, Herbert

1998-01-01

Purpose: During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewing's sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewing's Sarcoma Studies CESS 81 and CESS 86. Materials and Methods: From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewing's sarcoma trials CESS 81 (recruitment period 1981-1985) and CESS 86 (1986-1991). The systemic treatment in both studies consisted of a four-drug-regimen (VACA = vincristine, actinomycin D, cyclophosphamide, and adriamycin; or VAIA = vincristine, actinomycin D, ifosfamide, and adriamycin) and a total number of four courses, each lasting nine weeks, was recommended by the protocol. Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36-46Gy (n 274), or definitive radiotherapy with 46-60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years. Results: The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17-78 months for the four AMLs, 96 months for the MDS and 82-136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but

Diagnóstico pouco usual de obstrução da traqueia Unusual diagnosis of traqueal obstrution

Directory of Open Access Journals (Sweden)

C Damas

2006-05-01

Full Text Available Homem, 54 anos, caucasiano e fumador, que recorreu ao serviço de urgência por apresentar tosse produtiva e expectoração hemoptóica desde há cerca de dois meses, motivo porque foi agendada broncofibroscopia. Apresentava neoformações sésseis, cerca de 2 cm abaixo das cordas vocais e ao longo da vertente póstero-lateral do terço médio da traqueia, que condicionavam obstrução significativa, motivo pelo qual foi realizada broncoscopia rígida para colocação de prótese endo-traqueal. Dada a instabilidade clínica e grande suspeição de malignidade o doente inicia radioterapia. O diagnóstico obtido foi de linfoma anaplásico de células grandes, CD 30+. Por insuficiência respiratória, com estridor, foi necessário retirar a prótese que se encontrava obstruída por um rolhão de secreções, ficando a traqueia patente. O doente teve alta, estando actualmente estabilizado do ponto de vista respiratório e submetido a quimioterapia com CHOP (Ciclophosphamide, Adriamycin or Hydroxydorubicin, Vincristine or Oncovin and Prednisone. O linfoma de grandes células primário do mediastino corresponde a 11.5% dos linfomas de grandes células (2% dos linfomas não Hodgkin. Apesar da maioria dos estudos o classificarem como incurável, há registos de resultados positivos com o recurso à irradiação mediastínica combinada com quimioterapia podendo, quando existe compromisso da via aérea, a colocação de uma prótese permitir a patência da mesma.Male, 54 years old, with smoking habits. The patient complaints were cough, with bleeding secretions in the previous two months. Because of the persistence of the symptoms, a broncoscopy was proposed. This exam showed multiple lesions in the traquea, nearly 2 cm above the vocal cords that compromised the airway and did not allow the progression of the bronchoscope. For this reason, it was decided to introduce a tracheal prosthesis. Because of instability and the suspicion of malignancy we started

In vitro and in vivo reversal of cancer cell multidrug resistance by the semi-synthetic antibiotic tiamulin.

Science.gov (United States)

Baggetto, L G; Dong, M; Bernaud, J; Espinosa, L; Rigal, D; Bonvallet, R; Marthinet, E

1998-11-01

A large number of multidrug resistance (MDR) modulators, termed chemosensitizers, have been identified from a variety of chemicals, but most have been proven to be clinically toxic. Low concentrations of the pleuromutilin-derived semi-synthetic antibiotic tiamulin (0.1 to 10 microM) sensitized the three highly resistant P-glycoprotein (Pgp)-overexpressing tumor cell lines P388 (murine lymphoid leukemia), AS30-D (rat hepatoma), CEM (human lymphoblastic leukemia), and the barely resistant AS30-D/S cell lines to several MDR-related anticancer drugs. Flow cytometric analysis showed that tiamulin significantly increased the intracellular accumulation of daunomycin. When compared to reference modulating agents such as verapamil and cyclosporin A, tiamulin proved to be 1.1 to 8.3 times more efficient in sensitizing the resistant cell lines. Moreover, when given i.p. (1.6 microg/mg body weight), tiamulin increased the survival rate of adriamycin-treated mice bearing the P388/ADR25 tumor line by 29%. In the presence of an anticancer drug, tiamulin inhibited both ATPase and drug transport activities of Pgp in plasma membranes from tumor cells. Tiamulin is thus a potent chemosensitizer that antagonizes the Pgp-mediated chemoresistance in many tumor cell lines expressing the MDR phenotype at different levels and displays no toxic effects on contractile tissues at active doses, therefore providing the promise for potential clinical applications.

3-Aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione for circumvention of anticancer drug resistance.

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Shchekotikhin, Andrey E; Shtil, Alexander A; Luzikov, Yuri N; Bobrysheva, Tatyana V; Buyanov, Vladimir N; Preobrazhenskaya, Maria N

2005-03-15

A series of 3-aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione was synthesized by Mannich reaction or by the transamination of 3-dimethylaminomethyl 4,11-dihydroxy- or 4,11-dimethoxynaphtho[2,3-f]indole-5,10-dione. The potency of novel derivatives was tested on a National Cancer Institute panel of 60 human tumor cell lines as well as in cells with genetically defined determinants of cytotoxic drug resistance, P-glycoprotein (Pgp) expression, and p53 inactivation. Mannich derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione with an additional amino function in their side chain, demonstrated equal cytotoxicity against the parental K562 leukemia cells and their Pgp-positive subline, whereas the latter showed approximately 7-fold resistance to adriamycin, a Pgp transported drug. 3-(1-Piperazinyl)methyl and 3-(quinuclidin-3-yl)aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione killed HCT116 colon carcinoma cells (carrying wild type p53) and their p53-null variant within the similar range of concentrations. We conclude that Mannich modification of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione, especially when cyclic diamine (e.g., piperazine, quinuclidine) is used, confers an important feature to the resulting compounds, namely, the potency for tumor cells otherwise resistant to a variety of anticancer drugs.

Second acute leukemia and other malignancies following treatment for Hodgkin's disease

International Nuclear Information System (INIS)

Valagussa, P.; Santoro, A.; Fossati-Bellani, F.; Banfi, A.; Bonadonna, G.

1986-01-01

The records of 1329 patients with Hodgkin's disease admitted from 1965 to 1982 were analyzed to assess the relative frequency of second neoplasms. Within a median follow-up of 9.5 years, a total of 68 new cancers were documented. Nineteen cases of acute nonlymphocytic leukemia, 6 cases of non-Hodgkin's lymphomas, and 43 cases with different types of solid tumors were identified. The overall risk of non-Hodgkin's lymphoma was 1.3% +/- 0.6% and of solid tumors was 8.3% +/- 1.5% when basal cell carcinomas were included and 6.7% +/- 1.4% when basal cell carcinomas were excluded. No cases of leukemia were documented in patients treated with radiation therapy only. The 12-year estimate of leukemia by treatment was as follows: chemotherapy only 1.4% +/- 2.3%; radiation plus MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) 10.2% +/- 5.2%; radiation plus ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) 0; and radiation plus other drug regimens 4.8% +/- 1.6%. The risk of leukemia was particularly high (15.5% +/- 7.4%) in patients who received salvage MOPP after radiation failure. A positive association was also noted between increasing age and risk of second malignancies, especially leukemia. The incidence of second neoplasms can be markedly decreased by deleting from potentially curative therapy certain drugs such as alkylating agents, procarbazine, and nitrosourea derivatives

Acquisition of anoikis resistance in human osteosarcoma cells does not alter sensitivity to chemotherapeutic agents

International Nuclear Information System (INIS)

Díaz-Montero, C Marcela; McIntyre, Bradley W

2005-01-01

Chemotherapy-induced cell death can involve the induction of apoptosis. Thus, aberrant function of the pathways involved might result in chemoresistance. Since cell adhesion to the extracellular matrix acts as a survival factor that homeostatically maintains normal tissue architecture, it was tested whether acquisition of resistance to deadhesion-induced apoptosis (anoikis) in human osteosarcoma would result in resistance to chemotherapy. Osteosarcoma cell lines (SAOS-2 and TE-85) obtained from ATCC and were maintained in complete Eagle's MEM medium. Suspension culture was established by placing cells in tissue culture wells coated with poly-HEMA. Cell cytotoxicity was determined using a live/dead cytotoxicity assay. Cell cycle/apoptosis analyses were performed using propidium iodide (PI) staining with subsequent FACS analysis. Apoptosis was also assayed by Annexin-FITC/PI staining. Etoposide, adriamycin, vinblastine, cisplatin and paclitaxel were able to induce apoptosis in human osteosarcoma cells SAOS-2 regardless of their anoikis resistance phenotype or the culture conditions (adhered vs. suspended). Moreover, suspended anoikis resistant TE-85 cells (TE-85ar) retained their sensitivity to chemotherapy as well. Acquisition of anoikis resistance in human osteosarcoma cells does not result in a generalized resistance to all apoptotic stimuli, including chemotherapy. Moreover, our results suggest that the pathways regulating anoikis resistance and chemotherapy resistance might involve the action of different mediators

Acquisition of anoikis resistance in human osteosarcoma cells does not alter sensitivity to chemotherapeutic agents

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McIntyre Bradley W

2005-04-01

Full Text Available Abstract Background Chemotherapy-induced cell death can involve the induction of apoptosis. Thus, aberrant function of the pathways involved might result in chemoresistance. Since cell adhesion to the extracellular matrix acts as a survival factor that homeostatically maintains normal tissue architecture, it was tested whether acquisition of resistance to deadhesion-induced apoptosis (anoikis in human osteosarcoma would result in resistance to chemotherapy. Methods Osteosarcoma cell lines (SAOS-2 and TE-85 obtained from ATCC and were maintained in complete Eagle's MEM medium. Suspension culture was established by placing cells in tissue culture wells coated with poly-HEMA. Cell cytotoxicity was determined using a live/dead cytotoxicity assay. Cell cycle/apoptosis analyses were performed using propidium iodide (PI staining with subsequent FACS analysis. Apoptosis was also assayed by Annexin-FITC/PI staining. Results Etoposide, adriamycin, vinblastine, cisplatin and paclitaxel were able to induce apoptosis in human osteosarcoma cells SAOS-2 regardless of their anoikis resistance phenotype or the culture conditions (adhered vs. suspended. Moreover, suspended anoikis resistant TE-85 cells (TE-85ar retained their sensitivity to chemotherapy as well. Conclusion Acquisition of anoikis resistance in human osteosarcoma cells does not result in a generalized resistance to all apoptotic stimuli, including chemotherapy. Moreover, our results suggest that the pathways regulating anoikis resistance and chemotherapy resistance might involve the action of different mediators.

Oxidative stress in chemical toxicity

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Kappus, H.

1986-05-01

The toxic effect of compounds which undergo redox cycling enzymatic one-electron reduction are reviewed. First of all, the enzymatic reduction of these compounds leads to reactive intermediates, mainly radicals which react with oxygen, whereby superoxide anion radicals are formed. Further oxygen metabolites are hydrogen peroxide, singlet oxygen and hydroxyl radicals. The role of these oxygen metabolites in toxicity is discussed. The occurrence of lipid peroxidation during redox cycling of quinonoide compounds, e.g., adriamycin, and the possible relationship to their toxicity is critically evaluated. It is shown that iron ions play a crucial role in lipid peroxidation induced by redox cycling compounds. DNA damage by metal chelates, e.g., bleomycin, is discussed on the basis of findings that enzymatic redox cycling of a bleomycin-iron complex has been observed. The involvement of hydroxyl radicals in bleomycin-induced DNA damage occurring during redox cycling in cell nuclei is claimed. Redox cycling of other substances, e.g., aromatic amines, is discussed in relation to carcinogenesis. Other chemical groups, e.g., nitroaromatic compounds, hydroxylamines and azo compounds are included. Other targets for oxygen radical attack, e.g., proteins, are also dealt with. It is concluded that oxygen radical formation by redox cycling may be a critical event in toxic effects of several compounds if the protective mechanisms of cells are overwhelmed.

Does injection of metanephric mesenchymal cells improve renal function in rats?

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Yu-qing Jiao

2011-01-01

Full Text Available Chronic kidney disease (CKD is a massive global health-care problem. Cell therapy offers a potential treatment for CKD. The aim of this study was to investigate whether the administration of a population of stem cells could be used to treat adriamycin (ADR-induced glomerulopathy in rats, a form of CKD. We intravenously transplanted metanephric mesenchymal cells (MMCs into rats treated with ADR. We also induced MMC differentiation in vitro using a medium derived from serum and homogenates of ADR-induced glomerulopathy rats. We detected the induction of an early epithelial phenotype (cytokeratin-18 expression and a proximal tubule phenotype (vitamin D receptor expression in vitro, and MMC-derived epithelial cells corresponding to the proximal tubule and glomeruli in vivo. Transplantation of MMCs after induction of glomerulopathy significantly increased the creatinine clearance rate (Ccr, a marker for glomerular filtration rate, but had no significant effect on other parameters (24-hour urinary protein excretion, serum albumin, total cholesterol. In addition, there was no significant difference in blood urea nitrogen or serum creatinine levels in rats with and without ADR administration. Our results indicate that MMCs might survive, engraft and differentiate into renal epithelia in vivo when transplanted into ADR-treated rats. However, further studies are needed to determine whether MMC transplantation improves renal function and causes renal repair in this model.

The overexpression of MRP4 is related to multidrug resistance in osteosarcoma cells

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Zhonghui He

2015-01-01

Full Text Available Doxorubicin (Adriamycin, ADM is an antimitotic drug used in the treatment of a wide range of malignant tumors, including acute leukemia, lymphoma, osteosarcoma, breast cancer, and lung cancer. Multidrug resistance-associated proteins (MRPs are members of a superfamily of ATP-binding cassette (ABC transporters, which can transport various molecules across extra- and intra-cellular membranes. The aim of this study was to investigate whether there was a correlation between MRP4 and primary ADM resistance in osteosarcoma cells. In this paper, we chose the human osteosarcoma cell line MG63, ADM resistant cell line MG63/DOX, and the patient′s primary cell GSF-0686. We checked the ADM sensitivity and cytotoxicity of all the three cells by cell proliferation assay. The intracellular drug concentrations were measured by using LC-MS/MS. We also examined MRP4 gene expression by RT-PCR and Western Blot. We found that the intracellular ADM concentration of the parent osteosarcoma cell line MG63 was higher than the ADM resistant osteosarcoma MG63/DOX cell line or the GSF-0686 cell after ADM treatment (P < 0.05. In addition, MRP4 mRNA and protein levels in ADM resistant osteosarcoma cells were higher than in MG63 cell (P < 0.05. Taking together, this work suggests that overexpression of MRP4 may confer ADM resistance in osteosarcoma cells.

Successful therapy of convoluted T-lymphoblastic lymphoma in the adult

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Levine, A.M.; Forman, S.J.; Meyer, P.R.; Koehler, S.C.; Liebman, H.; Paganini-Hill, A.; Pockros, A.; Lukes, R.J.; Feinstein, D.I.

1983-01-01

Fifteen adult patients with biopsy-proven convoluted T-lymphoblastic lymphoma were treated with an aggressive regimen, modified from the LSA2-L2 protocol used for childhood lymphoma. The treatment schema consisted of induction phase, including cyclophosphamide, vincristine, prednisone, adriamycin, and 2000 rads to mediastinum, as well as intrathecal methotrexate. Consolidation phase included cytosine arabinoside, 6-thioguanine, L-asparaginase, and CCNU, along with cranial irradiation and further intrathecal methotrexate. Maintenance consisted of cyclical chemotherapy and intrathecal methotrexate, continuing for a total of 3 yr. Median age in the group was 25 yr (range 16-73). There were 8 males and 7 females. At diagnosis, 9 patients had mediastinal involvement, and 9 had bone marrow involvement. Five of these demonstrated malignant cells in the peripheral blood. Complete clinical response was attained in 11 patients. Three patients achieved partial response. Four complete responders have relapsed, 1 in the central nervous system at 6 mo. and 1 in nodal sites at 3 mo, 1 in multiple sites at 24 mo. and 1 in bone marrow at 42 mo while off all chemotherapy for 6 mos. At this time, median survival of all patients is 28.3 mo. and median relapse-free survival is 21 mo. The median survival for complete responders in excess of 71 mo. while the median relapse-free survival for this group is 41 mo.

Postgraduate Courses in Pharmaceutical Medicine in Italy

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Domenico Criscuolo

2017-06-01

Full Text Available Italy has a significant tradition of excellence in the area of clinical trials (CTRs: important achievements in the clinical development of rifampicin and adriamycin, the two most famous drugs discovered in the research laboratories of two Italian pharmaceutical companies, paved the way to the establishment of a culture of clinical development, mainly in the areas of antimicrobials and oncology. Despite the fact that now the Italian market of pharmaceuticals is largely dominated by multinational companies with headquarters outside Italy, the contribution of Italian studies to the clinical development of new drugs is still significant. Indeed, it largely exceeds the percentage of Italian inhabitants versus the ones living in the remaining EU countries, as Italy has about 12% of EU population, but has a 17% share of the EU CTRs. Education in Pharmaceutical Medicine is now a must for all professionals interested to work either in pharma companies or in contract research organizations: several Italian universities are offering high quality courses, and in the last 10 years, more than 1,200 professionals received a postgraduate education in pharmaceutical medicine. This result places Italy on top of countries concerned about the professional education of people involved in drug development and will represent an asset for a larger involvement of Italian clinical sites in the global process of clinical research.

Assessement of anthracycline cardiotoxicity with radionuclide angiocardiography

International Nuclear Information System (INIS)

Morikawa, Kachiko; Takada, Toru; Imura, Hiroshi

1987-01-01

The effect of anthracyclines on cardiac function was assessed by left ventricular ejection fraction (LVEF), peak ejection rate (PER) and peak filling rate (PFR), which were measured by using radionuclide angiocardiography. One hundred radionuclide angiocardiographies were done in 53 patients with malignancies who were treated with one of the following anthracyclines, adriamycin (ADM), daunomycin (DM), aclacynomycin A (ACM), 4'O-tetrahydropranyladriamycin (THP-ADM). In patients getting either ADM or DM, there was significant correlation between the changes of 3 parameters (LVEF, PER and PFR) and the cumulative dose each drug, which suggested that these parameters seemed to be useful for the early detection of cardiac dysfunction induced by these drugs. And it was estimated that the limiting total dose of ADM and DM was 360 ∼ 600 mg/m 2 , and 1,100 ∼ 1,300 mg/m 2 , respectively. In patients getting ACM, there was no significant correlation between the changes of these parameters and the cumulative dose of this drug (maximum dose: 1,552 mg/m 2 ), which suggested that the cardiotoxic effect of ACM was quite low. Among 3 parameters, only LVEF was correlated significantly with the cumulative dose in patients getting THP-ADM. It was estimated that the limiting total dose of THP-ADM was 900 mg/m 2 , which suggested that THP-ADM had apparently lower cardiotoxic effect than ADM. (author)

Expression of a novel stress-inducible protein, sestrin 2, in rat glomerular parietal epithelial cells

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Hamatani, Hiroko; Sakairi, Toru; Takahashi, Satoshi; Watanabe, Mitsuharu; Maeshima, Akito; Ohse, Takamoto; Pippin, Jeffery W.; Shankland, Stuart J.; Nojima, Yoshihisa

2014-01-01

Sestrin 2, initially identified as a p53 target protein, accumulates in cells exposed to stress and inhibits mammalian target of rapamycin (mTOR) signaling. In normal rat kidneys, sestrin 2 was selectively expressed in parietal epithelial cells (PECs), identified by the marker protein gene product 9.5. In adriamycin nephropathy, sestrin 2 expression decreased in PECs on day 14, together with increased expression of phosphorylated S6 ribosomal protein (P-S6RP), a downstream target of mTOR. Sestrin 2 expression was markedly decreased on day 42, coinciding with glomerulosclerosis and severe periglomerular fibrosis. In puromycin aminonucleoside nephropathy, decreased sestrin 2 expression, increased P-S6RP expression, and periglomerular fibrosis were observed on day 9, when massive proteinuria developed. These changes were transient and nearly normalized by day 28. In crescentic glomerulonephritis, sestrin 2 expression was not detected in cellular crescents, whereas P-S6RP increased. In conditionally immortalized cultured PECs, the forced downregulation of sestrin 2 by short hairpin RNA resulted in increased expression of P-S6RP and increased apoptosis. These data suggest that sestrin 2 is involved in PEC homeostasis by regulating the activity of mTOR. In addition, sestrin 2 could be a novel marker of PECs, and decreased expression of sestrin 2 might be a marker of PEC injury. PMID:25056347

Investigation of the interaction of radiation and cardiotoxic anticancer agents using a fetal mouse heart organ culture system

International Nuclear Information System (INIS)

Kimler, B.F.; Rethorst, R.D.; Cox, G.G.

1985-01-01

The fetal mouse heart organ culture was utilized in an attempt to predict the cardiotoxic effects of combinations of radiation, Adriamycin (ADR), and Dihydroxyanthraquinone (DHAQ), antineoplastic agents which have been shown to produce clinical cardiomyopathy. Seventeen-day fetal hearts were removed and placed in a culture system of micro-titer plates. A single heart was placed in each well on a piece of aluminum mesh to keep the heart above the culture medium but bathed by capillary action. The plates were then placed in a 100% oxygen environment at 37 0 C. Treatments were performed on day 1 after culture: radiation doses (Cs-137) of 10, 20, or 40 Gy; drug treatment with 10, 30, or 100 μg/ml of ADR; 5, 20, or 50 μg/ml of DHAQ; and combinations and sequences of drug and radiation. Hearts were checked every day for functional activity as evidenced by a continuous heart beat. Untreated hearts beat rhythmically for up to 9 days; treated hearts stopped beating earlier. Using an endpoint of functional retention time, dose response curves were obtained for all individual agents and for combinations of agents. This system may help to predict the cardiotoxic effects that result from the use of these drugs and radiation. It may also aid in the development of new anthracycline chemotherapeutic agents that lack cardiotoxicity

Rac1 in podocytes promotes glomerular repair and limits the formation of sclerosis.

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Asao, Rin; Seki, Takuto; Takagi, Miyuki; Yamada, Hiroyuki; Kodama, Fumiko; Hosoe-Nagai, Yoshiko; Tanaka, Eriko; Trejo, Juan Alejandro Oliva; Yamamoto-Nonaka, Kanae; Sasaki, Yu; Hidaka, Teruo; Ueno, Takashi; Yanagita, Motoko; Suzuki, Yusuke; Tomino, Yasuhiko; Asanuma, Katsuhiko

2018-03-22

Rac1, a Rho family member, is ubiquitously expressed and participates in various biological processes. Rac1 expression is induced early in podocyte injury, but its role in repair is unclear. To investigate the role of Rac1 expression in podocytes under pathological conditions, we used podocyte-specific Rac1 conditional knock-out (cKO) mice administered adriamycin (ADR), which causes nephrosis and glomerulosclerosis. Larger areas of detached podocytes, more adhesion of the GBM to Bowman's capsule, and a higher ratio of sclerotic glomeruli were observed in Rac1 cKO mice than in control mice, whereas no differences were observed in glomerular podocyte numbers in both groups after ADR treatment. The mammalian target of rapamycin (mTOR) pathway, which regulates the cell size, was more strongly suppressed in the podocytes of Rac1 cKO mice than in those of control mice under pathological conditions. In accordance with this result, the volumes of podocytes in Rac1 cKO mice were significantly reduced compared with those of control mice. Experiments using in vitro ADR-administered Rac1 knockdown podocytes also supported that a reduction in Rac1 suppressed mTOR activity in injured podocytes. Taken together, these data indicate that Rac1-associated mTOR activation in podocytes plays an important role in preventing the kidneys from developing glomerulosclerosis.

Culture of human cell lines by a pathogen-inactivated human platelet lysate.

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Fazzina, R; Iudicone, P; Mariotti, A; Fioravanti, D; Procoli, A; Cicchetti, E; Scambia, G; Bonanno, G; Pierelli, L

2016-08-01

Alternatives to the use of fetal bovine serum (FBS) have been investigated to ensure xeno-free growth condition. In this study we evaluated the efficacy of human platelet lysate (PL) as a substitute of FBS for the in vitro culture of some human cell lines. PL was obtained by pools of pathogen inactivated human donor platelet (PLT) concentrates. Human leukemia cell lines (KG-1, K562, JURKAT, HL-60) and epithelial tumor cell lines (HeLa and MCF-7) were cultured with either FBS or PL. Changes in cell proliferation, viability, morphology, surface markers and cell cycle were evaluated for each cell line. Functional characteristics were analysed by drug sensitivity test and cytotoxicity assay. Our results demonstrated that PL can support growth and expansion of all cell lines, although the cells cultured in presence of PL experienced a less massive proliferation compared to those grown with FBS. We found a comparable percentage of viable specific marker-expressing cells in both conditions, confirming lineage fidelity in all cultures. Functionality assays showed that cells in both FBS- and PL-supported cultures maintained their normal responsiveness to adriamycin and NK cell-mediated lysis. Our findings indicate that PL is a feasible serum substitute for supporting growth and propagation of haematopoietic and epithelial cell lines with many advantages from a perspective of process standardization, ethicality and product safety.

Therapy of Ewing's sarcoma

International Nuclear Information System (INIS)

Dunst, J.; Sauer, R.

1993-01-01

Therapy of Ewing's sarcoma requires a qualified clinical, radiological, and pathohistological diagnosis and, in particular, an optimal therapy by an experienced team of oncological specialists. Important prognostic factors are the presence of hematogenous metastases at diagnosis, the initial tumor volume, the response to chemotherapy, and adequate local therapy. Presently, cure rates of more than 60% can be achieved for localized Ewing's sarcoma by combination of local therapy and chemotherapy. The four-drug combination VACA (vincristin, actinomycin D, cyclophosphamide, adriamycin) can be considered as cytostatic gold standard. More aggressive regimens (VAIA, EVAIA, autologous bone marrow transplant) may be beneficial in subgroups and are under investigation. Concerning local therapy adequate radiotherapy plays a major role and achieves the same survival rates as radical surgery, comparable patient selection provided. Several factors have impact on radiotherapeutic results, especially total dose (45 Gy large volume, 55 Gy to the primary tumor), target volume (safety margin at least 2 cm according to the pretreatment volume, at least 5 cm in proximal and distal extension of long bones), timing of radiotherapy (as early as possible) and quality of treatment. Radiotherapy as sole local treatment is indicated in inoperable lesions (spine, sacrum, skull) and in small, good-responding tumors. High-risk patients should receive combined radiotherapeutic-surgical treatment, preferably as pre-operative irradiation. The value of hyperfractionation is not yet proven despite theoretical advantages. (orig.) [de

Dietary feeding of flavokawain A, a Kava chalcone, exhibits a satisfactory safety profile and its association with enhancement of phase II enzymes in mice

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Xuesen Li

2014-01-01

Full Text Available Flavokawain A (FKA, a major chalcone in the Kava plant, has recently demonstrated promising anti-cancer activities. A systematic evaluation of FKA's safety profile has not been reported before. In this study, male FVB/N mice were fed with an AIN-76A diet or AIN-76A diet supplemented with 0.6% (6 g/kg food FKA or 0.6% commercial kava root extract (KRE for three weeks. Dietary feeding of FKA did not affect food consumption and body weight. Histopathological examination of liver, kidney, colon, lung, heart, spleen, and thymus revealed no signs of FKA-induced toxicity. Biochemical serum analysis and histological examination confirmed normal organ function in FKA-treated mice. The cytotoxicity profile showed FKA had minimal side effects on bone marrow and small intestinal epithelial cells compared with Adriamycin. In addition, oral feeding of FKA increased activities of both glutathione S-transferase and quinone reductase in the liver, lung, prostate and bladder tissues of mice. In comparison, dietary feeding of 0.6% KRE increased liver/body weight ratio and decreased spleen, thymus, and testis/body weight ratios, as well as induced nodular proliferation in liver tissues. Therefore, dietary feeding FKA showed no adverse effects on major organ function and homeostasis in mice, suggesting the potential of FKA for chemoprevention study of human cancers.

Loss of p53 induces M-phase retardation following G2 DNA damage checkpoint abrogation.

Science.gov (United States)

Minemoto, Yuzuru; Uchida, Sanae; Ohtsubo, Motoaki; Shimura, Mari; Sasagawa, Toshiyuki; Hirata, Masato; Nakagama, Hitoshi; Ishizaka, Yukihito; Yamashita, Katsumi

2003-04-01

Most cell lines that lack functional p53 protein are arrested in the G2 phase of the cell cycle due to DNA damage. When the G2 checkpoint is abrogated, these cells are forced into mitotic catastrophe. A549 lung adenocarcinoma cells, in which p53 was eliminated with the HPV16 E6 gene, exhibited efficient arrest in the G2 phase when treated with adriamycin. Administration of caffeine to G2-arrested cells induced a drastic change in cell phenotype, the nature of which depended on the status of p53. Flow cytometric and microscopic observations revealed that cells that either contained or lacked p53 resumed their cell cycles and entered mitosis upon caffeine treatment. However, transit to the M phase was slower in p53-negative cells than in p53-positive cells. Consistent with these observations, CDK1 activity was maintained at high levels, along with stable cyclin B1, in p53-negative cells. The addition of butyrolactone I, which is an inhibitor of CDK1 and CDK2, to the p53-negative cells reduced the floating round cell population and induced the disappearance of cyclin B1. These results suggest a relationship between the p53 pathway and the ubiquitin-mediated degradation of mitotic cyclins and possible cross-talk between the G2-DNA damage checkpoint and the mitotic checkpoint.

Differential impact of diverse anticancer chemotherapeutics on the Cdc25A-degradation checkpoint pathway

International Nuclear Information System (INIS)

Agner, Jeppe; Falck, Jacob; Lukas, Jiri; Bartek, Jiri

2005-01-01

When exposed to DNA-damaging insults such as ionizing radiation (IR) or ultraviolet light (UV), mammalian cells activate checkpoint pathways to halt cell cycle progression or induce cell death. Here we examined the ability of five commonly used anticancer drugs with different mechanisms of action to activate the Chk1/Chk2-Cdc25A-CDK2/cyclin E cell cycle checkpoint pathway, previously shown to be induced by IR or UV. Whereas exposure of human cells to topoisomerase inhibitors camptothecin, etoposide, or adriamycin resulted in rapid (within 1 h) activation of the pathway including degradation of the Cdc25A phosphatase and inhibition of cyclin E/CDK2 kinase activity, taxol failed to activate this checkpoint even after a prolonged treatment. Unexpectedly, although the alkylating agent cisplatin also induced degradation of Cdc25A (albeit delayed, after 8-12 h), cyclin E/CDK2 activity was elevated and DNA synthesis continued, a phenomena that correlated with increased E2F1 protein levels and consequently enhanced expression of cyclin E. These results reveal a differential impact of various classes of anticancer chemotherapeutics on the Cdc25A-degradation pathway, and indicate that the kinetics of checkpoint induction, and the relative balance of key components within the DNA damage response network may dictate whether the treated cells arrest their cell cycle progression

Radiation induction of drug resistance in RIF-1 tumors and tumor cells

International Nuclear Information System (INIS)

Hopwood, L.E.; Moulder, J.E.

1989-01-01

The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not for ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance

Enhanced antitumor efficacy and counterfeited cardiotoxicity of combinatorial oral therapy using Doxorubicin- and Coenzyme Q10-liquid crystalline nanoparticles in comparison with intravenous Adriamycin

DEFF Research Database (Denmark)

Swarnakar, Nitin K; Thanki, Kaushik; Jain, Sanyog

2014-01-01

and strong synergism for combination at 1:10 dose ratio owing to higher cellular uptake, nuclear colocalization, higher apoptotic index and 8-OHdG levels. The prophylactic antitumor efficacy of the CoQ10-LCNPs was also established using tumor induction and progression studies. Finally, therapeutic antitumor......, with Dox-induced-cardiotoxicity was completely counterfeited in combination. In nutshell, LCNPs pose great potential in improving the therapeutic efficacy of drugs by oral route of administration. FROM THE CLINICAL EDITOR: This study describes the use of liquid crystalline nanoparticles containing coenzyme...

In vivo multimodality imaging of miRNA-16 iron nanoparticle reversing drug resistance to chemotherapy in a mouse gastric cancer model

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Sun, Zhongchan; Song, Xinxing; Li, Xiujuan; Su, Tao; Qi, Shun; Qiao, Ruirui; Wang, Fu; Huan, Yi; Yang, Weidong; Wang, Jing; Nie, Yongzhan; Wu, Kaichun; Gao, Mingyuan; Cao, Feng

2014-11-01

miRNA-16 (miR16) plays an important role in modulating the drug resistance of SGC7901 cell lines to adriamycin (ADR). A variety of viral carriers have been designed for miRNA delivery. However, the safety concerns are currently perceived as hampering the clinical application of viral vector-based therapy. Herein a type of magnetic nanoparticles (MNPs) was designed and synthesized using poly(ethylene glycol) (PEG)-coated Fe3O4 nanoparticles as a miRNA delivery system for the purpose of reducing drug resistance of gastric cancer cells by enforcing miR16 expression in SGC7901/ADR cells. The MNPs with good biocompatibility were synthesized by thermal decomposition, and then conjugated with miRNA via electrostatic interaction producing miR16/MNPs. After co-culture with miR16/MNPs, ADR-induced apoptosis of SGC7901/ADR was examined by MTT and TUNEL. miR16/MNPs treatment significantly increased cell apoptosis in vitro. SGC7901/ADRfluc tumor-bearing nude mice under ADR therapy were treated with miR16/MNPs by tail vein injection for in vivo study. After intraperitoneal injection of ADR, tumor volume measurement and fluorescence imaging were performed to for the death of SGC7901/ADR cells in vivo. Results showed that miR16/MNPs were able to significantly suppress SGC7901/ADR tumor growth, probably through increasing SGC7901/ADR cells' sensitivity to ADR. Our results suggest the efficient delivery of miR16 by MNPs as a novel therapeutic strategy for drug resistant tumor treatment.miRNA-16 (miR16) plays an important role in modulating the drug resistance of SGC7901 cell lines to adriamycin (ADR). A variety of viral carriers have been designed for miRNA delivery. However, the safety concerns are currently perceived as hampering the clinical application of viral vector-based therapy. Herein a type of magnetic nanoparticles (MNPs) was designed and synthesized using poly(ethylene glycol) (PEG)-coated Fe3O4 nanoparticles as a miRNA delivery system for the purpose of reducing drug

Effect of treatment in fractionated schedules with the combination of x-irradiation and six cytotoxic drugs on the RIF-1 tumor and normal mouse skin

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Lelieveld, P.; Scoles, M.A.; Brown, J.M.; Phil, D.; Kallman, R.F.

1985-01-01

RIF-1 tumors, implanted syngeneically in the gastrocnemius muscles of the right hind legs of C3H/Km mice, were treated either with X ray alone, drug alone, or drug and X ray combined. The drugs tested were bleomycin, BCNU, cis-diamminedichloro platinum, adriamycin, cyclophosphamide, and actinomycin-D. All drugs were administered either in the maximum tolerated dose or a dose that causes minimal tumor growth delay. Both drugs and X rays were administered either as a single dose or in five daily fractions. In addition to the single modality controls, seven different schedules of combined modalities were tested. Tumors were measured periodically after treatment in order that the day at which each tumor reached 4 times its initial cross-sectional area, i.e., its size at the time of treatment, could be determined. The effect of treatment on tumors was based upon excess growth delay (GD), i.e., T400% (treated)-T400% (untreated control). Treatment effects for the same combined modality schedules were also determined for normal skin, using the early skin reaction as an endpoint. Dose effect factors (DEF) were computed for all combined modality schedules and were based upon calculated radiation dose equivalents. We also calculated supra-additivity ratios, SR/sub I/ and SR/sub II/, therapeutic gain factors and adjusted therapeutic gain factors. The only drugs to produce significant supra-additivity with X rays were cis-Pt and cyclo

Knockdown of HOXA10 reverses the multidrug resistance of human chronic mylogenous leukemia K562/ADM cells by downregulating P-gp and MRP-1.

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Yi, Ying-Jie; Jia, Xiu-Hong; Wang, Jian-Yong; Li, You-Jie; Wang, Hong; Xie, Shu-Yang

2016-05-01

Multidrug resistance (MDR) of leukemia cells is a major obstacle in chemotherapeutic treatment. The high expression and constitutive activation of P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1) have been reported to play a vital role in enhancing cell resistance to anticancer drugs in many tumors. The present study aimed to investigate the reversal of MDR by silencing homeobox A10 (HOXA10) in adriamycin (ADR)-resistant human chronic myelogenous leukemia (CML) K562/ADM cells by modulating the expression of P-gp and MRP-1. K562/ADM cells were stably transfected with HOXA10-targeted short hairpin RNA (shRNA). The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis showed that the mRNA and protein expression of HOXA10 was markedly suppressed following transfection with a shRNA-containing vector. The sensitivity of the K562/ADM cells to ADR was enhanced by the silencing of HOXA10, due to the increased intracellular accumulation of ADR. The accumulation of ADR induced by the silencing of HOXA10 may be due to the downregulation of P-gp and MRP-1. Western blot analysis revealed that downregulating HOXA10 inhibited the protein expression of P-gp and MRP-1. Taken together, these results suggest that knockdown of HOXA10 combats resistance and that HOXA10 is a potential target for resistant human CML.

Microwave-Assisted Facile Synthesis, Anticancer Evaluation and Docking Study of N-((5-(Substituted methylene amino-1,3,4-thiadiazol-2-ylmethyl Benzamide Derivatives

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Shailee V. Tiwari

2017-06-01

Full Text Available In the present work, 12 novel Schiff’s bases containing a thiadiazole scaffold and benzamide groups coupled through appropriate pharmacophore were synthesized. These moieties are associated with important biological properties. A facile, solvent-free synthesis of a series of novel 7(a–l N-((5-(substituted methylene amino-1,3,4-thiadiazol-2-ylmethyl benzamide was carried out under microwave irradiation. Structures of the synthesized compounds were confirmed by IR, NMR, mass spectral study and elemental analysis. All the synthesized hybrids were evaluated for their in vitro anticancer activity against a panel of four human cancer cell lines, viz. SK-MEL-2 (melanoma, HL-60 (leukemia, HeLa (cervical cancer, MCF-7 (breast cancer and normal breast epithelial cell (MCF-10A using 3-(4,5-dimethythiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT assay method. Most of the synthesized compounds exhibited promising anticancer activity, showed comparable GI50 values comparable to that of the standard drug Adriamycin. The compounds 7k, 7l, 7b, and 7a were found to be the most promising anticancer agents in this study. A molecular docking study was performed to predict the probable mechanism of action and computational study of the synthesized compounds 7(a–l was performed to predict absorption, distribution, metabolism, excretion and toxicity (ADMET properties, by using QikProp v3.5 (Schrödinger LLC. The results showed the good oral drug-like behavior of the synthesized compounds 7(a–l.

CD68+ cell count, early evaluation with PET and plasma TARC levels predict response in Hodgkin lymphoma.

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Cuccaro, Annarosa; Annunziata, Salvatore; Cupelli, Elisa; Martini, Maurizio; Calcagni, Maria L; Rufini, Vittoria; Giachelia, Manuela; Bartolomei, Francesca; Galli, Eugenio; D'Alò, Francesco; Voso, Maria T; Leone, Giuseppe; Giordano, Alessandro; Larocca, Luigi M; Hohaus, Stefan

2016-03-01

Early response evaluation with [(18) F]fluordeoxyglucose (FDG) positron emission tomography after 2 cycles of chemotherapy (interim PET) has been indicated as the strongest predictor for outcome in classical Hodgkin lymphoma (HL). We studied the prognostic role of the number of tumor-infiltrating CD68+ cells and of the plasma levels of TARC (thymus and activation-regulated chemokine) in the context of interim PET in 102 patients with classical HL treated with Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD). After 2 ABVD cycles, interim PET according to Deauville criteria was negative (score 0-3) in 85 patients and positive (score 4-5) in 15 patients (2 patients technically not evaluable). TARC levels were elevated in 89% of patients at diagnosis, and decreased after 2 cycles in 82% of patients. Persistently elevated TARC levels in 18% of patients were significantly associated with a positive PET result (P = 0.007). Strong predictors for progression-free survival (PFS) were a negative interim PET (85% vs. 28%, P evaluation had no prognostic role. In multivariate analysis, interim PET, CD68+ cell counts and presence of B-symptoms were independently associated with PFS. We conclude that although TARC levels are a biomarker for early response evaluation, they cannot substitute for interim PET as outcome predictor in HL. The evaluation of CD68 counts and B-symptoms at diagnosis may help to identify low-risk patients regardless positive interim PET. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Neuroblastoma occurring in a 38-year old Nigerian man: a rare finding

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Aloy Aghaji

2009-07-01

Full Text Available Neuroblastoma (NB is a common malignancy in children, but rarely occurs in adults. Accepted unfavorable prognostic factors include age over one year, low histological grade and advanced stage, MYCN amplification, chromosomal aberrations, elevations of neuron specific enolase and lactate dehydrogenase, and increased catecholamine metabolites in urine or serum. In adults, abdomen/retroperitoneum are the primary sites and in children the adrenal gland. We report a 38-year old civil servant who presented at our urology clinic on the 21st of December 2007 with a six month history of right flank dull pain which was worse on walking and relieved by rest, hypertension and a large right retroperitoneal mass. Tumor resection revealed a grade III NB. Chemotherapy using a combination of vincristine, adriamycin and cyclophosphamide was started. Follow-up showed regression of the mass initially with a relapse after patient absconded for three months. He resurfaced with new masses and he had a repeat chemotherapy with disappearance of the masses and is currently undergoing further treatment. To our knowledge this is the only report of NB in an adult registered so far in Nigeria and perhaps the whole of Africa. Currently, there are no standard treatment guidelines for patients with NB in adulthood. This study emphasizes the need for a standard treatment regime for adult onset neuroblastoma and its recognition as a possible differential in intra-abdominal mass in adults.

