Sample records for anthracyclines

  1. Predicting Anthracycline Benefit

    DEFF Research Database (Denmark)

    Bartlett, John M S; McConkey, Christopher C; Munro, Alison F


    as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy.......6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A-adjusted model predicted anthracycline benefit across all five...... trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). CONCLUSION: This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose...

  2. Cardiac safety of liposomal anthracyclines. (United States)

    Ewer, Michael S; Martin, Francis J; Henderson, Craig; Shapiro, Charles L; Benjamin, Robert S; Gabizon, Alberto A


    Conventional anthracyclines are active against many tumor types, but cardiotoxicity related to the cumulative dose may limit their use; this is particularly problematic for patients with risk factors for increased toxicity, for those who have received any anthracycline in the past, or for those who are to receive other cardiotoxic agents. Preclinical studies determined that encapsulating conventional anthracyclines in liposomes reduced the incidence and severity of cumulative dose-related cardiomyopathy while preserving antitumor activity. In controlled clinical trials, the risk of cardiotoxicity was significantly lower when nonpegylated liposomal doxorubicin (Myocet [NPLD]) was substituted for conventional doxorubicin, but the risk was not significantly different when NPLD was used in place of conventional epirubicin. Direct comparisons to conventional doxorubicin therapy showed comparable efficacy but significantly lower risk of cardiotoxicity with pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) therapy. Retrospective and prospective trials have not identified a maximum "cardiac safe" dose of PLD, despite use of cumulative doses exceeding 2,000 mg/m2 in some patients. Liposomal daunorubicin (DaunoXome [DNX]) may be associated with a lower risk of cardiotoxicity than conventional anthracyclines, but comparative trials are not available. With respect to combination chemotherapy, early results of clinical trials suggest that combining trastuzumab or a taxane with NPLD or PLD instead of a conventional anthracycline significantly reduces cardiotoxicity risk without reducing chemotherapeutic efficacy. Further results are eagerly awaited from ongoing controlled trials of cardiac safety with long-term liposomal anthracycline therapy, either alone or in combination with other potentially cardiotoxic agents.

  3. Comparative serum protein binding of anthracycline derivatives. (United States)

    Chassany, O; Urien, S; Claudepierre, P; Bastian, G; Tillement, J P


    The binding of doxorubicin, iododoxorubicin, daunorubicin, epirubicin, pirarubicin, zorubicin, aclarubicin, and mitoxantrone to 600 microM human serum albumin and 50 microM alpha 1-acid glycoprotein was studied by ultrafiltration at 37 degrees C and pH 7.4. Anthracycline concentrations (total and free) were determined by high-performance liquid chromatography (HPLC) with fluorometric detection. Binding to albumin (600 microM) varied from 61% (daunorubicin) to 94% (iododoxorubicin). The binding to alpha 1-acid glycoprotein (50 microM) was more variable, ranging from 31% (epirubicin) to 64% (zorubicin), and was essentially related to the hydrophobicity of the derivatives. Simulations showed that the total serum binding varied over a broad range from 71% (doxorubicin) to 96% (iododoxorubicin). We recently reported that the binding to lipoproteins of a series of eight anthracycline analogues could be ascribed to chemicophysical determinants of lipophilicity [2]. The present study was conducted to evaluate in vitro the contribution of albumin and alpha 1-acid glycoprotein to the total serum binding of these drugs.

  4. Effect of anthracyclines and isoflurane on QTc interval

    Directory of Open Access Journals (Sweden)

    A. Venugopal


    Conclusions: Anthracycline chemotherapy can produce significant prolongation of QTc interval. In addition, use of 0.5% end tidal concentration of isoflurane can further augment the QTc interval significantly.

  5. Anthracycline-induced cardiomyopathy: favourable effects of cardiac resynchronization therapy

    DEFF Research Database (Denmark)

    Ahlehoff, Ole; Galløe, Anders M; Hansen, Peter R


    We report a case of severe refractory congestive heart failure after anthracycline chemotherapy in a patient with a narrow QRS interval on the electrocardiogram and echocardiographic evidence of left ventricular dyssynchrony, where cardiac resynchronization therapy resulted in normalization of left...

  6. Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. (United States)

    Barry, Elly; Alvarez, Jorge A; Scully, Rebecca E; Miller, Tracie L; Lipshultz, Steven E


    Although effective anti-neoplastic agents, anthracyclines are limited by their well recognized and pervasive cardiotoxic effects. The incidence of late progressive cardiovascular disease in long-term survivors of cancer is established and may contribute to heart failure and death. To maximize the benefits of these drugs, a high-risk population has been identified and new strategies have been investigated to minimize toxic effects, including limiting the cumulative dose, controlling the rate of administration and using liposomal preparations and novel anthracycline analogues. Dexrazoxane also shows promise as a cardioprotectant during treatment. This paper reviews these strategies, as well as medications used to manage anthracycline-induced cardiotoxicity, and functional and biochemical means of monitoring cardiotoxicity, including echocardiography, radionuclide scans and biomarker analysis. The treatment of adult cancer survivors who have had anthracycline-related cardiotoxicity has not been systematically studied. Empirically, anthracycline-associated cardiac dysfunction is treated very similarly to other forms of heart failure. These treatments include avoiding additional cardiotoxic regimens, controlling hypertension, lifestyle changes, medications and heart transplantation.

  7. Binding of anthracycline derivatives to human serum lipoproteins. (United States)

    Chassany, O; Urien, S; Claudepierre, P; Bastian, G; Tillement, J P


    The binding of eight anthracycline analogues (including mitoxantrone) to isolated serum lipoproteins (high, low and very low density lipoproteins) was studied in order to elucidate some determinants of their interaction with lipidic structures. Serum lipoproteins were isolated by ultracentrifugation. Drug binding experiments were run by ultrafiltration at 37 degrees C and pH 7.4. Anthracycline concentrations (total and free) were determined by HPLC with fluorometric detection. All the ligands were significantly bound to the three lipoprotein classes, and for each ligand the binding increased as the lipidic fraction of lipoprotein increased. From doxorubicin to iododoxorubicin, there was a tenfold increase in lipoprotein binding (doxorubicin < mitoxantrone < epirubicin < daunorubicin < pirarubicin < aclarubicin < zorubicin < iododoxorubicin). For all the ligands studied, the extent of lipoprotein binding appears to be related to chemical determinants of lipophilicity.

  8. Spectroscopic studies of anthracyclines: Structural characterization and in vitro tracking (United States)

    Szafraniec, Ewelina; Majzner, Katarzyna; Farhane, Zeineb; Byrne, Hugh J.; Lukawska, Malgorzata; Oszczapowicz, Irena; Chlopicki, Stefan; Baranska, Malgorzata


    A broad spectroscopic characterization, using ultraviolet-visible (UV-vis) and Fourier transform infrared absorption as well as Raman scattering, of two commonly used anthracyclines antibiotics (DOX) daunorubicin (DNR), their epimers (EDOX, EDNR) and ten selected analogs is presented. The paper serves as a comprehensive spectral library of UV-vis, IR and Raman spectra of anthracyclines in the solid state and in solution. The particular advantage of Raman spectroscopy for the measurement and analysis of individual antibiotics is demonstrated. Raman spectroscopy can be used to monitor the in vitro uptake and distribution of the drug in cells, using both 488 nm and 785 nm as source wavelengths, with submicrometer spatial resolution, although the cellular accumulation of the drug is different in each case. The high information content of Raman spectra allows studies of the drug-cell interactions, and so the method seems very suitable for monitoring drug uptake and mechanisms of interaction with cellular compartments at the subcellular level.

  9. Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials. (United States)

    Alberts, David S; Muggia, Franco M; Carmichael, James; Winer, Eric P; Jahanzeb, Mohammad; Venook, Alan P; Skubitz, Keith M; Rivera, Edgardo; Sparano, Joseph A; DiBella, Nicholas J; Stewart, Simon J; Kavanagh, John J; Gabizon, Alberto A


    Preclinical studies have established the pharmacologic advantages of liposomal anthracyclines, including pharmacokinetic profiles after bolus dosing that resemble continuous infusion of conventional anthracyclines, increased drug concentrations in tumor cells compared with the surrounding tissues, and reduced toxicity relative to conventional anthracycline treatment. Based on these studies, many phase I and phase II clinical trials were conducted to assess the safety and potential activity of liposomal anthracyclines in the management of both solid and hematologic tumors. These studies provided valuable insight into the safety of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), nonpegylated liposomal doxorubicin (Myocet [NPLD]), and liposomal daunorubicin (DaunoXome [DNX]) over a range of doses, either as single-agent therapy or in combination with other cytotoxic agents. Other liposomal anthracyclines in development may be well tolerated but their activity remains to be elucidated by clinical trials. The available data also suggest that liposomal anthracyclines have activity not only against tumor types with known sensitivity to conventional anthracyclines, but also potentially for tumors that are typically anthracycline-resistant. Despite the availability of clinical data from a wide variety of tumor types and patient populations, further studies of liposomal anthracycline therapy are needed to fully establish their safety, efficacy, and dosing in the treatment of these patients.

  10. The use of liposomal anthracycline analogues for childhood malignancies: A systematic review. (United States)

    Sieswerda, E; Kremer, L C M; Caron, H N; van Dalen, E C


    In an effort to prevent or reduce anthracycline-induced cardiotoxicity, liposomal anthracyclines have been developed. The objective of this systematic review was to summarise all available evidence on the benefits and risks of liposomal anthracyclines in children with cancer. We searched databases (MEDLINE (1966-September 2009), EMBASE (1980-September 2009) and CENTRAL (The Cochrane Library, issue 3 2009)), reference lists of relevant articles and ongoing trial databases for relevant studies. Two reviewers independently performed study selection, data extraction and quality assessment of included studies. No randomised controlled trials (RCTs) or controlled clinical trials (CCTs) were found. Fifteen observational studies described the use of liposomal anthracyclines in children with cancer. Most patients had been treated extensively in the past. Some patients developed cardiotoxicity, serious allergic reactions, mucositis, infections, hematotoxicities and/or hepatotoxicity after single agent treatment. However, due to the low quality of the currently available research, it is unclear what the exact risks are. In conclusion, there is no evidence available from RCTs or CCTs about the benefits and risks of liposomal anthracyclines in children with cancer. Limited data from observational studies suggest that children treated with liposomal anthracyclines are at risk for developing cardiotoxicity and other serious toxicities. There is an urgent need for results of well-designed studies which accurately evaluate the benefits and risks of liposomal anthracyclines in children with cancer. Until high quality evidence is available, we recommend monitoring of cardiac function in childhood cancer patients treated with a liposomal anthracycline and awareness of other serious toxicities.

  11. Molecular pathogenetic mechanisms and new therapeutic perspectives in anthracycline-induced cardiomyopathy


    Distefano Giuseppe


    Abstract Anthracyclines are among the most powerful drugs for the treatment of oncologic diseases both in childhood and in adulthood. Nevertheless, their major antineoplastic efficacy can be seriously impaired by collateral toxic cardiac effects causing cardiomyopathy with chronic heart failure that is refractory to conventional medical therapy. This article reports possible subcellular molecular alterations of anthracycline-induced cardiomyopathy (reactive oxygen species formation, apoptosis...

  12. Potential genetic predisposition for anthracycline-associated cardiomyopathy in families with dilated cardiomyopathy

    NARCIS (Netherlands)

    Wasielewski, Marijke; van Spaendonck-Zwarts, Karin Y; Westerink, Nico-Derk L; Jongbloed, Jan D H; Postma, Aleida; Gietema, Jourik A; van Tintelen, J Peter; van den Berg, Maarten P


    OBJECTIVE: Anthracyclines are successfully used in cancer treatment, but their use is limited by their cardiotoxic side effects. Several risk factors for anthracycline-associated cardiomyopathy (AACM) are known, yet the occurrence of AACM in the absence of these known risk factors suggests that othe

  13. Anthracyclines and Acquired Long QT Syndrome. A Case Report

    Directory of Open Access Journals (Sweden)

    Carlos Rodríguez Armada


    Full Text Available Acquired long QT syndrome results from secondary causes and can be caused by more than 100 non-antiarrhythmic drugs. Cardiac arrest due to Torsades de pointes induced by drugs causing prolonged QT syndrome is a rare but potentially fatal event, even in hospitals. The case of a 47-year-old patient diagnosed with non-Hodgkin lymphoma admitted to the hematology department of the Dr. Gustavo Aldereguía Lima University General Hospital in Cienfuegos is presented. The patient had been previously treated with anthracyclines and developed episodes of palpitations and syncope later. The treatment included monitoring the patient, avoiding other QT prolonging agents and administrating magnesium sulfate and potassium chloride with a proper maintenance of the fluid and acid-base balance. The presentation of this case aims at motivating interest in new reports on the subject and establishing a direct causal relationship through the evidence provided by new experiences.

  14. Structure-based design of a new bisintercalating anthracycline antibiotic. (United States)

    Chaires, J B; Leng, F; Przewloka, T; Fokt, I; Ling, Y H; Perez-Soler, R; Priebe, W


    A new bisintercalating anthracycline antibiotic, WP631, has been designed and synthesized. The rational design of the new compound was based upon the geometry of monomeric anthracyclines bound to DNA oligonucleotides observed in high-resolution crystal structures. Monomeric units of daunorubicin have been linked through their reactive 3' NH2 substituents on the daunosamine moieties to form the new bisanthracycline WP631. Viscosity studies confirmed that WP631 binds to DNA by bisintercalation. Differential scanning calorimetry and UV melting experiments were used to measure the ultratight binding of WP631 to DNA. The binding constant for the interaction of WP631 with herring sperm DNA was determined to be 2.7 x 10(11) M-1 at 20 degrees C. The large, favorable binding free energy of -15.3 kcal mol-1 was found to result from a large, negative enthalpic contribution of -30.2 kcal mol-1. A molecular model was generated that shows the favorable stereochemical fit of the linker in the DNA minor groove. The cytotoxicity of WP631 was compared to that of doxorubicin using MCF-7-sensitive and MCF-7/VP-16 MRP-mediated multidrug-resistant cell lines. These initial studies showed that while WP631 is slightly less cytotoxic than doxorubicin in the sensitive cell line, it appears to overcome MRP-mediated multidrug resistance and was much more cytotoxic against the MCF-7/VP-16 cell line than was doxorubicin. The design of new potential anticancer agents based on known structural principles was found to produce a compound with significantly increased DNA binding affinity and with interesting biological activity.

  15. Anthracyclines induce double-strand DNA breaks at active gene promoters. (United States)

    Yang, Fan; Kemp, Christopher J; Henikoff, Steven


    Doxorubicin is a widely used chemotherapeutic drug that intercalates between DNA base-pairs and poisons Topoisomerase II, although the mechanistic basis for cell killing remains speculative. Doxorubicin and related anthracycline compounds have been shown to increase nucleosome turnover and/or eviction around promoters, which suggests that the resulting enhanced exposure of DNA might underlie cell killing. Previously, we showed that low doses of anthracyclines increase nucleosome turnover around active gene promoters, which suggests that loss of nucleosomes might contribute to cancer cell killing. Here we apply a genome-wide method to precisely map DNA double-strand breaks (DSBs) in cancer cells. We find that spontaneous DSBs occur preferentially around promoters of active genes, and that both anthracyclines and etoposide, a Topoisomerase II poison, increase DSBs around promoters, although CpG islands are conspicuously protected from DSBs. We propose that torsion-based enhancement of nucleosome turnover by anthracyclines exposes promoter DNA, ultimately causing DSBs around promoters.

  16. Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper

    DEFF Research Database (Denmark)

    Aapro, M; Bernard-Marty, C; Brain, E G C;


    that prolongs life or improves its quality. The risk of cardiotoxicity with conventional anthracyclines is increased by the following factors: an existing or history of heart failure or cardiac dysfunction; hypertension, diabetes and coronary artery disease; older age (independent of comorbidities......BACKGROUND: Comorbidities and risk factors likely to complicate treatment are common in elderly cancer patients. Anthracyclines remain the cornerstone of first-line therapy for non-Hodgkin's lymphoma (NHL) and metastatic and early breast cancer but can cause congestive heart failure. Elderly......, for the assessment, treatment and monitoring of elderly patients requiring anthracyclines. Results and recommendations: Use of anthracycline-based chemotherapy illustrates many of the dilemmas facing elderly cancer patients. Age in itself should not prevent access to potentially curative treatment or treatment...

  17. Luminol-potassium permanganate chemiluminescence system for the determination of three anthracycline antibiotics

    Institute of Scientific and Technical Information of China (English)


    Objective To establish a flow-injection chemiluminescence method for the determination of doxorubicin,epirubicin and mitoxantrone and study its reaction mechanism.Methods In alkaline medium,chemiluminescence of luminol-potassium permanganate system could be inhibited obviously by anthracycline antibiotics.Combined with flow-injection technique,a new chemiluminescence method for determining the anthracycline antibiotics was set up.The chemiluminescence mechanism of the luminol-potassium permanganate system w...

  18. Abnormal Myocardial Strain Indices in Children Receiving Anthracycline Chemotherapy. (United States)

    Pignatelli, Ricardo H; Ghazi, Payam; Reddy, S Chandra-Bose; Thompson, Patrick; Cui, Qiqiong; Castro, Jacqueline; Okcu, Mehmet F; Jefferies, John Lynn


    Anthracycline chemotherapy (AC) is associated with impaired left ventricular (LV) systolic function. LV ejection fraction (EF %) obtained by two-dimensional echocardiography is the current gold standard for detection and monitoring of LV systolic function. However, dependence on LVEF has been shown to be unreliable due to its inherent limitations. Speckle tracking echocardiography (STE) measures myocardial strain and is a sensitive method to detect LV systolic dysfunction with demonstrated utility in such detection in adult and pediatric cohort studies. Compare myocardial strain indices derived by STE with LVEF to detect ACT-induced LV systolic dysfunction. Prospective, cross-sectional measurements of LV myocardial strain indices derived from STE with LVEF. Pediatric cohort of 25 patients (pts): 17 females, eight males with a mean age 9.8 ± 5.8 years, who received anthracyclines (AC); median cumulative dose ≥150 ± 124.4 mg/m(2), range 60-450 mg/m(2) showing normal LV end-diastolic diameter (mm) and normal LVEF (≥55 %) underwent STE to obtain LV myocardial strain indices: strain and strain rate. The inter- and intraobserver variability for the strain indices was 5 %. Fifteen of 25 pts (60 %) showed abnormal global longitudinal peak systolic strain (GLPSS) and 19/25 pts (76 %) showed abnormal peak circumferential strain (PCS) compared to age-matched controls (p = 0.005). In contrast, no significant differences was observed in either indices with the dose of AC. Likewise, no significant changes in the systolic or diastolic strain rate were noted with the dose of AC (r (2) = 0.0076 for peak E, r (2) = 0.072 for peak A, p = NS). GLPSS and PCS were diminished and, however, correlated poorly with the cumulative dose of AC. These observations indicate an early onset of LV systolic dysfunction by the strain indices in pts who continue to show a normal LVEF implying presence of occult LV systolic dysfunction. These novel strain indices may assist in

  19. Radiation Sterilization of Anthracycline Antibiotics in Solid State

    Directory of Open Access Journals (Sweden)

    A. Kaczmarek


    Full Text Available The impact of ionizing radiation generated by a beam of electrons of 25–400 kGy on the stability of such analogs of anthracycline antibiotics as daunorubicin (DAU, doxorubicin (DOX, and epidoxorubicin (EPI was studied. Based on EPR results, it was established that unstable free radicals decay exponentially with the half-time of 4 days in DAU and DOX and 7 days in EPI after irradiation. Radiation-induced structural changes were analyzed with the use of spectrophotometric methods (UV-Vis and IR and electron microscope imaging (SEM. A chromatographic method (HPLC-DAD was applied to assess changes in the contents of the analogs in the presence of their impurities. The study showed that the structures of the analogs did not demonstrate any significant alterations at the end of the period necessary for the elimination of unstable free radicals. The separation of main substances and related substances (impurities and potential degradation products allowed determining that no statistically significant changes in the content of particular active substances occurred and that their conversion due to the presence of free radicals resulting from exposure to an irradiation of 25 kGy (prescribed to ensure sterility was not observed.

  20. Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction

    DEFF Research Database (Denmark)

    Daugaard, Gedske; Lassen, Ulrik; Bie, Peter;


    BACKGROUND: The use of anthracyclines in treatment of cancer is limited by cardiotoxicity of these compounds and may lead to heart failure. Therefore monitoring of cardiac function is necessary during therapy. AIM: We evaluated the value of natriuretic peptides (N-terminal pro-atrial natriuretic...... measurements, 19% showed a significant EF decrease (>0.10) and ended with a final EF value below 0.50. Baseline EF was no predictor of a change in EF during treatment. Neither baseline levels of N-ANP or BNP nor a change in the same variables during therapy were predictive of a change in EF. CONCLUSIONS...... peptide (N-ANP) and brain natriuretic peptide (BNP)) for monitoring and predicting anthracycline induced cardiotoxicity using radionuclide left ventricular ejection fraction (EF) measurements as reference. METHODS AND RESULTS: A total of 107 consecutive patients receiving anthracycline as part...

  1. The diagnosis of anthracycline-induced cardiac damage and heart failure

    Directory of Open Access Journals (Sweden)

    Jarosław Dudka


    Full Text Available Routine examinations during chemotherapy containing anthracyclines evaluate heart function before treatment and monitor cardiotoxic effects during and after therapy. A number of methods are useful in cardiac assessment, including electrocardiography, radiology techniques (RTG, CT, MRI, PET-CT, PET-MRI, echocardiography, radioisotope imaging techniques (scyntygraphy, MUGA, PET, and ultra-structure evaluation in biopsy samples. Nevertheless, there is a continuous need for new methods to predict future damage at the initial stages of cardiac changes. In recent years the therapeutic usefulness of biochemical blood parameters in anthracycline-treated patients has been assessed. The levels of cardiac troponines (cTnI, cTnT, natriuretic peptides (ANP, BNP, and endothelin 1 have been included in the studies. Heart-type fatty acid binding protein (H-FABP is another promising factor showing cardiomyocytic impairment. However, the clinical use of biochemical parameters in diagnosing anthracycline-related cardiotoxicity is still a controversial issue.

  2. Molecular pathogenetic mechanisms and new therapeutic perspectives in anthracycline-induced cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Distefano Giuseppe


    Full Text Available Abstract Anthracyclines are among the most powerful drugs for the treatment of oncologic diseases both in childhood and in adulthood. Nevertheless, their major antineoplastic efficacy can be seriously impaired by collateral toxic cardiac effects causing cardiomyopathy with chronic heart failure that is refractory to conventional medical therapy. This article reports possible subcellular molecular alterations of anthracycline-induced cardiomyopathy (reactive oxygen species formation, apoptosis, inflammatory signalling, altered expression of cardiomyocytes specific genes, etc and indicates some new therapeutic perspectives resulting from a better understanding of the molecular pathogenetic mechanisms.

  3. Synthesis of prodrugs of anthracyclines and evaluation of their use in selective chemotherapy

    NARCIS (Netherlands)

    Leenders, R.G.G.


    This thesis is devoted to the synthesis and biological evaluation of prodrugs of anthracycline anti-tumor antibiotics designed for use in selective chemotherapy. The severe side effects caused by conventional cancer chemotherapeutic agents arises from the lack of distinction between tumor and normal

  4. Genome Sequence of Streptomyces olindensis DAUFPE 5622, Producer of the Antitumoral Anthracycline Cosmomycin D (United States)

    Rojas, Juan D.; Starcevic, Antonio; Baranas̆ić, Damir; Ferreira-Torres, Maria A.; Contreras, Camilo A.; Garrido, Leandro M.; Araújo, Welington L.; de Souza, Robson F.; Zucko, Jurica; Hranueli, Daslav; Long, Paul F.; Cullum, John


    Streptomyces olindensis DAUFPE 5622, which was isolated from a Brazilian soil sample, produces the antitumor anthracycline cosmomycin D. The genome sequence is 9.4 Mb in length, with a G+C content of 71%. Thirty-four putative secondary metabolite biosynthetic gene clusters were identified, including the cosmomycin D cluster. PMID:24970824

  5. BNP cannot replace gated equilibrium radionuclide ventriculography in monitoring of anthracycline-induced cardiotoxity

    DEFF Research Database (Denmark)

    Vogelsang, T.W.; Jensen, R.J.; Hesse, B.;


    BACKGROUND: Cardiotoxity is a side-effect of cancer treatment with anthracycline that is currently monitored by measuring the left ventricular ejection fraction (LVEF) by gated equilibrium radionuclide ventriculography (RNV). We hypothesized that BNP measurements could replace, at least in part...

  6. Chromosome 17 centromere duplication and responsiveness to anthracycline-based neoadjuvant chemotherapy in breast cancer. (United States)

    Tibau, Ariadna; López-Vilaró, Laura; Pérez-Olabarria, Maitane; Vázquez, Tania; Pons, Cristina; Gich, Ignasi; Alonso, Carmen; Ojeda, Belén; Ramón y Cajal, Teresa; Lerma, Enrique; Barnadas, Agustí; Escuin, Daniel


    Human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) genes have been proposed as predictive biomarkers of sensitivity to anthracycline chemotherapy. Recently, chromosome 17 centromere enumeration probe (CEP17) duplication has also been associated with increased responsiveness to anthracyclines. However, reports are conflicting and none of these tumor markers can yet be considered a clinically reliable predictor of response to anthracyclines. We studied the association of TOP2A gene alterations, HER2 gene amplification, and CEP17 duplication with response to anthracycline-based neoadjuvant chemotherapy in 140 patients with operable or locally advanced breast cancer. HER2 was tested by fluorescence in situ hybridization and TOP2A and CEP17 by chromogenic in situ hybridization. Thirteen patients (9.3%) achieved pathologic complete response (pCR). HER2 amplification was present in 24 (17.5%) of the tumors. TOP2A amplification occurred in seven tumors (5.1%). CEP17 duplication was detected in 13 patients (9.5%). CEP17 duplication correlated with a higher rate of pCR [odds ratio (OR) 6.55, 95% confidence interval (95% CI) 1.25-34.29, P = .026], and analysis of TOP2A amplification showed a trend bordering on statistical significance (OR 6.97, 95% CI 0.96-50.12, P = .054). TOP2A amplification and CEP17 duplication combined were strongly associated with pCR (OR 6.71, 95% CI 1.66-27.01, P = .007). HER2 amplification did not correlate with pCR. Our results suggest that CEP17 duplication predicts pCR to primary anthracycline-based chemotherapy. CEP17 duplication, TOP2A amplifications, and HER2 amplifications were not associated with prognosis.

  7. Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer

    NARCIS (Netherlands)

    Cheuka, Daniel K. L.; Sieswerda, Elske; van Dalen, Elvira C.; Postma, Aleida; Kremer, Leontien C. M.


    Background Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not kno

  8. Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis (United States)

    Figueiredo, Nuno; Chora, Angelo; Raquel, Helena; Pejanovic, Nadja; Pereira, Pedro; Hartleben, Björn; Neves-Costa, Ana; Moita, Catarina; Pedroso, Dora; Pinto, Andreia; Marques, Sofia; Faridi, Hafeez; Costa, Paulo; Gozzelino, Raffaella; Zhao, Jimmy L.; Soares, Miguel P.; Gama-Carvalho, Margarida; Martinez, Jennifer; Zhang, Qingshuo; Döring, Gerd; Grompe, Markus; Simas, J. Pedro; Huber, Tobias B.; Baltimore, David; Gupta, Vineet; Green, Douglas R.; Ferreira, João A.; Moita, Luis F.


    Summary Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fancony Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis. PMID:24184056

  9. Exercise echocardiography in asymptomatic survivors of childhood cancer treated with anthracyclines

    DEFF Research Database (Denmark)

    Sieswerda, Elske; Kremer, Leontien C M; Vidmar, Suzanna;


    BACKGROUND: Exercise echocardiography reveals abnormalities in asymptomatic childhood cancer survivors who previously have been treated with anthracyclines. We determined the added value of monitoring childhood cancer survivors with exercise echocardiography compared to monitoring with resting...... survivors, who had undergone cardiac tests including exercise echocardiography 10.5 years earlier, for new cardiac evaluation. Each subject underwent a resting echocardiogram at both evaluations. At first evaluation a repeat echocardiogram was performed following peak exercise. Resting echocardiographic......) decreased from -0.18 to -0.93. Higher cumulative anthracycline dose was a risk factor for a lower RFSz at late follow-up (P = 0.0002). Adding exercise fractional shortening (XFS) to a model containing RFSz did not improve prediction of abnormal RFSz at late follow-up. CONCLUSIONS: Monitoring with exercise...

  10. Exercise training in childhood cancer survivors with subclinical cardiomyopathy who were treated with anthracyclines. (United States)

    Smith, Webb A; Ness, Kirsten K; Joshi, Vijaya; Hudson, Melissa M; Robison, Leslie L; Green, Daniel M


    Childhood cancer survivors (CCS) treated with anthracyclines are at risk for cardiomyopathy. This case series evaluated the response of anthracycline exposed CCS with subclinical cardiomyopathy to aerobic and strength training. Body composition, strength and cardiopulmonary fitness were evaluated before and after the 12-week intervention. All equipment and materials were provided to five 10+ year CCS (3 males, mean age 38.0 ± 3.3 years) for a guideline-based home exercise program. All five completed the study with no adverse events. Compliance with exercise was 86%. These results suggest that exercise training may improve exercise capacity of CCS with subclinical cardiomyopathy. Pediatr Blood Cancer. © 2013 Wiley Periodicals, Inc.

  11. Relation of Pre-anthracycline Serum Bilirubin Levels to Left Ventricular Ejection Fraction After Chemotherapy. (United States)

    Vera, Trinity; D'Agostino, Ralph B; Jordan, Jennifer H; Whitlock, Matthew C; Meléndez, Giselle C; Lamar, Zanetta S; Porosnicu, Mercedes; Bonkovsky, Herbert L; Poole, Leslie B; Hundley, W Gregory


    Myocardial injury because of oxidative stress manifesting through reductions in left ventricular ejection fraction (LVEF) may occur after the administration of anthracycline-based chemotherapy (A-bC). We hypothesized that bilirubin, an effective endogenous antioxidant, may attenuate the reduction in LVEF that sometimes occurs after receipt of A-bC. We identified 751 consecutively treated patients with cancer who underwent a pre-A-bC LVEF measurement, exhibited a serum total bilirubin level bilirubin and LVEF changes. The LVEF decreased by 10.7 ± 13.7%, 8.9 ± 11.8%, and 7.7 ± 11.5% in group 1 (bilirubin at baseline ≤0.5 mg/dl), group 2 (bilirubin 0.6 to 0.8 mg/dl), and group 3 (bilirubin 0.9 to 1.9 mg/dl), respectively. More group 1 patients experienced >15% decrease in LVEF compared with those in group 3 (p = 0.039). After adjusting for age, coronary artery disease/myocardial infarction, diabetes mellitus, hematocrit, and the use of cardioactive medications, higher precancer treatment bilirubin levels and lesser total anthracycline doses were associated with LVEF preservation (p = 0.047 and 0.011, respectively). In patients treated with anthracyclines who subsequently develop symptoms associated with heart failure, pre-anthracycline treatment serum bilirubin levels inversely correlate with subsequent deterioration in post-cancer treatment LVEF. In conclusion, these results suggest that increased levels of circulating serum total bilirubin, an intrinsic antioxidant, may facilitate preservation of LVEF in patients receiving A-bC for cancer.

  12. Reducing risk of Anthracycline-related heart failure after childhood cancer | Division of Cancer Prevention (United States)

    DESCRIPTION (provided by applicant): Childhood cancer survivors are at a 15-fold risk of developing heart failure (HF) compared to age-matched controls. There is a strong dose-dependent association between anthracyclines and risk of HF;the incidence approaches 20% at cumulative doses between 300-600 mg/m2, and exceeds 30% for doses >600 mg/m2. Outcome following HF is poor;5-year survival rate is |

  13. Selenium in the Prevention of Anthracycline-Induced Cardiac Toxicity in Children with Cancer

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    Nurdan Tacyildiz


    Full Text Available High cumulative doses of anthracyclines (300–500 mg/m2 used in the treatment of children with cancer may result in cardiotoxicity, a major long-term adverse effect that limits clinical usefulness of this class of chemotherapeutic agents. We assessed anthracycline-induced cardiotoxicity by measuring Pro-BNP levels and echocardiographic (ECHO findings and investigated potential protective effect of selenium (Se supplementation in a group of pediatric cancer patients. Plasma level of Pro-BNP was measured, and ECHO was performed in 67 patients (45 boys, 22 girls; ages 2–18 years; median age 12 years after they completed anthracycline-containing chemotherapy. Serum Se level was measured in 37 patients. Eleven patients had high Pro-BNP levels and/or cardiac failure with Pro-BNP levels of 10–8,022 pg/mL (median 226.3 pg/mL; laboratory normal level is less than 120 pg/mL. Serum Se levels were low (20–129 mcg/L, median 62 mcg/L in ten of these eleven patients. Eight of 10 patients with low Se and high Pro-BNP levels were supplemented with Se 100 mcg/day for a period of 4–33 months (median 6 months which resulted in improvement in Pro-BNP and/or ECHO findings. These results suggest that Se supplementation may have a role in protection against anthracycline-induced cardiac toxicity.

  14. Comparative cardiac toxicity of anthracyclines in vitro and in vivo in the mouse.

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    Stefano Toldo

    Full Text Available PURPOSE: The antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo. METHODS: The cardiomyocytes were incubated with the three anthracyclines (1 µM to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF, heart rate (HR and cardiac output (CO both prior to and 10 days after drug treatment. RESULTS: In HL-1 cells, non-pegylated liposomal-doxorubicin generated significantly less reactive oxygen species (ROS, as well as less DNA damage and apoptosis activation when compared with doxorubicin and epirubicin. Cultured breast tumor cells showed similar sensitivity to the three anthracyclines. In the healthy mouse, non-pegylated liposomal doxorubicin showed a minimal and non-significant decrease in LVEF with no change in HR or CO, compared to doxorubicin and epirubicin. CONCLUSION: This study provides evidence for reduced cardiac toxicity of non-pegylated-liposomal doxorubicin characterized by attenuation of ROS generation, DNA damage and apoptosis in comparison to epirubicin and doxorubicin.

  15. Cardiac mechanics and dysfunction with anthracyclines in the community: results from the PREDICT study (United States)

    Narayan, Hari K; Wei, Wei; Feng, Ziding; Lenihan, Daniel; Plappert, Ted; Englefield, Virginia; Fisch, Michael; Ky, Bonnie


    Background Our objective was to determine the relevance of changes in myocardial mechanics in diagnosing and predicting cancer therapeutics-related cardiac dysfunction (CTRCD) in a community-based population treated with anthracyclines. Methods Quantitative measures of cardiac mechanics were derived from 493 echocardiograms in 165 participants enrolled in the PREDICT study (A Multicenter Study in Patients Undergoing AnthRacycline-Based Chemotherapy to Assess the Effectiveness of Using Biomarkers to Detect and Identify Cardiotoxicity and Describe Treatment). Echocardiograms were obtained primarily at baseline (prior to anthracyclines), 6 and 12 months. Predictors included changes in strain; strain rate; indices of contractile function derived from the end-systolic pressure–volume relationship (end-systolic elastance (Eessb) and the left ventricular (LV) volume at an end-systolic pressure of 100 mm Hg (V100)); total arterial load (effective arterial elastance (Ea)) and ventricular–arterial coupling (Ea/Eessb). Logistic regression models determined the diagnostic and prognostic associations of changes in these measures and CTRCD, defined as a LV ejection fraction decline ≥10 to mechanics are diagnostic and predictive of cardiac dysfunction with anthracycline chemotherapy in community populations. Our findings support the non-invasive assessment of measures of myocardial mechanics more broadly in clinical practice and emphasise the role of serial assessments of these measures during and after cardiotoxic cancer therapy. Trial registration number NCT01032278; Pre-results. PMID:28123764

  16. Anthracycline resistance mediated by reductive metabolism in cancer cells: The role of aldo-keto reductase 1C3

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    Hofman, Jakub; Malcekova, Beata; Skarka, Adam; Novotna, Eva; Wsol, Vladimir, E-mail:


    Pharmacokinetic drug resistance is a serious obstacle that emerges during cancer chemotherapy. In this study, we investigated the possible role of aldo-keto reductase 1C3 (AKR1C3) in the resistance of cancer cells to anthracyclines. First, the reducing activity of AKR1C3 toward anthracyclines was tested using incubations with a purified recombinant enzyme. Furthermore, the intracellular reduction of daunorubicin and idarubicin was examined by employing the transfection of A549, HeLa, MCF7 and HCT 116 cancer cells with an AKR1C3 encoding vector. To investigate the participation of AKR1C3 in anthracycline resistance, we conducted MTT cytotoxicity assays with these cells, and observed that AKR1C3 significantly contributes to the resistance of cancer cells to daunorubicin and idarubicin, whereas this resistance was reversible by the simultaneous administration of 2′-hydroxyflavanone, a specific AKR1C3 inhibitor. In the final part of our work, we tracked the changes in AKR1C3 expression after anthracycline exposure. Interestingly, a reciprocal correlation between the extent of induction and endogenous levels of AKR1C3 was recorded in particular cell lines. Therefore, we suggest that the induction of AKR1C3 following exposure to daunorubicin and idarubicin, which seems to be dependent on endogenous AKR1C3 expression, eventually might potentiate an intrinsic resistance given by the normal expression of AKR1C3. In conclusion, our data suggest a substantial impact of AKR1C3 on the metabolism of daunorubicin and idarubicin, which affects their pharmacokinetic and pharmacodynamic behavior. In addition, we demonstrate that the reduction of daunorubicin and idarubicin, which is catalyzed by AKR1C3, contributes to the resistance of cancer cells to anthracycline treatment. - Highlights: • Metabolism of anthracyclines by AKR1C3 was studied at enzyme and cellular levels. • Anthracycline resistance mediated by AKR1C3 was demonstrated in cancer cells. • Induction of AKR1C3

  17. Remission of chronic anthracycline-induced heart failure with support from a continuous-flow left ventricular assist device. (United States)

    Khan, Nadeem; Husain, Syed Arman; Husain, Syed Iman; Khalaf, Natalia; George, Joggy; Raissi, Farshad; Segura, Ana Maria; Kar, Biswajit; Bogaev, Roberta C; Frazier, O H


    We report the case of a patient who had chronic anthracycline-induced cardiomyopathy that was reversed after treatment with a left ventricular assist device. A 29-year-old woman had undergone anthracycline-based chemotherapy as a teenager in 1991 and 1992 and received a diagnosis of dilated cardiomyopathy 10 years later. Optimal medical therapy had initially controlled the symptoms of heart failure. However, in June 2006, the symptoms worsened to New York Heart Association functional class IV status. We implanted a continuous-flow left ventricular assist device as a bridge to cardiac transplantation; of note, a left ventricular core biopsy at that time showed no replacement fibrosis. The patient's clinical status improved thereafter, enabling left ventricular assist device ex-plantation after 17 months. To our knowledge, this is the first report of the use of left ventricular assist device support to reverse chronic anthracycline-induced heart failure.

  18. [Two cases of acute promyelocytic leukemia in pregnancy and the effect of anthracyclines on fetal development]. (United States)

    Takatsuki, H; Abe, Y; Goto, T; Sadamura, S; Taguchi, F; Muta, K; Miyoshi, T; Katsuno, M; Umemura, T; Nishimura, J


    Two patients with acute promyelocytic leukemia (APL) in 2nd and 3rd trimester of pregnancy are reported on. Case 1: 38-year-old female consulted our hospital because of bleeding tendency and pancytopenia in April, 1988. She was diagnosed as having APL with disseminated intravascular coagulopathy (DIC) and was found to be in the 14th week of gestation. Combined chemotherapy (BHAC-DMP) including the total dose (440 mg) of daunorubicin (DNR) resulted in intrauterine fetal death at 19 weeks of gestation. The fetus was severely anemic and the bone marrow was hypoplastic. Case 2: A 27-year-old female was diagnosed as having APL with DIC at 29 weeks of gestation. BHAC-DMP including 440 mg DNR achieved complete remission. At 35 weeks of gestation, she delivered a normal infant by Caesarean section. The child had normal hematological findings and showed normal growth. Both cases developed APL accompanied by DIC during pregnancy and were treated with a similar regimen including high dose of anthracyclines. Case 2 treated in the late period of gestation delivered a normal infant, while fetal death resulted in case 1, treated in the early period of gestation. We reviewed the literature regarding chemotherapy using anthracyclines during pregnancy.

  19. The integration of anthracyclines in the treatment of advanced ovarian cancer. (United States)

    Lück, H J; Du Bois, A; Weber, B; Pfisterer, J; Goupil, A; Kuhn, W; Barats, J C; Blohmer, J; Mousseau, M; Schröder, W; Meier, W; Möbus, V; Richter, B


    Since the publication of the Gynecologic Oncology Group (GOG) protocol 111 in 1996, and the results of the Arbeitgemeinschaft Gyna kologische Onkologie (AGO) trial Ovar-3 and the GOG protocol 158, the combination of platinum and paclitaxel has been adopted as the standard therapy in advanced ovarian cancer. One option for achieving further progress in the first-line treatment of advanced ovarian cancer might be the addition of noncross-resistant drugs to the two-drug regimen. Meta-analysis showed a survival benefit for platinum-anthracycline based combinations as compared to platinum-based combinations without anthracyclines. An AGO phase I/II trial compared epirubicin in combination with carboplatin and paclitaxel in untreated patients with gynecological malignancies. Based on the results of this study a randomized phase III trial together with the French GINECO group was conducted. The trial started 11/97 and was closed 11/99. All 1281 patients were randomized. Currently, 1132 end-of-therapy reports have been issued. Nine hundred eighty nine (87%) patients completed six cycles of treatment. Treatment and toxicity data are available for these patients. Three hundred thirty five patients had a measurable residual tumor after initial debulking surgery. Response data of 228 patients (111 ET-Carbo, 117 Carbo-T) are available.

  20. Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer

    NARCIS (Netherlands)

    Piccart-Gebhart, Martine J.; Burzykowski, Tomasz; Buyse, Marc; Sledge, George; Carmichael, James; Lueck, Hans-Joachim; Mackey, John R.; Nabholtz, Jean-Marc; Paridaens, Robert; Biganzoli, Laura; Jassem, Jacek; Bontenbal, Marijke; Bonneterre, Jacques; Chan, Stephen; Basaran, Gul Atalay; Therasse, Patrick


    Purpose Taxanes (paclitaxel or docetaxel) have been sequenced or combined with anthracyclines (doxorubicin or epirubicin) for the first-line treatment of advanced breast cancer. This meta-analysis uses data from all relevant trials to detect any advantages of taxanes in terms of tumor response, prog

  1. Cardiotoxicity of anthracycline agents for the treatment of cancer: Systematic review and meta-analysis of randomised controlled trials

    Directory of Open Access Journals (Sweden)

    Verrill Mark


    Full Text Available Abstract Background We conducted a systematic review and meta-analysis to clarify the risk of early and late cardiotoxicity of anthracycline agents in patients treated for breast or ovarian cancer, lymphoma, myeloma or sarcoma. Methods Randomized controlled trials were sought using comprehensive searches of electronic databases in June 2008. Reference lists of retrieved articles were also scanned for additional articles. Outcomes investigated were early or late clinical and sub-clinical cardiotoxicity. Trial quality was assessed, and data were pooled through meta-analysis where appropriate. Results Fifty-five published RCTs were included; the majority were on women with advanced breast cancer. A significantly greater risk of clinical cardiotoxicity was found with anthracycline compared with non-anthracycline regimens (OR 5.43 95% confidence interval: 2.34, 12.62, anthracycline versus mitoxantrone (OR 2.88 95% confidence interval: 1.29, 6.44, and bolus versus continuous anthracycline infusions (OR 4.13 95% confidence interval: 1.75, 9.72. Risk of clinical cardiotoxicity was significantly lower with epirubicin versus doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78, liposomal versus non-liposomal doxorubicin (OR 0.18 95% confidence interval: 0.08, 0.38 and with a concomitant cardioprotective agent (OR 0.21 95% confidence interval: 0.13, 0.33. No statistical heterogeneity was found for these pooled analyses. A similar pattern of results were found for subclinical cardiotoxicity; with risk significantly greater with anthracycline containing regimens and bolus administration; and significantly lower risk with epirubicin, liposomal doxorubicin versus doxorubicin but not epirubicin, and with concomitant use of a cardioprotective agent. Low to moderate statistical heterogeneity was found for two of the five pooled analyses, perhaps due to the different criteria used for reduction in Left Ventricular Ejection Fraction. Meta-analyses of any

  2. The prognostic and predictive power of redox protein expression for anthracycline-based chemotherapy response in locally advanced breast cancer (United States)

    Woolston, Caroline M; Zhang, Lei; Storr, Sarah J; Al-Attar, Ahmad; Shehata, Mohamed; Ellis, Ian O; Chan, Stephen Y; Martin, Stewart G


    Neoadjuvant chemotherapy has become the standard of care for locally advanced primary breast cancer. Anthracycline-based regimens have proven to be one of the most effective treatments in this setting. As certain cytotoxic antineoplastic agents, such as anthracyclines, generate reactive oxygen species as a by-product of their mechanism of action, we examined whether redox protein expression was involved in the response to anthracycline-based chemotherapy and with clinical outcome. Pre-treatment needle core biopsy and post-anthracycline treatment tumour sections were analysed from 98 cases. In all, 32 individuals had a complete clinical response and 17 had a complete pathological response. Immunohistochemical staining was performed for eight redox proteins: thioredoxin, thioredoxin reductase, thioredoxin interacting protein (TxNIP), glutathione S-transferase (GST) π, θ and α, catalase and manganese superoxide dismutase. GST π (P=0.05) and catalase (P=0.045) were associated with pathological complete response in pre-chemotherapy samples. TxNIP (P=0.017) and thioredoxin reductase (P=0.022) were independent prognostic factors for distant metastasis-free survival and TxNIP for overall survival (P=0.014). In oestrogen receptor negative patients that are known to have a poor overall survival, a considerably worse prognosis was seen in cases that exhibited low expression of TxNIP (P=0.000003), stratifying patients into more defined groups. This study indicates the importance of redox regulation in determining breast cancer response to anthracycline-based chemotherapy and provides ways of further stratifying pre-chemotherapy patients to potentially allow more tailored treatments. PMID:22481283

  3. 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.

  4. Atrial Function in Patients with Breast Cancer After Treatment with Anthracyclines (United States)

    Yaylali, Yalin Tolga; Saricopur, Ahmet; Yurtdas, Mustafa; Senol, Hande; Gokoz-Dogu, Gamze


    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. PMID:27812678

  5. In vitro antileukemic effect of a new anthracycline analogue, MEN 11079

    DEFF Research Database (Denmark)

    Biscardi, Monica; Caporale, Roberto; Pagliai, Gabriella


    The biological activity of MEN 11079, a new daunorubucin analogue with a fluorine atom in C(8) of ring A, was investigated in the human leukemic cell lines K-562 and in mononuclear cells (MNCs) of 40 patients with acute myeloid leukemia (AML) and the activity compared to two well.......002-0.670 microM for MEN 11079, in the MNCs. Therefore, the latter appeared to assure a smaller variability of response in the AML cells. Apoptosis assays (performed using Annexin-V assay and propidium iodide) and cell cycle studies demonstrated that the MEN 11079 effective concentration was 10-fold lower than...... the DOXO and IDA ones. MDR (Pgp and MRP1 proteins), as measured by semiquantitative RT-PCR, cytofluorimetric and functional analysis of proteins, was similarly elicited by IDA and MEN 11079. In conclusion, the response of the cells to the new anthracycline indicates that there is greater cytotoxic activity...

  6. Immunological cross-reactivities of various anthracycline antibiotics against aclacinomycin A antisera. (United States)

    Matsuzawa, Y; Kiyosaki, T; Yoshimoto, A; Ishikura, T; Takeuchi, T; Umezawa, H


    Aclacinomycin A (ACM) antisera were obtained from the rabbits immunized with 4"'-deoxo-4"'-(R)-amino-ACM- or N,N-didemethyl-ACM-bovine serum albumin conjugate, and their immunoreactivities were tested with ACM-related anthracyclines. It was found that the binding ability with the ACM antisera was markedly decreased by the following structural changes in ACM: N,N-didemethylation of the rhodosamine moiety; 6-O- or 4-O-methylation; removal of the methoxycarbonyl group at C-10; hydroxylation at C-1, C-2 or C-11. It was less affected by some alterations in a side chain at C-9 or by deglycosidation of the terminal mono or disaccharide. The binding of the aglycone (aklavinone) was very weak.