Feasibility of combined modality therapy for localized high-grade soft tissue sarcomas in adults

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Blum, R.H.; Greenberger, J.S.; Wilson, R.E.; Corson, J.M.

1979-01-01

Seventeen consecutive patients with localized, high grade soft tissue sarcomas had resection of their primary tumor, radiation therapy and chemotherapy. The soft tissue sarcoma was primary in 14 patients and regionally recurrent in 3 patients. Chemotherapy consisted of cyclophosphamide 500 mg/M 2 day 1, Adriamycin (ADR) 60 mg/M 2 day 2, and DTIC 400 mg/M 2 days 1 and 2, given every 21 days to a maximum ADR dose of 450 mg/M 2 . Cyclophosphamide and DTIC were then given to a total duration of 1 year. Radiation therapy consisted of 4000 to 5000 rad by megavoltage photons in 5 weeks, and in selected cases, an additional 1500 to 2000 rad by electron beam boost in the tumor bed delivered over 2 additional weeks. Following surgery, 12 patients were treated sequentially with an interval of chemotherapy, radiation therapy and then the completion of chemotherapy. The added morbidity of this sequential approach is minimal: one patient of 12 had delayed primary healing of her wound, 1 of 10 patients required a break in radiation therapy because of skin erythema. Four patients were treated with intensive pre-chemotherapy radiation therapy because of inadequate surgical margins. The median time on study was 18 months from onset of treatment (range, 8 to 41 months). Although there have been no local, regional or distant recurrences, the follow-up time is inadequate to assess the therapeutic benefit of this combined modality treatment

MicroRNA-101 regulates T-cell acute lymphoblastic leukemia progression and chemotherapeutic sensitivity by targeting Notch1.

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Qian, Lu; Zhang, Wanggang; Lei, Bo; He, Aili; Ye, Lianhong; Li, Xingzhou; Dong, Xin

2016-11-01

The present study aimed to investigate the role of microRNA (miR)-101 in acute lymphoblastic leukemia progression and chemoresistance. Furthermore, a novel target gene of miR-101 was identified. Here, we confirmed that miR-101 was significantly downregulated in the blood samples of patients with T-cell acute lymphoblastic leukemia (T-ALL) compared with the healthy controls, as determined by reverse transcription quantitative polymerase chain reaction (RTqPCR) analysis. The in vitro experiments demonstrated that miR-101 significantly repressed the proliferation and invasion, and induced potent apoptosis in Jurkat cells, as determined by CCK-8, flow cytometer and cell invasion assays. Luciferase assay confirmed that Notch1 was a target gene of miR-101, and western blotting showed that miR-101 suppressed the expression of Notch1 at the protein level. Moreover, functional restoration assays revealed that Notch1 mediates the effects of miR-101 on Jurkat cell proliferation, apoptosis and invasion. miR-101 enhanced the sensitivity of Jurkat cells to the chemotherapeutic agent adriamycin. Taken together, our results show for the first time that miR-101 acts as a tumor suppressor in T-cell acute lymphoblastic leukaemia and it could enhance chemotherapeutic sensitivity. Furthermore, Notch1 was identified to be a novel target of miR-101. This study indicates that miR-101 may represent a potential therapeutic target for T-cell acute lymphoblastic leukemia intervention.

Intracellular calcium overloading and oxidative stress in cardiomyocyte necrosis via a mitochondriocentric signal-transducer-effector pathway

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Shaheen, Mazen; Cheema, Yaser; Shahbaz, Atta U; Bhattacharya, Syamal K; Weber, Karl T

2011-01-01

Congestive heart failure (CHF), a common clinical syndrome, has reached epidemic proportions. Its disabling symptoms account for frequent hospitalizations and readmissions. Pathophysiological mechanisms that lead to CHF and account for its progressive nature are of considerable interest. Important scientific observations obtained from Dr Pawan K Singal’s laboratory in Winnipeg, Manitoba, have provided crucial insights to our understanding of the pathophysiological factors that contribute to cardiomyocyte necrosis (the heart is a postmitotic organ incapable of tolerating an ongoing loss of these cells without adverse functional consequences). This increment in knowledge and the mechanistic insights afforded by Dr Singal and his colleagues have highlighted the role of excessive intracellular calcium accumulation and the appearance of oxidative stress in CHF, in which the rate of reactive oxygen species generation overwhelms their rate of detoxification by antioxidant defenses. They have shown that this common pathophysiological scenario applies to diverse entities such as ischemia/reperfusion and hypoxia/reoxygenation forms of injury, myocardial infarction and the cardiomyopathies that accompany diabetes and excess levels of catecholamines and adriamycin. The authors are honoured to be invited to contribute to the present focus issue of Experimental & Clinical Cardiology in recognizing Dr Singal’s numerous scholarly accomplishments. The present article reviews the authors’ recent work on a mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis found in rats with either an acute stressor state that accompanies isoproterenol administration or a chronic stressor state manifested after four weeks of aldosterone/salt treatment. PMID:22131852

Successful treatment of mucosa-associated lymphoid tissue lymphoma in a patient with gastric and rectal lesions with metachronous and ectopic development

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Hajime Umezu

2011-04-01

Full Text Available A 75-year-old female, who had an abnormal stomach x-ray finding, was admitted to the hospital for further examination and therapy. Upper GI endoscopy showed reddish and swollen folds on the greater curvature of the gastric body and a biopsy was of this lesion revealed malignant lymphoma (small cell type or mucosa-associated lymphoid tissue (MALT lymphoma suspected. The patient was infected with Helicobacter pylori (H. pylori, however, in response to the patient’s wishes, a total gastrectomy, omentectomy and splenectomy were performed and the histological diagnosis was gastric MALT lymphoma. Two courses of CHOP therapy (cyclophosphamide (CPM 750 mg/m2/day, day 1, adriamycin (ADM 50 mg/m2/day, day 1, vincristine sulfate (VCR 1.4 mg/m2/day, day 1, prednisolone 100 mg/body, day 1-5 were administered as adjuvant chemotherapy. A colonoscopic examination performed about 4.5 yr after the operation revealed rectal submucosal tumors and the biopsied specimens were diagnosed as malignant lymphoma. A transanal focal resection was performed and the histological diagnosis was metachronous and ectopic development of MALT lymphoma. The histological finding was similar to the gastric lesion. About 4 and 7 yr after the first development of rectal MALT lymphoma, MALT lymphomas developed repeatedly in the rectal lesion, however, these were resected repeatedly and no developmenthas occurred during the past two years. This report presents a very rare case of metachronous and ectopic MALT lymphoma de

Radiotherapy in combination with misonidazole and ACNU (1-(4 amino-2 methyl-5 pyrimidinyl) methyl-3-(2 chloroethyl)-3-nitrosourea hydrochloride)

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Asakura, Hideo; Mashima, Yasuoki; Kanazawa, Atsuko (Toranomon Hospital, Tokyo (Japan)); Maruhashi, Akira

1983-11-01

Misonidazole and ACNU were intermittently combined one or several times with radiotherapy. Misonidazole was orally administered with a dose of 1.5g/m/sup 2/ 4 hours before irradiation. ACNU with a dose of 60mg/m/sup 2/ mixed with predonisolone (40 mg) was intravenously injected between misonidazole and irradiation. Irradiation was carried out with the fractionation of 120 rads per fraction and 5 fractions per week in lung cancer and of 200 rads per fraction and 3 fractions per week in head and neck cancer. Twenty lung cancer patients and 13 head and neck cancer patients were treated from July, 1980 to April, 1982. In lung cancer, BAI (bronchial artery infusion) of adriamycin was added besides the above-mentioned treatment. Complete plus partial response rate of lung cancer was 85%, one year survival rate by Kaplan-Meier's method 65 +- 10.7% and two year survival rate 39.8 +- 12.2%, which were promising. In head and neck cancer, complete plus partial response rate was 76.9%, and one year survival rate 67.3 +- 13.6%. Head and neck cancer contained many recurrent and many advanced stage cases. Side effects of this treatment were nausea, vomiting and thrombocytopenia due to ACNU. These were all transient. Any peripheral neuropathy due to misonidazole was not observed in this treatment scheme. The fractionation in multomodality therapy is discussed and the mechanism of chemosensitization is bibliographically discussed.

Effect of gemcitabine chemotherapy on immune function and VEGF in patients with middle and advanced liver cancer

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Ling Zuo

2016-09-01

Full Text Available Objective: To observe the effect of gemcitabine chemotherapy on the immune function and VEGF in patients with middle and advanced liver cancer. Methods: A total of 90 patients with middle and advanced liver cancer who were admitted in our hospital from June, 2014 to July, 2015 were included in the study and randomized into the observation group and the control group with 45 cases in each group. The patients in the control group were given adriamycin, and the patients in the observation group were given gemcitabine chemotherapy. The efficacy, immunological function indicators, VEGF level, and the occurrence of adverse reactions in the two groups were compared. Results: IL-6 and TNF-毩 levels after treatment in the two groups were significantly elevated, and the increased degree in the observation group was significantly greater than that in the control group (P0.05. VEGF level after treatment in the two groups was significantly reduced, and the reduced degree in the observation group was significantly greater than that in the control group (P<0.05. The improvement of T cell subsets after treatment in the observation group was significantly superior to that in the control group (P<0.05. The occurrence rate of adverse reactions in the observation group was significantly lower than that in the control group (P<0.05. Conclusions: Gemcitabine chemotherapy on patients with middle and advanced liver cancer can effectively improve the immunological function, and enhance the efficacy, with a higher safety.

Treatment outcome and prognostic factor analysis in transplant-eligible Chinese myeloma patients receiving bortezomib-based induction regimens including the staged approach, PAD or VTD

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Chim Chor

2012-06-01

Full Text Available Abstract Background We have reported promising outcomes using a staged approach, in which bortezomib/thalidomide/dexamethasone was used only in 14 patients with suboptimal response to VAD (vincristine/adriamycin/dexamethasone before autologous stem cell transplantation (ASCT. Here we compared the outcomes of the staged approach with frontline PAD (bortezomib/doxorubicin/dexamethasone or VTD (bortezomib/thalidomide/dexamethasone induction, and analysed prognostic factors for outcome. Patients and methods Ninety-one transplant-eligible Chinese patients received three induction regimens prior to ASCT [staged approach (N = 25, PAD (N = 31, VTD (N = 35]. and received thalidomide maintenance for 2 years post-ASCT. Results 43 (47.3% patients had International Staging System (ISS III disease. By an intention-to-treat analysis, the overall CR/nCR rate were 37.4% post-induction, and 62.6% post-ASCT. Five-year overall (OS and event-free (EFS survivals were 66% and 45.1%. There was no difference of the post-induction CR/nCR rate, EFS or OS between patients induced by these three regimens. Moreover, ISS III disease did not affect CR/nCR rates. Multivariate analysis showed that ISS and post-ASCT CR/nCR impacted OS while ISS and post-induction CR/nCR impacted EFS. Conclusions These three induction regimens produced comparable and favorable outcomes in myeloma. The unfavorable outcome of ISS stage III persisted despite upfront/early use of bortezomib. CR/nCR predicted favorable survivals.

Analysis of radiation-induced angiosarcoma of the breast.

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Zemanova, M; Rauova, K; Boljesikova, E; Machalekova, K; Krajcovicova, I; Lehotska, V; Mikulova, M; Svec, J

2014-01-01

Breast angiosarcoma may occur de novo, or as a complication of radiation therapy, or chronic lymphedema secondary to axillary lymph node dissection for mammary carcinoma. Both primary and secondary angiosarcomas may present with bruise like skin discoloration, which may delay the diagnosis. Imaging findings are nonspecific. In case of high-grade tumours, MRI may be used effectively to determine lesion extent by showing rapid enhancement, nevertheless earliest possible diagnostics is crucial therefore any symptoms of angiosarcoma have to be carefully analysed. The case analysed here reports on results of 44-year old premenopausal woman who was treated for a T1N1M0 invasive ductal carcinoma. After a biopsy diagnosis of carcinoma, the patient underwent quadrantectomy with axillary lymph node dissection. She received partial 4 cycles of chemotherapy with adriamycin and cyclophosphamide, followed by radiation treatment. Thereafter, a standard postoperative radiotherapy was applied at our institution four months after chemotherapy (TD 46 Gy in 23 fractions followed by a 10 Gy electron boost to the tumour bed). Adjuvant chemotherapy was finished six months after operation, followed by tamoxifen. Follow up: no further complications were detected during regular check-ups. However, 12-years later, patient reported significant changes at breast region which was exposed to radiation during treatment of original tumour. In this article, we describe the clinical presentation, imaging and pathological findings of secondary angiosarcoma of the breast after radiotherapy (Fig. 2, Ref. 26).

A target based approach identifies genomic predictors of breast cancer patient response to chemotherapy

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Hallett Robin M

2012-05-01

Full Text Available Abstract Background The efficacy of chemotherapy regimens in breast cancer patients is variable and unpredictable. Whether individual patients either achieve long-term remission or suffer recurrence after therapy may be dictated by intrinsic properties of their breast tumors including genetic lesions and consequent aberrant transcriptional programs. Global gene expression profiling provides a powerful tool to identify such tumor-intrinsic transcriptional programs, whose analyses provide insight into the underlying biology of individual patient tumors. For example, multi-gene expression signatures have been identified that can predict the likelihood of disease reccurrence, and thus guide patient prognosis. Whereas such prognostic signatures are being introduced in the clinical setting, similar signatures that predict sensitivity or resistance to chemotherapy are not currently clinically available. Methods We used gene expression profiling to identify genes that were co-expressed with genes whose transcripts encode the protein targets of commonly used chemotherapeutic agents. Results Here, we present target based expression indices that predict breast tumor response to anthracycline and taxane based chemotherapy. Indeed, these signatures were independently predictive of chemotherapy response after adjusting for standard clinic-pathological variables such as age, grade, and estrogen receptor status in a cohort of 488 breast cancer patients treated with adriamycin and taxotere/taxol. Conclusions Importantly, our findings suggest the practicality of developing target based indices that predict response to therapeutics, as well as highlight the possibility of using gene signatures to guide the use of chemotherapy during treatment of breast cancer patients.

Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein.

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Hongping Min

Full Text Available Development of multidrug resistance (MDR is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp for chronic myelogenous leukemia (CML patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression.

Diagnóstico pouco usual de obstrução da traqueia

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C. Damas

2006-05-01

Full Text Available Resumo: Homem, 54 anos, caucasiano e fumador, que recorreu ao serviço de urgência por apresentar tosse produtiva e expectoração hemoptóica desde há cerca de dois meses, motivo porque foi agendada broncofibroscopia. Apresentava neoformações sésseis, cerca de 2 cm abaixo das cordas vocais e ao longo da vertente póstero-lateral do terço médio da traqueia, que condicionavam obstrução significativa, motivo pelo qual foi realizada broncoscopia rígida para colocação de prótese endotraqueal.Dada a instabilidade clínica e grande suspeição de malignidade o doente inicia radioterapia. O diagnóstico obtido foi de linfoma anaplásico de células grandes, CD 30+. Por insuficiência respiratória, com estridor, foi necessário retirar a prótese que se encontrava obstruída por um rolhão de secreções, ficando a traqueia patente.O doente teve alta, estando actualmente estabilizado do ponto de vista respiratório e submetido a quimioterapia com CHOP (Ciclophosphamide, Adriamycin or Hydroxydorubicin, Vincristine or Oncovin and Prednisone.O linfoma de grandes células primário do mediastino corresponde a 11.5% dos linfomas de grandes células (2% dos linfomas não Hodgkin. Apesar da maioria dos estudos o classificarem como incurável, há registos de resultados positivos com o recurso à irradiação mediastínica combinada com quimioterapia podendo, quando existe compromisso da via aérea, a colocação de uma prótese permitir a patência da mesma.Rev Port Pneumol 2006; XII (3: 303-308 Abstract: Male, 54 years old, with smoking habits. The patient complaints were cough, with bleeding secretions in the previous two months. Because of the persistence of the symptoms, a broncoscopy was proposed. This exam showed multiple lesions in the traquea, nearly 2 cm above the vocal cords that compromised the airway and did not allow the progression

mPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis.

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Yu, Jing; Wu, Yimei; Wang, Lu; Zhang, Wen; Xu, Man; Song, Jiayu; Fu, Yu; Cui, Yiyun; Gong, Wei; Li, Shuzhen; Xia, Weiwei; Huang, Songming; Zhang, Aihua; Jia, Zhanjun

2017-11-01

We previously reported that microsomal prostaglandin E synthase-1 (mPGES-1) contributed to adriamycin (Adr)-induced podocyte apoptosis. However, the molecular mechanism remains unclear. Here we studied the role of mPGES-1/PGE2 cascade in activating Stat3 signaling and the contribution of Stat3 in PGE2- and Adr-induced podocyte apoptosis. In murine podocytes, PGE2 dose- and time-dependently increased the phosphorylation of Stat3 in line with the enhanced cell apoptosis and reduced podocyte protein podocin. In agreement with the increased Stat3 phosphorylation, Stat3-derived cytokines including IL-6, IL-17, MCP-1, and ICAM-1 were significantly upregulated following PGE2 treatment. By application of a specific Stat3 inhibitor S3I-201, PGE2-induced podocyte apoptosis was largely abolished in parallel with a blockade of podocin reduction. Next, we observed that Adr treatment also enhanced p-Stat3 and activated mPGES-1/PGE2 cascade. Blockade of Stat3 by S3I-201 significantly ameliorated Adr-induced cell apoptosis and podocin reduction. More interestingly, silencing mPGES-1 in podocytes by mPGES-1 siRNA blocked Adr-induced increments of Stat-3 phosphorylation, PGE2 production, and Stat3-derived inflammatory cytokines. Taken together, this study suggested that mPGES-1-derived PGE2 could activate Stat3 signaling to promote podocyte apoptosis. Targeting mPGES-1/PGE2/Stat3 signaling might be a potential strategy for the treatment of podocytopathy.

Combination therapy with hormonal, radiation and chemotherapy for stage C prostate cancer

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Iwasawa, Toshihisa; Matsumoto, Hidetsugu

1996-01-01

To improve the effectiveness of treatment for patients with stage C prostate cancer, therapy in combination with hormonal, radiation and chemotherapy was given for the initial period, and there after, hormonal therapy was continuously administered to 18 patients with chemotherapy and three patients without it. At the Social Health Insurance Medical Center, between May 1988 and August 1991, 21 patients were diagnosed to have stage C histologically confirmed adenocarcinoma of the prostate. The average age of the patients was 69.0 years. The tumor was well, moderate and poorly differentiated in 5, 6 and 10 patients, respectively. As hormonal therapy, orchiectomy was performed on 19 of the 21 patients. Furthermore, 11 patients were administered estramustine phosphate, 9 chlormadinone acetate, and one diethylstilbesterol diphosphate. As, radiation therapy, all patients were treated with AP-PA parallel opposing technique to small pelvis with a 12 cm x 12 cm treatment field (44-45 Gy) combined with conformation radiotherapy to prostate (20-26 Gy). Chemotherapy was performed using either one or a combination of the following; cis-diamminedichloroplatinum, adriamycin, cyclophosphamide, 5-fluorouracil, methotrexate and etoposide. The observation period was 54.5 months on the average. Recurrence was observed in 3 patients, for all of which the sites were at bone. The 5-year non-recurrence rate was 90.4% by Kaplan-Meier's method. There were 4 deaths, three were due to prostate cancer and one to gastric cancer. The 5-year cumulative survival rate by Kaplan-Meier's method was 90.5%. In conclusion, this treatment was effective for stage C cases of prostate cancer. (author)

The role of stem cell mobilization regimen on lymphocyte collection yield in patients with multiple myeloma.

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Hiwase, D K; Hiwase, S; Bailey, M; Bollard, G; Schwarer, A P

2008-01-01

The lymphocyte dose (LY-DO) infused during an autograft influences absolute lymphocyte (ALC) recovery and survival following autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients. Factors influencing lymphocyte yield (LY-C) during leukapheresis have been poorly studied. Factors that could influence survival, LY-C and CD34(+) cell yield were analyzed in 122 MM patients. Three mobilization regimens were used, granulocyte-colony-stimulating factor (G-CSF) alone (n=13), cyclophosphamide 1-2 g/m(2) plus G-CSF (LD-CY, n=62) and cyclophosphamide 3-4 g/m(2) and G-CSF (ID-CY, n=47). Using multivariate analysis, age, LY-C, ALC on day 30 (ALC-30) and International Staging System stage significantly influenced overall (OS) and progression-free survival (PFS) following ASCT. PFS (56 versus 29 months, P=0.05) and OS (72 versus 49 months; P=0.07) were longer in the LY-C>or=0.12x10(9)/kg group than the LY-Cradiotherapy and number of leukaphereses significantly influenced LY-C. Significantly higher LY-C was obtained with G-CSF alone compared with the LD-CY and ID-CY groups. CD34(+) count on the day of leukapheresis, prior chemotherapy with prednisone, cyclophosphamide, adriamycin and BCNU or melphalan, and stem cell mobilization regimen significantly influenced CD34(+) cell yield. LY-C influenced ALC-15 and survival following ASCT. Factors that influenced CD34(+) cell yield and LY-C during leukapheresis were different. Mobilization should be tailored to maximize the LY-C and CD34(+) cell yield.

Glutathione Depletion Induced by c-Myc Downregulation Triggers Apoptosis on Treatment with Alkylating Agents1

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Biroccio, Annamaria; Benassi, Barbara; Fiorentino, Francesco; Zupi, Gabriella

2004-01-01

Abstract Here we investigate the mechanism(s) involved in the c-Myc-dependent drug response of melanoma cells. By using three M14-derived c-Myc low-expressing clones, we demonstrate that alkylating agents, cisplatin and melphalan, trigger apoptosis in the c-Myc antisense transfectants, but not in the parental line. On the contrary, topoisomerase inhibitors, adriamycin and camptothecin, induce apoptosis to the same extent regardless of c-Myc expression. Because we previously demonstrated that c-Myc downregulation decreases glutathione (GSH) content, we evaluated the role of GSH in the apoptosis induced by the different drugs. In control cells treated with one of the alkylating agents or the others, GSH depletion achieved by l-buthionine-sulfoximine preincubation opens the apoptotic pathway. The apoptosis proceeded through early Bax relocalization, cytochrome c release, and concomitant caspase-9 activation, whereas reactive oxygen species production and alteration of mitochondria membrane potential were late events. That GSH was determining in the c-Myc-dependent drug-induced apoptosis was demonstrated by altering the intracellular GSH content of the c-Myc low-expressing cells up to the level of controls. Indeed, GSH ethyl ester-mediated increase of GSH abrogated apoptosis induced by cisplatin and melphalan by inhibition of Bax/cytochrome c redistribution. The relationship among c-Myc, GSH content, and the response to alkylating agent has been also evaluated in the M14 Myc overexpressing clones as well as in the melanoma JR8 c-Myc antisense transfectants. All together, these results demonstrate that GSH plays a key role in governing c-Myc-dependent drug-induced apoptosis. PMID:15153331

Comparison of the multi-drug resistant human hepatocellular carcinoma cell line Bel-7402/ADM model established by three methods

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Zhong Xingguo

2010-08-01

Full Text Available Abstract Background To compare the biological characteristics of three types of human hepatocellular carcinoma multi-drug resistant cell sub-lines Bel-7402/ADM models established by three methods. Methods Established human hepatocellular carcinoma adriamycin (ADM multi-drug resistant cell sub-lines models Bel-7402/ADMV, Bel-7402/ADML and Bel-7402/ADMS by three methods of in vitro concentration gradient increased induction, nude mice liver-implanted induction and subcutaneous-implanted induction respectively. Phase contrast microscopy was used to observe the cells and the MTT (methyl thiazolyl tetrazolium method was used to detect drug resistance of the three different sub-lines of cells. Results The three groups of drug resistant cells, Bel-7402/ADMV, Bel-7402/ADML and Bel-7402/ADMS generated cross-resistance to ADM and CDDP (cis-Diaminedichloroplatinum, but showed a significant difference in resistance to Bel-7402 IC50 value (P V, 46 h (Bel-7402/ADML, and 45 h (Bel-7402/ADMS. The excretion rates of ADM were significantly increased compared with the parent cell (34.14% line and were 81.06% (Bel-7402/ADMV, 66.56% (Bel-7402/ADML and 61.56% (Bel-7402/ADMS. Expression of P-gp and MRP in the three groups of resistant cells was significantly enhanced (P P > 0.05. Conclusions Stable resistance was involved in the resistant cell line model established by the above three methods. Liver implantation was a good simulation of human hepatocellular and proved to be an ideal model with characteristics similar to human hepatocellular biology and the pharmacokinetics of anticancer drugs.

Dual drug delivery using “smart” liposomes for triggered release of anticancer agents

International Nuclear Information System (INIS)

Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K.

2013-01-01

Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel–topotecan (Pac–Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-α) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG 2000 –DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG 2000 –DSPE:DSPE–PEG–folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 ± 0.5 °C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 ± 1 °C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac–Top free (20:1, w/w) to be more toxic (GI 50 = 6.5 μg/ml) than positive control (Adriamycin, GI 50 = 9.1 μg/ml) and FR-targeted PEGylated liposomes GI 50 (14.7 μg/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called “smart liposomes” which has not only mediated effective targeting to FR-α but also triggered release of drugs upon hyperthermia

Assessment of late cardiotoxicity of pirarubicin (THP) in children with acute lymphoblastic leukemia.

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Shimomura, Yasuto; Baba, Reizo; Watanabe, Arata; Horikoshi, Yasuo; Asami, Keiko; Hyakuna, Nobuyuki; Iwai, Asayuki; Matsushita, Takeshi; Yamaji, Kazutaka; Hori, Toshinori; Tsurusawa, Masahito

2011-09-01

Pirarubicin (tetrahydropyranyl-adriamycin: THP) is a derivative of doxorubicin with reportedly less cardiotoxicity in adults. However no studies of cardiotoxicity in children treated with THP have been reported. This study was performed to assess the THP-induced cardiotoxicity for children with acute lymphoblastic leukemia (ALL). This study comprised 61 asymptomatic patients aged from 7.6 to 25.7 years old. Median follow-up time after completion of anthracycline treatment was 8.1 years (range: 1.7-12.5). The cumulative dose of THP ranged from 120 to 740 mg/m(2) with a median of 180 mg/m(2) . Patients underwent electrocardiogram (ECG), echocardiography, the 6-min walk test (6MWT), and measurements of serum brain natriuretic peptide (BNP) before and after exercise. All subjects showed normal left ventricular function assessed by echocardiography. Ventricular premature contraction in Holter ECG and reduced exercise tolerance in the 6MWT were detected in 2/46 (3.3%) and 5/41(12.2%), respectively. Abnormal BNP levels were detected in 6/60 (10%) both before and after exercise. The cumulative dose of THP was significantly correlated with BNP levels after exercise (r = 0.27, P = 0.03), but not with any other cardiac measurements. Further analysis revealed that subjects with a high cumulative dose ≧300 mg/m(2) had significantly higher BNP levels after exercise compared with subjects with a low cumulative dose THP treatment. The use of post-exercise BNP level to indicate high cardiotoxicity risk should be verified by further study. Copyright © 2011 Wiley-Liss, Inc.

Intra-arterial chemotherapy for locally advanced bladder cancer

International Nuclear Information System (INIS)

Aota, Yasuhiro; Yoshida, Kazuhiko

1999-01-01

A total of 83 patients with locally advanced bladder cancer (T1, n=5; T2, n=28; T3a, n=21; T3b, n=21; T4, n=8) were treated with intra-arterial (i.a.) cisplatin and adriamycin (or epirubicin) chemotherapy. In 51 of the 83 cases, we combined this treatment with radiotherapy. The pathological complete response (CR) rate was 68% for all patients, 84% for i.a. chemotherapy combined with radiotherapy and only 41% for i.a. chemotherapy. The 5-year survival rate was 57% for all patients, 71% for i.a. chemotherapy combined with radiotherapy and only 44% for i.a. chemotherapy. The 5-year survival as a function of the clinical stage was 82% for T1+T2, 66% for T3a, 28% for T3b, 25% for T4 (T1+T2 vs. T3b: p<0.001, T1+T2 vs. T4: p<0.0001, T3a vs. T3b: p<0.0263, T3a vs. T4: p<0.0214, T3b vs. T4: p<0.029). In 46% of all patients, we succeeded in preserving the bladder; especially noteworthy, is that in 65% of the patients undergoing i.a. chemotherapy combined with radiotherapy, we succeeded in preserving the bladder. These results demonstrate that i.a. chemotherapy combined with radiotherapy is a useful method for locally advanced bladder cancer which may make preservation of the bladder function feasible. (author)

Analysis of prognostic factors in patients with hepatocellular carcinoma after transcatheter hepatic arterial chemoembolization(TAE)

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Kim, Tae Gwon; Byun, Kyung Hwan; Oh, Hyun Han; Ryeom, Hun Kyu; Kim, Yong Joo [Kyungpook National Univ. Hospital, Taegu (Korea, Republic of)

1996-07-01

To evaluate long-term survival rates and prognostic factors of patients with hepatocellular carcinoma after TAE. 225 patients with hepatocellular carcinoma treated with TAE between January 1988 and December 1994 were studied. Hepatocellular carcinoma was diagnosed either histologically(n=13) or clinically on the basis of findings characteristic for hepatocellular carcinoma obtained using such as diagnostic imaging methods such as ultrasonography, CT, MRI, and angiography as well as on the basis of high serum alpha-fetoprotein level(n=212). TAE was carried out between one and six times(mean, 1.4 time) using a mixture of lipiodol and Adriamycin, together with Gelfoam. Cumulative survival rates from the day of the first TAE were obtained by the Kaplan-Meier method. Parameters likely to influence the prognosis were subjected to univariate analysis using the log-rank test Cumulative survival rates at the end of the first, second, third, fourth, and fifth year were 55.9%, 32.6%, 21.9%, 17.9%, and 15.0%, respectively. The mean survival time was 727{+-}76 days. Several factors, including Child-Pugh classification, Okuda's stage, tumor size, presence of portal vein invasion by tumor, of arterio-portal shunt, and of extrahepatic metastases, catheter selection level, and number of TAE showed significant correlation with the outcome. Degrees of Lipiodol accumulation in a tumor on follow up CT were also correlated with survival rates. TAE is an effective measure for prolonging the patient's life expectancy and evaluation of prognostic factor is helpful for prognosis and in deciding on the optimal therapeutic modality.

Chaetominine reduces MRP1-mediated drug resistance via inhibiting PI3K/Akt/Nrf2 signaling pathway in K562/Adr human leukemia cells

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Yao, Jingyun; Wei, Xing [State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai (China); Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai (China); Lu, Yanhua, E-mail: luyanhua@ecust.edu.cn [State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai (China); Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai (China)

2016-05-13

Drug resistance limits leukemia treatment and chaetominine, a cytotoxic alkaloid that promotes apoptosis in a K562 human leukemia cell line via the mitochondrial pathway was studied with respect to chemoresistance in a K562/Adr human resistant leukemia cell line. Cytotoxicity assays indicated that K562/Adr resistance to adriamycin (ADR) did not occur in the presence of chaetominine and that chaetominine increased chemosensitivity of K562/Adr to ADR. Data show that chaetominine enhanced ADR-induced apoptosis and intracellular ADR accumulation in K562/Adr cells. Accordingly, chaetominine induced apoptosis by upregulating ROS, pro-apoptotic Bax and downregulating anti-apoptotic Bcl-2. RT-PCR and western-blot confirmed that chaetominine suppressed highly expressed MRP1 at mRNA and protein levels. But little obvious alternation of another drug transporter MDR1 mRNA was observed. Furthermore, inhibition of MRP1 by chaetominine relied on inhibiting Akt phosphorylation and nuclear Nrf2. In summary, chaetominine strongly reverses drug resistance by interfering with the PI3K/Akt/Nrf2 signaling, resulting in reduction of MRP1-mediated drug efflux and induction of Bax/Bcl-2-dependent apoptosis in an ADR-resistant K562/Adr leukemia cell line. - Highlights: • Chaetominine enhanced chemosensitivity of ADR against K562/Adr cells. • Chaetominine increased intracellular ADR levels via inhibiting MRP1. • Chaetominine induced apoptosis of K562/Adr cells through upregulation of ROS and modulation of Bax/Bcl-2. • Inhibition of MRP1 and Nrf2 by chaetominine treatment was correlative with blockade of PI3K/Akt signaling.

Clinical application of l-123 MlBG cardiac imaging

International Nuclear Information System (INIS)

Kang, Do Young

2004-01-01

Cardiac neurotransmission imaging allows in vivo assessment of presynaptic reuptake, neurotransmitter storage and postsynaptic receptors. Among the various neurotransmitter, I-123 MlBG is most available and relatively well-established. Metaiodobenzylguanidine (MIBG) is an analogue of the false neurotransmitter guanethidine. It is taken up to adrenergic neurons by uptake-1 mechanism as same as norepinephrine. As tagged with I-123, it can be used to image sympathetic function in various organs including heart with planar or SPECT techniques. I-123 MIBG imaging has a unique advantage to evaluate myocardial neuronal activity in which the heart has no significant structural abnormality or even no functional derangement measured with other conventional examination. In patients with cardiomyopathy and heart failure, this imaging has most sensitive technique to predict prognosis and treatment response of betablocker or ACE inhibitor. In diabetic patients, it allow very early detection of autonomic neuropathy. In patients with dangerous arrhythmia such as ventricular tachycardia or fibrillation, MIBG imaging may be only an abnormal result among various exams. In patients with ischemic heart disease, sympathetic derangement may be used as the method of risk stratification. In heart transplanted patients, sympathetic reinnervation is well evaluated. Adriamycin-induced cardiotoxicity is detected earlier than ventricular dysfunction with sympathetic dysfunction. Neurodegenerative disorder such as Parkinson's disease or dementia with Lewy bodies has also cardiac sympathetic dysfunction. Noninvasive assessment of cardiac sympathetic nerve activity with l-123 MlBG imaging may be improve understanding of the pathophysiology of cardiac disease and make a contribution to predict survival and therapy efficacy

Clinical application of l-123 MlBG cardiac imaging

Energy Technology Data Exchange (ETDEWEB)

Kang, Do Young [College of Medicine, Donga Univ., Busan (Korea, Republic of)

2004-10-01

Cardiac neurotransmission imaging allows in vivo assessment of presynaptic reuptake, neurotransmitter storage and postsynaptic receptors. Among the various neurotransmitter, I-123 MlBG is most available and relatively well-established. Metaiodobenzylguanidine (MIBG) is an analogue of the false neurotransmitter guanethidine. It is taken up to adrenergic neurons by uptake-1 mechanism as same as norepinephrine. As tagged with I-123, it can be used to image sympathetic function in various organs including heart with planar or SPECT techniques. I-123 MIBG imaging has a unique advantage to evaluate myocardial neuronal activity in which the heart has no significant structural abnormality or even no functional derangement measured with other conventional examination. In patients with cardiomyopathy and heart failure, this imaging has most sensitive technique to predict prognosis and treatment response of betablocker or ACE inhibitor. In diabetic patients, it allow very early detection of autonomic neuropathy. In patients with dangerous arrhythmia such as ventricular tachycardia or fibrillation, MIBG imaging may be only an abnormal result among various exams. In patients with ischemic heart disease, sympathetic derangement may be used as the method of risk stratification. In heart transplanted patients, sympathetic reinnervation is well evaluated. Adriamycin-induced cardiotoxicity is detected earlier than ventricular dysfunction with sympathetic dysfunction. Neurodegenerative disorder such as Parkinson's disease or dementia with Lewy bodies has also cardiac sympathetic dysfunction. Noninvasive assessment of cardiac sympathetic nerve activity with l-123 MlBG imaging may be improve understanding of the pathophysiology of cardiac disease and make a contribution to predict survival and therapy efficacy.

In vitro studies to evaluate the antioxidant property of salidroside and rosavin and protective effects of electron beam radiation induced damages in human dermal fibroblasts

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Tejashvi, Kedilaya R.; Padma, Shetty K.; Suchetha Kumari, N.

2014-01-01

Rosavin and Salidroside are active component of Rhodiola rosea, it is a phenylpropanoid derivative of plant. Rhodiola rosea, also known as 'golden root' or 'roseroot' belongs to the plant family Crassulaceae. Rhodiola grows primarily in dry sandy ground at high altitudes in the arctic areas of Europe and Asia. Plant is rich with phenolic compounds, known to have a strong antioxidant property. Studies have shown that Rhodiola rosea has a capacity to decrease toxicity of Adriamycin (anti-cancer drugs), while it enhances their anti-carcinogenic effects. Enhanced antioxidant activity of Rhodiola rosea play role in the prevention of both chronic disease and aging. Present study is aimed to determine the antioxidant property of Rosavin and Salidroside and dose determination on human dermal fibroblast against dermal fibroblast. Rosavin and Salidroside were dissolved in 10% DMSO. Invitro biochemical assays like DPPH radical scavenging assay, Ferric Anion Reducing Potential using TPTZ, Nitric Oxide scavenging assay, Total antioxidant determination assay, Super Anion Radical Scavenging assays were carried out to know property of the extract. Extracts were then treated on monolayer dermal fibroblast cells survival assay was performed. Salidroside has shown 80% total antioxidant property compare to Rosavin with respect Ascorbic acid as a standard. 100'R concentration of Salidroside and Rosavin has quite equal potential to scavenging DPPH similar like Ascorbic acid. Ferric Anion Reducing Potential using TPTZ, Nitric Oxide scavenging assays have also shown both Salidroside and Rosavin has a good antioxidant property. Invitro studies on dermal fibroblast have shown remarkable protective effect on normal and irradiated groups. (author)

Expression of agrin, dystroglycan, and utrophin in normal renal tissue and in experimental glomerulopathies.

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Raats, C J; van den Born, J; Bakker, M A; Oppers-Walgreen, B; Pisa, B J; Dijkman, H B; Assmann, K J; Berden, J H

2000-05-01

The dystrophin-glycoprotein complex, which comprises alpha- and beta-dystroglycan, sarcoglycans, and utrophin/dystrophin, links the cytoskeleton to agrin and laminin in the basal lamina in muscle and epithelial cells. Recently, agrin was identified as a major heparan sulfate proteoglycan in the glomerular basement membrane. In the present study, we found mRNA expression for agrin, dystroglycan, and utrophin in kidney cortex, isolated glomeruli, and cultured podocytes and mesangial cells. In immunofluorescence, agrin was found in the glomerular basement membrane. The antibodies against alpha- and beta-dystroglycan and utrophin revealed a granular podocyte-like staining pattern along the glomerular capillary wall. With immunoelectron microscopy, agrin was found in the glomerular basement membrane, dystroglycan was diffusely found over the entire cell surface of the podocytes, and utrophin was localized in the cytoplasm of the podocyte foot processes. In adriamycin nephropathy, a decrease in the glomerular capillary wall staining for dystroglycan was observed probably secondary to the extensive fusion of foot processes. Immunoelectron microscopy showed a different distribution pattern as compared to the normal kidney, with segmentally enhanced expression of dystroglycan at the basal side of the extensively fused podocyte foot processes. In passive Heymann nephritis we observed no changes in the staining intensity and distribution of the dystrophin-glycoprotein complex by immunofluorescence and immunoelectron microscopy. From these data, we conclude that agrin, dystroglycan, and utrophin are present in the glomerular capillary wall and their ultrastructural localization supports the concept that these molecules are involved in linking the podocyte cytoskeleton to the glomerular basement membrane.

Sentinel lymph node biopsy using dye alone method is reliable and accurate even after neo-adjuvant chemotherapy in locally advanced breast cancer - a prospective study

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Mishra Ashwani

2011-02-01

Full Text Available Abstract Background Sentinel lymph node biopsy (SLNB is now considered a standard of care in early breast cancers with N0 axillae; however, its role in locally advanced breast cancer (LABC after neo-adjuvant chemotherapy (NACT is still being debated. The present study assessed the feasibility, efficacy and accuracy of sentinel lymph node biopsy (SLNB using "dye alone" (methylene blue method in patients with LABC following NACT. Materials and methods Thirty, biopsy proven cases of LABC that had received three cycles of neo-adjuvant chemotherapy (cyclophosphamide, adriamycin, 5-fluorouracil were subjected to SLNB (using methylene blue dye followed by complete axillary lymph node dissection (levels I-III. The sentinel node(s was/were and the axilla were individually assessed histologically. The SLN accuracy parameters were calculated employing standard definitions. The SLN identification rate in the present study was 100%. The sensitivity of SLNB was 86.6% while the accuracy was 93.3%, which were comparable with other studies done using dual lymphatic mapping method. The SLN was found at level I in all cases and no untoward reaction to methylene blue dye was observed. Conclusions This study confirms that SLNB using methylene blue dye as a sole mapping agent is reasonably safe and almost as accurate as dual agent mapping method. It is likely that in the near future, SLNB may become the standard of care and provide a less morbid alternative to routine axillary lymph node dissection even in patients with LABC that have received NACT.

Uses of chemotherapy together with radiation, and its biological basis

International Nuclear Information System (INIS)

Watanabe, Ikuo; Terashima, Toyozo

1978-01-01

Effect of use of anticancer drugs together with radiation, especially effects of Actinomycin D (AMD), Bleomycin (BLM), and Adriamycin (Ad) which seemed to have synergistic effect, and other substances which have possibility to have synergistic effect were described. It was clarified that AMD out of them showed synergistic effect to inhibit repair of sublethel damage induced by irradiation in addition to anticancer effect itself. Therefore, it is thought that use of AMD is effective especially to cancer with high radioresistance and it is better to administer this drug just before or just after irradiation. It seems to be better to administer at one time with high concentration in the allowable range. It is difficult to come to a conclusion as to BLM and Ad, generalized as well as the conclusion of AMD, but it seems to be better to use BLM and Ad together with irradiation at the same time. As BLM is highly effective especially to epithelial cells, it must be necessary to investigate whether there is a difference of characteristics between cells. In any case, there are two great factors, the concentration and action time (containing the time remaining in vivo) of drugs, and moreover, another factor, time relation to irradiation is added. Therefore, an experiment schedule is complicated so much, and it is important to study quantitatively on the basis of systematic experimental plan. As to clinical application of them, it is necessary to perform an experiment in vitro which is exullent in estimation and an experiment in vivo which certified the effects in keeping organic cooperation. (Tsunoda, M.)

Dual drug delivery using "smart" liposomes for triggered release of anticancer agents

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Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K.

2013-07-01

Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-α) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG2000-DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG2000-DSPE:DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 ± 0.5 °C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 ± 1 °C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI50 = 6.5 μg/ml) than positive control (Adriamycin, GI50 = 9.1 μg/ml) and FR-targeted PEGylated liposomes GI50 (14.7 μg/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called "smart liposomes" which has not only mediated effective targeting to FR-α but also triggered release of drugs upon hyperthermia.

CHOD/BVAM Chemotherapy and Whole-Brain Radiotherapy for Newly Diagnosed Primary Central Nervous System Lymphoma

International Nuclear Information System (INIS)

Laack, Nadia N.; O'Neill, Brian Patrick; Ballman, Karla V.; O'Fallon, Judith Rich; Carrero, Xiomara W.; Kurtin, Paul J.; Scheithauer, Bernd W.; Brown, Paul D.; Habermann, Thomas M.; Colgan, Joseph P.; Gilbert, Mark R.; Hawkins, Roland B.; Morton, Roscoe F.; Windschitl, Harry E.; Fitch, Tom R.; Pajon, Eduardo R.

2011-01-01

Purpose: To assess the efficacy and toxicity of chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and dexamethasone (CHOD) plus bis-chloronitrosourea (BCNU), cytosine arabinoside, and methotrexate (BVAM) followed by whole-brain irradiation (WBRT) for patients with primary central nervous system lymphoma (PCNSL). Methods and Materials: Patients 70 years old and younger with newly diagnosed, biopsy-proven PCNSL received one cycle of CHOD followed by two cycles of BVAM. Patients then received WBRT, 30.6 Gy, if a complete response was evoked, or 50.4 Gy if the response was less than complete; both doses were given in 1.8-Gy daily fractions. The primary efficacy endpoint was 1-year survival. Results: Thirty-six patients (19 men, 17 women) enrolled between 1995 and 2000. Median age was 60.5 years (range, 34 to 69 years). Thirty (83%) patients had baseline Eastern Cooperative Oncology Group performance scores of 0 to 1. All 36 patients were eligible for survival and response evaluations. Median time to progression was 12.3 months, and median survival was 18.5 months. The percentages of patients alive at 1, 2, and 3 years were 64%, 36%, and 33%, respectively. The best response was complete response in 10 patients and immediate progression in 7 patients. Ten (28%) patients had at least one grade 3 or higher neurologic toxicity. Conclusions: This regimen did improve the survival of PCNSL patients but also caused substantial toxicity. The improvement in survival is less than that reported with high-dose methotrexate-based therapies.

Whole abdominal irradiation following chemotherapy in advanced ovarian carcinoma

International Nuclear Information System (INIS)

Kuten, A.; Stein, M.; Steiner, M.; Rubinov, R.; Epelbaum, R.; Cohen, Y.

1988-01-01

One hundred and sixteen patients with advanced ovarian carcinoma, who underwent primary cytoreductive surgery, received 6-11 courses of chemotherapy by cis-platin (50 mg/m2) and adriamycin (50 mg/m2) every 21 days. This was followed by second look laparotomy in 66 patients with no clinical evidence of disease. Consolidation abdominal irradiation was administered to 43 patients. Two techniques of irradiation were employed: between 1980-1983 whole abdominal irradiation was used and patients were to receive 3000 cGy in 4 weeks (Schedule I). Due to myelosuppression only 13 of 26 patients (50%) completed the planned dose of radiation. Between 1983-1985 the target volume was divided into upper and lower parts. First, the lower abdomen received 3000 cGy in 3 weeks, and then the upper abdomen received the same dose (Schedule II). Sixteen of seventeen patients (94%) thus treated, completed the planned dose of radiation. The actuarial survival for all 116 patients was 28% of 5 years. Irradiated patients with negative second look laparotomy had a survival probability of 100% at 24 months. Irradiated patients with microscopic disease at second look operation had an actuarial 5-year survival of 66%. Patients with minimal residual disease at second look laparotomy, receiving consolidation abdominal irradiation, had an actuarial survival of 5% only at 36 months. It is concluded that consolidation radiotherapy is effective in patients with negative or microscopic residual disease at second-look laparotomy. In regard to bone marrow tolerance, split field technique of irradiation is preferred

Waldenström makroglobulinemili hastada rituksimab tedavisi sonrası gelişen gizli hepatit B reaktivasyonu

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Vedat Aslan

2012-12-01

Full Text Available The anti-CD20 monoclonal antibody rituximab has beenused extensively in the treatment of B-cell lymphoma.Several studies reported hepatitis B virus (HBV reactivationafter rituximab. The majority of these cases havebeen described in chronic carriers of HBV, whereas reactivationin occult hepatitis B virus (OHBV carriers mayoccur.The presented case with the diagnosis of Waldenström’smacroglobulinemia was HBsAg negative and anti HBcIgGpositive before chemotherapy. The patient was started onCVP (cyclophosphamide, vincristine, prednisolone chemotherapy.However, no clinical or laboratory responsewas obtained and the patient was considered unresponsiveto three cycles of CVP therapy. Therefore R-CHOP(rituximab, cyclophosphamide, adriamycin, vincristineand prednisolone was planned as the second therapy.Laboratory work-up after the first cycle of R-CHOP therapyrevealed an aspartate aminotransferase (AST levelof 267 U/L and alanine aminotransferase (ALT level of318 U/L. HBsAg and anti HBcIgG were positive and HBVDNA was 56400 IU/ml. Lamivudin 100 mg/day was started.Four weeks after the initiation of lamivudin therapy,ALT and AST levels returned to normal. Currently, the patienthas received the fourth cycle of R-CHOP therapy.ALT and AST levels continue to be in normal range. Thiscondition was considered to be the reactivation of OHBVfollowing rituximab.The aim of this case presentation is to call attention toHBV reactivation possibility in cases taking immunosupressivemedications like Rituximab. J Clin Exp Invest2012; 3(4: 541-544Key words: Waldenström’s macroglobulinemia, rituximab,occult HBV infection

[Knockdown of DNA-PKcs inhibits cell cycle and its mechanism of drug-resistant Bel7402/5-Fu hepatocellular carcinoma cells].

Science.gov (United States)

Li, Dayu; Liu, Yun; Yu, Chunbo; Liu, Xiping; Fan, Fang

2017-12-01

Objective To study the effect of the knock-down of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) on the cell cycle of the multidrug-resistant (MDR) Bel7402/5-Fu hepatocellular carcinoma cells and its MDR mechanism. Methods After cationic liposome-mediated siDNA-PKcs oligonucleotide transfection, the drug sensitivity of Bel7402/5-Fu cells to 5-fluorouracil (5-Fu) and adriamycin (ADM) was determined by MTT assay; the cell cycle were detected by flow cytometry; meanwhile, the protein expressions of cell cycle-related proteins P21, cell cycle protein B1 (cyclin B1), cell cycle division protein 2 (CDC2) were tested by Western blotting; the expressions of ataxia telangiectasia mutated (ATM) and p53 at both mRNA and protein levels were detected by real-time PCR and Western blot analysis. Results The MTT results showed siDNA-PKcs increased the chemotherapeutic sensitivity of Bel7402/5-Fu cells to 5-Fu and ADM. The flow cytometric analysis showed siDNA-PKcs decreased the percentage of S-phase cells but increased the percentage of G2/M phase cells. Western blotting showed siDNA-PKcs increased the protein expression of P21 but decreased cyclinB1 and CDC2 proteins. In addition, siDNA-PKcs also increased the expressions of ATM and p53. Conclusion DNA-PKcs silencing increases P21 while decreases cyclin B1 and CDC2 expressions, and finally induces G2/M phase arrest in Bel7402/5-Fu cells, which may be related to ATM-p53 signaling pathway.

Chemoradiotherapy for muscle invading bladder carcinoma. final report of a single institutional organ-sparing program

International Nuclear Information System (INIS)

Arias, Fernando; Dominguez, Miguel A.; Martinez, Enrique; Illarramendi, Jose J.; Miquelez, Santiago; Pascual, Ignacio; Marcos, Marta

2000-01-01

Purpose: Chemoradiotherapy is becoming an alternative to radical cystectomy among patients with muscle invading bladder cancer. We began a prospective study in 1988 to determine the possibilities of conservative treatment and aiming to improve the results obtained by cystectomy alone in invasive bladder cancer. A combination of methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC), followed by radiotherapy and concomitant cisplatin was used. Methods: Fifty patients with good performance status and with stages T2 to T4 operable untreated invasive bladder cancer were entered in the study. Treatment protocol was as follows: (i) cytoreductive transurethral resection; (ii) two cycles of M-VAC chemotherapy; (iii) radiotherapy, 45 Gy on pelvic volume and, at the same time, 20 mg/m 2 cisplatin on days 1 to 5. Cystoscopic evaluation: if there was a complete response, radiotherapy was completed up to 65 Gy; if there was not a complete response, a cystectomy was performed. Median follow-up of the series was 73 months (18-180 m). Results: Tumor response was as follows: 34 complete responses (68%), 9 partial responses (18%), and 7 nonresponses (14%) were observed. The 5-year overall survival and local control were 48% and 47%, respectively. For the complete responder patient, 5-year survival and local control were 65% and 70%, respectively. Severe toxicity was uncommon. The most frequent were leucopenia and cystitis. No treatment-related deaths occurred with either treatment protocol. Conclusions: Conservative combination treatment may be an acceptable alternative to immediate cystectomy in selected patients with bladder cancer, although a randomized clinical trial would be required to produce definitive results

A prospective randomized study of Chop versus Chop plus alpha-2B interferon in patients with intermediate and high grade non-Hodgkin's lymphoma: the International Oncology Study Group NHL1 Study .

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Giles, F J; Shan, J; Advani, S H; Akan, H; Aydogdu, I; Aziz, Z; Azim, H A; Bapsy, P P; Buyukkececi, F; Chaimongkol, B; Chen, P M; Cheong, S K; Ferhanoglu, B; Hamza, R; Khalid, H M; Intragumtornchai, T; Kim, S W; Kim, S Y; Koc, H; Kumar, L; Kumar, R; Lei, K I; Lekhakula, A; Muthalib, A; Patel, M; Poovalingam, V P; Prayoonwiwat, W; Rana, F; Reksodiputro, A H; Ruff, P; Sagar, T G; Schwarer, A P; Song, H S; Suh, C W; Suharti, C; Supindiman, I; Tee, G Y; Thamprasit, T; Villalon, A H; Wickham, N R; Wong, J E; Yalcin, A; Jootar, S

2000-12-01

The addition of a brief alpha interferon regimen to each CHOP induction cycle, plus one year of alpha interferon thrice weekly maintenance therapy, has no early effect on response rates or survival in patients with Intermediate or High grade cell NHL. The CHOP (Cyclophosphamide, Adriamycin. Vincristine, Prednisone) regimen is the most widely used first-line therapy for patients with Intermediate or High Grade (IG/HG) non-Hodgkin's lymphoma (NHL). Alpha 2b interferon (INF) enhances response rates and improves survival in low-grade NHL. The International Oncology Study Group (IOSG) conducted a prospective randomized study comparing CHOP alone or combined with INF in patients with IG/HG-NHL. The primary study aim was to compare the objective response rates in these patient cohorts. Patients with a confirmed diagnosis of measurable NHL of International Working Formulation (IWF) groups D to H histology were randomized to receive CHOP alone or CHOP with 5Mu INF s.c. for 5 days on days 22 to 26 of each 28 day cycle with INF 5 million units (Mu) given three times per week subcutaneously for 52 weeks in those patients who responded to CHOP plus INF. The overall response rates were equivalent in both groups: CHOP alone (214 patients) 81% (complete 55%, partial 26%); CHOP plus INF (221 patients) 80% (complete 54%, partial 26%). At 36 months, the actuarial survival rate was equivalent in both groups. There is no apparent early advantage in terms of response or survival conferred by adding the study INF regimen to CHOP therapy for patients with IG/HG-NHL.

(Pro)renin Receptor Is an Amplifier of Wnt/β-Catenin Signaling in Kidney Injury and Fibrosis.

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Li, Zhen; Zhou, Lili; Wang, Yongping; Miao, Jinhua; Hong, Xue; Hou, Fan Fan; Liu, Youhua

2017-08-01

The (pro)renin receptor (PRR) is a transmembrane protein with multiple functions. However, its regulation and role in the pathogenesis of CKD remain poorly defined. Here, we report that PRR is a downstream target and an essential component of Wnt/ β -catenin signaling. In mouse models, induction of CKD by ischemia-reperfusion injury (IRI), adriamycin, or angiotensin II infusion upregulated PRR expression in kidney tubular epithelium. Immunohistochemical staining of kidney biopsy specimens also revealed induction of renal PRR in human CKD. Overexpression of either Wnt1 or β -catenin induced PRR mRNA and protein expression in vitro Notably, forced expression of PRR potentiated Wnt1-mediated β -catenin activation and augmented the expression of downstream targets such as fibronectin, plasminogen activator inhibitor 1, and α -smooth muscle actin ( α -SMA). Conversely, knockdown of PRR by siRNA abolished β -catenin activation. PRR potentiation of Wnt/ β -catenin signaling did not require renin, but required vacuolar H + ATPase activity. In the mouse model of IRI, transfection with PRR or Wnt1 expression vectors promoted β -catenin activation, aggravated kidney dysfunction, and worsened renal inflammation and fibrotic lesions. Coexpression of PRR and Wnt1 had a synergistic effect. In contrast, knockdown of PRR expression ameliorated kidney injury and fibrosis after IRI. These results indicate that PRR is both a downstream target and a crucial element in Wnt signal transmission. We conclude that PRR can promote kidney injury and fibrosis by amplifying Wnt/ β -catenin signaling. Copyright © 2017 by the American Society of Nephrology.

Primary spinal epidural extraosseous Ewing's sarcoma: Report of five cases and literature review

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Mukhopadhyay, P.; Gairola, M.; Julka, P.K.; Rath, G.K.; Sharma, M.C.; Thulkar, S.

2001-01-01

Ewing's sarcoma is the most common malignant bone tumour occurring in children and adolescents and exists in two different clinico pathological entities: osseous Ewing's sarcoma (OES) and extraosseous Ewing's sarcoma (EES). Five cases of primary epidural EES are described, which presented with non-specific symptoms leading to a long diagnostic delay. The median age at diagnosis was 22 years (range 13-36 years). The median diagnostic delay was 3 months. All patients had one or more neurological deficits. All underwent surgical exploration with a laminectomy and partial resection followed by adjuvant radiotherapy to a dose of 46-50 Gy and chemotherapy with VAC (vincristine, adriamycin and cyclophosphamide) alternating with ICE (ifosphamide, cisplatin and etoposide) for at least six cycles. The mean follow-up period is 21.2 months (range 11-32 months). Four of the five patients achieved a complete remission and are disease free at the time of writing this report. Two patients have a residual neurological deficit - both having presented with long history of neurological deficit. Primary spinal epidural EES should be suspected whenever young patients present with back pain and/or radicular pain, have abnormal neurology and an extradural mass is demonstrated on MRI. Surgical excision followed by adjuvant radiotherapy (50 Gy) and combination chemotherapy (VAC alternating with ICE) achieved local and systemic control in these patients. A greater number of patients and longer follow up are required to evolve a generally accepted treatment policy for this aggressive but potentially curable malignancy. Copyright (2001) Blackwell Science Pty Ltd

Secondary cutaneous Epstein-Barr virus-associated diffuse large B-cell lymphoma in a patient with angioimmunoblastic T-cell lymphoma: a case report and review of literature

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Yang Qing-Xu

2012-01-01

Full Text Available Abstract Only a few cases of extranodal Epstein-Barr virus (EBV-associated B-cell lymphomas arising from patients with angioimmunoblastic T-cell lymphoma (AITL have been described. We report a case of AITL of which secondary cutaneous EBV-associated diffuse large B-cell lymphoma (DLBCL developed after the initial diagnosis of AITL. A 65-year-old Chinese male patient was diagnosed as AITL based on typical histological and immunohistochemical characteristics in biopsy of the enlarged right inguinal lymph nodes. The patient initially received 6 cycles of chemotherapy with CHOP regimen (cyclophosphamide, vincristine, adriamycin, prednisone, but his symptoms did not disappear. Nineteen months after initial diagnosis of AITL, the patient was hospitalized again because of multiple plaques and nodules on the skin. The skin biopsy was performed, but this time the tumor was composed of large, polymorphous population of lymphocytes with CD20 and CD79a positive on immunohistochemical staining. The tumor cells were strong positive for EBER by in situ hybridization. The findings of skin biopsy were compatible with EBV-associated DLBCL. CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab was then administered, resulting in partial response of the disease with pancytopenia and suppression of cellular immunity. To our knowledge, this is the first case of cutaneous EBV-associated DLBCL originated from AITL in Chinese pepole. We suggest the patients with AITL should perform lymph node and skin biopsies regularly in the course of the disease to detect the progression of secondary lymphomas. Virtual slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1197421158639299

Whole-brain radiotherapy and high-dose methylprednisolone for elderly patients with primary central nervous system lymphoma: Results of North Central Cancer Treatment Group (NCCTG) 96-73-51

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Laack, Nadia N.; Ballman, Karla V.; Brown, Paul B.; O'Neill, Brian Patrick

2006-01-01

Purpose: The aim of this study was to evaluate the efficacy, toxicity, and survival of whole-brain radiotherapy-treated (WBRT) and high-dose methylprednisolone (HDMP)-treated in elderly patients with primary central nervous system lymphoma (PCNSL). Methods and Materials: Patients with PCNSL who were 70 years and older received 1 g of methylprednisolone daily for 5 days, 30 days after WBRT. Patients then received 1 g of methylprednisolone every 28 days until progression. The primary endpoint was overall survival (OS) at 6 months. Results were compared with those in patients on the previous North Central Cancer Treatment Group (NCCTG) trial who received pre-WBRT cytoxan, adriamycin, vincristine, prednisone (CHOP) and high-dose cytarabine (CHOP-WBRT). A planned interim analysis was performed. The current regimen would be considered inactive if survival was not improved from patients treated with CHOP-WBRT. Results: Nineteen patients were accrued between 1998 and 2003. Median age was 76 years. Interim analysis revealed a 6-month survival of 33%, resulting in closure of the trial. Toxicity, OS, and event-free survival (EFS) were similar to those in patients more than 70 years of age who received CHOP-WBRT. The subgroup of patients who received HDMP had longer OS (12.1 vs. 7.0 months, p = 0.76) and EFS (11.7 vs. 4.0 months, p = 0.04) compared with the CHOP-WBRT patients alive 60 days after the start of treatment. Conclusions: Patients on-study long enough to receive HDMP had prolongation of OS and EFS compared to patients receiving CHOP-WBRT. Although the numbers of patients are too small for statistical conclusions, the HDMP regimen deserves further study

Characterization of environmental chemicals with potential for DNA damage using isogenic DNA repair-deficient chicken DT40 cell lines.

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Yamamoto, Kimiyo N; Hirota, Kouji; Kono, Koichi; Takeda, Shunichi; Sakamuru, Srilatha; Xia, Menghang; Huang, Ruili; Austin, Christopher P; Witt, Kristine L; Tice, Raymond R

2011-08-01

Included among the quantitative high throughput screens (qHTS) conducted in support of the US Tox21 program are those being evaluated for the detection of genotoxic compounds. One such screen is based on the induction of increased cytotoxicity in seven isogenic chicken DT40 cell lines deficient in DNA repair pathways compared to the parental DNA repair-proficient cell line. To characterize the utility of this approach for detecting genotoxic compounds and identifying the type(s) of DNA damage induced, we evaluated nine of 42 compounds identified as positive for differential cytotoxicity in qHTS (actinomycin D, adriamycin, alachlor, benzotrichloride, diglycidyl resorcinol ether, lovastatin, melphalan, trans-1,4-dichloro-2-butene, tris(2,3-epoxypropyl)isocyanurate) and one non-cytotoxic genotoxic compound (2-aminothiamine) for (1) clastogenicity in mutant and wild-type cells; (2) the comparative induction of γH2AX positive foci by melphalan; (3) the extent to which a 72-hr exposure duration increased assay sensitivity or specificity; (4) the use of 10 additional DT40 DNA repair-deficient cell lines to better analyze the type(s) of DNA damage induced; and (5) the involvement of reactive oxygen species in the induction of DNA damage. All compounds but lovastatin and 2-aminothiamine were more clastogenic in at least one DNA repair-deficient cell line than the wild-type cells. The differential responses across the various DNA repair-deficient cell lines provided information on the type(s) of DNA damage induced. The results demonstrate the utility of this DT40 screen for detecting genotoxic compounds, for characterizing the nature of the DNA damage, and potentially for analyzing mechanisms of mutagenesis. Copyright © 2011 Wiley-Liss, Inc.

Breast-conserving surgery in locally advanced breast cancer submitted to neoadjuvant chemotherapy. Safety and effectiveness based on ipsilateral breast tumor recurrence and long-term follow-up

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Guilherme Freire Angotti Carrara

Full Text Available OBJECTIVE: To evaluate ipsilateral breast tumor recurrence after breast-conserving surgery for locally advanced breast cancer. METHODS: A retrospective observational cohort study was performed in patients with locally advanced breast cancer submitted to breast-conserving surgery after neoadjuvant chemotherapy based on an adriamycin-cyclophosphamide-paclitaxel regimen. We evaluated the clinical, pathologic, immunohistochemistry, and surgical factors that contribute to ipsilateral breast tumor recurrence and locoregional recurrence. A Kaplan-Meier analysis and Cox model were used to evaluate the main factors related to disease-free survival. RESULTS: Of the 449 patients who received neoadjuvant chemotherapy, 98 underwent breast-conserving surgery. The average diameter of the tumors was 5.3 cm, and 87.2% reached a size of up to 3 cm. Moreover, 86.7% were classified as clinical stage III, 74.5% had T3-T4 tumors, 80.5% had N1-N2 axilla, and 89.8% had invasive ductal carcinoma. A pathologic complete response was observed in 27.6% of the tumors, and 100.0% of samples had free margins. The 5-year actuarial overall survival rate was 81.2%, and the mean follow-up was 72.8 months. The rates of ipsilateral breast tumor recurrence and locoregional recurrence were 11.2% and 15.3%, respectively. Multifocal morphology response was the only factor related to ipsilateral breast tumor recurrence disease-free survival (p=0.04. A multivariate analysis showed that the pathologic response evaluation criteria in solid tumors (RECIST-breast cutoff was the only factor related to locoregional recurrence disease-free survival (p=0.01. CONCLUSIONS: Breast-conserving surgery is a safe and effective therapy for selected locally advanced breast tumors.

Wtip- and gadd45a-interacting protein dendrin is not crucial for the development or maintenance of the glomerular filtration barrier.

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Zhijie Xiao

Full Text Available Glomerular podocyte cells are critical for the function of the renal ultrafiltration barrier. Especially, the highly specialized cell-cell junction of podocytes, the slit diaphragm, has a central role in the filtration barrier. This is highlighted by the fact that mutations in molecular components of the slit diaphragm, including nephrin and Cd2-associated protein (Cd2ap, result in proteinuric diseases in man. Dendrin is a poorly characterized cytosolic component of the slit diaphragm in where it interacts with nephrin and Cd2ap. Dendrin is highly specific for the podocyte slit diaphragm, suggesting that it has a dedicated role in the glomerular filtration barrier. In this study, we have generated a dendrin knockout mouse line and explored the molecular interactions of dendrin. Dendrin-deficient mice were viable, fertile, and had a normal life span. Morphologically, the glomerulogenesis proceeded normally and adult dendrin-deficient mice showed normal glomerular histology. No significant proteinuria was observed. Following glomerular injury, lack of dendrin did not affect the severity of the damage or the recovery process. Yeast two-hybrid screen and co-immunoprecipitation experiments showed that dendrin binds to Wt1-interacting protein (Wtip and growth arrest and DNA-damage-inducible 45 alpha (Gadd45a. Wtip and Gadd45a mediate gene transcription in the nucleus, suggesting that dendrin may have similar functions in podocytes. In line with this, we observed the relocation of dendrin to nucleus in adriamycin nephropathy model. Our results indicate that dendrin is dispensable for the function of the normal glomerular filtration barrier and that dendrin interacts with Wtip and Gadd45a.

Knockdown of dual specificity phosphatase 4 enhances the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin

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Liu, Yu; Du, Feiya; Chen, Wei; Yao, Minya; Lv, Kezhen; Fu, Peifen

2013-01-01

Background: Breast cancer is the major cause of cancer-related deaths in females world-wide. Doxorubicin-based therapy has limited efficacy in breast cancer due to drug resistance, which has been shown to be associated with the epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms linking the EMT and drug resistance in breast cancer cells remain unclear. Dual specificity phosphatase 4 (DUSP4), a member of the dual specificity phosphatase family, is associated with cellular proliferation and differentiation; however, its role in breast cancer progression is controversial. Methods: We used cell viability assays, Western blotting and immunofluorescent staining, combined with siRNA interference, to evaluate chemoresistance and the EMT in MCF-7 and adriamycin-resistant MCF-7/ADR breast cancer cells, and investigate the underlying mechanisms. Results: Knockdown of DUSP4 significantly increased the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin, and MCF-7/ADR cells which expressed high levels of DUSP4 had a mesenchymal phenotype. Furthermore, knockdown of DUSP4 reversed the EMT in MCF-7/ADR cells, as demonstrated by upregulation of epithelial biomarkers and downregulation of mesenchymal biomarkers, and also increased the chemosensitivity of MCF-7/ADR cells to doxorubicin. Conclusions: DUSP4 might represent a potential drug target for inhibiting drug resistance and regulating the process of the EMT during the treatment of breast cancer. - Highlights: • We used different technologies to prove our conclusion. • DUSP4 knockdown increased doxorubicin chemosensitivity in breast cancer cells. • DUSP4 is a potential target for combating drug resistance in breast cancer. • DUSP4 is a potential target for regulating the EMT in breast cancer

Medullary thyroid carcinoma: prognostic factors and treatment

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Rougier, P.; Parmentier, C.; Laplanche, A.; Lefevre, M.; Travagli, J.P.; Caillou, B.; Schlumberger, M.; Lacour, J.; Tubiana, M.

1983-01-01

Seventy-five patients with medullary thyroid carcinoma (MTC) have been treated at Institut Gustave-Roussy from 1932 to 1979. Of these, 13 patients had distant metastases and received palliative treatment, their median survival was 3 years. Sixty-two patients with MTC limited to the neck received curative treatment: 6 had exclusive external radiotherapy for inoperable disease and 56 were surgically treated: 23 by total thyroidectomy and 33 by partial thyroidectomy. After surgery 29 patients received external radiotherapy for cervical lymph node involvement (25/29) and/or incomplete surgical resection (12/27). The survival rate was 69% at 5 years and 48% at 10 years. The 29 patients who received post-operative cervical radiotherapy had initially more extensive local disease (p<0.05) than the 27 patients treated by surgery alone, nevertheless their survival was slightly higher. No difference in survival rate was observed between patients treated by total thyroidectomy or partial thyroidectomy, among whom only 4 local recurrences occurred. Three of the 6 patients treated with external radiotherapy alone experienced long survival (4, 7 and 10 years) and a fourth is still in clinical remission 4 years after treatment. The effectiveness of chemotherapy in patients with metastases was poor, only one patient out of 6 had a partial remission following a treatment by adriamycin. In the familial form and multiple endocrine neoplasia type II, total thyroidectomy appears to be indicated. In the sporadic cases, partial thyroidectomy is usually sufficient. External radiotherapy is effective in MTC and seems to be able to eradicate small foci of residual tumor; it is indicated when surgical excision is impossible or incomplete

Quality of Life and Neutropenia in Patients with Early Stage Breast Cancer: A Randomized Pilot Study Comparing Additional Treatment with Mistletoe Extract to Chemotherapy Alone

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Wilfried Tröger

2009-01-01

Full Text Available Background: Chemotherapy for breast cancer often deteriorates quality of life, augments fatigue, and induces neutropenia. Mistletoe preparations are frequently used by cancer patients in Central Europe. Physicians have reported better quality of life in breast cancer patients additionally treated with mistletoe preparations during chemotherapy. Mistletoe preparations also have immunostimulant properties and might therefore have protective effects against chemotherapy-induced neutropenia.Patients and Methods: We conducted a prospective randomized open label pilot study with 95 patients randomized into three groups. Two groups received Iscador® M special (IMS or a different mistletoe preparation, respectively, additionally to chemotherapy with six cycles of cyclophosphamide, adriamycin, and 5-fluoro-uracil (CAF. A control group received CAF with no additional therapy. Here we report the comparison IMS (n = 30 vs. control (n = 31. Quality of life including fatigue was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30. Neutropenia was defined as neutrophil counts <1,000/µl and assessed at baseline and one day before each CAF cycle.Results: In the descriptive analysis all 15 scores of the EORTC-QLQ-C30 showed better quality of life in the IMS group compared to the control group. In 12 scores the differences were significant (p < 0.02 and nine scores showed a clinically relevant and significant difference of at least 5 points. Neutropenia occurred in 3/30 IMS patients and in 8/31 control patients (p = 0.182.Conclusions: This pilot study showed an improvement of quality of life by treating breast cancer patients with IMS additionally to CAF. CAF-induced neutropenia showed a trend to lower frequency in the IMS group.

Tumor boards and the quality of cancer care.

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Keating, Nancy L; Landrum, Mary Beth; Lamont, Elizabeth B; Bozeman, Samuel R; Shulman, Lawrence N; McNeil, Barbara J

2013-01-16

Despite the widespread use of tumor boards, few data on their effects on cancer care exist. We assessed whether the presence of a tumor board, either general or cancer specific, was associated with recommended cancer care, outcomes, or use in the Veterans Affairs (VA) health system. We surveyed 138 VA medical centers about the presence of tumor boards and linked cancer registry and administrative data to assess receipt of stage-specific recommended care, survival, or use for patients with colorectal, lung, prostate, hematologic, and breast cancers diagnosed in the period from 2001 to 2004 and followed through 2005. We used multivariable logistic regression to assess associations of tumor boards with the measures, adjusting for patient sociodemographic and clinical characteristics. All statistical tests were two-sided. Most facilities (75%) had at least one tumor board, and many had several cancer-specific tumor boards. Presence of a tumor board was associated with only seven of 27 measures assessed (all P < .05), and several associations were not in expected directions. Rates of some recommended care (eg, white blood cell growth factors with cyclophosphamide, adriamycin, vincristine, and prednisone in diffuse large B-cell lymphoma) were lower in centers with hematologic-specialized tumor boards (39.4%) than in centers with general tumor boards (61.3%) or no tumor boards (56.4%; P = .002). Only one of 27 measures was statistically significantly associated with tumor boards after applying a Bonferroni correction for multiple comparisons. We observed little association of multidisciplinary tumor boards with measures of use, quality, or survival. This may reflect no effect or an effect that varies by structural and functional components and participants' expertise.

miR-367 regulation of DOC-2/DAB2 interactive protein promotes proliferation, migration and invasion of osteosarcoma cells.

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Cai, Wei; Jiang, Haitao; Yu, Yifan; Xu, Yong; Zuo, Wenshan; Wang, Shouguo; Su, Zhen

2017-11-01

Recently, miR-367 is reported to exert either oncogenic or tumor suppressive effects in human malignancies. Recent study reports that miR-367 is up-regulated in OS tissues and cell lines, and abrogates adriamycin-induced apoptosis. The clinical significance of miR-367 and its function in OS need further investigation. In our study, miR-367 expression in OS was markedly elevated compared with corresponding non-tumor tissues. High miR-367 expression was associated with malignant clinical features and poor prognosis of OS patients. In accordance, the levels of miR-367 were dramatically up-regulated in OS cells. Loss of miR-367 expression in Saos-2 cells obviously inhibited the proliferation, migration and invasion of cancer cells in vitro. Meanwhile, miR-367 restoration promoted these malignant behaviors of MG-63 cells. Mechanistically, miR-367 negatively regulated DOC-2/DAB2 interactive protein (DAB2IP) abundance in OS cells. Hereby, DAB2IP was recognized as a direct target gene of miR-367 in OS. DAB2IP mRNA level was down-regulated and inversely correlated with miR-367 expression in OS specimens. DAB2IP overexpression prohibited proliferation, migration and invasion in Saos-2 cells, while DAB2IP knockdown showed promoting effects on proliferation, migration and invasion of MG-63 cells. Furthermore, the role of miR-367 might be mediated by DAB2IP-regulated phosphorylation of ERK and AKT in OS cells. To conclude, miR-367 may function as a biomarker for prediction of prognosis and a target for OS therapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Dual drug delivery using 'smart' liposomes for triggered release of anticancer agents

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Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K., E-mail: drskjainin@yahoo.com [Dr. Hari Singh Gour Vishwavidyalaya, Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences (India)

2013-07-15

Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-{alpha}) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG{sub 2000}-DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG{sub 2000}-DSPE:DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 {+-} 0.5 Degree-Sign C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 {+-} 1 Degree-Sign C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI{sub 50} = 6.5 {mu}g/ml) than positive control (Adriamycin, GI{sub 50} = 9.1 {mu}g/ml) and FR-targeted PEGylated liposomes GI{sub 50} (14.7 {mu}g/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called 'smart liposomes' which has not only mediated effective targeting to FR-{alpha} but also triggered release of drugs upon hyperthermia.

Renoprotective effect of the antioxidant curcumin: Recent findings☆

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Trujillo, Joyce; Chirino, Yolanda Irasema; Molina-Jijón, Eduardo; Andérica-Romero, Ana Cristina; Tapia, Edilia; Pedraza-Chaverrí, José

2013-01-01

For years, there have been studies based on the use of natural compounds plant-derived as potential therapeutic agents for various diseases in humans. Curcumin is a phenolic compound extracted from Curcuma longa rhizome commonly used in Asia as a spice, pigment and additive. In traditional medicine of India and China, curcumin is considered as a therapeutic agent used in several foods. Numerous studies have shown that curcumin has broad biological functions particularly antioxidant and antiinflammatory. In fact, it has been established that curcumin is a bifunctional antioxidant; it exerts antioxidant activity in a direct and an indirect way by scavenging reactive oxygen species and inducing an antioxidant response, respectively. The renoprotective effect of curcumin has been evaluated in several experimental models including diabetic nephropathy, chronic renal failure, ischemia and reperfusion and nephrotoxicity induced by compounds such as gentamicin, adriamycin, chloroquine, iron nitrilotriacetate, sodium fluoride, hexavalent chromium and cisplatin. It has been shown recently in a model of chronic renal failure that curcumin exerts a therapeutic effect; in fact it reverts not only systemic alterations but also glomerular hemodynamic changes. Another recent finding shows that the renoprotective effect of curcumin is associated to preservation of function and redox balance of mitochondria. Taking together, these studies attribute the protective effect of curcumin in the kidney to the induction of the master regulator of antioxidant response nuclear factor erythroid-derived 2 (Nrf2), inhibition of mitochondrial dysfunction, attenuation of inflammatory response, preservation of antioxidant enzymes and prevention of oxidative stress. The information presented in this paper identifies curcumin as a promising renoprotective molecule against renal injury. PMID:24191240

Renoprotective effect of the antioxidant curcumin: Recent findings

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Joyce Trujillo

2013-01-01

Full Text Available For years, there have been studies based on the use of natural compounds plant-derived as potential therapeutic agents for various diseases in humans. Curcumin is a phenolic compound extracted from Curcuma longa rhizome commonly used in Asia as a spice, pigment and additive. In traditional medicine of India and China, curcumin is considered as a therapeutic agent used in several foods. Numerous studies have shown that curcumin has broad biological functions particularly antioxidant and antiinflammatory. In fact, it has been established that curcumin is a bifunctional antioxidant; it exerts antioxidant activity in a direct and an indirect way by scavenging reactive oxygen species and inducing an antioxidant response, respectively. The renoprotective effect of curcumin has been evaluated in several experimental models including diabetic nephropathy, chronic renal failure, ischemia and reperfusion and nephrotoxicity induced by compounds such as gentamicin, adriamycin, chloroquine, iron nitrilotriacetate, sodium fluoride, hexavalent chromium and cisplatin. It has been shown recently in a model of chronic renal failure that curcumin exerts a therapeutic effect; in fact it reverts not only systemic alterations but also glomerular hemodynamic changes. Another recent finding shows that the renoprotective effect of curcumin is associated to preservation of function and redox balance of mitochondria. Taking together, these studies attribute the protective effect of curcumin in the kidney to the induction of the master regulator of antioxidant response nuclear factor erythroid-derived 2 (Nrf2, inhibition of mitochondrial dysfunction, attenuation of inflammatory response, preservation of antioxidant enzymes and prevention of oxidative stress. The information presented in this paper identifies curcumin as a promising renoprotective molecule against renal injury.

Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients' bed.

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Ferrari, Stefano; Perut, Francesca; Fagioli, Franca; Brach Del Prever, Adalberto; Meazza, Cristina; Parafioriti, Antonina; Picci, Piero; Gambarotti, Marco; Avnet, Sofia; Baldini, Nicola; Fais, Stefano

2013-10-24

Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H +-rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma. MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin. Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients. This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy.

Combination chemotherapy and radiotherapy of small cell lung cancer

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Saito, Yasuo; Chohtoh, Shuichi; Nishijima, Hiroshi; Kobayashi, Akihiko; Hirose, Jin-ichiro; Kamimura, Ryoichi; Takashima, Tsutomu; Konishi, Hideo; Miyata, Samon.

1986-01-01

Treatment results of 49 patients (25, limited disease, LD, 24, extensive disease, ED) with small cell lung cancer were retrospectively analyzed. Fifteen patients received chemotherapy with Cyclophosphamide (CPM) and Vincristine (VCR) following thoracic radiotherapy (RT). Twenty-two patients were given induction chemotherapy with CPM, Adriamycin (ADM), and VCR and were followed by thoracic RT. Other chemotherapy consisted of CPM, VCR, Methotrexate, and ADM in 2 patients, 5-FU, CPM, Mitomycin C, and Toyomycin in 1 patient. The remaining 9 patients (2, LD, 7, ED) were treated with RT alone. The response rate was 80 % (64 % CR; 16 % PR) for LD patients and 33 % (4 % CR; 29 % PR) for ED patients (P < 0.001). The three-year survival (Kaplan-Meier's product) of all patients was 14 %, with a median survival time (MST) of 8 months. For patients with LD, the 3-year survival was 27 % (MST 15 months). Survival of patients with ED was 14 % at 1 year, 0 % at 2 year (MST 5.5 months). The difference between these figures was statistically significant (P < 0.0003). The 3-year survival and relapse-free survival for complete responders with LD were 43 % (MST 21 months) and 36 % (median CR duration, 11.5 months) respectively. Six of 16 complete responders with LD are alive and well at over 2 years. Local recurrence rate of the complete responders with LD was 28.8 %. None of the 7 complete responders given more than 48 Gy relapsed within the radiation field. We believe that the addition of thoracic RT to patients with LD is necessary for the control of the primary tumors and for long-term disease-free survival. (author)

Study on predictive role of AR and EGFR family genes with response to neoadjuvant chemotherapy in locally advanced breast cancer in Indian women.

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Singh, L C; Chakraborty, Anurupa; Mishra, Ashwani K; Devi, Thoudam Regina; Sugandhi, Nidhi; Chintamani, Chintamani; Bhatnagar, Dinesh; Kapur, Sujala; Saxena, Sunita

2012-06-01

Locally advanced breast cancer (LABC) remains a clinical challenge as the majority of patients with this diagnosis develop distant metastases despite appropriate therapy. We analyzed expression of steroid and growth hormone receptor genes as well as gene associated with metabolism of chemotherapeutic drugs in locally advanced breast cancer before and after neoadjuvant chemotherapy (NACT) to study whether there is a change in gene expression induced by chemotherapy and whether such changes are associated with tumor response or non-response. Fifty patients were included with locally advanced breast cancer treated with cyclophosphamide, adriamycin, 5-fluorouracil (CAF)-based neoadjuvant chemotherapy before surgery. Total RNA was extracted from 50 match samples of pre- and post-NACT tumor tissues. RNA expression levels of epidermal growth factor receptor family genes including EGFR, ERBB2, ERBB3, androgen receptor (AR), and multidrug-resistance gene 1 (MDR1) were determined by quantitative real-time reverse transcriptase-polymerase chain reaction. Responders show significantly high levels of pre-NACT AR gene expression (P = 0.016), which reduces following NACT (P = 0.008), and hence can serve as a useful tool for the prediction of the success of neoadjuvant chemotherapy in individual cancer patients with locally advanced breast carcinoma. Moreover, a significant post-therapeutic increase in the expression levels of EGFR and MDR1 gene in responders (P = 0.026 and P < 0.001) as well as in non-responders (P = 0.055, P = 0.001) suggests that expression of these genes changes during therapy but they do not have any impact on tumor response, whereas a post-therapeutic reduction was observed in AR in responders. This indicates an independent predictive role of AR with response to NACT.

Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas.