  7. Utility of high-sensitivity cardiac troponin T in patients receiving anthracycline chemotherapy

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    Blaes AH


    Full Text Available Anne H Blaes,1 Aamer Rehman,2 David M Vock,3,4 Xianghua Luo,3,4 Mark Menge,5 Douglas Yee,3 Emil Missov,6 Daniel Duprez6 1Division of Hematology/Oncology/Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, 2Division of Cardiology, University of Louisville, Louisville, KY, 3Masonic Cancer Center, 4Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, 5Park Nicollet Frauenshuh Cancer Center, St Louis Park, 6Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, MN, USA Background: Anthracycline chemotherapy remains an integral part of the care for curative intent chemotherapy in breast cancer and non-Hodgkin lymphoma patients. Better tools need to be identified to predict cardiac complications of anthracycline chemotherapy. Materials and methods: We investigated the utility of high-sensitivity cardiac troponin T (hscTnT, N-terminal pro-B-type natriuretic peptide, cardiac troponin T and I, and creatine kinase (CK-MB in cancer patients receiving anthracycline-based chemotherapy, in order to determine whether baseline levels or changes in these biomarkers may help predict the onset of congestive heart failure. Results: Eighteen consecutive patients with a pathologic diagnosis of breast cancer or non-Hodgkin lymphoma were enrolled. The median dose of doxorubicin exposure was 240 mg/m2 (range 240–400 mg/m2. After treatment with doxorubicin, the hscTnT increased to 19.1 pg/mL (P<0.001. CKMB and N-terminal pro-B-type natriuretic peptide levels increased to 1.1 ng/mL and 88.3 pg/mL, respectively (P=0.02. When subjects who had a decline in left ventricular ejection fraction (LVEF by equilibrium radionuclide ventriculography were compared to those who did not have a change in LVEF, there was a suggestion that those subjects with an elevated baseline hscTnT were more likely to have a decline in LVEF (2.7 pg/mL and 0.1 pg/mL, respectively; P=0.07. Spearman

  8. Phase II study of pegylated liposomal doxorubicin plus vinorelbine in breast cancer with previous anthracycline exposure. (United States)

    Martin, Miguel; García-Donas, Jesus; Casado, Antonio; de la Gándara, Isabel; Pérez-Segura, Pedro; García-Saenz, Jose-Angel; Ibáñez, Gabriel; Loboff, Belen; García-Ledo, Gemma; Moreno, Fernando; Grande, Enrique; Diaz-Rubio, Eduardo


    Thirty-five patients with metastatic breast cancer (MBC) entered a phase II study of pegylated liposomal doxorubicin 35 mg/m2 intravenously (i.v.) on day 1 plus vinorelbine 30 mg/m2 i.v. on day 1 every 4 weeks. Patients were required to have measurable disease, previous chemotherapy with an anthracycline-containing regimen, and a normal left ventricular ejection fraction (LVEF). Thirty-four patients were assessable for response and toxicity. The overall response rate (on an intent-to-treat basis) was 35% (12 of 34; 95% CI, 20%-54%). One complete response and 11 partial responses were noted. In addition, 14 patients (41%) had stable disease of > 4 months duration, and 7 patients (20.5%) had disease progression. The response rates to the combination when it was used as first- and second-line chemotherapy were 31% (4 of 13) and 38% (8 of 21), respectively. Median time to disease progression was 7 months (range, 1-35 months) and median overall survival was 13 months (range, 2 to > 62 months). Neutropenia was the most frequent toxicity (grade 4 in 44% of patients and 19% of cycles), but neutropenic fever was seen in only 3 cases. No septic deaths occurred. Nonhematologic grade 3 side effects included skin toxicity (palmar-plantar erythrodysesthesia syndrome, 6%) and mucositis (15%). Late alopecia was seen in 53% of patients (grade 1 in 41%, and grade 2 in 12%). The median LVEFs were 64% (range, 50%-81%) at baseline and 62% (range, 37%-70%) after treatment. Three patients presented an LVEF decrease to < 50%; however, no clinical heart failure was noted, and 2 of these patients recovered normal values after cessation of therapy. The combination of pegylated liposomal doxorubicin and vinorelbine can be safely administered to patients with anthracycline-pretreated MBC and is active in this population.

  9. A murine experimental anthracycline extravasation model: pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage

    DEFF Research Database (Denmark)

    Thougaard, Annemette V; Langer, Seppo W; Hainau, Bo;


    The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found...

  10. CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children’s Oncology Group Genome-Wide Association Study (United States)

    Wang, Xuexia; Sun, Can-Lan; Quiñones-Lombraña, Adolfo; Singh, Purnima; Landier, Wendy; Hageman, Lindsey; Mather, Molly; Rotter, Jerome I.; Taylor, Kent D.; Chen, Yii-Der Ida; Armenian, Saro H.; Winick, Naomi; Ginsberg, Jill P.; Neglia, Joseph P.; Oeffinger, Kevin C.; Castellino, Sharon M.; Dreyer, Zoann E.; Hudson, Melissa M.; Robison, Leslie L.; Blanco, Javier G.


    Purpose Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests that genetic susceptibility could play a role. The current study uses an agnostic approach to identify genetic variants that could modify cardiomyopathy risk. Methods A genome-wide association study was conducted in childhood cancer survivors with and without cardiomyopathy (cases and controls, respectively). Single-nucleotide polymorphisms (SNPs) that surpassed a prespecified threshold for statistical significance were independently replicated. The possible mechanistic significance of validated SNP(s) was sought by using healthy heart samples. Results No SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10−5). Multivariable analyses adjusted for age at cancer diagnosis, sex, anthracycline dose, and chest radiation revealed that, among patients with the A allele, cardiomyopathy was infrequent and not dose related. However, among those exposed to greater than 300 mg/m2 of anthracyclines, the rs1786814 GG genotype conferred a 10.2-fold (95% CI, 3.8- to 27.3-fold; P < .001) increased risk of cardiomyopathy compared with those who had GA/AA genotypes and anthracycline exposure of 300 mg/m2 or less. This gene-environment interaction was successfully replicated in an independent set of anthracycline-related cardiomyopathy. CUG-BP and ETR-3-like factor proteins control developmentally regulated splicing of TNNT2, the gene that encodes for cardiac troponin T (cTnT), a biomarker of myocardial injury. Coexistence of more than one cTnT variant results in a temporally split myofilament response to calcium, which causes decreased contractility. Analysis of TNNT2 splicing variants in healthy human hearts suggested an association between the rs1786814 GG genotype and coexistence of more than one TNNT2 splicing variant (90.5% GG v 41.7% GA

  11. Clinical Implications of HER-2 and P53 in Taxane-Based and Anthracycline-Based Neoadjuvant Chemotherapy in Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    Xiaolan Wang; Fan Yao; Nan Liu; Yunfei Wu; Xinyu Zheng; Jiguang Li; Caigang Liu; Xueshan Qiu; Feng Jin


    OBTECTIVE To evaluate the predictive value of human epidermal growth factor receptor-2(HER-2)and P53 in taxane-based and anthracycline-based neoadjuvant chemotherapy(NAC)in breast cancer. METHODS Sixty-two patients with breast cancer were included in this study. Twenty-two patients were treated with taxane-based(taxane group) and 40 with anthracycline-based(anthracycline group).ER,PR,c-erbB2 and P53 were detected by immunohistochemistry staining before NAC, and Fluorescence In Situ Hybridization(FISH)was used to detect the HER-2 gene amplification for the cases with the expression of c-erbB2 protein as(++)or(+++).The efficacy of the regimens was evaluated after NAC. RESULTS In the anthracycline group, objective response(OR)was observed in 30 out of 40 patients(75%),whereas no response(NR)was observed in 10 patients(25%).In the taxane group, OR was observed in 15 patients out of 22 patients(68.2%), whereas NR was observed in 7 patients(31.8%).HER-2-negative status was correlated with a high OR in both taxane-based and anthracycline-based NAC(P=0.023 and P=0.029),whereas P53-negative status was correlated with high OR rate in anthracycline-based NAC(P=0.041).The significant difference of the CR rates was observed between the patients took<4 cycles and≥4 cycles NAC (4.65%vs.21.05%,P<0.05).CONCLUSION The patients with HER-2 gene non-amplication may be sensitive to both taxane-based and anthracycline-based chemotherapy; the patients without P53 overexpression may suitable to select anthracycline-based chemotherapy; and proper increased NAC cycles may increase CR rates.

  12. Moving forward with new data and approaches: a fresh look at anthracyclines in non-Hodgkin’s lymphoma

    Directory of Open Access Journals (Sweden)

    Dino Amadori


    Full Text Available Anthracyclines have a central role in the management of non-Hodgkin’s lymphoma (NHL. The cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP treatment regimen has been the standard of care for more than 20 years. Further improvements have been made to the efficacy of this chemotherapy by reducing the dosing interval and adding rituximab to the regimen. A major limitation to the use of anthracyclines is the development of cardiotoxicity as a late adverse event. Strategies to reduce cardiac events include changes to the dosing schedule for doxorubicin, use of the chelating agent dexrazoxane and the use of liposome-encapsulated doxorubicin. This latter strategy has demonstrated good efficacy and reduced cardiotoxicity in patients with NHL, including those at risk of developing cardiac effects.

  13. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. (United States)

    Gewirtz, D A


    The mechanisms responsible for the antiproliferative and cytotoxic effects of the anthracycline antibiotics doxorubicin (Adriamycin) and daunorubicin (daunomycin) have been the subject of considerable controversy. This commentary addresses the potential role of DNA synthesis inhibition, free radical formation and lipid peroxidation, DNA binding and alkylation, DNA cross-linking, interference with DNA strand separation and helicase activity, direct membrane effects, and the initiation of DNA damage via the inhibition of topoisomerase II in the interaction of these drugs with the tumor cell. One premise underlying this analysis is that only studies utilizing drug concentrations that reflect the plasma levels in the patient after either bolus administration or continuous infusion are considered to reflect the basis for drug action in the clinic. The role of free radicals in anthracycline cardiotoxicity is also discussed.

  14. Incidence of Chemotherapy-Induced Amenorrhea After Adjuvant Chemotherapy With Taxane and Anthracyclines in Young Patients With Breast Cancer



    Background Chemotherapy-induced amenorrhea is one of long term side effects of adjuvant chemotherapy in patients with breast cancer which may interfere with their future reproductive function. Although amenorrhea is well recognized, the actual incidence following taxanes remains uncertain. Methods In a cross sectional study, we identified breast cancer patients aged 45 years or younger who were treated with adjuvant anthracycline and taxane-based regimens at three different oncology departmen...

  15. HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data

    DEFF Research Database (Denmark)

    Di Leo, Angelo; Desmedt, Christine; Bartlett, John M S


    Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer.......Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer....

  16. Development of an analytical method for the determination of anthracyclines in hospital effluents. (United States)

    Mahnik, Susanne N; Rizovski, Blanka; Fuerhacker, Maria; Mader, Robert M


    Little is known about the fate of cytostatics after their elimination from humans into the environment. Being often very toxic compounds, their quantification in hospital effluents may be necessary to individualise the putative magnitude of pollution problems. We therefore developed a method for the determination of the very important group of anthracyclines (doxorubicin, epirubicin, and daunorubicin) in hospital effluents. Waste water samples were enriched by solid phase extraction (concentration factor 100), analysed by reversed-phase high performance liquid chromatography (RP-HPLC), and monitored by fluorescence detection. This method is reproducible and accurate within a range of 0.1-5 micro g l(-1) for all compounds (limits of quantification: 0.26-0.29 micro g l(-1) ; recoveries >80%). The applicability of the method was proven by chemical analysis of hospital sewage samples (range: 0.1-1.4 micro g l(-1) epirubicin and 0.1-0.5 micro g l(-1) doxorubicin). Obtained over a time period of one month, the results were in line with those calculated by an input-output model. These investigations show that the examined cytostatics are easily detectable and that the presented method is suitable to estimate the dimension of pharmaceutical contamination originating from hospital effluents.

  17. Docetaxel does not impair cardiac autonomic function in breast cancer patients previously treated with anthracyclines. (United States)

    Ekholm, Eeva; Rantanen, Virpi; Syvänen, Kari; Jalonen, Jarmo; Antila, Kari; Salminen, Eeva


    The effects of docetaxel treatment on autonomic cardiac function was studied with 24-h ECG recordings in breast cancer patients pretreated with anthracyclines. Twenty-four women were evaluated before docetaxel treatment and after 3-4 courses of docetaxel 100 mg/m(2). The heart rate, cardiac extrasystoles and heart rate variability (HRV) in both the time and frequency domain were assessed from 24-h ECG recordings. The acute effects of docetaxel were calculated from 1-h recordings immediately prior to, during and after infusion. Long-term effects were evaluated from 24-h recordings performed before treatment and after 3-4 courses of docetaxel. There was no increase in the number of cardiac extrasystoles during docetaxel infusion. The number of ventricular extrasystoles decreased from 14 (23) to 7 (14) during and 5 (10) after the first infusion (p=0.02). The heart rate, HRV and extrasystoles were similar before and after 3-4 courses of docetaxel. The treatment did not abolish circadian variability of the heart rate. Docetaxel did not deteriorate autonomic cardiac function. In conclusion, our findings suggest that docetaxel does not have harmful cumulative effects on autonomic control of the heart and is therefore unlikely to be cardiotoxic.

  18. The roots of modern oncology: from discovery of new antitumor anthracyclines to their clinical use. (United States)

    Cassinelli, Giuseppe


    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.

  19. The role of anthracyclines in second-line therapy of ovarian cancer. (United States)

    Vermorken, J B


    Anthracyclines (ANTs) have been in clinical practice since the 1960s and represent one of the most commonly used classes of anticancer drugs. In the 1990s, meta-analyses showed a favorable impact of doxorubicin (DOX/A) on the survival of patients with advanced ovarian cancer, when it was combined with cyclophosphamide and cisplatin (CAP) and compared to CP alone. With the acceptance of paclitaxel-carboplatin (TCb) as the new reference arm for first-line treatment, testing the addition of ANTs to TCb seems a logic next step. Trials presently testing this, make use of either epirubicin (EPI) or pegylated liposomal doxorubicin (PLD: Doxil(R)/Caelyx(R)). These are the two most favorable ANTs, based on data obtained with various ANTs in ovarian cancer failing platinum-based chemotherapy. EPI has not been evaluated in direct comparison with other antineoplastic agents. PLD has been compared with both paclitaxel and topotecan. No difference in efficacy parameters could be observed, but the toxicity profile of PLD scored favorably against those of the comparator in both trials, despite the fact that palmar-plantar erythrodysesthesia can be troublesome, and sometimes lead to treatment discontinuation. Data from four randomized trials evaluating the role of ANT combinations in patients with relapsed ovarian cancer suggest that the addition of EPI or DOX to paclitaxel does not lead to better outcomes in patients with platinum- refractory or resistant disease. In platinum-sensitive disease, any benefit of EPI-platinum or DOX-platinum combinations over platinum alone is uncertain. There are no randomized trials with PLD combinations in the second-line setting. It is concluded that both EPI and PLD can be recommended as a reasonable single-agent treatment option for relapsed patients, with a preference for PLD taking into account its more favorable toxicity profile.

  20. Divergent evolution of an atypical S-adenosyl-l-methionine-dependent monooxygenase involved in anthracycline biosynthesis. (United States)

    Grocholski, Thadée; Dinis, Pedro; Niiranen, Laila; Niemi, Jarmo; Metsä-Ketelä, Mikko


    Bacterial secondary metabolic pathways are responsible for the biosynthesis of thousands of bioactive natural products. Many enzymes residing in these pathways have evolved to catalyze unusual chemical transformations, which is facilitated by an evolutionary pressure promoting chemical diversity. Such divergent enzyme evolution has been observed in S-adenosyl-L-methionine (SAM)-dependent methyltransferases involved in the biosynthesis of anthracycline anticancer antibiotics; whereas DnrK from the daunorubicin pathway is a canonical 4-O-methyltransferase, the closely related RdmB (52% sequence identity) from the rhodomycin pathways is an atypical 10-hydroxylase that requires SAM, a thiol reducing agent, and molecular oxygen for activity. Here, we have used extensive chimeragenesis to gain insight into the functional differentiation of RdmB and show that insertion of a single serine residue to DnrK is sufficient for introduction of the monooxygenation activity. The crystal structure of DnrK-Ser in complex with aclacinomycin T and S-adenosyl-L-homocysteine refined to 1.9-Å resolution revealed that the inserted serine S297 resides in an α-helical segment adjacent to the substrate, but in a manner where the side chain points away from the active site. Further experimental work indicated that the shift in activity is mediated by rotation of a preceding phenylalanine F296 toward the active site, which blocks a channel to the surface of the protein that is present in native DnrK. The channel is also closed in RdmB and may be important for monooxygenation in a solvent-free environment. Finally, we postulate that the hydroxylation ability of RdmB originates from a previously undetected 10-decarboxylation activity of DnrK.

  1. A murine experimental anthracycline extravasation model: pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage

    DEFF Research Database (Denmark)


    The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found...... with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we...... tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe(2+) complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity...

  2. Complementation of the Yeast Model System Reveals that Caenorhabditis elegans OCT-1 Is a Functional Transporter of Anthracyclines.

    Directory of Open Access Journals (Sweden)

    Nicolas Brosseau

    Full Text Available The yeast plasma membrane protein Agp2 belongs to the family of amino acid transporters. It acts as a regulator that controls the expression of several uptake transporter genes such as DUR3 and SAM3 encoding two high-affinity polyamine permeases. agp2Δ mutants display extreme resistance to several cationic compounds including polyamines, the anticancer agent bleomycin, and cationic antifungal peptides. We propose that Agp2 might be involved in regulating the uptake of other cationic anticancer drugs. To date, an uptake transporter has not been reported for anthracyclines, a family of chemotherapeutic agents that are used for treating adult patients with acute myeloid leukemia. Herein, we develop assay conditions to monitor the uptake of the anthracycline doxorubicin into yeast cells and demonstrate for the first time that Agp2 is required for the drug uptake. Deletion of both the DUR3 and SAM3 genes reduced doxorubicin uptake, but not the deletion of either gene alone, while the agp2Δ mutant was severely compromised, suggesting that Agp2 controls the drug uptake via Dur3 and Sam3 and at least one additional transporter. Overexpression of DUR3 or SAM3 from the endogenous promoter rescued doxorubicin uptake into the sam3Δdur3Δ double mutant, consistent with a role for these transporters in the uptake of anthracyclines. We further show by cross-species complementation analysis that expression of the Caenorhabditis elegans oct-1 gene encoding an organic cation transporter restored full doxorubicin uptake in the agp2Δ mutant. Four separate variants of CeOCT-1 derived by substituting the amino acid residues Gln15, Cys31, Gln109 and Lys300 with alanine were stably expressed, but did not mediate doxorubicin uptake into the agp2Δ mutant. Moreover, we show that overexpression of CeOCT-1 sensitized parent yeast cells to doxorubicin, suggesting that CeOCT-1 related members might be key transporters to facilitate entry of anthracyclines into human

  3. Complementation of the Yeast Model System Reveals that Caenorhabditis elegans OCT-1 Is a Functional Transporter of Anthracyclines. (United States)

    Brosseau, Nicolas; Andreev, Emil; Ramotar, Dindial


    The yeast plasma membrane protein Agp2 belongs to the family of amino acid transporters. It acts as a regulator that controls the expression of several uptake transporter genes such as DUR3 and SAM3 encoding two high-affinity polyamine permeases. agp2Δ mutants display extreme resistance to several cationic compounds including polyamines, the anticancer agent bleomycin, and cationic antifungal peptides. We propose that Agp2 might be involved in regulating the uptake of other cationic anticancer drugs. To date, an uptake transporter has not been reported for anthracyclines, a family of chemotherapeutic agents that are used for treating adult patients with acute myeloid leukemia. Herein, we develop assay conditions to monitor the uptake of the anthracycline doxorubicin into yeast cells and demonstrate for the first time that Agp2 is required for the drug uptake. Deletion of both the DUR3 and SAM3 genes reduced doxorubicin uptake, but not the deletion of either gene alone, while the agp2Δ mutant was severely compromised, suggesting that Agp2 controls the drug uptake via Dur3 and Sam3 and at least one additional transporter. Overexpression of DUR3 or SAM3 from the endogenous promoter rescued doxorubicin uptake into the sam3Δdur3Δ double mutant, consistent with a role for these transporters in the uptake of anthracyclines. We further show by cross-species complementation analysis that expression of the Caenorhabditis elegans oct-1 gene encoding an organic cation transporter restored full doxorubicin uptake in the agp2Δ mutant. Four separate variants of CeOCT-1 derived by substituting the amino acid residues Gln15, Cys31, Gln109 and Lys300 with alanine were stably expressed, but did not mediate doxorubicin uptake into the agp2Δ mutant. Moreover, we show that overexpression of CeOCT-1 sensitized parent yeast cells to doxorubicin, suggesting that CeOCT-1 related members might be key transporters to facilitate entry of anthracyclines into human cells.

  4. Low expression of BMPRIB indicates poor prognosis of breast cancer and is insensitive to taxane-anthracycline chemotherapy. (United States)

    Dai, Kun; Qin, Fengxia; Zhang, Huikun; Liu, Xiaoli; Guo, Caixia; Zhang, Ming; Gu, Feng; Fu, Li; Ma, Yongjie


    Bone morphogenetic protein receptor type IB (BMPRIB) is one osteogenesis factor, which function in breast cancer has been rarely explored until recently. In the clinical study presented here, involving a cohort of 368 invasive ductal carcinoma (IDC) patients, we identified that patients with low expression of BMPRIB exhibited poor prognosis, especially in the luminal B subtype. We also provided the first piece of evidence that low level of BMPRIB was a promoting factor for breast cancer patients to develop bone metastasis, but not lung, liver or brain. The first of its kind, we reported that patients with high expression of BMPRIB exhibited favorable prognosis by a retrospective analysis consisting of 168 patients treated with TE (taxane and anthracycline) regimens. And the patients with high expression of BMPRIB were more sensitive to TE regimens in the detection of 32 paired pre-neoadjuvant and post-neoadjuvant specimens. Overall, our study concluded that low expression of BMPRIB indicated poor prognosis of breast cancer and was insensitive to taxane-anthracycline chemotherapy. Our findings also lay a foundation to help clinicians improve identification of patients for TE regimens by BMPRIB in the era of precision medicine.

  5. Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study

    NARCIS (Netherlands)

    Mavinkurve-Groothuis, A.M.C.; Marcus, K.A.; Pourier, M.; Loonen, J.; Feuth, T.; Hoogerbrugge, P.M.; Korte, C.L. de; Kapusta, L.


    AIMS: The aim of this study was to investigate myocardial 2D strain echocardiography and cardiac biomarkers in the assessment of cardiac function in children with acute lymphoblastic leukaemia (ALL) during and shortly after treatment with anthracyclines. METHODS AND RESULTS: Cardiac function of 60 c

  6. Long-term cardiac follow-up of children treated with anthracycline doses of 300 mg/m2 or less for acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Rathe, Mathias; Carlsen, Niels Lauritz Torp; Oxhøj, Henrik;


    The cardiotoxic effect of anthracyclines has been well described for moderate to high cumulative doses (>350 mg/m(2)). However, the question of whether sub-clinical signs of cardiomyopathy may develop and progress over time in children receiving doses of...

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

    Directory of Open Access Journals (Sweden)

    Aramita Saha


    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

  8. Redox biotransformation and delivery of anthracycline anticancer antibiotics: How interpretable structure-activity relationships of lethality using electrophilicity and the London formula for dispersion interaction work. (United States)

    Pang, Siu-Kwong


    Quantum chemical methods and molecular mechanics approaches face a lot of challenges in drug metabolism study because of their either insufficient accuracy or huge computational cost, or lack of clear molecular level pictures for building computational models. Low-cost QSAR methods can often be carried out even though molecular level pictures are not well defined; however, they show difficulty in identifying the mechanisms of drug metabolism and delineating the effects of chemical structures on drug toxicity because a certain amount of molecular descriptors are difficult to be interpreted. In order to make a breakthrough, it was proposed that mechanistically interpretable molecular descriptors were used to correlate with biological activity to establish structure-activity plots. The mechanistically interpretable molecular descriptors used in this study include electrophilicity and the mathematical function in the London formula for dispersion interaction, and they were calculated using quantum chemical methods. The biological activity is the lethality of anthracycline anticancer antibiotics denoted as log LD50, which were obtained by intraperitoneal injection into mice. The results reveal that the plots for electrophilicity, which can be interpreted as redox reactivity of anthracyclines, can describe oxidative degradation for detoxification and reductive bioactivation for toxicity induction. The plots for the dispersion interaction function, which represent the attraction between anthracyclines and biomolecules, can describe efflux from and influx into target cells of toxicity. The plots can also identify three structural scaffolds of anthracyclines that have different metabolic pathways, resulting in their different toxicity behavior. This structure-dependent toxicity behavior revealed in the plots can provide perspectives on design of anthracycline anticancer antibiotics.

  9. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial

    DEFF Research Database (Denmark)

    Francis, P.; Crown, J.; Di, Leo A.


    ). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided. RESULTS: Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients......BACKGROUND: Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration...... of doxorubicin and docetaxel. METHODS: Patients with lymph node-positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]); 2) concurrent...

  10. Benefits of antihypertensive medications for anthracycline- and trastuzumab-induced cardiotoxicity in patients with breast cancer: Insights from recent clinical trials

    Directory of Open Access Journals (Sweden)

    Katarzyna Rygiel


    Full Text Available Advances in oncologic therapies have allowed many patients with breast cancer to achieve better outcomes and longer survival. However, this progress has been tempered by cardiotoxicity, associated with anticancer therapies, ranging from subclinical abnormalities to irreversible life-threatening complications, such as congestive heart failure or cardiomyopathy. In particular, exposure to chemotherapy (CHT, including anthracyclines and trastuzumab, can lead to cardiac dysfunction with short- or long-term consequences, among patients with breast cancer. The aim of this study is to highlight the potential role of commonly used cardiac medications in the prevention of anthracycline- and trastuzumab-mediated cardiotoxicity, in women with breast cancer, based on evidence from recent clinical trials. This overview is focused on the use of antihypertensive medications, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, outlining their cardioprotective effects in this patient population. In addition, the importance of biomarkers and modern imaging tests, as potential tools for detection and monitoring of cardiac dysfunction, induced by CHT, as well as some practical preventive and therapeutic strategies for cardio-oncology treatment teams, involved in the management of a growing number of women with breast cancer have been outlined. The content of this overview is based on a literature search of PubMed, within the last 5 years, mostly in relevance to the human epidermal growth factor receptor 2-positive patients with breast cancer, treated with anthracycline or trastuzumab therapy (in addition to surgery and/or radiation therapy [RT] regimen.

  11. Comparison of vinorelbine plus cisplatin with vinorelbine plus capecitabine in patients with anthracyclines-and taxanes-refractory advanced breast cancer

    Institute of Scientific and Technical Information of China (English)

    Zhendong Zheng; Shuxian Qu; Xiaoxia Chen; Yongye Liu; Ying Piao; Yaling Han; Xiaodong Xie


    Objective:The aim of our study was to compare the ef icacy and toxicities of vinorelbine plus cisplatin (NP) regimen with that of vinorelbine plus capecitabine (NX) regimen in the treatment of anthracycline- and taxane-refractory advanced breast cancer. Methods:Forty-six patients with anthracycline-and taxane-refractory advanced breast cancer were equal y randomized into a NP group (n=23) and a NX group (n=23). Response rates and toxicities were evaluated after 2 cycles of chemotherapy. Results:The overal response rate were 48.0%in both groups. There were no significant dif erences in disease control rates (78.0%vs. 83%) or 1-year survival rates (54.6%vs. 55.9%). The main adverse events were bone marrow depression and gastrointestinal reaction, and no significant dif erence was found in toxicities between the groups. Conclusion:For anthracycline-and taxane-refractory advanced breast cancer, NP and NX regimens exerted similar curative ef ects with acceptable toxicity.

  12. iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Yuelin Zhang


    Full Text Available Mesenchymal stem cells (MSCs can donate mitochondria and rescue anthracycline-induced cardiomyocyte (CM damage, although the underlying mechanisms remain elusive. We determined that the superior efficiency of mitochondrial transfer by human induced-pluripotent-stem-cell-derived MSCs (iPSC-MSCs compared with bone marrow-derived MSCs (BM-MSCs is due to high expression of intrinsic Rho GTPase 1 (MIRO1. Further, due to a higher level of TNFαIP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-α-induced tunneling nanotube (TNT formation for mitochondrial transfer to CMs, which is regulated via the TNF-α/NF-κB/TNFαIP2 signaling pathway. Inhibition of TNFαIP2 or MIRO1 in iPSC-MSCs reduced the efficiency of mitochondrial transfer and decreased CMs protection. Compared with BM-MSCs, transplantation of iPSC-MSCs into a mouse model of anthracycline-induced cardiomyopathy resulted in more human mitochondrial retention and bioenergetic preservation in heart tissue. Efficacious transfer of mitochondria from iPSC-MSCs to CMs, due to higher MIRO1 expression and responsiveness to TNF-α-induced nanotube formation, effectively attenuates anthracycline-induced CM damage.

  13. Homogeneously staining region in anthracycline-resistant HL-60/AR cells not associated with MDR1 amplification. (United States)

    Gervasoni, J E; Taub, R N; Yu, M T; Warburton, D; Sabbath, M; Gilleran, S; Coppock, D L; D'Alessandri, J; Krishna, S; Rosado, M


    Anthracycline-resistant HL-60/AR cells and their drug-sensitive HL-60/S counterparts were characterized by karyotypic analysis and examined for the overexpression of DNA and mRNA sequences coding for P-glycoprotein (Pgp). The HL-60/S cells were karyotypically stable over a 5-year period of study (1986-1991), except for an additional small Giemsa-positive band noted at 7q22 in cultures harvested in 1987, but not in 1986. This change did not affect drug sensitivity. The drug-resistant HL-60/AR cells examined in 1986, 1987, and 1991 demonstrated a very stable karyotype. The most striking feature was a large homogeneously staining region in the long arm of chromosome 7 (7q11.2), and translocation of the remainder of the long arm to another centromere. Other changes in the HL-60/AR cells included inversion in 9q, partial deletion of the short arm of chromosome 10p, addition of material to the p arm of der(16), loss of chromosome 22, and the appearance of a new marker chromosome. Both HL-60/S and the HL-60/AR cells were found not to amplify DNA or mRNA sequences coding for the Pgp. Thus, although the HL-60/AR cells possess the classical multidrug resistance phenotype and demonstrate a homogeneously staining region near the region of the MDR1 gene, their resistance is due to mechanisms other than those coded for by MDR1.

  14. TP53 mutations are associated with higher rates of pathologic complete response to anthracycline/cyclophosphamide-based neoadjuvant chemotherapy in operable primary breast cancer. (United States)

    Wang, Yuxia; Xu, Ye; Chen, Jiuan; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao


    The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50-7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20-0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival.

  15. BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer (United States)

    Nishimura, Reiki; Osako, Tomofumi; Arima, Nobuyuki; Okumura, Yasuhiro; Okido, Masayuki; Yamada, Mai; Kai, Masaya; Kishimoto, Junji; Miyazaki, Tetsuyuki; Oda, Yoshinao; Otsuka, Takao; Nakamura, Masafumi


    Background Triple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases. Methods The BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens. Results Of the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter recurrence-free survival (RFS) compared with the non-BRCAness group (P = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC. Conclusions The 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs. PMID:27977696

  16. Response and Long-Term Effect of Patients with Triple-Negative Breast Cancer Receiving Neo-Adjuvant Anthracycline-Based

    Institute of Scientific and Technical Information of China (English)

    Zhengkui Sun; Xingtian Ma; Yudong Wu; Fan Fan; Xianghua Wan; Airong Fu


    OBJECTIVE The breast cancer lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) is defined as the Triple-negative breast cancer (TNBC). Our purpose is to compare the response and long-term effect of the TNBC and non-TNBC patients receiving neo-adjuvant anthracycline-based chemotherapy, and to investigate the mechanisms of TNBC affecting the survivals. METHODS Data of long-term follow-up (median, 5.4 years) of 326 patients who received neo-adjuvant chemotherapy with anthracycline-based regimen, during a period from 2000 to 2003, were analyzed. Expressions of ER, PR, HER-2, P53, Ki-67 and E-cadherin were determined using immunohistochemical staining method. A multivariate Cox regression analysis was used to analyze independent prognostic factors affecting the relapse-free survival (RFS) and overall survival (OS) rates. Clinical effects of the neo-adjuvant anthracycline-based chemotherapeutic regimen and the RFS and OS rates were compared between the patients with TNBC and non-TNBC, and the correlations among the triple- negative phenotype (TNP), tumor grading and the expressions of P53, Ki-67 and E-cadherins were analyzed. RESULTS TNP, TNM staging, histological grades, clinical response of the neo-adjuvant chemotherapy and pathological complete remission (pCR) rate were the independent prognostic factors affecting the survival rates. Furthermore, 70 (21.5%) of the 326 patients suffered TNBC. Compared with the subjects in non- TNBC group, the patients with TNBC had a significantly higher pCR rate (P=0.046) and clinical response rate (P=0.037), but also decreased 5-year RFS (P=0.001) and OS (P=0.004) rates. The RFS and OS rates were not improved in the TNBC patients who achieved a clinical remission after the neo-adjuvant chemotherapy. The triple-negative phenotype was positively correlated with the level of P53, Ki-67 expression (P=0.007, P=0.028), but negatively correlated with level of

  17. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. (United States)

    Burnett, A K; Hills, R K; Grimwade, D; Jovanovic, J V; Craig, J; McMullin, M F; Kell, J; Wheatley, K; Yin, J A L; Hunter, A; Milligan, D; Russell, N H


    Two hundred eighty-five patients, median age 42, with PML-RARα-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

  18. Maximizing the Benefit-Cost Ratio of Anthracyclines in Metastatic Breast Cancer: Case Report of a Patient with a Complete Response to High-Dose Doxorubicin

    Directory of Open Access Journals (Sweden)

    Kevin Shee


    Full Text Available Despite the clinical efficacy of anthracycline agents such as doxorubicin, dose-limiting cardiac toxicities significantly limit their long-term use. Here, we present the case of a 33-year-old female patient with extensive metastatic ER+/PR+/HER2– mucinous adenocarcinoma of the breast, who was started on doxorubicin/cyclophosphamide therapy after progressing on paclitaxel and ovarian suppressor goserelin with aromatase inhibitor exemestane. The patient was comanaged by cardiology, who carefully monitored measures of cardiac function, including EKGs, serial echocardiograms, and profiling of lipids, troponin, and pro-BNP every 2 months. The patient was treated with the cardioprotective agent dexrazoxane, and changes in cardiac markers [e.g. decreases in ejection fraction (EF] were immediately addressed by therapeutic intervention with the ACE inhibitor lisinopril and beta-blocker metoprolol. The patient had a complete response to doxorubicin therapy, with a cumulative dose of 1,350 mg/m2, which is significantly above the recommended limits, and to our knowledge, the highest dose reported in literature. Two and a half years after the last doxorubicin cycle, the patient is asymptomatic with no cardiotoxicity and an excellent quality of life. This case highlights the importance of careful monitoring and management of doxorubicin-mediated cardiotoxicity, and that higher cumulative doses of anthracyclines can be considered in patients with ongoing clinical benefit.

  19. An Upgrade on the Rabbit Model of Anthracycline-Induced Cardiomyopathy: Shorter Protocol, Reduced Mortality, and Higher Incidence of Overt Dilated Cardiomyopathy. (United States)

    Talavera, Jesús; Giraldo, Alejandro; Fernández-Del-Palacio, María Josefa; García-Nicolás, Obdulio; Seva, Juan; Brooks, Gavin; Moraleda, Jose M


    Current protocols of anthracycline-induced cardiomyopathy in rabbits present with high premature mortality and nephrotoxicity, thus rendering them unsuitable for studies requiring long-term functional evaluation of myocardial function (e.g., stem cell therapy). We compared two previously described protocols to an in-house developed protocol in three groups: Group DOX2 received doxorubicin 2 mg/kg/week (8 weeks); Group DAU3 received daunorubicin 3 mg/kg/week (10 weeks); and Group DAU4 received daunorubicin 4 mg/kg/week (6 weeks). A cohort of rabbits received saline (control). Results of blood tests, cardiac troponin I, echocardiography, and histopathology were analysed. Whilst DOX2 and DAU3 rabbits showed high premature mortality (50% and 33%, resp.), DAU4 rabbits showed 7.6% premature mortality. None of DOX2 rabbits developed overt dilated cardiomyopathy; 66% of DAU3 rabbits developed overt dilated cardiomyopathy and quickly progressed to severe congestive heart failure. Interestingly, 92% of DAU4 rabbits showed overt dilated cardiomyopathy and 67% developed congestive heart failure exhibiting stable disease. DOX2 and DAU3 rabbits showed alterations of renal function, with DAU3 also exhibiting hepatic function compromise. Thus, a shortened protocol of anthracycline-induced cardiomyopathy as in DAU4 group results in high incidence of overt dilated cardiomyopathy, which insidiously progressed to congestive heart failure, associated to reduced systemic compromise and very low premature mortality.

  20. An Upgrade on the Rabbit Model of Anthracycline-Induced Cardiomyopathy: Shorter Protocol, Reduced Mortality, and Higher Incidence of Overt Dilated Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Jesús Talavera


    Full Text Available Current protocols of anthracycline-induced cardiomyopathy in rabbits present with high premature mortality and nephrotoxicity, thus rendering them unsuitable for studies requiring long-term functional evaluation of myocardial function (e.g., stem cell therapy. We compared two previously described protocols to an in-house developed protocol in three groups: Group DOX2 received doxorubicin 2 mg/kg/week (8 weeks; Group DAU3 received daunorubicin 3 mg/kg/week (10 weeks; and Group DAU4 received daunorubicin 4 mg/kg/week (6 weeks. A cohort of rabbits received saline (control. Results of blood tests, cardiac troponin I, echocardiography, and histopathology were analysed. Whilst DOX2 and DAU3 rabbits showed high premature mortality (50% and 33%, resp., DAU4 rabbits showed 7.6% premature mortality. None of DOX2 rabbits developed overt dilated cardiomyopathy; 66% of DAU3 rabbits developed overt dilated cardiomyopathy and quickly progressed to severe congestive heart failure. Interestingly, 92% of DAU4 rabbits showed overt dilated cardiomyopathy and 67% developed congestive heart failure exhibiting stable disease. DOX2 and DAU3 rabbits showed alterations of renal function, with DAU3 also exhibiting hepatic function compromise. Thus, a shortened protocol of anthracycline-induced cardiomyopathy as in DAU4 group results in high incidence of overt dilated cardiomyopathy, which insidiously progressed to congestive heart failure, associated to reduced systemic compromise and very low premature mortality.

  1. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: Further improvements in treatment outcome

    NARCIS (Netherlands)

    M.A. Sanz (Miguel Angel); P. Montesinos (Pau); C. Rayón (Chelo); A. Holowiecka (Aleksandra); J. De La Serna (Javier); G. Milone (Gustavo); E. de Lisa (Elena); S. Brunet (Salut); V. Rybio (Vicente); J.M. Ribera (Josep Maria); C. Rivas (Concha); I. Krsnik (Isabel); J.M. Bergua (Juan Miguel); J.D. González (José David); J. Díaz-Mediavilla (Joaquín); R. Rojas (Rafael); F. Manso (Félix); G.J. Ossenkoppele (Gert); B. Löwenberg (Bob)


    textabstractA risk-adapted strategy based on all-trans retinoic acid (ATRA) and anthracycline monochemotherapy (PETHEMALPA99 trial) has demonstrated a high antileukemic efficacy in acute promyelocytic leukemia. We designed a new trial (LPA2005) with the objective of achieving stepwise improvements i

  2. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: Long-term outcome of the LPA 99 multicenter study by the PETHEMA Group

    NARCIS (Netherlands)

    M.A. Sanz (Miguel Angel); P. Montesinos (Pau); E. Vellenga (Edo); C. Rayón (Consuelo); J. de Serna (Javier); R. Parody (Ricardo); J.M. Bergua (Juan Miguel); A. León (Angel); S. Negri (Silvia); M. González (Marcos); C. Rivas (Concha); J. Esteve (Jordi); G. Milone (Gustavo); E. Amutio (Elena); S. Brunet (Salut); J. García-Laraña; D. Colomer (Dolors); M.J. Calasanz (Maria); C. Chillón (Carmen); E. Barragán (Eva); P. Bolufer (Pascual); B. Löwenberg (Bob)


    textabstractA previous report of the Programa de Estudio y Tratamiento de las Hemopatfas Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leu

  3. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy : long-term outcome of the LPA 99 multicenter study by the PETHEMA Group

    NARCIS (Netherlands)

    Sanz, Miguel A.; Montesinos, Pau; Vellenga, Edo; Rayon, Consuelo; de la Serna, Javier; Parody, Ricardo; Bergua, Juan M.; Leon, Angel; Negri, Silvia; Gonzalez, Marcos; Rivas, Concha; Esteve, Jordi; Milone, Gustavo; Gonzalez, Jose D.; Amutio, Elena; Brunet, Salut; Garcia-Larana, J.; Colomer, Dolors; Calasanz, Maria J.; Chillon, Carmen; Barragan, Eva; Bolufer, Pascual; Lowenberg, Bob


    A previous report of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leukemia result

  4. Topoisomerase II alpha and TLE3 as predictive markers of response to anthracycline and taxane-containing regimens for neoadjuvant chemotherapy in breast cancer

    Directory of Open Access Journals (Sweden)

    Susini T


    Full Text Available Tommaso Susini,1 Barbara Berti,1 Carlo Carriero,1 Ketty Tavella,2 Jacopo Nori,3 Ermanno Vanzi,3 Cecilia Molino,1 Mariarosaria Di Tommaso,1 Marco Santini,1 Valeria Saladino,4 Simonetta Bianchi4 1Department of Health Science, Gynecology Section, 2Department of Health Science, Chemotherapy Section, University of Florence, Italy; 3Diagnostic Senology Unit, Azienda Ospedaliera-Universitaria Careggi, Florence, Italy; 4Department of Surgery and Translational Medicine, Pathology Unit, University of Florence, Italy Purpose: Anthracyclines and taxanes are considered the standard for neoadjuvant chemotherapy of breast cancer, although they are often associated with serious side effects and wide variability of individual response. In this study, we analyzed the value of topoisomerase II alpha (TOP2A and transducin-like enhancer of split 3 (TLE3 as predictive markers of response to therapy with anthracyclines and taxanes. Materials and methods: TOP2A and TLE3 protein expressions were evaluated using immunohistochemistry on 28 samples, obtained by core needle biopsy in patients with locally advanced breast carcinoma, subsequently subjected to epirubicin- and paclitaxel-based neoadjuvant chemotherapy. The immunohistochemical staining was correlated with the clinical response measured by the tumor size reduction evaluated by breast magnetic resonance imaging, prior and after chemotherapy, and by pathologic evaluation of the surgical specimen. Results: Neoadjuvant chemotherapy achieved a size reduction in 26/28 tumors (92.9%, with an average percentage decrease of 45.6%. A downstaging was achieved in 71.4% of the cases of locally advanced carcinoma. TOP2A positivity was correlated with a greater reduction in tumor diameter (P=0.06; negative staining for TLE3 was predictive of a better response to neoadjuvant chemotherapy (P=0.07. A higher reduction in tumor diameter (P=0.03 was also found for tumors that were concurrently TLE3-negative and TOP2A

  5. First efficacy results of capecitabine with anthracycline- and taxane-based adjuvant therapy in high-risk early breast cancer: a meta-analysis.

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    Yiwei Jiang

    Full Text Available BACKGROUND: Capecitabine is effective and indicated for the salvage treatment of metastatic breast cancer. Therefore, it is essential to evaluate the efficacy of capecitabine in the adjuvant setting. There have been two large randomized studies to determine whether patients with high-risk early breast cancer benefit from the addition of capecitabine to standard chemotherapy, but they have yielded inconsistent results. We first undertook a meta-analysis to evaluate the efficacy of the addition of capecitabine over standard treatment. METHODS: PubMed, EBSCO, Web of Science, conference proceedings and key trials were searched from 1998 to 2011. The hazard ratio (HR was used to evaluate the efficacy of a taxane-anthracycline regimen and a taxane-anthracycline-capecitabine regimen in early breast cancer. All of the data from each study use either fixed-effects or random-effects by Stata. FINDINGS: We found significant improvement in the additional capecitabine arm versus control in disease-free survival (DFS (HR = 0.83, 95% CI: 0.71-0.98, P = 0.027, overall survival (OS (HR = 0.71, 95% CI: 0.57-0.88, P = 0.002, distant recurrence (HR = 0.79, 95% CI: 0.66-0.94, P = 0.008 and the death from breast cancer only (HR = 0.65, 95% CI: 0.51-0.83, P = 0.001. Meanwhile, the subgroup analysis revealed that capecitabine improved the DFS in triple negative (HR = 0.71, 95% CI: 0.53-0.96, P = 0.028, hormone receptor negative (HR = 0.73, CI: 0.56-0.94, P = 0.017 and HER2 negative (HR = 0.81, CI: 0.67-0.98, P = 0.034 patients. CONCLUSION: Due to the synergistic effect of taxane and capecitabine, taxane-anthracycline-capecitabine regimen may effectively improve the efficacy in the adjuvant setting and may be a novel generation of adjuvant chemotherapy regimen. The results of the current meta-analysis support this hypothesis and indicate that taxane-based regimen with capecitabine may be an effective, convenient

  6. Is TIMP-1 immunoreactivity alone or in combination with other markers a predictor of benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial?

    DEFF Research Database (Denmark)

    Munro, Alison F.; Bartels, Annette; Balslev, Eva;


    INTRODUCTION: Predictive cancer biomarkers to guide the right treatment to the right patient at the right time are strongly needed. The purpose of the present study was to validate prior results that tissue inhibitor of metalloproteinase 1 (TIMP-1) alone or in combination with either HER2 or TOP2A......, which randomized patients to E-CMF versus CMF, were analyzed for TIMP-1 immunoreactivity. Using previously collected data for HER2 amplification and TOP2A gene aberrations, we defined patients as "anthracycline non-responsive", that is, 2T (TIMP-1 immunoreactive and TOP2A normal) and HT (TIMP-1...... survival or overall survival) nor with a differential effect of E-CMF and CMF. Also, TIMP-1 did not add to the predictive value of HER2, TOP2A gene aberrations, or to Ki67 immunoreactivity. CONCLUSION: This study could not confirm the predictive value of TIMP-1 immunoreactivity in patients randomized...

  7. A meta-analysis of combination therapy versus single-agent therapy in anthracycline- and taxane-pretreated metastatic breast cancer: results from nine randomized Phase III trials

    Directory of Open Access Journals (Sweden)

    Xu L


    Full Text Available Liang Xu,1,2,* Xiaobo Wu,3,* Chun Hu,1,2 Zhiying Zhang,4 Le Zhang,1,2 Shujing Liang,1,2 Yingchun Xu,5 Fengchun Zhang1,2 1Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, 2Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 3Prevention and Cure Center of Breast Disease, Third Hospital of Nanchang, Nanchang, 4Graduate School, Xuzhou Medical College, Xuzhou, 5Department of Oncology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Nowadays, the philosophy of treating metastatic breast cancer (MBC is slowly evolving. Especially for the anthracycline- and taxane-pretreated MBC patients, no standard therapy exists in this setting. Whether to choose doublet agents or single agent as salvage treatment remains fiercely debated. Thus, we conducted a meta-analysis to resolve this problem. Databases including PubMed, EMBASE, and Cochrane library were searched for Phase III randomized clinical trials (published before August 2015 comparing the efficacy and adverse effects between the combination therapy and single-agent therapy in anthracycline- and taxane-pretreated MBC patients. The primary end point was the overall survival (OS, and the secondary end points were the progression-free survival (PFS, overall response rate (ORR, and grade 3 or 4 toxicities. The pooled hazard ratio (HR and pooled risk ratio (RR were used to evaluate the efficacy. Analyses were also performed to estimate the side effects and safety of both groups. In all, nine eligible randomized clinical trials were included in this meta-analysis. Improvements were proven in the doublet agents group on OS (HR 0.90, 95% confidence interval [CI] 0.84–0.96, P=0.002, PFS (HR 0.81, 95% CI 0.76–0.88, P<0.001, and ORR (RR 1.72, 95% CI 1.34–2.21, P<0.001. Notably, subgroup analysis

  8. Metabolic products of microorganisms. 225. Elloramycin, a new anthracycline-like antibiotic from Streptomyces olivaceus. Isolation, characterization, structure and biological properties. (United States)

    Drautz, H; Reuschenbach, P; Zähner, H; Rohr, J; Zeeck, A


    Elloramycin (1), a new antibiotic produced by Streptomyces olivaceus strain Tü 2353, was detected by chemical screening. The dark yellow compound, molecular formula C32H36O15, is weakly active against a variety of Gram-positive bacteria, especially streptomycetes and against stem cells of L-1210 leukemia. Acidic hydrolysis of the antibiotic liberated elloramycinone (3) as aglycone and 2,3,4-tri-O-methyl-L-rhamnose, which was identified as methyl glycoside 5b. The structure of elloramycin was established by comparison of the spectra (UV, 1H NMR, 13C NMR) with those of the known tetracenomycin C (2), 3 and the fact that 2 and 3 gave the same tetramethyl ether after permethylation. Elloramycin is an anthracycline-like antibiotic, the aglycone resembles tetracenomycin C, the sugar is connected in a phenolic alpha-glycosidic linkage.

  9. Randomized Phase III Trial of Ixabepilone Plus Capecitabine Versus Capecitabine in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane (United States)

    Sparano, Joseph A.; Vrdoljak, Eduard; Rixe, Oliver; Xu, Binghe; Manikhas, Alexey; Medina, Carlos; Ventilari Da Costa, Susanne Crocamo; Ro, Jungsil; Rubio, Gonzalo; Rondinon, Monica; Perez Manga, Gumersindo; Peck, Ronald; Poulart, Valerie; Conte, Pierfranco


    Purpose We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. Patients and Methods A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m2 intravenously on day 1) plus capecitabine (2,000 mg/m2 orally on days 1 through 14) or capecitabine alone (2,500 mg/m2 on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death. Results There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible. Conclusion This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival. PMID:20530276

  10. Apoptosis-modulating interaction of the neuregulin/erbB pathway with anthracyclines in regulating Bcl-xS and Bcl-xL in cardiomyocytes. (United States)

    Rohrbach, Susanne; Muller-Werdan, Ursula; Werdan, Karl; Koch, Susanne; Gellerich, Norbert F; Holtz, Juergen


    During chemotherapy with anthracyclines, attenuated neuregulin signaling by the erbB2 receptor inactivating antibody Trastuzumab enhances the heart failure risk. We compared the effects of attenuated neuregulin/erbB signaling and of daunorubicin on splicing of the Bcl-x gene and on mitochondrial activation of apoptosis in cardiomyocytes. Attenuating erbB signals in cultured neonatal rat cardiomyocytes by the erbB2 antagonist tyrphostin AG825, by the erbB1/4 antagonist AG1478 or by antisense-induced lowering of erbB2 receptors resulted in an augmented Bcl-xS/Bcl-xL ratio, mitochondrial release of cytochrome c, activation of caspase 9 and caspase 3, and nucleosome-sized DNA fragmentation. A similar DNA fragmentation and caspase 3 activation was induced by TNF-alpha, but without Bcl-xS/Bcl-xL increase, cytochrome c release or caspase 9 activation. A BH4-domain containing HIV TAT fusion protein added to cardiomyocytes under attenuated erbB signaling lowered the enhanced Bcl-xS/Bcl-xL ratio, the cytochrome c release, the caspase 3 activation and the DNA fragmentation, while apoptosis was not modified by the fusion protein in TNF-alpha treated cardiomyocytes. Enhancement of Bcl-xS/Bcl-xL by reducing Bcl-xL via siRNA transfection mimicked the mitochondrial apoptotic activation due to erbB signal attenuation. Daunorubicin also caused Bcl-xS/Bcl-xL enhancement and mitochondrial apoptotic activation in cultured cardiomyocytes; this was attenuated by BH4-fusion protein or by neuregulin-1 and augmented by siRNA-mediated Bcl-xL lowering. We conclude that activation of mitochondrial apoptosis due to altered Bcl-x splicing contributes as a common mechanism of anthracyclines and erbB signal attenuation to the enhanced heart failure risk under this combination.