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Fairchild, C R; Ivy, S P; Rushmore, T; Lee, G; Koo, P; Goldsmith, M E; Myers, C E; Farber, E; Cowan, K H

1987-11-01

We have previously reported the isolation of a human breast cancer cell line resistant to doxorubicin (adriamycin; AdrR MCF-7 cells) that has also developed the phenotype of multidrug resistance (MDR). MDR in this cell line is associated with increased expression of mdr (P glycoprotein) gene sequences. The development of MDR in AdrR MCF-7 cells is also associated with changes in the expression of several phase I and phase II drug-detoxifying enzymes. These changes are remarkably similar to those associated with development of xenobiotic resistance in rat hyperplastic liver nodules, a well-studied model system of chemical carcinogenesis. Using an mdr-encoded cDNA sequence isolated from AdrR MCF-7 cells, we have examined the expression of mdr sequences in rat livers under a variety of experimental conditions. The expression of mdr increased 3-fold in regenerating liver. It was also elevated (3- to 12-fold) in several different samples of rat hyperplastic nodules and in four of five hepatomas that developed in this system. This suggests that overexpression of mdr, a gene previously associated with resistance to antineoplastic agents, may also be involved in the development of resistance to xenobiotics in rat hyperplastic nodules. In addition, although the acute administration of 2-acetylaminofluorene induced an 8-fold increase in hepatic mdr-encoded RNA, performance of a partial hepatectomy either before or after administration of 2-acetylaminofluorene resulted in a greater than 80-fold increase in mdr gene expression over that in normal untreated livers. This represents an important in vivo model system in which to study the acute regulation of this drug resistance gene.

Preoperative balloon occluded arterial infusion chemotherapy for locally invasive bladder cancer. Accurate staging for bladder preservation

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Hayashi, Norio; Arima, Kiminobu; Kawamura, Juichi; Tochigi, Hiromi

1999-01-01

The possibility of bladder preservation by preoperative balloon occluded arterial infusion (BOAI) chemotherapy was studied in 111 patients with locally invasive bladder cancer. BOAI was performed by blocking the blood flow of the internal iliac artery and by performing intra-arterial infusion of adriamycin (50 mg/body) and cisplatin (100 mg/body). Before BOAI the clinical diagnosis was T2 in 36, T3a in 29, T3b in 27, T4 in 11 and after BOAI it was T0 in 1, T1 in 27, T2 in 25, T3a in 20, T3b in 20, and T4 in 10. Down staging was observed on diagnostic images in 46.6%. Thirty patients (27.0%) received transurethral resection of bladder tumor (TUR-Bt) and their bladder could be preserved. The 5-year cancer-specific survival rate was 100% in pT0 (n=9), 97.5% in pT1 (n=47), 79.9% in pT2 (n=21), 80.0% in pT3a (n=6), 39.9% in pT3b (n=18) and 51.9% in pT4 cases (n=9). For the bladder preservation, accurate staging diagnosis is required. Since 1992, endorectal magnetic resonance imaging (MRI) has been used in addition to imaging diagnosis for improving the accuracy of staging diagnosis. The accuracies of staging diagnosis with and without endorectal MRI were 62.5% and 44.0%, respectively. BOAI as a neoadjuvant chemotherapy has the possibility of bladder-preserving therapy in locally invasive bladder cancer. Also, the endorectal MRI can improve the accuracy of staging diagnosis, which is important for the bladder preservation. (author)

Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis

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Van Beneden, Katrien, E-mail: kvbenede@vub.ac.be [Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Geers, Caroline [Department of Pathology, Universitair Ziekenhuis Brussel, Brussels (Belgium); Pauwels, Marina [Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Mannaerts, Inge [Department of Cell Biology, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Wissing, Karl M. [Department of Nephrology, Universitair Ziekenhuis Brussel, Brussels (Belgium); Van den Branden, Christiane [Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Grunsven, Leo A. van, E-mail: lvgrunsv@vub.ac.be [Department of Cell Biology, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium)

2013-09-01

Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors. - Highlights: • Valproic acid is a potent antiproteinuric drug, whereas trichostatin A is not. • Trichostatin A and valproic acid reduce kidney fibrosis in doxorubicin nephropathy. • Both valproic acid and trichostatin A attenuate renal inflammation.

Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis

International Nuclear Information System (INIS)

Van Beneden, Katrien; Geers, Caroline; Pauwels, Marina; Mannaerts, Inge; Wissing, Karl M.; Van den Branden, Christiane; Grunsven, Leo A. van

2013-01-01

Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors. - Highlights: • Valproic acid is a potent antiproteinuric drug, whereas trichostatin A is not. • Trichostatin A and valproic acid reduce kidney fibrosis in doxorubicin nephropathy. • Both valproic acid and trichostatin A attenuate renal inflammation

The effect of TACE with endostatin on hemodynamics in hepatic implantation tumor using Doppler ultrasonography

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Zhou Guangli; Wu Yuanyuan; Wang Bin; Liu Yan; Zheng Chuanli; Sang Li; Liu Feng

2009-01-01

Objective: To investigate the hemodynamic changes in the rabbit liver and VX2 hepatic implantation tumor after treatment by transcatheter arterial chemoembolization (TACE)/endostatin using Doppler ultrasonography. Methods: Twenty rabbits with VX2 hepatic tumor were randomly distributed into the control group (n=10) and the anti- angiogenesis group (n=10). The rabbits were administered with endostatin and adriamycin-lipiodol in the anti-angiogenesis group and with 37℃ saline in the control group via hepatic artery. The hemodynamic changes of the tumors, hepatic artery, and portal vein were recorded with Doppler ultrasonography 1 week after the treatment. The results before and after the treatment were compared. Results: In the control group, the maximal hepatic artery blood flow velocity was significantly higher than that before the treatment (P<0.05). However, the resistance index and the portal vein blood flow velocities had no significantly change compared with those before the treatment (P>0.05). In the anti-angiogenesis group, the hepatic artery blood flow velocity was significantly lower than that before the treatment (P<0.05), and the resistance index was increased (P<0.05). However, the portal vein blood flow velocity had no significantly change (P>0.05). The blood flow signal in all tumors was rich before embolization. After TACE, the blood flow signal was significantly decreased, even partly disappeared in the anti-angiogenesis group. Conclusion: TACE with endostatin can effectively block the blood supplement of VX2 hepatic implantation tumor. Doppler ultrasonography can detected the blood flow changes and can be used in evaluating the therapeutic effect in hepatic implantation tumor. (authors)

Radiation Therapy Overcomes Adverse Prognostic Role of Cyclooxygenase-2 Expression on Reed-Sternberg Cells in Early Hodgkin Lymphoma

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Mestre, Francisco; Gutiérrez, Antonio; Rodriguez, Jose; Ramos, Rafael; Garcia, Juan Fernando; Martinez-Serra, Jordi; Casasus, Marta; Nicolau, Cristina; Bento, Leyre; Herraez, Ines; Lopez-Perezagua, Paloma; Daumal, Jaime; Besalduch, Joan

2015-01-01

Purpose: To analyze the role of radiation therapy (RT) on the adverse prognostic influence of cyclooxygenase-2 (COX-2) expression on Reed-Sternberg (RS) cells, in the setting of early Hodgkin lymphoma (HL) treated with ABVD (adriamycin, vinblastine, bleomycin, dacarbazine). Methods and Materials: In the present study we retrospectively investigated the prognostic value of COX-2 expression in a large (n=143), uniformly treated early HL population from the Spanish Network of HL using tissue microarrays. Univariate and multivariate analyses were done, including the most recognized clinical variables and the potential role of administration of adjuvant RT. Results: Median age was 31 years; the expression of COX-2 defined a subgroup with significantly worse prognosis. Considering COX-2 + patients, those who received RT had significantly better 5-year progression-free survival (PFS) (80% vs 54% if no RT; P=.008). In contrast, COX-2 − patients only had a modest, nonsignificant benefit from RT in terms of 5-year PFS (90% vs 79%; P=.13). When we compared the outcome of patients receiving RT considering the expression of COX-2 on RS cells, we found a nonsignificant 10% difference in terms of PFS between COX-2 + and COX-2 − patients (P=.09), whereas the difference between the 2 groups was important (25%) in patients not receiving RT (P=.04). Conclusions: Cyclooxygenase-2 RS cell expression is an adverse independent prognostic factor in early HL. Radiation therapy overcomes the worse prognosis associated with COX-2 expression on RS cells, acting in a chemotherapy-independent way. Cyclooxygenase-2 RS cell expression may be useful for determining patient candidates with early HL to receive consolidation with RT

Effect of doxorubicin on cell survival and micronuclei formation in HeLa cells exposed to different doses of gamma-radiation

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Jagetia, G.C.; Nayak, V.

2000-01-01

Purpose: The present study was undertaken to obtain an insight into the combined effects of doxorubicin with radiation on the cell survival and micronuclei induction in HeLa cells. Material and Methods: HeLa S3 cells were allowed to grow till they reached plateau phase, inoculated with 10 μg/ml doxorubicin hydrochloride and then exposed to 0, 0.5, 1, 2 and 3 Gy γ-radiation. Clonogenicity of cell was measured using the colony forming assay, micronuclei formation using the micronucleus assay. Results: The treatment of HeLa cells with doxorubicin (adriamycin) for 2 hours before exposure to different doses of γ-radiation resulted in a significant and dose-dependent decline in the cell survival and cell proliferation when compared to the PBS+irradiation group. Conversely, the frequency of micronuclei increased in a dose-related manner in both the PBS+irradiation and doxorubicin+irradiation groups. The pretreatment of HeLa cells with doxorubicin before irradiation to various doses of γ-rays resulted in a significant elevation in the frequency of micronuclei when compared with the concurrent PBS+irradiation group. The dose-response relationship for both PBS+irradiation and doxorubicin+irradiation groups was linear. The correlation between cell survival and micronuclei induction was also determined for PBS or doxorubicin+irradiation group, where the clonogenicity of cells declined with the increase in micronuclei formation. The correlation between cell survical and micronuclei induction was linear quadratic for both PBS+irradiation and doxorubicin+irradiation groups. Conclusion: From our study it can be concluded that combination treatment with doxorubicin and radiation increased the genotoxic effect of the either treatment given alone. (orig.) [de

Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity: The Rizzoli experience in 20 cases

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Bacci, Gaetano; Longhi, Alessandra; Forni, Cristiana R.N.; Fabbri, Nicola; Briccoli, Antonio; Barbieri, Enza; Mercuri, Mario; Balladelli, Alba B.A.; Ferrari, Stefano; Picci, Piero

2007-01-01

Purpose: Evaluate treatment and outcome of 20 patients with radioinduced osteosarcoma (RIO). Because of previous primary tumor treatment, RIO protocols were different from others we used for non-RIO. Patients and Methods: Between 1983 and 1998, we treated 20 RIO patients, ages 4-36 years (mean 16 years), with chemotherapy (two cycles before surgery, three postoperatively). The first preoperative cycle consisted of high-dose Methotrexate (HDMTX)/Cisplatinum (CDP)/Adriamycin (ADM) and the second of HDMTX/CDP/Ifosfamide (IFO). The three postoperative treatments were performed with cycles of MTX/CDP; IFO was used as single agent per cycle repeated three times. Results: Two patients received palliative treatment because their osteosarcoma remained unresectable after preoperative chemotherapy. The remaining 18 patients had surgery (7 amputations, 11 resections); histologic response to preoperative chemotherapy was good in 8 patients, poor in 10. At a mean follow-up of 11 years (range, 7-22 years), 9 patients remained continuously disease-free, 10 died from osteosarcoma and 1 died from a third neoplasm (myeloid acute leukemia). These results are not significantly different from those achieved in 754 patients with conventional osteosarcoma treated in the same period with protocols used for conventional treatment. However, this later group had an 18% 3-year event-free survival after treatment of relapse vs. 0% in the RIO group. Conclusion: Treated with neoadjuvant chemotherapy RIO seem to have an outcome that is not significantly different from that of comparable patients with conventional primary high grade osteosarcoma (5-year event-free survival: 40% vs. 60%, p = NS; 5-year overall survival 40% vs. 67%, p < 0.01)

Radiation therapy in the multimodal management of Ewing's sarcoma of bone: report of the Intergroup Ewing's Sarcoma Study

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Perez, C.A.; Tefft, M.; Nesbit, M.E. Jr.; Burgert, E.O. Jr.; Vietti, T.J.; Kissane, J.; Pritchard, D.J.; Gehan, E.A.

1981-01-01

This paper is a progress report on the role of radiation therapy (RT) in local tumor control and the decreased incidence of pulmonary metastasis in 251 patients entered in the Intergroup Ewing's Sarcoma Study. All were followed for more that 1 year, and their RT records were reviewed. Doses to the primary tumor in the range of 4,500--6,500 rad were administered over approximately 5 to 6 weeks in combination with 4 drugs, i.e., vincristine (VCR), dactinomycin (DAC), cyclophosphamide (CY), and adriamycin, or only the first 3. One group of patients received the 3 drugs and bilateral pulmonary irradiation (approximately 1,500 rad in 2 wk). Preliminary analysis showed a local primary tumor control of approximately 90%. Patients with lesions in the pelvis and humerus had local failure rates of 13% (7 of 54) and 21.4% (6 of 28), respectively. The treatment groups differed significantly in the incidence of pulmonary metastasis. Patients treated with the 4 drugs (regimen 1) had a 14% incidence, whereas 42% of those treated with only 3 drugs (regimen 2) developed pulmonary metastases. Of all patients treated with 3 drugs and pulmonary irradiation (regimen 3), 18% showed lung metastases. The study indicated that intensive chemotherapy and RT significantly improved the local control and survival of patients with localized Ewing's sarcoma. However, the high incidence of metastasis indicated the need for more effective systemic chemotherapy for further improvement of treatment results. More studies are needed so we can define the volume to be treated and the optimal dose of irradiation to determine a therapeutic strategy that will yield optimal survival and tumor control with the fewest sequelae

Protective specific immunity induced by doxorubicin plus TNF-alpha combination treatment of EL4 lymphoma-bearing C57BL/6 mice.

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Ehrke, M J; Verstovsek, S; Maccubbin, D L; Ujházy, P; Zaleskis, G; Berleth, E; Mihich, E

2000-07-01

The therapeutic efficacy of a single (day 8), moderate dose (4 mg/kg, i.v.) of doxorubicin (DOX, Adriamycin) combined with recombinant human TNF-alpha (3 different doses and 5 different schedules, i.v.) was evaluated in C57BL/6 mice bearing an implant (s.c.) of the DOX-sensitive, TNF-alpha-resistant EL4 lymphoma. In parallel to monitoring survival, the levels of several host anti-tumor cytolytic effector functions of splenocytes and thymocytes were evaluated throughout the treatment period and in long-term survivors (LTS). DOX treatment alone resulted in a moderate (approx. 20%) increase in life span but no cures. TNF-alpha alone, at any tested dose or schedule, had little or no positive effect on survival. The combinations of DOX and TNF-alpha were only slightly better than DOX alone with respect to the time to death of mice that died (approx. 29% increase); however, each of the combinations involving 1,000 U TNF-alpha/injection produced a fraction (20% to 80%) of LTS. The host defense activities examined included those of splenic and thymic cytolytic T lymphocytes (CTL) and lymphokine-activated killer cells as well as splenic tumoricidal macrophages. Although most activities were modulated by tumor growth and/or treatment, only CTL responsiveness appeared to correlate with survival. CTL activity in the treated groups with LTS was significantly higher than in control groups late in the treatment period. Finally, ex vivo analyses of splenocytes and thymocytes together with the rejection of implanted tumor at 17 months established that LTS displayed specific long-term immune memory. Copyright 2000 Wiley-Liss, Inc.

Management of breast cancer following Hodgkin's disease

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Wolden, Suzanne L.; Carlson, Robert W.; Jeffrey, Stefanie S.; Hancock, Steven L.

1997-01-01

because of prior radiation. Two patients received a lumpectomy with breast irradiation. In one case, the breast irradiation overlapped the prior mantle field for a cumulative dose of 89.6 Gy. This patient suffered severe fat necrosis. Of 48 patients who had axillary dissections, 31% had involved nodes. One patient presented with bilateral disease and two others developed subsequent invasive cancers in the opposite breast. Three patients had prophylactic contralateral mastectomies. The patient with LCIS was followed after biopsy and Tamoxifen only. Adjuvant chemotherapy was given to 55% and hormonal therapy to 36% of women with invasive breast cancer. Adriamycin containing regimens were used infrequently due to concerns about prior cardiotoxic chemotherapy and radiation. Ten year, disease specific actuarial survival was 100% for patients with carcinoma in situ, 71% for those with stage I or II breast cancer, and 43% for stages III and IV. Two women died from third cancers (lung and bladder) and two from myocardial infarction (ages 45 and 60). Conclusion: The risk of breast cancer is increased in patients treated for Hodgkin's disease. Our data suggested that mammography may be underutilized, as most cases in this series were detected by the patient. Histology and tumor grade do not appear to differ from that expected in the general breast cancer population. Generally, breast cancer following Hodgkin's disease is most appropriately treated with mastectomy because of prior radiation. One of two patients in this series had an unacceptable complication following breast conserving therapy. Axillary node dissection is possible after mantle radiotherapy and as many as 31% of patients may have involved nodes. Prophylactic contralateral mastectomy is not recommended because the incidence of bilateral breast cancer is relatively low. Adjuvant chemotherapy and hormonal therapy should be used according to general guidelines, but adriamycin is relatively contraindicated in patients

LRRK2 interacts with ATM and regulates Mdm2-p53 cell proliferation axis in response to genotoxic stress.

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Chen, Zhongcan; Cao, Zhen; Zhang, Wei; Gu, Minxia; Zhou, Zhi Dong; Li, Baojie; Li, Jing; Tan, Eng King; Zeng, Li

2017-11-15

Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are recognized as the most common cause of familial Parkinson's disease in certain populations. Recently, LRRK2 mutations were shown to be associated with a higher risk of hormone-related cancers. However, how LRRK2 itself contributes to cancer risk remains unknown. DNA damage causes cancer, and DNA damage responses are among the most important pathways in cancer biology. To understand the role of LRRK2 in DNA damage response pathway, we induced DNA damage by applying genotoxic stress to the cells with Adriamycin. We found that DNA damage enhances LRRK2 phosphorylation at Serine 910, Serine 935 and Serine 1292. We further showed that LRRK2 phosphorylation is abolished in the absence of ATM, suggesting that LRRK2 phosphorylation requires ATM. It should also be noted that LRRK2 interacts with ATM. In contrast, overexpression or knockdown of LRRK2 does not affect ATM phosphorylation, indicating that LRRK2 is the downstream target of ATM in response to DNA damage. Moreover, we demonstrated that LRRK2 increases the expression of p53 and p21 by increasing the Mdm2 phosphorylation in response to DNA damage. Loss-of-function in LRRK2 has the opposite effect to that of LRRK2. In addition, FACS analysis revealed that LRRK2 enhances cell cycle progression into S phase in response to DNA damage, a finding that was confirmed by 5-bromo-2'-deoxyuridine immunostaining. Taken together, our findings demonstrate that LRRK2 plays an important role in the ATM-Mdm2-p53 pathway that regulates cell proliferation in response to DNA damage. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Drug and radiation sensitivity measurements of successful primary monolayer culturing of human tumor cells using cell-adhesive matrix and supplemented medium

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Baker, F.L.; Spitzer, G.; Ajani, J.A.

1986-01-01

The limitations of the agar suspension culture method for primary culturing of human tumor cells prompted development of a monolayer system optimized for cell adhesion and growth. This method grew 83% of fresh human tumor cell biopsy specimens, cultured and not contaminated, from a heterogeneous group of 396 tumors including lung cancer (93 of 114, 82%); melanoma (54 of 72, 75%); sarcoma (46 of 59, 78%); breast cancer (35 of 39, 90%); ovarian cancer (16 of 21, 76%); and a miscellaneous group consisting of gastrointestinal, genitourinary, mesothelioma, and unknown primaries (78 of 91, 86%). Cell growth was characterized morphologically with Papanicolaoustained coverslip cultures and cytogenetically with Giemsastained metaphase spreads. Morphological features such as nuclear pleomorphism, chromatin condensation, basophilic cytoplasm, and melanin pigmentation were routinely seen. Aneuploid metaphases were seen in 90% of evaluable cultures, with 15 of 28 showing 70% or more aneuploid metaphases. Colony-forming efficiency ranged between 0.01 and 1% of viable tumor cells, with a median efficiency of 0.2%. This culture system uses a low inoculum of 25,000 viable cells per well which permitted chemosensitivity testing of nine drugs at four doses in duplicate from 2.2 X 10(6) viable tumor cells and radiation sensitivity testing at five doses in quadruplicate from 0.6 X 10(6) cells. Cultures were analyzed for survival by computerized image analysis of crystal violet-stained cells. Drug sensitivity studies showed variability in sensitivity and in survival curve shape with exponential cell killing for cisplatin, Adriamycin, and etoposide, and shouldered survival curves for 5-fluorouracil frequently seen. Radiation sensitivity studies also showed variability in both sensitivity and survival curve shape. Many cultures showed exponential cell killing, although others had shouldered survival curves

A Pilot Study of IL2 in Drug-Resistant Idiopathic Nephrotic Syndrome.

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Alice Bonanni

Full Text Available Tregs infusion reverts proteinuria and reduces renal lesions in most animal models of nephrotic syndrome (i.e. Buffalo/Mna, Adriamycin, Promycin, LPS. IL2 up-regulates Tregs and may be an alternative to cell-therapy in this setting. To evaluate a potential role of IL2 as Tregs inducer and proteinuria lowering agent in human nephrotic syndrome we treated 5 nephrotic patients with 6 monthly cycles of low-dose IL2 (1x106 U/m2 first month, 1.5x106 U/m2 following months. The study cohort consisted of 5 children (all boys, 11–17 years resistant to all the available treatments (i.e. steroids, calcineurin inhibitors, mycophenolate, Rituximab. Participants had Focal Segmental Glomerulosclerosis (3 cases or Minimal Change Nephropathy (2 cases. IL2 was safe in all but one patient who had an acute asthma attack after the first IL2 dose and did not receive further doses. Circulating Tregs were stably increased (>10% during the whole study period in 2 cases while were only partially modified in the other two children who started with very low levels and partially responded to single IL2 Proteinuria and renal function were not modified by IL2 at any phase of the study. We concluded that low-dose IL2 given in monthly pulses is safe and modifies the levels of circulating Tregs. This drug may not be able to lower proteinuria or affect renal function in children with idiopathic nephrotic syndrome. We were unable to reproduce in humans the effects of IL2 described in rats and mice reducing de facto the interest on this drug in nephrotic syndrome.ClinicalTrials.gov NCT02455908.

Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy

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Carvalho, Rui A.; Sousa, Rui P.B.; Cadete, Virgilio J.J.; Lopaschuk, Gary D.; Palmeira, Carlos M.M.; Bjork, James A.; Wallace, Kendall B.

2010-01-01

Doxorubicin (Adriamycin ® ) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is restricted by a cumulative and progressive cardiomyopathy that develops with repeated dosing. Fundamental to the cardiac failure is an interference with mitochondrial respiration and inhibition of oxidative phosphorylation. Global gene expression arrays in cardiac tissue indicate that inhibition of mitochondrial oxidative phosphorylation by doxorubicin (DOX) is accompanied by a decreased expression of genes related to aerobic fatty acid oxidation and a corresponding increase in expression of genes involved in anaerobic glycolysis, possibly as an alternate source for ATP production. The aim of this investigation was to determine whether this is also manifest at the metabonomic level as a switch in metabolic flux in cardiac tissue, and whether this can be averted by co-administering the cardioprotective drug, dexrazoxane (DZR). 13 C-isotopomer analysis of isolated perfused hearts from male Sprague-Dawley rats receiving 6 weekly s.c. injections of 2 mg/kg DOX demonstrated a shift from the preferential oxidation of fatty acids to enhanced oxidation of glucose and lactate plus pyruvate, indicative of a compensatory shift towards increased pyruvate dehydrogenase activity. Substrate-selective isotopomer analysis combined with western blots indicate an inhibition of long-chain fatty acid oxidation and not MCAD activity or fatty acyl-carnitine transport. Co-administering DZR averted many treatment-related changes in cardiac substrate metabolism, consistent with DZR being an effective cardioprotective agent against DOX-induced cardiomyopathy. This switch in substrate metabolism resembles that described for other models of cardiac failure; accordingly, this change in metabolic flux may represent a general compensatory response of cardiac tissue to imbalances in bioenergetic demand and supply, and not a characteristic unique to DOX-induced cardiac failure itself.

Clinical survey of prostate cancer

International Nuclear Information System (INIS)

Takada, Tsuyoshi; Hatano, Koji; Satoh, Mototaka; Tsujimoto, Yuichi; Honda, Masahito; Matsumiya, Kiyomi; Fujioka, Hideki

2007-01-01

Treatment trends and outcomes for prostate cancer in our hospital were reported. A total of 482 patients with prostate cancer treated in our hospital between January, 1990 and December, 2004. The age distribution was from 51 to 99 years-old, with the mean age of 72.9 years-old at onset. The number of prostate cancer patients, especially asymptomatic patients with prostatic specific antigen (PSA) elevation, have increased recently. As for the clinical stage, 92 cases (19.1%), 238 cases (49.4%), 48 cases (10.0%) and 104 cases (21.6%) were stage A, B, C and D, respectively. 425 cases (88.2%) received some form of endocrine therapy. Retropubic prostatectomy or external beam radiation therapy was performed in 77 and 57 cases, respectively all cases. The cause-specific 5-year survival rate of the 482 cases was 79.7%, comprising 100% for stage A1, 96.8% for stage A2, 89.4% for stage B, 79.9% for stage C and 42.9% for stage D. The cause-specific 5-year survival was significantly better in the latter patients (1997-2004) than the former patients (1990-1996) in stage C (p=0.0226), D (p=0.0448). In stage C patients, the retropubic prostatectomy (with endocrine therapy) group, increased in the latter period and showed longer cause-specific 5-year survival than the endocrine therapy group (p=0.0027). In stage D2 patients, chemo-endocrine therapy with etoposide (VP-16), adriamycin (ADM) and cisplatin (CDDP) refractory and cause-specific 5-year survival was longer than endocrine therapy alone (p=0.0467, P=0.0381). Our results suggest that retropubic prostatectomy with endocrine therapy and chemo-endocrine therapy are useful for stage C and D prostate cancer patients, respectively. (author)

Bendamustine in the treatment of non-Hodgkin’s lymphomas

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Fredrick Hagemeister

2009-12-01

Full Text Available Fredrick Hagemeister1, George Manoukian21Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center Houston, TX, USA; 2Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USAPurpose: To review available data using bendamustine alone and in combination with other chemotherapeutic agents in treatment of patients with non-Hodgkin’s lymphomas.Methods: Internet database searches and literature review.Results: Bendamustine was approved in March 2008 by the United States Food and Drug Administration for the treatment of patients with chronic lymphocytic leukemia. Many trials have been performed over the last decade using bendamustine not only as monotherapy, but also in combination with other agents including rituximab, vincristine, mitoxantrone, fludarabine, and other agents as therapy for patients with relapsed non-Hodgkin’s lymphomas, and recently was approved for use in therapy of patients with relapsed indolent lymphomas considered refractory to rituximab therapy. As monotherapy, bendamustine induces good responses with only minor side effects. In combination with other agents, efficacy improves, especially when given in combination with rituximab. The drug has also been studied in combination with rituximab as initial therapy for indolent lymphomas, and has excellent activity with less toxicity than R-CHOP (rituximab – cyclophosphamide, hydroxydaunorubicin [Adriamycin], Oncovin [vincristine], and prednisone/prednisolone.Conclusion: Overall, bendamustine has demonstrated promising results as therapy for non-Hodgkin’s lymphomas and should be included in the armamentarium of agents used to treat relapsed indolent non-Hodgkin’s lymphomas and may prove valuable as initial therapy for these diseases. Further studies are being conducted to demonstrate the efficacy of this drug in combination with other agents.Keywords: bendamustine, non-Hodgkin’s lymphomas, relapsed lymphoma

[Axillary pathologic response after neoadjuvant chemotherapy in locally advanced breast cancer with axillary involvement].

Science.gov (United States)

Jiménez-Ballvé, A; Serrano-Palacio, A; García-Sáenz, J A; Ortega Candil, A; Salsidua-Arroyo, O; Román-Santamaría, J M; Pelayo Alarcón, A; Fuentes Ferrer, M E; Carreras-Delgado, J L

2015-01-01

To compare axillary involvement (N+) at initial staging in locally advanced breast cancer (LABC) with axillary lymphadenectomy histologic results after neoadjuvant chemotherapy treatment (NeoChemo). Retrospective study between November 2011 and September 2013 of LABC cases treated with neoadjuvant chemotherapy based on docetaxel (associated with trastuzumab in HER2 positive cases and carboplatin/adriamycin in HER2 negative cases). Those clinically or radiologically suspected cases of axillary involvement were histologically confirmed. When there was no suspicion of axillary involvement, sentinel lymph node radioguided biopsy (SLNRB) was performed using intradermal injection of (99m)Tc-nanocolloid albumin prior to neoadjuvant treatment. Axillary lymphadenectomy after NeoChemo was undertaken in all cases with positive axilla. Final pathologic response was classified as complete (pCR) when there was no evidence of tumoral disease and as non-pathologic complete response (no pCR) in the opposite case. A total of 346 patients treated with docetaxel were reviewed, identifying 105 LABC. Axillary involvement at initial staging was detected in 70 (67%) before starting NeoChemo. From these 70, 73% (n=51) were N+ (fine needle biopsy and/or biopsy) and the remaining 19 (27%) were occult N+ detected by SLNRB. Axillary lymphadenectomy detected pCR in 56% (39/70), increasing up to 84% pCR when initial N+ status was reached using SNLB. On the other hand, when N+ was detected using fine needle biopsy/lymph biopsy, pCR was only 45%. More than 50% of women affected by locally advanced breast cancer with tumoral axillary involvement at initial diagnosis present free metastatic axilla after therapeutic neoadjuvant chemotherapy effect. This increases up to almost 90% in case of occult metastatic axilla detected with sentinel node biopsy prior starting neoadjuvant chemotherapy. Copyright © 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

Radiation Therapy Overcomes Adverse Prognostic Role of Cyclooxygenase-2 Expression on Reed-Sternberg Cells in Early Hodgkin Lymphoma

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Mestre, Francisco [Service of Radiation Therapy, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Gutiérrez, Antonio, E-mail: antoniom.gutierrez@ssib.es [Service of Hematology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Rodriguez, Jose [MD Anderson Cancer Center, Madrid (Spain); Ramos, Rafael [Service of Pathology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Garcia, Juan Fernando [Spanish National Cancer Research Centre, Madrid (Spain); Martinez-Serra, Jordi [Service of Hematology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Casasus, Marta; Nicolau, Cristina [Service of Radiation Therapy, Policlinica Miramar, Palma de Mallorca (Spain); Bento, Leyre; Herraez, Ines [Service of Hematology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain); Lopez-Perezagua, Paloma [Service of Radiology, IDISPA, Palma de Mallorca (Spain); Daumal, Jaime [Service of Nuclear Medicine, IDISPA, Palma de Mallorca (Spain); Besalduch, Joan [Service of Hematology, University Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca (Spain)

2015-05-01

Purpose: To analyze the role of radiation therapy (RT) on the adverse prognostic influence of cyclooxygenase-2 (COX-2) expression on Reed-Sternberg (RS) cells, in the setting of early Hodgkin lymphoma (HL) treated with ABVD (adriamycin, vinblastine, bleomycin, dacarbazine). Methods and Materials: In the present study we retrospectively investigated the prognostic value of COX-2 expression in a large (n=143), uniformly treated early HL population from the Spanish Network of HL using tissue microarrays. Univariate and multivariate analyses were done, including the most recognized clinical variables and the potential role of administration of adjuvant RT. Results: Median age was 31 years; the expression of COX-2 defined a subgroup with significantly worse prognosis. Considering COX-2{sup +} patients, those who received RT had significantly better 5-year progression-free survival (PFS) (80% vs 54% if no RT; P=.008). In contrast, COX-2{sup −} patients only had a modest, nonsignificant benefit from RT in terms of 5-year PFS (90% vs 79%; P=.13). When we compared the outcome of patients receiving RT considering the expression of COX-2 on RS cells, we found a nonsignificant 10% difference in terms of PFS between COX-2{sup +} and COX-2{sup −} patients (P=.09), whereas the difference between the 2 groups was important (25%) in patients not receiving RT (P=.04). Conclusions: Cyclooxygenase-2 RS cell expression is an adverse independent prognostic factor in early HL. Radiation therapy overcomes the worse prognosis associated with COX-2 expression on RS cells, acting in a chemotherapy-independent way. Cyclooxygenase-2 RS cell expression may be useful for determining patient candidates with early HL to receive consolidation with RT.

Intrahepatic chemoembolization in unresectable pediatric liver malignancies

International Nuclear Information System (INIS)

Arcement, C.M.; Towbin, R.B.; Meza, M.P.; Kaye, R.D.; Carr, B.I.; Gerber, D.A.; Mazariegos, G.V.; Reyes, J.

2000-01-01

Objective. To determine the effectiveness of a new miltidisciplinary approach using neoadjuvant intrahepatic chemoembolization (IHCE) and liver transplant (OLTx) in patients with unresectable hepatic tumors who have failed systemic chemotherapy. Materials and methods. From November 1989 to April 1998, 14 children (2-15 years old) were treated with 50 courses of intra-arterial chemotherapy. Baseline and post-treatment contrast-enhanced CT and alpha-fetoprotein levels were performed. Seven had hepatoblastoma, and 7 had hepatocellular carcinoma (1 fibrolamellar variant). All patients had subselective hepatic angiography and infusion of cisplatin and/or adriamycin (36 courses were followed by gelfoam embolization). The procedure was repeated every 3-4 weeks based on hepatic function and patency of the hepatic artery. Results. Six of 14 children received orthotopic liver transplants (31 courses of IHC). Pretransplant, 3 of 6 showed a significant decrease in alpha-fetoprotein, while only 1 demonstrated a significant further reduction in tumor size. Three of 6 patients are disease free at this time. Three of 6 patients died of metastatic tumor 6, 38, and 58 months, respectively post-transplant. One of 14 is currently undergoing treatment, has demonstrated a positive response, and is awaiting OLTx. Three of 14 withdrew from the program and died. Four of 14 patients developed an increase in tumor size, developed metastatic disease, and were not transplant candidates. Two hepatic arteries thrombosed, and one child had a small sealed-off gastric ulcer as complications of intrahepatic chemoembolization. Conclusion. The results of intrahepatic chemoembolization are promising and suggest that some children who do not respond to systemic therapy can be eventually cured by a combination of intrahepatic chemoembolization orthotopic liver transplant. Alpha-fetoprotein and cross-sectional imaging appear to be complementary in evaluating tumor response. IHCE does not appear to convert

Intrahepatic chemoembolization in unresectable pediatric liver malignancies

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Arcement, C.M.; Towbin, R.B.; Meza, M.P.; Kaye, R.D.; Carr, B.I. [Department of Radiology, Children' s Hospital of Pittsburgh, PA (United States); Gerber, D.A.; Mazariegos, G.V.; Reyes, J. [Department of Transplant Surgery, Children' s Hospital of Pittsburgh, PA (United States)

2000-11-01

Objective. To determine the effectiveness of a new miltidisciplinary approach using neoadjuvant intrahepatic chemoembolization (IHCE) and liver transplant (OLTx) in patients with unresectable hepatic tumors who have failed systemic chemotherapy. Materials and methods. From November 1989 to April 1998, 14 children (2-15 years old) were treated with 50 courses of intra-arterial chemotherapy. Baseline and post-treatment contrast-enhanced CT and alpha-fetoprotein levels were performed. Seven had hepatoblastoma, and 7 had hepatocellular carcinoma (1 fibrolamellar variant). All patients had subselective hepatic angiography and infusion of cisplatin and/or adriamycin (36 courses were followed by gelfoam embolization). The procedure was repeated every 3-4 weeks based on hepatic function and patency of the hepatic artery. Results. Six of 14 children received orthotopic liver transplants (31 courses of IHC). Pretransplant, 3 of 6 showed a significant decrease in alpha-fetoprotein, while only 1 demonstrated a significant further reduction in tumor size. Three of 6 patients are disease free at this time. Three of 6 patients died of metastatic tumor 6, 38, and 58 months, respectively post-transplant. One of 14 is currently undergoing treatment, has demonstrated a positive response, and is awaiting OLTx. Three of 14 withdrew from the program and died. Four of 14 patients developed an increase in tumor size, developed metastatic disease, and were not transplant candidates. Two hepatic arteries thrombosed, and one child had a small sealed-off gastric ulcer as complications of intrahepatic chemoembolization. Conclusion. The results of intrahepatic chemoembolization are promising and suggest that some children who do not respond to systemic therapy can be eventually cured by a combination of intrahepatic chemoembolization orthotopic liver transplant. Alpha-fetoprotein and cross-sectional imaging appear to be complementary in evaluating tumor response. IHCE does not appear to convert

A controlled clinical trial testing two potentially non-cross-resistant chemotherapeutic regimens in small-cell carcinoma of the lung.

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Broder, L E; Selawry, O S; Charyulu, K N; Ng, A; Bagwell, S

1981-03-01

With the objectives of improving response rate, duration of response, and survival in small-cell carcinoma of the lung, 39 patients were randomized to remission-induction with either one of two potentially non-cross-resistant drug combinations: APE (consisting of adriamycin, 35 mg/m2 IV, D1 Q 3 weeks; procarbazine, 60 mg/m2 PO, D1-10 Q 3 weeks; and the epipodophyllotoxin (VP16-213), 130 mg/m2 IV, D8, 15 Q 3 weeks) or MOCC (composed of methotrexate, 15 mg/m2 IV (with [vincristine] Oncovin) or PO twice weekly D8-21 Q 3 weeks; Oncovin, 1.5 mg/m2 IV, D8, 15 Q 3 weeks; cyclophosphamide, 600 mg/m2 IV, D1 Q 3 weeks, and CCNU, 60 mg/m2 PO Q 6 weeks). A fixed crossover to the alternate regimen occurred at three months. Radiotherapy was delivered to the primary tumor (locoregional disease only) by a split course technique (1,750 rads for five days with a three-week split, followed by 3,400 rads over 17 days). The median survival including both arms was 11 months for regional and nine months for extensive disease. The chemotherapeutic activity of both regimens was comparable, with 15/17 (88 percent) of the patients responding to APE (including six complete) and 14/17 (82 percent) responding to MOCC (including five complete). The median survival for the complete responders was 11.7 months, while the partial responders survived for a median of 9.7 months. There were 2/9 (22 percent) responders to the alternate regimen at progressive disease. The overall incidence of CNS progression was 17 percent. The toxicity of the regimens was moderate, except for one instance of granulocytopenic death. This study establishes two equipotent drug combinations for the treatment of small-cell carcinoma of the lung.

Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity

International Nuclear Information System (INIS)

Mitra, Mayurranjan S.; Donthamsetty, Shashikiran; White, Brent; Latendresse, John R.; Mehendale, Harihara M.

2007-01-01

Clinical use of doxorubicin (Adriamycin (registered) ), an antitumor agent, is limited by its oxyradical-mediated cardiotoxicity. We tested the hypothesis that moderate diet restriction protects against doxorubicin-induced cardiotoxicity by decreasing oxidative stress and inducing cardioprotective mechanisms. Male Sprague-Dawley rats (250-275 g) were maintained on diet restriction [35% less food than ad libitum]. Cardiotoxicity was estimated by measuring biomarkers of cardiotoxicity, cardiac function, lipid peroxidation, and histopathology. A LD 100 dose of doxorubicin (12 mg/kg, ip) administered on day 43 led to 100% mortality in ad libitum rats between 7 and 13 days due to higher cardiotoxicity and cardiac dysfunction, whereas all the diet restricted rats exhibited normal cardiac function and survived. Toxicokinetic analysis revealed equal accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the ad libitum and diet restricted hearts. Mechanistic studies revealed that diet restricted rats were protected due to (1) lower oxyradical stress from increased cardiac antioxidants leading to downregulation of uncoupling proteins 2 and 3, (2) induction of cardiac peroxisome proliferators activated receptor-α and plasma adiponectin increased cardiac fatty acid oxidation (666.9 ±14.0 nmol/min/g heart in ad libitum versus 1035.6 ± 32.3 nmol/min/g heart in diet restriction) and mitochondrial AMPα2 protein kinase. The changes led to 51% higher cardiac ATP levels (17.7 ± 2.1 μmol/g heart in ad libitum versus 26.7 ± 1.9 μmol/g heart in diet restriction), higher ATP/ADP ratio, and (3) increased cardiac erythropoietin and decreased suppressor of cytokine signaling 3, which upregulates cardioprotective JAK/STAT3 pathway. These findings collectively show that moderate diet restriction renders resiliency against doxorubicin cardiotoxicity by lowering oxidative stress, enhancing ATP synthesis, and inducing the JAK/STAT3 pathway

The benefit of cisplatin-based polychemotherapy for adenocarcinoma of the lung. The Kyushu Lung Cancer Chemotherapy Study Group.

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Hara, N; Ohta, M; Ichikawa, Y; Kanda, T; Shima, K; Tamura, K; Hokama, M

1990-01-01

We studied the efficacy of cisplatin-based polychemotherapy for adenocarcinoma of the lung. A total of 136 patients were randomized for treatment with either cyclophosphamide, Adriamycin, cisplatin and mitomycin C (CAPM) or mitomycin C, cytosine arabinoside and tegafur (MCT). Radiation was given to the chests of patients at stage III. The differences in the response rate (35% in the CAPM arm and 13% in the MCT arm) were statistically significant (P less than 0.01). However, the significant difference was observed in stage-IV patients (CAPM, 33%; MCT, 4%; P less than 0.001) and not in stage-III patients (CAPM, 40%; MCT, 40%). The median period of survival was 9.5 months for the CAPM arm and 5.5 months for the MCT arm (P less than 0.035, Wilcoxon-Gehan test; P less than 0.1, log-rank test). Improved median survival for the CAPM regimen was demonstrated only by stage-IV patients (CAPM, 10 months; MCT, 5.5 months; P less than 0.025, Wilcoxon-Gehan test; P less than 0.05, log-rank test). The duration of the response, including PRs and NCs, was significantly different depending on the treatment, showing 5 months for the CAPM arm and 3 months for the MCT arm (P less than 0.05). The significant difference was also only observed in stage-IV patients. Myelosuppression was more severe with CAPM than with the MCT regimen. Nausea and vomiting were significantly increased in patients receiving the CAPM regimen. However, all toxicities were acceptable and there were no treatment-related deaths. We concluded that cisplatin-based chemotherapy, CAPM therapy, was of more benefit to patients with adenocarcinoma of the lung than MCT therapy.

Quantitative analysis of cellular glutathione by flow cytometry utilizing monochlorobimane: some applications to radiation and drug resistance in vitro and in vivo.

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Rice, G C; Bump, E A; Shrieve, D C; Lee, W; Kovacs, M

1986-12-01

An assay using a bimane derivative has been developed to detect free glutathione (GSH) in individual viable cells by flow cytometry. Monochlorobimane [syn-(ClCH2CH3)-1,5-diazabicycla[3.30]acta-3,6-diene-2,8-dio ne], itself nonfluorescent, reacts with GSH to form a highly fluorescent derivative. High pressure liquid chromatography analysis showed that, using specific staining conditions, the only low molecular weight fluorescent derivative formed in Chinese hamster ovary cells was that formed with GSH. Very little reaction with protein sulfhydryls was observed. Rates of GSH depletion in Chinese hamster ovary cells exposed to diethylmaleate were essentially the same, whether measured by relative fluorescence intensity, by flow cytometry or by enzymatic assay on cellular extracts. This method was shown to be useful for measurement of GSH resynthesis, uptake, and depletion by prolonged hypoxia and misonidazole treatment. Since measurements are made on individual cells, cell-to-cell variation and populational heterogeneity in GSH content are revealed by flow cytometry. Although under most conditions in vitro GSH content is relatively homogeneous, under certain circumstances, such as release from hypoxia, heterogeneity in populational GSH levels was observed. The significance of this heterogeneity is discussed in regard to the induction of gene amplification and drug resistance by transient hypoxia. Numerous subclones of Chinese hamster ovary cells selected by growth in Adriamycin or methotrexate-containing medium express elevated levels of GSH per cell. The method was extended to quantitate the GSH content of cells excised from EMT-6/SF mouse tumors that had been treated in vivo with L-buthionine-S-R-sulfoximine, an inhibitor of GSH synthesis. The bivariate analysis (forward angle light scatter versus monochlorobimane fluorescence) of cells derived from these tumors gave excellent resolution of normal and tumor cells and demonstrated extensive heterogeneity in the tumor

C-X-C Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury.

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Mo, Hongyan; Wu, Qinyu; Miao, Jinhua; Luo, Congwei; Hong, Xue; Wang, Yongping; Tang, Lan; Hou, Fan Fan; Liu, Youhua; Zhou, Lili

2017-08-20

Oxidative stress plays a role in mediating podocyte injury and proteinuria. However, the underlying mechanism remains poorly understood. In this study, we investigated the potential role of C-X-C chemokine receptor type 4 (CXCR4), the receptor for stromal cell-derived factor 1α (SDF-1α), in mediating oxidative stress-induced podocyte injury. In mouse model of adriamycin nephropathy (ADR), CXCR4 expression was significantly induced in podocytes as early as 3 days. This was accompanied by an increased upregulation of oxidative stress in podocyte, as demonstrated by malondialdehyde assay, nitrotyrosine staining and secretion of 8-hydroxy-2'-deoxyguanosine in urine, and induction of NOX2 and NOX4, major subunits of NADPH oxidase. CXCR4 was also induced in human kidney biopsies with proteinuric kidney diseases and colocalized with advanced oxidation protein products (AOPPs), an established oxidative stress trigger. Using cultured podocytes and mouse model, we found that AOPPs induced significant loss of podocyte marker Wilms tumor 1 (WT1), nephrin, and podocalyxin, accompanied by upregulation of desmin both in vitro and in vivo. Furthermore, AOPPs worsened proteinuria and aggravated glomerulosclerosis in ADR. These effects were associated with marked activation of SDF-1α/CXCR4 axis in podocytes. Administration of AMD3100, a specific inhibitor of CXCR4, reduced proteinuria and ameliorated podocyte dysfunction and renal fibrosis triggered by AOPPs in mice. In glomerular miniorgan culture, AOPPs also induced CXCR4 expression and downregulated nephrin and WT1. Innovation and Conclusion: These results suggest that chemokine receptor CXCR4 plays a crucial role in mediating oxidative stress-induced podocyte injury, proteinuria, and renal fibrosis. CXCR4 could be a new target for mitigating podocyte injury, proteinuria, and glomerular sclerosis in proteinuric chronic kidney disease. Antioxid. Redox Signal. 27, 345-362.

N-Butyrate alters chromatin accessibility to DNA repair enzymes

International Nuclear Information System (INIS)

Smith, P.J.

1986-01-01

Current evidence suggests that the complex nature of mammalian chromatin can result in the concealment of DNA damage from repair enzymes and their co-factors. Recently it has been proposed that the acetylation of histone proteins in chromatin may provide a surveillance system whereby damaged regions of DNA become exposed due to changes in chromatin accessibility. This hypothesis has been tested by: (i) using n-butyrate to induce hyperacetylation in human adenocarcinoma (HT29) cells; (ii) monitoring the enzymatic accessibility of chromatin in permeabilised cells; (iii) measuring u.v. repair-associated nicking of DNA in intact cells and (iv) determining the effects of n-butyrate on cellular sensitivity to DNA damaging agents. The results indicate that the accessibility of chromatin to Micrococcus luteus u.v. endonuclease is enhanced by greater than 2-fold in n-butyrate-treated cells and that there is a corresponding increase in u.v. repair incision rates in intact cells exposed to the drug. Non-toxic levels of n-butyrate induce a block to G1 phase transit and there is a significant growth delay on removal of the drug. Resistance of HT29 cells to u.v.-radiation and adriamycin is enhanced in n-butyrate-treated cells whereas X-ray sensitivity is increased. Although changes in the responses of cells to DNA damaging agents must be considered in relation to the effects of n-butyrate on growth rate and cell-cycle distribution, the results are not inconsistent with the proposal that increased enzymatic-accessibility/repair is biologically favourable for the resistance of cells to u.v.-radiation damage. Overall the results support the suggested operation of a histone acetylation-based chromatin surveillance system in human cells

Factors influencing caries incidence in permanent teeth in children/adolescents under and after anti-neoplastic treatment

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Ewa Krasuska-Sławińska

2016-02-01

Full Text Available Aim of the study : To determine reasons for the increase in caries among children/adolescents treated for neoplasms. Material and methods : Health promoting behaviour, oral hygiene (PLI, gingiva (GI, dentition (DMFt/DMFs, number of teeth with white spot lesions (WSL, and enamel defects (ED were assessed in three groups of 60 patients each. The three groups were as follows: under chemotherapy (CH, after chemotherapy (PCH, and generally healthy (CG. Medical files supplied information on neoplasm type, chemotherapeutic type and dose, age at treatment start, chemotherapy duration, and complications. Statistical analysis was performed with Mann-Whitney U test and Spearman’s rho test. Results: The age at which chemotherapy was started/its duration was 5.9 ±4.0/1.3 ±0.5 years in PCH and 9.12 ±4.44/0.8 ±0.3 years in CH; PCH completed treatment 4.9 ±3.4 years ago. Chemotherapy most often included vincristine (VCR, etoposide (VP-16, adriamycin (ADM, cyclophosphamide (CTX, cisplatin (CDDP, and ifosphamide (IF. Mucositis occurrence was 28.33% in PCH and 45.00% in CH; vomiting occurrence was 43.33% and 50.00%, respectively. Nutrition and prophylaxis mistakes occurred more often in CH/PCH than in CG; PLI, GI, caries incidence and severity, and the number of teeth with WSL were higher. Correlation between caries incidence and chemotherapeutic type and dose, age at treatment start and treatment duration, mucositis, emesis, PLI, GI, ED, no fluoride prophylaxis, and nutritional mistakes was established. Ifosphamide and mucositis treatment played a major role in chemotherapy; after chemotherapy – ED and CTX, ADM, IF, and VP-16. Conclusions : Caries in permanent teeth in children/adolescents undergoing chemotherapy result from nutritional mistakes, poor prophylaxis, and indirectly from chemotherapy complications (first mucositis and emesis, and later developmental ED.

Multimodal treatment combining chemotherapy, hyperthermia and radiotherapy for ovarian cancer

International Nuclear Information System (INIS)

Nagashima, Kei

1992-01-01

There has been increasing interest in the use of heat in the treatment of cancer. Theoretically cells are the most sensitive to ionizing radiation at mitosis, whereas the cycle phase that is the most resistant to ionizing radiation namely late in the DNA. Synthetic phase (late S) is the most sensitive to hyperthermia. Hyperthermia has been reported to enhance the cytocidal effects of several active chemotherapeutic agents. When thermal potentiation of chemotherapeutic agents against malignant cells is contemplated, normal tissues have a relatively high ambient blood flow which increases in response to thermal stress, thereby dissipating heat, compared to tumors. Tumors, with relatively poor blood flow and a responsive neovasculature, are in capable of augmenting flow and acting as a heat reservoir. This is the phenomenon of a heat reservoir which is one factor to enhance the cytocidal effects of several active anticancer agents for enhancing the uptake in tumor. The importance is in the adjuvant chemotherapy treated for post operative, advanced and recurrent ovarian cancer. Heating enhances the effects of radiotherapy and chemotherapy. Thirty patients with ovarian cancer were subjected to the multidisciplinary treatment with combination of hyperthermochemotherapy and radiation. The 30 patients consisted of 18 with endometrioid adenocarcinoma and 7 with serious post operative or recurrent status. Two types of equipments with rediofrequencies of 70 MHz (BSD-1000) or 434 MHZ (TAG MED·HS 434) were used for hyperthermia. Chemotherapeutic agents such as adriamycin, cis DDP, cyclophosphamide and etoposide were injected intravenously. Arterial infusion with reservoir was very effective in advanced stage of ovarian cancer. No severe or fatal side effects were observed. Hyperthermochemotherapy is useful and effective for the postoperative management or the treatment of recurrent cancer of the ovary. (J.P.N.)

Radiosensitization by overexpression of the nonphosphorylation form of IκB-α in human glioma cells

International Nuclear Information System (INIS)

Honda, Naoko; Yagi, Kasumi; Ding, Gui-Rong; Miyakoshi, Junji

2002-01-01

To assess the role of NF-κB in cellular radiosensitivity, we constructed mutated IκB expression plasmids for SY-IκB (with mutations at residues of 32, 36 and 42) expression in human malignant glioma cells (radiosensitive MO54 and radioresistant T98 cells), giving respective cell types referred to as MO54-SY4 and T98-SY14. Both of the clones expressing SY-IκB became radiosensitive, compared with the parental MO54 and T98 cells. A treatment with herbimycin A or genistein did not change the radiosensitivity of cells expressing SY-IκB, but made both the MO54 and T98 parental cells more sensitive to ionizing radiation. A treatment with TNF-α induced DNA fragmentation and apoptosis in cells expressing SY-IκB, but not in MO54 and T98 cells. The survival after X-ray exposure of the parental MO54 cells was slightly increased by a TNF-α treatment, but that of the parental T98 cells did not change. The change in sensitivity to ultra-violet (UV) radiation and adriamycin in MO54-SY4 cells was very similar to that for X-ray sensitivity, but no change was observed in T98-SY14 cells. Significant sublethal damage repair was observed in T98 cells, whereas MO54 cells showed little repair activity. The expression of p53 was enhanced in the parental MO54 cells, while the p53 levels in the MO54-SY4, and in the parent and clonal T98 cells, did not change. Our data suggest that the serine and tyrosine phosphorylation of IκB-α may play a role in determining the radiosensitivity of malignant glioma cells. (author)

Long term (five-year survival following radical surgical treatment plus adjuvant chemotherapy (FAM in advanced gastric cancer: a controlled study

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Bresciani Cláudio

2000-01-01

Full Text Available Several drugs and their associations are being used for adjuvant or complementary chemotherapy with the aim of improving results of gastric cancer treatment. The objective of this study was to verify the impact of these drugs on nutrition and on survival rate after radical treatment of 53 patients with gastric cancer in stage III of the TNM classification. A control group including 28 patients who had only undergone radical resection was compared to a group of 25 patients who underwent the same operative technique followed by adjuvant polychemotherapy with FAM (5-fluorouracil, Adriamycin, and mitomycin C. In this latter group, chemotherapy toxicity in relation to hepatic, renal, cardiologic, neurological, hematologic, gastrointestinal, and dermatological functions was also studied. There was no significant difference on admission between both groups in relation to gender, race, macroscopic tumoral type of tumor according to the Borrmann classification, location of the tumor in the stomach, length of the gastric resection, or response to cutaneous tests on delayed sensitivity. Chemotherapy was started on average, 2.3 months following surgical treatment. Clinical and laboratory follow-up of all patients continued for 5 years. The following conclusions were reached: 1 The nutritional status and incidence of gastrointestinal manifestation were similar in both groups; 2 There was no occurrence of cardiac, renal, neurological, or hepatic toxicity or death due to the chemotherapeutic method per se; 3 Dermatological alterations and hematological toxicity occurred exclusively in patients who underwent polychemotherapy; 4 There was no significant difference between the rate and site of tumoral recurrence, the disease-free interval, or the survival rate of both study groups; 5 Therefore, we concluded, after a 5-year follow-up, chemotherapy with the FAM regimen did not increase the survival rate.

High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity

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Mitra, Mayurranjan S.; Donthamsetty, Shashikiran; White, Brent; Mehendale, Harihara M.

2008-01-01

Often, chemotherapy by doxorubicin (Adriamycin) is limited due to life threatening cardiotoxicity in patients during and posttherapy. Recently, we have shown that moderate diet restriction remarkably protects against doxorubicin-induced cardiotoxicity. This cardioprotection is accompanied by decreased cardiac oxidative stress and triglycerides and increased cardiac fatty-acid oxidation, ATP synthesis, and upregulated JAK/STAT3 pathway. In the current study, we investigated whether a physiological intervention by feeding 40% high fat diet (HFD), which induces obesity in male Sprague-Dawley rats (250-275 g), sensitizes to doxorubicin-induced cardiotoxicity. A LD 10 dose (8 mg doxorubicin/kg, ip) administered on day 43 of the HFD feeding regimen led to higher cardiotoxicity, cardiac dysfunction, lipid peroxidation, and 80% mortality in the obese (OB) rats in the absence of any significant renal or hepatic toxicity. Doxorubicin toxicokinetics studies revealed no change in accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the normal diet-fed (ND) and OB hearts. Mechanistic studies revealed that OB rats are sensitized due to: (1) higher oxyradical stress leading to upregulation of uncoupling proteins 2 and 3, (2) downregulation of cardiac peroxisome proliferators activated receptor-α, (3) decreased plasma adiponectin levels, (4) decreased cardiac fatty-acid oxidation (666.9 ± 14.0 nmol/min/g heart in ND versus 400.2 ± 11.8 nmol/min/g heart in OB), (5) decreased mitochondrial AMP-α2 protein kinase, and (6) 86% drop in cardiac ATP levels accompanied by decreased ATP/ADP ratio after doxorubicin administration. Decreased cardiac erythropoietin and increased SOCS3 further downregulated the cardioprotective JAK/STAT3 pathway. In conclusion, HFD-induced obese rats are highly sensitized to doxorubicin-induced cardiotoxicity by substantially downregulating cardiac mitochondrial ATP generation, increasing oxidative stress and downregulating the JAK/STAT3

Second malignancies after chemotherapy and radiotherapy for Hodgkin disease.

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Chronowski, Gregory M; Wilder, Richard B; Levy, Larry B; Atkinson, Edward N; Ha, Chul S; Hagemeister, Fredrick B; Barista, Ibrahim; Rodriguez, Maria A; Sarris, Andreas H; Hess, Mark A; Cabanillas, Fernando; Cox, James D

2004-02-01

The purpose of this preliminary study was to determine the incidence of second malignancies after combined-modality therapy for adults with Hodgkin disease and relate it to the details of initial treatment. We retrospectively studied 286 patients ranging in age from 16 to 88 years with stage I or II Hodgkin disease who were treated between 1980 and 1995 with chemotherapy followed 3 to 4 weeks later by radiotherapy. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone was used in 161 cases, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) in 67 cases, Adriamycin, bleomycin, vinblastine, and dacarbazine in 19 cases, lomustine, vinblastine, procarbazine, and prednisone/doxorubicin, bleomycin, dacarbazine, and lomustine in 18 cases, and other chemotherapeutic regimens in the remaining 21 cases. The median radiotherapy dose was 40 Gy given in 20 daily 2-Gy fractions. Median follow-up of surviving patients was 7.4 years. There were 2,230 person-years of observation. Significantly increased relative risks (RR) were observed for acute myeloid leukemia (RR, 69.3; 95% CI, 14.3-202.6) and melanoma (RR, 7.3; 95% CI, 1.5-21.3). The 5-, 10-, and 15-year actuarial risks of acute myeloid leukemia were 0.8%, 1.3%, and 1.3%, respectively. Patients treated with MOPP had the highest 15-year actuarial risk of leukemia (1.6%). The 5-, 10-, and 15-year actuarial risks of solid tumors were 1.9%, 9.3%, and 16.8%, respectively. Consolidative radiotherapy to both sides of the diaphragm resulted in a trend toward an increased risk of solid tumors relative to radiotherapy to only one side of the diaphragm (p = 0.08). In an effort to reduce the risk of second malignancies, we have stopped using the alkylating agents nitrogen mustard and procarbazine and elective paraaortic and splenic radiotherapy after chemotherapy.

Role of radiation therapy in the management of nonmetastatic Ewing's sarcoma of bone. Report of the intergroup Ewing's sarcoma study

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Perez, C.A.; Tefft, M.; Nesbit, M.; Burgert, E.O. Jr.; Vietti, T.; Kissane, J.; Pritchard, D.J.; Gehan, E.A.

1981-01-01

The role of radiation therapy in local tumor control and decreased incidence of pulmonary metastasis is reported in 271 patients who were entered into the Intergroup Ewing's Sarcoma Study with more than one year follow-up and on whom all radiotherapy records were reviewed. The majority of the patients were irradiated to the primary tumor with doses of 4500 to 6500 rad in five to six weeks in combination with systemic administration of three drugs (vincristine, actinomycin-D and cyclophosphamide) or four drugs (vincristine, actinomycin-D, cyclophosphamide and adriamycin). One of the groups of patients was treated with three drugs and bilateral pulmonary irradiation (1500 rad, uncorrected dose, in two weeks). Preliminary analysis shows an overall local primary tumor control of 89%. Patients with lesions in the pelvis had a local failure rate of 17% (9 of 52) and in the humerus 23% (7 of 31). Factors affecting local recurrences are analyzed in detail. Distant metastases have been noted in 40% of all patients; the highest proportion was noted in the pelvis (49%). There was a significant difference in the appearance of pulmonary metastases in the patients who were treated with four drugs (9.7%) and in the group who received three drugs and pulmonary irradiation (23.5%) when compared with the patients treated with three drugs only (37%). Intensive chemotherapy and radiotherapy significantly improve local tumor control and survival of patients with localized Ewing's sarcoma. However, the high incidence of metastasis suggests the need for more effective systemic chemotherapy to further improve treatment results. It is very important to determine the optimal dose of irradiation and minimal volume to be treated in order to achieve optimal survival and primary tumor control with the least sequela

Bypassing multidrug resistance in human breast cancer cells with lipid/polymer particle assemblies

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Li B

2012-01-01

Full Text Available Bo Li1, Hui Xu2, Zhen Li1, Mingfei Yao1, Meng Xie1, Haijun Shen1, Song Shen1, Xinshi Wang1, Yi Jin11College of Pharmaceutical sciences, Zhejiang University, Hangzhou, 2No. 202 Hospital of People's Liberation Army, Shenyang, ChinaBackground: Multidrug resistance (MDR mediated by the overexpression of adenosine triphosphate (ATP-binding cassette (ABC transporters, such as P-glycoprotein (P-gp, remains one of the major obstacles to effective cancer chemotherapy. In this study, lipid/particle assemblies named LipoParticles (LNPs, consisting of a dimethyldidodecylammonium bromide (DMAB-modified poly(lactic-co-glycolic acid (PLGA nanoparticle core surrounded by a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC shell, were specially designed for anticancer drugs to bypass MDR in human breast cancer cells that overexpress P-gp.Methods: Doxorubicin (DOX, a chemotherapy drug that is a P-gp substrate, was conjugated to PLGA and encapsulated in the self-assembled LNP structure. Physiochemical properties of the DOX-loaded LNPs were characterized in vitro. Cellular uptake, intracellular accumulation, and cytotoxicity were compared in parental Michigan Cancer Foundation (MCF-7 cells and P-gp-overexpressing, resistant MCF-7/adriamycin (MCF-7/ADR cells.Results: This study found that the DOX formulated in LNPs showed a significantly increased accumulation in the nuclei of drug-resistant cells relative to the free drug, indicating that LNPs could alter intracellular traffic and bypass drug efflux. The cytotoxicity of DOX loaded-LNPs had a 30-fold lower half maximal inhibitory concentration (IC50 value than free DOX in MCF-7/ADR, measured by the colorimetric cell viability (MTT assay, correlated with the strong nuclear retention of the drug.Conclusion: The results show that this core-shell lipid/particle structure could be a promising strategy to bypass MDR.Keywords: chemotherapy, drug delivery, polymeric nanoparticles, multidrug resistance

Doxorubicin plus tumor necrosis factor alpha combination treatments in EL4-lymphoma-bearing C57BL/6 mice.

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Ehrke, M J; Verstovsek, S; Ujházy, P; Meer, J M; Eppolito, C; Maccubbin, D L; Mihich, E

1998-02-01

The therapeutic efficacy of a total of 42 single-agent or combination protocols involving doxorubicin (Adriamycin, ADM) and tumor necrosis factor alpha (TNFalpha) were evaluated in the syngeneic murine lymphoma model, C57BL/6-EL4. Combination treatments were the most effective and the therapeutic effects were schedule-dependent; e.g. it was generally advantageous for ADM to precede TNFalpha administration. Two protocols selected for further study were 4 mg/kg ADM i.v. on days 1 and 8 plus TNFalpha, i.v., at either 16000 U (7 microg)/injection, on days 1 and 8 or 4000 U (1.7 microg)/injection, on days 11-15. Survival of mice bearing one of four EL4 sublines having different in vitro drug sensitivities was assessed. These sublines were E10 (ADM-sensitive/TNFalpha-resistant), E16 (sensitive/sensitive), ER2 (ADM-resistant/TNFalpha-sensitive) and ER13 (resistant/resistant). Between 80% and 100% long-term survivors (i.e. tumor free on day 60) were obtained with the two treatments in mice bearing ADM-sensitive sublines, even though one of these sublines, E10, was resistant to TNFalpha in vitro. Induction of long-term survival appeared, therefore, to correlate with in vitro defined sensitivity/resistance to ADM, but not to TNFalpha Treatment-induced modulations of tumoricidal immune effector functions were also examined. Taken together, the results indicated that induction of long-term survival involved complex interactions of: (1) ADM-induced tumor modifications, including, but not limited to, tumor debulking, (2) combination-treatment-induced modifications of splenic cytolytic T cell and macrophage activities, and (3) the restoration of thymus cellularity. Finally, when long-term survivors resulting from treatment of E10- or E16-bearing mice were implanted with ER2 on day 120, the majority survived, indicating that long-term immune memory, capable of recognizing drug resistant variants, had been established.

Adenoma clear cell carcinoma of prostatic utricle. Report of a case. Literature Review

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Cataldi, S.; Castillo, L.; Rodrígue, R.

2004-01-01

The prostatic utricle (UP) is a rudimentary structure derived from the Müllerian ducts (paramesonephric), which gives rise to the female genital tract in its portion flow and Wollfianos products (mesonephric), which causes the male seminal tubes urogenital sinus and in the caudal segment. It is located in the central portion of the prostatic urethra. UP pathology is rare in the literature and only few isolated cases have been reported and rare reviews. UP neoplasms are extremely rare. The first report on the literature is the year 1967 in a man 66 years in which the diagnosis was incidental in a piece of prostatectomy. Objective: The aim of this paper is to review the literature on this rare condition from the report of a clinical case. Case report: Male patient, 15 years who presented with hematuria. the tomography showed right renal agenesis, hypertrophic left kidney and a solid mass retrovesical in prostate topography. The transrectal ultrasound guided biopsy remains informed embryonic kidney blastoma and immunohistochemical profile is specific to urothelial epithelium and glomerular (BPM CK7 strongly positive). It is involved, resecting the tumor whose pelvic pathology (AP) corresponded to clear cell adenocarcinoma UP. Pursuing a post-operative complications and remains without clinical tomographic control locoregional relapse was diagnosed 5 months after. Get chemotherapy type adriamycin-cisplatin with complete clinical response after the 2nd cycle of treatment and rapid lesion progression at the end of the 6th cycle. Was re hospitalized resecting one laterovesical mass right, leaving in situ a left laterovesical similar mass. the AP was similar to the original. Currently, the patient underwent a left nephrostomy is planned initiation of palliative chemotherapy of weekly Docetaxel type. Conclusions: Given the rarity of the disease, and little literature there is no data on evolution and sensitivity to treatment. In the case of this patient highlight the high

Involved-Site Image-Guided Intensity Modulated Versus 3D Conformal Radiation Therapy in Early Stage Supradiaphragmatic Hodgkin Lymphoma

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Filippi, Andrea Riccardo, E-mail: andreariccardo.filippi@unito.it [Department of Oncology, University of Torino, Torino (Italy); Ciammella, Patrizia [Radiation Therapy Unit, Department of Oncology and Advanced Technology, ASMN Hospital IRCCS, Reggio Emilia (Italy); Piva, Cristina; Ragona, Riccardo [Department of Oncology, University of Torino, Torino (Italy); Botto, Barbara [Hematology, Città della Salute e della Scienza, Torino (Italy); Gavarotti, Paolo [Hematology, University of Torino and Città della Salute e della Scienza, Torino (Italy); Merli, Francesco [Hematology Unit, ASMN Hospital IRCCS, Reggio Emilia (Italy); Vitolo, Umberto [Hematology, Città della Salute e della Scienza, Torino (Italy); Iotti, Cinzia [Radiation Therapy Unit, Department of Oncology and Advanced Technology, ASMN Hospital IRCCS, Reggio Emilia (Italy); Ricardi, Umberto [Department of Oncology, University of Torino, Torino (Italy)

2014-06-01

Purpose: Image-guided intensity modulated radiation therapy (IG-IMRT) allows for margin reduction and highly conformal dose distribution, with consistent advantages in sparing of normal tissues. The purpose of this retrospective study was to compare involved-site IG-IMRT with involved-site 3D conformal RT (3D-CRT) in the treatment of early stage Hodgkin lymphoma (HL) involving the mediastinum, with efficacy and toxicity as primary clinical endpoints. Methods and Materials: We analyzed 90 stage IIA HL patients treated with either involved-site 3D-CRT or IG-IMRT between 2005 and 2012 in 2 different institutions. Inclusion criteria were favorable or unfavorable disease (according to European Organization for Research and Treatment of Cancer criteria), complete response after 3 to 4 cycles of an adriamycin- bleomycin-vinblastine-dacarbazine (ABVD) regimen plus 30 Gy as total radiation dose. Exclusion criteria were chemotherapy other than ABVD, partial response after ABVD, total radiation dose other than 30 Gy. Clinical endpoints were relapse-free survival (RFS) and acute toxicity. Results: Forty-nine patients were treated with 3D-CRT (54.4%) and 41 with IG-IMRT (45.6%). Median follow-up time was 54.2 months for 3D-CRT and 24.1 months for IG-IMRT. No differences in RFS were observed between the 2 groups, with 1 relapse each. Three-year RFS was 98.7% for 3D-CRT and 100% for IG-IMRT. Grade 2 toxicity events, mainly mucositis, were recorded in 32.7% of 3D-CRT patients (16 of 49) and in 9.8% of IG-IMRT patients (4 of 41). IG-IMRT was significantly associated with a lower incidence of grade 2 acute toxicity (P=.043). Conclusions: RFS rates at 3 years were extremely high in both groups, albeit the median follow-up time is different. Acute tolerance profiles were better for IG-IMRT than for 3D-CRT. Our preliminary results support the clinical safety and efficacy of advanced RT planning and delivery techniques in patients affected with early stage HL, achieving complete

Chemosensitivity and radiosensitivity of small cell lung cancer cell lines studied by a newly developed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) hybrid assay

International Nuclear Information System (INIS)

Hida, T.; Ueda, R.; Takahashi, T.; Watanabe, H.; Kato, T.; Suyama, M.; Sugiura, T.; Ariyoshi, Y.

1989-01-01

The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) hybrid assay was developed by technically combining the human tumor clonogenic assay and the MTT assay to make the most of both assays. This assay was able to estimate the in vitro growth of cultured cell lines and of tumor cells in pleural effusion, suggesting the possibility of its use for assessment of chemosensitivity and radiosensitivity of fresh tumor samples. Multiple cell lines [including morphological and/or phenotypical in vitro converters and cisplatin (CDDP)-resistant lines] were established from three patients with small cell lung cancer at different stages of the disease. Chemosensitivity of these cell lines to four commonly used chemotherapeutic drugs was tested by the MTT hybrid assay. SK1 and SK3 lines were established from Patient S. K. before and after chemotherapy and radiotherapy, respectively. SK3/CDDP, a CDDP-resistant line derived from the SK3 line, was 30-fold more resistant to CDDP [50% inhibiting dose (IC50), 21.5 micrograms/ml] than the SK1 line. In Patient M. O., MOA2/CDDP, a CDDP-resistant line derived from MOA2 (an in vitro converter from the MO line), was 41-fold more resistant to CDDP (IC50, 37 micrograms/ml) than the parent MO line. From Patient T. M., TM1 and TM2 lines were established before and after chemotherapy, respectively. The latter showed 6-fold more resistance to CDDP than the former. Chemosensitivity of these lines to three other drugs, 4-hydroperoxycyclophosphamide, Adriamycin, and etoposide, suggested cross-resistance between CDDP and 4-hydroperoxycyclophosphamide. Radiosensitivity study was also carried out with the MTT hybrid assay. The MOA2 line was more resistant [Do, 3.0 Gy; extrapolation number (n), 4.0] than the parental MO line (Do, 1.6 Gy; n, 2.1). There was no clear difference in radiosensitivity between the cell lines established before and after radiation therapy in Patient S. K

Prophylactic CNS therapy in childhood leukemia

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Yokoyama, Takashi; Hiyoshi, Yasuhiko; Fujimoto, Takeo

1982-01-01

This study was designed to evaluate the efficacy of CNS-prophylaxis with high-dose methotrexate (MTX). Seventy children with previously untreated acute lymphoblastic leukemia (ALL) entered to this study between July 1978 and December 1980. According to initial white blood count (WBC), they were stratified to induce remission with; vincristine and prednine in low initial WBC ( lt 25,000/mm 3 ) group and these two agents plus adriamycin in high initial WBC ( gt 25,000/mm 3 ) group. After inducing remission, 62 children who achieved CR, received different CNS-prophlaxis; using a regimen of three doses of weekly high-dose MTX (1,000 mg/m 2 ) 6-hour infusion, which was repeated every 12 weeks-Group A (n = 14); high-dose MTX followed by 2400 rad cranial irradiation plus three doses of i.t. MT X-Group B (n = 15), 2400 rad cranial irradiation plus three doses of i.t. MTX-Group C (n = 16), and in 17 patients with high initial WBC, same as in Group A-Group D (n = 17). During an intravenous 6-h infusion of MTX at a dose of 1,000 mg/m 2 , the CSF concentration of MTX rose to 2.3 +- 2.4 x 10 -6 M after initiation of infusion and remained in 10 -7 M level for 48 hours. CNS-leukemia terminated complete remission in one of 14 children in Group A, two of 15 in Group B, two of 16 in Group C and two of 17 in Group D. The cumulative incidence of CNS-leukemia at 20 months calculated by the technique of Kaplan and Meier was 0% i n Group A, 18.1% in Group B, 7.1% in Group C and 50.8% in Group D. There was no statistical difference among Groups A, B and C. These data suggested that CNS-prophylaxis with high-dose intravenous MTX was effective as well as 2400 rad cranial irradiation plus three doses of i.t. MTX in childhood ALL with low initial WBC. (author)

The long term effect and outcome of preoperative chemotherapy combined with radiation therapy for bladder cancer

International Nuclear Information System (INIS)

Nasu, Takahito; Nakane, Hiroshi; Kamata, Seiji; Mitsui, Hiroshi; Hayashida, Shigeaki; Shinohara, Youichi.

1996-01-01

The object of this study is to evaluate the efficacy of preoperative chemotherapy combined with radiation therapy for bladder cancer. A total of 44 patients with bladder cancer were treated by preoperative chemotherapy combined with radiation therapy between October, 1981 and December, 1986. Clinical stages included 4 patients in Ta, 25 in T1, 11 in T2, and 4 in T3. Each patient was treated twice with 15 gray of radiation to the small pelvic cavity and a chemotherapy combination of adriamycin, cis-platinum, tegaful, and peplomycin. The average observation time after the therapy was 83 month, with the maximum being 146 months. Complete remission was included in 5 patients, partial remission in 27, and no change in 12. Thus, the overall effective rate was 72.8%. Operations, selected by the results of the preoperative therapy, included transurethral resection on 28 patients, transurethral fulguration on 2, partial cystectomy on 4, resection of tumor on 4, and total cystectomy on 3. Operations were not performed on 2 patients and not allowed on 1 patient. The outcome during the long-term follow-up included cancer related deaths in 4 patients, and death resulting from other disorders in 9. The 5-year survival rates for superficial and invasive bladder cancer were 92.4%, and 83.9%, respectively. The 10-year survival rates for superficial and invasive bladder cancer were also 92.4% and 83.9%, respectively. The 3-year and 5-year non-recurrence rates for superficial bladder cancer were 75.8%, and 66.9% respectively, according to the Kaplan-Meier method. On the other hand, the 3-year and 5-year non-recurrence rates for invasive bladder cancer were both 73.8%. During the follow-up between 9 and 11 years, 3 upper tract tumor were diagnosed (2 ureteral cancer, and 1 renal pelvic cancer). We concluded that preoperative chemotherapy combined with radiation therapy may be effective for the treatment of bladder cancer. (author)

Fifteen years' review of advanced childhood neuroblastoma from a single institution in Hong Kong.

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Leung, C K

1998-05-01

To assess the progress in the treatment of advanced childhood neuroblastoma. From 1981 to 1996, there were 32 children with neuroblastoma (NB) diagnosed, staged and treated in our institution. There were 4 patients with stage II NB (12%), 5 stage III (16%), 21 stage IV (66%) and 2 stage IV s (6%). The NBs were excised if CT scan indicated that the tumors were operable. For advanced NB, stages III and IV, multiple drug chemotherapy was started first and operability was assessed with serial CT scan examinations. Once the X-ray imaging indicated the tumors were operable, surgical interventions were done. The medical records of the advanced NB were reviewed. In the initial period of the study, 9 patients were treated using the VAC protocol [vincristine (vcr), adriamycin (adria) and cyclophosphamide (cyc)]. No patient was convertible to operable and all died with a mean survival of 10 months. OPEC [vcr, cyc, VM26, cisplatin (cis)], Rapid COJEC (carboplatin, VP16, vcr, cis and cyc) and more recently N6 protocol (cyc, adria, vcr, VP16, cis) was used for 17 patients. 80% of them were converted to operable. In 4 patients, surgical specimens showed only necrotic tissue without viable tumor tissue and 6 (35%) tumors were converted to ganglioneuroma or ganglioneuroblastoma. Although 2 (12%) patients died of fungal septicemia and 1 (6%) developed Fanconi's syndrome after chemotherapy, the mean survival period increased to 27 months. In the 10 survivors (60%), 4 had megatherapy with melphalan followed by autologous peripheral blood stem cell (PBSC) transplantation and 2 were waiting for transplantation. There is a high percentage of advanced NB on presentation in Hong Kong. With more potent multiple drug chemotherapy for advanced stage NB there are (1) improvement in the survival of these patients, (2) opportunities for more operations for tumor excision and (3) opportunities for autologous PBSC transplantation for better tumor eradication.

Differential scanning calorimetry study on the binding of nucleic acids to dimyristoylphosphatidylcholine-sphingosine liposomes.

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Kõiv, A; Mustonen, P; Kinnunen, P K

1994-03-31

Binding of DNA and RNA to sphingosine-containing dimyristoylphosphatidylcholine (DMPC) liposomes was characterized by differential scanning calorimetry. The thermal phase behaviour of neat DMPC liposomes was unaffected by the presence of the nucleic acids. However, significant alterations in the melting profiles of the DMPC/sphingosine composite membranes were produced by DNA and RNA, thus revealing their binding to the liposomes. For example, for 79:21 (molar ratio) DMPC/sphingosine liposomes a single endotherm at 29.1 degrees C with an enthalpy of 6.3 kcal/mol lipid was observed. In the presence of DNA at the nucleotide/sphingosine ratio of 0.6 this endotherm separated into three distinct peaks at 28.0, 31.4 and 35.1 degrees C, together with an approximately 22% reduction in the total enthalpy. Further increase in DNA concentration up to 1.5 nucleotides per sphingosine led to complete loss of the original heat absorption peak of the DMPC/sphingosine liposomes, while an endotherm at 34.3 degrees C with delta H of 2.7 kcal/mol developed. By visual inspection, rapid and extensive aggregation of the liposomes due to DNA was evident. Evidence for DNA-induced phase separation was also provided by compression isotherms of sphingosine containing DMPC monolayers recorded over an aqueous buffer both in the presence and absence of DNA. The effects of RNA on the thermal phase behaviour of the composite liposomes were qualitatively similar to those described above for DNA. Notably, the presence of eggPA abolished the nucleic acid induced heat capacity changes for DMPC/sphingosine liposomes probably because of neutralization of the positive charge of sphingosine. The binding of DNA to DMPC/sphingosine liposomes occurred both below and above the lipid phase transition temperature, as shown by fluorescence resonance energy transfer utilizing adriamycin-labelled DNA as a quencher and membrane incorporated pyrene-labelled phospholipid as a donor. However, the apparent binding to

Effect of dose of thoracic irradiation on recurrence in patients with limited stage small cell lung cancer. Initial results of a Canadian Multicenter Randomized Trial

International Nuclear Information System (INIS)

Coy, P.; Hodson, I.; Payne, D.G.; Evans, W.K.; Feld, R.; MacDonald, A.S.; Osoba, D.; Pater, J.L.

1988-01-01

Patients with limited stage small cell lung cancer were initially randomized to receive either three courses of Cyclophosphamide, Adriamycin, and Vincristine (CAV) followed by three courses of VP-16 and Cis-platin (VP-PT) or six courses of alternating CAV and VP-PT. Responding patients received prophylactic cranial radiation (PCI) after three courses of chemotherapy (CT) and loco-regional thoracic radiation (LRTR) after six courses. No maintenance chemotherapy was given. Patients receiving LRTR were randomized to receive either 25 Gy in ten fractions over 2 weeks (SD) or 37.5 Gy in 15 fractions over 3 weeks (HD). In both arms the pre-chemotherapy disease was treated with a 2 cm margin around the primary tumor volume. The mediastinum was included in the treatment volume and the supraclavicular nodes were also included if involved originally. The spinal cord was shielded after 32 Gy. Of the 333 patients enrolled by the time the trial closed in October 1984, 168 were eventually randomized to LRTR and are eligible for response assessment. The overall response rate after combined RT and CT was 94% (CR 67%, PR 27%). The CR rate for SD was 65% and for HD 69%. The combined treatment was well tolerated by most patients. Forty-nine percent of HD patients developed dysphagia compared to 26% of those SD (p less than 0.01). At the time of this analysis the median duration of follow-up since randomization to radiotherapy is 30 months. The median local progression-free survival on HD is 49 weeks. On SD it is 38 weeks (p = 0.05, one sided). The actuarial incidence of local progression by 2 years is 69% on HD and 80% on LD. There is as yet no significant difference in overall survival between the two arms. It appears that HD radiotherapy as administered in this study may have an impact on local control, but it is too early to determine if this will translate into a survival benefit

Radiobiological studies on the importance of tumor oxygenation for anti-neoplastic therapy

International Nuclear Information System (INIS)

Grau, C.