  11. Weekly paclitaxel in escalating doses in a patient with anthracycline-resistant, triple-negative, metastatic breast cancer with severe liver dysfunction

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    Ajay Gupta


    Full Text Available Liver dysfunction in a patient with anthracycline-resistant breast cancer and liver metastases with poor performance status (PS represents a serious situation. Taxanes are the drugs of choice, but once the transaminase enzyme levels are raised more than 10-times the upper limit of normal (>10 ULN, paclitaxel administration is contraindicated. We present the report of one such case who had a gratifying response to escalating doses of weekly paclitaxel thus suggesting that even patients with severe liver dysfunction can derive benefits from such a strategy. The patient, a 54-year-old lady with breast cancer metastatic to the liver and bones and previous receipt of anthracycline-based therapy, presented to us with a PS of 3. Her liver functions (LFT were: serum bilirubin 2.2 mg% (0.3-1.1 mg%, aspartate aminotransferase 375 IU/L (0-25 IU/L, alanine aminotransferase 369 IU/L (0-35 IU/L and alkaline phosphatase 363 IU/L (38-126 IU/L. She was started on weekly paclitaxel 20 mg/m 2 and zoledronate. After the first dose, the LFTs rose marginally but the skin lesions stabilized. Dose was subsequently escalated to 40 mg/m 2 . At the end of the 10th week, her PS improved to 1 and the disease showed a partial response. LFTs improved markedly. However, 5 days after the administration of the 13 th dose, the disease progressed and paclitaxel had to be discontinued. It is possible to derive maximum palliative benefit with escalating doses of weekly paclitaxel even in patients whose liver functions are deranged with transaminase levels (>10 ULN and in whom conventional administration of paclitaxel is contraindicated.

  12. Determination of differences in the left ventricular ejection fraction (LVEF) by radionuclides and echocardiography pre and post treatment with anthracycline in pediatric patients with oncology diagnostic of the La Raza Medical Center; Determinacion de diferencias en la fraccion de eyeccion del ventriculo izquierdo (FEVI) por radionuclidos y ecocardiografia pre y post tratamiento con antraciclinas en pacientes pediatricos con diagnostico oncologico del Centro Medico La Raza

    Energy Technology Data Exchange (ETDEWEB)

    Veras R, H


    The objective of this work was to correlate the left ventricular ejection fraction determine by radionuclide angiocardiography and echocardiography in pediatric patients under anthracycline treatment. Material and methods: 41 patients were studied with range age from 3 to 14 years, with oncology diagnostic that were treated with anthracycline. Radionuclide angiocardiography and echocardiography were performed before an after anthracycline administration to determine the changes in the Ieft ventricular ejection fraction. Results: Anthracycline treatment caused no changes in the electrocardiography, echocardiogram and radionuclide angiocardiography. Conclusions: In our study anthracycline treatment caused no changes in the electrocardiography, echocardiography and both radionuclide angiocardiography techniques, first-pass and equilibrium. A high correlation was obtaining when left ventricular ejection fraction is compared between radionuclide angiocardiography and echocardiogram. (Author)

  13. Research progress on cardio-protective drug for preventing anthracycline cardiotoxicity%蒽环类药物心脏毒性防治药物研究进展

    Institute of Scientific and Technical Information of China (English)

    曲敬琨; 张佳; 张靖; 王健生


    Anthracyclines, which include doxorubicin, epirubicin, daunorubicin, and aclarubicin, are widely used chemotherapeu-tic agents for treating hematologic and solid tumors, such as acute leukemia, lymphoma, breast cancer, gastric cancer, soft tissue sarco-mas, and ovarian cancer. Anthracyclines can be combined with other chemotherapeutics and molecular targeted drugs for cancer treat-ment. The combination of anthracyclines with other chemotherapeutic drugs is usually the standard of first-line treatment. Anthracy-clines are efficacious and potent agents with broad antitumor effects. However, these drugs may cause adverse reactions, such as hair loss, myelotoxicity, and cardiotoxicity. Hematopoietic stimulating factors, such as granulocyte colony-stimulating factor, erythropoietin, and thrombopoietin, can be used to control myelotoxicity. However, cardiotoxicity is the most serious anthracycline side effect. Clinical study results and practical observations indicate that the anthracycline cardiotoxicity is usually progressive and irreversible, especially after the first use of the drug, which may particularly cause heart damage. Therefore, the early detection and prevention of anthracy-cline-induced cardiotoxicity are important and have already gained considerable attention in clinical applications. Relevant experts from the China Society of Clinical Oncology and Hematology Branch of the Chinese Medical Association prepared the guidelines for the pre-vention and cure of anthracycline-induced cardiotoxicity in 2013. The authors reviewed the effective drugs currently used to prevent and cure anthracycline cardiotoxicity.%蒽环类药物包括阿霉素、表阿霉素、柔红霉素和阿克拉霉素等,广泛地用于治疗血液系统恶性肿瘤和实体肿瘤,如急性白血病、淋巴瘤、乳腺癌、胃癌、软组织肉瘤和卵巢癌等。蒽环类药物可以与其他化疗药物及分子靶向药物联合应用,以蒽环类药物为基础的联合治疗

  14. p53 Expression in Pretreatment Specimen Predicts Response to Neoadjuvant Chemotherapy Including Anthracycline and Taxane in Patients with Primary Breast Cancer.

    Directory of Open Access Journals (Sweden)



    Full Text Available While clinical and pathologic responses are important prognostic parameters, biological markers from core needle biopsy (CNB are needed to predict neoadjuvant chemotherapy (NAC response, to individualize treatment, and to achieve maximal efficacy. We retrospectively evaluated the cases of 183 patients with primary breast cancer who underwent surgery after NAC (anthracycline and taxane at the National Cancer Center Hospital (NCCH. We analyzed EGFR, HER2, and p53 expression and common clinicopathological features from the CNB and surgical specimens of these patients. These biological markers were compared between sensitive patients (pathological complete response;pCR and insensitive patients (clinical no change;cNC and clinical progressinve disease;cPD. In a comparison between the 9 (5% sensitive patients and 30 (16% insensitive patients, overexpression of p53 but not overexpression of either HER2 or EGFR was associated with a good response to NAC. p53 (p=0.045 and histological grade 3 (p=0.011 were important and significant predictors of the response to NAC. The correspondence rates for histological type, histological grade 3, ER, PgR, HER2, p53, and EGFR in insensitive patients between CNB and surgical specimens were 70%, 73%, 67%, 70%, 80%, 93%, and 73%. The pathologic response was significantly associated with p53 expression and histological grade 3. The correspondence rate of p53 expression between CNB and surgical specimens was higher than that of other factors. We conclude that the level of p53 expression in the CNB was an effective and reliable predictor of treatment response to NAC.

  15. Development and validation of a liquid chromatographic method for the simultaneous determination of four anthracyclines and their respective 13-S-dihydro metabolites in plasma and saliva. (United States)

    Maudens, Kristof E; Stove, Christophe P; Cocquyt, Veronique F J; Denys, Hannelore; Lambert, Willy E


    A quantitative HPLC method with fluorescence detection has been developed for the simultaneous determination of four anthracyclines (doxorubicin, epirubicin, daunorubicin and idarubicin) and their respective 13-S-dihydro metabolites (doxorubicinol, epirubicinol, daunorubicinol and idarubicinol) in plasma and saliva, using epidaunorubicin as internal standard. A progressive optimization matrix led to a two-step extraction based on a protein precipitation with ethanol followed by a liquid-liquid extraction with dichloromethane after pH adjustment to 8.5. The chromatographic separation was performed in 14min on a C18 column, applying gradient elution with a mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The analytes were detected and quantified at an excitation and emission wavelength of 480 and 555nm, respectively. Limit of detection (LOD) and lower limit of quantification (LLOQ) were 0.3 or 0.75, and 1 or 2.5ng/mL, respectively. Linearity by means of weighted (1/x) regression was obtained from the LLOQ up to 1000 or 2500ng/mL for the parent drugs and up to 400 or 1000ng/mL for the metabolites. Intra-assay and inter-assay relative standard deviation values were all less than 14% at low, medium and high levels, and below 17% at the LLOQ. Accuracy ranged between 91 and 113% at low, medium and high concentrations and between 83 and 118% at the LLOQ. Absolute recoveries were between 78 and 88% in plasma, and between 70 and 79% in saliva, respectively. Autosampler, benchtop, freeze-thaw and long-term stability samples fulfilled acceptance criteria. This selective method was applied successfully to the analysis of plasma and saliva samples from patients administered epirubicin intravenously.

  16. Resistant mechanisms of anthracyclines--pirarubicin might partly break through the P-glycoprotein-mediated drug-resistance of human breast cancer tissues. (United States)

    Kubota, T; Furukawa, T; Tanino, H; Suto, A; Otan, Y; Watanabe, M; Ikeda, T; Kitajima, M


    Juliano and Ling initially reported the expression of a 170 kDa glycoprotein in the membrane of Chinese hamster ovarian cells in 1976, and named this glycoprotein P-glycoprotein (P-gp) based on its predicted role of causing "permeability" of the cell membrane. After much research on anthracycline-resistance, this P-gp was finally characterized as a multidrug-resistant protein coded by the mdr1 gene. Multidrug resistance associated protein (MRP) was initially cloned from H69AR, a human small cell-lung carcinoma cell line which is resistant to doxorubicin (DXR) but does not express P-gp. MRP also excretes substrates through the cell membrane using energy from ATP catabolism. The substrate of MRP is conjugated with glutathione before active efflux from cell membrane. Recently, membrane transporter proteins were re-categorized as members of "ATP-Binding Cassette transporter"(ABC-transporter) superfamily, as shown at and A total of ABC transporters have been defined, and MDR1 and multidrug resistance associated protein 1 (MRP1) were reclassified as ABCB1 and ABCC1, respectively. Their associated superfamilies include 11 and 13 other protein, in addition to ABCB and ABCC, respectively. Lung resistance-related protein (LRP) is not a member of the superfamily of ABC transporter proteins, because it shows nuclear membrane expression and transports substrate between nucleus and cytoplasm. LRP was initially cloned from a non-small cell lung carcinoma cell line, SW1573/2R120 which is resistant to DXR, vincristine, etoposide and gramicidin D and does not express P-gp. The mechanisms of resistance remains unclear, and why some resistant cell lines express P-gp and others express MRP and/or LRP is likewise unclear.

  17. 海洋放线菌代谢产物蒽环类化合物研究进展%Research Progress in Anthracycline Compounds Produced by Marine Actinomycetes

    Institute of Scientific and Technical Information of China (English)

    马毅敏; 陆园园; 邢莹莹; 奚涛


    The marine actinomycetes are likely to be important sources of new natural products. In recent years,plenty of novel structures have been isolated from marine actinomycetes. Among them,there are many novel anthracycline metabolites with good antibacterial and antitumor activities. Anthracycline compounds isolated from marine actinomycetes and their activities were summarized in this paper,and a perspective in regard to the future development of the marine natural products was also discussed.%海洋放线菌代谢产物是抗肿瘤活性物质的重要来源.近年来,从海洋放线菌中分离到很多新化合物,其中许多结构新颖的蒽环类代谢产物具有良好的抗菌抗肿瘤活性.文章对近年来从海洋放线菌中分离得到的蒽环类代谢产物进行了归纳,并展望今后海洋天然产物的发展方向.

  18. Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study. (United States)

    Lucena-Araujo, Antonio R; Kim, Haesook T; Jacomo, Rafael H; Melo, Raul A; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Fagundes, Evandro M; Chauffaille, Maria de Lourdes; Chiattone, Carlos S; Lima, Ana Silvia; Ruiz-Argüelles, Guillermo; Undurraga, Maria Soledad; Martinez, Lem; Kwaan, Hau C; Gallagher, Robert; Niemeyer, Charlotte M; Schrier, Stanley L; Tallman, Martin S; Grimwade, David; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C; Lo-Coco, Francesco; Löwenberg, Bob; Sanz, Miguel A; Rego, Eduardo M


    Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITD(positive) patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD(negative) patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.

  19. Coenzyme Q10 (CoQ10) reduce the heart toxicity caused by anthracycline-based chemotherapy drugs%辅酶Q10治疗蒽环类药物致心脏毒性的疗效

    Institute of Scientific and Technical Information of China (English)

    孙玉书; 高德荣


    Objective:To study the protective effect of CoQl0 on the cardiovascular toxicity induced by anthracycline, and investigate the possible mechanisms. Methods: Sixty tumor patients were randomly divided into treatment group(30 cases) and control group(30 cases). Receiving chemotherapy,at the same time,CoQ10 and a large dose of vitamin E were given in two groups. Electrocardiography and cardiac enzymes were examined before and after treatment. Results: ECG and myocardial enzyme were all improved significantly in the treatment group, and the changes were superior to those of the control group ( P < 0 05 ) . Conclusion: CoQl0 had protective effects on the cardiovascular toxicity induced by anthracycline.%目的:研究辅酶Q10 (CoQ10)对使用蒽环类化疗药物致心脏毒性的保护作用,并探讨可能的机理.方法:60例肿瘤患者随机分为治疗组(30例)和对照组(30例),化疗同时分别予CoQ10及大剂量维生素E治疗,治疗前后行心电图、心肌酶检查.结果:化疗后CoQ10组心电图和血清心肌酶学指标均优于对照组(P<0.05).结论:CoQ10对蒽环类化疗药物所致心脏毒性有保护作用.

  20. Impact of aerobic exercise on cardiac function of breast cancer patients receiving anthracyclines%有氧运动对应用蒽环类药物治疗的乳腺癌患者心功能的影响

    Institute of Scientific and Technical Information of China (English)

    张宁; 孔雁; 李欢; 孙芳毅; 刘宇


    Objective To study the impact of postoperative aerobic exercise on the cardiac function of breast cancer patients during anthracyclines-based chemotherapy. Methods Sixty cases of female breast cancer pa-tients, from June 2014 to December 2015 for anthracyclines-based chemotherapy, were randomly divided into ex-perimental group (n = 30) and control group (n = 30). Four cycles of conventional anthracyclines-based chemotherapy were conducted in control group, while three times of aerobic exercise per week were added in exper-imental group until the end of treatment course apart from conventional treatment. The peak oxygen consumption (VO2max) and maximum heart rate (HRmax) were measured before and after chemotherapy in both groups, ac-companied by ECG monitoring and blood collecting to measure the changes in their N-terminal pro-brain natriuretic peptide (NT-proBNP), serum creatinine (SCr) and kinase isoenzyme (CK-MB). Results No significant differ-ences in various indicators before chemotherapy were reported between two groups (P>0.05). After chemotherapy, VO2 max/kg [(21.9 ± 3.6) vs. (14.5 ± 2.8) mL/(min·kg)], VO2 max [(1 523 ± 186) vs. (911 ± 185) mL/min] and HRmax[(115 ± 15) vs. (129 ± 16) beats/min] in experimental group were significantly improved when com-pared with those in control group; significant differences in hematological levels and ECG changes were also ob-served between two groups. Conclusion Aerobic exercise during chemotherapy can mitigate the cardiotoxicity of anthracyclines to patients, which provides a new idea and therapy to reduce the incidence of clinical cardiovascular events induced by anthracyclines-based chemotherapy.%目的:研究乳腺癌患者术后应用蒽环类药物化疗期间进行有氧运动对患者心功能的影响。方法:选取2014年6月至2015年12月在我院肿瘤内科应用蒽环类药物进行化疗的女性乳腺癌术后患者60例,将其随机分成观察组(n =30)和对照组(n =30

  1. 紫杉醇及蒽环类药物联合化疗治疗晚期乳腺癌的临床疗效%Clinical Efficacy of Paclitaxel and MDT Anthracycline-based Drugs for Advanced Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    袁鹏; 岳天华; 肖艳华; 朱梁军; 李晟; 陈宝安


    Objective To study the cinical efficacy of paclitaxel and MDT anthracycline-based drugs for advanced breast cancer.Methods 68 cases of elderly patients with advanced breast cancer according to random number table method were grouped into the control group and the treatment group .The control group received the CAF regimen ,The treatment group received the joint anthracycline-based drugs paclitaxel and ±CTX treatment .5-year survival rates , local recurrence rates , axillary lymph node recurrence rates,quality of life,short-term curative effects and adverse reactions of the 2 groups were compared.Results Local recurrence rate,axillary lymph node recurrence rate,and 5-year survival rate in the treatment group were 5.88%(2/34), 2.94%(1/34),and 41.18%(14/34),and those of the control group were 14.71%(5/34),11.76%(4/34),and 29.41%(10/34)(P<0.05).Quality of life score,adverse reaction rate and short-term curative effects of the 2 groups had statistical difference (P<0.05).Conclusion Paclitaxel and ±CTX anthracycline-based drugs for advanced breast cancer can reduce local recur-rence and axillary lymph nodes recurrence ,improve the effect of treatment .And it has less adverse reactions during the treatment , improve tolerance ,promote the smooth progress of the treatment ,and improve quality of life .%目的:探讨紫杉醇及蒽环类药物联合化疗治疗晚期乳腺癌的临床疗效。方法68例老年晚期乳腺癌患者按照随机数字表法分为对照组和治疗组。对照组:采用CAF方案治疗;治疗组:采用紫杉醇联合蒽环类药物±CTX方案治疗。比较2组患者5年生存率和局部复发率、腋淋巴结复发率、生活质量、近期疗效、不良反应。结果治疗组局部复发率和腋淋巴结复发率、5年生存率分别为5.88%(2/34)、2.94%(1/34)、41.18%(14/34),与对照组14.71%(5/34)、11.76%(4/34)、29.41%(10/34)比较,P均<0.05。治疗组

  2. 儿童药物性心肌病4例并文献回顾%Four case report of anthracycline-induced cardiomyopathy in children and literature review

    Institute of Scientific and Technical Information of China (English)

    邢长青; 齐建光; 刘雪芹; 杜军保


    目的 探讨儿童蒽环类药物致心肌病的临床特征、高危因素、检测手段、预防和治疗手段.方法 总结4例蒽环类药物致心肌病患儿的临床资料,并回顾分析相关文献.结果 4例患儿在2.5 ~6.5岁时因急性淋巴细胞性白血病开始化疗,1例化疗8个月时出现心慌,未重视.4例均在化疗结束后逐渐出现水肿、胸闷、活动后气促、肝脏肿大等心力衰竭的表现.柔红霉素总剂量达525 ~1038mg/m2.超声心动图类似扩张型心肌病表现,以左心扩大为主的全心扩大,心脏收缩功能障碍.经抗心衰治疗,1例患儿在1年后死亡.另3例存活4~6年以上,曾有过一段时间的临床症状相对稳定期,但是疾病仍然会缓慢进展.结论 蒽环类药物致心肌病一旦发生将是不可逆性的改变,虽然合理的抗心衰治疗能使病情暂时稳定.药物累积剂量是其主要危险因素.化疗前中后可选择心电图、超声心动图以及血清学指标等监测药物毒性反应.%Objective To explore the clinical characteristics, risk factors, test facility, prevention and therapeutic regimen of anthracycline-induced cardiomyopathy in children. Methods Clinical data of four children with anthracy-cline-induced cardiomyopathy was retrospectively analyzed, and relevant literatures were reviewed. Results Four cases aged from 2. 5 to 6. 5 years, were diagnosed as acute lymphocytic leukemia and undertaked chemotherapy. One case felt flustered after 8-months chemotherapy, but this was not taken attention. Four cases all gradually showed the manifestation of heart failure, like edema, chest distress, exertion breathlessness, hepatic enlargement and so on, after the termination of chemotherapy. The cumulated doses of daunorubicin reached 525 ~ 1038mg/m . Findings of dilated cardiomyopathy were demonstrated by echocardiography. The therapy was aimed mainly to heart failure. One case died 1 year later, and the life spans of the other three

  3. Comparison and analysis of influencing factors of amenorrhea due to adjuvant chemotherapies of anthracycline-based and anthracycline followed by taxen in women with early breast cancer%含蒽环类和蒽环类序贯紫杉类方案辅助化疗对早期乳腺癌患者致闭经作用的比较及影响因素分析

    Institute of Scientific and Technical Information of China (English)

    王佳玉; 李青; 张频; 袁芃; 马飞; 蔡锐刚; 罗扬; 樊英; 李俏


    前早期乳腺癌患者发生CIA,两组CIA的发生率及转归相似.年龄是CIA发生及其转归的重要影响因素.对于发生CIA的年轻患者,术后辅助化疗后的内分泌治疗选择应慎重.%Objective To determine the effect and influence factors of amenorrhea due to adjuvant chemotherapies of anthracycline-based and anthracycline followed by taxen in premenopausal patients with early breast cancer.Methods Case records of the patients who were premenopausal and estrogen receptor-positive with early breast cancer and received adjuvant chemotherapies of anthracycline-based and anthracycline followed by taxen in Cancer Hospital,Chinese Academy of Medical Sciences,Peking Union Medical College from 2008 to 2010 were collected and retrospectively analysed.The chemotherapy regimens included anthracycline-based regimen 6EC (epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2 for 6 cycles and each cycle taking 21 days) and the anthracycline followed by taxen regimen 4EC-4T (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 for 4 cycles and each cycle taking 21 days,followed by paclitaxel 175 mg/n2 or docetaxel 75 mg/m2 for 4 cycles and each cycle taking 21 days).The patients were divided into two groups by the regiments.The incidence of chemotherapy-induced amenorrhea (CIA) was calculated and the recovery situation of menses and ovarian function in the patients with CIA during two years after the end of chemotherapy was recorded.The ovarian function was showed by luteinizing hormone,follicle-stimulating hormone,and estradiol levels.Influence factors of CIA was analysed in Logistic regression and x2 test methods.Results Ninety-six patients were enrolled in this study.Of them,45 patients were in the 6EC group with a media age of 43-year-old and 51 patients were in the 4EC-4T group with a media age of 42-year-old.Seventy-seven of ninety-six patients (80.2%) suffered from CIA during two years after the end of chemotherapy.Of the 77 patients with CIA,51

  4. Docetaxel and cisplatin combination chemotherapy in anthracyclines-resistant advanced breast cancer%多西紫杉醇联合顺铂治疗蒽环类耐药的晚期乳腺癌

    Institute of Scientific and Technical Information of China (English)

    Hailin Xiong; Zhujun Liu; Xin Cheng; Kai Li


    Objective: To observe the effect and toxicity of docetaxel with cisplatin in anthracyclines-resistant advanced breast cancer. Methods: Forty-five female patients received docetaxel 60 mg/m2 on d1 and cisplatin 30 mg/m2 on d1-d3 of every 28 days. Every patient was treated with at least 2 cycles and a median of 3 cycles (2-6 cycles ). Results: Five patients achieved complete response (11.1%) and 18 partial response (40.0%), 10 stable disease (22.2%). The overall response rate was 51.1%. The clinical disease control rate was 73.3%, median time to tumor progression (TTP) was 7.8 months (1.0-34.5months), median survival time was 17.6 months (range 1.9-48.0 months), and one year survival rate was 65.2%. The main side effect was marrow suppression. The treatment was well tolerated with grades Ⅲ and Ⅳ leukopenia in nine (20%) and ten (22.2%) patients.Conclusion:Combinative chemotherapy of docetaxel and cisplatin has a good anti-tumor activity on refractory advanced breast cancer cancer with manageable toxicity.

  5. Evaluating the impact of Relative Total Dose Intensity (RTDI on patients' short and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer- a pooled analysis

    Directory of Open Access Journals (Sweden)

    Brodowicz Thomas


    Full Text Available Abstract Background Chemotherapy dose delay and/or reduction lower relative total dose intensity (RTDI and may affect short- and long-term outcome of metastatic breast cancer (MBC patients. Methods Based on 933 individual patients' data of from 3 randomized MBC trials using an anthracycline and taxane we examined the impact of RTDI on efficacy and determined the lowest optimal RTDI for MBC patients. Results Median time to disease progression (TTDP and overall survival (OS of all patients were 39 and 98 weeks. Overall higher RTDI was correlated with a shorter TTDP (log-rank p = 0.0525 for 85% RTDI cut-off. Proportional hazards assumption was violated, there was an early drop in the TTDP-curve for the high RTDI group. It was explained by the fact that patients with primary disease progression (PDP do have a high RTDI per definition. Excluding those 114 patients with PDP the negative correlation between RTDI and TTDP vanished. However, non-PDP patients with RTDI-cut-off levels Conclusions Optimizing RTDI above 85% appears to improve long-term outcome of MBC patients receiving first-line chemotherapy. Lowering RTDI had no negative influence on short term outcome like OR and TTDP.

  6. Facile one-pot synthesis of a aptamer-based organic-silica hybrid monolithic capillary column by "thiol-ene" click chemistry for detection of enantiomers of chemotherapeutic anthracyclines. (United States)

    Jiang, Han-Peng; Zhu, Jiu-Xia; Peng, Chunyan; Gao, Jiajia; Zheng, Fang; Xiao, Yu-Xiu; Feng, Yu-Qi; Yuan, Bi-Feng


    In the current study, we developed a facile strategy for the one-pot synthesis of an aptamer-based organic-silica hybrid monolithic capillary column. A 5'-SH-modified aptamer, specifically targeting doxorubicin, was covalently modified in the hybrid silica monolithic column by a sol-gel method combined with "thiol-ene" click reaction. The prepared monolithic column had good stability and permeability, large specific surface, and showed excellent selectivity towards chemotherapeutic anthracyclines of doxorubicin and epirubicin. In addition, the enantiomers of doxorubicin and epirubicin can be easily separated by aptamer-based affinity monolithic capillary liquid chromatography. Furthermore, doxorubicin and epirubicin spiked in serum and urine were also successfully determined, which suggested that the complex biological matrix had a negligible effect on the detection of doxorubicin and epirubicin. Finally, we quantified the concentration of epirubicin in the serum of breast cancer patients treated with epirubicin by intravenous injection. The developed analytical method is cost-effective and rapid, and biological samples can be directly analyzed without any tedious sample pretreatment, which is extremely useful for monitoring medicines in serum and urine for pharmacokinetic studies.

  7. 卡培他滨在蒽环和紫杉类失败的晚期乳腺癌中疗效与安全性的分析%Analysis of the Efficacy and Safety of Capecitabine in Advanced Breast Cancer with Anthracycline and Taxane Failure

    Institute of Scientific and Technical Information of China (English)

    曾娟紫; 吴国武


      目的:探究卡培他滨在蒽环和紫杉类失败的晚期乳腺癌中的疗效与安全性。方法:选择20例蒽环和紫杉类失败的晚期乳腺癌患者,给予卡培他滨治疗,观察临床疗效及用药安全。结果:结束化疗4周后 ORR 率为25%,5例 PR 患者均接受蒽环和紫杉类单纯使用或联合使用方案治疗。主要药物不良反应有手足综合征、食欲不振、恶心、呕吐、便秘、中性粒细胞减少,且大部分为1~2级,3~4级毒性发病率较低。结论:卡培他滨在蒽环和紫杉类失败的晚期乳腺癌患者中疗效确切,且用药较安全,口服用药方便,成为晚期乳腺癌首选药物。%Objective:To explore efficacy and safety of capecitabine in advanced breast cancer with anthracycline and taxane failure.Method:20 patients with anthracycline and taxane failure in patients with advanced breast cancer,capecitabine,to observe the clinical efficacy and drug safety. Result:4 weeks after the end of chemotherapy,the ORR was 25%,five cases of PR patients underwent anthracycline and taxane simple to use or joint use regimen.The main adverse drug reactions hand-foot syndrome,loss of appetite,nausea,vomiting,constipation,neutropenia,and most of 1 to 2,3 to 4 toxicity incidence is relatively low.Conclusion:The exact efficacy of capecitabine in anthracycline and taxane failure in patients with advanced breast cancer,and the drug is safer,convenient oral medication,the drug of choice for advanced breast cancer.

  8. 斑点追踪技术评价蒽环类药物对乳腺癌患者左心室跨壁力学的影响%Evaluation of left ventricular transmural mechanics after anthracycline chemotherapy in patients with breast cancer by speckle tracking imaging

    Institute of Scientific and Technical Information of China (English)

    薛继平; 苏莉莉; 康春松; 王智芬; 李帅; 吕虹


    目的:应用二维斑点追踪成像(2D-STI)技术评价乳腺癌蒽环类药物化疗前后左室跨壁力学的变化,早期预测蒽环类药物化疗导致的心脏毒性。方法乳腺癌术后蒽环类药物化疗患者46例,分别于化疗前及化疗1、3、6周期后行超声心动图检查,应用2D-STI 获取左室收缩期整体纵向峰值应变(GLS)、径向峰值应变(GRS)、环向峰值应变(GCS),心内膜下纵向峰值应变(LS-endo)、径向峰值应变(RS-endo)、环向峰值应变(CS-endo),心外膜下纵向峰值应变(LS-epi)、径向峰值应变(RS-epi)、环向峰值应变(CS-epi),计算跨壁应变梯度(TMSG)。比较化疗前后常规超声心动图参数及应变相关参数,并应用ROC 曲线比较应变参数对蒽环类药物心脏毒性的检验效能。结果①蒽环类药物化疗6周期后,9例(19.6%)发生心脏毒性,37例(80.4%)未达到心脏毒性的诊断标准;②与化疗前基础状态比较,蒽环类药物化疗各周期后心脏结构参数差异无统计学意义(P >0.05);6周期后左室射血分数、短轴缩短率、E/A 减低,E/e 升高,差异有统计学意义(P LS-endo>GLS>LS-epi。结论化疗3周 期 TMSG-LS、LS-endo、GLS、LS-epi 减低,早于 LVEF 及其他应变参数,化疗3周期 TMSG-LS、LS-endo 检测心脏毒性具有较高的准确性,能早期监测乳腺癌蒽环类药物化疗导致的心脏损害。%Objective To evaluate the left ventricular transmural mechanics changes of breast cancer patients between before and after anthracycline chemotherapy by two-dimensional speckle tracking imaging (2D-STI),and to predict early cardiotoxicity caused by anthracycline.Methods Forty-six breast cancer patients with postoperative anthracycline-based chemotherapy were recruited.Echocardiography were performed on all subjects before and at 1 ,3 and 6 anthracycline-based chemotherapeutic cycle.Global longitudinal strain(GLS),endocardial longitudinal strain(LS-endo),epicardial longitudinal strain

  9. Q -T间期离散度和心脏超声对蒽环类药物早期心肌损伤的预测价值%Predictive value of QT interval dispersion and echocardiography in early myocardium injury induced by anthracycline

    Institute of Scientific and Technical Information of China (English)

    张英; 张海峰; 李青山; 赵景新


    目的:探讨Q-T间期离散度和心脏超声对预测蒽环类药物引起的早期心肌损伤的敏感性及应用价值。方法入选29例乳腺癌患者,且均采用含蒽环类药物的方案化疗,应用表阿霉素剂量为75 mg /m2,进行2~6个周期,随化疗进行体内蒽环类药物累积剂量不同,动态监测心电图Q-T间期离散度及心脏超声变化,并进行分析与评价。结果化疗后Q-T间期离散度较化疗前明显延长,差异有显著性意义,P<0.001。化疗后左室舒张末期前后径较化疗前轻度增大、左室射血分数较化疗前轻度下降,但差异无显著性意义, P>0.05。结论化疗药物对心肌损伤的评价指标中,心电图Q-T间期离散度较心脏超声的左室舒张末期前后径和左室射血分数更为敏感,具有对蒽环类药物引起的心肌损伤的早期预测价值,通过监测心电图Q-T间期离散度变化,能及早在心肌损伤亚临床阶段发现其心脏毒性的发生与进展。%Objective To discuss the application value and sensitivity of QT interval dispersion and echocardiography in early myocardium injury induced by anthracycline .Methods The study included 29 breast cancer patients , who received chemotherapy with anthracycline ,The dosage of epidoxorubicina was 75 mg/m2 for 2-6 cycles.QT interval dispersion by ECG and echocardiography were analyzed in accordance with the accumulation of anthracycline by chemotherapy .Results Q-T interval dispersion became longer after chemotherapy compared to that before chemotherapy .The differences were sta-tistically significant (P0.05). Conclusion Among the indexes of myocardium injury induced by chemotherapy drugs , Q-T interval dispersion is more sensitive than left ventricular end -diastolic diameter and LVEF by echocardiography , and can be a useful marker for early prediction of anthracycline -induced myocardium injury .We can discover the early occurrence and progress of

  10. Observation on the Effect of GP Regimen and NP Regimen in the Treatment of 39 Advanced Breast Cancer Patients with Anthracycline and Taxane Re_sistance%39例蒽环类及紫杉类耐药晚期乳腺癌应用GP方案与NP方案治疗的疗效观察

    Institute of Scientific and Technical Information of China (English)

    郑德文; 韩玉秋


    Objective To observe the short-term effect and adverse reactions of gemcitabine and cisplatin (GP) regimen and vi_norelbine and cisplatin(NP) regimen in the treatment of advanced breast cancer patients failed to the third-line medication (anthra_cycline and taxane). Methods 39 advanced breast cancer patients failed to the treatment of anthracycline and taxane were ran_domly divided into two groups, 20 patients in the GP group were treated by the GP regimen and 19 patients in the NP group were treated by the NP regimen. The efficacy of the chemotherapy was evaluated after 2 courses of treatment, and the patients with ef_fective curative effect went on the chemotherapy. Results The total effective rate was 40.09% in GP group and 42.11% in NP group, the difference between the two groups was not significant(P>0.05).The main adverse reactions were bone marrow depression and gastrointestinal reactions, but two groups had no significant differences(P>0.05). Conclusion For advanced breast cancer failed to the third-line drug therapy (anthracycline and taxane), the short-term effect of GP and NP regimens are confirmed and the ad_verse reactions can be tolerated.%目的:对于晚期乳腺癌,三线药物治疗﹙即蒽环类及紫杉类治疗﹚失败,采用 GP方案﹙吉西他滨联合顺铂﹚与NP方案﹙长春瑞滨联合顺铂﹚,观察近期疗效和不良反应。方法将既往曾接受蒽环类及紫杉类药物治疗失败的39例晚期乳腺癌患者随机分组,GP方案组20例,NP方案组19例,化疗2周期后评价疗效,有效者继续化疗。结果GP组与NP组总有效率分别为40.09%和42.11%,两组比较差异无统计学意义(P>0.05)。主要不良反应为骨髓抑制及消化道反应,两组比较差异无显著性(P>0.05)。结论对于三线药物治疗﹙即蒽环类及紫杉类治疗﹚失败的晚期乳腺癌,GP方案与NP方案治疗的近期疗效得到肯定,而且不良反应也可以忍受。

  11. 蒽环类联合紫杉类方案在乳腺癌新辅助化疗中的有效性及安全性评价%Efficacy and safety of anthracyclines in combination with taxanes for neo-adjuvant chemotherapy in patients with breast cancer

    Institute of Scientific and Technical Information of China (English)

    刘伟; 李健斌; 王涛; 边莉; 张少华; 张会强; 周金妹; 宋三泰; 江泽飞


    目的:探讨蒽环类联合紫杉类方案在乳腺癌新辅助化疗中的有效性及安全性。方法收集2005年6月至2014年10月接受蒽环类联合紫杉类方案新辅助化疗的早期或局晚期乳腺癌192例患者的临床资料,探讨化疗方案的疗效以及安全性,并分析影响病理完全缓解的相关因素。结果192例患者均可评价疗效,有效率为84�9%(163/192),病理完全缓解率为20�3%(39/192),其中 HR(+)/HER⁃2(-)组为8�5%(10/118)、HR(-)/HER⁃2(+)组为42�8%(6/14)、HR(+)/HER⁃2(+)组为25�0%(5/20)、HR (-)/HER⁃2(-)组为45�0%(18/40)。 HR (-)组病理完全缓解率显著高于 HR (+)组( P<0�001);在HR(-)组中,HR(-)/HER⁃2(+)与HR(-)/HER⁃2(-)组之间病理完全缓解率的差异无统计学意义( P>0�05)。Logistic回归分析显示,ER 状态是影响病理完全缓解率的独立因素。主要的剂量限制性毒性为3、4级中性粒细胞减少(94�8%);非血液学毒性包括2、3级呕吐(6�2%),骨骼肌肉疼痛、麻木(14�1%),中性粒细胞缺乏性发热(16�7%),黏膜炎(2�1%)以及心脏毒性(5�7%)等。结论蒽环类联合紫杉类方案在乳腺癌新辅助化疗疗效确切,不良反应可耐受,可作为乳腺癌新辅助化疗的优选方案。%Objective To assess the efficacy and safety of anthracyclines in combination with taxanes for neo⁃adjuvant chem⁃otherapy in patients with breast cancer. Methods The data of 192 breast cancer patients treated by taxanes and anthracyclines neoad⁃juvant regimens was reviewed. The efficacy and safety of taxanes and anthracyclines neoadjuvant regimens, as well as factors influencing pathological complete remission were analyzed. Results The efficacy of 192 patients could be evaluated. The

  12. 吉西他滨联合希罗达治疗蒽环类和紫杉类药物治疗失败乳腺癌肝转移的疗效分析%Analysis on efficacy of gemcitabine combined with xeloda in treating patients with liver metastases of breast cancer after anthracycline-based and taxane combinations drug treatment failure

    Institute of Scientific and Technical Information of China (English)

    黄文金; 罗建文; 杨凤玲; 陈志勇; 温婷


    Objective To observe curative effect of gemcitabine combined with xeloda in treating patients with liver metastases of breast cancer after anthracycline-based and taxane combinations drug treatment failure. Methods Thirty-six female cases of breast cancer with liver metastases were given intravenous gemcitabine 1000 mg/m2 on the day 1 and 8,and oral xeloda 2000 mg/m2 on the days 1-14, three weeks as a cycle. The curative effect of chemotherapy was evaluted after continuous treatment for 2 cycles. Results In 36 patients, there were 0(0% ) CR, 6( 16. 7% ) PR, 9 (25. 0% ) SD, 21 (58. 3% ) PD.the response rate( CR + PR) was 16. 7% (6/36), the clinical benefit rate (CR + PR + SD) was 41. 7% ( 15/36). The adverse reactions were leukopenia [72. 2% (26/36) grade Ⅰ Ⅱ , 16. 7% (6/36) grade Ⅲ Ⅳ] , throm-bocytopenia [ 44. 4% ( 16/36 ) grade I - II , 2. 8% ( 1/36 ) grade III -IV ] , gastrointestinal reaction [44.4% (16/36) grade Ⅰ Ⅱ and 0% grade ID -IV], diarrhea [2.8% (1/36) grade Ⅲ Ⅳ] and Brotherhood syndrome [ 19.4% (7/36), grade I - II ] · Conclusion For breast cancer with liver metastases after anthracycline-based and taxane combinations drug treatment failure, alternative treatment is very few, the chemotherapy with gemcitabine combined with Xeloda is a quite good choice.%目的 观察吉西他滨联合希罗达治疗蒽环类和紫杉类药物治疗失败乳腺癌肝转移的疗效.方法 收治36例女性乳腺癌化疗后合并肝转移患者,采取吉西他滨1000 mg/m2,静脉滴注,第1,8天;希罗达2000 mg/m2,口服,第1~14天.3周为1个周期.连续做2个周期化疗后评价疗效.结果 36例患者CR 0例,PR 6例(16.7%),SD 9例(25.0%),PD 21例(58.3%),有效率(CR+PR)为16.7% (6/36),临床获益率(CR+ PR+ SD)为41.7% (15/36).不良反应:白细胞减少Ⅰ~Ⅱ度占72.2% (26/36),Ⅲ~Ⅳ度占16.7% (6/36),血小板减少Ⅰ~Ⅱ度占44.4% (16/36),Ⅲ~Ⅳ度占2.8% (1/36).消化道反应Ⅰ~Ⅱ度发生率44.4

  13. Study of paclitaxel and MDT anthracycline-based drugs clinical efficacy of treatment of advanced breast cancer%蒽环类耐药乳腺癌患者应用盖诺联合顺铂治疗效果观察

    Institute of Scientific and Technical Information of China (English)

    王建逵; 杨庄青; 王茂华; 杨晓娟


    Objective Anthracycline-resistant advanced breast cancer chemotherapy treatment vinorelbine plus cispla-tin, observation and analysis of its clinical efficacy. Methods Select the hospital in June 2006 and June 2009 were treated 144 patients with advanced breast cancer research. According to a random number table to be grouped into a control group and thetreatment group. The control group received docetaxel plus cisplatin treatment; treatment group with vinorelbine plus cisplatin therapy. 5-year survival rate between the two groups of patients, quality of life, short-term efficacy, adverse reactions. Results 5-year survival rate of the treatment group were 38.89% (28/72) in the control group and 27.78% (20/72) comparison. Quality of life in the treatment group scores and adverse reaction rates and short-term efficacy compared with control group. Conclusions Compared to docetaxel, the clinical use of vinorelbine and cisplatin in the treatment of anthracycline-resistant advanced breast cancer patients, improve the therapeutic effect. While fewer adverse reactions that occurred during treatment, improve patient tolerance, and promote the smooth conduct of treatment and improve the quality of life of patients.%目的:对蒽环类耐药晚期乳腺癌患者采用盖诺联合顺铂化疗治疗,观察和分析其临床疗效。方法:选取本院2006年6月~2009年6月期间收治的144例晚期乳腺癌患者进行研究。按照随机数字表法将其分组为对照组和治疗组。对照组采用多西他赛联合顺铂治疗;治疗组采用盖诺联合顺铂治疗。比较两组患者5年生存率、生活质量、近期疗效、不良反应。结果:治疗组5年生存率分别38.89%(28/72)与对照组27.78%(20/72)比较。治疗组生活质量评分和不良反应率及近期疗效与对照组比较。结论:相比多西他赛来说,临床采用盖诺联合顺铂治疗蒽环类耐药晚期乳腺癌患者,提高治疗效果。同时治疗期间所

  14. Influence of the medication administration sequence of taxanes and anthracyclines on the recent effect in patients with breast cancer%紫杉烷类药物与蒽环类药物用药顺序对乳腺癌患者近期疗效影响研究

    Institute of Scientific and Technical Information of China (English)



    Objective To observe the influence of the medication administration sequence of taxanes and anthracyclines on the recent effect in patients with breast cancer,in order to improve the prognosis of patients with breast cancer. Methods From June 2010 to June 2013,60 patients with breast cancer were selected as the research object according to the medication administration sequence, they were divided into observation group and control group,with 30 cases in each group. The observation group was treated with docetaxel on the first day and epirubicin on the second day;the control group was treated with epirubicin on the first day,and docetaxel on the second day. The clinical efficacy,adverse reactions and short-term survival rates were compared between the two groups. Results The total effec-tive rate and clinical benefit rate of the observation group were 76. 67% and 93. 33% ,there were no sig-nificant difference between the two groups(P ﹥ 0. 05). The 1,2 year survival rate in observation group was 93. 33% and 86. 67% ,there were no significant difference between the two groups(P ﹥ 0. 05). There was no significant difference in the incidence of adverse reactions between the two groups(P ﹥0. 05). Conclusions In the neoadjuvant treatment of breast cancer,there were not significantly differ-ence between taxanes and anthracyclines drugs in sequence on the patient’s clinical curative effect and short-term survival.%目的:探讨紫杉烷类药物与蒽环类药物用药顺序对乳腺癌患者近期疗效的影响,旨在为改善乳腺癌患者预后提供参考依据。方法选择2010年6月至2013年6月收治的60例乳腺癌患者作为研究对象,根据不同用药顺序分为观察组和对照组,每组30例,观察组第1天用多西他赛,第2天用表柔比星;对照组第1天用表柔比星,第2天用多西他赛。比较两组患者的临床疗效、不良反应及近期生存率。结果观察组总有效率、临床获益率分别为76

  15. 穴位埋线联合GT方案治疗蒽环类耐药转移性乳腺癌的临床研究%Clinical Research of Acupoint Catgut Implantation and GT Program in the treatment of Anthracycline-Resistance Metastatic Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    王志光; 向培; 范先基; 邢晓娟; 王三虎; 王志祥; 张定进


    目的 评估穴位埋线在GT方案[即紫杉醉(PTX)和吉西他滨(GEM)3周联合化疗方案]在转移性乳腺癌(mBC)患者治疗中的临床作用.方法 63例既往应用蒽环类药物治疗的mBC患者,随机分成两组,治疗组32例,接受GT方案化疗,每3周重复,同时化疗第1天和第8天接受穴位埋线治疗;对照组31例,只接受化疗.所有患者均评估不良反应,评价疗效.结果 两组疗效差异无统计学意义.平均随访25个月,平均疾病进展时间为7.1个月,治疗组及对照组中位无进展生存期分别为(7.92±0.59)、(6.41±0.33)月,差异有统计学意义(P=0.028).粒细胞降低两组差异有统计学意义(P=0.044).消化道反应两组差异有统计学意义(P=0.047).结论 埋线配合GT方案化疗对既往接受过蒽环类药物治疗的mBC患者有效,埋线干预能降低化疗药物的血液学及消化道毒性,并能延长无进展生存期.%Objective To evaluate the clinical function of acupoint catgut implantation in GT pro-gram( the three weeks allied chemotherapy of paclitaxel and gemcitabline )in the treatment of metastatic breast cance(MBC ). Methods 63 cases of MBC, which had been treated with anthracycline were randomized into two groups. 32 cases in a treatment group were treated with GT chemotherapy,repeated every 3 weeks; at the same time,on the 1st and 8th days of chemotherapy,the acupoint catgut implantation was applied. 31 cases in a control group only received chemotherapy. The adverse reactions and therapeutic effect were evaluated for all the patients. Results The therapeutic effect was not significantly different in statistics between two groups. The mean of the follow - up visit time was 25 months. The mean of the disease progression time was 7. 1 months. The median progression -free survival was( 7. 92 ±0. 59 )months and( 6. 41 ±0. 33 )months in the treatment group and the control group respectively, presenting the statistically significant difference( P = 0

  16. Clinical Observation of Aprepitant Triple Therapy on Prevention of Nausea and Vomiting Caused by Anthracycline Combined Cyclophosphamide Chemotherapy Regimen for Breast Cancer%阿瑞匹坦三联用药预防乳腺癌蒽环类药物联合环磷酰胺化疗致恶心呕吐的效果观察

    Institute of Scientific and Technical Information of China (English)

    童雅兰; 韩涛; 宋树玺; 郑振东; 屈淑贤; 邱佳宁; 刘兆喆; 郭放; 谢晓冬


    Objective To investigate the effect of combined therapy consisting of aprepitant, tropisetron and dexam-ethasone in prevention of nausea and vomiting induced by breast cancer chemotherapy based on anthracycline and cyclophos-phamide. Methods A total of 62 cases of breast cancer collected from Oncology Department in General Hospital of Shenyang Military Area Command during January 2014 and June 2015 were selected, and those patients all underwent chemotherapy consisting of anthracycline (epirubicin or doxorubicin) combined cyclophosphamide and they were divided into experimental group ( n=31 ) and control group ( n =31 ) by CINV ( chemotherapy-induced nausea and vomiting ) regimen. The control group was given tropisetron and dexamethasone combined regimen in prevention of CINV while the experimental group was added with aprepitant based on the drug used by the control group. The effect and adverse reaction of two groups in acute phase (0-24 h) and delay period (24-120 h) on preventing nausea and vomiting were observed. Results The complete re-sponse rate and the control rate of acute phase had no statistical difference between the two groups (Z=-1. 579, P=0. 114);however, for the delayed vomiting, the complete response rate and control rate of the experimental group were higher than that of the control group and there was significant statistical difference (Z=-2. 196, P=0. 028). Adverse reactions were mild and tolerable with no significant differences between the 2 groups (P>0. 05). Conclusion The combined therapy of aprepitant is definitely effective for the delayed vomiting induced by anthracycline combined cyclophosphamide chemotherapy regimen of breast cancer, and the toxic reaction is tolerable.%目的:评估阿瑞匹坦、托烷司琼、地塞米松三联方案预防乳腺癌蒽环类药物联合环磷酰胺化疗致恶心呕吐的效果及安全性。方法选择2014年1月—2015年6月沈阳军区总医院肿瘤科收治的接收蒽环类药物(表柔

  17. [Anthracycline-induced cardiotoxicity: report of fatal cases]. (United States)

    Vargas-Neri, Jessica Liliana; Castelán-Martínez, Osvaldo Daniel; de Jesús Estrada-Loza, María; Betanzos-Cabrera, Yadira; Rivas-Ruiz, Rodolfo


    Introducción: las antraciclinas son fármacos eficaces en el tratamiento de pacientes pediátricos con cáncer. Sin embargo, la cardiotoxicidad inducida por antraciclinas (CIA) es una reacción adversa grave que afecta la sobrevida de niños y jóvenes. Casos clínicos: el caso 1 estuvo constituido por una paciente de nueve años con linfoma de Hodgkin estadio IV con 12 ciclos de quimioterapia con epirrubicina y una dosis acumulada de 576 mg/m2. Después del último ciclo de quimioterapia, la paciente ingresó con respuesta inflamatoria sistémica, astenia y adinamia. El ecocardiograma reportó una FEVI de 22 %, FA de 11 % e insuficiencia mitral moderada. La paciente falleció dos días después con diagnóstico de cardiomiopatía dilatada secundaria a antraciclinas. El caso 2 fue el de una paciente de 15 años con linfoma no Hodgkin tipo Burkitt estadio IV, con dos ciclos de quimioterapia con epirrubicina y una dosis acumulada de 90 mg/m2. Después del último ciclo, la paciente presentó diversos focos infecciosos. El ecocardiograma reportó una FEVI de 49 %, una FA de 20 % y dilatación del ventrículo izquierdo con aplanamiento septal. La paciente falleció 13 días después del diagnóstico de cardiomiopatía dilatada por antraciclinas. Conclusión: la CIA es un problema en los pacientes pediátricos que reciben antraciclinas. El monitoreo durante y después de la quimioterapia es indispensable para detectar el inicio del daño cardiaco a fin de brindar una intervención oportuna que evite la evolución a una insuficiencia cardiaca.

  18. 老年乳腺癌患者应用非蒽环类辅助化疗方案的安全性及耐受性临床研究%Safety and tolerance of non-anthracyclin regimen adjuvant chemotherapy in elderly breast cancer patients

    Institute of Scientific and Technical Information of China (English)

    韩颖; 李俏; 李青; 徐兵河; 张频; 袁芃; 王佳玉; 马飞; 蔡瑞刚; 樊英


    younger. The aim of this study was to investigate the safety and tolerance with non-anthracyclin regimen as adjuvant chemotherapy in elderly breast cancer patients. Methods:From Nov. 2008 to Jan. 2012, 56 patients (≥65 years) after surgical excision were enrolled into this study. The patients were divided into two groups:TC and PC groups. Each patient received 4 or 6 cycles of chemotherapy of PC (175 and 600 mg/m2, respectively;n=21) or TC (75 and 600 mg/m2, respectively;n=35), administered intravenously every 3 weeks, as adjuvant chemotherapy. Radiation therapy (as indicated) and endocrine therapy, for patients with hormone receptor-positive disease, were administered after completion of chemotherapy. Results: In this study, 50 patients completed chemotherapy as plan, the proportion of two groups were above 90%. After a median follow-up of 33 months, the median disease-free survival(DFS) and overall survival(OS) were not reached. The relapse-free rate and survival rate were 89.5%and 100%in the PC regime group, which were 90.3%and 96.8%in the TC regime group. Major toxicities included:neutropenia, leucopenia, alopecia, nausea, vomiting and various degree of peripheral neuropathy. The incidence of gradeⅢ-Ⅳneutropenia was 76.2%in PC group vs 48.6%in TC group (P=0.044). The most common cause for withdrawing from treatment was to be unable to tolerate the adverse effects. Conclusion:Adjuvant chemotherapy with paclitaxel and cyclophosphamide is safe, tolerable and promising for elderly breast cancer patients.

  19. 索拉非尼联合蒽环类化疗药对乳腺癌MCF-7细胞增殖周期的影响%Affect of the Coadministration of Sorafenib and anthracycline chemother-apy drug on the cell cycle of breast cancer MCF-7 cell

    Institute of Scientific and Technical Information of China (English)

    胡燕; 吴冰; 张钧; 王亮和; 戈伟; 罗荣城


    目的:探讨索拉非尼联合蒽环类化疗药表阿霉素对乳腺癌MCF-7细胞增殖周期的作用。方法细胞做四甲基偶氮唑盐实验,绘制细胞增殖曲线。实验分为4组:对照组、索拉非尼单药组、表阿霉素单药组、联合组(索拉非尼+表阿霉素)。用聚酰亚胺染色后,经流式细胞仪检测各组细胞增殖周期的变化。结果细胞增殖曲线可见细胞传代后开始增殖,4~5d达到峰值,后随着时间的延长,细胞增殖受抑越来越明显。流式细胞仪检测细胞周期结果显示,索拉非尼单药组使MCF-7细胞阻滞于G0/G1期[(62.837±0.511)%]与对照组[(49.250±0.826)%]比较,差异有统计学意义(P<0.05);表阿霉素单药组使细胞阻滞于S期[(24.976±0.409)%],与对照组[(23.473±1.009)%]比较,差异有统计学意义(P<0.05);联合组G0/G1期细胞比率[(64.373±0.429)%]高于对照组及表阿霉素单药组[(50.980±0.403)%],差异均有统计学意义(均P<0.05)。结论索拉非尼和表阿霉素的联合应用可以使乳腺癌MCF-7细胞明显阻滞于G0/G1,可以为乳腺癌的联合化疗提供一定的理论±据。%Objective To investigate the affect of Sorafenib combined with anthracycline chemotherapy Epirubicin on the proliferation of breast cancer MCF-7 cell cycle. Methods Cells growth curve were drawn after the MTT experiment. Four different groups were set up: control group, Sorafenib group, EPI group and Sorafenib+EPI (combination) group. The change of cell cycles were detected by PI single staining and flow cytometry. Results Cell growth curve showed, passaged cells began to proliferate, and reached the peak after 4-5 days, with the prolongation of time, cell prolifera-tion was inhibited more and more obvious. The cell cycle by flow cytometry showed that, the Sorafenib group [(62.837±0.511)%] induced G0/G1 phase mitosis arrest, compared with control group [(49.250±0.826)%], the difference was statis-tically significant

  20. Subclinical Ventricular Dysfunction Detected by Speckle Tracking Two Years after Use of Anthracycline

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    André Luiz Cerqueira de Almeida


    Full Text Available Background: Heart failure is a severe complication associated with doxorubicin (DOX use. Strain, assessed by two-dimensional speckle tracking (2D-STE, has been shown to be useful in identifying subclinical ventricular dysfunction. Objectives: a To investigate the role of strain in the identification of subclinical ventricular dysfunction in patients who used DOX; b to investigate determinants of strain response in these patients. Methods: Cross-sectional study with 81 participants: 40 patients who used DOX ±2 years before the study and 41 controls. All participants had left ventricular ejection fraction (LVEF ≥55%. Total dose of DOX was 396mg (242mg/ms2. The systolic function of the LV was evaluated by LVEF (Simpson, as well as by longitudinal (εLL, circumferential (εCC, and radial (εRR strains. Multivariate linear regression (MLR analysis was performed using εLL (model 1 and εCC (model 2 as dependent variables. Results: Systolic and diastolic blood pressure values were higher in the control group (p < 0.05. εLL was lower in the DOX group (-12.4 ±2.6% versus controls (-13.4 ± 1.7%; p = 0.044. The same occurred with εCC: -12.1 ± 2.7% (DOX versus -16.7 ± 3.6% (controls; p < 0.001. The S’ wave was shorter in the DOX group (p = 0.035. On MLR, DOX was an independent predictor of reduced εCC (B = -4.429, p < 0.001. DOX (B = -1.289, p = 0.012 and age (B = -0.057, p = 0.029 were independent markers of reduced εLL. Conclusion: a εLL, εCC and the S’ wave are reduced in patients who used DOX ±2 years prior to the study despite normal LVEF, suggesting the presence of subclinical ventricular dysfunction; b DOX was an independent predictor of reduced εCC; c prior use of DOX and age were independent markers of reduced εLL.

  1. Late cardiac effects of anthracycline containing therapy for childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Rathe, Mathias; Carlsen, Niels L T; Oxhøj, Henrik


    At present about 80% of children with acute lymphoblastic leukemia (ALL) will be cured following treatment with multi-drug chemotherapy. A major concern for this growing number of survivors is the risk of late effects of treatment. The aim of this study was to determine whether signs of cardiomyo...

  2. On the possibility of determining anthracycline antibiotics in aqueous solutions using optical analytical system (biosensor) (United States)

    Yevdokimov, Yu. M.; Skuridin, S. G.; Salyanov, V. I.; Semenov, S. V.; Sol'ev, P. N.; Valuev-Elliston, V. T.; Vereshchagin, F. V.; Chulkov, D. P.; Kompanets, O. N.


    We propose a version of the theory describing the circular dichroism spectra of cholesteric liquidcrystal dispersion particles of double-stranded DNA. The basis of the theory is the concept of absorption of electromagnetic waves by large molecular systems. The effect of physical parameters of dispersion particles on their circular dichroism is theoretically determined. It is experimentally demonstrated that circular dichroism can be used as a convenient tool for creating an optical analytical system for the determination of biologically active compounds that interact with DNA molecules.

  3. Potential role of pemetrexed in metastatic breast cancer patients pre-treated with anthracycline or taxane

    Institute of Scientific and Technical Information of China (English)

    Li-Yan Zhou; Ye-Hui Shi; Yong-Sheng Jia; Zhong-Sheng Tong


    Objectives: This article reviews pharmacology, pharmacokinetic properties, clinical efficacy, and safety in metastatic breast cancer patients, as well as the predictive biomarkers for outcome of treatment with pemetrexed-based regimens. Methods: PubMed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were‘‘pemetrexed’’ or‘‘LY231514’’ or“Alimta”,“metastatic breast cancer”, and“advanced breast cancer”. Results: There were 15 studies (n ¼ 1002) meeting our criteria for evaluation. Eight single-agent trials (n ¼ 551) and seven using combinations with other agents (n ¼ 451) were identified that evaluated pemetrexed for use in patients with metastatic breast cancer. Response rates to pemetrexed as a single agent varied from 8%to 31%, and with combination therapy have been reported to be between 15.8% and 55.7%. With routine supplementation of patients with folic acid, dexamethasone, and vitamin B12, the toxicity profile of these patients was mild, including dose-limiting neutropenia and thrombocytopenia, as well as lower grades of reversible hepatotoxicity and gastrointestinal toxicity. Expression of thymidylate synthase (TS) and other biomarkers are associated with the prognosis and sensitivity for pemetrexed in breast cancer. Conclusion: Pemetrexed has shown remarkable activity with acceptable toxicities for treatment of metastatic breast cancer patients. Translational research on pemetrexed in breast cancer identified biomarkers as well as additional genes important to its clinical activity and toxicity. Further research is needed to clarify the role of pemetrexed in breast cancer treatment in order to guide oncologists. Copyright © 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Com-munications Co., Ltd. This is an open access article under the CC BY-NC-ND license (

  4. Complementation of the Yeast Model System Reveals that Caenorhabditis elegans OCT-1 Is a Functional Transporter of Anthracyclines


    Nicolas Brosseau; Emil Andreev; Dindial Ramotar


    The yeast plasma membrane protein Agp2 belongs to the family of amino acid transporters. It acts as a regulator that controls the expression of several uptake transporter genes such as DUR3 and SAM3 encoding two high-affinity polyamine permeases. agp2Δ mutants display extreme resistance to several cationic compounds including polyamines, the anticancer agent bleomycin, and cationic antifungal peptides. We propose that Agp2 might be involved in regulating the uptake of other cationic anticance...

  5. Interobserver, intraobserver and intrapatient reliability scores of myocardial strain imaging with 2-d echocardiography in patients treated with anthracyclines.

    NARCIS (Netherlands)

    Mavinkurve-Groothuis, A.M.C.; Weijers, G.; Groot-Loonen, J.J.; Pourier, M.S.; Feuth, A.B.; Korte, C.L. de; Hoogerbrugge, P.M.; Kapusta, L.


    Myocardial strain imaging with 2-D echocardiography is a relatively new noninvasive method to assess myocardial deformation. To determine the interobserver, intraobserver and intrapatient reliability scores, we evaluated myocardial strain measurements of 10 asymptomatic survivors of childhood cancer

  6. Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity. (United States)

    Batrakova, E V; Dorodnych, T Y; Klinskii, E Y; Kliushnenkova, E N; Shemchukova, O B; Goncharova, O N; Arjakov, S A; Alakhov, V Y; Kabanov, A V


    The chemosensitising effects of poly(ethylene oxide)-poly(propylene oxide)-poly-(ethylene oxide) (PEO-PPO-PEO) block copolymers (Pluronic) in multidrug-resistant cancer cells has been described recently (Alakhov VY, Moskaleva EY, Batrakova EV, Kabanov AV 1996, Biocon. Chem., 7, 209). This paper presents initial studies on in vivo evaluation of Pluronic copolymers in the treatment of cancer. The anti-tumour activity of epirubicin (EPI) and doxorubicin (DOX), solubilised in micelles of Pluronic L61, P85 and F108, was investigated using murine leukaemia P388 and daunorubicin-sensitive Sp2/0 and -resistant Sp2/0(DNR) myeloma cells grown subcutaneously (s.c.). The study revealed that the lifespan of the animals and inhibition of tumour growth were considerably increased in mice treated with drug/copolymer compositions compared with animals treated with the free drugs. The anti-tumour activity of the drug/copolymer compositions depends on the concentration of the copolymer and its hydrophobicity, as determined by the ratio of the lengths of hydrophilic PEO and hydrophobic PPO segments. The data suggest that higher activity is associated with more hydrophobic copolymers. In particular, a significant increase in lifespan (T/C> 150%) and tumour growth inhibition (> 90%) was observed in animals with Sp2/0 tumours with EPI/P85 and DOX/L61 compositions. The effective doses of these compositions caused inhibition of Sp2/0 tumour growth and complete disappearance of tumour in 33-50% of animals. Future studies will focus on the evaluation of the activity of Pluronic-based compositions against human drug-resistant tumours.

  7. Anthracycline Drugs on Modified Surface of Quercetin-Loaded Polymer Nanoparticles: A Dual Drug Delivery Model for Cancer Treatment.

    Directory of Open Access Journals (Sweden)

    Chabita Saha

    Full Text Available Polymer nanoparticles are vehicles used for delivery of hydrophobic anti-cancer drugs, like doxorubicin, paclitaxel or chemopreventors like quercetin (Q. The present study deals with the synthesis and characterisation of nano formulations (NFs from Q loaded PLGA (poly lactic-co-glycolic acid nano particles (NPs by surface modification. The surface of Q-loaded (NPs is modified by coating with biopolymers like bovine serum albumin (BSA or histones (His. Conventional chemotherapeutic drugs adriamycin (ADR and mitoxantrone (MTX are bound to BSA and His respectively before being coated on Q-loaded NPs to nano formulate NF1 and NF2 respectively. The sizes of these NFs are in the range 400-500 nm as ascertained by SEM and DLS measurements. Encapsulation of Q in polymer NPs is confirmed from shifts in FT-IR, TGA and DSC traces of Q-loaded NPs compared to native PLGA and Q. Surface modification in NFs is evidenced by three distinct regions in their TEM images; the core, polymer capsule and the coated surface. Negative zeta potential of Q-loaded NPs shifted to positive potential on surface modification in NF1 and NF2. In vitro release of Q from the NFs lasted up to twenty days with an early burst release. NF2 is better formulation than NF1 as loading of MTX is 85% compared to 23% loading of ADR. Such NFs are expected to overcome multi-drug resistance (MDR by reaching and treating the target cancerous cells by virtue of size, charge and retention.

  8. Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle (United States)

    Gouspillou, Gilles; Scheede-Bergdahl, Celena; Spendiff, Sally; Vuda, Madhusudanarao; Meehan, Brian; Mlynarski, Heather; Archer-Lahlou, Elodie; Sgarioto, Nicolas; Purves-Smith, Fennigje M.; Konokhova, Yana; Rak, Janusz; Chevalier, Stéphanie; Taivassalo, Tanja; Hepple, Russell T.; Jagoe, R. Thomas


    Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are now implicated in causing impaired muscle function in long-term survivors. However, no comprehensive assessment of skeletal muscle mitochondrial functions in long-term survivors has been performed and the presence of persistent chemotherapy-induced skeletal muscle mitochondrial dysfunction remains a strong possibility. Non-tumour-bearing mice were treated with two drugs that have been used frequently in ALL treatment (doxorubicin and dexamethasone) for up to 4 cycles at 3-week intervals and euthanized 3 months after the 4th cycle. Treated animals had impaired growth and lower muscle mass as well as reduced mitochondrial respiration and increased reactive oxygen species production per unit oxygen consumption. Mitochondrial DNA content and protein levels of key mitochondrial membrane proteins and markers of mitochondrial biogenesis were unchanged, but protein levels of Parkin were reduced. This suggests a novel pattern of chemotherapy-induced mitochondrial dysfunction in skeletal muscle that persists because of an acquired defect in mitophagy signaling. The results could explain the observed functional impairments in adult survivors of childhood ALL and may also be relevant to long-term survivors of other cancers treated with similar regimes. PMID:25732599

  9. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens

    NARCIS (Netherlands)

    Montesinos, Pau; Rayon, Chelo; Vellenga, Edo; Brunet, Salut; Gonzalez, Jose; Gonzalez, Marcos; Holowiecka, Aleksandra; Esteve, Jordi; Bergua, Juan; Gonzalez, Jose D.; Rivas, Concha; Tormo, Mar; Rubio, Vicente; Bueno, Javier; Manso, Felix; Milone, Gustavo; de la Serna, Javier; Perez, Inmaculada; Perez-Encinas, Manuel; Krsnik, Isabel; Ribera, Josep M.; Escoda, Lourdes; Lowenberg, Bob; Sanz, Miguel A.


    The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthr

  10. Pneumocystis jiroveci pneumonia (PCP) in patients receiving neoadjuvant and adjuvant anthracycline-based chemotherapy for breast cancer: incidence and risk factors. (United States)

    Waks, Adrienne G; Tolaney, Sara M; Galar, Alicia; Arnaout, Amal; Porter, Julie B; Marty, Francisco M; Winer, Eric P; Hammond, Sarah P; Baden, Lindsey R


    Opportunistic infection with Pneumocystis jiroveci pneumonia (PCP) has not been recognized as a significant complication of early-stage breast cancer treatment. However, we have observed an increase in PCP incidence among patients receiving chemotherapy for early-stage breast cancer. Herein we identify risk factors for and calculate incidence of PCP in this population. We identified all cases of PCP at Dana-Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH) from 1/1/2000 to 12/31/2013 in patients with stage I-III breast cancer treated with an adriamycin/cyclophosphamide (AC)-containing regimen. Nineteen cases of PCP in non-metastatic breast cancer patients were identified. All patients with PCP were diagnosed after receipt of either three or four cycles of AC chemotherapy on a dose-dense schedule. Patients who developed PCP were treated with median 16.4 mg prednisone equivalents/day as nausea prophylaxis for a median 64 days. The overall incidence of PCP among 2057 patients treated with neoadjuvant or adjuvant dose-dense AC for three or more cycles was 0.6 % (95 % confidence interval 0.3-1.0 %). No PCP was diagnosed in 1001 patients treated with non-dose-dense AC. There was one death from PCP. Women receiving dose-dense AC chemotherapy for early-stage breast cancer are at risk for PCP. Administering the same chemotherapy and corticosteroid dose over an 8-week versus 12-week non-dose-dense schedule appears to have created a novel infectious vulnerability. Replacing dexamethasone with alternative anti-emetics may mitigate this risk.

  11. Clinico pathologic session: case 4/2000 - heart failure in a 9-year-old child after treatment with anthracycline for Wilm's tumor

    Energy Technology Data Exchange (ETDEWEB)

    Mansur, Alfredo Jose [Sao Paulo Univ., SP (Brazil). Faculdade de Medicina. Instituto do Coracao] (ed.)


    The evolution of the case is studied. The patient was diagnosed with state III nephroblastoma and underwent nephrectomy, followed by chemotherapy and radiotherapy. Diagnostic examinations (electrocardiogram, chest X-ray and radiocardiography with technetium-99m labelled red blood cell) are discussed. Several differential diagnoses are reported as well as urologist's comments. Autopsy results are presented.

  12. Pharmacokinetics of DA-125, a new anthracycline, after intravenous administration to uranyl nitrate-induced acute renal failure rats or protein-calorie malnutrition rats. (United States)

    Kim, Y G; Yoon, E J; Yoon, W H; Shim, H J; Lee, S D; Kim, W B; Yang, J; Lee, M G


    The pharmacokinetics of DA-125 were compared after intravenous (i.v.) administration of the drug, 10 mg kg-1, to control male Sprague-Dawley rats (n = 9) and uranyl nitrate-induced acute renal failure (U-ARF, n = 12) rats, or male Sprague-Dawley rats fed on a 23% (control, n = 8) or a 5% (protein-calorie malnutrition, PCM, n = 9) protein diet. After i.v. administration of DA-125, almost 'constant' plasma concentrations of M1, M2, and M4 were maintained from 1-2 h to 8-10 h in all rat groups due to the continuous formation of M2 from M1 and M4 from M3. The plasma concentrations of M3 were the lowest among M1-M4 for all rat groups due to the rapid and almost complete conversion of M3 to M4 and other metabolite(s). The AUCt values of M1 (115 against 82.5 micrograms min mL-1), M2 (33.0 against 23.6 micrograms min mL-1), and M4 (26.3 against 15.1 micrograms min mL-1) were significantly higher in the U-ARF rats than in the control rats. The percentages of i.v. dose excreted in 24 h urine as M1 (under the detection limit against 0.316%), M2 (under the detection limit against 5.58%), and M4 (0.0174 against 0.719%)--expressed in terms of DA-125--were significantly lower in the U-ARF rats than in the control rats, and this could be due to the decreased kidney function in the U-ARF rats. However, the percentages of i.v. dose recovered from the GI tract at 24 h as M1 (0.0532% against under the detection limit), M3 (0.0286% against under the detection limit), and M4 (0.702% against 0.305%)--expressed in terms of DA-125--were significantly greater in the U-ARF rats than in the control rats. All U-ARF rats had ascites, but the concentrations of M1 (0.0320 micrograms mL-1), M2 (0.0265 micrograms mL-1), M3 (under the detection limit), and M4 (0.032 micrograms mL-1) in the ascites from one rat were almost negligible. The plasma concentrations and most of the pharmacokinetic parameters of M1, M2, and M4 were not significantly different between the PCM rats and their control rats.

  13. Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy

    NARCIS (Netherlands)

    Barragan, Eva; Montesinos, Pau; Camos, Mireia; Gonzalez, Marcos; Calasanz, Maria J.; Roman-Gomez, Jose; Gomez-Casares, Maria T.; Ayala, Rosa; Lopez, Javier; Fuster, Oscar; Colomer, Dolors; Chillon, Carmen; Larrayoz, Maria J.; Sanchez-Godoy, Pedro; Gonzalez-Campos, Jose; Manso, Felix; Amador, Maria L.; Vellenga, Edo; Lowenberg, Bob; Sanz, Miguel A.


    Background Fms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established. Design and Methods We evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoic acid and a

  14. Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy

    NARCIS (Netherlands)

    P. Montesinos (Pau); M. González (Marcos); F. Manso (Félix); E. Vellenga (Edo); B. Löwenberg (Bob); M.A. Sanz (Miguel Angel)


    textabstractBackground Fms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established. Design and Methods We evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoi

  15. TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

    DEFF Research Database (Denmark)

    Hertel, Pernille Bræmer; Tu, Dongsheng; Ejlertsen, Bent Laursen


    , 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus...... treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF...... these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF...

  16. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all- trans retinoic acid and anthracycline chemotherapy: Characteristics, outcome, and prognostic factors

    NARCIS (Netherlands)

    P. Montesinos (Pau); J.M. Bergua (Juan Miguel); E. Vellenga (Edo); C. Rayón (Chelo); R. Parody (Ricardo); J. de Serna (Javier); A. León (Angel); J. Esteve (Jordi); G. Milone (Gustavo); G. Debén (Guillermo); C. Rivas (Concha); M. González (Marcos); M. Tormo (Mar); D.M. Joaquín; J.D. González (José David); S. Negri (Silvia); E. Amutio (Elena); S. Brunet (Salut); B. Löwenberg (Bob); M.A. Sanz (Miguel Angel)


    textabstractDifferentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all- trans retinoic acid (ATRA). Detailed knowl- edge about DS has remained limited. We present an analysis of the incidence, char- a

  17. Lack of TIMP-1 tumour cell immunoreactivity predicts effect of adjuvant anthracycline-based chemotherapy in patients (n=647) with primary breast cancer

    DEFF Research Database (Denmark)

    Willemoe, Gro L.; Hertel, Pernille Bræmer; Bartels, Annette;


    PURPOSE: A number of prospective studies have shown that adjuvant CEF significantly improves disease-free and overall survival as compared to CMF in breast cancer patients. Our aim was to determine whether the benefit of epirubicin versus methotrexate differs according to TIMP-1 tumour cell...

  18. HER2,TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients

    DEFF Research Database (Denmark)

    Ejlertsen, Bent; Jensen, Maj-Britt; Nielsen, Kirsten V.


    PURPOSE To evaluate whether the combination of HER2 with TIMP-1 (HT) or TOP2A with TIMP-1 (2T) more accurately identifies patients who benefit from cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) than these markers do when...... nonresponsive and otherwise HT responsive. Similarly, the 2T panel was constructed by combining TOP2A and TIMP-1; tumors with normal TOP2A status and TIMP-1 immunoreactivity were classified as 2T-nonresponsive and otherwise 2T-responsive. Results In total, 623 tumors were available for analysis, of which 154...... lacked TIMP-1 immunoreactivity, 188 were HER2 positive, and 139 had a TOP2A aberration. HT status was a statistically significant predictor of benefit from CEF compared with CMF (P(interaction) = .036 for invasive disease-free survival [IDFS] and .047 for overall survival [OS]). The 269 (43%) patients...

  19. HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients

    DEFF Research Database (Denmark)

    Ejlertsen, Bent; Jensen, Maj-Britt; Nielsen, Kirsten


    PURPOSE To evaluate whether the combination of HER2 with TIMP-1 (HT) or TOP2A with TIMP-1 (2T) more accurately identifies patients who benefit from cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) than these markers do when...... nonresponsive and otherwise HT responsive. Similarly, the 2T panel was constructed by combining TOP2A and TIMP-1; tumors with normal TOP2A status and TIMP-1 immunoreactivity were classified as 2T-nonresponsive and otherwise 2T-responsive. Results In total, 623 tumors were available for analysis, of which 154...... lacked TIMP-1 immunoreactivity, 188 were HER2 positive, and 139 had a TOP2A aberration. HT status was a statistically significant predictor of benefit from CEF compared with CMF (P(interaction) = .036 for invasive disease-free survival [IDFS] and .047 for overall survival [OS]). The 269 (43%) patients...

  20. The role of TNF-α, Fas/Fas ligand system and NT-proBNP in the early detection of asymptomatic left ventricular dysfunction in cancer patients treated with anthracyclines

    Directory of Open Access Journals (Sweden)

    Alexandros Kouloubinis


    Conclusion: SFas, sFas-L and NT-proBNP correlate with reductions in LVEF and could be used as sensitive biochemical indices for the detection of asymptomatic left ventricular dysfunction in cancer patients under cardiotoxic chemotherapy.

  1. High WT1 expression is an early predictor for relapse in patients with acute promyelocytic leukemia in first remission with negative PML-RARa after anthracycline-based chemotherapy: a single-center cohort study

    Directory of Open Access Journals (Sweden)

    Jae-Ho Yoon


    Full Text Available Abstract Wilms’ tumor gene 1 (WT1 expression is a well-known predictor for relapse in acute myeloid leukemia. We monitored WT1 decrement along the treatment course to identify its significant role as a marker for residual disease in acute promyelocytic leukemia (APL and tried to suggest its significance for relapse prediction. In this single center retrospective study, we serially measured PML-RARa and WT1 expression from 117 APL patients at diagnosis, at post-induction and post-consolidation chemotherapies, and at every 3 months after starting maintenance therapy. All 117 patients were in molecular remission after treatment of at least 2 consolidation chemotherapies. We used WT1 ProfileQuant™ kit (Ipsogen for WT1 monitoring. High WT1 expression (>120 copies/104 ABL1 after consolidation and at early period (3 months after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR were not detected except for one sample with early relapse. Patients with high WT1 expression at 3 months after maintenance therapy (n = 40 showed a significantly higher relapse rate (30.5 vs. 6.9%, P < 0.001 and inferior disease free survival (62.8 vs. 91.4%, P < 0.001. Multivariate analysis revealed that high peak leukocyte counts at diagnosis (HR = 6.4, P < 0.001 and high WT1 expression at 3 months after maintenance therapy (HR = 7.1, P < 0.001 were significant factors for prediction of relapse. Our data showed high post-remission WT1 expression was a reliable marker for prediction of subsequent molecular relapse in APL. In this high-risk group, early intervention with ATRA ± ATO, anti-CD33 antibody therapy, and WT1-specific therapy may be used for relapse prevention. Trial registration Clinical Research Information Service (CRIS, KCT0002079

  2. Treatment of experimental extravasation of amrubicin, liposomal doxorubicin, and mitoxantrone with dexrazoxane

    DEFF Research Database (Denmark)

    Langer, Seppo W; Thougaard, Annemette V; Sehested, Maxwell;


    Dexrazoxane is an established treatment option in extravasation of the classic anthracyclines such as doxorubicin, epirubicin, and daunorubicin. However, it is not known whether the protection against the devastating tissue injuries extends into extravasation with new types of anthracyclines, the......, the anthracenediones, or the liposomal pegylated anthracycline formulations. We therefore tested the antidotal efficacy of dexrazoxane against extravasation of amrubicin, mitoxantrone, and liposomal pegylated doxorubicin in mice....

  3. Paclitaxel and doxorubicin in metastatic breast cancer

    DEFF Research Database (Denmark)

    Gehl, J; Boesgaard, M; Paaske, T;


    be explored. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been demonstrated to be highly effective in treating patients with advanced breast cancer, including those with anthracycline-resistant breast cancer, a fact that has led to efforts to combine paclitaxel and anthracyclines...

  4. Results of a randomized trial in children with Acute Myeloid Leukaemia : Medical Research Council AML12 trial

    NARCIS (Netherlands)

    Gibson, Brenda E. S.; Webb, David K. H.; Howman, Andrew J.; De Graaf, Siebold S. N.; Harrison, Christine J.; Wheatley, Keith


    The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (

  5. Myocardial function in children after fetal chemotherapy exposure. A tissue Doppler and myocardial deformation imaging study

    NARCIS (Netherlands)

    Gziri, M.M.; Hui, W.; Amant, F.; Calsteren, K. van; Ottevanger, N.; Kapusta, L.; Mertens, L.


    Chemotherapy and particularly anthracycline exposure are associated with acute and chronic cardiotoxicity. Few data exist on the effect of cardiac function after in utero exposure to maternal chemotherapy. Our recently published multicenter prospective study showed no significant changes in systolic


    Directory of Open Access Journals (Sweden)

    L. V. Bolotina


    Full Text Available Modern-day drug therapy has significantly increased the life expectancy of patients with breast cancer, therefore now this is the quality if the therapy itself which is of major importance. Cardiac toxicity of some cytostatics may come out in years after the therapy. Anthracycline antibiotics are considered to be the main factor leading to cardiotoxicity. In case of recurrent use of anthracycline antibiotics, the overall dose of these should have to be limited. The combination of anthracyclines with trastuzumab increases essentially the risk of cardiotoxicity. To reduce the risk of developing such severe epiphenomenon it is recommended to use pegylated liposomal forms of anthracyclines, to detect background diseases in due time, as well as to generally take preventive actions.

  7. A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo

    DEFF Research Database (Denmark)

    Grauslund, Morten; Vinding, Annemette; Füchtbauer, Annette C.;


    as an antidote for alleviating tissue damage and necrosis after accidental anthracycline extravasation. This dual modality of bisdioxopiperazines, including ICRF-187, raises the question of whether their pharmacological in vivo effects are mediated through interaction with topoisomerase II or via...

  8. How circulating tumor cells escape from multidrug resistance: translating molecular mechanisms in metastatic breast cancer treatment. (United States)

    Gradilone, Angela; Raimondi, Cristina; Naso, Giuseppe; Silvestri, Ida; Repetto, Lazzaro; Palazzo, Antonella; Gianni, Walter; Frati, Luigi; Cortesi, Enrico; Gazzaniga, Paola


    Resistance to anthracyclines is responsible for treatment failure in most patients with metastatic breast cancer. According to recent studies, the expression of specific drug transporters (MRPs) on circulating tumor cells is predictive of prognosis in different cancer types. We observed that patients whose circulating tumor cells expressed MRP1 and MRP2, two drug-export pumps responsible for anthracyclines efflux, who received conventional anthracyclines had a significantly shorter time to progression compared with patients sharing same characteristics who received non pegylated liposomal doxorubicin (P < 0.005). These results may highlight a new appealing role of the liposomal doxorubicin formulation, not only because of its reduced cardiac toxicity but especially referring to its theoretical efficacy in anthracycline-resistant breast cancer patients.

  9. Drug: D01264 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 301] 4 Agents affecting cellular function 42 Antineoplastics 423 Antibiotics 4235 Anthracycline antibiotics ...264 Daunorubicin hydrochloride (JP16/USP) Antineoplastics [BR:br08308] Natural products Antibiotics Daunorub

  10. Drug: D01275 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ng cellular function 42 Antineoplastics 423 Antibiotics 4235 Anthracycline antibiotics D01275 Doxorubicin hy...tics [BR:br08308] Natural products Antibiotics Doxorubicin [ATC:L01DB01] D01275 D

  11. Potential Therapeutic Strategies for Hypertension-Exacerbated Cardiotoxicity of Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Robin K. Kuriakose


    Full Text Available Despite their recognized cardiotoxic effects, anthracyclines remain an essential component in many anticancer regimens due to their superior antitumor efficacy. Epidemiologic data revealed that about one-third of cancer patients have hypertension, which is the most common comorbidity in cancer registries. The purpose of this review is to assess whether anthracycline chemotherapy exacerbates cardiotoxicity in patients with hypertension. A link between hypertension comorbidity and anthracycline-induced cardiotoxicity (AIC was first suggested in 1979. Subsequent preclinical and clinical studies have supported the notion that hypertension is a major risk factor for AIC, along with the cumulative anthracycline dosage. There are several common or overlapping pathological mechanisms in AIC and hypertension, such as oxidative stress. Current evidence supports the utility of cardioprotective modalities as adjunct treatment prior to and during anthracycline chemotherapy. Several promising cardioprotective approaches against AIC pathologies include dexrazoxane, early hypertension management, and dietary supplementation of nitrate with beetroot juice or other medicinal botanical derivatives (e.g., visnagin and Danshen, which have both antihypertensive and anti-AIC properties. Future research is warranted to further elucidate the mechanisms of hypertension and AIC comorbidity and to conduct well-controlled clinical trials for identifying effective clinical strategies to improve long-term prognoses in this subgroup of cancer patients.

  12. Predictors for severe cardiac complications after hematopoietic stem cell transplantation. (United States)

    Sakata-Yanagimoto, M; Kanda, Y; Nakagawa, M; Asano-Mori, Y; Kandabashi, K; Izutsu, K; Imai, Y; Hangaishi, A; Kurokawa, M; Tsujino, S; Ogawa, S; Chiba, S; Motokura, T; Hirai, H


    The value of pre-transplant factors for predicting the development of cardiac complications after transplantation has been inconsistent among studies. We analyzed the impact of pre-transplant factors on the incidence of severe cardiac complications in 164 hematopoietic stem cell transplant recipients. We identified eight patients (4.8%) who experienced grade III or IV cardiac complications according to the Bearman criteria. Seven died of cardiac causes a median of 3 days after the onset of cardiac complications. On univariate analysis, both the cumulative dose of anthracyclines and the use of anthracyclines within 60 days before transplantation affected the incidence of severe cardiac complications (P=0.0091 and 0.011). The dissociation of heart rate and body temperature, which reflects "relative tachycardia", was also associated with a higher incidence of cardiac complications (P=0.024). None of the variables obtained by electrocardiography or echocardiography were useful for predicting cardiac complications after transplantation, although the statistical power might not be sufficient to detect the usefulness of ejection fraction. On a multivariate analysis, the cumulative dose of anthracyclines was the only independent significant risk factor for severe cardiac complications. We conclude that the cumulative dose of anthracyclines is the most potent predictor of cardiac complications and the administration of anthracyclines should be avoided within two months before transplantation.

  13. Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer

    DEFF Research Database (Denmark)

    Szallasi, Zoltan Imre; Li, Yang; Zou, Lihua


    Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific...... chemotherapy drugs is a challenge but is necessary to improve outcomes. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed...... of LAPTM4B resulted in sequestration of the anthracycline doxorubicin, delaying its appearance in the nucleus. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a neoadjuvant chemotherapy trial in women with primary breast cancer. Our results suggest...

  14. Lack of independent prognostic and predictive value of centromere 17 copy number changes in breast cancer patients with known HER2 and TOP2A status

    DEFF Research Database (Denmark)

    Nielsen, Kirsten Vang; Ejlertsen, Bent; Møller, Susanne


    The clinical benefit of anthracyclines has been connected to HER2 status, TOP2A status and centromere 17 copy numbers (CEN-17). Data from a clinical trial randomizing patients to anthracyclines was used to assess whether the number of CEN-17 in breast cancers may predict incremental responsiveness...... to anthracyclines besides what is obtained when used relatively to TOP2A and HER2. As cut sections of paraffin-embedded tissue are prone to truncation of nuclei, strict definition of ploidy levels is lacking. We therefore used normal breast tissue to assist define ploidy levels in cut sections. Fluorescence in situ...... hybridization (FISH) with centromere 17 (CEN-17) and TOP2A was performed on 120 normal breast specimens. The diploid CEN-17 copy number was reduced from the expected two signals in whole nuclei to an average of 1.68 signals per nucleus in cut sections of normal breast. Ploidy levels determined in normal breast...

  15. Synthesis of Enantiomerically Pure Anthracyclinones (United States)

    Achmatowicz, Osman; Szechner, Barbara

    The anthracycline antibiotics are among the most important clinical drugs used in the treatment of human cancer. The search for new agents with improved therapeutic efficacy and reduced cardiotoxicity stimulated considerable efforts in the synthesis of new analogues. Since the biological activity of anthracyclines depends on their natural absolute configuration, various strategies for the synthesis of enantiomerically pure anthracyclinones (aglycones) have been developed. They comprise: resolution of racemic intermediate, incorporation of a chiral fragment derived from natural and non-natural chiral pools, asymmetric synthesis with the use of a chiral auxiliary or a chiral reagent, and enantioselective catalysis. Synthetic advances towards enantiopure anthracyclinones reported over the last 17 years are reviewed.

  16. Overview, prevention and management of chemotherapy extravasation. (United States)

    Kreidieh, Firas Y; Moukadem, Hiba A; El Saghir, Nagi S


    Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the clinical aspects of chemotherapy extravasation and latest advances in definitions, classification, prevention, management and guidelines. We review the grading of extravasation and tissue damage according to various chemotherapeutic drugs and present an update on treatment and new antidotes including dexrazoxane for anthracyclines extravasation. We highlight the importance of education and training of the oncology team for prevention and prompt pharmacological and non-pharmacological management and stress the availability of new antidotes like dexrazoxane wherever anthracyclines are being infused.

  17. Duxorubicin-induced cardiotoxicity

    Directory of Open Access Journals (Sweden)

    Mukund Joshi


    Full Text Available The survival rate of cancer patients has greatly increased over the last 20 years. However, to achieve this result, a considerable price has been paid in terms of the side-effects associated with the intensive anticancer treatment. Cardiotoxicity of anticancer drugs is a serious problem. It is defined, by the National Cancer Institute, as the and ldquo;toxicity that affects the heart. and rdquo; This definition not only includes a direct effect of the drug on the heart, but also an indirect effect due to enhancement of hemodynamic flow alterations or due to thrombotic events. Cardiotoxicity can develop in a subacute, acute, or chronic manner. The risk for such effects depends upon: cumulative dose, rate of drug administration, mediastinal radiation, advanced age, younger age, female gender, pre-existing heart disease and hypertension. Anthracyclines, such as doxorubicin (DOX, cause serious cardiac side-effects. Acute tachyarrhythmias and acute heart failure (HF may occur after high doses, but these reactions are now rare due to changed dosage schemes (e.g. slower infusion with the aim to prevent this. However, the sub-acute or chronic cardiac effects of anthracyclines remain a clinical problem. Clinically, anthracycline induced cardiotoxicity manifests itself as left ventricular failure, which develops insidiously over months to years after completion of the anthracycline based chemotherapy and may result in congestive HF. The mechanism of anthracyclin induced cardiotoxicity is not totally unraveled. It is likely that the decline in myocardial function is related to apoptosis of cardiac myocytes that occurs apparently at random in the myocardium. Anthracyclin induced formation of reactive oxygen species (ROS in the presence of intracellular iron, impaired homeostasis of intracellular iron and calcium (that may facilitate the apoptosis induced by the ROS have been put forward as mechanisms. Cardiac protection can be achieved by limitation of the

  18. Drug: D07100 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07100 Drug Amrubicin hydrochloride (JAN/USAN); Calsed (TN) C25H25NO9. HCl 519.1296 519.9282 D07100...on 42 Antineoplastics 423 Antibiotics 4235 Anthracycline antibiotics D07100 Amrubicin hydrochloride (JAN/USA... L01DB Anthracyclines and related substances L01DB10 Amrubicin D07100 Amrubicin hydrochloride (JAN/USAN) Tar...4] Amrubicin [ATC:L01DB10] D07100 Amrubicin hydrochloride (JAN/USAN) Antineoplast...ics [BR:br08308] Natural products Antibiotics Amrubicin [ATC:L01DB10] D07100 Amrubicin hydrochloride (JAN/US

  19. All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia : a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies

    NARCIS (Netherlands)

    Sanz, Miguel A.; Montesinos, Pau; Kim, Haesook T.; Ruiz-Argueelles, Guillermo J.; Undurraga, Maria S.; Uriarte, Maria R.; Martinez, Lem; Jacomo, Rafael H.; Gutierrez-Aguirre, Homero; Melo, Raul A. M.; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Fagundes, Evandro M.; Vellenga, Edo; Holowiecka, Alexandra; Gonzalez-Huerta, Ana J.; Fernandez, Pascual; De la Serna, Javier; Brunet, Salut; De Lisa, Elena; Gonzalez-Campos, Jose; Ribera, Jose M.; Krsnik, Isabel; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C.; Lo-Coco, Francesco; Lowenberg, Bob; Rego, Eduardo M.


    Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diag

  20. Early myocardial deformation abnormalities in breast cancer survivors

    NARCIS (Netherlands)

    Bulten, B.F.; Mavinkurve-Groothuis, A.M.C.; Geus-Oei, L.F. de; Haan, A.F.J. de; Korte, C.L. de; Bellersen, L.; Laarhoven, H.W.M. van; Kapusta, L.


    To evaluate the role of 2D myocardial strain (rate) imaging in the detection of early subclinical cardiotoxicity in breast cancer survivors treated with an anthracycline-based chemotherapeutic regimen. 57 adult breast cancer survivors were analyzed 1 year after therapy. All patients underwent biomar

  1. Breast Cancer Chemoresistance Mechanisms Through PI 3-Kinase and Akt Signaling (United States)


    for overcoming chemotherapy resistance . INTRODUCTION As a component of both monotherapy and combination therapy regimens, the anthracycline antibiotic to these drugs evade cell death by apoptosis and thus become resistant to the damaging effects of clinically-relevant chemotherapy a clinically relevant biomarker for resistance to doxorubicin. 15. SUBJECT TERMS Akt, MERIT40, PI 3-K, chemotherapy, signaling, chemoresistance

  2. Long-term heart function after adjuvant epirubicin chemotherapy for breast cancer

    DEFF Research Database (Denmark)

    Appel, Jon M; Zerahn, Bo; Møller, Susanne


    Newer studies raise concern that adjuvant anthracycline treatment for breast cancer (BC) causes long-term heart damage. We aimed to examine whether heart failure or impairment could be demonstrated several years after low-dose epirubicin-based adjuvant treatment....

  3. Combined doxorubicin and paclitaxel in advanced breast cancer

    DEFF Research Database (Denmark)

    Gehl, J; Boesgaard, M; Paaske, T


    BACKGROUND: Paclitaxel has shown activity in metastatic breast cancer, including anthracycline-resistant breast cancer. The efficacy, toxicity and optimal scheduling of the combination of the two drugs needs to be defined. PATIENTS AND METHODS: Thirty women with advanced breast cancer who had...

  4. Identification of new compounds with high activity against stationary phase Borrelia burgdorferi from the NCI compound collection. (United States)

    Feng, Jie; Shi, Wanliang; Zhang, Shuo; Zhang, Ying


    Lyme disease is the leading tick-borne disease in the USA. Whereas the majority of Lyme disease patients with early disease can be cured with standard treatment, some patients suffer from chronic fatigue and joint and muscular pain despite treatment, a syndrome called posttreatment Lyme disease syndrome. Although the cause is unclear, ineffective killing of Borrelia burgdorferi persisters by current Lyme disease antibiotics is one possible explanation. We took advantage of our recently developed high-throughput viability assay and screened the National Cancer Institute compound library collection consisting of 2526 compounds against stationary phase B. burgdorferi. We identified the top 30 new active hits, including the top six anthracycline antibiotics daunomycin 3-oxime, dimethyldaunomycin, daunomycin, NSC299187, NSC363998 and nogalamycin, along with other compounds, including prodigiosin, mitomycin, nanaomycin and dactinomycin, as having excellent activity against B. burgdorferi stationary phase culture. The anthracycline or anthraquinone compounds, which are known to have both anti-cancer and antibacterial activities, also had high activity against growing B. burgdorferi with low minimum inhibitory concentration. Future studies on the structure-activity relationship and mechanisms of action of anthracyclines/anthraquinones are warranted. In addition, drug combination studies with the anthracycline class of compounds and the current Lyme antibiotics to eradicate B. burgdorferi persisters in vitro and in animal models are needed to determine if they improve the treatment of Lyme disease.

  5. Efflux kinetics and intracellular distribution of daunorubicin are not affected by major vault protein/lung resistance-related protein (vault) expression.

    NARCIS (Netherlands)

    Zon, van A; Mossink, MH; Schoester, M.; Scheper, R.J.; Sonneveld, P.; Wiemer, EA


    Vaults may contribute to multidrug resistance by transporting drugs away from their subcellular targets. To study the involvement of vaults in the extrusion of anthracyclines from the nucleus, we investigated the handling of daunorubicin by drug-sensitive and drug-resistant non-small lung cancer cel

  6. Multidrug resistance in oncology and beyond : from imaging of drug efflux pumps to cellular drug targets

    NARCIS (Netherlands)

    Nagengast, Wouter B; Oude Munnink, Thijs H; Dijkers, Eli; Hospers, Geesiena; Brouwers, Adrienne H; Schröder, Carolien P; Lub-de Hooge, Marjolijn; de Vries, Elisabeth G E


    Resistance of tumor cells to several structurally unrelated classes of natural products, including anthracyclines, taxanes, and epipodophyllotoxines, is often referred as multidrug resistance (MDR). This is associated with ATP-binding cassette transporters, which function as drug efflux pumps such a

  7. The impact of medical education and networking on the outcome of leukemia treatment in developing countries. The experience of International Consortium on Acute Promyelocytic Leukemia (IC-APL)

    NARCIS (Netherlands)

    E.M. Rego (Eduardo); H.T. Kim (Haesook); G. Ruiz-Argüelles (Guillermo); M.R. Uriarte (Maria del Rosario); R.H. Jacomo (Rafael); H. Gutiérrez-Aguirre (Homero); R.A. Melo (Raul); H.N.S. Bittencourt (Henrique); R. Pasquini (Ricardo); K. Pagnano (Katia); E.M. Fagundes (Evandro); M.d.L. Chauffaille (Maria de Lourdes); C.S. Chiattone (Carlos); L. Martinez (Lem); L.A. Meillón (Luis); D. Gómez-Almaguer (David); H.C. Kwaan (Hau); J. Garcés-Eisele (Javier); R. Gallagher (Robert); C.M. Niemeyer (Charlotte); B. Löwenberg (Bob); R.C. Ribeiro (Raul); F. Lo-Coco (Francesco); M.A. Sanz (Miguel Angel)


    textabstractObjectives: Several clinical trials conducted in Europe and US reported favorable outcomes of patients with APL treated with the combination of all trans retinoic acid (ATRA) and anthracyclines. Nevertheless, the results observed in developing countries with the same regimen was poorer,

  8. Modulators of Response to Tumor Necrosis-related Apoptosis Inducing Ligand (TRAIL) Therapy in Ovarian Cancer (United States)


    shifted its movement on the gel, suggesting an interaction and supporting previously reported data . -------#1------- --------#2...anthracycline (doxorubicin), a proteosome inhibitor (MG132), DNA damaging agents (UV, temozolomide ) and an antimetabolite (5-fluorouracil). Similarly...collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources

  9. Treatment of newly diagnosed acute promyelocytic leukemia (APL) : a comparison of French-Belgian-Swiss and PETHEMA results

    NARCIS (Netherlands)

    Ades, Lionel; Sanz, Miguel A.; Chevret, Sylvie; Montesinos, Pau; Chevallier, Patrice; Raffoux, Emmanuel; Vellenga, Edo; Guerci, Agnbs; Pigneux, Arnaud; Huguet, Francoise; Rayon, Consuelo; Stoppa, Anne Marie; de la Serna, Javier; Cahn, Jean-Yves; Meyer-Monard, Sandrine; Pabst, Thomas; Thomas, Xavier; de Botton, Stephane; Parody, Ricardo; Bergua, Juan; Lamy, Thierry; Vekhoff, Anne; Negri, Silvia; Ifrah, Norbert; Dombret, Herve; Ferrant, Augustin; Bron, Dominique; Degos, Laurent; Fenaux, Pierre


    All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para

  10. Predictive role of HER2/neu, topoisomerase-II-alpha, and tissue inhibitor of metalloproteinases (TIMP-1) for response to adjuvant taxane-based chemotherapy in patients with intermediate-risk breast cancer

    DEFF Research Database (Denmark)

    Erber, Ramona; Gluz, Oleg; Brünner, Nils;


    Taxane-anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In t...

  11. Comparative analysis of stress responses of H9c2 rat cardiomyoblasts following treatment with doxorubicin and tBOOH

    DEFF Research Database (Denmark)

    Döhrmann, Mareike; Schorr, Anne; Hülsenbeck, Johannes;


    Cardiotoxicity is the major dose-limiting adverse effect of anthracyclines and is hypothesized to result from damage induced by reactive oxygen species (ROS) or inhibition of topoisomerase II. Here, we comparatively analyzed the effect of doxorubicin and the organic peroxide tertiary...

  12. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10.

    NARCIS (Netherlands)

    Mandelli, F.; Vignetti, M.; Suciu, S.; Stasi, R.; Petti, M.C.; Meloni, G.; Muus, P.; Marmont, F.; Marie, J.P.; Labar, B.; Thomas, X.; Raimondo, F. Di; Willemze, R.; Liso, V.; Ferrara, F.; Baila, L.; Fazi, P.; Zittoun, R.; Amadori, S.; Witte, T.J.M. de


    PURPOSE: To compare the antitumor efficacy of three different anthracyclines in combination with cytarabine and etoposide in adult patients with newly diagnosed acute myeloid leukemia (AML). PATIENTS AND METHODS: We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive in

  13. Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin. (United States)

    Tufi, R; Panaretakis, T; Bianchi, K; Criollo, A; Fazi, B; Di Sano, F; Tesniere, A; Kepp, O; Paterlini-Brechot, P; Zitvogel, L; Piacentini, M; Szabadkai, G; Kroemer, G


    Some chemotherapeutic agents can elicit apoptotic cancer cell death, thereby activating an anticancer immune response that influences therapeutic outcome. We previously reported that anthracyclins are particularly efficient in inducing immunogenic cell death, correlating with the pre-apoptotic exposure of calreticulin (CRT) on the plasma membrane surface of anthracyclin-treated tumor cells. Here, we investigated the role of cellular Ca(2+) homeostasis on CRT exposure. A neuroblastoma cell line (SH-SY5Y) failed to expose CRT in response to anthracyclin treatment. This defect in CRT exposure could be overcome by the overexpression of Reticulon-1C, a manipulation that led to a decrease in the Ca(2+) concentration within the endoplasmic reticulum lumen. The combination of Reticulon-1C expression and anthracyclin treatment yielded more pronounced endoplasmic reticulum Ca(2+) depletion than either of the two manipulations alone. Chelation of intracellular (and endoplasmic reticulum) Ca(2+), targeted expression of the ligand-binding domain of the IP(3) receptor and inhibition of the sarco-endoplasmic reticulum Ca(2+)-ATPase pump reduced endoplasmic reticulum Ca(2+) load and promoted pre-apoptotic CRT exposure on the cell surface, in SH-SY5Y and HeLa cells. These results provide evidence that endoplasmic reticulum Ca(2+) levels control the exposure of CRT.