1994-01-01

The aim of the twelve studies included in the present thesis was to determine the importance of hypoxia for various anti-neoplastic treatment modalities, and to evaluate possible ways of overcoming the hypoxia problem by combined modality therapy. The murine tumor systems were the C3H mammary carcinoma with 5-12% hypoxic cells, and the SCCVII squamous cell carcinoma with 2% hypoxic cells. The radiation response was significantly improved by the use of hypoxic cell radiosensitizers such as nimorazole or misonidazole, or by allowing the mice to breathe oxygen or carbogen during irradiation. In contrast, the radiation response was significantly impaired by carbon monoxide breathing at a level comparable to what has been observed in heavy smokers. The clamped TCD 50 assay was used to classify cancer chemotherapeutic drugs according to their preferential cytotoxicity towards the different tumor subpopulations. Methotrexate had no effect on hypoxic cells and was only borderline toxic towards aerobic cells. Three drugs had significant effect against oxic cells only (5-fluorouracil, bleomycin and cisplatin). Similarly, three drugs were toxic towards hypoxic cells only (etoposide, carmustine, and mitomycin c). Three drugs were effective towards both cell types (vincristine, adriamycin, cyclophosphamide). Hypoxic cells in areas with insufficient blood supply, poor nutrition and increased acidity is known to be highly sensitive to hyperthermia. In a study where cisplatin, heat and x-rays were given together, the local tumor control was not improved when compared to radiation + heat, apparently due to a lack of enhancement in the killing of hypoxic cells. These studies have demonstrated the influence of tumor oxygenation on tumor response to treatment with drugs, hyperthermia and irradiation. New strategies targeted also against perfusion-limited hypoxia is needed. One of the most important conclusions from the present thesis can be implemented without expensive trials or

In vitro and in vivo studies of pirarubicin-loaded SWNT for the treatment of bladder cancer

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Chen, Gang; He, Yunfeng; Wu, Xiaohou; Zhang, Yao [Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing (China); Luo, Chunli [Department of Laboratory Medicine, Chongqing Medical University, Chongqing (China); Jing, Peng [Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing (China)

2012-07-13

Intravesical chemotherapy is an important part of the treatment for superficial bladder cancer. However, the response to it is limited and its side effects are extensive. Functional single-walled carbon nanotubes (SWNT) have shown promise for tumor-targeted accumulation and low toxicity. In the present study, we performed in vivo and in vitro investigations to determine whether SWNT-based drug delivery could induce high tumor depression in rat bladder cancer and could decrease the side effects of pirarubicin (tetrahydropyranyl-adriamycin, THP). We modified SWNT with phospholipid-branched polyethylene glycol and constructed an SWNT-THP conjugate via a cleavable ester bond. The cytotoxicity of SWNT-THP against the human bladder cancer cell line BIU-87 was evaluated in vitro. Rat bladder cancer in situ models constructed by N-methyl-N-nitrosourea intravesical installation (1 g/L, 2 mg/rat once every 2 weeks for 8 weeks) were used for in vivo evaluation of the cytotoxicity of SWNT and SWNT-THP. Specific side effects in the THP group including urinary frequency (N = 12), macroscopic hematuria (N = 1), and vomiting (N = 7) were identified; however, no side effects were observed with SWNT-THP treatment. Flow cytometry was used to assess the cytotoxicity in vitro and in vivo. Results showed that SWNT alone did not yield significant tumor depression compared to saline (1.74 ± 0.56 and 1.23 ± 0.42%) in vitro. SWNT-THP exhibited higher tumor depression than THP-saline in vitro (74.35 ± 2.56 and 51.24 ± 1.45%) and in vivo (52.46 ± 2.41 and 96.85 ± 0.85%). The present findings indicate that SWNT delivery of THP for the treatment of bladder cancer leads to minimal side effects without loss of therapeutic efficacy. Therefore, this nanotechnology may play a crucial role in the improvement of intravesical treatment of bladder cancer. Key words: Single-walled carbon nanotubes; Bladder cancer; Drug vehicle; THP; Intravesical chemotherapy.

Glomerular sieving of high molecular weight proteins in proteinuric rats

International Nuclear Information System (INIS)

Bertolatus, J.A.; Abuyousef, M.; Hunsicker, L.G.

1987-01-01

To characterize the permeability of the glomerular capillary wall to high molecular weight proteins in normal and proteinuric rats, we determined the glomerular sieving coefficients (GSC) of radioiodinated marker proteins of known size and charge by means of a paired label, tissue accumulation method previously validated in this laboratory. In one group of rats (Series A) the GSCs of 125 I-anionic IgG (aIgG-molecular weight [mol wt] 150,000, pI 4.9) and 131 I-neutral IgG (nIgG-pI 7.4 to 7.6) were measured simultaneously. In Series B, the GSC of a second anionic marker, 131 I-human ceruloplasmin (Crp-mol wt 137,000, pI 4.9) was compared to that of 125 I-nIgG. As in the previous report, the labeled proteins were not degraded or deiodinated during the 20 minute clearance period for GSC determination. Within Series A and B, three subgroups of rats were studied: control saline-infused rats, rats made acutely proteinuric by infusion of the polycation hexadimethrine (HDM), and rats with chronic doxorubicin (Adriamycin-Adria) nephrosis. In the control rats, GSCs for the anionic markers aIgG (Series A) or Crp (Series B) were significantly greater than that of nIgG (both series). These large proteins crossed the filtration barrier by a different pathway from that available to smaller neutral molecules the size of albumin, which in our previous study had a much higher GSC than a native, anionic albumin marker. In a third group of control rats only (Series C), the GSCs of native anionic bovine albumin (BSA) and nIgG were compared directly. The GSC of BSA (0.0029) was only slightly larger than the GSC of nIgG (0.0025), indicating that most of the native albumin crosses the glomerular capillary wall via a nonselective pathway similar to that available to nIgG. The results in the control groups are compatible with recently-described heteroporous models of glomerular size selectivity

Prevalidation of a model for predicting acute neutropenia by colony forming unit granulocyte/macrophage (CFU-GM) assay.

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Pessina, A; Albella, B; Bueren, J; Brantom, P; Casati, S; Gribaldo, L; Croera, C; Gagliardi, G; Foti, P; Parchment, R; Parent-Massin, D; Sibiril, Y; Van Den Heuvel, R

2001-12-01

This report describes an international prevalidation study conducted to optimise the Standard Operating Procedure (SOP) for detecting myelosuppressive agents by CFU-GM assay and to study a model for predicting (by means of this in vitro hematopoietic assay) the acute xenobiotic exposure levels that cause maximum tolerated decreases in absolute neutrophil counts (ANC). In the first phase of the study (Protocol Refinement), two SOPs were assessed, by using two cell culture media (Test A, containing GM-CSF; and Test B, containing G-CSF, GM-CSF, IL-3, IL-6 and SCF), and the two tests were applied to cells from both human (bone marrow and umbilical cord blood) and mouse (bone marrow) CFU-GM. In the second phase (Protocol Transfer), the SOPs were transferred to four laboratories to verify the linearity of the assay response and its interlaboratory reproducibility. After a further phase (Protocol Performance), dedicated to a training set of six anticancer drugs (adriamycin, flavopindol, morpholino-doxorubicin, pyrazoloacridine, taxol and topotecan), a model for predicting neutropenia was verified. Results showed that the assay is linear under SOP conditions, and that the in vitro endpoints used by the clinical prediction model of neutropenia are highly reproducible within and between laboratories. Valid tests represented 95% of all tests attempted. The 90% inhibitory concentration values (IC(90)) from Test A and Test B accurately predicted the human maximum tolerated dose (MTD) for five of six and for four of six myelosuppressive anticancer drugs, respectively, that were selected as prototype xenobiotics. As expected, both tests failed to accurately predict the human MTD of a drug that is a likely protoxicant. It is concluded that Test A offers significant cost advantages compared to Test B, without any loss of performance or predictive accuracy. On the basis of these results, we proposed a formal Phase II validation study using the Test A SOP for 16-18 additional

The role of F-18 FDG PET/CT in evaluating the impact of HIV infection on tumor burden and therapy outcome in patients with Hodgkin lymphoma

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Lawal, Ismaheel O.; Mokgoro, Neo P.; Boshomane, Tebatso G.; Sathekge, Mike M. [University of Pretoria and Steve Biko Academic Hospital, Department of Nuclear Medicine, Pretoria (South Africa); Nyakale, Nozipho E.; Harry, Lerwine M.; Msomi, Alphonse P. [Inkosi Albert Lithuli Central Hospital, Department of Nuclear Medicine, Durban (South Africa); Modiselle, Moshe R. [University of Pretoria and Steve Biko Academic Hospital, Department of Nuclear Medicine, Pretoria (South Africa); KVNR Nuclear and Molecular Imaging, Pretoria (South Africa); Ankrah, Alfred O. [University of Pretoria and Steve Biko Academic Hospital, Department of Nuclear Medicine, Pretoria (South Africa); University Medical Center Groningen, University of Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Wiele, Christophe van de [University of Pretoria and Steve Biko Academic Hospital, Department of Nuclear Medicine, Pretoria (South Africa); University Ghent, Department of Radiology and Nuclear Medicine, Ghent (Belgium)

2017-11-15

To evaluate the impact of HIV infection on tumor burden and therapy outcome following treatment with chemotherapy in patients with Hodgkin lymphoma. A total of 136 patients with classical Hodgkin lymphoma were studied (mean age ± SD = 32.31 ± 1.39 years, male = 86, female = 50). Advanced disease (stage III and IV) was present in 64% of patients. HIV infection was present in 57 patients while 79 patients were HIV-negative. Baseline F-18 FDG PET/CT was obtained in all patients. SUVmax, MTV and TLG were determined on the baseline scan to evaluate for tumor burden. All patients completed a standard regimen of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). After a median period of 8 weeks (range = 6 to 17 weeks), a repeat F-18 FDG PET/CT scan was obtained to evaluate response to therapy using Deauville 5-point scoring system. The HIV-positive and HIV-negative groups were similar with regards to age and disease stage. The groups were heterogeneous with respect to gender (p = 0.029). The SUVmax, MTV and TLG of lesions were not significant different between the two groups. Complete response was seen in 72.8% of the study population. Presence of HIV infection was associated with higher rate of treatment failure with 40.4% of the HIV-positive patients having treatment failure while only 17.7% of the HIV-negative patients had treatment failure (p = 0.0034). HIV infection was a significant predictor of response to chemotherapy. Effects of SUVmax, MTV, TLG and Ann Arbor stage of the disease were not statistically significant as predictors of therapy outcome. In a multiple logistic regression, presence of HIV infection still remained an independent predictor of therapy outcome in the presence of other factors such as SUVmax, MTV, TLG and the Ann Arbor stage of the disease. HIV infection is not associated with a higher tumor burden in patients with Hodgkin lymphoma. HIV infection is, however, a strong predictor of poor therapy outcome in patients treated with

Notochord manipulation does not impact oesophageal and tracheal formation from isolated foregut in 3D explant culture.

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Mc Laughlin, Danielle; Murphy, Paula; Puri, Prem

2016-01-01

Tracheo-oesophageal malformations result from disturbed foregut separation during early development. The notochord, a specialised embryonic structure, forms immediately adjacent to the dividing foregut. In the Adriamycin mouse model of oesophageal atresia, foregut and notochord abnormalities co-exist, and the site and severity of foregut malformations closely correlate to the position and extent of the notochord defects. Notochord and foregut abnormalities also co-exist in the Noggin Knockout mouse as well in a small number of human cases. The notochord is a source of powerful molecular signals during early embryogenesis, being particularly important for neural crest development. The influence of notochord signaling on the adjacent foregut is not known. The purpose of this study was to examine the impact of notochord manipulation on foregut separation using a robust 3D explant method for culturing isolated foregut which permits oeosphageal and tracheal formation in vitro. Foregut was micro-dissected from embryonic day 9 mice (License B100/4447 Irish Medicines Board), embedded in collagen and cultured for 48 h with native notochord intact (n = 6), notochord removed (n = 10) or additional notochord transplanted from stage matched controls (n = 8). Specimens were analysed for foregut morphology and molecular patterning using immunohistochemistry for Hnf3b (an endoderm marker) and Sox2 (a notochord and oesophageal marker) on cryosections. Foregut separation into distinct oesophagus and trachea was observed in isolated foregut specimens with or without their native notochord. In specimens with additional notochord transplants, foregut morphology and molecular patterning were comparable to controls whether or not the native notochord was maintained. In particular foregut separation was not disrupted by the transplantation of additional notochord at the dorsal foregut endoderm. The relationship between the embryonic foregut and notochord is complex and ill

Cytotoxic effect of essential oil of thyme (Thymus broussonettii on the IGR-OV1 tumor cells resistant to chemotherapy

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L. Ait M'Barek

2007-11-01

Full Text Available The anti-tumor effect of the Moroccan endemic thyme (Thymus broussonettii essential oil (EOT was investigated in vitro using the human ovarian adenocarcinoma IGR-OV1 parental cell line OV1/P and its chemoresistant counterparts OV1/adriamycin (OV1/ADR, OV1/vincristine (OV1/VCR, and OV1/cisplatin (OV1/CDDP. All of these cell lines elicited various degrees of sensitivity to the cytotoxic effect of EOT. The IC50 values (mean ± SEM, v/v were 0.40 ± 0.02, 0.39 ± 0.02, 0.94 ± 0.05, and 0.65 ± 0.03% for OV1/P, OV1/ADR, OV1/VCR, and OV1/CDDP, respectively. Using the DBA-2/P815 (H2d mouse model, tumors were developed by subcutaneous grafting of tumor fragments of similar size obtained from P815 (murin mastocytoma cell line injected in donor mouse. Interestingly, intra-tumoral injection of EOT significantly reduced solid tumor development. Indeed, by the 30th day of repeated EOT treatment, the tumor volumes of the animals were 2.00 ± 0.27, 1.35 ± 0.20, and 0.85 ± 0.18 cm³ after injection with 10, 30, or 50 µL per 72 h (six times, respectively, as opposed to 3.88 ± 0.50 cm³ for the control animals. This tumoricidal effect was associated with a marked decrease of mouse mortality. In fact, in these groups of mice, the recorded mortality by the 30th day of treatment was 30 ± 4, 18 ± 4, and 8 ± 3%, respectively, while the control animals showed 75 ± 10% of mortality. These data indicate that the EOT which contains carvacrol as the major component has an important in vitro cytotoxic activity against tumor cells resistant to chemotherapy as well as a significant antitumor effect in mice. However, our data do not distinguish between carvacrol and the other components of EOT as the active factor.

The role of F-18 FDG PET/CT in evaluating the impact of HIV infection on tumor burden and therapy outcome in patients with Hodgkin lymphoma

International Nuclear Information System (INIS)

Lawal, Ismaheel O.; Mokgoro, Neo P.; Boshomane, Tebatso G.; Sathekge, Mike M.; Nyakale, Nozipho E.; Harry, Lerwine M.; Msomi, Alphonse P.; Modiselle, Moshe R.; Ankrah, Alfred O.; Wiele, Christophe van de

2017-01-01

To evaluate the impact of HIV infection on tumor burden and therapy outcome following treatment with chemotherapy in patients with Hodgkin lymphoma. A total of 136 patients with classical Hodgkin lymphoma were studied (mean age ± SD = 32.31 ± 1.39 years, male = 86, female = 50). Advanced disease (stage III and IV) was present in 64% of patients. HIV infection was present in 57 patients while 79 patients were HIV-negative. Baseline F-18 FDG PET/CT was obtained in all patients. SUVmax, MTV and TLG were determined on the baseline scan to evaluate for tumor burden. All patients completed a standard regimen of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). After a median period of 8 weeks (range = 6 to 17 weeks), a repeat F-18 FDG PET/CT scan was obtained to evaluate response to therapy using Deauville 5-point scoring system. The HIV-positive and HIV-negative groups were similar with regards to age and disease stage. The groups were heterogeneous with respect to gender (p = 0.029). The SUVmax, MTV and TLG of lesions were not significant different between the two groups. Complete response was seen in 72.8% of the study population. Presence of HIV infection was associated with higher rate of treatment failure with 40.4% of the HIV-positive patients having treatment failure while only 17.7% of the HIV-negative patients had treatment failure (p = 0.0034). HIV infection was a significant predictor of response to chemotherapy. Effects of SUVmax, MTV, TLG and Ann Arbor stage of the disease were not statistically significant as predictors of therapy outcome. In a multiple logistic regression, presence of HIV infection still remained an independent predictor of therapy outcome in the presence of other factors such as SUVmax, MTV, TLG and the Ann Arbor stage of the disease. HIV infection is not associated with a higher tumor burden in patients with Hodgkin lymphoma. HIV infection is, however, a strong predictor of poor therapy outcome in patients treated with

Effectiveness of transarterial chemoembolization in hepatoblastoma: a preliminary study

International Nuclear Information System (INIS)

Park, Hark Hoon; Han, Young Min; Kang, Sung Soo; Kim, Jae Chun; Lee, Dong Geun; Hwang, Pyoung Han; Kim, Chong Soo; Lee, Jeong Min

1998-01-01

To evaluate the therapeutic effectiveness and useful as well as the ness, systemic effect and effectiveness, of preoperative TACE when used in patients with unresectable or high risk hepatoblastoma. We retrospectively evaluated four patients with pathologically proven hepatoblastoma. One was male and three were female, and they were aged between 8 and 27 (mean, 15) months. All underwent selective hepatic angiography and chemoembolization after superselection of tumor feeding vessels. Cisplatin 90mg/m 2 (50-80mg), adriamycine 40mg/m 2 (20mg) and lipiodol suspension 4cc ere used as chemotherapeutic agents. Embolization was then performed, gelfoam particles. TACE was repeated at intervals of 3 weeks, and after the second episode, all patients underwent hepatic resection. To evaluate changes in the size, volume, internal texture and margin of the mass, as well as the systemic toxicity of chemotherapeutic drugs, we performed con-trast-enhanced CT and checked AFP,CBC and GOT/GPT before and after TACE. In all patients, TACE was successfully performed and major problems related to the procedure and toxicity of chemotherapeutic agents used were not noted. The largest diameter and volume of tumors were reduced by 33% (from 8.3 to 5.6 cm) and 69% respectively. Tumor necrosis was evident in all patients. Lipiodol uptake by tumors was homogenous and tumors were well distingulished from normal parenchyma. Compared to pre-TACE, serum alpha-feto-protein was reduced from 994(range:615--1690 ng/ml) to 46 ng/ml(42-- 47ng/ml) after the second TACE, and six months after surgery was in the normal range(13ng/ml;3--23ng/ml). SGOT/SGPT levels were temporally elevated after TACE but normalized within a few weeks. TACE can be a useful technique for preoperative treatment of hepatoblestomas. In tomors which are high-risk or inoperable, the therapeutio agents involved were not shown to be toxic.=20

Predictive role of GSTP1-containing exosomes in chemotherapy-resistant breast cancer.

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Yang, Su-Jin; Wang, Dan-Dan; Li, Jian; Xu, Han-Zi; Shen, Hong-Yu; Chen, Xiu; Zhou, Si-Ying; Zhong, Shan-Liang; Zhao, Jian-Hua; Tang, Jin-Hai

2017-08-05

Anthracycline/taxane-based chemotherapy regimens are usually used as neoadjuvant chemotherapies to decrease tumour size and prevent metastasis of advanced breast cancer. However, patients have a high risk of developing chemo-resistance during treatment through still unknown mechanisms. Glutathione S-transferase P1 (GSTP1), which belongs to the family of phase II metabolic enzymes, has been reported to function in detoxifying several anti-cancer drugs by conjugating them with glutathione. Previous studies have identified GSTP1 as a predictor of prognosis and chemo-resistance in breast cancer patients, but the mechanisms governing GSTP1-dependent drug resistance are still unclear. We have found that GSTP1 expression is much higher in adriamycin-resistant cells and their corresponding exosomes. The role of GSTP1-containing exosomes in conferring drug resistance was analysed through cell apoptosis and immunofluorescence staining assays. Furthermore, we analysed 42 cases of paired breast cancer tissues collected before and after anthracycline/taxane-based neoadjuvant chemotherapy by immunohistochemistry. Higher GSTP1 expression was shown in the progressive disease (PD)/stable disease (SD) group than in the partial response (PR)/complete response (CR) group both in the samples collected before and after the chemotherapy treatment. Interestingly, GSTP1 partly re-localized from the cell nucleus to the cytoplasm upon treatment, and similar results were obtained for the exosomal marker Tumour susceptibility gene 101 protein (TSG101), which also increased in the cytoplasm after chemotherapy. After analysing the serum exosomes of 30 patients treated with anthracycline/taxane-based neoadjuvant chemotherapy, we discovered that the levels of GSTP1 in exosomes from patients in the PD/SD group were significantly higher than those in the PR/CR group. Here, for the first time, we investigated a novel role for GSTP1-containing exosomes and their capability to transfer drug resistance

Downregulation of eIF4G by microRNA-503 enhances drug sensitivity of MCF-7/ADR cells through suppressing the expression of ABC transport proteins.

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Pan, Xia; Yang, Xiaoyan; Zang, Jinglei; Zhang, Si; Huang, Nan; Guan, Xinxin; Zhang, Jianhua; Wang, Zhihui; Li, Xi; Lei, Xiaoyong

2017-06-01

Overexpression of adenosine triphosphate-binding cassette (ABC) transport protein is emerging as a critical contributor to anticancer drug resistance. The eukaryotic translation initiation factor (eIF) 4F complex, the key modulator of mRNA translation, is regulated by the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway in anticancer drug-resistant tumors. The present study demonstrated the roles of ABC translation protein alterations in the acquisition of the Adriamycin (ADM)-resistant phenotype of MCF-7 human breast cells. Quantitative polymerase chain reaction and western blot analysis were applied to examine the differences in mRNA and protein levels, respectively. It was found that the expression of the ABC sub-family B member 1, ABC sub-family C member 1 and ABC sub-family G member 2 transport proteins were upregulated in MCF-7/ADR cells. An MTT assay was used to detect the cell viability, from the results MCF-7/ADR cells were less sensitive to ADM, tamoxifen (TAM) and taxol (TAX) treatment compared with MCF-7 cells. We predicted that the 3'-untranslated region of eukaryotic translation initiation factor 4-γ 1 (eIF4G) contains a potential miRNA binding site for microRNA (miR)-503 through using computational programs. These binding sites were confirmed by luciferase reporter assays. eIF4G mRNA degradation was accelerated in cells transfected with miR-503 mimics. Furthermore, it was demonstrated that eIF4G and ABC translation proteins were significantly downregulated in MCF-7/ADR cells after transfection with miR-503. It was found that miR-503 mimics could sensitize the cells to treatment with ADM, TAM and TAX. These findings demonstrated for the first time that eIF4G acted as a key factor in MCF-7/ADR cells, and may be an efficient agent for preventing and reversing multi-drug resistance in breast cancer.

An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer.

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Kelly H Salter

Full Text Available A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective.Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%. When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06. Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8% of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04, representing a viable alternative therapy.Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding micro

p-TSA-promoted syntheses of 5H-benzo[h] thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs: molecular modeling and in vitro antitumor activity against hepatocellular carcinoma.

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Keshari, Amit K; Singh, Ashok K; Raj, Vinit; Rai, Amit; Trivedi, Prakruti; Ghosh, Balaram; Kumar, Umesh; Rawat, Atul; Kumar, Dinesh; Saha, Sudipta

2017-01-01

In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a p -toluenesulfonic acid ( p -TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs bearing a bridgehead nitrogen atom. This domino protocol constructed one new ring by the concomitant formation of multiple bonds (C-C, C-N, and C=N) involving multiple steps without the use of any metal catalysts in one-pot, with all reactants effi-ciently exploited. All the newly synthesized compounds were authenticated by means of Fourier transform infrared spectroscopy, liquid chromatography-mass spectrometry, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy, together with elemental analysis, and their antitumor activity was evaluated in vitro on a Hep-G2 human cancer cell line by sulforhodamine B assay. Computational molecular modeling studies were carried out on cancer-related targets, including interleukin-2, interleukin-6, Caspase-3, and Caspase-8. Two compounds (4A and 6A) showed growth inhibitory activity comparable to the positive control Adriamycin, with growth inhibition of 50% <10 μg/mL. The results of the comprehensive structure-activity relationship study confirmed the assumption that two or more electronegative groups on the phenyl ring attached to the thiazolo[2,3-b]quinazoline system showed the optimum effect. The in silico simulations suggested crucial hydrogen bond and π-π stacking interactions, with a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and molecular dynamics, in order to explore the molecular targets of HCC which were in complete agreement with the in

Effectiveness of multi-drug regimen chemotherapy treatment in osteosarcoma patients: a network meta-analysis of randomized controlled trials.

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Wang, Xiaojie; Zheng, Hong; Shou, Tao; Tang, Chunming; Miao, Kun; Wang, Ping

2017-03-29

Osteosarcoma is the most common malignant bone tumour. Due to the high metastasis rate and drug resistance of this disease, multi-drug regimens are necessary to control tumour cells at various stages of the cell cycle, eliminate local or distant micrometastases, and reduce the emergence of drug-resistant cells. Many adjuvant chemotherapy protocols have shown different efficacies and controversial results. Therefore, we classified the types of drugs used for adjuvant chemotherapy and evaluated the differences between single- and multi-drug chemotherapy regimens using network meta-analysis. We searched electronic databases, including PubMed (MEDLINE), EmBase, and the Cochrane Library, through November 2016 using the keywords "osteosarcoma", "osteogenic sarcoma", "chemotherapy", and "random*" without language restrictions. The major outcome in the present analysis was progression-free survival (PFS), and the secondary outcome was overall survival (OS). We used a random effect network meta-analysis for mixed multiple treatment comparisons. We included 23 articles assessing a total of 5742 patients in the present systematic review. The analysis of PFS indicated that the T12 protocol (including adriamycin, bleomycin, cyclophosphamide, dactinomycin, methotrexate, cisplatin) plays a more critical role in osteosarcoma treatment (surface under the cumulative ranking (SUCRA) probability 76.9%), with a better effect on prolonging the PFS of patients when combined with ifosfamide (94.1%) or vincristine (81.9%). For the analysis of OS, we separated the regimens to two groups, reflecting the disconnection. The T12 protocol plus vincristine (94.7%) or the removal of cisplatinum (89.4%) is most likely the best regimen. We concluded that multi-drug regimens have a better effect on prolonging the PFS and OS of osteosarcoma patients, and the T12 protocol has a better effect on prolonging the PFS of osteosarcoma patients, particularly in combination with ifosfamide or vincristine

Atrial Function in Patients with Breast Cancer After Treatment with Anthracyclines

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Yalin Tolga Yaylali

Full Text Available Abstract Background: Atrial electromechanical delay (EMD is used to predict atrial fibrillation, measured by echocardiography. Objectives: The aim of this study was to assess atrial EMD and mechanical function after anthracycline-containing chemotherapy. Methods: Fifty-three patients with breast cancer (48 ± 8 years old who received 240 mg/m2of Adriamycin, 2400 mg/m2 of cyclophosphamide, and 960 mg/m2 of paclitaxel were included in this retrospective study, as were 42 healthy subjects (47 ± 9 years old. Echocardiographic measurements were performed 11 ± 7 months (median 9 months after treatment with anthracyclines. Results: Left intra-atrial EMD (11.4 ± 6.0 vs. 8.1 ± 4.9, p=0.008 and inter-atrial EMD (19.7 ± 7.4 vs. 14.7 ± 6.5, p=0.001 were prolonged; LA passive emptying volume and fraction were decreased (p=0.0001 and p=0.0001; LA active emptying volume and fraction were increased (p=0.0001 and p=0.0001; Mitral A velocity (0.8 ± 0.2 vs. 0.6 ± 0.2, p=0.0001 and mitral E-wave deceleration time (201.2 ± 35.6 vs. 163.7 ± 21.8, p=0.0001 were increased; Mitral E/A ratio (1.0 ± 0.3 vs. 1.3 ± 0.3, p=0.0001 and mitral Em (0.09 ± 0.03 vs. 0.11 ± 0.03, p=0.001 were decreased; Mitral Am (0.11 ± 0.02 vs. 0.09 ± 0.02, p=0.0001 and mitral E/Em ratio (8.8 ± 3.2 vs. 7.6 ± 2.6, p=0.017 were increased in the patients. Conclusions: In patients with breast cancer after anthracycline therapy: Left intra-atrial, inter-atrial electromechanical intervals were prolonged. Diastolic function was impaired. Impaired left ventricular relaxation and left atrial electrical conduction could be contributing to the development of atrial arrhythmias.

Does Bleomycin Lung Toxicity Increase the Risk of Radiation Pneumonitis in Hodgkin Lymphoma?

International Nuclear Information System (INIS)

Abou Yehia, Zeinab; Mikhaeel, George N.; Smith, Grace; Pinnix, Chelsea C.; Milgrom, Sarah A.; Tang, Chad; Jiang, Wen; Fanale, Michelle A.; Oki, Yasuhiro; Shank, JoAnn H.; Horace, Trisha; Reddy, Jay; Akhtari, Mani; Gunther, Jillian R.; Suki, Tina; Allen, Pamela K.; Turner, Shryll; Mawlawi, Osama; Dabaja, Bouthaina S.

2016-01-01

Purpose: Bleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in patients with Hodgkin lymphoma (HL). We undertook the present study to investigate the risk of radiation pneumonitis (RP) in the setting of BPT and to determine the need for delay or omission of radiation therapy (RT) in these patients. Methods and Materials: We identified 123 HL patients treated with ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) followed by RT to the chest from January 2009 to December 2014. The medical records were reviewed for clinical, pathologic, and treatment information and toxicities. Our primary outcome was RP of any grade. Univariate and multivariate analyses were used to assess the association of BPT, baseline patient characteristics, and treatment variables with the incidence of RP. Results: A total of 123 patients were included, of whom 99 (80%) received consolidation intensity modulated RT after ABVD treatment. We identified 31 patients (25.2%) with BPT after frontline ABVD. Seventeen patients (13.8%) developed RP a median of 8 weeks (range 1-39) after RT completion. BPT did not correlate with the risk of developing RP (P=.36). We evaluated the RP outcomes with respect to the bleomycin to RT interval (≤6 weeks vs >6 weeks), and we found that this interval did not predict for RP risk (P=.60). Dosimetric parameters such as the volume covered by 5 Gy and the mean lung dose were analyzed. A volume covered by 5 Gy of >55% and mean lung dose >13.5 Gy increased the risk of RP by 1.14-fold (P=.002) and 4.24-fold (P=.007), respectively. Conclusions: The results of our study suggest that BPT does not increase the risk of developing RP. Furthermore, RT initiation does not need to be delayed after chemotherapy, except to allow for the completion of steroid therapy or clinical recovery from BPT.

A unique carrier for delivery of therapeutic compounds beyond the blood-brain barrier.

Directory of Open Access Journals (Sweden)

Delara Karkan

Full Text Available BACKGROUND: Therapeutic intervention in many neurological diseases is thwarted by the physical obstacle formed by the blood-brain barrier (BBB that excludes most drugs from entering the brain from the blood. Thus, identifying efficacious modes of drug delivery to the brain remains a "holy grail" in molecular medicine and nanobiotechnology. Brain capillaries, that comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, termed p97 (melanotransferrin, across the BBB. Here, we explored the hypothesis that therapeutic drugs "piggybacked" as conjugates of p97 can be shuttled across the BBB for treatment of otherwise inoperable brain tumors. APPROACH: Human p97 was covalently linked with the chemotherapeutic agents paclitaxel (PTAX or adriamycin (ADR and following intravenous injection, measured their penetration into brain tissue and other organs using radiolabeled and fluorescent derivatives of the drugs. In order to establish efficacy of the conjugates, we used nude mouse models to assess p97-drug conjugate activity towards glioma and mammary tumors growing subcutaneously compared to those growing intracranially. PRINCIPAL FINDINGS: Bolus-injected p97-drug conjugates and unconjugated p97 traversed brain capillary endothelium within a few minutes and accumulated to 1-2% of the injected by 24 hours. Brain delivery with p97-drug conjugates was quantitatively 10 fold higher than with free drug controls. Furthermore, both free-ADR and p97-ADR conjugates equally inhibited the subcutaneous growth of gliomas growing outside the brain. Evocatively, only p97-ADR conjugates significantly prolonged the survival of animals bearing intracranial gliomas or mammary tumors when compared to similar cumulated doses of free-ADR. SIGNIFICANCE: This study provides the initial proof of concept for p97 as a carrier capable of shuttling therapeutic levels of drugs from the blood to the brain for the treatment of neurological disorders

Early Activation of Apoptosis and Caspase-independent Cell Death Plays an Important Role in Mediating the Cytotoxic and Genotoxic Effects of WP 631 in Ovarian Cancer Cells.

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Gajek, Arkadiusz; Denel-Bobrowska, Marta; Rogalska, Aneta; Bukowska, Barbara; Maszewski, Janusz; Marczak, Agnieszka

2015-01-01

The purpose of this study was to provide a detailed explanation of the mechanism of bisanthracycline,?WP 631 in comparison to doxorubicin (DOX), a first generation anthracycline, currently the most widely used pharmaceutical in clinical oncology. Experiments were performed in SKOV-3 ovarian cancer cells which are otherwise resistant to standard drugs such as cis-platinum and adriamycin. As attention was focused on the ability of WP 631 to induce apoptosis, this was examined using a double staining method with Annexin V and propidium iodide probes, with measurement of the level of intracellular calcium ions and cytosolic cytochrome c. The western blotting technique was performed to confirm PARP cleavage. We also investigated the involvement of caspase activation and DNA degradation (comet assay and immunocytochemical detection of phosphorylated H2AX histones) in the development of apoptotic events. WP 631 demonstrated significantly higher effectiveness as a pro-apoptotic drug than DOX. This was evident in the higher levels of markers of apoptosis, such as the externalization of phosphatidylserine and the elevated level of cytochrome c. An extension of incubation time led to an increase in intracellular calcium levels after treatment with DOX. Lower changes in the calcium content were associated with the influence of WP 631. DOX led to the activation of all tested caspases, 8, 9 and 3, whereas WP 631 only induced an increase in caspase 8 activity after 24h of treatment and consequently led to the cleavage of PARP. The lack of active caspase 3 had no outcome on the single and double-stranded DNA breaks. The obtained results show that WP 631 was considerably more genotoxic towards the investigated cell line than DOX. This effect was especially visible after longer times of incubation. The above detailed studies indicate that WP 631 generates early apoptosis and cell death independent of caspase-3, detected at relatively late time points. The observed differences in the

Does Bleomycin Lung Toxicity Increase the Risk of Radiation Pneumonitis in Hodgkin Lymphoma?

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Abou Yehia, Zeinab [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mikhaeel, George N. [Department of Clinical Oncology, Guy' s & St Thomas' Hospital, London (United Kingdom); Smith, Grace; Pinnix, Chelsea C.; Milgrom, Sarah A.; Tang, Chad; Jiang, Wen [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Fanale, Michelle A.; Oki, Yasuhiro [Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Shank, JoAnn H.; Horace, Trisha; Reddy, Jay [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Akhtari, Mani [Department of Radiation Oncology, The University of Texas Medical Branch Hospitals, Galveston, Texas (United States); Gunther, Jillian R. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Suki, Tina [The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Allen, Pamela K.; Turner, Shryll [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mawlawi, Osama [Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Dabaja, Bouthaina S., E-mail: bdabaja@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

2016-12-01

Purpose: Bleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in patients with Hodgkin lymphoma (HL). We undertook the present study to investigate the risk of radiation pneumonitis (RP) in the setting of BPT and to determine the need for delay or omission of radiation therapy (RT) in these patients. Methods and Materials: We identified 123 HL patients treated with ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) followed by RT to the chest from January 2009 to December 2014. The medical records were reviewed for clinical, pathologic, and treatment information and toxicities. Our primary outcome was RP of any grade. Univariate and multivariate analyses were used to assess the association of BPT, baseline patient characteristics, and treatment variables with the incidence of RP. Results: A total of 123 patients were included, of whom 99 (80%) received consolidation intensity modulated RT after ABVD treatment. We identified 31 patients (25.2%) with BPT after frontline ABVD. Seventeen patients (13.8%) developed RP a median of 8 weeks (range 1-39) after RT completion. BPT did not correlate with the risk of developing RP (P=.36). We evaluated the RP outcomes with respect to the bleomycin to RT interval (≤6 weeks vs >6 weeks), and we found that this interval did not predict for RP risk (P=.60). Dosimetric parameters such as the volume covered by 5 Gy and the mean lung dose were analyzed. A volume covered by 5 Gy of >55% and mean lung dose >13.5 Gy increased the risk of RP by 1.14-fold (P=.002) and 4.24-fold (P=.007), respectively. Conclusions: The results of our study suggest that BPT does not increase the risk of developing RP. Furthermore, RT initiation does not need to be delayed after chemotherapy, except to allow for the completion of steroid therapy or clinical recovery from BPT.

A survey of nine years heart transplantation at Erasme Hospital, University of Brussels.

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Primo, G; Le Clerc, J L; Antoine, M; De Smet, J M; Joris, M

1991-01-01

Between March 1982 and March 1991, 225 heart transplantations (HTx) have been performed in 220 patients suffering end stage cardiac disease. Thirteen percent were females and 87% were males. Age range was from 5 to 68 years. The underlying cardiac disease was ischemic cardiopathy in 51.5%, congestive dilated cardiomyopathy in 42%, valvular cardiomyopathy in 3.5%, toxic myocarditis (post-adriamycin) in 1.5% and chronic rejection in 2.5% (retransplantation). Selection of the recipients was done following the currently well established criteria also taking into account the absolute major contraindications for HTx. Due to the still increasing demand of donor organs, currently donor age has been extended up to 50 years for male and 55 years for female donors. One quarter of the grafts were harvested on site in our institution, two other quarters were harvested somewhere else in Belgium and the last quarter provided by other countries cooperating with Eurotransplant. All patients have undergone orthotopic cardiac transplantation using the standard Lower and Shumway technique. Immunosuppression protocols have changed four times throughout the years. Nevertheless all were based on the use of Ciclosporine variously combined with other current immunosuppressive drugs. Rejection monitoring relied on routine endocardiac biopsy and was diagnosed according to the Billingham criteria. The in-hospital mortality is currently 11%. Infection, early right heart graft failure and acute rejection were the leading causes of death. The major causes of early morbidity were several curable infections, reversible rejection episodes, transient acute renal failure and controllable arterial hypertension. Among the survivors followed for at least one month up to nine years, half of late mortality was caused by chronic rejection followed by infection, sudden death, metabolic disorders, stroke and malignancy. Late morbidity involves cases of mild coronary graft diseases, biological renal

Prophylactic CNS therapy in childhood leukemia. Randomized controlled study of high-dose intravenous methotrexate and cranial irradiation

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Yokoyama, Takashi; Hiyoshi, Yasuhiko [Kurume Univ., Fukuoka (Japan). School of Medicine; Fujimoto, Takeo

1982-12-01

This study was designed to evaluate the efficacy of CNS-prophylaxis with high-dose methotrexate (MTX). Seventy children with previously untreated acute lymphoblastic leukemia (ALL) entered to this study between July 1978 and December 1980. According to initial white blood count (WBC), they were stratified to induce remission with; vincristine and prednine in low initial WBC ( lt 25,000/mm/sup 3/) group and these two agents plus adriamycin in high initial WBC ( gt 25,000/mm/sup 3/) group. After inducing remission, 62 children who achieved CR, received different CNS-prophlaxis; using a regimen of three doses of weekly high-dose MTX (1,000 mg/m/sup 2/) 6-hour infusion, which was repeated every 12 weeks-Group A (n = 14); high-dose MTX followed by 2400 rad cranial irradiation plus three doses of i.t. MT X-Group B (n = 15), 2400 rad cranial irradiation plus three doses of i.t. MTX-Group C (n = 16), and in 17 patients with high initial WBC, same as in Group A-Group D (n = 17). During an intravenous 6-h infusion of MTX at a dose of 1,000 mg/m/sup 2/, the CSF concentration of MTX rose to 2.3 +- 2.4 x 10/sup -6/M after initiation of infusion and remained in 10/sup -7/ M level for 48 hours. CNS-leukemia terminated complete remission in one of 14 children in Group A, two of 15 in Group B, two of 16 in Group C and two of 17 in Group D. The cumulative incidence of CNS-leukemia at 20 months calculated by the technique of Kaplan and Meier was 0% in Group A, 18.1% in Group B, 7.1% in Group C and 50.8% in Group D. There was no statistical difference among Groups A, B and C. These data suggested that CNS-prophylaxis with high-dose intravenous MTX was effective as well as 2400 rad cranial irradiation plus three doses of i.t. MTX in childhood ALL with low initial WBC.

Metastatic extraskeletal Ewing's sarcoma treated with trabectedin: A case report.

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Hernando-Cubero, Jorge; Sanz-Moncasi, Pilar; Hernández-García, Alba; Pajares-Bernard, Isabel; Martínez-Trufero, Javier

2016-10-01

The Ewing's sarcoma family of tumors (ESFT) comprises a number of rare malignant tumors. Standard first-line treatment for patients with these tumors includes chemotherapy with a five-drug regimen of vincristine, doxorubicin (Adriamycin ® ) and cyclophosphamide, alternating with ifosfamide and etoposide (VAC/IE). In cases of inadequate response, there are a number of second-line regimens available. However, further treatment options are required for those patients with disease unresponsive to standard treatment. Trabectedin is a novel treatment option for patients with ESFT. The present study reports the case of a Caucasian 69-year-old female patient who presented with a soft tissue mass on the chest wall that had developed 7 months earlier. A computed tomography scan revealed a 9×8×7-cm mass on the anterior chest wall above the pectoral muscle. Histopathological evaluations and molecular analysis indicated that it was consistent with a metastatic extraskeletal Ewing's sarcoma. The patient was treated with an alternating VAC/IE regimen; however, an inadequate response was observed. The patient received second-line treatment with a gemcitabine and dacarbazine combination regimen, but the disease progressed. Subsequently, treatment with trabectedin (1.5 mg/m 2 as a 24-h continuous infusion every 3 weeks) was initiated. Trabectedin treatment resulted in long-lasting (18 months) progression-free survival. It is vital that novel drugs continue to being developed for patients with ESFT following progression subsequent to standard chemotherapy. The current report presents a case of a patient with metastatic, pre-treated Ewing's sarcoma achieving disease stabilization with trabectedin. Based on these results and the observed tolerability profile, trabectedin represents an alternative treatment for patients with ESFT. Further studies are required in order to determine the efficacy of trabectedin as monotherapy or in combination with other drugs. It is also important to

Cape gooseberry (Physalis peruviana) juice as a modulator agent for hepatocellular carcinoma-linked apoptosis and cell cycle arrest.