  14. Ferric Carboxymaltose-Mediated Attenuation of Doxorubicin-Induced Cardiotoxicity in an Iron Deficiency Rat Model

    Directory of Open Access Journals (Sweden)

    Jorge Eduardo Toblli


    Full Text Available Since anthracycline-induced cardiotoxicity (AIC, a complication of anthracycline-based chemotherapies, is thought to involve iron, concerns exist about using iron for anaemia treatment in anthracycline-receiving cancer patients. This study evaluated how intravenous ferric carboxymaltose (FCM modulates the influence of iron deficiency anaemia (IDA and doxorubicin (3–5 mg per kg body weight [BW] on oxidative/nitrosative stress, inflammation, and cardiorenal function in spontaneously hypertensive stroke-prone (SHR-SP rats. FCM was given as repeated small or single total dose (15 mg iron per kg BW, either concurrent with or three days after doxorubicin. IDA (after dietary iron restriction induced cardiac and renal oxidative stress (markers included malondialdehyde, catalase, Cu,Zn-superoxide dismutase, and glutathione peroxidase, nitrosative stress (inducible nitric oxide synthase and nitrotyrosine, inflammation (tumour necrosis factor-alpha and interleukin-6, and functional/morphological abnormalities (left ventricle end-diastolic and end-systolic diameter, fractional shortening, density of cardiomyocytes and capillaries, caveolin-1 expression, creatinine clearance, and urine neutrophil gelatinase-associated lipocalin that were aggravated by doxorubicin. Notably, iron treatment with FCM did not exacerbate but attenuated the cardiorenal effects of IDA and doxorubicin independent of the iron dosing regimen. The results of this model suggest that intravenous FCM can be used concomitantly with an anthracycline-based chemotherapy without increasing signs of AIC.

  15. Correction to: Direct effects of doxorubicin on skeletal muscle contribute to fatigue

    NARCIS (Netherlands)

    Norren, van K.; Helvoort, van A.; Agriles, J.M.; Tuijl, van S.; Arts, K.; Gorselink, M.; Laviano, A.; Kegler, D.; Haagsman, H.P.; Beek, van der E.M.


    Chemotherapy-induced fatigue is a multidimensional symptom. Oxidative stress has been proposed as a working mechanism for anthracycline-induced cardiotoxicity. In this study, doxorubicin (DOX) was tested on skeletal muscle function. Doxorubicin induced impaired ex vivo skeletal muscle relaxation fol

  16. Primary granulocyte colony-stimulating factor prophylaxis during the first two cycles only or throughout all chemotherapy cycles in patients with breast cancer at risk for febrile neutropenia

    NARCIS (Netherlands)

    Aarts, M.J.; Peters, F.P.; Mandigers, C.M.P.W.; Dercksen, M.W.; Stouthard, J.M.; Nortier, H.J.; Laarhoven, H.W.M. van; Warmerdam, L.J. van; Wouw, A.J. van de; Jacobs, E.M.G.; Mattijssen, V.; Rijt, C.C. van der; Smilde, T.J.; Velden, A.W. van der; Temizkan, M.; Batman, E.; Muller, E.W.; Gastel, S.M. van; Borm, G.F.; Tjan-Heijnen, V.C.


    PURPOSE: Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF d

  17. Cardiac status in bone tumor survivors up to nearly 19 years after treatment with doxorubicin : A longitudinal study

    NARCIS (Netherlands)

    Postma, A; Elzenga, NJ; Haaksma, J; Schasfoort-Van Leeuwen, MJM; Kamps, WA; Bink-Boelkens, MTE


    Background. Longitudinal assessment of cardiac toxicity in anthracycline-treated long-term bone tumor survivors. Procedures. Cardiac status was assessed in 29 patients 14.1 (range 7-18.7) years after treatment with duxorubicin (DOXO) 360 mg/m(2) (median 225-550). The median age of the patients at th

  18. Tissue-Doppler assessment of cardiac left ventricular function during short-term adjuvant epirubicin therapy for breast cancer

    DEFF Research Database (Denmark)

    Appel, Jon M; Sogaard, Peter; Mortensen, Christiane E;


    It has been hypothesized that the extent of acute anthracycline-induced cardiotoxicity reflects the risk for late development of heart failure. The aim of this study was to examine if short-term changes in cardiac function can be detected even after low-dose adjuvant epirubicin therapy for breast...... cancer when using Doppler tissue imaging of longitudinal left ventricular function....

  19. CEF is superior to CMF for tumours with TOP2A aberrations

    DEFF Research Database (Denmark)

    Gunnarsdóttir, Katrín A; Jensen, Maj-Britt; Zahrieh, David;


    The aim of this study was to examine TOP2A gene copy number changes as a means to identify groups of breast cancer patients with superior benefit from treatment with anthracyclines. Tumour tissue was retrospectively collected and successfully analysed for TOP2A in 773 of 980 Danish patients...


    Doxorubicin (DOX) is a widely used anthracycline anti-neoplastic drug used to treat tumors. However it has been implicated in irreversible cardiac toxicity via the generation of a proxidant semiquinone free radical, which often results in cardiomyopathy and changes in the ECG. Ac...

  1. Drug: D01747 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available tics [BR:br08308] Natural products Antibiotics Idarubicin [ATC:L01DB06] D01747 Idarubicin hydrochloride (JP1...ibiotics 4235 Anthracycline antibiotics D01747 Idarubicin hydrochloride (JP16/USP) ...ic category of drugs in Japan [BR:br08301] 4 Agents affecting cellular function 42 Antineoplastics 423 Ant

  2. Drug: D08386 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available function 42 Antineoplastics 423 Antibiotics 4235 Anthracycline antibiotics D08386 Pirarubicin hydrochloride...bicin [ATC:L01DB08] D08386 Pirarubicin hydrochloride Antineoplastics [BR:br08308] Natural products Antibio...tics Pirarubicin [ATC:L01DB08] D08386 Pirarubicin hydrochloride CAS: 95343-20-7 Pub

  3. Impact of neoadjuvant single or dual HER2 inhibition and chemotherapy backbone upon pathological complete response in operable and locally advanced breast cancer: Sensitivity analysis of randomized trials. (United States)

    Bria, Emilio; Carbognin, Luisa; Furlanetto, Jenny; Pilotto, Sara; Bonomi, Maria; Guarneri, Valentina; Vicentini, Cecilia; Brunelli, Matteo; Nortilli, Rolando; Pellini, Francesca; Sperduti, Isabella; Giannarelli, Diana; Pollini, Giovanni Paolo; Conte, Pierfranco; Tortora, Giampaolo


    The role of the dual HER2 inhibition, and the best chemotherapy backbone for neoadjuvant chemotherapy still represent an issue for clinical practice. A literature-based meta-analysis exploring single versus dual HER2 inhibition in terms of pathological complete response (pCR, breast plus axilla) rate and testing the interaction according to the chemotherapy (anthracyclines-taxanes or taxanes) was conducted. In addition, an event-based pooled analysis by extracting activity and safety events and deriving 95% confidence intervals (CI) was accomplished. Fourteen trials (4149 patients) were identified, with 6 trials (1820 patients) included in the meta-analysis and 31 arms (14 trials, 3580 patients) in the event-based pooled analysis. The dual HER2 inhibition significantly improves pCR rate, in the range of 16-19%, regardless of the chemotherapy backbone (relative risk 1.37, 95% CI 1.23-1.53, p<0.0001); pCR was significantly higher in the hormonal receptor negative population, regardless of the HER2 inhibition and type of chemotherapy. pCR and the rate of breast conserving surgery was higher when anthracyclines were added to taxanes, regardless of the HER2 inhibition. Severe neutropenia was higher with the addition of anthracyclines to taxanes, with an absolute difference of 19.7%, despite no differences in febrile neutropenia. While no significant differences according to the HER2 inhibition were found in terms of cardiotoxicity, a slightly difference for grade 3-4 (1.2%) against the addition of anthracyclines was calculated. The dual HER2 inhibition for the neoadjuvant treatment of HER2-positive breast cancer significantly increases pCR; the combination of anthracyclines, taxanes and anti-Her2 agents should be currently considered the standard of care.

  4. Cardiac Sympathetic Hyperactivity after Chemotherapy: Early Sign of Cardiotoxicity?

    Energy Technology Data Exchange (ETDEWEB)

    Guimarães, Sarita Lígia Pessoa de Melo Machado [Pós-Graduação em Ciências da Saúde da Universidade Federal de Pernambuco (PGCS-UFPE), Recife, PE (Brazil); Hospital Agamenon Magalhães (HAM), Recife, PE (Brazil); Brandão, Simone Cristina Soares, E-mail: [Pós-Graduação em Ciências da Saúde da Universidade Federal de Pernambuco (PGCS-UFPE), Recife, PE (Brazil); Andrade, Luciana Raposo [Hospital Santa Joana, Recife, PE (Brazil); Maia, Rafael José Coelho [Pós-Graduação em Ciências da Saúde da Universidade Federal de Pernambuco (PGCS-UFPE), Recife, PE (Brazil); Hospital Agamenon Magalhães (HAM), Recife, PE (Brazil); Markman Filho, Brivaldo [Pós-Graduação em Ciências da Saúde da Universidade Federal de Pernambuco (PGCS-UFPE), Recife, PE (Brazil)


    Chemotherapy with anthracyclines and trastuzumab can cause cardiotoxicity. Alteration of cardiac adrenergic function assessed by metaiodobenzylguanidine labeled with iodine-123 ({sup 123}I-mIBG) seems to precede the drop in left ventricular ejection fraction. To evaluate and to compare the presence of cardiovascular abnormalities among patients with breast cancer undergoing chemotherapy with anthracyclines and trastuzumab, and only with anthracycline. Patients with breast cancer were analyzed clinical, laboratory, electrocardiographic and echocardiographic and cardiac sympathetic activity. In scintigraphic images, the ratio of {sup 123}I-mIBG uptake between the heart and mediastinum, and the washout rate were calculated. The variables were compared between patients who received anthracyclines and trastuzumab (Group 1) and only anthracyclines (Group 2). Twenty patients, with mean age 57 ± 14 years, were studied. The mean left ventricular ejection fraction by echocardiography was 67.8 ± 4.0%. Mean washout rate was 28.39 ± 9.23% and the ratio of {sup 123}I-mIBG uptake between the heart and mediastinum was 2.07 ± 0.28. Of the patients, 82% showed an increased in washout rate, and the ratio of {sup 123}I-mIBG uptake between the heart and mediastinum decreased in 25%. Concerning the groups, the mean washout rate of Group 1 was 32.68 ± 9.30% and of Group 2 was 24.56 ± 7.72% (p = 0,06). The ratio of {sup 123}I-mIBG uptake between the heart and mediastinum was normal in all patients in Group 2, however, the Group 1, showed 50% the ratio of {sup 123}I-mIBG uptake between the heart and mediastinum ≤ 1.8 (p = 0.02). In women with breast cancer undergoing chemotherapy, assessment of cardiac sympathetic activity with {sup 123}I-mIBG appears to be an early marker of cardiotoxicity. The combination of chemotherapy showed higher risk of cardiac adrenergic hyperactivity.

  5. Progress in systemic chemotherapy of primary breast cancer: an overview. (United States)

    Hortobagyi, G N


    Substantial progress has been made in the multidisciplinary management of primary breast cancer during the last 30 years. Adjuvant chemotherapy has been shown to significantly reduce the annual risk of cancer recurrence and mortality, and these effects persist even 15 years after diagnosis. Combination chemotherapy is superior to single-agent therapy and anthracycline-containing regimens. Those that combine an anthracycline with 5-fluorouracil and cyclophosphamide are more effective than regimens without an anthracycline. Six cycles of a single regimen appear to provide optimal benefit. Dose reductions below the standard range are associated with inferior results. Dose increases that require growth factor or hematopoietic stem cell support are under investigation; at this time, the existing results provide no compelling reason to use this strategy outside a clinical trial. Regimens using fixed crossover designs with two non-cross-resistant regimens are being evaluated. The addition of a taxane to anthracycline-containing regimens is currently under intense scrutiny, and preliminary analysis of the first three clinical trials has shown encouraging, albeit not compelling, results. For patients with estrogen receptor-positive breast cancer, the sequential administration of chemotherapy and 5 years of tamoxifen therapy provides additive benefits. No compelling evidence exists to combine ovarian ablation with chemotherapy. Most side effects and toxic effects are self-limited, although premature menopause requires monitoring and preventive interventions to preserve bone mineral density. The small risk of acute leukemia is of concern, and additional research to develop safer regimens is clearly indicated. The overall effect of optimal local/regional treatment combined with an anthracycline-containing adjuvant chemotherapy and a taxane (and, for patients with estrogen receptor-positive tumors, 5 years of tamoxifen therapy) is a greater than 50% reduction in annual risks of

  6. HER2 over-expression and response to different chemotherapy regimens in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Jin ZHANG; Yan LIU


    Purpose: To exam the relationship between HER2 over-expression and different adjuvant chemotherapies in breast cancer. Patients and Methods: A total of 1625 primary breast cancer patients who received post-surgery adjuvant chemotherapy in Tianjin Cancer Hospital, China, from July 2002 to November 2005 were included in the study. Among them, 600 patients were given CMF (CTX+MTX+5-Fu) regimen, 600 given CEF (CTX+E-ADM+5-Fu) regimen, and 425 given anthracyclines plus taxanes regimen, with mean follow-up time of 42 months. Results: In CMF treatment group, the 3-year disease free survival (DFS)in HER2 over-expressed patients was lower than that of the HER2-negative ones (89.80% vs 91.24%, P=0.0348); in node-positive subgroup, the 3-year DFS was 84.72% in HER2 over-expressed patients, and 90.18% in the HER-2-negative ones (P=0.0271).Compared to CMF regimen, anthracyclines and anthracyclines plus taxanes regimens are more effective (P<0.05) in node-positive HER2 over-expression than those in the node-negative. Conclusion: HER2 over-expression is an independent index for predicting poor prognosis and short DFS for breast cancer patients. HER2 over-expressed patients are resistant to CMF regimen chemotherapy, but sensitive to anthracyclines-based or anthracyclines plus taxanes regimen. HER2 expression can be taken as a marker for therapies in breast cancer.

  7. Adjuvant chemotherapy in early breast cancer

    DEFF Research Database (Denmark)

    Ejlertsen, Bent


    % of patients aged 40 or younger in 77B had regular menses throughout chemotherapy, the corresponding percentage was 37 in 82B and 47 in 89B. The DBCG in collaboration with a Swedish and a Dutch centre participating in the DBCG trial 89B compared CMF with ovarian ablation in premenopausal high-risk breast...... are not clinically useful by themselves as other chemotherapy regimens have been more efficacious, and knowledge is still lacking regarding the benefits from adding ovarian suppression to chemotherapy plus tamoxifen. The results from the DBCG 77B and 82C are in accordance with other large adjuvant trials...... adjuvant trials demonstrated that patients with either TOP2A or centromere 17 aberrations, but not with HER2 amplification, benefit from anthracycline-containing adjuvant chemotherapy. Anthracyclins have additional distinct biological mechanisms; and results from the DBCG 89D suggested that tumours...

  8. Place of pegylated liposomal doxorubicin in the therapy of metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    E. V. Artamonova


    Full Text Available The review deals with trials of pegylated liposomal doxorubicin (PLD used to treat metastatic breast cancer (mBC, including first-line monotherapy, maintenance therapy, combinations with other cytostatics, trastuzumab regimens for a HER-2-positive subvariant, and rescue therapy for intensively pretreated forms of the disease. PLD is shown to be highly competitive with conventional anthracyclines in efficacy and to greatly surpass them in safety particularly in patients at high cardiac risk; the lack of cumulative toxicity and maximum allowable dose makes it possible to perform therapy until the disease progresses, to use the drug as a support, and to effectively and safely combine PLD with trastuzumab in HER-2-positive mBC. A clinical benefit from the administration of PLD does not depend on susceptibility to anthracyclines. The drug is also an important treatment option for taxane-refractory mBC.

  9. Therapy-induced secondary acute myeloid leukemia with t(11;19)(q23;p13.1) in a pediatric patient with relapsed acute promyelocytic leukemia. (United States)

    Dang, Daniel N; Morris, Heather D; Feusner, James H; Koduru, Prasad; Wilson, Kathleen; Timmons, Charles F; Cavalier, MaryEllen; Luu, Hung S


    Acute myeloid leukemia is classified based upon recurrent cytogenetic abnormalities. The t(15;17)(q24.1;q21.1) abnormality is found in 5% to 8% of de novo acute myeloid leukemia and is diagnostic of acute promyelocytic leukemia (APL). The translocation results in fusion of the retinoic acid receptor-α (RARA) gene at 17q21.1 and the promyelocytic leukemia (PML) gene at 15q24.1. Standard APL therapy is a combination of all-trans retinoic acid and anthracycline-based chemotherapy. Anthracycline treatment is associated with secondary clonal chromosomal aberrations that can lead to therapy-related secondary myeloid neoplasms. We present a pediatric case of relapsed APL coexistent with treatment-associated secondary myeloid neoplasm with t(11;19)(q23;p13.1).

  10. Daunorubicin and doxorubicin inhibit the [{sup 11}C]choline accumulation in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Mikecz, Pal [Department of Nuclear Medicine, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary)], E-mail:; Marian, Terez; Miklovicz, Tuende; Galuska, Laszlo [Department of Nuclear Medicine, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary); Krasznai, Zoltan; Toth, Agnes; Goda, Katalin [Department of Biophysics and Cell Biology, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary); Tron, Lajos [Department of Nuclear Medicine, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary); Hernadi, Zoltan; Krasznai, Zoard T. [Department of Obstetrics and Gynecology, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary)


    We studied how very short (10-40 min) incubation with anthracycline derivatives modifies the accumulation of PET tumor-diagnostic radiotracers in cancer cells. The human ovarian A2780 and A2780AD, human B lymphoid JY, human epidermoid KB-3-1 and KB-V-1, and smooth muscle DDT1 MF-2 cells were pre-incubated with daunorubicin and doxorubicin, and the uptake of [{sup 18}F]FDG and [{sup 11}C]choline was measured. Anthracycline treatment decreased remarkably the [{sup 11}C]choline accumulation in a concentration dependent manner, while it did not modify significantly the [{sup 18}F]FDG uptake of the cells.

  11. Erythropoietin: from erythropoiesis to cardioprotection

    Directory of Open Access Journals (Sweden)

    Liermis Michael Dita Salabert


    Full Text Available Many of the drugs that has shown promise in the treatment of hematologic malignancies and solid tumors, associated with a high potential cardiotoxic. Within this group stand anthracyclines, identified as the type of chemotherapy most likely to cause heart damage, short or long term. With the improvement achieved in the survival of patients with these diseases, this adverse event has become a major concern for the scientific community. Although many agents have been evaluated as potential cardioprotective therapeutic, clinical data are limited and does not suggest that the use of these agents promotes the survival of patients undergoing cardiotoxic treatments. The identification of erythropoietin receptor in hematopoietic tissues, including the heart, as well as its marked cardioprotective effect during ischemia have led to the hypothesis that erythropoietin may be able to prevent anthracycline-induced cardiomyopathy. Addressing this hypothesis is the objective of this work.

  12. Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy

    DEFF Research Database (Denmark)

    Martin, E.; Thougaard, A.V.; Grauslund, M.


    Anthracycline-induced cardiomyopathy is a major problem in anti-cancer therapy. The only approved agent for alleviating this serious dose limiting side effect is ICRF-187 (dexrazoxane). The current thinking is that the ring-opened hydrolysis product of this agent, ADR-925, which is formed inside......-inactive 3 carbon linker bisdioxopiperazine analog ICRF-161 as a cardioprotectant. We demonstrate that this compound does chelate iron and protects against doxorubicin-induced LDH release from primary rat cardiomyocytes in vitro, similarly to ICRF-187. The compound does not target topoisomerase II in vitro...... or in cells, it is well tolerated and shows similar exposure to ICRF-187 in rodents, and it does not induce myelosuppression when given at high doses to mice as opposed to ICRF-187. However, when tested in a model of chronic anthracycline-induced cardiomyopathy in spontaneously hypertensive rats, ICRF-161...


    Directory of Open Access Journals (Sweden)

    Adrian Tase


    Full Text Available Anthracyclines and molecular targeted therapy, pharmacologic agents currently used in breast cancer, are potentially cardiotoxic, leading to cardiac dysfunction, and even to overt heart failure. This paper reviews the art of protecting the heart in breast cancer recipients of chemotherapy with betablockers. The main mechanism of anthracycline induced cardiotoxicity is the oxydative stress, occurring in mitochondrial arena. Recent trials supporting β-blockers cardioprotection in this particular population of patients are discussed. As a result of these studies, betablockers are, along with renin-angiotensin-aldosterone antagonists, statins, and dexrazoxane, the most cardioprotective drugs. The paper also covers some methods (biomarkers, imaging, integrating the sphere of prevention with those of monitoring and treatment. The trials outcomes are illustrated by curves, plots, histograms, tables, etc.

  14. Tumor tissue levels of tissue inhibitor of metalloproteinases-I (TIMP-I) and outcome following adjuvant chemotherapy in premenopausal lymph node-positive breast cancer patients

    DEFF Research Database (Denmark)

    Schrohl, Anne-Sofie; Look, Maxime P.; Gelder, Marion E. Meijer-van


    an association between shorter survival after treatment in TIMP-1 high patients compared with TIMP-1 low patients, especially in patients receiving anthracycline-based therapy. This suggests that high tumor tissue levels of TIMP-1 might be associated with reduced benefit from classical adjuvant chemotherapy. Our......BACKGROUND: We have previously demonstrated that high tumor tissue levels of TIMP-1 are associated with no or limited clinical benefit from chemotherapy with CMF and anthracyclines in metastatic breast cancer patients. Here, we extend our investigations to the adjuvant setting studying outcome...... after adjuvant chemotherapy in premenopausal lymph node-positive patients. We hypothesize that TIMP-1 high tumors are less sensitive to chemotherapy and accordingly that high tumor tissue levels are associated with shorter survival. METHODS: From our original retrospectively collected tumor samples we...

  15. Study on the Interaction between Antitumor Drug Daunomycin and DNA

    Institute of Scientific and Technical Information of China (English)

    CHENG Gui-Fang; ZHAO Jie; TU Yong-Hua; HE Pin-Gang; FANG Yu-Zhi


    A detection of anthracycline antitumor drug daunomycin (DNR) reacting with DNA in simulate metabolism in vitro has been made. It was found that DNR could react with DNA to form DNR-DNA adducts. The adduct compositions of DNR with fish sperm DNA and thermally denaturated DNA were determined. The equilibrium association constant K of DNR with fish sperm DNA is 1.98 × 105 L/mol and that of DNR with denaturated DNA is 2.29 × 104 L/mol. Semiquinone free radicals, metabolic products of DNR, can destroy both fish sperm DNA and its thermally denaturated DNA. It is verified by hyperchromic effect increase observed in UV spectrum and AFM experiments. The mechanism of DNA degradation has also been investigated. Results obtained allow one to explain the reason of side effect of anthracycline drug and give the way to depress, which were of clinical significance.

  16. A systematic review on topoisomerase 1 inhibition in the treatment of metastatic breast cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Brünner, Nils Aage; Stenvang, Jan;


    Following treatment with anthracyclines and taxanes, few established options exist for the treatment of metastatic breast cancer (MBC). Although the topoisomerase 1 inhibitors irinotecan, etirinotecan, and topotecan have been used in clinical trials on MBC, the drugs have never been introduced...... showed very limited effect. Topotecan was studied in combination with either another chemotherapeutic or a biologic agent in two trials, both studies failing to show any effect of topotecan. The most common grade 3 and 4 adverse events (AE) for irinotecan were neutropenia, diarrhea, and nausea....../vomiting. The dosing schedule appears to affect the toxicity profile of the drug. Hematologic AEs are most frequently reported for topotecan. Conclusively, topotecan does not seem to be efficient in the treatment of MBC. Irinotecan seem to be effective in some patients previously treated with anthracyclines...

  17. A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification

    DEFF Research Database (Denmark)

    Tarpgaard, Line S.; Qvortrup, Camilla; Nygård, Sune Boris


    UNLABELLED: ᅟ: The overall purpose of this study is to provide proof of concept for introducing the anthracycline epirubicin as an effective, biomarker-guided treatment for metastatic colorectal cancer (mCRC) patients who are refractory to treatment with oxaliplatin-based chemotherapy and have TOP2......A gene amplification in their tumor cells. BACKGROUND: Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin...... in patients with breast cancer and thus could be an alternative option for patients with CRC and amplified TOP2A gene. We have previously analysed the frequency of TOP2A gene aberrations in CRC and found that 46.6 % of these tumors had TOP2A copy gain and 2.0 % had loss of TOP2A when compared to adjacent...

  18. Selektion von Aptameren gegen Antibiotika und deren Einsatz in empflindlichen Assayformaten


    Wochner, Aniela


    Due to its toxicity, the use of daunomycin, an anthracycline antibiotic that is widely used in cancer therapy, poses a risk for everyone involved with the substance. Therefore, a strict surveillance of the working area of producers, pharmacists, and hospital staff is equally necessary as monitoring the actual dose of the drug in a patient's blood. Since a relevant proportion of administered daunomycin is excreted unmetabolised, contaminated waste water can also have an impact on the environme...

  19. 5-Fluorouracil induces apoptosis in rat cardiocytes through intracellular oxidative stress


    Lamberti Monica; Porto Stefania; Marra Monica; Zappavigna Silvia; Grimaldi Anna; Feola Daniela; Pesce Delia; Naviglio Silvio; Spina Annamaria; Sannolo Nicola; Caraglia Michele


    Abstract Background Cardiotoxicity is a major complication of anticancer drugs, including anthracyclines and 5-fluorouracil(5-FU) and it can have detrimental effects both in patients and workers involved in the preparation of chemotherapy. Methods Specifically, we have assessed the effects of increasing concentrations of 5-FU and doxorubicin (DOXO) on proliferation of H9c2 rat cardiocytes and HT-29 human colon adenocarcinoma cells by MTT assay. Cells were treated for 24, 48 and 72 h with diff...

  20. Acute renal failure secondary to ingestion of alternative medication in a patient with breast cancer. (United States)

    Gulia, S; Gota, V; Kumar, Sangita D; Gupta, Sudeep


    Complementary and alternative medicine (CAM) use among cancer patients is widely prevalent and often underreported. Advanced stage of disease is significantly associated with CAM use. The concurrent use of alternative medicines and chemotherapy drugs has the potential to lead to toxicities as well as altered therapeutic activity due to unknown interactions. We report a case of early breast cancer who presented to us with non-oliguric acute renal failure related concurrent use of Ayurvedic medicines and adjuvant anthracycline based.

  1. Gemcitabine Based Combination Regimens for Treatment of Refractory Advanced Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    CHE Li; DI Li-jun; SONG Guo-hong; JIA Jun; YU Jing; WANG Xiao-li; ZHU Yu-lin; JIANG Han-fang; LIANG Xu


    Objective:Anthracycline and taxane are the standard agents in combined chemotherapy of advanced breast cancer.However,when these agents based chemotherapy is failure,the selection of salvage regimen is still of problem.Gemcitabine,an active agent in both lung cancer and pancreas cancer,is demonstrated effective in breast caner.But there have been relatively less data of gemcitabine in anthracycline and/or taxane-resistant breast cancer.Therefore we employe this study to explore the efficacy and safety of gemcitabine based combination regimen in this population.Methods:From May 2002 to March 2006,28 patients with measurable lesion of advanced metastatic breast cancer who were resistant to prior anthracycline and taxane based chemotherapy were enrolled.Patients were treated with gemcitabine based combination chemotherapy with a median cycles of 3(range 2-6).Results:The overall response rate was 28.6%(8/28),with 1 CR(Complete response 3.5%)and 7 PRs(Partial response 25%).Stable disease was seen in 8 patients(28.6%)while disease progressed in 12 patiens(42.8%).The median time to progression was 4.5 m(range,2-23 m).The main toxicity included bone marrow depression,alopecia,mucositis and peripheral neurotoxicity.The grade 3 to 4 clinical adverse effect was leukopenia in 5 cases(17.9%)and thrombocytopenia in 8 cases(30%).Conclusion:Gemcitabine based combination regimens is feasible in anthracycline and taxane-resistant advanced breast cancer.The clinical response and TTP is acceptable with limited toxicity pattern.

  2. Reversal of Multidrug Resistance in Breast Cancer (United States)


    cellular resistance to multiple therapeutic agents such as anthracyclines, vinca alkaloids , epipodophyllotoxins, taxol, and actinomycin-D. MDR1 gene...Sci USA 84:3004.1987. Zacher, V., Thomas, R.A., and Goustin, A.S. Absolute quantification of target DNA: a simple competitive PCR for appears to be the microtubular apparatus, but unlike vinca alkaloids or epipodophyllotoxin, Paclitaxel actually promotes microtubular assemblyin

  3. Evaluation of host quality of life and immune function in breast cancer patients treated with combination of adjuvant chemotherapy and oral administration of Lentinula edodes mycelia extract

    Directory of Open Access Journals (Sweden)

    Nagashima Y


    Full Text Available Yukiko Nagashima,1 Noriko Maeda,2 Shigeru Yamamoto,2 Shigefumi Yoshino,2 Masaaki Oka21Department of Breast and Thyroid Surgery, Shakaihoken Shimonoseki Kosei Hospital, Shimonoseki City, Yamaguchi, Japan; 2Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, JapanPurpose: Anthracycline-based chemotherapies for breast cancer are well known to have adverse effects and can also negatively affect host immune function. There is therefore a necessity for an adjuvant that maintains the quality of life (QOL and immune function of cancer patients receiving anthracycline-based chemotherapies.Patients and methods: The present study investigated the effectiveness of the concomitant use of Lentinula edodes mycelia extract (LEM, an oral immunomodulator, with FEC75 (5-fluorouracil + epirubicin + cyclophosphamide therapy on host QOL and immune function in breast cancer patients with nodal metastases. Ten breast cancer patients with nodal metastases receiving surgery were enrolled in this study. Treatment with 5-fluorouracil (500 mg/m2, epirubicin (75 mg/m2, and cyclophosphamide (500 mg/m2 was performed every 21 days for two courses, and LEM (1800 mg/day by mouth was administered during the second course.Results: In the first course, hematological toxicity was observed and host QOL and immune function were exacerbated. In the second course, however, the number of white blood cells and lymphocytes did not decrease and host QOL was maintained. Furthermore, the cytotoxic activities of natural killer (NK and lymphokine-activated killer cells and the proportion of activated NK and NK T-cells in lymphocytes were maintained in the second course.Conclusion: It has been suggested that the concomitant use of LEM with FEC75 therapy can maintain host QOL and immune function, and offer important implications for an application of LEM as a useful oral adjuvant to anthracycline-based chemotherapies

  4. Concurrent chemo-radiotherapy in the treatment of early breast cancer: Current status

    Directory of Open Access Journals (Sweden)

    Nabil Ismaili


    Full Text Available Concurrent chemo-radiotherapy (CCRT in early breast cancer was investigated by few authors and remains controversial. This treatment is more commonly used for locally advanced breast cancer and showed high rate of complete pathological response. A search of articles published in English literature, between 1980 and November 2012, was conducted on Medline using the following terms: "breast cancer", "chemotherapy", "concurrent radiotherapy", and "Trastuzumab". We identified five phase I/II trials and three randomized phase three trials evaluating concurrent chemoradiotherapy in the adjuvant of breast cancer. In patients with early breast cancer having positive lymph nodes, phases III clinical trials showed that CCRT improved local control after conservative breast surgery. However, these randomized trials used non-standard regimen: Cyclophosphamide, methotrexate and fluorouracil (CMF or fluorouracil, mitoxantrone and cyclophosphamide (FNC. In addition, in phases II clinical trials, concurrent use of taxanes and anthracycline with standard whole-breast irradiation showed high rate of toxicity: Pulmonary toxicity with taxane; and cardiac and skin toxicity with anthracycline. Consequentely, CCRT is not be used in practice because of concerns of toxicity with the standard drugs (anthracyclines and taxanes and radiation. Anthracyclines with partial breast irradiation (PBI was feasible according to one phase I clinical trial, and should be investigated in randomized clinical trials. Concurrent Trastuzumab plus radiotherapy is safe and can be used in HER2-positive breast cancer; in this case, cardiac volume sparing and patient selections for internal mammary chain irradiation are highly recommended. The present paper aimed to review the current data evaluating the efficacy and safety of CCRT in early breast cancer.

  5. Use of Computed Tomography Angiography in Hodgkin Lymphoma Survivors


    Küpeli, Serhan


    In the treatment of Hodgkin lymphoma, anthracyclines known to be cardiotoxic and radiotherapy to the involved lymphatic areas are frequently used. In literature deaths from myocardial infarction at young ages after Hodgkin lymphoma have been reported. The real incidence of cardiovascular diseases in patients treated for Hodgkin lymphoma is not known. There is a significant correlation between mediastinal radiotherapy and development of a coronary artery abnormality. Coronary computed tomogra...

  6. Center of Excellence for Individuation of Therapy for Breast Cancer (United States)


    L. A Hierarchical Statistical Model to Assess the Confidence of Peptides and Proteins Inferred from Tandem Mass Spectrometry. Bioinformatics...2008;24: 202-208. Shen, C., Sheng, Q., Dai, J., Li, Yi., Zeng, R., and Tang, H. On the estimation of false positives in peptide identifications using...IIalpha gene status and prediction of pathological complete remission after anthracycline-based neoadjuvant chemotherapy in endocrine non-responsive

  7. Development, Maintenance, and Reversal of Multiple Drug Resistance: At the Crossroads of TFPI1, ABC Transporters, and HIF1α


    Terra Arnason; Troy Harkness


    Early detection and improved therapies for many cancers are enhancing survival rates. Although many cytotoxic therapies are approved for aggressive or metastatic cancer; response rates are low and acquisition of de novo resistance is virtually universal. For decades; chemotherapeutic treatments for cancer have included anthracyclines such as Doxorubicin (DOX); and its use in aggressive tumors appears to remain a viable option; but drug resistance arises against DOX; as for all other classes o...

  8. Autologous cytokine-induced killer cells therapy on the quality of life of patients with breast cancer after adjuvant chemotherapy: A prospective study

    Institute of Scientific and Technical Information of China (English)



    Objective To explore the effect of autologous cytokine-induced killer cells on the quality of life in patient with breast cancer who have already finished the adjuvant chemotherapy.Methods One hundred and twenty-eight postoperative patients with breast cancer who underwent anthracycline-based adjuvant chemotherapy were enrolled in this prospective study,and they were randomized into2 groups,i.e.,treatment group,which received the therapy of CIK cells transfusion,and control group,

  9. The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes

    Directory of Open Access Journals (Sweden)

    F. Misiti


    Full Text Available Anthracyclines, a class of antitumor drugs widely used for the treatment of solid and hematological malignancies, cause a cumulative dose-dependent cardiac toxicity whose biochemical basis is unclear. Recent studies of the role of the metabolites of anthracyclines, i.e., the alcohol metabolite doxorubicinol and aglycone metabolites, have suggested new hypotheses about the mechanisms of anthracycline cardiotoxicity. In the present study, human red blood cells were used as a cell model. Exposure (1 h at 37ºC of intact human red blood cells to doxorubicinol (40 µM and to aglycone derivatives of doxorubicin (40 µM induced, compared with untreated red cells: i a ~2-fold stimulation of the pentose phosphate pathway (PPP and ii a marked inhibition of the red cell antioxidant enzymes, glutathione peroxidase (~20% and superoxide dismutase (~60%. In contrast to doxorubicin-derived metabolites, doxorubicin itself induced a slighter PPP stimulation (~35% and this metabolic event was not associated with any alteration in glutathione reductase, glutathione peroxidase, catalase or superoxide dismutase activity. Furthermore, the interaction of hemoglobin with doxorubicin and its metabolites induced a significant increase (~22% in oxygen affinity compared with hemoglobin incubated without drugs. On the basis of the results obtained in the present study, a new hypothesis, involving doxorubicinol and aglycone metabolites, has been proposed to clarify the mechanisms responsible for the doxorubicin-induced red blood cell toxicity.

  10. Two-Dimensional Speckle Tracking Echocardiography Detects Subclinical Left Ventricular Systolic Dysfunction among Adult Survivors of Childhood, Adolescent, and Young Adult Cancer

    Directory of Open Access Journals (Sweden)

    Anthony F. Yu


    Full Text Available Two-dimensional speckle tracking echocardiography (2DSTE provides a sensitive measure of left ventricular (LV systolic function and may aid in the diagnosis of cardiotoxicity. 2DSTE was performed in a cross-sectional study of 134 patients (mean age: 31.4±8.8 years; 55% male; mean time since diagnosis: 15.4±9.4 years previously treated with anthracyclines (mean cumulative dose: 320±124 mg/m2, with (n=52 or without (n=82 mediastinal radiotherapy. The prevalence of LV systolic dysfunction, defined as fractional shortening < 27%, LV ejection fraction (LVEF < 55%, and global longitudinal strain (GLS ≤ 16%, was 5.2%, 6.0%, and 23.1%, respectively. Abnormal GLS was observed in 24 (18% patients despite a normal LVEF. Indices of LV systolic function were similar regardless of anthracycline dose. However, GLS was worse (18.0 versus 19.0, p=0.003 and prevalence of abnormal GLS was higher (36.5% versus 14.6%, p=0.004 in patients treated with mediastinal radiotherapy. Mediastinal radiotherapy was associated with reduced GLS (p=0.040 after adjusting for sex, age, and cumulative anthracycline dose. In adult survivors of childhood, adolescent, and young adult cancer, 2DSTE frequently detects LV systolic dysfunction despite a normal LVEF and may be useful for the long-term cardiac surveillance of adult cancer survivors.


    Institute of Scientific and Technical Information of China (English)

    Xu Binghe; Zhou Jichang; Zhou Aiping; Wang Yan; Feng Fengyi; Sun yan


    Objective:To analyze the clinical course and treatment result of lung metastases from breast cancer. Method:122 cases with lung metastases from breast cancer were treated with chemotherapy or chemotherapy plus endocrine therapy, response was assessed according to WHO criteria and survival rate estimated using the life Table. Results: The median time from initial treatment of primary tumor to lung metastases was 22 months. Sites of common consecutive metastases were lung, liver and bone. The overall response rate was 48% with a CR rate of 15%. Compared to non- DDP- encompassing regimen, the CR rate was higher in DDP-based chemotherapy (7%versus 21%, P<0.05) with a longer median survival time (MST). The PR rate was higher in regimens containing anthracycline (48%) than in those without anthracycline (20%, P<0.01). The response rate was similar between chemotherapy and chemotherapy plus endocrine therapy (P>0.05). No difference in MST was observed between patients receiving anthracycline-and non-anthracyclineencompassing regimens. The 1-, 3-, 5-, and 10-year survival rate was 77%, 22 %, 11%, and 10%, respectively.Conclusion: Size of primary tumor, the length of diseasefree interval, the number of lung metastases may provide additional information for predicting patients survival after treatment of lung metastases. Combination chemotherapy, especially DDP-based chemotherapy may prolong survival time of patients with lung metastases from breast cancer.

  12. Cardiac damage after treatment of childhood cancer: A long-term follow-up

    Directory of Open Access Journals (Sweden)

    Demšar Damjan


    Full Text Available Abstract Background With improved childhood cancer cure rate, long term sequelae are becoming an important factor of quality of life. Signs of cardiovascular disease are frequently found in long term survivors of cancer. Cardiac damage may be related to irradiation and chemotherapy. We have evaluated simultaneous influence of a series of independent variables on the late cardiac damage in childhood cancer survivors in Slovenia and identified groups at the highest risk. Methods 211 long-term survivors of different childhood cancers, at least five years after treatment were included in the study. The evaluation included history, physical examination, electrocardiograpy, exercise testing and echocardiograpy. For analysis of risk factors, beside univariate analysis, multivariate classification tree analysis statistical method was used. Results and Conclusion Patients treated latest, from 1989–98 are at highest risk for any injury to the heart (73%. Among those treated earlier are at the highest risk those with Hodgkin's disease treated with irradiation above 30 Gy and those treated for sarcoma. Among specific forms of injury, patients treated with radiation to the heart area are at highest risk of injury to the valves. Patients treated with large doses of anthracyclines or concomitantly with anthracyclines and alkylating agents are at highest risk of systolic function defect and enlarged heart chambers. Those treated with anthracyclines are at highest risk of diastolic function defect. The time period of the patient's treatment is emerged as an important risk factor for injury of the heart.

  13. Development of a CART Model to Predict the Synthesis of Cardiotoxic Daunorubicinol in Heart Tissue Samples From Donors With and Without Down Syndrome. (United States)

    Hoefer, Carrie C; Blair, Rachael Hageman; Blanco, Javier G


    Daunorubicin (DAUN) and doxorubicin (DOX) are used to treat a variety of cancers. The use of DAUN and DOX is hampered by the development of cardiotoxicity. Clinical evidence suggests that patients with leukemia and Down syndrome are at increased risk for anthracycline-related cardiotoxicity. Carbonyl reductases and aldo-keto reductases (AKRs) catalyze the reduction of DAUN and DOX into cardiotoxic C-13 alcohol metabolites. Anthracyclines also exert cardiotoxicity by triggering mitochondrial dysfunction. In recent studies, a collection of heart samples from donors with and without Down syndrome was used to investigate determinants for anthracycline-related cardiotoxicity including cardiac daunorubicin reductase activity (DA), carbonyl reductase/AKRs protein expression, mitochondrial DNA content (mtDNA), and AKR7A2 DNA methylation status. In this study, the available demographic, biochemical, genetic, and epigenetic data were integrated through classification and regression trees analysis with the aim of pinpointing the most relevant variables for the synthesis of cardiotoxic daunorubicinol (i.e., DA). Seventeen variables were considered as potential predictors. Leave-one-out-cross-validation was performed for model selection and to estimate the generalization error. The classification and regression trees analysis model and variable importance measures suggest that cardiac mtDNA content, mtDNA(4977) deletion frequency, and AKR7A2 protein content are the most important variables in determining DA.

  14. Extracellular Matrix Proteins Modulate Antimigratory and Apoptotic Effects of Doxorubicin

    Directory of Open Access Journals (Sweden)

    Georges Said


    Full Text Available Anticancer drug resistance is a multifactorial process that includes acquired and de novo drug resistances. Acquired resistance develops during treatment, while de novo resistance is the primary way for tumor cells to escape chemotherapy. Tumor microenvironment has been recently shown to be one of the important factors contributing to de novo resistance and called environment-mediated drug resistance (EMDR. Two forms of EMDR have been described: soluble factor-mediated drug resistance (SFM-DR and cell adhesion-mediated drug resistance (CAM-DR. Anthracyclines, among the most potent chemotherapeutic agents, are widely used in clinics against hematopoietic and solid tumors. Their main mechanism of action relies on the inhibition of topoisomerase I and/or II and the induction of apoptosis. Beyond this well-known antitumor activity, it has been recently demonstrated that anthracyclines may display potent anti-invasive effects when used at subtoxic concentrations. In this paper, we will describe two particular modes of EMDR by which microenvironment may influence tumor-cell response to one of these anthracyclines, doxorubicin. The first one considers the influence of type I collagen on the antimigratory effect of doxorubicin (CAM-DR. The second considers the protection of tumor cells by thrombospondin-I against doxorubicin-induced apoptosis (SFM-DR.

  15. Personalized chemotherapy selection for breast cancer using gene expression profiles (United States)

    Yu, Kaixian; Sang, Qing-Xiang Amy; Lung, Pei-Yau; Tan, Winston; Lively, Ty; Sheffield, Cedric; Bou-Dargham, Mayassa J.; Liu, Jun S.; Zhang, Jinfeng


    Choosing the optimal chemotherapy regimen is still an unmet medical need for breast cancer patients. In this study, we reanalyzed data from seven independent data sets with totally 1079 breast cancer patients. The patients were treated with three different types of commonly used neoadjuvant chemotherapies: anthracycline alone, anthracycline plus paclitaxel, and anthracycline plus docetaxel. We developed random forest models with variable selection using both genetic and clinical variables to predict the response of a patient using pCR (pathological complete response) as the measure of response. The models were then used to reassign an optimal regimen to each patient to maximize the chance of pCR. An independent validation was performed where each independent study was left out during model building and later used for validation. The expected pCR rates of our method are significantly higher than the rates of the best treatments for all the seven independent studies. A validation study on 21 breast cancer cell lines showed that our prediction agrees with their drug-sensitivity profiles. In conclusion, the new strategy, called PRES (Personalized REgimen Selection), may significantly increase response rates for breast cancer patients, especially those with HER2 and ER negative tumors, who will receive one of the widely-accepted chemotherapy regimens. PMID:28256629

  16. An Exploratory Study to Determine Whether BRCA1 and BRCA2 Mutation Carriers Have Higher Risk of Cardiac Toxicity (United States)

    Sajjad, Monique; Fradley, Michael; Sun, Weihong; Kim, Jongphil; Zhao, Xiuhua; Pal, Tuya; Ismail-Khan, Roohi


    Anthracycline-based cardiotoxicity is concerning for women with breast cancer and portends a dose-dependent risk of developing left ventricular dysfunction. Overall, the prevalence of heart failure (HF) is ≈2% of the total US population; however, BRCA-deficient mice have shown increased HF. We evaluated for the inherent risk of HF in women with BRCA mutations to determine whether treatment with anthracycline-based therapy increased this risk. We obtained results on BRCA mutation carriers regarding cancer treatment and HF, identified through the BRCA patient advocacy organization Facing Our Risk for Cancer Empowered (FORCE) and the Moffitt-based Inherited Cancer Registry. In our patient group (232 BRCA1 and 159 BRCA2 patients; 10 with both mutations), 7.7% reported HF, with similar proportions in BRCA1 versus BRCA2 carriers (7.4% and 8.2%, respectively). These proportions are significantly higher than published rates (p BRCA1 carriers and 8.2% of BRCA2 carriers reported arrhythmias. BRCA mutation carriers showed increased risk of cardiotoxicity versus the general population and an overall increased risk of cardiotoxicity from anthracycline-based therapy. Our study supports data that BRCA carriers have increased non-cancer mortality from cardiotoxicity. A prospective trial to determine HF and conduction abnormalities in this population is warranted. PMID:28157161

  17. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Henninger, Christian [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany); Huelsenbeck, Johannes; Huelsenbeck, Stefanie [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Grösch, Sabine [Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main (Germany); Schad, Arno [Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Lackner, Karl J. [Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Kaina, Bernd [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Fritz, Gerhard, E-mail: [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany)


    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  18. Estimation of the cost of treatment by chemotherapy for early breast cancer in Morocco

    Directory of Open Access Journals (Sweden)

    Boutayeb Saber


    Full Text Available Abstract Background Breast cancer is the first cancer in women both in incidence and mortality. The treatment of breast cancer benefited from the progress of chemotherapy and targeted therapies, but there was a parallel increase in treatment costs. Despite a relatively high incidence of many sites of cancer, so far, there is no national register for this disease in Morocco. The main goal of this paper is to estimate the total cost of chemotherapy in the early stages of breast cancer due to its frequency and the chances of patients being cured. This study provides health decision-makers with a first estimate of costs and the opportunity to achieve the optimal use of available data to estimate the needs of antimitotics and trastuzumab in Morocco. Method We start by evaluating the individual cost according to the therapeutic sub-groups, namely: 1. Patients needing chemotherapy with only anthracycline-based therapy. 2. Patients needing chemotherapy with both anthracycline and taxane but without trastuzumab. 3. Patients needing trastuzumab in addition to chemotherapy. For each sub-group, the protocol of treatment is described, and the individual costs per unit, and for the whole cycle, are evaluated. Then we estimate the number of women suffering from breast cancer on the basis of two data bases available in Morocco. Finally, we calculate the total annual cost of treatment of breast cancer in Morocco. Results The total cost of breast cancer in Morocco is given in Moroccan dirhams (MAD, the US dollar at the current exchange rate (MAD 10 = USD 1.30 and in international dollars or purchasing power parity (MAD 10 = PPP 1.95. The cost of a therapy with trastuzumab is 8.4 times the cost of a sequential chemotherapy combining anthracycline and taxane, and nearly 60 times the cost of chemotherapy based on anthracycline alone. Globally, between USD 13.3 million and USD 28.6 million need to be devoted every year by the Moroccan health authorities to treat

  19. Recent advances in the diagnosis and management of childhood acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Eun Sun Yoo


    Full Text Available Since the successful introduction of all-trans-retinoic acid (ATRA and its combination with anthracycline-containing chemotherapy, the prognosis for acute promyelocytic leukemia (APL has markedly improved. With ATRA and anthracycline-based-chemotherapy, the complete remission rate is greater than 90%, and the long-term survival rate is 70&#8210;89%. Moreover, arsenic trioxide (ATO, which was introduced for APL treatment in 1994, resulted in excellent remission rates in relapsed patients with APL, and more recently, several clinical studies have been designed to explore its role in initial therapy either alone or in combination with ATRA. APL is a rare disease in children and is frequently associated with hyperleukocytosis, which is a marker for higher risk of relapse and an increased incidence of microgranular morphology. The frequency of occurrence of the promyelocytic leukemia/ retinoic acid receptor-alpha (PML/RAR?#6752;isoforms bcr 2 and bcr 3 is higher in children than in adults. Although recent clinical studies have reported comparable long-term survival rates in patients with APL, therapy for APL in children is challenging because of the risk of early death and the potential long-term cardiac toxicity resulting from the need to use high doses of anthracyclines. Additional prospective, randomized, large clinical trials are needed to address several issues in pediatric APL and to possibly minimize or eliminate the need for chemotherapy by combining ATRA and ATO. In this review article, we discuss the molecular pathogenesis, diagnostic progress, and most recent therapeutic advances in the treatment of children with APL.

  20. Strain measurement by cardiovascular magnetic resonance in pediatric cancer survivors: validation of feature tracking against harmonic phase imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Jimmy C. [C.S. Mott Children' s Hospital, University of Michigan Congenital Heart Center, Ann Arbor, MI (United States); University of Michigan, Department of Pediatrics and Communicable Diseases, Division of Pediatric Cardiology, Ann Arbor, MI (United States); University of Michigan, Department of Radiology, Section of Pediatric Radiology, Ann Arbor, MI (United States); Connelly, James A. [University of Michigan, Department of Pediatrics and Communicable Diseases, Division of Hematology-Oncology, Ann Arbor, MI (United States); Zhao, Lili [University of Michigan, Department of Biostatistics, Ann Arbor, MI (United States); Agarwal, Prachi P. [University of Michigan, Department of Radiology, Division of Cardiothoracic Radiology, Ann Arbor, MI (United States); Dorfman, Adam L. [University of Michigan, Department of Pediatrics and Communicable Diseases, Division of Pediatric Cardiology, Ann Arbor, MI (United States); University of Michigan, Department of Radiology, Section of Pediatric Radiology, Ann Arbor, MI (United States)


    Left ventricular strain may be a more sensitive marker of left ventricular dysfunction than ejection fraction in pediatric cancer survivors after anthracycline therapy, but there is limited validation of strain measurement by feature tracking on cardiovascular magnetic resonance (MR) images. To compare left ventricular circumferential and radial strain by feature tracking vs. harmonic phase imaging analysis (HARP) in pediatric cancer survivors. Twenty-six patients (20.2 ± 5.6 years old) underwent cardiovascular MR at least 5 years after completing anthracycline therapy. Circumferential and radial strain were measured at the base, midventricle and apex from short-axis myocardial tagged images by HARP, and from steady-state free precession images by feature tracking. Left ventricular ejection fraction more closely correlated with global circumferential strain by feature tracking (r = -0.63, P = 0.0005) than by HARP (r = -0.39, P = 0.05). Midventricular circumferential strain did not significantly differ by feature tracking or HARP (-20.8 ± 3.4 vs. -19.5 ± 2.5, P = 0.07), with acceptable limits of agreement. Midventricular circumferential strain by feature tracking strongly correlated with global circumferential strain by feature tracking (r = 0.87, P < 0.0001). Radial strain by feature tracking had poor agreement with HARP, particularly at higher values of radial strain. Intraobserver and interobserver reproducibility was excellent for feature tracking circumferential strain, but reproducibility was poor for feature tracking radial strain. Midventricular circumferential strain by feature tracking is a reliable and reproducible measure of myocardial deformation in patients status post anthracycline therapy, while radial strain measurements are unreliable. Further studies are necessary to evaluate potential relation to long-term outcomes. (orig.)

  1. TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer. (United States)

    Fagerholm, Rainer; Khan, Sofia; Schmidt, Marjanka K; García-Closas, Montserrat; Heikkilä, Päivi; Saarela, Jani; Beesley, Jonathan; Jamshidi, Maral; Aittomäki, Kristiina; Liu, Jianjun; Ali, H Raza; Andrulis, Irene L; Beckmann, Matthias W; Behrens, Sabine; Blows, Fiona M; Brenner, Hermann; Chang-Claude, Jenny; Couch, Fergus J; Czene, Kamila; Fasching, Peter A; Figueroa, Jonine; Floris, Giuseppe; Glendon, Gord; Guo, Qi; Hall, Per; Hallberg, Emily; Hamann, Ute; Holleczek, Bernd; Hooning, Maartje J; Hopper, John L; Jager, Agnes; Kabisch, Maria; Keeman, Renske; Kosma, Veli-Matti; Lambrechts, Diether; Lindblom, Annika; Mannermaa, Arto; Margolin, Sara; Provenzano, Elena; Shah, Mitul; Southey, Melissa C; Dennis, Joe; Lush, Michael; Michailidou, Kyriaki; Wang, Qin; Bolla, Manjeet K; Dunning, Alison M; Easton, Douglas F; Pharoah, Paul D P; Chenevix-Trench, Georgia; Blomqvist, Carl; Nevanlinna, Heli


    TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

  2. Pregnancy-Associated Cardiomyopathy in Survivors of Childhood Cancer (United States)

    Hines, Melissa R.; Mulrooney, Daniel A.; Hudson, Melissa M.; Ness, Kirsten K.; Green, Daniel M.; Howard, Scott C.; Krasin, Matthew; Metzger, Monika L.


    Purpose Current information regarding pregnancy-associated cardiomyopathy among women treated for childhood cancer is insufficient to appropriately guide counseling and patient management. This study aims to characterize its prevalence within a large cohort of females exposed to cardiotoxic therapy. Methods Retrospective cohort study of female cancer survivors treated at St. Jude Children’s Research Hospital between 1963 and 2006, at least 5 years from diagnosis, ≥ 13 years old at last follow-up, and with at least one successful pregnancy. Pregnancy-associated cardiomyopathy was defined as shortening fraction < 28% or ejection fraction < 50% or treatment for cardiomyopathy during or up to 5 months after completion of pregnancy. Results Among 847 female cancer survivors with 1554 completed pregnancies only 3 (0.3%) developed pregnancy-associated cardiomyopathy, 40 developed non-pregnancy-associated cardiomyopathy either 5 months post-partum (n=14), or prior to pregnancy (n=26). Among those with cardiomyopathy prior to pregnancy (n=26), cardiac function deteriorated during pregnancy in 8 patients (3 patients with normalization of cardiac function prior to pregnancy, 3 with persistently abnormal cardiac function, and 2 for whom resolution of cardiomyopathy was unknown prior to pregnancy). Patients that developed cardiomyopathy recevied a higher median dose of anthracyclines compared to those that did not (321 mg/m2 versus 164 mg/m2; p< 0.01). Conclusions Pregnancy-associated cardiomyopathy in childhood cancer survivors is rare. Implications for cancer survivors Most female childhood cancer survivors will have no cardiac complications during or after childbirth, however those with a history of cardiotoxic therapies should be followed carefully during pregnancy particularly those with a history of anthracycline exposures and if they had documented previous or current subclinical or symptomatic cardiomyopathy. Female childhood cancer survivors with a history of

  3. Camptothecin induces urokinase-type plasminogen activator gene-expression in human RC-K8 malignant lymphoma and H69 small cell lung cancer cells.


    Shibakura M; Niiya K; Kiguchi T; Nakata Y; Tanimoto M


    We previously reported that anthracyclines, which could generate reactive oxygen species (ROS), could induce the urokinase-type plasminogen activator (uPA) gene expression in human RC-K8 malignant lymphoma cells and in H69 small cell lung cancer (SCLC) cells. In screening other uPA-inducible anti-cancer agents, we found that camptothecin (CPT) and its derivative, SN38, could induce uPA in RC-K8 and H69 cells. CPT and SN38, which are also used for the treatment of lymphoma and SCLC, significan...

  4. Exatecan in pretreated adult patients with advanced soft tissue sarcoma: results of a phase II--study of the EORTC Soft Tissue and Bone Sarcoma Group

    DEFF Research Database (Denmark)

    Reichardt, P; Nielsen, Ole Steen; Bauer, S;


    No standard treatment is established for patients with advanced soft tissue sarcoma after previous chemotherapy with anthracyclines and ifosfamide, given either in combination or sequentially. Exatecan (DX-8951f) is a totally synthetic analogue of the topoisomerase I-inhibitor camptothecin, which...... modification. The main toxicity was haematotoxicity with grade 3/4 neutropenia in 49%, grade 3/4 thrombocytopenia in 23%, and grade 3/4 anaemia in 15% of patients, respectively. Non-haematological toxicity consisted mainly of grade 2/3 dyspnoea in 36% of patients and grade 2/3 fatigue in 28%. One treatment...

  5. Isolation and characterization of stable mutants of Streptomyces peucetius defective in daunorubicin biosynthesis

    Indian Academy of Sciences (India)

    K. S. Vetrivel; K. Dharmalingam


    Daunorubicin and its derivative doxorubicin are antitumour anthracycline antibiotics produced by Streptomyces peucetius. In this study we report isolation of stable mutants of S. peucetius blocked in different steps of the daunorubicin biosynthesis pathway. Mutants were screened on the basis of colony colour since producer strains are distinctively coloured on agar plates. Different mutants showed accumulation of aklaviketone, -rhodomycinone, maggiemycin or 13-dihydrocarminomycin in their culture filtrates. These results indicate that the mutations in these isolates affect steps catalysed by dnrE (mutants SPAK and SPMAG), dnrS (SPFS and SPRHO) and doxA (SPDHC) gene products.

  6. Drug transporters in breast cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Stenvang, Jan; Moreira, José


    Despite the advances that have taken place in the past decade, including the development of novel molecular targeted agents, cytotoxic chemotherapy remains the mainstay of cancer treatment. In breast cancer, anthracyclines and taxanes are the two main chemotherapeutic options used on a routine...... basis. Although effective, their usefulness is limited by the inevitable development of resistance, a lack of response to drug-induced cancer cell death. A large body of research has resulted in the characterization of a plethora of mechanisms involved in resistance; ATP-binding cassette transporter...

  7. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. (United States)

    Pommier, Yves; Leo, Elisabetta; Zhang, HongLiang; Marchand, Christophe


    DNA topoisomerases are the targets of important anticancer and antibacterial drugs. Camptothecins and novel noncamptothecins in clinical development (indenoisoquinolines and ARC-111) target eukaryotic type IB topoisomerases (Top1), whereas human type IIA topoisomerases (Top2alpha and Top2beta) are the targets of the widely used anticancer agents etoposide, anthracyclines (doxorubicin, daunorubicin), and mitoxantrone. Bacterial type II topoisomerases (gyrase and Topo IV) are the targets of quinolones and aminocoumarin antibiotics. This review focuses on the molecular and biochemical characteristics of topoisomerases and their inhibitors. We also discuss the common mechanism of action of topoisomerase poisons by interfacial inhibition and trapping of topoisomerase cleavage complexes.

  8. [Treatment of acute leukemias]. (United States)

    Gross, R; Gerecke, D


    The effective treatment of acute (myeloblastic and lymphoblastic) leukaemias depends on the induction of remissions as well as on the maintenance of these remissions. Whereas the use of anthracyclines and of cytosine arabinoside in different combinations notably increased the rate of induction of remissions, their maintenance was less successful until now. We present a scheme using, beside MTX and 6-MP, modified COAP regimes periodically every 3 months. The follow-up of 26 patients treated in this way is encouraging since nearly one third remained in full haematological remission after 3 years of observation.

  9. HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Reynolds, Joseph G.; Geretti, Elena; Hendriks, Bart S.; Lee, Helen; Leonard, Shannon C.; Klinz, Stephan G.; Noble, Charles O. [Merrimack Pharmaceuticals, 1 Kendall Square, Suite B7201, Cambridge, MA 02139 (United States); Lücker, Petra B.; Zandstra, Peter W. [University of Toronto, 160 College Street, Office 1116, Toronto, Ontario M5S 3E1 (Canada); Drummond, Daryl C.; Olivier, Kenneth J.; Nielsen, Ulrik B.; Niyikiza, Clet; Agresta, Samuel V. [Merrimack Pharmaceuticals, 1 Kendall Square, Suite B7201, Cambridge, MA 02139 (United States); Wickham, Thomas J., E-mail: [Merrimack Pharmaceuticals, 1 Kendall Square, Suite B7201, Cambridge, MA 02139 (United States)


    Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers. While documenting the enhanced therapeutic potential of HER2-targeted liposomal doxorubicin can be done with existing models, there has been no validated human cardiac cell-based assay system to rigorously assess the cardiotoxicity of anthracyclines. To understand if HER2-targeting of liposomal doxorubicin is possible with a favorable cardiac safety profile, we applied a human stem cell-derived cardiomyocyte platform to evaluate the doxorubicin exposure of human cardiac cells to HER2-targeted liposomal doxorubicin. To the best of our knowledge, this is the first known application of a stem cell-derived system for evaluating preclinical cardiotoxicity of an investigational agent. We demonstrate that HER2-targeted liposomal doxorubicin has little or no uptake into human cardiomyocytes, does not inhibit HER2-mediated signaling, results in little or no evidence of cardiomyocyte cell death or dysfunction, and retains the low penetration into heart tissue of liposomal doxorubicin. Taken together, this data ultimately led to the clinical decision to advance this drug to Phase I clinical testing, which is now ongoing as a single agent in HER2-expressing cancers. -- Highlights: ► Novel approach using stem cell-derived cardiomyocytes to assess preclinical safety. ► HER2-targeted liposomal doxorubicin has improved safety profile vs free doxorubicin

  10. Systolic versus diastolic cardiac function variables during epirubicin treatment for breast cancer

    DEFF Research Database (Denmark)

    Appel, Jon Michael; Jensen, Benny Vittrup; Nielsen, Dorthe L.;


    Anthracyclines are important in the treatment of numerous malignant diseases but the use is limited by a risk of heart failure (CHF). LVEF (left ventricular ejection fraction) measurements by radionuclide ventriculography with multiple gated acquisition (MUGA) is often used for cardiac monitoring....... However, diastolic variables have been proposed as sensitive supplements. It was hypothesized that a change in diastolic filling variables measured by MUGA could identify individuals after epirubicin treatment (ET) in risk of developing heart failure. A retrospective analysis of registered raw data...

  11. 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

    Energy Technology Data Exchange (ETDEWEB)

    Garcia P, S


    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

  12. Study on the interaction of anticancer drug mitoxantrone with DNA by fluorescence and Raman spectroscopies

    Institute of Scientific and Technical Information of China (English)

    Lingjuan Tang; Zhenrong Sun; Jianyu Guo; Zugeng Wang


    @@ Mitoxantrone, a clinically useful antitumour antibiotic for leukaemia and breast cancer, has received more attentions. In this paper, the interaction between mitoxantrone and calf thymus DNA is investigated by Raman and fluorescence spectroscopies, and the binding site of mitoxantrone to calf thymus DNA is explored. The results showed that mitoxantrone interacts with calf thymus DNA bases by the intercalation of anthracycline into the base pair plane of adenine (A) and thymine (T), and it results in the disruption of the hydrogen bonds between calf thymus DNA bases, and thus the calf thymus DNA double-strand can be disrupted into the B-form DNA double-strand segments.

  13. Systolic versus diastolic cardiac function variables during epirubicin treatment for breast cancer

    DEFF Research Database (Denmark)

    Appel, Jon Michael; Jensen, Benny V; Nielsen, Dorthe L.;


    Anthracyclines are important in the treatment of numerous malignant diseases but the use is limited by a risk of heart failure (CHF). LVEF (left ventricular ejection fraction) measurements by radionuclide ventriculography with multiple gated acquisition (MUGA) is often used for cardiac monitoring....... Individuals completing high-dose ET for breast cancer were selected from a 2-year period. All had MUGA-scans performed prior to and after ET and were observed clinically for late development of CHF. Eleven of 34 individuals developed CHF. A significant LVEF-reduction was recorded after ET with only minor...

  14. Trombose arterial em leucemia promielocítica aguda Arterial thrombosis in acute promyelocytic leukemia

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    Sonia Regina Iantas


    Full Text Available Acute promyeloclocytic leukemia can present coagulopathies which are frequently very serious due to hemorrhagic conditions. Treatment using anthracyclines and retinoids provide a good response. The development of arterial thrombosis is uncommon. In this work a 56-year-old male patient with acute arterial insufficiency was evaluated. This patient was immediately submitted to thromboembolectomy with the removal of a white thrombus. Postoperative tests showed acute promyelocytic leukemia with transposition (15;17 Treatment with ATRA and Idarubicin chemotherapy was initiated with the patients's response being satisfactory. Currently, the patient is incomplete remission and a recent cytogenetics test does not show the t(15;17.

  15. Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia.

    Directory of Open Access Journals (Sweden)

    Umayal Sivagnanalingam

    Full Text Available Cytogenetically normal acute myeloid leukemia (CN-AML patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH. Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches.

  16. Thioredoxin interacting protein and its association with clinical outcome in gastro-oesophageal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Caroline M. Woolston


    Full Text Available The overall prognosis for operable gastro-oesophageal adenocarcinoma remains poor and therefore neoadjuvant chemotherapy has become the standard of care, in addition to radical surgery. Certain anticancer agents (e.g. anthracyclines and cisplatin generate damaging reactive oxygen species as by-products of their mechanism of action. Drug effectiveness can therefore depend upon the presence of cellular redox buffering systems that are often deregulated in cancer. The expression of the redox protein, thioredoxin interacting protein, was assessed in gastro-oesophageal adenocarcinomas. Thioredoxin interacting protein expression was assessed using conventional immunohistochemistry on a tissue microarray of 140 adenocarcinoma patients treated by primary surgery alone and 88 operable cases treated with neoadjuvant chemotherapy. In the primary surgery cases, high thioredoxin interacting protein expression associated with a lack of lymph node involvement (p=0.005, no perineural invasion (p=0.030 and well/moderate tumour differentiation (p=0.033. In the neoadjuvant tumours, high thioredoxin interacting protein expression was an independent marker for improved disease specific survival (p=0.002 especially in cases with anthracycline-based regimes (p=0.008. This study highlights the potential of thioredoxin interacting protein as a biomarker for response in neoadjuvant treated gastro-oesophageal adenocarcinoma and may represent a useful therapeutic target due to its association with tumour progression.

  17. Normal tissue tolerance to external beam radiation therapy: Cardiac structures; Dose de tolerance des tissus sains: le coeur

    Energy Technology Data Exchange (ETDEWEB)

    Doyen, J. [Service d' oncologie-radiotherapie, centre Antoine-Lacassagne, 06 - Nice (France); Giraud, P. [Universite Rene-Descartes Paris 5, 75 - Paris (France); Service d' oncologie-radiotherapie, hopital europeen Georges-Pompidou, 75 - Paris (France); Belkacemi, Y. [Faculte de medecine de Creteil, universite Paris 12, 94 - Creteil (France); Service d' oncologie-radiotherapie, CHU Henri-Mondor, 94 - Creteil (France)


    Radiation thoracic tumors may be associated with cardiac toxicity because of the central position of the heart in the thorax. The present review aims to describe the cardiotoxicity during radiotherapy of different tumor sites most associated with this complication and the risk factors of cardiotoxicity during radiation therapy. Medline literature searches were performed using the following cardiac - heart - radiotherapy - toxicity - cardiotoxicity - breast cancer - lymphoma. Cardiac toxicity after breast cancer and mediastinal lymphoma is the most reported radiation-induced complication. The most frequent clinical complications are pericarditis, congestive heart failure, and heart infarction. These events are mostly asymptomatic. Thus clinicians have to give particular attention to these complications. Anthracycline treatment is a major risk factor for additional cardiotoxicity during radiotherapy with a synergistic effect. Correction of cardiovascular risk is an important point of the prevention of heart complications. Total dose delivered to the planned target volume (PTV), the dose per fraction and the irradiated volume were correlated to the risk of cardiotoxicity. Volume of heart receiving 35 Gy must be inferior to 30% and dose per fraction should not exceed 2 Gy when dose of prescription exceeds 30 Gy. Maximum heart distance (maximal thickness of heart irradiated) must be less than 1 cm during irradiation of breast cancer. Modern irradiation techniques seem to be associated with a limited risk of heart complication. The use of anthracycline, other cardio-toxic chemotherapies and targeted therapies should incite for great caution by performing a careful treatment planning and optimisation. (authors)

  18. Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats. (United States)

    Wang, Yu; Mei, Xueting; Yuan, Jingquan; Lu, Wenping; Li, Binglong; Xu, Donghui


    The clinical efficacy of anthracycline anti-neoplastic agents is limited by cardiac and hepatic toxicities. The aim of this study was to assess the hepatoprotective and cardioprotective effects of taurine zinc solid dispersions, which is a newly-synthesized taurine zinc compound, against doxorubicin-induced toxicity in Sprague-Dawley rats intraperitoneally injected with doxorubicin hydrochloride (3mg/kg) three times a week (seven injections) over 28 days. Hemodynamic parameters, levels of liver toxicity markers and oxidative stress were assessed. Taurine zinc significantly attenuated the reductions in blood pressure, left ventricular pressure and ± dp/dtmax, increases in serum alanine aminotransferase and aspartate aminotransferase activities, and reductions in serum Zn(2+) and albumin levels (Pzinc dose-dependently increased liver superoxide dismutase activity and glutathione concentration, and decreased malondialdehyde level (Pzinc dose-dependently increased liver heme oxygenase-1 and UDP-glucuronyl transferase mRNA and protein expression (Pzinc inhibited c-Jun N-terminal kinase phosphorylation by upregulating dual-specificity phosphoprotein phosphatase-1. Additionally, taurine zinc inhibited cardiomyocyte apoptosis as there was decreased TUNEL/DAPI positivity and protein expression of caspase-3. These results indicate that taurine zinc solid dispersions prevent the side-effects of anthracycline-based anticancer therapy. The mechanisms might be associated with the enhancement of antioxidant defense system partly through activating transcription to synthesize endogenous phase II medicine enzymes and anti-apoptosis through inhibiting JNK phosphorylation.

  19. Clinical outcomes of systemic therapy for patients with deep fibromatoses (desmoid tumors) (United States)

    de Camargo, Veridiana Pires; Keohan, Mary L.; D’Adamo, David R.; Antonescu, Cristina R.; Brennan, Murray F.; Singer, Samuel; Ahn, Linda S.; Maki, Robert G.


    Objectives We examined outcomes of patients with desmoid tumors receiving systemic therapy at a single institution to provide a basis for examination of newer agents. Methods We reviewed records of patients with desmoid tumors treated with chemotherapy at our institution. The activity of NSAIDs was not addressed. Patients without measurable disease, those receiving therapy we could not document, and those receiving prophylactic therapy were excluded. Results Sixty-eight patients received 157 lines of therapy. Nine patients died, 7 of progressive disease. The cohort was 62% female with median age 32.5, 32% with Gardner syndrome, median follow-up 63 months, and median of 2 lines of therapy. Intra-abdominal primary location was most common (44%). The greatest RECIST response rate was observed with anthracyclines and hormonal therapy and lowest with single agent dacarbazine/temozolomide or tyrosine kinase inhibitors, principally imatinib. In a multivariate analysis, only nodular gross morphology and presence of Gardner syndrome were the only tumor factors associated with greater time to progression. Conclusions Anti-estrogens and anthracycline-containing regimens are associated with a higher radiological response rate against desmoid tumors than other agents. Systemic therapy for desmoid tumors can be successful in patients with desmoids, and is a viable option in lieu of morbid or disabling surgery. PMID:20187095

  20. A multicentric observational trial of pegylated liposomal doxorubicin for metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Wischnik Arthur


    Full Text Available Abstract Background Pegylated liposomal doxorubicin (PLD is active in metastatic breast cancer. This observational study evaluated the efficacy and safety of PLD in patients treated during routine clinical practice. Methods Eligible patients had metastatic breast cancer and were treated with PLD according to the dose and schedule determined by their physician as part of routine practice. The primary objectives were to analyze the efficacy and toxicity of PLD therapy. Results 125 patients were assessable. Median age was 62 years, 78% had performance status 0-1, and 60% had estrogen-receptor-positive disease. PLD treatment was second- or third-line in 69% of patients. Prior anthracyclines (adjuvant or metastatic had been used in 56% of patients. The majority of patients (79% received PLD every 4 weeks at a median dose of 40 mg/m2. Overall response rate was 43% in all patients and 34% in those previously treated with anthracyclines. The most common grade 3/4 adverse events were skin toxicity/hand-foot syndrome (6%, and leukopenia (3%. Conclusions This observational study supports the activity and tolerability of PLD in metastatic breast cancer as demonstrated in PLD clinical trials.


    Directory of Open Access Journals (Sweden)



    Full Text Available Breast cancer currently is a major health problem among women worldwide accounting for around 13.7% cancer deaths, nearly 1/3rd of it being due to Locally advanced breast cancer (LABC. Despite progress achieved in diagnosis & therapy of Breast cancer, LABC remains a major clinical challenge and in efforts to increase pCR, CCR & DFS in LABC, Neoadjuvant or primary chemotherapy followed by locoregional therapy and adjuvant systemic CT is well accepted treatment strategy since last 3 decades. Further to address the issue of drug resistance in NACT sequential anthracycline-taxane NACT has been evaluated by many researchers and has resulted in better outcome in terms of overall survival and pCR. In this study we have evaluated 4 cycles of sequential anthracycline-taxane, 2 cycles of Cyclophosphamide, Epirubicin, Fluracil +2 cycles of Docetaxel, Epirubicin (CEF- DE NACT in a series of 10 cases of ER/PR +ve, Her -2 neu negative patients of LABC. 9/10 cases were rendered operable after primary chemotherapy and were subjected to further 4 cycles of adjuvant chemotherapy (1 cycle CEF, 1 cycle DE, 2cycles single agent Docetaxel, followed by locoregional RT. This tailored sequential NACT protocol in our subgroup of patient was well tolerated, well accepted and resulted in substantial increase in operability with CCR & DFS in 6/10 cases on 3 years follow up and pCR in one patient. Sequential NACT needs further validation by more RCT with extensive follow up

  2. The clinically relevant pharmacogenomic changes in acute myelogenous leukemia. (United States)

    Emadi, Ashkan; Karp, Judith E


    Acute myelogenous leukemia (AML) is an extremely heterogeneous neoplasm with several clinical, pathological, genetic and molecular subtypes. Combinations of various doses and schedules of cytarabine and different anthracyclines have been the mainstay of treatment for all forms of AMLs in adult patients. Although this combination, with the addition of an occasional third agent, remains effective for treatment of some young-adult patients with de novo AML, the prognosis of AML secondary to myelodysplastic syndromes or myeloproliferative neoplasms, treatment-related AML, relapsed or refractory AML, and AML that occurs in older populations remains grim. Taken into account the heterogeneity of AML, one size does not and should not be tried to fit all. In this article, the authors review currently understood, applicable and relevant findings related to cytarabine and anthracycline drug-metabolizing enzymes and drug transporters in adult patients with AML. To provide a prime-time example of clinical applicability of pharmacogenomics in distinguishing a subset of patients with AML who might be better responders to farnesyltransferase inhibitors, the authors also reviewed findings related to a two-gene transcript signature consisting of high RASGRP1 and low APTX, the ratio of which appears to positively predict clinical response in AML patients treated with farnesyltransferase inhibitors.

  3. 乳腺癌雌激素受体、孕激素受体和C-erbB-2在不同新辅助化疗前后的变化%Changes of estrogen receptor, progesterone receptor and C-erbB-2 expressions in different scheme pre-and post-neoadjuvant chemotherapies for breast cancer

    Institute of Scientific and Technical Information of China (English)

    史蓬亮; 张乃千; 张国强


    新辅助化疗在局部晚期乳腺癌的治疗中已被越来越广泛的应用.近年来研究表明,不同新辅助化疗前后肿瘤组织中雌激素受体(ER)、孕激素受体(PR)和人类表皮生长因子受体-2(C-erbB-2)的表达可能发生变化.在同时含有蒽环类及紫衫类化疗药物的新辅助化疗方案中改变较为明显,而在以蒽环类化疗药物为主的方案中无明显变化.%Neoadjuvant chemotherapy is widely used in the therapy of locally advanced breast cancer.In the recent studies,the expressions of ER,PR and C-erbB-2 in tumor may change in different scheme preand post-neoadjuvant chemotherapies for breast cancer.It is obviously changed in the neoadjuvant chemotherapy scheme of anthracyclines and paclitaxel/docetaxel,but hardly changed in anthracycline-based neoadjuvant chemotherapy scheme.

  4. 丝裂霉素加顺铂治疗难治性晚期乳腺癌%Phase Ⅱ study of mitomycin C and cisplatin in heavily pretreated advanced breast cancer

    Institute of Scientific and Technical Information of China (English)

    胡夕春; 郭海宜; 赵欣民


    Objective: The mitomycin C and cisplatin combination was investigated in patients with advanced breast cancer who had been exposed to anthracyclines, vinorelbine and taxanes. Methods: Three-weekly regimen consisted of mitomycin,6 mg/m2 administered intravenously on day 1, and cisplatin, 25 mg/m2 intravenously on day 1-3. Results: Thirty-eight patients aged 25-75 years (median, 46 years) were treated with an overall response rate of 31.6%. The median time to progression(TTP) was 4.0 months. Median TTP for 12 patients with a complete or partial response was 9.0 months, while stable disease and progression of disease 4.0 months, ,P=-0.002. Grade 3/4 side effects of neutropenia, thrombocytopenia and nausea/vomiting were documented in 4 (10.5%), 4 (10.5%) and 3 (7.9%) patients, respectively. The median overall survival was 13+ months. Conclusion: Mitomycin C/cisplatin doublet showed antitumor activity for anthracycline-, vinorelbine- and taxane-resistant breast cancer comparable to other regimens. This well-tolerated regimen provides an affordable option for patients in China.

  5. [Studies on the absorption, excretion and distribution of aclacinomycin A: absorption, excretion and distribution of aclacinomycin A in mice, rabbits and dogs by photometric assay (author's transl)]. (United States)

    Iguchi, H; Matsushita, Y; Ohmori, K; Hirano, S; Kiyosaki, T; Hori, S; Tone, H; Oki, T


    An anthracycline antitumor antibiotic, aclacinomycin A, was given to mice, rabbits or dogs intravenously to study the pharmacokinetics by photometric assay based on the absorption of anthracycline ring. The drug was rapidly eliminated from the blood in these animals. Drug levels were much higher in the blood cells than in the plasma. Tissue levels in dogs were 50 approximately 100 times higher than the blood levels, which showed the drug was rapidly transferred from the blood to tissues after administration. Higher levels were observed in the lungs, spleen and lymph nodes, where the drug was present as aclacinomycin A itself and the glycoside-type metabolites that were biologically active. The active form was also detected in the pancreas, heart, thymus, bone marrow and gastrointestinal tract. In the liver and kidneys, biologically inactive aglycone-type metabolites were observed. About 2 approximately 4% of the drug given to rabbits or dogs was recovered in the urine by 72 hours after administration, in which only 10% of the excreted drug was active form in rabbits but about 65% in dogs. The rest was inactive aglycone-type metabolites that were excreted almost in the conjugated form. Biliary excretion also contributed to the total clearance of the drug. Aclacinomycin A was absorbed even by oral administration in rabbits and dogs. Tissue distribution of the drug orally given to dogs was similar to that in intravenous administration, except that higher levels of active form were detected in the gastrointestinal tract and of inactive form in the liver.

  6. NT-proBNP as Early Marker of Subclinical Late Cardiotoxicity after Doxorubicin Therapy and Mediastinal Irradiation in Childhood Cancer Survivors

    Directory of Open Access Journals (Sweden)

    Amal Zidan


    Full Text Available Background. Childhood cancer survivors treated with anthracyclines and mediastinal irradiation are at risk for late onset cardiotoxicity. Aims of the Study. To assess the role of N-terminal pro-brain natriuretic peptide (NT-proBNP and tissue Doppler imaging (TDI as early predictors of late onset cardiotoxicity in asymptomatic survivors of childhood cancer treated with doxorubicin with or without mediastinal irradiation. Methods. A cross-sectional study on 58 asymptomatic survivors of childhood cancer who received doxorubicin in their treatment protocols and 32 asymptomatic Hodgkin’s lymphoma survivors who received anthracycline and mediastinal irradiation. Levels of NT-proBNP, TDI, and conventional echocardiography were determined. Results. Thirty percent of survivors had abnormal NT-proBNP levels. It was significantly related to age at diagnosis, duration of follow-up, and cumulative dose of doxorubicin. TDI detected myocardial affection in 20% more than conventional echocardiography. Furthermore, abnormalities in TDI and NT-pro-BNP levels were more common in Hodgkin lymphoma survivors receiving both chemotherapy and radiotherapy. Conclusions. TDI could detect early cardiac dysfunction even in those with normal conventional echocardiography. Measurement of NT-proBNP represents an interesting strategy for detecting subclinical cardiotoxicity. We recommend prospective and multicenter studies to validate the role of NT-proBNP as an early marker for late onset doxorubicin-induced cardiotoxicity.

  7. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. (United States)

    Panaretakis, Theocharis; Kepp, Oliver; Brockmeier, Ulf; Tesniere, Antoine; Bjorklund, Ann-Charlotte; Chapman, Daniel C; Durchschlag, Michael; Joza, Nicholas; Pierron, Gérard; van Endert, Peter; Yuan, Junying; Zitvogel, Laurence; Madeo, Frank; Williams, David B; Kroemer, Guido


    Dying tumour cells can elicit a potent anticancer immune response by exposing the calreticulin (CRT)/ERp57 complex on the cell surface before the cells manifest any signs of apoptosis. Here, we enumerate elements of the pathway that mediates pre-apoptotic CRT/ERp57 exposure in response to several immunogenic anticancer agents. Early activation of the endoplasmic reticulum (ER)-sessile kinase PERK leads to phosphorylation of the translation initiation factor eIF2alpha, followed by partial activation of caspase-8 (but not caspase-3), caspase-8-mediated cleavage of the ER protein BAP31 and conformational activation of Bax and Bak. Finally, a pool of CRT that has transited the Golgi apparatus is secreted by SNARE-dependent exocytosis. Knock-in mutation of eIF2alpha (to make it non-phosphorylatable) or BAP31 (to render it uncleavable), depletion of PERK, caspase-8, BAP31, Bax, Bak or SNAREs abolished CRT/ERp57 exposure induced by anthracyclines, oxaliplatin and ultraviolet C light. Depletion of PERK, caspase-8 or SNAREs had no effect on cell death induced by anthracyclines, yet abolished the immunogenicity of cell death, which could be restored by absorbing recombinant CRT to the cell surface.

  8. Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway. (United States)

    Zitvogel, Laurence; Kepp, Oliver; Senovilla, Laura; Menger, Laurie; Chaput, Nathalie; Kroemer, Guido


    In response to some chemotherapeutic agents such as anthracyclines and oxaliplatin, cancer cells undergo immunogenic apoptosis, meaning that their corpses are engulfed by dendritic cells and that tumor cell antigens are presented to tumor-specific CD8(+) T cells, which then control residual tumor cells. One of the peculiarities of immunogenic apoptosis is the early cell surface exposure of calreticulin (CRT), a protein that usually resides in the lumen of the endoplasmic reticulum (ER). When elicited by anthracyclines or oxaliplatin, the CRT exposure pathway is activated by pre-apoptotic ER stress and the phosphorylation of the eukaryotic translation initiation factor eIF2alpha by the kinase PERK, followed by caspase-8-mediated proteolysis of the ER-sessile protein BAP31, activation of the pro-apoptotic proteins Bax and Bak, anterograde transport of CRT from the ER to the Golgi apparatus and exocytosis of CRT-containing vesicles, finally resulting in CRT translocation onto the plasma membrane surface. Interruption of this complex pathway abolishes CRT exposure, annihilates the immunogenicity of apoptosis, and reduces the immune response elicited by anticancer chemotherapies. We speculate that human cancers that are incapable of activating the CRT exposure pathway are refractory to the immune-mediated component of anticancer therapies.

  9. Changes in Pathological Complete Response Rates after Neoadjuvant Chemotherapy for Breast Carcinoma over Five Years

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    Daniel C. McFarland


    Full Text Available Historically, neoadjuvant chemotherapy (NACT was extrapolated from adjuvant regimens. Dual HER2 blockade and the introduction of carboplatin for triple negative breast cancers (TNBC emerged by December 2013 and have improved pathological complete response (pCR rates. The objective of this study was to assess the pCR rates before and after the introduction of these new neoadjuvant regimens. Materials and Methods. Stage I–III breast cancer patients who received NACT were analyzed for rates of pCR by clinical characteristics (i.e., age, BMI, axillary lymphadenopathy, and histologic subtype, by time period (1 = 3/2010–11/2013, 2 = 12/2013–3/2015, and by type of chemotherapy (e.g., anthracycline/taxane only, carboplatin-containing, and HER2 blockade. Results. 113 patients received NACT. Overall pCR rate was 26.5 percent (n=30. The pCR rate increased from 14% to 43.1% (p=0.001 from time period 1 to time period 2 and were associated with HER2 positivity (p=0.003, receiving treatment during time period 2 (p=0.001 and using an anthracycline/taxane plus additional agent type of regimen (p=0.004. Conclusions. Our study revealed a significant difference in rates of pCR over five years. Window of opportunity trials and other trials that utilize pCR analysis should be encouraged.

  10. Changes in Pathological Complete Response Rates after Neoadjuvant Chemotherapy for Breast Carcinoma over Five Years. (United States)

    McFarland, Daniel C; Naikan, Jessica; Rozenblit, Mariya; Mandeli, John; Bleiweiss, Ira; Tiersten, Amy


    Historically, neoadjuvant chemotherapy (NACT) was extrapolated from adjuvant regimens. Dual HER2 blockade and the introduction of carboplatin for triple negative breast cancers (TNBC) emerged by December 2013 and have improved pathological complete response (pCR) rates. The objective of this study was to assess the pCR rates before and after the introduction of these new neoadjuvant regimens. Materials and Methods. Stage I-III breast cancer patients who received NACT were analyzed for rates of pCR by clinical characteristics (i.e., age, BMI, axillary lymphadenopathy, and histologic subtype), by time period (1 = 3/2010-11/2013, 2 = 12/2013-3/2015), and by type of chemotherapy (e.g., anthracycline/taxane only, carboplatin-containing, and HER2 blockade). Results. 113 patients received NACT. Overall pCR rate was 26.5 percent (n = 30). The pCR rate increased from 14% to 43.1% (p = 0.001) from time period 1 to time period 2 and were associated with HER2 positivity (p = 0.003), receiving treatment during time period 2 (p = 0.001) and using an anthracycline/taxane plus additional agent type of regimen (p = 0.004). Conclusions. Our study revealed a significant difference in rates of pCR over five years. Window of opportunity trials and other trials that utilize pCR analysis should be encouraged.

  11. Thioredoxin interacting protein and its association with clinical outcome in gastro-oesophageal adenocarcinoma. (United States)

    Woolston, Caroline M; Madhusudan, Srinivasan; Soomro, Irshad N; Lobo, Dileep N; Reece-Smith, Alexander M; Parsons, Simon L; Martin, Stewart G


    The overall prognosis for operable gastro-oesophageal adenocarcinoma remains poor and therefore neoadjuvant chemotherapy has become the standard of care, in addition to radical surgery. Certain anticancer agents (e.g. anthracyclines and cisplatin) generate damaging reactive oxygen species as by-products of their mechanism of action. Drug effectiveness can therefore depend upon the presence of cellular redox buffering systems that are often deregulated in cancer. The expression of the redox protein, thioredoxin interacting protein, was assessed in gastro-oesophageal adenocarcinomas. Thioredoxin interacting protein expression was assessed using conventional immunohistochemistry on a tissue microarray of 140 adenocarcinoma patients treated by primary surgery alone and 88 operable cases treated with neoadjuvant chemotherapy. In the primary surgery cases, high thioredoxin interacting protein expression associated with a lack of lymph node involvement (p=0.005), no perineural invasion (p=0.030) and well/moderate tumour differentiation (p=0.033). In the neoadjuvant tumours, high thioredoxin interacting protein expression was an independent marker for improved disease specific survival (p=0.002) especially in cases with anthracycline-based regimes (p=0.008). This study highlights the potential of thioredoxin interacting protein as a biomarker for response in neoadjuvant treated gastro-oesophageal adenocarcinoma and may represent a useful therapeutic target due to its association with tumour progression.

  12. Anticancer efficacy and absorption, distribution, metabolism, and toxicity studies of Aspergiolide A in early drug development

    Directory of Open Access Journals (Sweden)

    Wang Y


    Full Text Available Yuanyuan Wang, Xin Qi, Dehai Li, Tianjiao Zhu, Xiaomei Mo, Jing LiKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's Republic of ChinaAbstract: Since the first anthracycline was discovered, many other related compounds have been studied in order to overcome its defects and improve efficacy. In the present paper, we investigated the anticancer effects of a new anthracycline, aspergiolide A (ASP-A, from a marine-derived fungus in vitro and in vivo, and we evaluated the absorption, distribution, metabolism, and toxicity drug properties in early drug development. We found that ASP-A had activity against topoisomerase II that was comparable to adriamycin. ASP-A decreased the growth of various human cancer cells in vitro and induced apoptosis in BEL-7402 cells via a caspase-dependent pathway. The anticancer efficacy of ASP-A on the growth of hepatocellular carcinoma xenografts was further assessed in vivo. Results showed that, compared with the vehicle group, ASP-A exhibited significant anticancer activity with less loss of body weight. A pharmacokinetics and tissue distribution study revealed that ASP-A was rapidly cleared in a first order reaction kinetics manner, and was enriched in cancer tissue. The maximal tolerable dose (MTD of ASP-A was more than 400 mg/kg, and ASP-A was not considered to be potentially genotoxic or cardiotoxic, as no significant increase of micronucleus rates or inhibition of the hERG channel was seen. Finally, an uptake and transport assay of ASP-A was performed in monolayers of Caco-2 cells, and ASP-A was shown to be absorbed through the active transport pathway. Altogether, these results indicate that ASP-A has anticancer activity targeting topoisomerase II, with a similar structure and mechanism to adriamycin, but with much lower toxicity. Nonetheless, further molecular structure optimization is necessary.Keywords: aspergiolide A, anticancer

  13. What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis. (United States)

    Zhao, Jianli; Liu, Jieqiong; Chen, Kai; Li, Shunrong; Wang, Ying; Yang, Yaping; Deng, Heran; Jia, Weijuan; Rao, Nanyan; Liu, Qiang; Su, Fengxi


    To evaluate the incidence of chemotherapy-induced amenorrhea (CIA) and its therapeutic impact in premenopausal breast cancer patients. A systematic search was performed to identify clinical studies that compared the incidence of CIA with different chemotherapy regimens and oncological outcomes with and without CIA. The fixed-effects and random-effects models were used to assess the pooled estimates. Heterogeneity and sensitivity analyses were performed to explore heterogeneity among studies and to assess the effects of study quality. A total of 15,916 premenopausal breast cancer patients from 46 studies were included. The cyclophosphamide-based regimens, taxane-based regimens, and anthracycline/epirubicin-based regimens all increased the incidence of CIA with pooled odds ratios of 2.25 (95 % CI 1.26-4.03, P = 0.006), 1.26 (95 % CI 1.11-1.43, P = 0.0003) and 1.39 (95 % CI 1.15-1.70, P = 0.0008), respectively. The three-drug combination regimens of cyclophosphamide,anthracycline/epirubicin, and taxanes (CAT/CET) caused the highest rate of CIA compared with the other three drug combinations (OR 1.41, 95 % CI 1.16-1.73, P = 0.0008). Tamoxifen therapy was also correlated with a higher incidence of CIA, with an OR of 1.48. Patients with CIA were found to exhibit better disease-free survival (DFS) and overall survival (OS) compared with patients without CIA. With respect to molecular subtype, this DFS advantage remained significant in hormone-sensitive patients (HR 0.61, 95 % CI 0.52-0.72, P < 0.00001). The current meta-analysis has demonstrated that anthracycline/epirubicin, taxanes, cyclophosphamide, and tamoxifen all contributed to elevated rates of CIA, and CIA was not merely a side effect of chemotherapy but was a better prognostic marker, particularly for ER-positive premenopausal early-stage breast cancer patients. However, this topic merits further randomized control studies to detect the associations between CIA and patient prognosis after adjusting for age, ER

  14. Valvular Abnormalities Detected by Echocardiography in 5-Year Survivors of Childhood Cancer: A Long-Term Follow-Up Study

    Energy Technology Data Exchange (ETDEWEB)

    Pal, Helena J. van der, E-mail: [Department of Medical Oncology, Emma Children' s Hospital/Academic Medical Center, Amsterdam (Netherlands); Department of Pediatric Oncology, Emma Children' s Hospital/Academic Medical Center, Amsterdam (Netherlands); Dijk, Irma W. van [Department of Radiation Oncology, Emma Children' s Hospital/Academic Medical Center, Amsterdam (Netherlands); Geskus, Ronald B. [Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Emma Children' s Hospital/Academic Medical Center, Amsterdam (Netherlands); Kok, Wouter E. [Department of Cardiology, Emma Children' s Hospital/Academic Medical Center, Amsterdam (Netherlands); Koolen, Marianne; Sieswerda, Elske [Department of Pediatric Oncology, Emma Children' s Hospital/Academic Medical Center, Amsterdam (Netherlands); Oldenburger, Foppe; Koning, Caro C. [Department of Radiation Oncology, Emma Children' s Hospital/Academic Medical Center, Amsterdam (Netherlands); Leeuwen, Flora E. van [Department of Epidemiology, Netherlands Cancer Institute, Amsterdam (Netherlands); Caron, Huib N.; Kremer, Leontien C.; Dalen, Elvira C. van [Department of Pediatric Oncology, Emma Children' s Hospital/Academic Medical Center, Amsterdam (Netherlands)


    Purpose: To determine the prevalence of valvular abnormalities after radiation therapy involving the heart region and/or treatment with anthracyclines and to identify associated risk factors in a large cohort of 5-year childhood cancer survivors (CCS). Methods and Materials: The study cohort consisted of all 626 eligible 5-year CCS diagnosed with childhood cancer in the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 and treated with radiation therapy involving the heart region and/or anthracyclines. We determined the presence of valvular abnormalities according to echocardiograms. Physical radiation dose was converted into the equivalent dose in 2-Gy fractions (EQD{sub 2}). Using multivariable logistic regression analyses, we examined the associations between cancer treatment and valvular abnormalities. Results: We identified 225 mainly mild echocardiographic valvular abnormalities in 169 of 545 CCS (31%) with a cardiac assessment (median follow-up time, 14.9 years [range, 5.1-36.8 years]; median attained age 22.0 years [range, 7.0-49.7 years]). Twenty-four CCS (4.4%) had 31 moderate or higher-graded abnormalities. Most common abnormalities were tricuspid valve disorders (n=119; 21.8%) and mitral valve disorders (n=73; 13.4%). The risk of valvular abnormalities was associated with increasing radiation dose (using EQD{sub 2}) involving the heart region (odds ratio 1.33 per 10 Gy) and the presence of congenital heart disease (odds ratio 3.43). We found no statistically significant evidence that anthracyclines increase the risk. Conclusions: Almost one-third of CCS treated with potentially cardiotoxic therapy had 1 or more asymptomatic, mostly mild valvular abnormalities after a median follow-up of nearly 15 years. The most important risk factors are higher EQD{sub 2} to the heart region and congenital heart disease. Studies with longer follow-up are necessary to investigate the clinical course of asymptomatic valvular abnormalities

  15. The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2)

    DEFF Research Database (Denmark)

    Litman, Thomas; Brangi, M; Hudson, E;


    known as ABCP1 or BCRP. The pharmacodynamics of mitoxantrone and 12 other fluorescent drugs were evaluated by confocal microscopy in four multidrug-resistant human colon (S1) and breast (MCF-7) cancer cell lines. We utilized two sublines, MCF-7 AdVp3000 and S1-M1-80, and detected overexpression of MXR...... by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein- and MRP-mediated resistance. High levels of cross-resistance were observed for mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of mitoxantrone......, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were observed in the two sublines with high MXR expression. Neither the P-glycoprotein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells. Thus...

  16. BNP predicts chemotherapy-related cardiotoxicity and death

    DEFF Research Database (Denmark)

    Skovgaard, Dorthe; Hasbak, Philip; Kjaer, Andreas


    ) or death in a population of anthracycline-treated cancer patients. METHODS: We prospectively followed 333 cancer patients referred to our department for routine monitoring of LVEF with MUGA and measurement of BNP, January-December 2004. Study end points were hospitalization for CHF and death during follow...... death. In multivariate Cox analysis both BNP and LVEF were independent predictors of CHF while age remained the only independent predictor of overall death. CONCLUSION: In cancer patients treated with cardiotoxic chemotherapy both BNP and LVEF can significantly predict subsequent hospitalization...... with CHF. In addition, BNP and not LVEF has a prognostic value in detecting overall death. This prospective study based on the hitherto largest study population supports BNP as a clinical relevant method for monitoring chemotherapy-related cardiac failure and death....


    Directory of Open Access Journals (Sweden)

    Caterina Giovanna Valentini


    Full Text Available Breast cancer is the most frequent cancer among women and the leading cause of death among middle-aged women. Early detection by mammography screening and improvement of therapeutic options have increased breast cancer survival rates, with the consequence that late side effects of cancer treatment become increasingly important. In particular, patients treated with adjuvant chemotherapy regimens, commonly including alkylating agents and anthracyclines, are at increased risk of developing leukemia, further enhanced by the use of radiotherapy. In the last few years also the use of growth factors seems to increase the risk of secondary leukemia. The purpose of this review is to update epidemiology of therapy-related myeloid neoplasms occurring in breast cancer patients

  18. Inhibition of RNA Helicases of ssRNA+ Virus Belonging to Flaviviridae, Coronaviridae and Picornaviridae Families

    Directory of Open Access Journals (Sweden)

    Irene Briguglio


    Full Text Available Many viral pathogens encode the motor proteins named RNA helicases which display various functions in genome replication. General strategies to design specific and selective drugs targeting helicase for the treatment of viral infections could act via one or more of the following mechanisms: inhibition of the NTPase activity, by interferences with ATP binding and therefore by limiting the energy required for the unwinding and translocation, or by allosteric mechanism and therefore by stabilizing the conformation of the enzyme in low helicase activity state; inhibition of nucleic acids binding to the helicase; inhibition of coupling of ATP hydrolysis to unwinding; inhibition of unwinding by sterically blocking helicase translocation. Recently, by in vitro screening studies, it has been reported that several benzotriazole, imidazole, imidazodiazepine, phenothiazine, quinoline, anthracycline, triphenylmethane, tropolone, pyrrole, acridone, small peptide, and Bananin derivatives are endowed with helicase inhibition of pathogen viruses belonging to Flaviviridae, Coronaviridae, and Picornaviridae families.