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Hassan, Hanaa A; Serag, Hanaa M; Qadir, Makwan S; Ramadan, Mohamed Fawzy

2017-10-01

Cape gooseberry (Physalis peruviana) fruit is highly nutritious with high content of health-promoting compounds including minerals, phenolic compounds, as well as vitamins A and C. Physalis peruviana fruits were used as mutagenic, antispasmodic, anticoagulant, and antileucemis agents. The objective of the present work was to study the role of cape gooseberry juice (CG) as a natural modulator agent for adverse aspects associated with hepatocellular carcinoma (HCC). The results recorded that HCC rats had a significant disturbance in blood indices. An elevation in serum level of the inflammatory (TNF-ά, CRP, and Argenase), hepatic apoptotic markers (P53, Bax, and Caspase 3) and a reduction of Blc2% were recorded in HCC rats. The results exhibited the significant disturbance and arrest in hepatic cell cycle (% of M1: SubG1 phase, M2: G0/1 phase of diploid cycle, M3: S phase, and M4: G2/M phase) as well as liver cell viability status in HCC rats. Numerous histopathological alterations were detected in hepatic tissues of HCC rats such as inflammation, damage of hepatocytes, dilated congested central vein with degenerated endothelial cells and congested blood sinusoids in addition to collagen fibers in hepatocytes and central vein indicating hepatic fibrosis. The tested parameters were little improved upon treatment of HCC rats with Adriamycin (ADR, Doxorubicin is a generic name of a drug). HCC rats received CG showed an improvement in all tested parameters. The effects of CG were through down regulation of p53 expression and up-regulation of Bcl2 domain protected hepatic structure from extensive damage. CG plus ADR exhibited an enhanced antitumor impact in HCC and this combination might have an important value in the treatment of HCC. CG was more effective than ADR, and it has a remarkable role in the management of hepatic disorders besides its success as a chemo-sensitizer for ADR treatment of hepatocellular carcinoma. Copyright © 2017 Elsevier Masson SAS. All rights

In vitro detection of mdr1 mRNA in murine leukemia cells with 111In-labeled oligonucleotide

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Bai Jingming; Yokoyama, Kunihiko; Kinuya, Seigo; Michigishi, Takatoshi; Tonami, Norihisa; Shiba, Kazuhiro; Matsushita, Ryo; Nomura, Masaaki

2004-01-01

The feasibility of intracellular mdr1 mRNA expression detection with radiolabeled antisense oligonucleotide (ODN) was investigated in the murine leukemia cell line, P388/S, and its subclonal, adriamycin-resistant cell line, P388/R. The expression level of mdr1 mRNA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Existence of the multidrug resistance (MDR) phenomenon was assessed via cellular uptake of 99m Tc-sestamibi (MIBI), a known substrate for P-glycoprotein. A 15-mer phosphorothioate antisense ODN complementary to the sequences located at -1 to 14 of mdr1 mRNA and its corresponding sense ODN were conjugated with the cyclic anhydride of diethylene triamine penta-acetic acid (cDTPA) via an amino group linked to the terminal phosphate at the 5' end at pH 8-9. The DTPA-ODN complexes at concentrations of 0.1-17.4 μMwere reacted with 111 InCl 3 at pH 5 for 1 h. The hybridization affinity of labeled ODN was evaluated with size-exclusion high-performance liquid chromatography following incubation with the complementary sequence. Cellular uptake of labeled ODN was examined in vitro. Furthermore, enhancing effects of synthetic lipid carriers (Transfast) on transmembrane delivery of ODN were assessed. P388/R cells displayed intense mdr1 mRNA expression in comparison with P388/S cells. 99m Tc-MIBI uptake in P388/S cells was higher than that in P388/R cells. Specific radioactivity up to 1,634 MBq/nmol was achieved via elevation of added radioactivity relative to ODN molar amount. The hybridization affinity of antisense 111 In-ODN was preserved at approximately 85% irrespective of specific activity. Cellular uptake of antisense 111 In-ODN did not differ from that of sense 111 In-ODN in either P388/S cells or P388/R cells. However, lipid carrier incorporation significantly increased transmembrane delivery of 111 In-ODN; moreover, specific uptake of antisense 111 In-ODN was demonstrated in P388/R cells. Radiolabeling of ODN at high specific

Interim PET After Two ABVD Cycles in Early-Stage Hodgkin Lymphoma: Outcomes Following the Continuation of Chemotherapy Plus Radiotherapy

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Simontacchi, Gabriele [Radiotherapy Unit, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence (Italy); Filippi, Andrea Riccardo, E-mail: andreariccardo.filippi@unito.it [Department of Oncology, University of Torino, Torino (Italy); Ciammella, Patrizia [Radiation Oncology Unit, Department of Advanced Technology, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia (Italy); Buglione, Michela [Radiation Oncology Department, University and Spedali Civili, Brescia (Italy); Saieva, Calogero [Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute, Florence (Italy); Magrini, Stefano Maria [Radiation Oncology Department, University and Spedali Civili, Brescia (Italy); Livi, Lorenzo [Radiotherapy Unit, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence (Italy); Iotti, Cinzia [Radiation Oncology Unit, Department of Advanced Technology, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia (Italy); Botto, Barbara [Hematology Unit, Città della Salute e della Scienza Hospital, Torino (Italy); Vaggelli, Luca [Nuclear Medicine Department, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence (Italy); Re, Alessandro [Hematology Unit, University and Spedali Civili, Brescia (Italy); Merli, Francesco [Hematology Unit, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia (Italy); Ricardi, Umberto [Department of Oncology, University of Torino, Torino (Italy)

2015-08-01

Purpose: This multicenter retrospective study was designed to evaluate the prognostic role of interim fluorodeoxyglucose-labeled positron emission tomography (i-FDG-PET) in a cohort of patients affected with early-stage Hodgkin lymphoma (HL) treated initially with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by radiation therapy, and to assess the role of chemotherapy continuation plus radiation therapy for i-FDG-PET-positive patients. Methods and Materials: Data from 257 patients were retrieved from 4 hematology and radiation oncology departments. Inclusion criteria were stage I to IIAB HL, “intention-to-treat” AVBD plus radiation therapy, and FDG-PET at diagnosis and after the first 2 ABVD cycles. All i-FDG-PET scans underwent blinded local review by using the Deauville 5-point scoring system; patients were stratified as negative or positive using 2 Deauville score cutoff values, ≥3 or ≥4. Results: Median follow-up time was 56 months (range: 9-163 months); 5-year overall survival (OS) and disease-specific survival (DSS) for the whole cohort were 97.5% and 98.3%, respectively. Five-year progression-free survival (PFS) was 95.6%. After i-FDG-PET revision, 43 of 257 patients (16.7%) had a positive i-FDG-PET (Deauville scores: 3-5). Five-year PFS rates for i-FDG-PET-negative and i-FDG-PET-positive patients were 98.1% and 83.7%, respectively, if using a Deauville score cutoff of 3, and 97.7% and 78.6%, respectively, if using a cutoff of 4 (P=.0001). Five-year OS for i-FDG-PET-negative and i-FDG-PET-positive patients was 98.5% and 93.0%, respectively, if using a cutoff of 3, and 98.6% and 89.3%, respectively, if using a cutoff of 4 (P=.029 and P=.002). At univariate regression analysis, i-FDG-PET positivity was associated with worse OS and PFS. At multivariate analysis, performed only for PFS, i-FDG-PET positivity confirmed its negative impact (P=.002). Conclusions: i-FDG-PET is prognostic for PFS and OS in early-stage HL

Novel Immunotherapy Options for Extranodal NK/T-Cell Lymphoma

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Boyu Hu

2018-04-01

Full Text Available Extranodal NK/T-cell lymphoma (ENKTCL is a highly aggressive mature NK/T-cell neoplasm marked by NK-cell phenotypic expression of CD3ε and CD56. While the disease is reported worldwide, there is a significant geographic variation with its highest incidence in East Asian countries possibly related to the frequent early childhood exposure of Epstein–Barr virus (EBV and specific ethnic–genetical background, which contributes to the tumorigenesis. Historically, anthracycline-based chemotherapy such as CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone was used, but resulted in poor outcomes. This is due in part to intrinsic ENKTCL resistance to anthracycline caused by high expression levels of P-glycoprotein. The recent application of combined modality therapy with concurrent or sequential radiation therapy for early stage disease, along with non-anthracycline-based chemotherapy regimens consisting of drugs independent of P-glycoprotein have significantly improved clinical outcomes. Particularly, this neoplasm shows high sensitivity to l-asparaginase as NK-cells lack asparagine synthase activity. Even still, outcomes of patients with advanced stage disease or those with relapsed/recurrent disease are dismal with overall survival of generally a few months. Thus, novel therapies are needed for this population. Clinical activity of targeted antibodies along with antibody–drug conjugates, such as daratumumab (naked anti-CD38 antibody and brentuximab vedotin (anti-CD30 antibody conjugated with auristatin E, have been reported. Further promising data have been shown with checkpoint inhibitors as high levels of programmed death-ligand 1 expression are observed in ENKTCL due to EBV-driven overexpression of the latent membrane proteins [latent membrane protein 1 (LMP1 and LMP2] with activation of the NF-κB/MAPK pathways. Initial case series with programmed death 1 inhibitors showed an overall response rate of 100% in seven relapsed

Multi-institutional randomized clinical study on the comparative effects of intracavital chemotherapy alone versus immunotherapy alone versus immunochemotherapy for malignant effusion

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Nio, Y; Nagami, H; Tamura, K; Tsubono, M; Nio, M; Sato, M; Kawabata, K; Hayashi, H; Shiraishi, T; Imai, S; Tsuchitani, T; Mizuta, J; Nakagawa, M; Fukumoto, M

1999-01-01

The current prospective randomized study was designed to compare the effects of intracavitary (i.c.) chemotherapy vs immunotherapy vs immunochemotherapy for malignant effusion. Between 1992 and 1995, a total of 42 patients with malignant effusion were registered, and 41 patients were eligible for statistical analysis. The primary diseases of the eligible patients included 27 gastric, four colorectal, four pancreatic, three lung, two liver and one oesophageal cancers. The patients with malignant effusion were randomly assigned into one of three i.c. therapeutic regimens: chemotherapy alone with weekly injection of anticancer agents (ACAs: cisplatin, mitomycin-C, adriamycin, etc.) (Group A, n = 13); immunotherapy alone with weekly injection of streptococcal preparation OK-432 (Group B, n = 14); or immunochemotherapy with ACAs and OK-432 (Group C, n = 14). The response of the effusion, patient survival and the kinetics of cytokines in the effusion were compared. There were no differences in the patients' backgrounds. The side-effects of the regimens included pain, anorexia, fever, leucopenia and anaemia and there were no differences in their incidence among the three groups. One patient died after cisplatin (CDDP) administration in Group A. Cytologic examination revealed that tumour cells in the effusion disappeared in 23% of Group A cases, 36% of Group B cases and 36% of Group C cases. The malignant effusion did not disappear in any of the Group A cases; however, the effusion disappeared in 29% of Group B cases and 43% of Group C cases (P = 0.03, Group A vs Group C). Furthermore, the 50% survival period was 1.6 months for Group A, 2.4 months for Group B and 3.5 months for Group C. The 6-month survival rate was 7% for Group A, 6% for Group B and 34% for Group C, and the 1-year survival rate was 0%, 0% and 17% respectively (P = 0.048, Group A vs Group C by the log-rank test). The analysis of the cytokine kinetics revealed a prominent increase in the level of

Preoperative Transcatheter Selective Arterial Chemoembolization in Treatment of Unresectable Hepatoblastoma in Infants and Children

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Li Jiaping; Chu Jianping; Yang Jianyong; Chen Wei; Wang Yu; Huang Yonghui

2008-01-01

The purpose of this study was to evaluate the clinical feasibility and efficacy of transcatheter selective arterial chemoembolization (TACE) for unresectable hepatoblastoma in infants and children. The study was performed with the approval of our institutional review board. Sixteen patients (13 boys, 3 girls) with unresectable hepatoblastoma were treated one to three times with preoperative TACE in an effort to improve the surgical and clinical outcome. Their ages ranged from 50 days to 60 months, with a mean age of 20.4 months. All cases were pathologically proved hepatoblastoma by fine-needle biopsy. After an intra-arterial catheter was selectively inserted into the main feeding artery of the tumor, cycles of cisplatin (40 to 50 mg/m 2 ) and adriamycin (20 to 30 mg/m 2 ) mixed with lipiodol were given, followed by gelatin foam particles or stainless-steel coils. Tumor response was evaluated according to tumor shrinkage, α-fetoprotein (AFP) levels, and pathological findings. TACE procedure was performed one to three times, depending on the patient's response. Surgical resection was carried out when the tumor volume appeared sufficiently reduced to allow safe resection by either lobectomy or extended lobectomy. A marked reduction in tumor size associated with decreased AFP level occurred after treatment. According to paired-samples test, tumor shrinkage ranged from 19.0% to 82.0%, with a mean value of 59.2%. AFP levels decreased 99.0% to 29.0% from initial levels, with a mean decrease of 60.0%. TACE allowed subsequent complete surgical resection in 13 cases and the other 3 cases underwent partial resection. One patient underwent successful orthotopic liver transplantation after receiving TACE therapy. Pathological examination showed that the mean percentage of necrotic area in the surgical specimens was 87%. Overall survival rate at 1, 3, and 5 years was 87.5%, 68.7%, and 50%, respectively. Correspondingly, event-free survival rate was 75%, 62.5%, and 43

Improved outcome for children with acute lymphoblastic leukemia after risk-adjusted intensive therapy: a single institution experience

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Al-Nasser, A.; El-Solh, H.; Al-Mahr, M.

2008-01-01

Because of need for more comprehensive information on the least toxic and most effective forms of therapy for children with acute lymphoblastic leukemia (ALL), we reviewed our experience in the treatment of children with ALL at King Faisal Specialist Hospital and Research Centre (KFSHRC) and King Fahd National Center for Children's Cancer and Research (KFNCCCR) over a period of 18 years with a focus on patient characteristics and outcome. During the period of 1981 to 1988, records of children with ALL were retrospectively reviewed with respect to clinical presentation, laboratory findings, risk factors, stratification, therapy and outcome. The protocols used in treatment included 4 local protocols (KFSH 81, 84, 87 and 90) and subsequently. Children's Cancer Group (CCG) protocols and these were grouped as Era (1981-1992) and Era 2 (1993-1998). Of 509 children with ALL treated during this period, 316 were treated using local protocols and 193 using CCG protocols. Drugs used in Era 1 included a 4-drug induction using etoposid (VP-16) instead of L-asparaginase. Consolidation was based on high dose methotexate (MTX) 1g/m2 and maintenance was based on oral mercaptopurine (6-MP) and MTX with periodic pulses using intravenous teniposide (VM-26), Ara-C, L-asparaginase, adriamycin, prednisone, VP-16 cyclophosphamide .International protocols were introduced in Era 2, which was also marked by intensification of early treatment, a wider selection of cytoreductive agents, and the alternating use of non-cross-resistant pairs of drugs using the post-remission period. The end of induction remission rate improved from 90% in Era 1 to 95% in Era 2, which was of borderline statistical significance (P=0.49). The 5-year event-free survival (EFS) improved from 30.6% in Era 1 to 64.2% in Era 2 (P<.001). Improvement in outcome was achieved without any significant increase in morbidity or mortality, due to improvement in both systemic therapy and supportive care. The most important

Ethacrynic acid: a novel radiation enhancer in human carcinoma cells

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Khil, Mark S.; Sang, Hie Kim; Pinto, John T.; Jae, Ho Kim

1996-01-01

Purpose: Because agents that interfere with thiol metabolism and glutathione S-transferase (GST) functions have been shown to enhance antitumor effects of alkylating agents in vitro and in vivo, the present study was conceived on the basis that an inhibitor of GST would enhance the radiation response of some selected human carcinoma cells. Ethacrynic acid (EA) was chosen for the study because it is an effective inhibitor of GST and is a well known diuretic in humans. Methods and Materials: Experiments were carried out with well-established human tumor cells in culture growing in Eagle's minimum essential medium (MEM) supplemented with 10% fetal calf serum (FCS). Cell lines used were MCF-7, MCF-7 adriamycin resistant (AR) cells (breast carcinoma), HT-29 cells (colon carcinoma), DU-145 cells (prostate carcinoma), and U-373 cells (malignant glioma). Cell survival following the exposure of cells to drug alone, radiation alone, and a combined treatment was assayed by determining the colony-forming ability of single plated cells in culture to obtain dose-survival curves. The drug enhancement ratio was correlated with levels of GST. Results: The cytotoxicity of EA was most pronounced in MCF-7, U-373, and DU-145 cells compared to MCF-7 AR and HT-29 cells. The levels of GST activity were found to be lower in those EA-sensitive cells. A significant radiation enhancement was obtained with EA-sensitive cells exposed to nontoxic concentrations of the drug immediately before or after irradiation. The sensitizer enhancement ratio (SER) of MCF-7 cells was 1.55 with EA (20 μg/ml), while the SER of MCF-7 AR was less than 1.1. Based on five different human tumor cells, a clear inverse relationship was demonstrated between the magnitude of SER and GST levels of tumor cells prior to the combined treatment. Conclusion: The present results suggest that EA, which acts as both a reversible and irreversible inhibitor of GST activity, could significantly enhance the radiation response of

Comparative Effectiveness of Chemotherapy Regimens in Prolonging Survival for Two Large Population-Based Cohorts of Elderly Adults with Breast and Colon Cancer in 1992-2009.

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Du, Xianglin L; Zhang, Yefei; Parikh, Rohan C; Lairson, David R; Cai, Yi

2015-08-01

To compare the effectiveness of chemotherapy in prolonging survival according to age in breast and colon cancer. Retrospective cohort study with a matched cohort analysis based on the conditional probability of receiving chemotherapy. The 16 Surveillance, Epidemiology, and End Results (SEER) areas from the SEER-Medicare linked database. Women diagnosed with Stage I to IIIa hormone receptor-negative breast cancer (n = 14,440) and 26,893 men and women with Stage III colon cancer (n = 26,893) aged 65 and older in 1992 to 2009. The main exposure was the receipt of chemotherapy, and the main outcome was mortality. In women with breast cancer aged 65 to 69, the risk of all-cause mortality was statistically significantly lower in those who received chemotherapy than in those who did not in the entire cohort (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.57-0.88) and in a propensity-matched cohort (HR = 0.82, 95% CI = 0.70-0.96) after adjusting for measured confounders. These patterns were similar in participants aged 70 to 74 and 75 to 79, but in women aged 80 to 84 and 85 to 89, risk of all-cause mortality was no longer significantly lower in those receiving chemotherapy in the entire and matched cohorts, except that, in a small number of women who received doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan), risk of mortality was significantly lower for those aged 80 to 84. Chemotherapy appeared to be effective in all ages from 65 through 84 in participants with Stage III colon cancer. For example, in those aged 85 to 89, chemotherapy was significantly associated with lower risk of mortality in the entire cohort (HR = 0.79, 95% CI = 0.67-0.92) and the matched cohort (HR = 0.79, 95% CI = 0.66-0.95). The effectiveness of chemotherapy decreased with age in participants with breast cancer, in whom chemotherapy appears to be effective until age 79 except for the doxorubicin-cyclophosphamide combination, which was effective in participants aged 80 to 84. In

The Reversal Effect and Its Mechanisms of Tetramethylpyrazine on Multidrug Resistance in Human Bladder Cancer.

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Shanshan Wang

Full Text Available Chemotherapy is an important strategy for the treatment of bladder cancer. However, the main problem limiting the success of chemotherapy is the development of multidrug resistance (MDR. To improve the management of bladder cancer, it is an urgent matter to search for strategies to reverse MDR. We chose three kinds of herbal medicines including ginsenoside Rh2, (--Epigallocatechin gallate (EGCG and Tetramethylpyrazine (TMP to detect their effects on bladder cancer. Reversal effects of these three herbal medicines for drug resistance in adriamycin (ADM-resistant Pumc-91 cells (Pumc-91/ADM were assessed by Cell Counting Kit-8 (CCK-8 cell proliferation assay system. The mechanisms of reversal effect for TMP were explored in Pumc-91/ADM and T24/DDP cells. After Pumc-91/ADM and T24/DDP cells were treated with TMP, cell cycle distribution analysis was performed by flow cytometry. The expression of MRP1, GST, BCL-2, LRP and TOPO-II was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR, immunefluorescence assay and western blot. It was observed that TMP was capable of enhancing the cytotoxicity of anticancer agents on Pumc-91/ADM cells in response to ADM, however Rh2 and EGCG were unable to. The reversal effect of TMP was also demonstrated in T24/DDP cells. Moreover, the treatment with TMP in Pumc-91/ADM and T24/DDP cells led to an increased of G1 phase accompanied with a concomitant decrease of cell numbers in S phase. Compared to the control group, an obvious decrease of MRP1, GST, BCL-2 and an increase of TOPO-II were shown in TMP groups with a dose-dependency in mRNA and protein levels. However, there was no difference on LRP expression between TMP groups and the control group. TMP could effectively reverse MDR of Pumc-91/ADM and T24/DDP cells and its mechanisms might be correlated with the alteration of MRP1, GST, BCL-2 and TOPO-II. TMP might be a potential candidate for reversing drug resistance in bladder cancer

Combined Treatment of Residual, Recurrent and Unresectable Gastric Cancer

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Bae, Hoon Sik

1990-01-01

A series of 25 patients with residual, recurrent, and unresectable gastric cancer received various combination of surgery, radiotherapy (RT), chemotherapy (CT), and hyperthermia (HT). They were placed INTO 7 categories; 1) CT and HT-14 patients; 2) RT and HT-15 patients; 3) surgery, RT and HT-2 patients; 4) surgery, RT, HT and CT-1 patient; 5) RT, HT and CT-1 patient; 6) RT and CT-1 patient; 7) RT alone-1 patient. Three patients had curative resection. 21 patients received irradiation with tightly contoured portals to spare as much small bowel, kidney and marrow as possible. Hyperthermia was applied regionally once or twice a week for 23 patients using 8 MHz radiofrequency capacitive heating device (Thermotron RF-8). HT was given approximately 30 min after RT. 7 patients were treated with CT: 4 patients received HT and concomitant Mitomycin-C; 3 patients received HT and sequential 5-FU+Adriamycin+Mitomycin-C. There was not any treatment related deaths. There was also no evidence of treatment related problems with liver, kidney, stomach, or spinal cord except only one case of transient diabetic ketoacidosis. The tumor response was evaluable in 22 patients. None achieved complete remission. 11(50%) achieved partial remission. The response rate was correlated with total radiation dose and achieved maximum temperature. 9 of 14 (64%) received more than 4000 cGy showed partial remission; especially, all 3 patients received more than 5500 cGy achieved partial response. 8 of the 12 patients (67%) who achieved maximal temperature more than 41 .deg. C showed partial response in comparing with 25% (2 of 8 patients, below 41 .deg. C). The numbers of HT, however, was not correlated with the response. 3 of the 25 patients (12%) remain alive. The one who was surgically unresectable and underwent irradiation alone is in progression of the disease with distant metastases. The remaining two patients with curative resection are alive with free of disease, 24 and 35 months

Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity assay

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Fehm, Tanja; Zwirner, Manfred; Wallwiener, Diethelm; Seeger, Harald; Neubauer, Hans

2012-01-01

The NeoAzure study has demonstrated that the use of the bisphosphonate zoledronic acid (Zol) in the neoadjuvant setting increases the rate of complete response in primary breast cancer and therefore indicates direct antitumor activity. The purpose of this study was to compare the antitumor effect of Zol with standard chemotherapy in primary breast cancer cells using ATP-tumor chemosensitivity assay (ATP-TCA). Breast cancer specimens were obtained from patients with breast cancer who underwent primary breast cancer surgery at the Department of Obstetrics and Gynecology, Tübingen, Germany, between 2006 through 2009. Antitumor effects of Zol, TAC (Docetaxel, Adriamycin, Cyclophosphamide) and FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) were tested in 116 fresh human primary breast cancer specimens using ATP-TCA. ATP-TCA results were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50), for IC90 and for the sensitivity index (IndexSUM). Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC) derived from the plasma peak concentrations determined by pharmacokinetic data. The assay was carried out in duplicate wells with positive and negative controls. The median IndexSUM value was lower for Zol than for the combined regimen FEC (36.8%) and TAC (12.9%), respectively, indicating increased antitumor activity of Zol in primary breast cancer cells. The difference regarding Zol and FEC was significant (p < 0.05). The median IC50 value for Zol (8.03% TDC) was significantly lower than the IC50 values for FEC (33.5% TDC) and TAC (19.3% TDC) treatment (p < 0.05). However, the median IC90 value for Zol (152.5% TDC) was significantly higher than the IC90 value obtained with TAC (49.5% TDC; p < 0.05), but similar to the IC90 value for FEC (180.9% TDC). In addition a significant positive correlation was observed for the IndexSum of Zol and the ER status

[Analysis of the diagnosis and treatment of desmoplastic small round cell tumor].

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Lu, Baojian; Zhang, Wei; Shang, Zhiqun; Sun, Erlin; Nian, Xuewu; Gao, Jingda; Ma, Chengquan; Han, Ruifa

2015-09-01

To explore the clinical diagnostic features and treatment of desmoplastic small round cell tumor (DSRCT), and to improve the understanding and management of this tumor. The clinicopathological data of nine patients treated in our hospital from October 2004 to June 2014 were retrospectively analyzed and a review of the literature was made. The clinical manifestations, pathological characteristics, diagnosis and differential diagnosis, treatment and prognosis of this tumor were summarized and analyzed. Nine patients with DSRCT, 5 males and 4 females, with an average age of 21 years (range 8-56 years) were included in this study. Ultrasound examination revealed irregular low-density mass shadow in the abdominal cavity. CT examination found that 6 cases had abdominal and retroperitoneal multiple solid tumor nodules, uneven density, and visible low density fluid area. Postoperative pathological examination revealed that the tumor cells were small, mostly elliptic, gathered to form clear structure of nests with clear irregular boundaries. The central portion of large tumor nests often showed necrosis. Scattered fibroblasts and large amount of hyalinization of collagen fibers were seen in the interstitial tissue around the nests. Six patients received laparotomy surgery, however, all failed to resect the tumor completely. Three patients received postoperative chemotherapy, i. e. two cases had carboplatin and paclitaxel chemotherapy, and one case of chemotherapy regimen not specified. Two patients had radiation and chemotherapy (no concrete plan was available). Another case was lost to follow-up. Two of the three patients without surgery received chemotherapy with CAP (cyclophosphamide+adriamycin+carboplatin) and total rectal lesions, pelvic and inguinal lymph nodes, ilium metastases radiation therapy. Another one patient received EP regimen (DDP+VP16) which was then changed into a TP chemotherapy alone. Eight of the nine cases died shortly after surgery, and only one

Factors affecting intrapatient liver and mediastinal blood pool ¹⁸F-FDG standardized uptake value changes during ABVD chemotherapy in Hodgkin's lymphoma.

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Chiaravalloti, Agostino; Danieli, Roberta; Abbatiello, Paolo; Di Pietro, Barbara; Travascio, Laura; Cantonetti, Maria; Guazzaroni, Manlio; Orlacchio, Antonio; Simonetti, Giovanni; Schillaci, Orazio

2014-06-01

The aim of our study was to assess the intrapatient variability of 2-deoxy-2-((18)F)-fluoro-D-glucose ((18)F-FDG) uptake in the liver and in the mediastinum among patients with Hodgkin's lymphoma (HL) treated with doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy (CHT). The study included 68 patients (30 men, 38 women; mean age 32 ± 11 years) with biopsy-proven HL. According to Ann Arbor criteria, 6 were stage I, 34 were stage II, 12 were stage 3 and 16 were stage 4. All of them underwent a baseline (PET0) and an interim (PET2) (18)F-FDG whole-body positron emission tomography (PET)/CT. All patients were treated after PET0 with two ABVD cycles for 2 months that ended 15 ± 5 days prior to the PET2 examination. All patients were further evaluated 15 ± 6 days after four additional ABVD cycles (PET6). None of the patients presented a serum glucose level higher than 107 mg/dl. The mean and maximum standardized uptake values (SUV) of the liver and mediastinum were calculated using the same standard protocol for PET0, PET2 and PET6, respectively. Data were examined by means of the Wilcoxon matched pairs test and linear regression analysis. The main results of our study were an increased liver SUVmean in PET2 (1.76 ± 0.35) as compared with that of PET0 (1.57 ± 0.31; p  0.05). Another finding is a relationship in PET0 between liver SUVmean and SUVmax with the stage, which was lower in those patients with advanced disease (r (2) = 0.1456 and p = 0.0013 for SUVmean and r (2) = 0.1277 and p = 0.0028 for SUVmax). The results of our study suggest that liver (18)F-FDG uptake is variable in patients with HL during the CHT treatment and the disease course and should be considered carefully when used to define the response to therapy in the interim PET in HL.

Diffusion Lung Capacity Changes in Hodgkin Lymphoma Patients Before and After ABVD Chemotherapy

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Abdullah, M.; Alam, S.; Majid, A.; Zafar, W.

2016-01-01

Background: Chemotherapy consisting of Adriamycin, Bleomycin, Vinblastine, and Doxorubicin (ABVD), which is the mainstay of treatment in Hodgkins Lymphoma (HL), is associated with both acute and long-term pulmonary toxicity primarily due to Bleomycin. Bleomycin induced pulmonary toxicity (BPT) is clinically detected using diffusing lung capacity for carbon monoxide (DLCO). The objective of this study was to evaluate changes in DLCO in HL patients before and after ABVD chemotherapy. Methods: Medical records of all adult HL patients treated with ABVD chemotherapy at a single centre in Lahore, Pakistan during the entire calendar year 2012 were analysed. Patients with pre-existing pulmonary dysfunction, history of thoracic surgery and smokers were excluded. Results: A total of 179 HL patients were identified during the study period who received ABVD chemotherapy. Out of these, 93 (51.95 percent) patients had undergone both a pre- and post-chemotherapy DLCO measurements. The remaining patients had only one DLCO reading available and were not included in the analysis. The mean percentage difference between pre- and post-chemotherapy values for DLCO (5.49 percent; 95 percent confidence interval [CI] 1.56-9.43 percent) and for Haemoglobin-adjusted DLCO (8.24 percent; 95 percent CI 3.90-12.57 percent) were statistically significant at p<0.01. Diffusing lung capacity for carbon (DLCO) values declined from pre-treatment to post-treatment by 1-10 percent in 23 (24.7 percent) patients, by 10-20 percent in 19 (20.4 percent) patients, by 20-30 percent in 10 (10.8 percent) patients and >30 percent in 10 (10.8 percent) patients. After adjusting for age, a 1mg/m/sup 2/ increase in dose of Bleomycin was significantly associated with 0.14 percent (95 percent CI: 0.03-0.25 percent) decline in DLCO and 0.13 percent (95 percent CI: 0.10-0.26 percent) decline in haemoglobin-adjusted DLCO from pre-treatment value. Conclusions: Mild to moderate dysfunction in diffusion lung capacity is

Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

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Chintamani; Singhal, Vinay; Singh, JP; Lyall, Ashima; Saxena, Sunita; Bansal, Anju

2004-01-01

Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins) brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio). Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide) were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was assessed using chi-square test and coefficient

Interim PET After Two ABVD Cycles in Early-Stage Hodgkin Lymphoma: Outcomes Following the Continuation of Chemotherapy Plus Radiotherapy

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Simontacchi, Gabriele; Filippi, Andrea Riccardo; Ciammella, Patrizia; Buglione, Michela; Saieva, Calogero; Magrini, Stefano Maria; Livi, Lorenzo; Iotti, Cinzia; Botto, Barbara; Vaggelli, Luca; Re, Alessandro; Merli, Francesco; Ricardi, Umberto

2015-01-01

Purpose: This multicenter retrospective study was designed to evaluate the prognostic role of interim fluorodeoxyglucose-labeled positron emission tomography (i-FDG-PET) in a cohort of patients affected with early-stage Hodgkin lymphoma (HL) treated initially with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by radiation therapy, and to assess the role of chemotherapy continuation plus radiation therapy for i-FDG-PET-positive patients. Methods and Materials: Data from 257 patients were retrieved from 4 hematology and radiation oncology departments. Inclusion criteria were stage I to IIAB HL, “intention-to-treat” AVBD plus radiation therapy, and FDG-PET at diagnosis and after the first 2 ABVD cycles. All i-FDG-PET scans underwent blinded local review by using the Deauville 5-point scoring system; patients were stratified as negative or positive using 2 Deauville score cutoff values, ≥3 or ≥4. Results: Median follow-up time was 56 months (range: 9-163 months); 5-year overall survival (OS) and disease-specific survival (DSS) for the whole cohort were 97.5% and 98.3%, respectively. Five-year progression-free survival (PFS) was 95.6%. After i-FDG-PET revision, 43 of 257 patients (16.7%) had a positive i-FDG-PET (Deauville scores: 3-5). Five-year PFS rates for i-FDG-PET-negative and i-FDG-PET-positive patients were 98.1% and 83.7%, respectively, if using a Deauville score cutoff of 3, and 97.7% and 78.6%, respectively, if using a cutoff of 4 (P=.0001). Five-year OS for i-FDG-PET-negative and i-FDG-PET-positive patients was 98.5% and 93.0%, respectively, if using a cutoff of 3, and 98.6% and 89.3%, respectively, if using a cutoff of 4 (P=.029 and P=.002). At univariate regression analysis, i-FDG-PET positivity was associated with worse OS and PFS. At multivariate analysis, performed only for PFS, i-FDG-PET positivity confirmed its negative impact (P=.002). Conclusions: i-FDG-PET is prognostic for PFS and OS in early-stage HL

Pyramidatine (Z88) Sensitizes Vincristine-Resistant Human Oral Cancer (KB/VCR) Cells to Chemotherapeutic Agents by Inhibition of P-glycoprotein.

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Liu, Zulong; Zhu, Hengrui; Qu, Shijin; Tang, Lisha; Cao, Lihuan; Yu, Wenbo; Yang, Xianmei; Jiang, Songmin; Zhu, Dayuan; Tan, Changheng; Yu, Long

2018-01-01

Multi-drug resistance (MDR) remains a major impediment in cancer therapy. A major goal for scientists is to discover more effective compounds that are able to circumvent MDR and simultaneously have minimal adverse side effects. In the present study, we aim to determine the anti-MDR effects of pyramidatine (Z88), a cinnamic acid-derived bisamide compound isolated from the leaves of Aglaia perviridis, on KB/VCR (vincristineresistant human oral cancer cells) and MCF-7/ADR (adriamycin-resistant human breast adenocarcinoma) cells. Cell viability and average resistant fold (RF) of Z88 were examined by Cell Counting Kit-8 (CCK-8) assay. Flow cytometry, western blot, RT-PCR, Rhodamine 123 accumulation assay and P-glycoprotein (P-gp) ATPase assay were used to demonstrate the anti-MDR activity and mechanism of Z88. The average RF of Z88 is 0.09 and 0.51 in KB/VCR and MCF-7/ADR cells. A CCK-8 assay showed that Z88 could enhance the cytotoxicity of VCR toward KB/VCR cells. A FACS analysis revealed that Z88 could enhance the VCR-induced apoptosis as well as G2/M arrest in a dose-dependent manner in KB/VCR cells. Western blot results showed that the expression levels of PARP, Bax, and cyclin B1 all increased after treatment with 0.2 µmol/L (µM) of VCR combined with 10 µM of Z88 for 24 h in KB/VCR cells. Z88 also could enhance the accumulation of rhodamine 123. Further studies showed that Z88 could inhibit the verapamil stimulated Pgp ATPase activity. Additionally, qPCR detection and western blot assays revealed that Z88 could decrease the expression of P-gp at both RNA and protein level. Z88 exerted potent anti-MDR activity in vitro and its mechanisms are associated with dualinhibition of the function and expression of P-gp. These findings encourage efforts to develop more effective reversal agents to circumvent MDR based on Z88. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis

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Semedo, Patricia; Buscariollo, Bruna N.; Donizetti-Oliveira, Cassiano; Cenedeze, Marcos A.; Soares, Maria Fernanda; Pacheco-Silva, Alvaro; Savage, Paul B.; Câmara, Niels O. S.; Keller, Alexandre C.

2012-01-01

A growing body of evidence demonstrates a correlation between Th2 cytokines and the development of focal and segmental glomerulosclerosis (FSGS). Therefore, we hypothesized that GSL-1, a monoglycosylceramide from Sphingomonas ssp. with pro-Th1 activity on invariant Natural Killer T (iNKT) lymphocytes, could counterbalance the Th2 profile and modulate glomerulosclerosis. Using an adriamycin(ADM)-based model of FSGS, we found that BALB/c mice presented albuminuria and glomerular degeneration in association with a Th2-like pro-fibrogenic profile; these mice also expressed a combination of inflammatory cytokines, such as IL-4, IL-1α, IL-1β, IL-17, TNF-α, and chemokines, such as RANTES and eotaxin. In addition, we observed a decrease in the mRNA levels of GD3 synthase, the enzyme responsible for GD3 metabolism, a glycolipid associated with podocyte physiology. GSL-1 treatment inhibited ADM-induced renal dysfunction and preserved kidney architecture, a phenomenon associated with the induction of a Th1-like response, increased levels of GD3 synthase transcripts and inhibition of pro-fibrotic transcripts and inflammatory cytokines. TGF-β analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-β could be associated with both FSGS pathology and iNKT-mediated immunosuppression; therefore, we analyzed the kidney expression of phosphorylated SMAD2/3 and SMAD7 proteins, molecules associated with the deleterious and protective effects of TGF-β, respectively. We found high levels of phosphoSMAD2/3 in ADM mice in contrast to the GSL-1 treated group in which SMAD7 expression increased. These data suggest that GSL-1 treatment modulates the downstream signaling of TGF-β through a renoprotective pathway. Finally, GSL-1 treatment at day 4, a period when proteinuria was already established, was still able to improve renal function, preserve renal structure and inhibit fibrogenic transcripts. In

Factor estimulante de colonias de granulocitos en pacientes con cáncer Granulocyte-colony stimulating factor in patients with cancer

Directory of Open Access Journals (Sweden)

María Cristina Céspedes Quevedo

2013-01-01

myelosuppressive effect of cytotoxic drugs nor the myelostimulating effect of hormone, and cisplatin and adriamycin were related to higher neutropenia and lack of reaction to the factor. Finally, the Ior® LeukoCIM stimulated the granulopoietic system of most patients.

PEG-PE/clay composite carriers for doxorubicin: Effect of composite structure on release, cell interaction and cytotoxicity.

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Kohay, Hagay; Sarisozen, Can; Sawant, Rupa; Jhaveri, Aditi; Torchilin, Vladimir P; Mishael, Yael G

2017-06-01

A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was developed. DOX was incorporated in micelles (M-DOX) of polyethylene glycol-phosphatidylethanolamine (PEG-PE) which in turn were adsorbed by the clay, montmorillonite (MMT). The nano-structures of the PEG-PE/MMT composites of LOW and HIGH polymer loadings were characterized by XRD, TGA, FTIR, size (DLS) and zeta measurements. These measurements suggest that for the LOW composite a single layer of polymer intercalates in the clay platelets and the polymer only partially covers the external surface, while for the HIGH composite two layers of polymer intercalate and a bilayer may form on the external surface. These nanostructures have a direct effect on formulation stability and on the rate of DOX release. The release rate was reversely correlated with the degree of DOX interaction with the clay and followed the sequence: M-DOX>HIGH formulation>LOW formulation>DOX/MMT. Despite the slower release from the HIGH formulation, its cytotoxicity effect on sensitive cells was as high as the "free" DOX. Surprisingly, the LOW formulation, with the slowest release, demonstrated the highest cytotoxicity in the case of Adriamycin (ADR) resistant cells. Confocal microscopy images and association tests provided an insight into the contribution of formulation-cell interactions vs. the contribution of DOX release rate. Internalization of the formulations was suggested as a mechanism that increases DOX efficiency, particularly in the ADR resistant cell line. The employment of organic-inorganic hybrid materials as drug delivery systems, has not reached its full potential, however, its functionality as an efficient tunable release system was demonstrated. DOX PEG-PE/clay formulations were design as an efficient drug delivery system. The main aim was to develop PEG-PE/clay formulations of different structures based on various PEG-PE/clay ratios in order to achieve tunable release rates, to control

Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence

International Nuclear Information System (INIS)

Hernandez-Flores, Georgina; Bravo-Cuellar, Alejandro; Ortiz-Lazareno, Pablo C; Lerma-Diaz, Jose Manuel; Dominguez-Rodriguez, Jorge R; Jave-Suarez, Luis F; Aguilar-Lemarroy, Adriana del C; Celis-Carrillo, Ruth de; Toro-Arreola, Susana del; Castellanos-Esparza, Yessica C

2011-01-01

Worldwide, cervical cancer is the second most common causes of cancer in women and represents an important mortality rate. Cisplatin (CIS) is a very important antitumoral agent and can lead tumor cells toward two important cellular states: apoptosis and senescence. In some types of cancers pentoxifylline (PTX) sensitizes these cells to the toxic action of chemotherapeutics drugs such as adriamycin, inducing apoptosis. In the present work, we studied in vitro whether PTX alone or in combination with CIS induces apoptosis and/or senescence in cervix cancer HeLa and SiHa cell lines infected with HPV types 16 and 18, respectively, as well as in immortalized keratinocytyes HaCaT cells. HeLa (HPV 18+), SiHa (HPV 16+) cervix cancer cells and non-tumorigenic immortalized HaCaT cells (control) were treated with PTX, CIS or both. The cellular toxicity and survival fraction of PTX and CIS were determinate by WST-1 and clonogenic assays respectively. Apoptosis, caspase activation and phosphorylation of ERK1/2, p38, p65 (NF-κB), Bcl-2 and Bcl-XL anti-apoptotic proteins were determinated by flow cytometry. Senescence by microscopy. Phosphorylation of IκBα and IκB total were measured by ELISA. Pro-apoptotic, anti-apoptotic and senescence genes, as well as HPV-E6/7 mRNA expression, were detected by RT-PCR. Our results show that after 24 hours of incubation PTX per se is toxic for cancer cells affecting cell viability and inducing apoptosis. The toxicity in HaCaT cells was minimal. CIS induces apoptosis in HeLa and SiHa cells and its effect was significantly increases when the cells were treated with PTX + CIS. In all studies there was a direct correlation with levels of caspases (-3, -6, -7, -9 and -8) activity and apoptosis. CIS induces important levels of senescence and phosphorylation of ERK1/2, p38, p65/RELA, and IκBα, and decreased the expression of anti-apoptotic protein Bcl-XL. Surprisingly these levels were significantly reduced by PTX in tumor cells, and at the same

[Evaluation of breast cancer treatment at a tertiary-level institution with Popular Health Insurance in Mexico].