  19. Potential risk and benefit of the combination of trastuzumab to chemotherapy and radiation therapy in non-metastatic breast cancer; Benefice et risques potentiels de l'association du trastuzumab a la chimiotherapie et a la radiotherapie dans le cancer du sein non metastatique

    Energy Technology Data Exchange (ETDEWEB)

    Belkacemi, Y. [CLCC Oscar-Lambret, Universite de Lille-2, Dept. d' Oncologie-Radiotherapie, 59 - Lille (France); Laharie-Mineur, H. [CLCC, institut Bergonie, 33 - Bordeaux (France); Gligorov, J. [APHP, Hopital Tenon, Cancer-Est, 75 - Paris (France); Azria, D. [CLCC Val d' Aurelle-Paul-Lamarque, Inserm, EMI 0227, 34 - Montpellier (France)


    Trastuzumab (Herceptin) is the first humanized monoclonal antibody targeting the HER2 antigen in breast cancer. HER2 receptor has been individualised 20 years ago. During the past 10 years, trastuzumab administration has radically modified the prognosis of the patients that are treated for HER2 positive breast cancer. Its efficacy has been demonstrated in the metastatic and adjuvant settings. While, trastuzumab based-regimens became the standard of care in the treatment of HER2/neu positive breast cancer, the optimal combination (concurrently or sequentially) to chemotherapy and radiation therapy is still unknown. Indeed, while the concurrent administration of trastuzumab and anthracyclines is not recommended because of a high risk of cardiac toxicity, there is no published data on the best sequence of trastuzumab and radiation therapy administration, particularly when internal mammary chain is involved. The benefit/risk ratio of the concurrent and sequential administration of trastuzumab with chemotherapy and radiation therapy will be discussed in this review. (authors)

  20. Breast conserving treatment of breast carcinoma T2 ({<=} 4 cm) and T3 by neoadjuvant chemotherapy, quadrantectomy, high dose rate brachytherapy as a boost, external beam radiotherapy and adjuvant chemotherapy: local control and overall survival analysis; Tratamento conservador do cancer de mama T2 ({<=} 4 cm) e T3 por quimioterapia neoadjuvante, quadrantectomia, braquiterapia com alta taxa de dose como reforco de dose, teleterapia complementar e quimioterapia adjuvante: analise de controle local e sobrevida global

    Energy Technology Data Exchange (ETDEWEB)

    Soares, Celia Regina; Miziara Filho, Miguel Abrao; Fogaroli, Ricardo Cesar; Baraldi, Helena Espindola; Pellizzon, Antonio Cassio Assis; Pelosi, Edilson Lopes [Instituto do Cancer Dr. Arnaldo Vieira de Carvalho (ICAVC), Sao Paulo, SP (Brazil). Servico de Radioterapia], e-mail:; Fristachi, Carlos Elias [Instituto do Cancer Dr. Arnaldo Vieira de Carvalho (ICAVC), Sao Paulo, SP (Brazil). Servico de Onco-Ginecologia e Mastologia; Paes, Roberto Pinto [Instituto do Cancer Dr. Arnaldo Vieira de Carvalho (ICAVC), Sao Paulo, SP (Brazil)


    Objective: to assess the treatment of breast cancer T2 ({<=} 4 cm) and T3 through neoadjuvant chemotherapy, quadrantectomy and high dose rate brachytherapy as a boost, complementary radiotherapy and adjuvant chemotherapy, considering local control and overall survival. Material and method: this clinical prospective descriptive study was based on the evaluation of 88 patients ranging from 30 to 70 years old, with infiltrating ductal carcinoma, clinical stage IIb and IIIa, responsive to the neoadjuvant chemotherapy, treated from June/1995 to December/2006. Median follow-up was 58 months. Using clinical methods the tumor was evaluated before and after three or four cycles of chemotherapy based on anthracyclines. Overall survival and local control were assessed according to Kaplan-Meier methodology. Results: Local control and overall survival in five years were 90% and 73.5%, respectively. Conclusion: local control and overall survival were comparable to other forms of treatment. (author)

  1. Daunomycin accumulation and induction of programmed cell death in rat hair follicles

    DEFF Research Database (Denmark)

    Shin, Masashi; Larsson, Lars-Inge; Hougaard, David M.


    The anthracycline antibiotic daunomycin (DM) is useful for the treatment of leukemia but has side-effects such as alopecia. Using immunocytochemistry, we show that, after a single i.v. injection, DM accumulates in the nuclei of matrix cells and in the outer root sheath of hair follicles. DM......-positive matrix cells are detectable up to 48 h after injection and exhibit a characteristic granular morphology, which is not observed in saline-injected controls. TUNEL-staining has revealed that DM injection induces programmed cell death (PCD) in rat hair follicles. Cells undergoing PCD are detectable as late...... (PCD type 2). Interestingly, little, if any, DM accumulation or apoptosis has been detected in the dermal hair papillae. This may have a bearing on potential regeneration of the hair follicles. Thus, DM accumulates in a characteristic pattern in hair follicles. This accumulation is associated...

  2. Characterization and functional capacity in women with breast cancer, gynaecological cancer and gestational trophoblastic disease

    Directory of Open Access Journals (Sweden)

    Thaís Cristina Elias

    Full Text Available Objective: to describe the social, demographic and clinical profile, and functional capacity of women diagnosed with gynecological cancer, breast cancer and gestational trophoblastic disease during chemotherapy. Method: longitudinal retrospective study that evaluated the records of women treated in hospital clinics from January 2000 to December 2012. Results: they evaluated the records of 438 women. The analysis showed that were not able to perform their daily activities, limited to the activities of self-care. Older patients had greater functional impairment during therapy. Conclusions: the sample was women 41 to 50 years, diagnosed with breast cancer (50.9% and made use of anthracycline based protocols (47%; the scores of the functional capacity of the sample fell from 78.22 to 73.57. It is evident that nursing care should focus on the control of signs and symptoms that impact the functional capacity of women under chemotherapy.

  3. Acute emesis: moderately emetogenic chemotherapy

    DEFF Research Database (Denmark)

    Herrstedt, Jørn; Rapoport, Bernardo; Warr, David


    This paper is a review of the recommendations for the prophylaxis of acute emesis induced by moderately emetogenic chemotherapy as concluded at the third Perugia Consensus Conference, which took place in June 2009. The review will focus on new studies appearing since the Second consensus conference...... receiving multiple cycles of moderately emetogenic chemotherapy will be reviewed. Consensus statements are given, including optimal dose and schedule of serotonin(3) receptor antagonists, dexamethasone, and neurokinin(1) receptor antagonists. The most significant recommendations (and changes since the 2004...... version of the guidelines) are as follows: the best prophylaxis in patients receiving moderately emetogenic chemotherapy (not including a combination of an anthracycline plus cyclophosphamide) is the combination of palonosetron and dexamethasone on the day of chemotherapy, followed by dexamethasone...

  4. Treatment of Acute Myeloid Leukemia in Adolescent and Young Adult Patients

    Directory of Open Access Journals (Sweden)

    Guldane Cengiz Seval


    Full Text Available The objectives of this review were to discuss standard and investigational treatment strategies for adolescent and young adult with acute myeloid leukemia, excluding acute promyelocytic leukemia. Acute myeloid leukemia (AML in adolescent and young adult patients (AYAs may need a different type of therapy than those currently used in children and older patients. As soon as AML is diagnosed, AYA patient should be offered to participate in well-designed clinical trials. The standard treatment approach for AYAs with AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or stem cell transplantation, depending on the ability of the patient to tolerate intensive treatment and cytogenetic features. Presently, continuing progress of novel drugs targeting specific pathways in acute leukemia may bring AML treatment into a new era.

  5. Acute promyelocytic leukemia during pregnancy: a systematic analysis of outcome. (United States)

    Verma, Vivek; Giri, Smith; Manandhar, Samyak; Pathak, Ranjan; Bhatt, Vijaya Raj


    The outcomes of acute promyelocytic leukemia (APL) in pregnancy are largely unknown. The MEDLINE database was systematically searched to obtain 43 articles with 71 patients with new-onset APL during pregnancy. Induction therapy included various regimens of all-trans retinoic acid (ATRA), cytarabine, and anthracycline and resulted in a complete remission rate of 93%. Obstetric and fetal complications included pre-term deliveries (46%), spontaneous/therapeutic abortion/intrauterine death (33.3%) and other neonatal complications (25.9%). Mothers diagnosed in the first trimester were more likely to experience obstetric (p pregnancy. The vast majority of APL patients in pregnancy may achieve remission with initial induction therapy. APL or its therapy in pregnancy, however, is associated with a high risk of fetal and obstetrical complications. The results of our study may help in patient counseling and informed decision-making.

  6. Targeting Chromosomal Instability and Tumour Heterogeneity in HER2-Positive Breast Cancer

    DEFF Research Database (Denmark)

    Burrell, Rebecca A.; Birkbak, Nicolai Juul; Johnston, Stephen R.;


    Chromosomal instability (CIN) is a common cause of tumour heterogeneity and poor prognosis in solid tumours and describes cell-cell variation in chromosome structure or number across a tumour population. In this article we consider evidence suggesting that CIN may be targeted and may influence...... response to distinct chemotherapy regimens, using HER2-positive breast cancer as an example. Pre-clinical models have indicated a role for HER2 signalling in initiating CIN and defective cell-cycle control, and evidence suggests that HER2-targeting may attenuate this process. Anthracyclines and platinum...... agents may target tumours with distinct patterns of karyotypic complexity, whereas taxanes may have preferential activity in tumours with relative chromosomal stability. A greater understanding of karyotypic complexity and identification of methods to directly examine and target CIN may support novel...

  7. High-dose ifosfamide and mesna in advanced breast cancer. A phase II study. (United States)

    Sanchiz, F; Milla, A


    Thirty-two patients with metastatic breast cancer had previously been treated with chemotherapy (including anthracyclines). They were included in a trial to receive 6 g/m3 ifosfamide, mixed with 6 g/m2 mesna in 1000 ml saline infusion, infused over 4 h. Therapy was repeated every 21 days; the dose was reduced by 50%. Twenty-eight patients could be evaluated. An average of 4.2 cycles (range 2-8) was applied. One patient (4%) showed complete remission. Ten patients (36%) had a partial response. Ten patients (36%) experienced SD and the remaining patients (25%) PD. We conclude that high-dose ifosfamide shows activity in this group of pretreated patients and merits further investigation.

  8. Clinico-Epidemiological Profile And Factors Affecting Severity Of Atopic Dermatitis In North Indian Children

    Directory of Open Access Journals (Sweden)

    Wollina Uwe


    Full Text Available Liposomes are lamellar structures composed of a lipid bilayer. They are used as carriers for different drugs. The present paper reviews the use of intravenous liposomal anticancer drugs in dermato-oncology. The broadest application is found today for liposomal anthracyclines, i.e., doxorubicin and daunorubicin. The practical experiences with liposomal drugs in skin cancer are still limited. There is clear evidence for liposomal drug efficacy and safety in AIDS- related Kaposi’s sarcoma. Their use in other conditions, such as cutaneous T-cell lymphoma, malignant melanoma and cutaneous angiosarcoma, has been investigated in uncontrolled trials. The preliminary data, however, are promising in particular for cutaneous T-cell lymphoma.

  9. [Pneumothorax after treatment with bevacizumab-containing chemotherapy for breast cancer - a case report]. (United States)

    Makino, Takatoshi; Kudo, Shun; Ogata, Takashi


    A 62-year-old woman presented with a right breast tumor. Examination yielded a diagnosis of right breast cancer (T4bN3bM1[lung]). After right breast mastectomy for local control, 9 sessions of chemotherapy containing an anthracycline and taxane were administered. Because of progression of lung metastasis, bevacizumab and paclitaxel were administered. Follow-up computed tomography(CT)scans showed that the multiple solid lung metastases had reduced in size, but a hollowing effect was noted. Eight months later, the patient developed left pneumothorax. The origin of the pneumothorax was unclear, but the hollowing due to the lung metastases seen after bevacizumab treatment was thought to be the cause. The pneumothorax resolved after tube thoracostomy, but disease progression occurred because of the lack of chemotherapy, and the patient's general condition worsened. Although rare, we speculate that there is a risk of pneumothorax after bevacizumab- containing chemotherapy.

  10. [Peripartum cardiomyopathy]. (United States)

    Mouquet, Frédéric; Bouabdallaoui, Nadia


    The peripartum cardiomyopathy is a rare form of dilated cardiomyopathy resulting from alteration of angiogenesis toward the end of pregnancy. The diagnosis is based on the association of clinical heart failure and systolic dysfunction assessed by echocardiography or magnetic resonance imaging. Diagnoses to rule out are myocardial infarction, amniotic liquid embolism, myocarditis, inherited cardiomyopathy, and history of treatment by anthracycline. Risk factors are advance maternal age (>30), multiparity, twin pregnancy, African origin, obesity, preeclampsia, gestational hypertension, and prolonged tocolytic therapy. Treatment of acute phase is identical to usual treatment of acute systolic heart failure. After delivery, VKA treatment should be discussed in case of systolic function <25% because of higher risk of thrombus. A specific treatment by bromocriptine can be initiated on a case-by-case basis. Complete recovery of systolic function is observed in 50% of cases. The mortality risk is low. Subsequent pregnancy should be discouraged, especially if systolic function did not recover.

  11. Exploiting the Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imaging of Liposomal Nanomedicines

    DEFF Research Database (Denmark)

    Edmonds, Scott; Volpe, Alessia; Shmeeda, Hilary;


    The clinical value of current and future nanomedicines can be improved by introducing patient selection strategies based on noninvasive sensitive whole-body imaging techniques such as positron emission tomography (PET). Thus, a broad method to radiolabel and track preformed nanomedicines...... such as liposomal drugs with PET radionuclides will have a wide impact in nanomedicine. Here, we introduce a simple and efficient PET radiolabeling method that exploits the metal-chelating properties of certain drugs (e.g., bisphosphonates such as alendronate and anthracyclines such as doxorubicin) and widely used...... ionophores to achieve excellent radiolabeling yields, purities, and stabilities with 89Zr, 52Mn, and 64Cu, and without the requirement of modification of the nanomedicine components. In a model of metastatic breast cancer, we demonstrate that this technique allows quantification of the biodistribution...

  12. [Development of novel synthetic organic reactions: synthesis of antitumor natural products and leading compounds for new pharmaceuticals]. (United States)

    Kita, Yasuyuki


    Biologically active natural products with unique, highly complex molecular skeletons have been used as leading compounds for raw materials of new drugs. Due to the limitations of natural supply, highly efficient, large-scale syntheses and molecular design have been sought in drug discovery. For this purpose, we have focused on a synthetic strategy effective in developing novel reactions and reagents and found several useful regio- and stereospecific reactions, contributing to the synthesis of otherwise unattainable target molecules. The application of these reactions for the total synthesis of three types of potent cytotoxic natural products for the first time is described in this paper. The basic concept is first described. Then the total synthesis of anthracyclines, fredericamycin A, and discorhabdins is reported. Novel reactions using hypervalent iodine reagents under environmentally benign conditions are also described. The future prospects for this method are discussed.

  13. [Methods of development of recommendations for clinical practice (RCP) and of setting-up of a platform cancer heart vessels (PTF-CHV) in the inter3C Vaucluse-Arles]. (United States)

    Debourdeau, Philippe; Meuleman, Catherine; Dufaitre, Ghislaine; Laroche, Jean-Pierre; Slama, Borhane; Chebrek, Safia; Aboukhoudir, Falah; Mège, Alice; Dotigny, Robert; Serin, Daniel


    Monitoring and prevention of cardiovascular complications of anti-neoplastic treatment are currently well known for anthracyclines and trastuzumab but remain poorly implemented. The management of cardiac and vascular side effects of targeted therapies is not codified. The purpose of the platform heart-vessel cancer is to optimize the management of such complications within a small area (Vaucluse region of Arles). The platform will offer prescribers an easily accessible database, doctors performing exams standardized monitoring forms and patients a uniform follow-up. We report here the methodology of the elaboration of recommendations for clinical practice and the ways to develop the platform. After a year of active process, an analysis of the will be performed to see opportunities for improvement and dissemination on a larger scale.

  14. Factors predicting long-term survival in low-risk diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Møller, Michael B; Pedersen, Niels T; Christensen, Bjarne E


    population-based data from the Danish Lymphoma Group, we analyzed if prognostic clinical pretreatment factors could be identified in patients with low-risk DLBCL. One hundred seventy-seven patients, all with a prognostic profile as favorable as possible according to the IPI and treated with anthracycline-based...... combination chemotherapy (92%) or loco-regional radiotherapy/surgery (8%) with curative intent were included. The median age was 50 years and 170 achieved complete remission. The median follow-up time was 11 years. Twenty-six patients relapsed, with a median time to relapse of 12.1 months. Overall survival...... at 5 years and 10 years was 85% and 75%, respectively. Stage II was associated with poor response to treatment (P=0.044). In a multivariate analysis, Stage II (P=0.001) and age >50 years (P=0.043) were independently associated with poor outcome. Patients without these adverse factors had an excellent...

  15. Radioimmunoassay for aclacinomycin A. (United States)

    Matsuzawa, Y; Kiyosaki, T; Oki, T; Takeuchi, T; Umezawa, H


    An antibody against aclacinomycin A (ACM) was produced in a rabbit by immunization with ACM-bovine serum albumin conjugate. The radioimmunoassay (RIA) was based on the competition of unlabeled anthracycline with 3H-labeled ACM for binding sites on a specific antibody. Antibody-bound and free antigen were separated by selective adsorption on dextran-coated charcoal. The antibody reacted equally with ACM and its metabolites, MA144 M1, MA144 S1 and aklavin, and could precisely distinguish aklavinone-related aglycones, adriamycin and daunomycin. RIA was sensitive in the range of 1 approximately 10 pmol per assay. The quantities of ACM and its metabolites in human plasma were practically determined without any pretreatment of physiological samples.

  16. [Irritative effect of aclacinomycin A on the eye mucous membrane, skin and muscle (author's transl)]. (United States)

    Ohmori, K; Hirano, S; Kiyosaki, T; Hori, S; Tone, H


    Aclacinomycin A, a new anthracycline antitumor antibiotic, was given to rabbits by single instillation or single intracutaneous injection and to guinea pigs by single subcutaneous or intramuscular injection to examine the irritative effect. Slight dilatation of blood vessel and swelling in the conjunctiva and nictitating membrane were observed in the eyes of rabbits given 1% solution. Edema in the bulbar conjunctiva, iris and cornea was histologically noted. Washing of the eyes after drug instillation prevented these damages. Subcutaneous and intracutaneous injections of 1% solution (0.2 ml) gave hyperemia, swelling and necrosis at injection site. Cellular infiltration, fibrosis and necrosis were histologically detected. Intramuscular injection of 1% solution (0.2 ml) also provided induration and swelling at injection site. Histologically cellular infiltration and necrosis were observed. These irritative effects were much slighter in administration of 0.1% solution. No change was observed with 0.01% solution.

  17.   Tumor tissue levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and survival following adjuvant chemotherapy in pre-menopausal lymph node-positive breast cancer patients (N=525)

    DEFF Research Database (Denmark)

    Rasmussen, Anne-Sofie Schrohl; Look, Maxime P.; Meijer-van Gelder, Marion E.

    for the analysis of DFS. A similar pattern was seen in the analyses of OS. In the group treated with CMF, both TIMP-1 low and high patients had significantly better survival than untreated patients (Ppatients, those with TIMP-1 low tumors appear to benefit more from the adjuvant...... Predictive markers are needed to guide planning of adjuvant therapy for patients with breast cancer. We have recently shown that high tumor tissue levels of TIMP-1 are associated with decreased response to chemotherapy in metastatic breast cancer patients (Schrohl et al, Clin Cancer Res, 2006......) suggesting that TIMP-1 may be a predictive marker in breast cancer patients. Purpose: This study investigates the association of tumor tissue TIMP-1 levels with response to adjuvant chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil) or an anthracycline-containing regimen. Patients...

  18. [Multiple organ failure presumably due to alkylating agents used as preconditioning drugs for autologous peripheral blood stem cell transplantation in an acute promyelocytic leukemia]. (United States)

    Ida, Tori; Hashimoto, Shigeo; Suzuki, Nobuaki; Ebe, Yusuke; Yano, Toshio; Sato, Naoko; Koike, Tadashi


    A 52-year-old male was diagnosed as having acute promyelocytic leukemia (APL) in 2006. He received induction chemotherapy including all-trans retinoic acid and initially achieved a complete remission (CR). After several courses of consolidation therapy combining anthracyclines and cytarabine, he maintained CR. In 2009, an APL relapse was diagnosed, and he was treated with arsenic trioxide. Since he achieved a second CR, he underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) with a conditioning regimen consisting of busulfan and melphalan. At four months after auto-PBSCT, he developed a pneumothorax and acute respiratory failure. He died despite intensive therapy. Autopsy findings included various atypical and apoptotic cells in his pulmonary tissue. These changes were confirmed in multiple organs throughout the body, suggesting them to be drug-induced. The findings in this case suggested multiple organ failure due to alkylating agents.

  19. The influence of proteasome inhibitor on the expression of cardiomyocytes damage markers after incubation with doxorubicin

    Directory of Open Access Journals (Sweden)

    Tereszkiewicz Sylwia


    Full Text Available The aim of the study was to verify the thesis that the cardiotoxic effects of doxorubicin are connected with activation of the ubiquitin - proteasome pathway followed by protein degradation. The expression of myocardial damage markers - fatty acid binding protein (H-FABP and brain natriuretic peptide (BNP was evaluated in rat fetal cardiomyocytes simultaneously treated with doxorubicin and the proteasome inhibitor - bortezomib. The level of H-FABP and BNP protein under the influence of doxorubicin was decreased below the detection threshold with unchanged (H-FABP or elevated (BNP mRNA expression level. Against the expectations, the inhibitor of proteasome did not abolish this effect. The observed abnormal expression of BNP and H-FABP protein after doxorubicin treatment makes their diagnostic significance in anthracycline cardiotoxicity questionable.

  20. Cross-resistance patterns and antigen expression in Vinca alkaloid- and other multiple drug-resistant human leukemic cell lines. (United States)

    Beck, W T; Danks, M K; Cirtain, M C; van Heiningen, J N


    The studies presented in this report demonstrate that Vinca alkaloid-resistant human leukemic lymphoblasts display patterns of cross-resistance to other drugs that differ from those of cell lines selected for primary resistance to anthracyclines or epipodophyllotoxins. These various drug-resistant cell lines also showed differential expression of an antigen recognized by an antibody that distinguishes VLB-resistant from VLB-sensitive cells. Furthermore, comparable levels of resistance or cross-resistance to one drug are not predictive of cross-resistance to other drugs. Our data suggest, then, that the MDR phenotype is complex and may be the result of many and different biochemical lesions. Thus, in order to predict MDR, it may be necessary to document more than one of these changes with specific reagents.

  1. Detection of myocarditis with indium-111-labelled monoclonal antimyosin antibodies. A review; Znaczenie antymiozyn znakowanych indem-111 w diagnostyce zapalenia miesnia sercowego

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    Wojnicz, R. [Slaskie Centrum Chorob Serca, Zabrze (Poland)


    Indium-111 labelled monoclonal antimyosin antibody (AMA-In111) is a sensitive immunoscintigraphic agent for detecting of myocyte necrosis. Due to some limitations including low specificity for myocarditis (MCI) and a very high cost of the study, this agent should be used in only part of patients with clinically suspected MCI. Non-invasive and invasive (coronary angiography) diagnostic procedures should precede AMA-In111 scintigraphy in these patients. The utility of AMA-In111 scintigraphy seems to be greatest in following clinical conditions characterized by myocyte necrosis: 1. diagnosis of MCI in patients with myocardial infarction demonstrated to have normal coronary arteries by selective angiography, 2. detection and quantification of anthracycline-induced myocardial damage, 3. assessment of myocardial damage in cardiac rejection after one post-transplant year. (author)

  2. Drug-DNA intercalation: from discovery to the molecular mechanism. (United States)

    Mukherjee, Arnab; Sasikala, Wilbee D


    The ability of small molecules to perturb the natural structure and dynamics of nucleic acids is intriguing and has potential applications in cancer therapeutics. Intercalation is a special binding mode where the planar aromatic moiety of a small molecule is inserted between a pair of base pairs, causing structural changes in the DNA and leading to its functional arrest. Enormous progress has been made to understand the nature of the intercalation process since its idealistic conception five decades ago. However, the biological functions were detected even earlier. In this review, we focus mainly on the acridine and anthracycline types of drugs and provide a brief overview of the development in the field through various experimental methods that led to our present understanding of the subject. Subsequently, we discuss the molecular mechanism of the intercalation process, free-energy landscapes, and kinetics that was revealed recently through detailed and rigorous computational studies.

  3. Exclusive Alternating Chemotherapy and Radiotherapy in Nonmetastatic Inflammatory Breast Cancer: 20 Years of Follow-Up

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    Bourgier, Celine, E-mail: [Department of Radiation Oncology, Breast Unit, Institut Gustave Roussy, Villejuif (France); Pessoa, Eduardo Lima [Department of Radiation Oncology, Breast Unit, Institut Gustave Roussy, Villejuif (France); Dunant, Ariane [Biostatistics and Epidemiology Unit, Institut Gustave Roussy, Villejuif (France); Heymann, Steve [Department of Radiation Oncology, Breast Unit, Institut Gustave Roussy, Villejuif (France); Spielmann, Marc [Department of Medical Oncology, Institut Gustave Roussy, Villejuif (France); Uzan, Catherine [Department of Breast Surgery, Institut Gustave Roussy, Villejuif (France); Mathieu, Marie-Christine [Department of Pathology, Institut Gustave Roussy, Villejuif (France); Arriagada, Rodrigo [Department of Radiation Oncology, Breast Unit, Institut Gustave Roussy, Villejuif (France); Department of Radiation Oncology, Karolinska Institutet, Stockholm (Sweden); Marsiglia, Hugo [Department of Radiation Oncology, Breast Unit, Institut Gustave Roussy, Villejuif (France); Radiation Department University of Florence, Florence (Italy)


    Background: Locoregional treatment of inflammatory breast cancer (IBC) is crucial because local relapses may be highly symptomatic and are commonly associated with distant metastasis. With a median follow-up of 20 years, we report here the long-term results of a monocentric clinical trial combining primary chemotherapy (CT) with a schedule of anthracycline-based CT and an alternating split-course of radiotherapy (RT Asterisk-Operator CT) without mastectomy. Methods and Materials: From September 1983 to December 1989, 124 women with nonmetastatic IBC (T4d M0) were treated with three cycles of primary AVCMF chemotherapy (anthracycline, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil) and then an alternating RT Asterisk-Operator CT schedule followed by three cycles of FAC. Hormonal therapy was systematically administered: ovarian irradiation (12 Gy in four fractions) or tamoxifen 20 mg daily. Results: Local control was achieved in 82% of patients. The 10- and 20-year local relapse rates were 26% and 33%, respectively, but only 10% of locally controlled cases were not associated with concurrent distant metastasis. The 10- and 20-year overall survival rates were 39% and 19%, respectively. Severe fibrosis occurred in 54% of patients, grade 3 brachial plexus neuropathy in 4%, grade 2 pneumonitis in 9%. Grade 1, 2 and 3 cardiac toxicity was observed in 3.8%, 3.8% and 1.2% of cases respectively. Conclusions: This combined regimen allowed good long-term local control without surgery. Survival rates were similar to those obtained with conventional regimens (primary chemotherapy, total mastectomy, and adjuvant radiotherapy). Since IBC continues to be an entity with a dismal prognosis, this approach, safely combining preoperative or postoperative radiation therapy and systemic treatments, should be reassessed when suitable targeted agents are available.

  4. Current problems in the first-line treatment of metastatic breast cancer: focus on the role of docetaxel

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    Filippo Montemurro


    Full Text Available Metastatic breast cancer is a very heterogeneous disease, both from a clinical and a biological point of view. Despite being still incurable, the expanding therapeutic repertoire has determined a progressive increase in median survival. We describe the clinical course of a 67-year-old woman with a locally advanced, hormone-receptor positive breast cancer with synchronous liver metastases. Single-agent docetaxel at the dose of 100 mg/m2 for 8 cycles determined a pathological complete remission in the breast and a near complete remission of liver metastases. After more than 4 years from diagnosis, the patient is alive and without signs of tumour progression. Based on this clinical case, we discuss management issues like the choice of the initial treatment, the use of monochemotherapy vs polychemotherapy, the worth of surgery of the primary tumour in patients with stage IV disease, and the issue of maintenance endocrine therapy. Furthermore, we reviewed the pivotal role of docetaxel in the management of advanced breast cancer. Whether monochemotherapy or polychemotherapy is felt to be an adequate choice in the clinical practice, docetaxel qualifies as one of the most active and manageable agents. Single agent activity ranging from 20-48% in terms of response rate has been reported in several clinical trials in patients treated in various clinical settings. Docetaxel-based combinations with other cytotoxic agents have become established in the first line treatment both in patients with anthracycline-resistant and anthracycline-sensitive metastatic breast cancer. Finally, docetaxel has been shown to be an optimal companion drug for biologically targeted agents like trastuzumab or bevacizumab, resulting in further treatment options.

  5. EndoPredict predicts for the response to neoadjuvant chemotherapy in ER-positive, HER2-negative breast cancer. (United States)

    Bertucci, François; Finetti, Pascal; Viens, Patrice; Birnbaum, Daniel


    The EndoPredict (EP) signature is a prognostic 11-gene expression signature specifically developed in ER+/HER2- node-negative/positive breast cancer. It is associated with relapse-free survival in patients treated with adjuvant hormone therapy, suggesting that EP low-risk patients could be treated with adjuvant hormone therapy alone whereas high-risk patients would deserve addition of adjuvant chemotherapy. Thus, it is important to determine whether EP high-risk patients are or are not more sensitive to chemotherapy than low-risk patients. Here, we have assessed the EP predictive value for pathological complete response to neoadjuvant chemotherapy in ER+/HER2- breast cancer. We gathered gene expression and histoclinical data of 553 pre-treatment ER+/HER2- breast carcinomas treated with anthracycline-based neoadjuvant chemotherapy. We searched for correlation between the pathological complete response (pCR) and the EP score-based classification. The overall pCR rate was 12%. Fifty-one percent of samples were classified as low-risk according to the EP score and 49% as high-risk. EP classification was associated with a pCR rate of 7% in the low-risk group and 17% in the high-risk group (p < 0.001). In multivariate analysis, the EP score remained significantly associated with pCR. Many genes upregulated in the high-risk tumours were involved in cell proliferation, whereas many genes upregulated in the low-risk tumours were involved in ER-signalling and stroma. Despite higher chemosensitivity, the high-risk group was associated with worse disease-free survival. In conclusion, EP high-risk ER+/HER2- breast cancers are more likely to respond to anthracycline-based chemotherapy.

  6. The curability of breast cancer and the treatment of advanced disease

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    Guarneri, Valentina; Conte, Pier Franco [Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena (Italy)


    Breast cancer represents a major health problem, with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of an increasing incidence, breast cancer mortality has been declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. Better knowledge of breast cancer biology now allows the cosmetic, physical and psychological consequences of radical mastectomy to be spared in the majority of breast cancer patients. Use of the sentinel node technique is rapidly expanding and this will further reduce the extent and the consequences of surgery. Several clinico-pathological factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse. Nodal status, tumour size, tumour grade and age are accepted universally as important factors to define risk categories. Newer factors such as uPA/PAI-1, HERer2-neu, proliferative indices and gene expression profile are promising and will allow better discrimination between patients at different risk. Endocrine manipulation with tamoxifen, ovarian ablation or both is the preferred option in the case of endocrine-responsive tumours. Tamoxifen administered for 5 years is the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen, with a different safety profile. At present, anastrozole can be used in the adjuvant setting in cases of tamoxifen intolerance or toxicity. Chemotherapy is the treatment of choice for steroid receptor-negative tumours. Polychemotherapy is superior to single agents and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four

  7. HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy

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    Fountzilas George


    Full Text Available Abstract Background HER2 and TOP2A parameters (gene status, mRNA and protein expression have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy. Methods In a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization, mRNA expression (quantitative reverse transcription PCR, as well as HER2 and TopoIIa protein expression (immunohistochemistry. Results HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values Conclusions This study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12611000506998.

  8. Enhanced anti-tumour effects of Vinca alkaloids given separately from cytostatic therapies (United States)

    Ehrhardt, H; Pannert, L; Pfeiffer, S; Wachter, F; Amtmann, E; Jeremias, I


    Background and Purpose In polychemotherapy protocols, that is for treatment of neuroblastoma and Ewing sarcoma, Vinca alkaloids and cell cycle-arresting drugs are usually administered on the same day. Here we studied whether this combination enables the optimal antitumour effects of Vinca alkaloids to be manifested. Experimental Approach Vinca alkaloids were tested in a preclinical mouse model in vivo and in vitro in combination with cell cycle-arresting drugs. Signalling pathways were characterized using RNA interference. Key Results In vitro, knockdown of cyclins significantly inhibited vincristine-induced cell death indicating, in accordance with previous findings, Vinca alkaloids require active cell cycling and M-phase transition for induction of cell death. In contrast, anthracyclines, irradiation and dexamethasone arrested the cell cycle and acted like cytostatic drugs. The combination of Vinca alkaloids with cytostatic therapeutics resulted in diminished cell death in 31 of 36 (86%) tumour cell lines. In a preclinical tumour model, anthracyclines significantly inhibited the antitumour effect of Vinca alkaloids in vivo. Antitumour effects of Vinca alkaloids in the presence of cytostatic drugs were restored by caffeine, which maintained active cell cycling, or by knockdown of p53, which prevented drug-induced cell cycle arrest. Therapeutically most important, optimal antitumour effects were obtained in vivo upon separating the application of Vinca alkaloids from cytostatic therapeutics. Conclusion and Implications Clinical trials are required to prove whether Vinca alkaloids act more efficiently in cancer patients if they are applied uncoupled from cytostatic therapies. On a conceptual level, our data suggest the implementation of polychemotherapy protocols based on molecular mechanisms of drug–drug interactions. Linked Article This article is commented on by Solary, pp 1555–1557 of this issue. To view this commentary visit

  9. Spectroscopic, computational and electrochemical studies on the formation of the copper complex of 1-amino-4-hydroxy-9,10-anthraquinone and effect of it on superoxide formation by NADH dehydrogenase. (United States)

    Roy, Sanjay; Mondal, Palash; Sengupta, Partha Sarathi; Dhak, Debasis; Santra, Ramesh Chandra; Das, Saurabh; Guin, Partha Sarathi


    A 1 : 2 copper(II) complex of 1-amino-4-hydroxy-9,10-anthraquinone (QH) having the molecular formula CuQ2 was prepared and characterized by elemental analysis, NMR, FTIR, UV-vis and mass spectroscopy. The powder diffraction of the solid complex, magnetic susceptibility and ESR spectra were also recorded. The presence of the planar anthraquinone moiety in the complex makes it extremely difficult to obtain a single crystal suitable for X-ray diffraction studies. To overcome this problem, density functional theory (DFT) was used to evaluate an optimized structure of CuQ2. In the optimized structure, it was found that there is a tilt of the two planar aromatic anthraquinone rings of the complex with respect to each other in the two planes containing the O-Cu(II)-O plane. The present study is an important addition to the understanding of the structural aspects of metal-anthracyclines because there are only a few reports on the actual structures of metal-anthracyclines. The theoretical vibrational spectrum of the complex was assigned with the help of vibrational energy distribution analysis (VEDA) using potential energy distribution (PED) and compared with experimental results. Being important in producing the biochemical action of this class of molecules, the electrochemical behavior of the complex was studied in aqueous and non-aqueous solvents to find certain electrochemical parameters. In aqueous media, reduction involves a kinetic effect during electron transfer at an electrode surface, which was characterized very carefully using cyclic voltammetry. Electrochemical studies showed a significant modification in the electrochemical properties of 1-amino-4-hydroxy-9,10-anthraquinone (QH) when bound to Cu(II) in the complex compared to those observed for free QH. This suggests that the copper complex might be a good choice as a biologically active molecule, which was reflected in the lack of stimulated superoxide generation by the complex.

  10. Meta-analysis of clinical and preclinical studies comparing the anticancer efficacy of liposomal versus conventional non-liposomal doxorubicin. (United States)

    Petersen, Grant H; Alzghari, Saeed K; Chee, Wayne; Sankari, Sana S; La-Beck, Ninh M


    While liposome-mediated delivery of cytotoxic chemotherapy has been shown to significantly enhance drug tolerability in patients as compared to the conventional formulation, the fundamental question remains whether they also improve anticancer efficacy. Thus, we performed a systematic literature search for randomized clinical trials directly comparing efficacy of liposomal cytotoxic chemotherapy versus their equivalent conventional formulation. The search yielded 14 clinical trials (8 anthracycline, 4 cisplatin, 1 paclitaxel, 1 irinotecan) that meet inclusion criteria, with a total of 2589 patients. We found that efficacy in patients was not different between liposomal and conventional chemotherapy as assessed by objective response (odds ratio 1.03; 95% confidence interval [CI] 0.82-1.30), overall survival (hazard ratio [HR] 1.05; 95% CI 0.95-1.17), and progression free survival rates (HR 1.01; 95% CI, 0.92-1.11). Subgroup analyses of only the anthracycline trials also did not show any efficacy advantage for the liposomal formulation. Since pegylated liposomal doxorubicin (PLD) was the most prevalent formulation in these clinical trials, we also performed a meta-analysis of 11 preclinical studies comparing efficacy of PLD and conventional doxorubicin in tumor-bearing mice. In contrast with clinical results, animal studies showed significantly increased survival in mice treated with PLD compared to conventional doxorubicin (HR 0.39; 95% CI 0.27-0.56). We discuss the possible reasons why the pharmacological advantages of carrier-mediated chemotherapy did not translate into enhanced clinical efficacy including the role of the enhanced permeability and retention (EPR) effect and the tumor microenvironment, the optimal dosing regimen for carrier-mediated agents, and the lack of standardization in the conduct and reporting of preclinical studies evaluating anticancer efficacy of these agents. Our study shows that the full clinical potential of carrier-mediated drugs

  11. A Prospective Cohort Study on Cardiotoxicity of Adjuvant Trastuzumab Therapy in Breast Cancer Patients (United States)

    Matos, Erika; Jug, Borut; Blagus, Rok; Zakotnik, Branko


    Background Cardiotoxicity is an important side effect of trastuzumab therapy and cardiac surveillance is recommended. Objectives The aim of our study was to prospectively assess baseline patients' characteristics, level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic parameters as possible predictors of trastuzumab-related cardiac dysfunction. Methods In a prospective cohort study, clinical, echocardiographic and neurohumoral assessment was performed at baseline, after 4, 8 and 12 months in breast cancer patients undergoing post-anthracycline (3-4 cycles) adjuvant therapy with trastuzumab. Trastuzumab-related cardiac dysfunction was defined as a decline of ≥ 10% in left ventricular ejection fraction (LVEF). Results 92 patients (mean age, 53.6 ± 9.0 years) were included. Patients who developed trastuzumab-related LVEF decline ≥ 10% (20.6%) during treatment had significantly higher baseline LVEF (70.7 ± 4.4%) than those without (64.8 ± 5.5%) (p = 0.0035). All other measured baseline parameters (age, body mass index, arterial hypertension, level of NT-proBNP and other echocardiographic parameters) were not identified as significant. Conclusions Our findings suggest that baseline patient' characteristics, level of NT-proBNP and echocardiographic parameters, as long as they are within normal range, are not a reliable tool to predict early trastuzumab-related cardiac dysfunction in patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. A LVEF decline in patients with high-normal baseline level although statistically significant is not clinically relevant. PMID:27305108

  12. Systemic chemotherapy for metastatic breast cancer

    Institute of Scientific and Technical Information of China (English)

    Yannan Zhao; Biyun Wang


    Breast cancer is the leading cause of cancer among women worldwide and the most common cancer in China. Many factors influence the treatment strategy for metastatic breast cancer (MBC). Chemotherapy should be administered to patients with hormone receptor-negative tumors, symptomatic visceral metastasis, and a short disease-free interval. Sequential single-agent chemotherapy has similar efficacy as combination agents in terms of overall survival and quality of life. Anthracyclines are the cornerstone of first-line treatment for MBC, and taxanes represent the second treatment option after resistance. When progression or intolerable toxicity occurs after optimal treatment, the alternative treatments include capecitabine, vinorel-bine, and gemcitabine. Ixabepilone and eribulin are relatively new effective single agents. A combination of cytotoxic agents for patients with rapid clinical progression can further improve the overall response rate and time to progression compared to single-agent treatment. For patients with MBC who were pretreated with anthracyclines in the neoadjuvant/adjuvant setting, a taxane-containing regimen such as docetaxel plus capecitabine or gemcitabine plus paclitaxel should be administered. Platinum-based therapies such as cisplatin or carboplatin have a role in the treatment of triple-negative breast cancer. Meanwhile, the efficacy of the addition of targeted drugs such as iniparib, bevacizumab, and cetuximab to chemotherapy remains unproven. Maintenance chemotherapy is routinely recommended in clinical practice at present. Patients who were previously treated with paclitaxel and gemcitabine have better progression-free and overall survival with maintenance chemotherapy according to a Korean phase Ⅲ clinical trial. Sequential maintenance treatment with capecitabine monotherapy after capecitabine-based combination chemotherapy (X-based X) appears favorable based on a series of domestic studies.


    Directory of Open Access Journals (Sweden)

    Tamer M Fouad


    Full Text Available

    The current study reports the clinical features and treatment outcome of 67 patients with acute promyelocytic leukemia (APL presented to National Cancer Institute (NCI-Cairo, in Egypt from January 2007 to January 2011. The median follow-up time was 36 months. All patients were treated with the simultaneous administration of all-trans retinoic acid (ATRA and anthracyclin. The treatment protocol was modified due to resource limitations at the NCI-Cairo by replacing of idarubicin with doxorubicin in most of the cases and the inclusion of cytarbine during the consolidation phase only in pediatric patients. All patients who achieved molecular complete remission (CRm after consolidation received two-year maintenance treatment with low dose chemotherapy composed of 6 mercaptopurine, methotrexate and intermittent ATRA courses. The median age at presentation was 29 years. There was a slight male predominance (53%.  Bleeding was the most common presenting symptom (79%. Most patients had an intermediate risk Sanz score (49% and 34% had a high risk score.  All patients achieved molecular CR at end of consolidation therapy with a median duration of 100 days. The main therapeutic complications during the induction phase were febrile neutropenia (42%, bleeding (18% and differentiation syndrome (11%. Five patients died at diagnosis due to bleeding, three died during induction chemotherapy due to febrile neutropenia (n=2 and bleeding (n=1 and one patient died during consolidation therapy due to febrile neutropenia.  The 3-year OS was 89% and relapse rate was 3%. Adapting standard AIDA treatment protocols to limited resources by reducing dose-intensity during treatment consolidation, using ATRA in the consolidation phase and alternative anthracyclin (doxorubicin may be a valid treatment option in developing countries. In spite of the increased incidence of high and intermediate risk score APL in our sample, we reported an acceptable CR rate


    Directory of Open Access Journals (Sweden)

    Ola Khorshid


    Full Text Available The current study reports the clinical features and treatment outcome of 67 patients with acute promyelocytic leukemia (APL presented to National Cancer Institute (NCI-Cairo, in Egypt from January 2007 to January 2011. The median follow-up time was 36 months. All patients were treated with the simultaneous administration of all-trans retinoic acid (ATRA and anthracyclin. The treatment protocol was modified due to resource limitations at the NCI-Cairo by replacing of idarubicin with doxorubicin in most of the cases and the inclusion of cytarbine during the consolidation phase only in pediatric patients. All patients who achieved molecular complete remission (CRm after consolidation received two-year maintenance treatment with low dose chemotherapy composed of 6 mercaptopurine, methotrexate and intermittent ATRA courses. The median age at presentation was 29 years. There was a slight male predominance (53%.  Bleeding was the most common presenting symptom (79%. Most patients had an intermediate risk Sanz score (49% and 34% had a high risk score.  All patients achieved molecular CR at end of consolidation therapy with a median duration of 100 days. The main therapeutic complications during the induction phase were febrile neutropenia (42%, bleeding (18% and differentiation syndrome (11%. Five patients died at diagnosis due to bleeding, three died during induction chemotherapy due to febrile neutropenia (n=2 and bleeding (n=1 and one patient died during consolidation therapy due to febrile neutropenia.  The 3-year OS was 89% and relapse rate was 3%. Adapting standard AIDA treatment protocols to limited resources by reducing dose-intensity during treatment consolidation, using ATRA in the consolidation phase and alternative anthracyclin (doxorubicin may be a valid treatment option in developing countries. In spite of the increased incidence of high and intermediate risk score APL in our sample, we reported an acceptable CR rate, toxicity and OS.

  15. Adjuvant breast cancer chemotherapy during late-trimester pregnancy: not quite a standard of care

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    Epstein Richard J


    Full Text Available Abstract Background Diagnosis of breast cancer during pregnancy was formerly considered an indication for abortion. The pendulum has since swung to the other extreme, with most reviews now rejecting termination while endorsing immediate anthracycline-based therapy for any pregnant patient beyond the first trimester. To assess the evidence for this radical change in thinking, a review of relevant studies in the fields of breast cancer chemotherapy, pregnancy, and drug safety was conducted. Discussion Accumulating evidence for the short-term safety of anthracycline-based chemotherapy during late-trimester pregnancy represents a clear advance over the traditional norm of therapeutic abortion. Nonetheless, the emerging orthodoxy favoring routine chemotherapy during gestation should continue to be questioned on several grounds: (1 the assumed difference in maternal survival accruing from chemotherapy administered earlier – i.e., during pregnancy, rather than after delivery – has not been quantified; (2 the added survival benefit of adjuvant cytotoxic therapy prescribed within the hormone-rich milieu of pregnancy remains presumptive, particularly for ER-positive disease; (3 the maternal survival benefit associated with modified adjuvant regimens (e.g., weekly schedules, omission of taxanes, etc. has not been proven equivalent to standard (e.g., post-delivery regimens; and (4 the long-term transplacental and transgenerational hazards of late-trimester chemotherapy are unknown. Summary Although an incrementally increased risk of cancer-specific mortality is impossible to exclude, mothers who place a high priority on the lifelong well-being of their progeny may be informed that deferring optimal chemotherapy until after delivery is still an option to consider, especially in ER-positive, node-negative and/or last-trimester disease.

  16. [Studies on the absorption, excretion and distribution of aclacinomycin A: absorption, excretion and distribution of 14C- or 3H-aclacinomycin A in mice, rats and rabbits (author's transl)]. (United States)

    Iguchi, H; Seryu, Y; Kiyosaki, T; Hori, S; Tone, H; Oki, T


    A new anthracycline antitumor antibiotic, aclacinomycin A, was labeled with 3H uniformly or with 14C simultaneously at the anthracycline nucleus and L-rhodosamine. These labeled drugs were administered intravenously to normal dd mice, solid type Sarcoma 180 tumor-bearing ICR mice, normal or pregnant Wistar rats and normal rabbits, respectively. 14C-Aclacinomycin A given to rabbits (5 mg/kg) was rapidly cleared from the blood and transferred to tissues. But low level of radioactivity (equivalent to about 0.5 mcg/ml) was remained in the blood even 8 approximately 10 hours after administration. About 45% of the radioactivity were recovered from the urine and 20% from the feces by 72 hours after administration. Tissue levels of 3H-14C-aclacinomycin A given to normal and tumor-bearing mice were highest in the lungs and spleen. Higher distribution was observed also in the liver and kidneys 2 hours after administration. Bioassay revealed that the drug was present in the lungs and spleen in biologically active form and in the liver and kidneys in inactive form, respectively. In the tumor tissue the radioactivity was low but it persisted for 48 hours. Autoradiography with 14C-aclacinomycin A in rats demonstrated that radioactivity due to the drug distributed in the lungs, spleen, kidneys, thymus, intestine, lymph nodes, bone marrow, salivary gland, hypophysis and pineal body but it was rapidly cleared. About 0.2% of radioactivity given to a pregnant rat were transferred to a fetus when 14C-aclacinomycin A was administered intravenously on the 18 approximately 19th day of pregnancy.

  17. Management of chemotherapy-induced nausea and vomiting by risk profile: role of netupitant/palonosetron

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    Lorusso V


    Full Text Available Vito Lorusso National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy Abstract: As recommended by most recent antiemetic guidelines, the optimal prophylaxis of chemotherapy-induced nausea and vomiting (CINV requires the combination of 5-HT3 receptor antagonist (RA with an NK1-RA. Moreover, the major predictors of acute and delayed CINV include: young age, female sex, platinum- or anthracycline-based chemotherapy, nondrinker status, emesis in the earlier cycles of chemotherapy, and previous history of motion/morning sickness. Despite improved knowledge of the pathophysiology of CINV and advances in the availability of active antiemetics, an inconsistent compliance with their use has been reported, thereby resulting in suboptimal control of CINV in several cases. In this scenario, a new antiemetic drug is now available, which seems to be able to guarantee better prophylaxis of CINV and improvement of adherence to guidelines. In fact, netupitant/palonosetron (NEPA is a ready-to-use single oral capsule, combining an NK1-RA (netupitant and a 5-HT3-RA (palonosetron, which is to be taken 1 hour before the administration of chemotherapy, ensuring the coverage from CINV for 5 days. We reviewed the role of NEPA in patients at high risk of CINV receiving highly emetogenic chemotherapy. In these patients, NEPA plus dexamethasone, as compared to standard treatments, achieved superior efficacy in all primary and secondary end points during the acute, delayed, and overall phases, including nausea assessment. Moreover, these results were also achieved in female patients receiving anthracycline plus cyclophosphamide-based chemotherapy. NEPA represents a real step forward in the prophylaxis of CINV. Keywords: NEPA, netupitant, NK1, CINV, vomiting, risk factors

  18. Risk Factors Associated With Secondary Sarcomas in Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study

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    Henderson, Tara O., E-mail: [University of Chicago, Chicago, IL (United States); Rajaraman, Preetha [National Cancer Institute, Bethesda, MD (United States); Stovall, Marilyn [M.D. Anderson Cancer Center, University of Texas, Houston, TX (United States); Constine, Louis S. [University of Rochester, Rochester, NY (United States); Olive, Aliza [Drexel University, Philadelphia, PA (United States); Smith, Susan A. [M.D. Anderson Cancer Center, University of Texas, Houston, TX (United States); Mertens, Ann [Emory University, Atlanta, GA (United States); Meadows, Anna [Children' s Hospital of Philadelphia, Philadelphia, PA (United States); Neglia, Joseph P. [University of Minnesota, Minneapolis, MN (United States); Hammond, Sue [Nationwide Children' s Hospital, Columbus, OH (United States); Whitton, John [Fred Hutchinson Cancer Research Center, Seattle, WA (United States); Inskip, Peter D. [National Cancer Institute, Bethesda, MD (United States); Robison, Leslie L. [St. Jude Children' s Research Hospital, Memphis, TN (United States); Diller, Lisa [Dana-Farber Cancer Institute/Children' s Hospital Cancer Center, Boston, MA (United States)


    Purpose: Childhood cancer survivors have an increased risk of secondary sarcomas. To better identify those at risk, the relationship between therapeutic dose of chemotherapy and radiation and secondary sarcoma should be quantified. Methods and Materials: We conducted a nested case-control study of secondary sarcomas (105 cases, 422 matched controls) in a cohort of 14,372 childhood cancer survivors. Radiation dose at the second malignant neoplasm (SMN) site and use of chemotherapy were estimated from detailed review of medical records. Odds ratios (ORs) and 95% confidence intervals were estimated by conditional logistic regression. Excess odds ratio (EOR) was modeled as a function of radiation dose, chemotherapy, and host factors. Results: Sarcomas occurred a median of 11.8 years (range, 5.3-31.3 years) from original diagnosis. Any exposure to radiation was associated with increased risk of secondary sarcoma (OR = 4.1, 95% CI = 1.8-9.5). A dose-response relation was observed, with elevated risks at doses between 10 and 29.9 Gy (OR = 15.6, 95% CI = 4.5-53.9), 30-49.9 Gy (OR = 16.0, 95% CI 3.8-67.8) and >50 Gy (OR = 114.1, 95% CI 13.5-964.8). Anthracycline exposure was associated with sarcoma risk (OR = 3.5, 95% CI = 1.6-7.7) adjusting for radiation dose, other chemotherapy, and primary cancer. Adjusting for treatment, survivors with a first diagnosis of Hodgkin lymphoma (OR = 10.7, 95% CI = 3.1-37.4) or primary sarcoma (OR = 8.4, 95% CI = 3.2-22.3) were more likely to develop a sarcoma. Conclusions: Of the risk factors evaluated, radiation exposure was the most important for secondary sarcoma development in childhood cancer survivors; anthracycline chemotherapy exposure was also associated with increased risk.