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Arce-Salinas, Claudia; Lara-Medina, Fernando Ulises; Alvarado-Miranda, Alberto; Castañeda-Soto, Noel; Bargalló-Rocha, Enrique; Ramírez-Ugalde, María Teresa; Pérez-Sánchez, Víctor; Rivera, Lesbia; Gambo-Vignole, Carlos; Santamaría-Galicia, Julieta; Nieves-Casas, Rosa Isela; Morán-Muñoz, Héctor; Mohar-Betancourt, Alejandro

2012-01-01

In our country breast cancer represents a major health problem. Only 45% of all population has access to health services, the consequence is delay in diagnosis and treatment. In Mexico, 66% of all new cases of breast cancer are diagnosed in locally advanced stages. From May 2007 the Health System Protection Against Catastrophic Expenses, called Seguro Popular (SP), breast cancer was included in covering the treatment of this neoplasm in any patient without access to social security. To evaluate the results and impact of SP in the adjuvant and neoadjuvant treatment of a group of patients diagnosed with breast cancer at an institution of national reference. We analyzed a group of 259 patients in stages (I-IIIC). The clinical stages I and II (55 patients) were treated with adjuvant chemotherapy FAC -T (fluorouracil 500 mg/m2, adriamycin 50 mg/m2 and cyclophosphamide 500 mg/m2 (FAC) followed by 12 weeks of paclitaxel 80 mg/m2 +/- trastuzumab loading dose of 4 mg/kg followed by 2 mg/kg); 204 patients in locally advanced stages (IIB-IIIC) received FAC-T +/- trastuzumab followed by surgery. Adjuvant treatment consisted of endocrine therapy for hormone-sensitive patients and radiotherapy 50 cGy according to international standards. The age at diagnosis was 47 years (range 23-68). 80% of them were locally advanced stages (IIB-IIIC) and were treated in a neoadjuvant setting, 20% was in early stages, treated with surgery and adjuvant chemotherapy The disease-free survival and overall survival at 30 months was 85.7 and 90% respectively. Overall pathologic complete response was obtained in 15% of cases. In the subgroup analysis showed that 41% of patients HER2 (+), 29% of triple-negative patients and 9% of hormone-sensitive tumors achieved complete pathological response (p = 0.0001). This is the first analysis of efficacy of adjuvant and neoadjuvant treatment in breast cancer since the introduction of popular secure non-entitled population. It is clear that treatment efficacy

Factors affecting intrapatient liver and mediastinal blood pool 18F-FDG standardized uptake value changes during ABVD chemotherapy in Hodgkin's lymphoma

International Nuclear Information System (INIS)

Chiaravalloti, Agostino; Danieli, Roberta; Abbatiello, Paolo; Di Pietro, Barbara; Travascio, Laura; Cantonetti, Maria; Guazzaroni, Manlio; Orlacchio, Antonio; Simonetti, Giovanni; Schillaci, Orazio

2014-01-01

The aim of our study was to assess the intrapatient variability of 2-deoxy-2-( 18 F)-fluoro-D-glucose ( 18 F-FDG) uptake in the liver and in the mediastinum among patients with Hodgkin's lymphoma (HL) treated with doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy (CHT). The study included 68 patients (30 men, 38 women; mean age 32 ± 11 years) with biopsy-proven HL. According to Ann Arbor criteria, 6 were stage I, 34 were stage II, 12 were stage 3 and 16 were stage 4. All of them underwent a baseline (PET0) and an interim (PET2) 18 F-FDG whole-body positron emission tomography (PET)/CT. All patients were treated after PET0 with two ABVD cycles for 2 months that ended 15 ± 5 days prior to the PET2 examination. All patients were further evaluated 15 ± 6 days after four additional ABVD cycles (PET6). None of the patients presented a serum glucose level higher than 107 mg/dl. The mean and maximum standardized uptake values (SUV) of the liver and mediastinum were calculated using the same standard protocol for PET0, PET2 and PET6, respectively. Data were examined by means of the Wilcoxon matched pairs test and linear regression analysis. The main results of our study were an increased liver SUV mean in PET2 (1.76 ± 0.35) as compared with that of PET0 (1.57 ± 0.31; p max in PET2 (3.13 ± 0.67) as compared with that of PET0 (2.82 ± 0.64; p mean and SUV max in PET0, PET2 and PET6 (p > 0.05). Another finding is a relationship in PET0 between liver SUV mean and SUV max with the stage, which was lower in those patients with advanced disease (r 2 = 0.1456 and p = 0.0013 for SUV mean and r 2 = 0.1277 and p = 0.0028 for SUV max ). The results of our study suggest that liver 18 F-FDG uptake is variable in patients with HL during the CHT treatment and the disease course and should be considered carefully when used to define the response to therapy in the interim PET in HL. (orig.)

A possible coincidence of cytomegalovirus retinitis and intraocular lymphoma in a patient with systemic non-Hodgkin’s lymphoma

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Svozílková Petra

2013-01-01

Full Text Available Abstract Purpose To present a possible coincidence of cytomegalovirus retinitis and intraocular lymphoma in a patient with systemic non-Hodgkin’s lymphoma. Case presentation A 47-year-old woman presented with decreased visual acuity associated with white retinal lesions in both eyes. A history of pneumonia of unknown aetiology closely preceded the deterioration of vision. Five years previously the patient was diagnosed with follicular non-Hodgkin’s lymphoma. She was treated with a chemotherapy regimen comprised of cyclophosphamide, adriamycin, vincristin, and prednisone with later addition of the anti-CD20 antibody rituximab. She experienced a relapse 19 months later with involvement of the retroperitoneal lymph nodes, and commenced treatment with rituximab and 90Y-ibritumomab tiuxetan. A second relapse occurred 22 months after radioimmunotherapy and was treated with a combination of fludarabine, cyclophosphamide, and mitoxantrone followed by rituximab. The patient experienced no further relapses until the current presentation (April, 2010. Pars plana vitrectomy with vitreous fluid analysis was performed in the right eye. PCR testing confirmed the presence of cytomegalovirus in the vitreous. Atypical lymphoid elements, highly suspicious of malignancy were also found on cytologic examination. Intravenous foscarnet was administered continually for three weeks, followed by oral valganciclovir given in a dose of 900 mg twice per day. In addition, the rituximab therapy continued at three monthly intervals. Nevertheless, cessation of foscarnet therapy was followed by a recurrence of retinitis on three separate occasions during a 3-month period instigating its reinduction to the treatment regime after each recurrence. Conclusions Cytomegalovirus retinitis is an opportunistic infection found in AIDS patients as well as in bone marrow and solid organ transplant recipients being treated with systemic immunosuppressive drugs. This case presents a less

Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

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Singh JP

2004-08-01

Full Text Available Abstract Background Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. Methods 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio. Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was

Functional study of the novel multidrug resistance gene HA117 and its comparison to multidrug resistance gene 1

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Chen Tingfu

2010-07-01

Full Text Available Abstract Background The novel gene HA117 is a multidrug resistance (MDR gene expressed by all-trans retinoic acid-resistant HL-60 cells. In the present study, we compared the multidrug resistance of the HA117 with that of the classical multidrug resistance gene 1 (MDR1 in breast cancer cell line 4T1. Methods Transduction of the breast cancer cell line 4T1 with adenoviral vectors encoding the HA117 gene and the green fluorescence protein gene (GFP (Ad-GFP-HA117, the MDR1 and GFP (Ad-GFP-MDR1 or GFP (Ad-GFP was respectively carried out. The transduction efficiency and the multiplicity of infection (MOI were detected by fluorescence microscope and flow cytometry. The transcription of HA117 gene and MDR1 gene were detected by reverse transcription polymerase chain reaction (RT-PCR. Western blotting analysis was used to detect the expression of P-glycoprotein (P-gp but the expression of HA117 could not be analyzed as it is a novel gene and its antibody has not yet been synthesized. The drug-excretion activity of HA117 and MDR1 were determined by daunorubicin (DNR efflux assay. The drug sensitivities of 4T1/HA117 and 4T1/MDR1 to chemotherapeutic agents were detected by Methyl-Thiazolyl-Tetrazolium (MTT assay. Results The transducted efficiency of Ad-GFP-HA117 and Ad-GFP-MDR1 were 75%-80% when MOI was equal to 50. The transduction of Ad-GFP-HA117 and Ad-GFP-MDR1 could increase the expression of HA117 and MDR1. The drug resistance index to Adriamycin (ADM, vincristine (VCR, paclitaxel (Taxol and bleomycin (BLM increased to19.8050, 9.0663, 9.7245, 3.5650 respectively for 4T1/HA117 and 24.2236, 11.0480, 11.3741, 0.9630 respectively for 4T1/MDR1 as compared to the control cells. There were no significant differences in drug sensitivity between 4T1/HA117 and 4T1/MDR1 for the P-gp substrates (ADM, VCR and Taxol (P Conclusions These results confirm that HA117 is a strong MDR gene in both HL-60 and 4T1 cells. Furthermore, our results indicate that the MDR

The cooperative effect of p53 and Rb in local nanotherapy in a rabbit VX2 model of hepatocellular carcinoma

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Dong S

2013-10-01

Full Text Available Shengli Dong,1 Qibin Tang,2 Miaoyun Long,3 Jian Guan,4 Lu Ye,5 Gaopeng Li6 1Department of General Surgery, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, Shanxi Province, 2Department of Hepatobiliopancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 3Department of Thyroid and Vascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 4Department of Radiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 5Infection Department, Guangzhou No 8 Hospital, Guangzhou, Guangdong Province, 6Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, People's Republic of China Background/aim: A local nanotherapy (LNT combining the therapeutic efficacy of trans-arterial embolization, nanoparticles, and p53 gene therapy has been previously presented. The study presented here aimed to further improve the incomplete tumor eradication and limited survival enhancement and to elucidate the molecular mechanism of the LNT. Methods: In a tumor-targeting manner, recombinant expressing plasmids harboring wild-type p53 and Rb were either co-transferred or transferred separately to rabbit hepatic VX2 tumors in a poly-L-lysine-modified hydroxyapatite nanoparticle nanoplex and Lipiodol® (Guerbet, Villepinte, France emulsion via the hepatic artery. Subsequent co-expression of p53 and Rb proteins within the treated tumors was investigated by Western blotting and in situ analysis by laser-scanning confocal microscopy. The therapeutic effect was evaluated by the tumor growth velocity, apoptosis and necrosis rates, their sensitivity to Adriamycin® (ADM, mitomycin C, and fluorouracil, the microvessel density of tumor tissue, and the survival time of animals. Eventually, real-time polymerase chain reaction and enhanced chemiluminescence Western blotting

The 2013 Discovery Award from the Society for Free Radical Biology and Medicine: Selected Discoveries from the Butterfield Laboratory of Oxidative Stress and Its Sequelae in Brain in Cognitive Disorders Exemplified by Alzheimer Disease and Chemotherapy Induced Cognitive Impairment

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Butterfield, D. Allan

2014-01-01

This retrospective review on discoveries of the roles of oxidative stress in brain of subjects with Alzheimer disease (AD) and animal models thereof as well as brain from animal models of chemotherapy induced cognitive impairment (CICI) results from the author receiving the 2013 Discovery Award from the Society for Free Radical Biology and Medicine. The paper reviews our laboratory's discovery of: protein oxidation and lipid peroxidation in AD brain regions rich in amyloid β-peptide (Aβ) but not in Aβ-poor cerebellum; redox proteomics as a means to identify oxidatively modified brain proteins in AD and its earlier forms that are consistent with the pathology, biochemistry, and clinical presentation of these disorders; how Aβ in in vivo, ex vivo, and in vitro studies can lead to oxidative modification of key proteins that also are oxidatively modified in AD brain; the role of the single methionine residue of Aβ(1-42) in these processes; and some of the potential mechanisms in the pathogenesis and progression of AD. CICI affects a significant fraction of the 14 million American cancer survivors, and due to diminished cognitive function, reduced quality of life of the persons with CICI (called “chemobrain” by patients) often results. A proposed mechanism for CICI employed the prototypical ROS-generating and non-blood brain barrier (BBB)-penetrating chemotherapeutic agent doxorubicin (Dox, also called adriamycin, ADR). Because of the quinone moiety within the structure of Dox, this agent undergoes redox cycling to produce superoxide free radical peripherally. This, in turn, leads to oxidative modification of the key plasma protein, Apolipoprotein A1 (ApoA1). Oxidized ApoA1 leads to elevated peripheral TNFα, a pro-inflammatory cytokine that crosses the BBB to induce oxidative stress in brain parenchyma that affects negatively brain mitochondria. This subsequently leads to apoptotic cell death resulting in CICI. This review outlines aspects of CICI consistent

Formation of intestinal atresias in the Fgfr2IIIb-/- mice is not associated with defects in notochord development or alterations in Shh expression.

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Reeder, Amy L; Botham, Robert A; Franco, Marta; Zaremba, Krzysztof M; Nichol, Peter F

2012-09-01

The etiology of intestinal atresia remains elusive but has been ascribed to a number of possible events including in utero vascular accidents, failure of recanalization of the intestinal lumen, and mechanical compression. Another such event that has been postulated to be a cause in atresia formation is disruption in notochord development. This hypothesis arose from clinical observations of notochord abnormalities in patients with intestinal atresias as well as abnormal notochord development observed in a pharmacologic animal model of intestinal atresia. Atresias in this model result from in utero exposure to Adriamycin, wherein notochord defects were noted in up to 80% of embryos that manifested intestinal atresias. Embryos with notochord abnormalities were observed to have ectopic expression of Sonic Hedgehog (Shh), which in turn was postulated to be causative in atresia formation. We were interested in determining whether disruptions in notochord development or Shh expression occurred in an established genetic model of intestinal atresia and used the fibroblast growth factor receptor 2IIIb homozygous mutant (Fgfr2IIIb-/-) mouse model. These embryos develop colonic atresias (100% penetrance) and duodenal atresias (42% penetrance). Wild-type and Fgfr2IIIb-/- mouse embryos were harvested at embryonic day (E) 10.5, E11.5, E12.5, and E13.5. Whole-mount in situ hybridization was performed on E10.5 embryos for Shh. Embryos at each time point were harvested and sectioned for hematoxylin-eosin staining. Sections were photographed specifically for the notochord and resulting images reconstructed in 3-D using Amira software. Colons were isolated from wild-type and Fgfr2IIIb-/- embryos at E10.5, then cultured for 48 hours in Matrigel with FGF10 in the presence or absence of exogenous Shh protein. Explants were harvested, fixed in formalin, and photographed. Fgfr2IIIb-/- mouse embryos exhibit no disruptions in Shh expression at E10.5, when the first events in atresia

Prediction of chemotherapy outcome in patients with metastatic soft tissue sarcomas based on dynamic FDG PET (dPET) and a multiparameter analysis

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Dimitrakopoulou-Strauss, Antonia; Strauss, Ludwig G.; Vasamiliette, Julie; Egerer, Gerlinde; Schmitt, Thomas; Kasper, Bernd; Haberkorn, Uwe

2010-01-01

Dynamic PET studies with 18 F-FDG were performed in patients with metastatic soft tissue sarcomas who received conventional chemotherapy with doxorubicin hydrochloride (Adriamycin) and ifosfamide (AI-G). The goal of the study was to evaluate the impact of full kinetic analysis and assess its value with regard to the therapy outcome based on survival data. The evaluation included 17 patients with 29 metastatic lesions of soft tissue sarcomas, who were treated with chemotherapy consisting of an AI-G regimen prior to high-dose chemotherapy and peripheral blood stem cell transplantation where applicable. Patients were examined prior to onset of therapy and after completion of the first cycle of AI-G. Restaging data (n = 17) based on Response Evaluation Criteria in Solid Tumors were available. Survival data (n = 14) served for reference. The following parameters were retrieved from the dynamic PET studies: standardized uptake value (SUV), fractal dimension, two-compartment model with computation of k1, k2, k3, k4 (unit: 1/min), the fractional blood volume and the FDG influx calculated according to Patlak. The mean SUV was 6.9 prior to therapy and 4.7 after one cycle. The mean influx was 0.066 prior to therapy in comparison to 0.058 after one cycle. We dichotomized the patients according to the median survival time of 320 days into response (n = 6) and non-response (n = 8). The mean SUV was 7.6 in the group of responders and 5.4 in the group of non-responders prior to therapy. Responders revealed a mean SUV of 3.8 after therapy as compared to 5.0 SUV for non-responders. We used discriminant analysis to classify the patients into the two response groups. The classification of the non-responders was generally higher (negative predictive value > 61%) than for the responders. Finally, the combined use of the four predictor variables, namely mean SUV and k1 of both studies led to the highest accuracy of 90% for both groups. The data demonstrate that only a multiparameter

Electron energy loss spectroscopy microanalysis and imaging in the transmission electron microscope: example of biological applications

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Diociaiuti, Marco

2005-01-01

diffraction (SAED) to study clay particle engulfed in the alveolar macrophages of human silicotic patients, demonstrating that the particle was surrounded by a Fe coating formed by ferritin. Moreover, the analysis of the EXELFS of Fe-L 2,3 edge allowed me to study the mineral core of the ferritin, which showed great similarity to the hematite structure. Finally, I performed ESI in a Zeiss EM902 (80 keV) TEM to study the subcellular localization of the anti-neoplastic drug 4'-deoxy-4'-iododoxorubicin, analogous to adriamycin, in treated human breast tumoral cell, showing that this technique is useful in the identification of the drug target

CLDN6 promotes chemoresistance through GSTP1 in human breast cancer

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Minlan Yang

2017-11-01

Full Text Available Abstract Background Claudin-6 (CLDN6, a member of CLDN family and a key component of tight junction, has been reported to function as a tumor suppressor in breast cancer. However, whether CLDN6 plays any role in breast cancer chemoresistance remains unclear. In this study, we investigated the role of CLDN6 in the acquisition of chemoresistance in breast cancer cells. Methods We manipulated the expression of CLDN6 in MCF-7 and MCF-7/MDR cells with lv-CLDN6 and CLDN6-shRNA and investigated whether CLDN6 manipulation lead to different susceptibilities to several chemotherapeutic agents in these cells. The cytotoxicity of adriamycin (ADM, 5-fluorouracil (5-FU, and cisplatin (DDP was tested by cck-8 assay. Cell death was determined by DAPI nuclear staining. The enzyme activity of glutanthione S-transferase-p1 (GSTP1 was detected by a GST activity kit. Then lv-GSTP1 and GSTP1-shRNA plasmids were constructed to investigate the potential of GSTP1 in regulating chemoresistance of breast cancer. The TP53-shRNA was adopted to explore the regulation mechanism of GSTP1. Finally, immunohistochemistry was used to explore the relationship between CLDN6 and GSTP1 expression in breast cancer tissues. Results Silencing CLDN6 increased the cytotoxicity of ADM, 5-FU, and DDP in MCF-7/MDR cells. Whereas overexpression of CLDN6 in MCF-7, the parental cell line of MCF-7/MDR expressing low level of CLDN6, increased the resistance to the above drugs. GSTP1 was upregulated in CLDN6-overexpressed MCF-7 cells. RNAi –mediated silencing of CLDN6 downregulated both GSTP1 expression and GST enzyme activity in MCF-7/MDR cells. Overexpresssion of GSTP1 in CLDN6 silenced MCF-7/MDR cells restored chemoresistance, whereas silencing GSTP1 reduced the chemoresistance due to ectopic overexpressed of CLDN6 in MCF-7 cells. These observations were also repeated in TNBC cells Hs578t. We further confirmed that CLDN6 interacted with p53 and promoted translocation of p53 from nucleus to

Factors affecting intrapatient liver and mediastinal blood pool {sup 18}F-FDG standardized uptake value changes during ABVD chemotherapy in Hodgkin's lymphoma

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Chiaravalloti, Agostino; Danieli, Roberta; Abbatiello, Paolo; Di Pietro, Barbara; Travascio, Laura; Cantonetti, Maria; Guazzaroni, Manlio; Orlacchio, Antonio; Simonetti, Giovanni [University Tor Vergata, Department of Biomedicine and Prevention, Rome (Italy); Schillaci, Orazio [University Tor Vergata, Department of Biomedicine and Prevention, Rome (Italy); IRCCS Neuromed, Pozzilli (Italy)

2014-06-15

The aim of our study was to assess the intrapatient variability of 2-deoxy-2-({sup 18}F)-fluoro-D-glucose ({sup 18}F-FDG) uptake in the liver and in the mediastinum among patients with Hodgkin's lymphoma (HL) treated with doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy (CHT). The study included 68 patients (30 men, 38 women; mean age 32 ± 11 years) with biopsy-proven HL. According to Ann Arbor criteria, 6 were stage I, 34 were stage II, 12 were stage 3 and 16 were stage 4. All of them underwent a baseline (PET0) and an interim (PET2) {sup 18}F-FDG whole-body positron emission tomography (PET)/CT. All patients were treated after PET0 with two ABVD cycles for 2 months that ended 15 ± 5 days prior to the PET2 examination. All patients were further evaluated 15 ± 6 days after four additional ABVD cycles (PET6). None of the patients presented a serum glucose level higher than 107 mg/dl. The mean and maximum standardized uptake values (SUV) of the liver and mediastinum were calculated using the same standard protocol for PET0, PET2 and PET6, respectively. Data were examined by means of the Wilcoxon matched pairs test and linear regression analysis. The main results of our study were an increased liver SUV{sub mean} in PET2 (1.76 ± 0.35) as compared with that of PET0 (1.57 ± 0.31; p < 0.0001) and PET6 (1.69 ± 0.28; p = 0.0407). The same results were obtained when considering liver SUV{sub max} in PET2 (3.13 ± 0.67) as compared with that of PET0 (2.82 ± 0.64; p < 0.0001) and PET6 (2.96 ± 0.52; p = 0.0105). No significant differences were obtained when comparing mediastinum SUV{sub mean} and SUV{sub max} in PET0, PET2 and PET6 (p > 0.05). Another finding is a relationship in PET0 between liver SUV{sub mean} and SUV{sub max} with the stage, which was lower in those patients with advanced disease (r{sup 2} = 0.1456 and p = 0.0013 for SUV{sub mean} and r{sup 2} = 0.1277 and p = 0.0028 for SUV{sub max}). The results of our

Aparición de episodios de neutropenia febril tras la quimioterapia citostática en el paciente oncológico Appearance of febrile neutropenia episodes after cytostatic therapy on Oncology patients

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Leonardo Lami Casaus

2009-12-01

the presence of other factors that may to increase the risk to these reactions. A total of 42 patients were studied admitted with febrile neutropenia after above therapy from February to August, 2007. Biomedical variables from included patient group were achieved and the previously applied cytostatic therapy. The prevalent age-group was those patients aged over 50 and predominance of male sex and advanced stages with associated affections. The more frequent tumor locations were in breast, lung, and non-Hodgkin lymphoma. The cytostatic agent more used in cases of febrile neutropenia was Adriamycin (71.4 % followed by Cyclophosphamide (52.4 %. The factors more associated with febrile neutropenia appearance were: Anthracycline chemotherapy, age over 50, advanced stages, and presence of associated diseases.

Cost-effectiveness analysis of treating transplant-eligible multiple myeloma patients in Macedonia

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Qerimi V

2018-06-01

Full Text Available Vjollca Qerimi,1,2 Aleksandra Kapedanovska Nestorovska,1 Zoran Sterjev,1 Sonja Genadieva-Stavric,3 Ljubica Suturkova1 1Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia; 2Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT – University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria; 3Medical Faculty, University Hematology Clinic, Skopje, Macedonia Purpose: A decision-analytic model was developed to study the impact of induction regimens vincristine, adriamycin, dexamethasone (VAD; thalidomide, dexamethasone (TD; and bortezomib, dexamethasone (BorD, followed by autologous stem cell transplantation (ASCT for treating multiple myeloma (MM patients in Macedonia. Additionally, a cost-effectiveness analysis (CEA of treatment sequences to predict health effects and costs of different treatment sequences was performed.Methods: Model strategies were based on a previously published study for treating patients with MM in Macedonia. The data on disease progression and treatment effectiveness were obtained from the published reports of randomized clinical trials (GIMEMA M-B02005, IFM 2005-01. Utility parameters were extracted from the literature. To compare treatment combinations, a decision tree model was developed. Additionally, a cost analysis for one-time per-protocol costs was performed from a Macedonian national health care perspective. The incremental cost-effectiveness ratios (ICERs/quality-adjusted life years (QALYs gained for 1-, 10-, and 20-year time horizons were determined. Costs and health outcomes were discounted to evaluate the effects of time in the model.Results: The one-time costs of BorD (EUR 5,656 were higher compared to VAD (EUR 303 and TD (EUR 329, increasing the overall costs for BorD. Thus, the BorD combination dominated in the baseline

A multi-disciplinary study investigating radiotherapy in Ewing's sarcoma - a final report of POG 8346

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Donaldson, S.; Torrey, M.; Link, M.; Glicksman, A.; Laurie, F.; Manning, J.; Neff, J.; Thompson, E.; Shuster, J.

1997-01-01

Purpose: To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event free (EFS) and overall survival rates from multi-disciplinary therapy in Ewing's Sarcoma (ES). Materials and Methods: Between 1983 and 1988, 184 children with ES were enrolled onto POG 8346. 178 (97%) met eligibility criteria; 6 had non-ES pathology. Induction treatment of Cyclophosphamide/Adriamycin (C/A) x 12 weeks was followed by local treatment either surgery or radiation therapy (XRT) and C/A, Dactinomycin and Vincristine for 50 weeks. Resection was advised for patients with small primary tumors if accomplished without functional loss. 40 patients were randomized to receive SF, whole bone XRT to 39.6 Gy plus a 16.2 Gy boost (total 55.8 Gy) or IF to 55.8 Gy while 84 were assigned to IF XRT. Results: Of 179 eligible patients, 141 (79%) had localized disease and 37 (21%) had metastases. Their 5 yr. EFS was 51% (SE = 5%) and 23% (SE = 7%) respectively. The response rate (RR) to induction chemotherapy was 88% (28% complete, 60% partial), but after XRT the RR increased to 98%. 37 of the localized patients underwent resection of whom 16 (43%) required post-operative XRT with 5 yr. EFS of 80% (SE = 7%). 104 of the localized patients received XRT and had a 5 year EFS of 41% (SE = 5%), with no difference in EFS between those randomized to SF vs. IF. Site of primary tumor correlated with 5 year EFS: Distal extremity - 65% (SE = 8%), Central - 63% (SE = 9%), Proximal extremity - 46% (SE = 8%), and Pelvis - 24% (SE = 10%). Tumor size did not influence EFS. Patterns of failure among the 141 localized patients were: local only - 18 (13%), local and systemic 14 (10%), systemic only 28 (20%). There were 4 (11%) local failures among those resected +/- XRT, but 28 (27%) following XRT alone. By protocol, patients suffering a relapse were required to undergo a biopsy

Radiation therapy for retinoblastoma: a retrospective review of 120 patients

International Nuclear Information System (INIS)

Pradhan, Deepak G.; Sandridge, Amy L.; Mullaney, Paul; Abboud, Emad; Karcioglu, Zeynel A.; Kandil, Alaa; Mustafa, Mahmoud M.; Gray, Alan J.

1997-01-01

Purpose: To characterize the patient population and treatment outcomes in patients with Retinoblastoma (RB) referred for External Beam Orbital Radiotherapy (EBORT) to King Faisal Specialist Hospital and Research Centre (KFSH and RC), Riyadh, Saudi Arabia from 1976 to 1993. Methods and Materials: A retrospective study of 120 patients with RB affecting a total of 192 eyes. Patients were divided into three groups. Group A are 60 patients (64 eyes) treated with EBORT to the intact eye to preserve vision. Reese-Ellsworth (RE) Staging was: 1: 12%; 2: 10%; 3: 12%; 4: 23%; and 5: 43%. Twenty-eight patients (47%) also received Vincristine, Adriamycin, and Cyclophosphamide chemotherapy (C/T). Mean follow-up, per patient, was 48.5 months. Standard treatment until 1992 was 45 Gy in 12 fractions of 3.75 Gy, three times weekly over 18 days. Assuming the α/β ratio for early effects and tumor control at 10, Tk = 21 days, T pot = 5 days, then the Biological Equivalent Dose (BED) was 62 Gy 10 for early effects, and 101 Gy 3 for late effects. Group B are 28 patients (28 eyes) treated for curative intent with EBORT to the orbit for locally advanced disease, usually after enucleation (24 eyes). Nineteen patients (83%) also had C/T. Mean follow-up was 22.6 months. Group C are 37 patients with advanced disease treated with radiotherapy for palliation. Seventeen (46%) also received C/T. Mean follow-up was 11.7 months. Results: Group A-following EBORT useful vision was retained in RE Stage 1 to 5: 7 of 7, 6 of 6, 4 of 8, 10 of 15, and 7 of 28 eyes, respectively. There was no significant difference between patients who received adjuvant chemotherapy and those who did not. Complications included cataract (27%), retinopathy (25%), vitreous hemorrhage (19%), and orbital deformities (11%). In Group B the local control rate was 71%. In Group C, 10 (27%) of the 37 patients were alive at last contact, and 27 (73%) were either terminal or dead of disease. None of Group A or B patients had

Assessment of response of limb sarcoma to neoadjuant chemotherapy with Tc99m SESTAMIBI

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Krishnakumar, R.; Priyadarshini, R.; Begum, Balkis; Manivannan, K.; Shanmugasundaram, B.; Anuradha, S.

2004-01-01

scans was high did not respond well and had to undergo amputation. Those patients who are likely to respond to conventional chemotherapy drugs like Adriamycin, Iphosphamide should have retention of the tracer at the tumor site by 2 hrs. Any patient with washout rate of the tracer (>50-60%) when compared to original 5 minutes uptake is unlikely to respond to these drugs. But this could not be corroborated in this study, may be due to chondromatous or myxoid content of the tumor tissue interfering with the MIBI uptake. We conclude that due to the heterogeneous expression of p-glycoprotein, both immunohistochemistry and 99mTc-MIBI scintigraphy may yield confounding results if the presence or absence of p-glycoprotein is not extensively explored. Although our data found that 99mTc-MIBI imaging is useful in the determination of the presence of multi drug resistance in patients with limb tumor, the issue of heterogeneous expression of the antigen should be further investigated when unexpected results are obtained. (author)

Thymoma - prognostic factors and treatment results

International Nuclear Information System (INIS)

Gripp, S.; Hilgers, K.; Schmitt, G.

1997-01-01

Purpose/Objective: To assess the prognostic factors and treatment results of thymoma with emphasis on surgery and radiotherapy. Materials and Methods: Thymoma patients treated at Duesseldorf University Hospital from 1954 to 1991 were studied in this retrospective analysis. Depending on stage and residual disease, treatment was surgery (sternotomy or thoracotomy) with and without radiotherapy and chemotherapy (Holoxan, Endoxan, Vinblastin, Adriamycin, Bleomycin, CDDP, Vepesid). 70 patients (38f, 32m) were enrolled in this study. The mean age was 46,5 years. At presentation the median Karnofsky's index was 90%. In 19% thymoma was accidentally diagnosed, 81% presented symptoms at diagnosis. Masaoka's staging system was used (I: intact capsule; II: invasion of the capsule; III: invasion of neighboring organs; IV: dissemination). Stage at presentation was I:21%; II: 26%; III: 43%; IV: 10%. All histologic slices were peer reviewed. Histologic classification according to Lewis (predominantly lymphocytic: 36%; predominantly epithelial: 23%; mixed type: 33%, spindle cell thymoma: 9%) was applied. All available paraffin embedded specimens (36) were studied with DNA cytometric analysis after Feulgen staining. Occasionally thymoma was accompanied by Myasthenia gravis (23%) or other paraneoplastic syndromes (19%). Statistical analysis was performed using the Kaplan-Meier method and logrank-tests. Multivariate analysis was also performed. Results: From 70 patients treated surgically, 68% were radically resected (R0), 26% incompletely resected (R1,2) and 6% had biopsy only. The median cause specific survival (CSS) was 132 months. All patients with localized disease (stage I and II) were completely resected and received no further therapy, whereas only 50% (15 pat) in stage III and 0% in stage IV were amenable to radical resection. 36% (25 pat) received an additional therapy (CMT): 31% (22 pat) postoperative irradiation and 4% (3 pat) combined radio-chemotherapy. The radiation

Beneficial effect of all-trans retinoic acid (ATRA) on glomerulosclerosis rats via the down-regulation of the expression of alpha-smooth muscle actin: a comparative study between ATRA and benazepril.

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Hu, Peng; Qin, Yuan Han; Pei, Juan; Lei, Feng Ying; Hu, Bo; Lu, Ling

2010-08-01

Although ATRA is a potent renoprotective agent, relatively little is known regarding the mechanisms of its action. The present study was designed to further elucidate the mechanisms of ATRA's action to GS rats and compare that with the beneficial effect of benazepril. Male SD rats weighting 160 to 200g were used in this study. GS was induced by unilateral nephrectomy and intravenous injection of adriamycin (6mg/kg). They were divided randomly 20 ones per group into GS group, GS treated with ATRA (20mg/kg/day) group, and GS treated with benazepril (10mg/kg/day) group. The other 20 ones were taken as sham-operation group, injected normal saline into caudal vein. 12weeks later, all rats were subjected to sacrifice. As expected, the GS group exhibited significant lower serum TP and Alb, and higher BUN, Cr and proteinuria than those of the sham group. Administration of ATRA or benazepril did ameliorate these above disorders of biochemical parameters in GS rats. Extensive renal damage was observed in the GS group, such as mononuclear infiltration, mesangial proliferation, focal segment glomerular sclerosis, and tubulointerstitial fibrosis. The pathological changes in both ATRA and benazepril group were alleviated remarkably. Semiquantitative GSI was used to evaluate the degree of GS in all groups. GSI was significantly higher in the GS group than in sham group. GSI decreased from 21.9+/-6.7 in the GS group to 6.9+/-2.8 in the ATRA group and 7.0+/-2.7 in benazepril group respectively. However, no significant difference in GSI between rats treated with ATRA and rats treated with benazepril was found. RT-PCR analysis revealed the renal expression of alpha-SMA mRNA was induced substantially in GS group as compared to sham group, which could be offset completely by ATRA or benazepril administration. However, expression level of alpha-SMA mRNA in GS rats treated with ATRA was identical to that in GS rats treated with benazepril. We also examined immunohistochemical staining

Expression of LRP and MDR1 in locally advanced breast cancer predicts axillary node invasion at the time of rescue mastectomy after induction chemotherapy

International Nuclear Information System (INIS)

Schneider, José; Gonzalez-Roces, Severino; Pollán, Marina; Lucas, Raul; Tejerina, Armando; Martin, Miguel; Alba, Alfonso

2001-01-01

Axillary node status after induction chemotherapy for locally advanced breast cancer has been shown on multivariate analysis to be an independent predictor of relapse. However, it has been postulated that responders to induction chemotherapy with a clinically negative axilla could be spared the burden of lymphadenectomy, because most of them will not show histological nodal invasion. P-glycoprotein expression in the rescue mastectomy specimen has finally been identified as a significant predictor of patient survival. We studied the expression of the genes encoding multidrug resistance associated protein (MDR1) and lung cancer associated resistance protein (LRP) in formalin-fixed, paraffin-embedded tumor samples from 52 patients treated for locally advanced breast cancer by means of induction chemotherapy followed by rescue mastectomy. P-glycoprotein expression was assessed by means of immunohistochemistry before treatment in 23 cases, and by means of reverse-transcriptase-mediated polymerase chain reaction (RT-PCR) after treatment in 46 (6 failed). LRP expression was detected by means of immunohistochemistry, with the LRP-56 monoclonal antibody, in 31 cases before treatment. Immunohistochemistry for detecting the expression of c-erb-B2, p53, Ki67, estrogen receptor and progesterone receptor are routinely performed in our laboratory in every case, and the results obtained were included in the study. All patients had received between two and six cycles of standard 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) chemotherapy, with two exceptions [one patient received four cycles of a docetaxel-adriamycin combination, and the other four cycles of standard cyclophosphamide-methotrexate-5-fluorouracil (CMF) polychemotherapy]. Response was assessed in accordance with the Response Evaluation Criteria In Solid Tumors (RECIST). By these, 2 patients achieved a complete clinical response, 37 a partial response, and the remaining 13 showed stable disease. This makes a

Accelerated partial breast irradiation: An analysis of variables associated with late toxicity and long-term cosmetic outcome after high-dose-rate interstitial brachytherapy

International Nuclear Information System (INIS)

Wazer, David E.; Kaufman, Seth; Cuttino, Laurie; Di Petrillo, Thomas; Arthur, Douglas W.

2006-01-01

. Suboptimal cosmetic outcome was significantly associated with the number of source dwell positions, V150, and V200 and inversely associated with DHI (0.77 vs. 0.73; p = 0.05). Late skin toxicity was rated as Grade 0, 1, or 2 in 77%, 19%, and 4% of patients, respectively. The risk of Grade 1/2 skin toxicity was significantly associated with V150 and V200 and inversely associated with DHI (0.77 vs. 0.71; p = 0.009). Late subcutaneous toxicity was rated as Grade 0, 1, 2, 3, or 4 in 55%, 15%, 12%, 5%, and 13% of patients, respectively. The risk of Grade 0/1 vs. Grade 2-4 subcutaneous toxicity was significantly associated only with a lower value of DHI (0.77 vs. 0.73; p = 0.02). To further explore factors that might contribute to the risk of fat necrosis (symptomatic or asymptomatic), a separate analysis showed that only dose hotspots as reflected in V150 and V200 were significantly associated with elevated risk. The use of adriamycin-based chemotherapy after APBI was found to be associated with a significant increase in the incidence of higher-grade skin toxicity and a higher risk of fat necrosis and suboptimal cosmetic outcome. Patient age, volume of resection, extent of axillary surgery, a history of diabetes or hypertension, and the use of tamoxifen were not found to be significantly associated with cosmetic outcome or late normal tissue complications. Conclusions: Long-term cosmetic results and the risk of late skin and subcutaneous toxicity after APBI with interstitial HDR brachytherapy can be correlated with specific treatment-related variables. These data provide dosimetric parameters that might be used to minimize the risk of normal tissue injury after APBI interstitial brachytherapy

Once vs. twice daily thoracic irradiation in limited stage small cell lung cancer

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Kim, Jun Sang; Kim, Jae Sung; Kim, Ju Ock; Kim, Sun Young; Cho, Moon June

1998-01-01

A retrospective study was conducted comparing single dally fraction (SDF) thoracic radiotherapy (TRT) with twice daily (BID) TRT to determine the potential benefit of BID TRT in limited-stage small cell lung cancer (SCLC). Endpoints of the study were response, survival, pattern of failure, and acute toxicity. Between November 1989 to December 1996, 78 patients with histologically proven limited-stage SCLC were treated at the Department of Therapeutic Radiology, Chungnam National University Hospital. Of these, 9 were irradiated for palliative intent, and 1 had recurrent disease. Remaining 68 patients were enrolled in this study. There were 26 patients with a median age of 58 years, and 22 (85%) ECOG performance score of less than 1 in SDF TRT. There were 42 patients with a median age of 57 years, and 36 (86%) ECOG performance score of less than 1 in BID TRT. By radiation fractionation regimen, there were 26 in SDF TRT and 42 in BID TRT. SDF TRT consisted of 180 cGy, 5 days a week. BID TRT consisted of 150 cGY BID, 5 days a week in 13 of 42 and 120 cGy BID, in 29 of 42. And the twice daily fractions were separated by at least 4 hours. Total radiotherapy doses were between 5040 and 6940 cGy (median, 5040 cGy) in SDF TRT and was between 4320 and 5100 cGy (median, 4560 cGy) in BID TRT. Prophylactic cranial irradiation (PCI) was recommended for patients who achieved a CR. The recommended PCI dose was 2500 cGy/10 fractions. Chemotherapy consisted of CAV (cytoxan 1000 mg/m 2 , adriamycin 40 mg/m 2 , vincristine 1 mg/m 2 ) alternating with VPP (cisplatin 60 mg/m 2 , etoposide 100 mg/m 2 ) every 3 weeks in 25 (96%) of SDF TRT and in 40 (95%) of BID TRT. Median cycle of chemotherapy was six in both group. Timing for chemotherapy was sequential in 23 of SDF TRT and in 3 BID TRT, and concurrent in 3 of SDF TRT and in 39 of BID TRT. Follow-up ranged from 2 of 99 months (median, 14 months) in both groups. Of the 26 SDF TRT, 9 (35%) achieved a complete response (CR) and 14 (54