  19. Locally advanced non inflammatory breast cancer treated by combined chemotherapy and preoperative irradiation: updated results in a series of 120 patients; Cancer du sein localement evolue non inflammatoire traite par association de chimiotherapie et de radiotherapie a dose preoperatoire: reactualisation des resultats d'une serie de 120 patientes

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    Lerouge, D.; Touboul, E.; Moureau-Zabotto, L. [Hopital Tenon AP-HP, Service d' oncologie-radiotherapie, 75 - Paris (France); Lefran, J.P.; Blondon, J. [Hopital Pitie-Salpetriere AP-HP, Service de chirurgie generale et gynecologique, 75 - Paris (France); Genestie, C. [Hopital Pitie-Salpetriere AP-HP, Service d' anatomopathologie, 75 - Paris (France)


    Purpose. - To evaluate our updated data concerning survival and locoregional control in a study of locally advanced non inflammatory breast cancer after primary chemotherapy followed by external preoperative irradiation. Patients and methods. - Between 1982 and 1998, 120 patients (75 stage IIIA, 41 stage IIIB, and 4 stage IIIC according to AJCC staging system 2002) were consecutively treated by four courses of induction chemotherapy with anthracycline-containing combinations followed by preoperative irradiation (45 Gy to the breast and nodal areas) and a fifth course of chemotherapy. Three different locoregional approaches were proposed, depending on tumour characteristics and tumour response. After completion of local therapy, all patients received a sixth course of chemotherapy and a maintenance adjuvant chemotherapy regimen without anthracycline. The median follow-up from the beginning of treatment was 140 months. Results. - Mastectomy and axillary dissection were performed in 49 patients (with residual tumour larger than 3 cm in diameter or located behind the nipple or with bifocal tumour), and conservative treatment in 71 patients (39 achieved clinical complete response or partial response >90% and received additional radiation boost to initial tumour bed; 32 had residual mass {<=}3 cm in diameter and were treated by wide excision and axillary dissection followed by a boost to the excision site). Ten-year actuarial local failure rate was 13% after irradiation alone, 23% after wide excision and irradiation, and 4% after mastectomy (p =0.1). After multivariate analysis, possibility of breast-conserving therapy was related to initial tumour size (<6 vs. {>=}6 cm in diameter, p =0.002). Ten-year overall metastatic disease-free survival rate was 61%. After multivariate analysis, metastatic disease-free survival rates were significantly influenced by clinical stage (stage IIIA-B vs. IIIC, p =0.0003), N-stage (N0 vs. N1-2a, and 3c, p = 0.017), initial tumour size (<6

  20. Immune cell-based screening assay for response to anticancer agents: applications in pharmacogenomics

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    Frick A


    were generated using GraphPad Prism 6. Results: Phenotypes were quantified using flow cytometry, yielding interstrain variation for measured endpoints in different immune cells. The flow cytometry assays produced over 16,000 data points that were used to generate dose-response curves. The more targeted agents, BEZ-235 and selumetinib, were less toxic to immune cells than the anthracycline agents. The calculated heritability for the viability of immune cells was higher with anthracyclines than the novel agents, making them better suited for downstream genetic analysis. Conclusion: Using this approach, we identify cell lines of variable sensitivity to chemotherapeutic agents and aim to identify robust, replicable endpoints of cellular response to drugs that provide the starting point for identifying candidate genes and cellular toxicity pathways for future validation in human studies. Keywords: immunomodulation, cytotoxicity, chemotherapy, precision medicine

  1. Clinical study of gemcitabine plus cisplatin in 2-line treatment of advanced TNBC%吉西他滨联合顺铂二线治疗晚期三阴乳腺癌的临床观察

    Institute of Scientific and Technical Information of China (English)

    吴立新; 黄玉霞; 方月兰; 夏国安


    目的 评估GP方案二线治疗蒽环类和紫杉类失败的晚期三阴乳腺癌近期疗效和安全性.方法 37例蒽环类和紫杉类一线治疗失败的晚期三阴乳腺癌患者给予吉西他滨1.0 g·m-2,静脉滴注,第1、8天;顺铂40 mg·m-2,静脉滴注,第1、2天,3周重复,2周期后评价客观疗效,CR、PR及SD患者均继续治疗直至进展,所有患者随访均超过6个月.结果 37例患者近期疗效CR:0例,PR:16例(43.3%),SD:14例(37.8%),PD:7例(18.9%);总有效率CR+PR:43.3%.中位至疾病进展时间(TTP)5.5月.该方案的主要毒副作用为骨髓毒性和胃肠道反应.结论 GP方案二线治疗晚期三阴乳腺癌具有良好的近期疗效,安全性良好.%Aim To evaluate the efficacy and safety of gemcitabine(GEM) plus cisplatin (DDP) in 2-line treatment of advanced TNBC after the failure of anthracyclines and taxanes. Methods 37 cases of advanced TNBC with anthracyclines and taxanes resistance were treated with GEM 1.0 g · m- 2, day 1,8 and DDP 40 mg · m- 2 ,day 1,2,21 days repeatedly. After 2 cycles,the response and side effects were evaluated. All cases were followed up for more than 6 months. Results Efficacy of the 37 cases were as follows: PR 16 cases (43.3%) , SD 14 cases (37.8 % ), PD 7 cases ( 18.9 % ), with a total rate of 43.3%. Main side effects were neutrogena and gastrointesti nal tract toxicity. Conclusions The combination of gemcitabine and cisplatin is effective and safe in the 2-line treatment of advanced TNBC.

  2. Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II.

    Directory of Open Access Journals (Sweden)

    Rachael E Hawtin

    Full Text Available BACKGROUND: Topoisomerase II is critical for DNA replication, transcription and chromosome segregation and is a well validated target of anti-neoplastic drugs including the anthracyclines and epipodophyllotoxins. However, these drugs are limited by common tumor resistance mechanisms and side-effect profiles. Novel topoisomerase II-targeting agents may benefit patients who prove resistant to currently available topoisomerase II-targeting drugs or encounter unacceptable toxicities. Voreloxin is an anticancer quinolone derivative, a chemical scaffold not used previously for cancer treatment. Voreloxin is completing Phase 2 clinical trials in acute myeloid leukemia and platinum-resistant ovarian cancer. This study defined voreloxin's anticancer mechanism of action as a critical component of rational clinical development informed by translational research. METHODS/PRINCIPAL FINDINGS: Biochemical and cell-based studies established that voreloxin intercalates DNA and poisons topoisomerase II, causing DNA double-strand breaks, G2 arrest, and apoptosis. Voreloxin is differentiated both structurally and mechanistically from other topoisomerase II poisons currently in use as chemotherapeutics. In cell-based studies, voreloxin poisoned topoisomerase II and caused dose-dependent, site-selective DNA fragmentation analogous to that of quinolone antibacterials in prokaryotes; in contrast etoposide, the nonintercalating epipodophyllotoxin topoisomerase II poison, caused extensive DNA fragmentation. Etoposide's activity was highly dependent on topoisomerase II while voreloxin and the intercalating anthracycline topoisomerase II poison, doxorubicin, had comparable dependence on this enzyme for inducing G2 arrest. Mechanistic interrogation with voreloxin analogs revealed that intercalation is required for voreloxin's activity; a nonintercalating analog did not inhibit proliferation or induce G2 arrest, while an analog with enhanced intercalation was 9.5-fold more

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

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


    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

  4. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice

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    Guenancia, Charles [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Cardiology Department, University Hospital, Dijon (France); Li, Na [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Hachet, Olivier [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Cardiology Department, University Hospital, Dijon (France); Rigal, Eve [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Cottin, Yves [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Cardiology Department, University Hospital, Dijon (France); Dutartre, Patrick; Rochette, Luc [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France); Vergely, Catherine, E-mail: [INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon (France)


    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran–iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran–iron (15 mg/kg) for 3 weeks (D0–D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6 mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran–iron (125–1000 μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+ 22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. - Highlights: • The effects of iron on cardiomyocytes were opposite to those on cancer cell lines. • In our model, iron overload did not potentiate anthracycline cardiotoxicity. • Chronic oxidative stress induced by iron could mitigate doxorubicin cardiotoxicity. • The role of iron in

  5. Erythropoietin: from erythropoiesis to cardioprotection La eritropoyetina: de la eritropoyesis a la cardioprotección

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    Aramis Núñez Quintana


    Full Text Available Many of the drugs that has shown promise in the treatment of hematologic malignancies and solid tumors, associated with a high potential cardiotoxic. Within this group stand anthracyclines, identified as the type of chemotherapy most likely to cause heart damage, short or long term. With the improvement achieved in the survival of patients with these diseases, this adverse event has become a major concern for the scientific community. Although many agents have been evaluated as potential cardioprotective therapeutic, clinical data are limited and does not suggest that the use of these agents promotes the survival of patients undergoing cardiotoxic treatments. The identification of erythropoietin receptor in hematopoietic tissues, including the heart, as well as its marked cardioprotective effect during ischemia have led to the hypothesis that erythropoietin may be able to prevent anthracycline-induced cardiomyopathy. Addressing this hypothesis is the objective of this work.Muchas de las drogas que han mostrado resultados alentadores en el tratamiento de las enfermedades hematológicas y los tumores sólidos, asocian un elevado potencial cardiotóxico. Dentro de este grupo sobresalen las antraciclinas, identificadas como el tipo de quimioterapia que con mayor probabilidad puede causar daño cardiaco, a corto o largo plazo. Con la mejoría alcanzada en la supervivencia de los pacientes portadores de estas enfermedades, este evento adverso se ha convertido en una de las principales preocupaciones para la comunidad científica. Aun cuando han sido muchos los agentes terapéuticos evaluados como posibles cardioprotectores, los datos clínicos disponibles son limitados y no permiten afirmar que el uso de estos agentes favorezca la supervivencia de los pacientes sometidos a tratamientos cardiotóxicos. La identificación del receptor para la eritropoyetina en tejidos no hematopoyéticos, incluyendo el corazón, así como su marcado efecto

  6. Myelodysplastic syndrome and acute myeloid leukemia following adjuvant chemotherapy with and without granulocyte colony-stimulating factors for breast cancer. (United States)

    Calip, Gregory S; Malmgren, Judith A; Lee, Wan-Ju; Schwartz, Stephen M; Kaplan, Henry G


    Risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) post-breast cancer treatment with adjuvant chemotherapy and granulocyte colony-stimulating factors (G-CSF) is not fully characterized. Our objective was to estimate MDS/AML risk associated with specific breast cancer treatments. We conducted a retrospective cohort study of women aged ≥66 years with stage I-III breast cancer between 2001 and 2009 using the Surveillance, Epidemiology, and End Results-Medicare database. Women were classified as receiving treatment with radiation, chemotherapy, and/or G-CSF. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95 % confidence intervals (CI) for MDS/AML risk. Among 56,251 breast cancer cases, 1.2 % developed MDS/AML during median follow-up of 3.2 years. 47.1 % of women received radiation and 14.3 % received chemotherapy. Compared to breast cancer cases treated with surgery alone, those treated with chemotherapy (HR = 1.38, 95 %-CI 0.98-1.93) and chemotherapy/radiation (HR = 1.77, 95 %-CI 1.25-2.51) had increased risk of MDS/AML, but not radiation alone (HR = 1.08, 95 % CI 0.86-1.36). Among chemotherapy regimens and G-CSF, MDS/AML risk was differentially associated with anthracycline/cyclophosphamide-containing regimens (HR = 1.86, 95 %-CI 1.33-2.61) and filgrastim (HR = 1.47, 95 %-CI 1.05-2.06), but not pegfilgrastim (HR = 1.10, 95 %-CI 0.73-1.66). We observed increased MDS/AML risk among older breast cancer survivors treated with anthracycline/cyclophosphamide chemotherapy that was enhanced by G-CSF. Although small, this risk warrants consideration when determining adjuvant chemotherapy and neutropenia prophylaxis for breast cancer patients.

  7. Prolonged weightlessness affects promyelocytic multidrug resistance. (United States)

    Piepmeier, E H; Kalns, J E; McIntyre, K M; Lewis, M L


    An immortalized promyelocytic cell line was studied to detect how doxorubicin uptake is affected by microgravity. The purpose of this experiment was to identify the effect that microgravity may have on multidrug resistance in leukocytes. HL60 cells and HL60 cells resistant to anthracycline (HL60/AR) were grown in RPMI and 10% FBS. Upon reaching orbit in the Space Shuttle Endeavour, the cells were robotically mixed with doxorubicin. Three days after mixing, cells were fixed with paraformaldehyde/glutaraldehyde. Ground control experiments were conducted concurrently using a robot identical to the one used on the Shuttle. Fixed cells were analyzed within 2 weeks of launch. Confocal micrographs identified changes in cell structure (transmittance), drug distribution (fluorescence), and microtubule polymerization (fluorescence). Flight cells showed a lack of cytoskeletal polymerization resulting in an overall amorphic globular shape. Doxorubicin distribution in ground cells included a large numbers of vesicles relative to flight cells. There was a greater amount of doxorubicin present in flight cells (85% +/- 9.7) than in ground control cells (43% +/- 26) as determined by image analysis. Differences in microtubule formation between flight cells and ground cells could be partially responsible for the differences in drug distribution. Cytoskeletal interactions are critical to the function of P-glycoprotein as a drug efflux pump responsible for multidrug resistance.

  8. Methylation-regulated miR-149 modulates chemoresistance by targeting GlcNAc N-deacetylase/N-sulfotransferase-1 in human breast cancer. (United States)

    He, Dong-Xu; Gu, Xiao-Ting; Li, You-Ran; Jiang, Li; Jin, Jian; Ma, Xin


    Dysregulation of microRNA is strongly implicated in the chemoresistance of cancer. In this study, we found that miR-149 was downregulated and involved in chemoresistance in adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM). Downregulation of miR-149 was related to hypermethylation of its 5'-UTR; this methylation also affected the expression of the glypican 1 gene, which is both the host and the target gene of miR-149. Furthermore, we found that miR-149 modulated chemoresistance through targeting the expression of GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST1). With downregulated miR-149, NDST1 expression was increased in chemoresistant MCF-7/ADM cells versus control MCF-7 wild-type cells. The increased NDST1 then activated a heparan sulfate-related pathway involving activation of heparanase. Finally, expression of miR-149 and NDST1 was confirmed in clinical chemoresistant samples of breast cancers receiving anthracycline/taxane-based chemotherapies. The high expression of NDST1 was also an unfavorable predictor for distant relapse-free survival in Her2 and basal breast cancers. Taken together, our findings demonstrate that miR-149 is regulated by methylation, and is a modulator of cancer chemoresistance by targeting NDST1.

  9. Human cytosolic sulfotransferase SULT1C4 mediates the sulfation of doxorubicin and epirubicin. (United States)

    Luo, Lijun; Zhou, Chunyang; Hui, Ying; Kurogi, Katsuhisa; Sakakibara, Yoichi; Suiko, Masahito; Liu, Ming-Cheh


    Doxorubicin, an anthracycline, has been reported to be excreted in sulfate conjugated form. The current study aimed to identify the human cytosolic sulfotransferase(s) (SULT(s)) that is(are) capable of sulfating doxorubicin and its analog epirubicin, and to verify whether sulfation of doxorubicin and epirubicin may occur under metabolic conditions. A systematic analysis of thirteen known human SULTs, previously cloned, expressed, and purified, revealed SULT1C4 as the only human SULT capable of sulfating doxorubicin and epirubicin. Cultured HepG2 human hepatoma cells and Caco-2 human colon carcinoma cells were labeled with [(35)S]sulfate in the presence of different concentrations of doxorubicin or epirubicin. Analysis of spent labeling media showed the generation and release of [(35)S]sulfated doxorubicin and epirubicin by HepG2 cells and Caco-2 cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the expression of SULT1C4 in both HepG2 cells and Caco-2 cells. These results provided a molecular basis underlying the previous finding that sulfate-conjugated doxorubicin was excreted in the urine of patients treated with doxorubicin.

  10. Rituximab and escalated chemotherapy in elderly patients with aggressive diffuse large-cell lymphoma: a controlled clinical trial. (United States)

    Avilés, Agustin; Nambo, María Jesus; Castañeda, Claudia; Cleto, Sergio; Neri, Natividad; Murillo, Edgar; Huerta-Guzmán, Judith; Contreras, Margarita


    The treatment of elderly patients with aggressive malignant lymphoma has not been defined. The addition of rituximab to conventional chemotherapy has been reported to improve the outcome, but most patients have good prognostic factors (performance status < 2, no severe associated diseases, low or low-intermediate clinical risk). Thus, we developed a combined regimen, including escalated doses of anthracycline and rituximab. The endpoint was to improve event-free survival (EFS) and overall survival. Two hundred and four (204) patients were randomly assigned to receive an escalated chemotherapy regimen (CEOP) with escalated dose of epirubicin, compared to the same regimen and addition of rituximab. All patients had poor prognostic factors: high- or high-intermediate clinical risk, poor performance status, bulky disease, and more than 2 with extranodal involvement. In an intent-to-treat analysis, all patients were evaluable for efficacy and toxicity. The complete response rates were similar in both arms: 74% in chemotherapy and 78% in the rituximab + chemotherapy program. EFS and overall survival were similar: 77% and 84%, respectively, in combined chemotherapy and 75% and 81% in the rituximab-chemotherapy regimen. Toxicity was mild and well tolerated. In elderly patients with diffuse large-cell lymphoma and poor prognostic factors, rituximab did not improve their outcome.

  11. Serum Biomarkers for the Detection of Cardiac Toxicity after Chemotherapy and Radiation Therapy in Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Sibo eTian


    Full Text Available Multi-modality cancer treatments that include chemotherapy, radiation therapy, and targeted agents are highly effective therapies. Their use, especially in combination, is limited by the risk of significant cardiac toxicity. The current paradigm for minimizing cardiac morbidity, based on serial cardiac function monitoring, is suboptimal. An alternative approach based on biomarker testing, has emerged as a promising adjunct and a potential substitute to routine echocardiography. Biomarkers, most prominently cardiac troponins and natriuretic peptides, have been evaluated for their ability to describe the risk of potential cardiac dysfunction in clinically asymptomatic patients. Early rises in cardiac troponin concentrations have consistently predicted the risk and severity of significant cardiac events in patients treated with anthracycline-based chemotherapy. Biomarkers represent a novel, efficient, and robust clinical decision tool for the management of cancer therapy-induced cardiotoxicity. This article aims to review the clinical evidence that supports the use of established biomarkers such as cardiac troponins and natriuretic peptides, as well as emerging data on proposed biomarkers.

  12. Serial measurements of cardiac biomarkers in patients after allogeneic hematopoietic stem cell transplantation

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    Roziakova Lubica


    Full Text Available Abstract Background Previous therapy with anthracyclines (ANT and conditioning regimen followed by hematopoietic stem cell transplantation (HSCT represents a high risk for development of cardiotoxicity. The aim of this study was to assess subclinical myocardial damage after HSCT using echocardiography and cardiac biomarkers - high sensitive cardiac troponin T (hs-cTnT and N-terminal pro-B-type natriuretic peptide (NT-proBNP and to identify patients at risk of developing clinical cardiotoxicity. Patients and methods Thirty-seven patients who were treated with allogeneic HSCT for hematologic diseases at median age of 28 years at time of HSCT were studied. Conditioning regimen included either chemotherapy without total body irradiation (TBI or combination of chemotherapy with TBI. Twenty-nine (78,3% patients were pretreated with ANT therapy. Cardiac biomarkers were serially measured before conditioning regimen and at days 1, 14 and 30 after HSCT. Cardiac systolic and diastolic functions were assessed before conditioning regimen and 1 month after HSCT by echocardiography. Results The changes in plasma NT-proBNP and hs-cTnT levels during the 30 days following the HSCT were statistically significant (P P Conclusions Elevations in both cardiac biomarkers were found before clinical signs of cardiotoxicity developed. Persistent elevations in NT-pro-BNP and hs-cTnT concentrations simultaneously for a period exceeding 14 days might be used for identification of patients at risk of developing cardiotoxicity and requiring further cardiological follow up.


    Institute of Scientific and Technical Information of China (English)

    张红军; 张立建; 刘杰


    Objective To assess the efficacy and safety of sunitinib monotherapy for triple-negative breast cancer (TN-BC) patient with chest wall metastasis. Methods One TNBC advanced patient who failed to response previous anthracycline, docetaxel and pemetrexed therapy was treated with oral sunitinib. Results Monotherapy with sunitinib for this case was effective, with mild side effects and the patient was well tolerated. This case indicated that sunitinib was well tolerated and efficiency. Conclusion Sunitinib monotherapy may be an effective choice for advanced-stage TNBC patients with a poor physical status.%目的 观察舒尼替尼单药治疗胸壁转移的晚期三阴乳癌的有效性和安全性.方法 应用舒尼替尼单药治疗蒽环类、紫杉类及培美曲塞治疗无效的三阴乳癌晚期病人1例.结果 舒尼替尼单药治疗晚期三阴乳癌胸壁转移有效,毒副作用轻,病人耐受良好.结论 舒尼替尼单药可能是体质差的晚期三阴乳癌病人治疗的一种有效的选择.

  14. DAFODIL: A novel liposome-encapsulated synergistic combination of doxorubicin and 5FU for low dose chemotherapy. (United States)

    Camacho, Kathryn M; Menegatti, Stefano; Vogus, Douglas R; Pusuluri, Anusha; Fuchs, Zoë; Jarvis, Maria; Zakrewsky, Michael; Evans, Michael A; Chen, Renwei; Mitragotri, Samir


    PEGylated liposomes have transformed chemotherapeutic use of doxorubicin by reducing its cardiotoxicity; however, it remains unclear whether liposomal doxorubicin is therapeutically superior to free doxorubicin. Here, we demonstrate a novel PEGylated liposome system, named DAFODIL (Doxorubicin And 5-Flurouracil Optimally Delivered In a Liposome) that inarguably offers superior therapeutic efficacies compared to free drug administrations. Delivery of synergistic ratios of this drug pair led to greater than 90% reduction in tumor growth of murine 4T1 mammary carcinoma in vivo. By exploiting synergistic ratios, the effect was achieved at remarkably low doses, far below the maximum tolerable drug doses. Our approach re-invents the use of liposomes for multi-drug delivery by providing a chemotherapy vehicle which can both reduce toxicity and improve therapeutic efficacy. This methodology is made feasible by the extension of the ammonium-sulfate gradient encapsulation method to nucleobase analogues, a liposomal entrapment method once conceived useful only for anthracyclines. Therefore, our strategy can be utilized to efficiently evaluate various chemotherapy combinations in an effort to translate more effective combinations into the clinic.

  15. Management of endocrino-metabolic dysfunctions after allogeneic hematopoietic stem cell transplantation. (United States)

    Vantyghem, Marie-Christine; Cornillon, Jérôme; Decanter, Christine; Defrance, Frédérique; Karrouz, Wassila; Leroy, Clara; Le Mapihan, Kristell; Couturier, Marie-Anne; De Berranger, Eva; Hermet, Eric; Maillard, Natacha; Marcais, Ambroise; Francois, Sylvie; Tabrizi, Reza; Yakoub-Agha, Ibrahim


    Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.

  16. Inhibition of N-terminal lysines acetylation and transcription factor assembly by epirubicin induced deranged cell homeostasis.

    Directory of Open Access Journals (Sweden)

    Shahper N Khan

    Full Text Available Epirubicin (EPI, an anthracycline antitumour antibiotic, is a known intercalating and DNA damaging agent. Here, we study the molecular interaction of EPI with histones and other cellular targets. EPI binding with histone core protein was predicted with spectroscopic and computational techniques. The molecular distance r, between donor (histone H3 and acceptor (EPI was estimated using Förster's theory of non-radiation energy transfer and the detailed binding phenomenon is expounded. Interestingly, the concentration dependent reduction in the acetylated states of histone H3 K9/K14 was observed suggesting more repressed chromatin state on EPI treatment. Its binding site near N-terminal lysines is further characterized by thermodynamic determinants and molecular docking studies. Specific DNA binding and inhibition of transcription factor (Tf-DNA complex formation implicates EPI induced transcriptional inhibition. EPI also showed significant cell cycle arrest in drug treated cells. Chromatin fragmentation and loss of membrane integrity in EPI treated cells is suggestive of their commitment to cell death. This study provides an analysis of nucleosome dynamics during EPI treatment and provides a novel insight into its action.

  17. Protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats. (United States)

    Mohan, Mahalaxmi; Kamble, Sarika; Gadhi, Prakash; Kasture, Sanjay


    Nephrotoxicity is one of the important side effects of anthracycline antibiotics. The aim of the study was to determine the protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats using biochemical and histopathological approaches. Oxidative stress is the main factor in doxorubicin (DOX) induced nephrotoxicity. Wistar rats received either DOX (67.75 mg/kg, i.v, 2 days before sacrifice) or S. torvum (100mg/kg and 300 mg/kg, p.o.) prior to DOX treatment or S. torvum (100mg/kg and 300 mg/kg, p.o.) extract alone for 4 weeks. Nephrotoxicity was assessed by measuring the abnormal levels of serum creatinine and blood urea nitrogen (BUN). The anti-oxidant defence enzymes superoxide dismutase (SOD) and catalase (CAT) of kidney tissue were also measured at the end of the treatment schedule. Treatment with S. torvum (100mg/kg and 300 mg/kg) significantly (pnephrotoxicity induced by doxorubicin.

  18. Camptothecin induces urokinase-type plasminogen activator gene-expression in human RC-K8 malignant lymphoma and H69 small cell lung cancer cells.

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    Shibakura M


    Full Text Available We previously reported that anthracyclines, which could generate reactive oxygen species (ROS, could induce the urokinase-type plasminogen activator (uPA gene expression in human RC-K8 malignant lymphoma cells and in H69 small cell lung cancer (SCLC cells. In screening other uPA-inducible anti-cancer agents, we found that camptothecin (CPT and its derivative, SN38, could induce uPA in RC-K8 and H69 cells. CPT and SN38, which are also used for the treatment of lymphoma and SCLC, significantly increased the uPA accumulation in the conditioned media of both cells in a dose-dependent manner. The maximum induction of uPA mRNA levels was observed 24 h after stimulation. Pretreatment with pyrrolidine dithiocarbamate (PDTC, an anti-oxidant, inhibited the CPT-induced uPA mRNA expression. Thus, CPT induces uPA through gene expression, and, therefore, CPT may influence the tumor-cell biology by up-regulating the uPA/plasmin system.

  19. Camptothecin induces urokinase-type plasminogen activator gene-expression in human RC-K8 malignant lymphoma and H69 small cell lung cancer cells. (United States)

    Shibakura, Misako; Niiya, Kenji; Kiguchi, Toru; Nakata, Yasunari; Tanimoto, Mitsune


    We previously reported that anthracyclines, which could generate reactive oxygen species (ROS), could induce the urokinase-type plasminogen activator (uPA) gene expression in human RC-K8 malignant lymphoma cells and in H69 small cell lung cancer (SCLC) cells. In screening other uPA-inducible anti-cancer agents, we found that camptothecin (CPT) and its derivative, SN38, could induce uPA in RC-K8 and H69 cells. CPT and SN38, which are also used for the treatment of lymphoma and SCLC, significantly increased the uPA accumulation in the conditioned media of both cells in a dose-dependent manner. The maximum induction of uPA mRNA levels was observed 24 h after stimulation. Pretreatment with pyrrolidine dithiocarbamate (PDTC), an anti-oxidant, inhibited the CPT-induced uPA mRNA expression. Thus, CPT induces uPA through gene expression, and, therefore, CPT may influence the tumor-cell biology by up-regulating the uPA/plasmin system.

  20. Down-regulation of the Nucleotide Excision Repair gene XPG as a new mechanism of drug resistance in human and murine cancer cells

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    Geroni Cristina


    Full Text Available Abstract Background Drug resistance is one of the major obstacles limiting the activity of anticancer agents. Activation of DNA repair mechanism often accounts for increase resistance to cancer chemotherapy. Results We present evidence that nemorubicin, a doxorubicin derivative currently in clinical evaluation, acts through a mechanism of action different from classical anthracyclines, requiring an intact nucleotide excision repair (NER system to exert its activity. Cells made resistant to nemorubicin show increased sensitivity to UV damage. We have analysed the mechanism of resistance and discovered a previously unknown mechanism resulting from methylation-dependent silencing of the XPG gene. Restoration of NER activity through XPG gene transfer or treatment with demethylating agents restored sensitivity to nemorubicin. Furthermore, we found that a significant proportion of ovarian tumors present methylation of the XPG promoter. Conclusions Methylation of a NER gene, as described here, is a completely new mechanism of drug resistance and this is the first evidence that XPG gene expression can be influenced by an epigenetic mechanism. The reported methylation of XPG gene could be an important determinant of the response to platinum based therapy. In addition, the mechanism of resistance reported opens up the possibility of reverting the resistant phenotype using combinations with demethylating agents, molecules already employed in the clinical setting.

  1. Clinical Efficacy of Capecitabine and Cyclophosphamide (XC in Patients with Metastatic Breast Cancer

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    Full Text Available Combined low-dose therapy of oral capecitabine (Xeloda and cyclophosphamide (XC has been demonstrated to be useful for long-term control of lesions in patients with metastatic breast cancer (MBC and is aimed at symptomatic alleviation and prolongation of survival. Here, a retrospective review was conducted of MBC patients administered XC at the Okayama University Hospital (OUH, to evaluate responses to XC, adverse events and time to progression (TTP. Twenty patients with MBC received XC between 2006 and 2009. With the exception of 2 elderly patients who were over the age of 70 at the initial examination, all of the patients had received prior treatment with an anthracycline and/or a taxane. No complete response (CR cases were observed, but partial response (PR was achieved in 6 patients (30% and SD in 9 (45%, of whom 5 (20% sustained SD status for >12 months. The median TTP was 6 months (range:3-27 mo.. Three patients developed Grade 3 adverse events (diarrhea, nausea and stomatitis, but no other patients developed adverse reactions causing interruption of the therapy. XC was safe even in previously treated and elderly MBC patients;moreover, it yielded remarkable clinical responses.

  2. Effectiveness of evaluating tumor vascularization using 3D power Doppler ultrasound with high-definition flow technology in the prediction of the response to neoadjuvant chemotherapy for T2 breast cancer: a preliminary report (United States)

    Shia, Wei-Chung; Chen, Dar-Ren; Huang, Yu-Len; Wu, Hwa-Koon; Kuo, Shou-Jen


    The aim of this study was to evaluate the effectiveness of advanced ultrasound (US) imaging of vascular flow and morphological features in the prediction of a pathologic complete response (pCR) and a partial response (PR) to neoadjuvant chemotherapy for T2 breast cancer. Twenty-nine consecutive patients with T2 breast cancer treated with six courses of anthracycline-based neoadjuvant chemotherapy were enrolled. Three-dimensional (3D) power Doppler US with high-definition flow (HDF) technology was used to investigate the blood flow in and morphological features of the tumors. Six vascularity quantization features, three morphological features, and two vascular direction features were selected and extracted from the US images. A support vector machine was used to evaluate the changes in vascularity after neoadjuvant chemotherapy, and pCR and PR were predicted on the basis of these changes. The most accurate prediction of pCR was achieved after the first chemotherapy cycle, with an accuracy of 93.1% and a specificity of 85.5%, while that of a PR was achieved after the second cycle, with an accuracy of 79.31% and a specificity of 72.22%. Vascularity data can be useful to predict the effects of neoadjuvant chemotherapy. Determination of changes in vascularity after neoadjuvant chemotherapy using 3D power Doppler US with HDF can generate accurate predictions of the patient response, facilitating early decision-making.

  3. Dose-dense and sequential strategies in adjuvant breast cancer therapy. (United States)

    Untch, M; Von Koch, F; Crohns, C; Sobotta, K; Kahlert, S; Konecny, G; Hepp, H


    Several attempts have been made to improve the survival rates of breast cancer patients. The benefit of adjuvant chemotherapy was clearly shown, but the absolute difference of 2% to 11% in overall survival, depending on the patient group, is disappointingly small. In particular, high-risk patients, such as those with > or = 10 involved lymph nodes, extracapsular spread, or vascular invasion, still have an excessive risk of recurrence even after standard adjuvant chemotherapy. To increase the survival rates after adjuvant therapy, new chemotherapeutic agents and new strategies of application are currently being evaluated in clinical trials. Chemotherapy with cyclophosphamide (Cytoxan, Neosar), methotrexate, and fluorouracil (CMF) seems to be safe and effective in patients with breast cancer. In addition, in metastatic patients, dose-intensified chemotherapy is being investigated. The introduction of epirubicin (Ellence), an agent less cardiotoxic and equally active compared to doxorubicin, enabled the escalation of anthracyclines in adjuvant therapy without serious cardiotoxic effects. The combination of dose-intensified chemotherapy and sequential application in the treatment of breast cancer is reviewed.

  4. Trabectedin in the Neoadjuvant Treatment of High-Grade Pleomorphic Sarcoma: Report of a Rare Case and Literature Review

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    Markus K. Schuler


    Full Text Available Background. Pleomorphic sarcoma is an aggressive soft tissue sarcoma. In patients with high-risk extremity sarcomas, the significant survival benefits conferred by an intense regimen of neoadjuvant chemoradiotherapy and surgery were reported. To our knowledge, this is the first report in the literature of the neoadjuvant use of trabectedin in a patient with high-grade pleomorphic sarcoma, ineligible for standard neoadjuvant combination therapy with an anthracycline-based regimen. Case Presentation. Here we present a 58-year-old White male with a large tumor in the left thigh, but with no signs of metastases. Owing to the history of severe heart attack, three cycles of neoadjuvant trabectedin were administrated to achieve surgically wide margins. After two cycles, an 18F-FDG-PET showed a large proportion of the central tumor area was without metabolic activity. According to RECIST and Choi criteria, the tumor was stable. After the third cycle of trabectedin, the patient underwent a complete resection, which revealed completely necrotic high-grade pleomorphic sarcoma (stage pT2b, with only a small vital area. Conclusion. The present paper on a promising treatment with neoadjuvant trabectedin of patients with high-grade pleomorphic sarcoma might suggest that such treatment approach may provide a greater chance of cure and survival of such patients.

  5. Cardioprotective Potentials of Plant-Derived Small Molecules against Doxorubicin Associated Cardiotoxicity

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    Shreesh Ojha


    Full Text Available Doxorubicin (DOX is a potent and widely used anthracycline antibiotic for the treatment of several malignancies. Unfortunately, the clinical utility of DOX is often restricted due to the elicitation of organ toxicity. Particularly, the increased risk for the development of dilated cardiomyopathy by DOX among the cancer survivors warrants major attention from the physicians as well as researchers to develop adjuvant agents to neutralize the noxious effects of DOX on the healthy myocardium. Despite these pitfalls, the use of traditional cytotoxic drugs continues to be the mainstay treatment for several types of cancer. Recently, phytochemicals have gained attention for their anticancer, chemopreventive, and cardioprotective activities. The ideal cardioprotective agents should not compromise the clinical efficacy of DOX and should be devoid of cumulative or irreversible toxicity on the naïve tissues. Furthermore, adjuvants possessing synergistic anticancer activity and quelling of chemoresistance would significantly enhance the clinical utility in combating DOX-induced cardiotoxicity. The present review renders an overview of cardioprotective effects of plant-derived small molecules and their purported mechanisms against DOX-induced cardiotoxicity. Phytochemicals serve as the reservoirs of pharmacophore which can be utilized as templates for developing safe and potential novel cardioprotective agents in combating DOX-induced cardiotoxicity.

  6. Tetracyclines and prion infectivity. (United States)

    Forloni, Gianluigi; Salmona, Mario; Marcon, Gabriella; Tagliavini, Fabrizio


    In the last decade information has accumulated on the potential anti-prion activity of polycyclic compounds. Initially we showed that the antitumoral idodoxorubicin reduced the infectivity in experimental scrapie. On the basis of the chemical homology with anthracyclines, we rapidly moved to tetracyclines, compounds that are safer and widely used as antibiotics in clinical practice. The tetracyclines, essentially doxycycline and minocycline, were characterized as a therapeutical tool in transmissible spongiform encephalopathies (TSE) through the cell-free condition, in cellular and animal models and they are now being investigated clinically with this indication. Tetracyclines interact with aggregates obtained by synthetic PrP peptides or pathological PrP (PrPsc) extracted from TSE brains, and they destabilize the structure of amyloid fibrils, reducing their resistance to digestion by proteinase K. Tetracyclines also interact with peptide oligomeric structures and inhibit the protein misfolding associated with PrPsc formation. These activities have been accompanied by a reduction of infectivity, verified by doxycycline treatment in experimental scrapie, and some curative effects after either peripheral or intracerebral infection. The anti-amyloidogenic activity of tetracyclines was tested in other forms of peripheral and central amyloidosis, with interesting results. This article analyzes the development of tetracyclines as a therapeutic tool in TSE in the light of recent results obtained in our laboratories.

  7. Chirality-mediated polypeptide micelles for regulated drug delivery. (United States)

    Ding, Jianxun; Li, Chen; Zhang, Ying; Xu, Weiguo; Wang, Jincheng; Chen, Xuesi


    Two kinds of triblock poly(ethylene glycol)-polyleucine (PEG-PLeu) copolymers were synthesized through the ring-opening polymerization of L-Leu N-carboxyanhydride (NCA), or equivalent D-Leu NCA and L-Leu NCA with amino-terminated PEG as a macroinitiator. The amphiphilic copolymers spontaneously self-assembled into spherical micellar aggregations in an aqueous environment. The micelle with a racemic polypeptide core exhibited smaller critical micelle concentration and diameter compared to those with a levorotatory polypeptide core. A model anthracycline antineoplastic agent, i.e., doxorubicin (DOX), was loaded into micelles through nanoprecipitation, and the PEG-P(D,L-Leu) micelle exhibited higher drug-loading efficacy than that with a P(L-Leu) core-this difference was attributed to the flexible and compact P(L-Leu) core. Sustained in vitro DOX release from micelles with both levorotatory and racemic polypeptide cores was observed, and the DOX-loaded PEG-P(D,L-Leu) micelle exhibited a slower release rate. More interestingly, DOX-loaded micelles exhibited chirality-mediated antitumor efficacy in vitro and in vivo, which are all better than that of free DOX. Furthermore, both enhanced tumor inhibition and excellent security in vivo were confirmed by histopathological or in situ cell apoptosis analyses. Therefore, DOX-loaded PEG-PLeu micelles appear to be an interesting nanoscale polymeric formulation for promising malignancy chemotherapy.

  8. Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast. (United States)

    Tay, Zoey; Eng, Ru Jun; Sajiki, Kenichi; Lim, Kim Kiat; Tang, Ming Yi; Yanagida, Mitsuhiro; Chen, Ee Sin


    Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance.

  9. Role of multidrug resistance in photodynamic therapy (United States)

    Diddens, Heyke C.


    Multidrug resistance in cancer chemotherapy is a well established phenomenon. One of the most common phenotypical changes in acquired or intrinsic multidrug resistance in human tumor cells is the overexpression of the mdrl gene product P-glycoprotein, which acts as an active efflux pump. Increased levels of P-glycoprotein are associated with resistance to a variety of anticancer drugs commonly used in tumor chemotherapy like anthracyclins, vinca- alcaloids, epipodophyllotoxins or actinomycin D. We investigated the efficacy or photodynamic therapy in the treatment of tumor cells expressing the multidrug resistance phenotype. Our data show that multidrug resistant cells are highly cross resistant to the phototoxic stain rhodamine 123 but exhibit only low degrees of cross resistance (2 - 3 -folds) to the photosensitizers Photosan-3, Clorin-2, methylene blue and meso-tetra (4- sulfonatophenyl) porphine (TPPS4). Resistance is associated with a decrease in intracellular accumulation of the photosensitizer. Verapamil, a membrane active compound known to enhance drug sensitivity in multidrug resistant cells by inhibition of P-glycoprotein, also increases phototoxicity in multidrug resistant cells. Our results imply that tumors expressing the multidrug resistance phenotype might fail to respond to photochemotherapy with rhodamine 123. On the other hand, multidrug resistance may not play an important role in photodynamic therapy with Photosan-3, Chlorin-2, methylene blue or TPPS4.

  10. Expression of BCRP Gene in the Normal Lung Tissue and Lung Cancer

    Institute of Scientific and Technical Information of China (English)


    Objective: To investigate the expression of novel multidrugresistance transporter (BCRP gene) from human MCF-7/AdrVp breast cancer cells in normal lung tissue and non-small lung cancer tissue. Methods: RNA was extracted immediately from fresh normal lung tissue and viable tumor tissue harvested from surgically resected specimens of non-small cell lung cancer patients. cDNA of BCRP gene was prepared by RT-PCR and was then amplified by PCR. cDNA products from those specimens were transferred to blotting membrane through electrophoresis and transferring technique and southern blot hybridization was eventually performed to detect the expression of BCRP gene. Results: RNA were extracted from 8 tumor tissue alone and 12 pairs of tumor tissue and normal lung tissue harvested from the same lung. Four patients' RNA samples with poor quality due to degrading were discarded. cDNA products of BCRP gene were obtained by RT-PCR and were then amplified by PCR in the remain 16 patients' RNA samples. Through southern blot hybridization, BCRP gene was found to be slightly expressed in various amounts in all normal lung tissue (10/10) and only in a half of tumor tissue samples (8/16). Conclusion: BCRP gene is slightly expressed in different amount in all normal lung tissue and only in a half of tumor tissue of non-small cell lung cancer patients. It is possible to induce it's overexpression and to develop multidrug resistance during chemotherapy if using anthracycline anticancer drugs.

  11. Two Cases of Mastectomy after Paclitaxel + Bevacizumab Therapy for Locally Advanced Breast Cancer

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    Chika Shinoda


    Full Text Available Introduction: Locally advanced breast cancer (LABC deteriorates the quality of life (QOL of the affected patients. Combination chemotherapy or extended chemotherapy is considered to help to shrink local lesions. Case 1: A 71-year-old female with a history of tympanitis and cystitis with methicillin-resistant Staphylococcus aureus (MRSA visited our hospital. There was a tumor of 7 cm in diameter in her right breast with skin ulceration. Paclitaxel + bevacizumab therapy was started, and after five cycles of therapy, a mastectomy with axillary dissection was performed. Chemotherapy with anthracycline was avoided for fear of activating the MRSA. After the operation, the patient's wound opened. However, it naturally epithelialized. Case 2: A 41-year-old female visited our hospital due to a tumor of 8 cm in diameter in her right breast with skin ulceration. Four cycles of paclitaxel + bevacizumab therapy were started, and her tumor almost disappeared during the first cycle. Then, doxorubicin + cyclophosphamide therapy was performed for four cycles, and a mastectomy with axillary dissection was performed. Her postoperative course was good. Discussion: Chemotherapy with bevacizumab or extended chemotherapy is generally not considered to contribute to a survival improvement. However, such therapy contributes in increasing the response to chemotherapy, and should be considered for patients with LABC to shrink the local lesions and improve the QOL.

  12. Hodgkin's Lymphoma: A Review of Neurologic Complications

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    Sean Grimm


    Full Text Available Hodgkin's lymphoma is a hematolymphoid neoplasm, primarily of B cell lineage, that has unique histologic, immunophenotypic, and clinical features. Neurologic complications of Hodgkin's Lymphoma can be separated into those that result directly from the disease, indirectly from the disease, or from its treatment. Direct neurologic dysfunction from Hodgkin's Lymphoma results from metastatic intracranial spinal disease, epidural metastases causing spinal cord/cauda equina compression, leptomeningeal metastases, or intradural intramedullary spinal cord metastases. Indirect neurologic dysfunction may be caused by paraneoplastic disorders (such as paraneoplastic cerebellar degeneration or limbic encephalitis and primary angiitis of the central nervous system. Hodgkin's lymphoma treatment typically includes chemotherapy or radiotherapy with potential treatment-related complications affecting the nervous system. Neurologic complications resulting from mantle-field radiotherapy include the “dropped head syndrome,” acute brachial plexopathy, and transient ischemic attacks/cerebral infarcts. Chemotherapy for Hodgkin's lymphoma may cause cerebral infarction (due to emboli from anthracycline-induced cardiomyopathy and peripheral neuropathy.

  13. Affinity of anticancer drug, daunomycin, to core histones in solution:comparison of free and cross-linked proteins

    Institute of Scientific and Technical Information of China (English)



    Aim: The interaction of anthracyclinc anticancer drugs with chromatin, nuclco-somes and historic H1 has been extensively studied. In the present study, for the first time, we have investigated the binding of anthracycline antibiotic, daunomycin,to free and cross-linked thymus core histones (CL-core) in solution and in the absence of DNA. Methods: Fluorescence, UV/Vis spectroscopy and equilibrium dialysis techniques were used. Results: The UV spectroscopy results show that daunomycin induces hypochromicity in the absorption spectra of the core histones.Fluorescence emission intensity is decreased upon daunomycin binding and the process is concentration dependent. The equilibrium dialysis shows that the bind-ing is positive cooperative with the binding sites as Scatchard plot and Hill Coef-ficient confirm it. Conclusion: The results suggest that daunomycin shows much higher affinity to core histories free in solution than to CL-core, implying that the binding is most likely due to the accessibility of these proteins to the environment.It is suggested that daunomycin binds strongly to open state of histones, such as in tumor cells, rather than to their compact structure seen in normal chromatin.

  14. Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints. (United States)

    Wahid, Mohd; Mandal, Raju K; Dar, Sajad A; Jawed, Arshad; Lohani, Mohtashim; Areeshi, Mohammad Y; Akhter, Naseem; Haque, Shafiul


    Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies.

  15. Trastuzumab (Herceptin)-associated cardiomyopathy presented as new onset of complete left bundle-branch block mimicking acute coronary syndrome: a case report and literature review. (United States)

    Tu, Chung-Ming; Chu, Kai-Ming; Yang, Shin-Ping; Cheng, Shu-Mung; Wang, Wen-Been


    Trastuzumab (Herceptin) is well documented in reducing suffering and mortality from breast cancer. The clinically most important side effect of Herceptin is cardiotoxicity, which is reported in 2.6% to 4.5% of patients receiving trastuzumab alone and in as many as 27% of patients when trastuzumab is combined with an anthracycline in metastatic disease. We reported the case of a 50-year-old woman who presented to our emergency department (ED) because of chest pain and shortness of breath. On physical examination, holosystolic murmur over apex could be heard. Pulmonary and abdominal examinations were unremarkable. Twelve-lead electrocardiography showed sinus tachycardia and new onset of complete left bundle-branch block. Emergent transthoracic echocardiography revealed generalized hypokinesia of left ventricle and akinesia over interventricular septum and apex. She subsequently underwent immediate coronary angiography that revealed normal coronary angiography, and left ventriculogram revealed generalized hypokinesia with severe left ventricle dysfunction with ejection fraction of 33%. During right heart catheterization and endomyocardial biopsy, cardiac tamponade developed and was successfully relieved by pericardial window. She was discharged event-free 3 weeks later with conservative treatment. Although new onset of complete left bundle-branch block in a patient with chest pain may be acute coronary syndrome, careful review of medicine history is mandatory to avoid unnecessary procedure and complications.

  16. Cyclic AMP induces IPC leukemia cell apoptosis via CRE-and CDK-dependent Bim transcription. (United States)

    Huseby, S; Gausdal, G; Keen, T J; Kjærland, E; Krakstad, C; Myhren, L; Brønstad, K; Kunick, C; Schwede, F; Genieser, H-G; Kleppe, R; Døskeland, S O


    The IPC-81 cell line is derived from the transplantable BNML model of acute myelogenic leukemia (AML), known to be a reliable predictor of the clinical efficiency of antileukemic agents, like the first-line AML anthracycline drug daunorubicin (DNR). We show here that cAMP acted synergistically with DNR to induce IPC cell death. The DNR-induced death differed from that induced by cAMP by (1) not involving Bim induction, (2) being abrogated by GSK3β inhibitors, (3) by being promoted by the HSP90/p23 antagonist geldanamycin and truncated p23 and (4) by being insensitive to the CRE binding protein (CREB) antagonist ICER and to cyclin-dependent protein kinase (CDK) inhibitors. In contrast, the apoptosis induced by cAMP correlated tightly with Bim protein expression. It was abrogated by Bim (BCL2L11) downregulation, whether achieved by the CREB antagonist ICER, by CDK inhibitors, by Bim-directed RNAi, or by protein synthesis inhibitor. The forced expression of BimL killed IPC-81(WT) cells rapidly, Bcl2-overexpressing cells being partially resistant. The pivotal role of CREB and CDK activity for Bim transcription is unprecedented. It is also noteworthy that newly developed cAMP analogs specifically activating PKA isozyme I (PKA-I) were able to induce IPC cell apoptosis. Our findings support the notion that AML cells may possess targetable death pathways not exploited by common anti-cancer agents.

  17. Folate-targeted single-wall metal-organic nanotubes used as multifunctional drug carriers (United States)

    Yang, Linyan; Liu, Min; Huang, Kebin; Ai, Xia; Li, Cun; Ma, Jifei; Jin, Tianming; Liu, Xin


    Doxorubicin (DOX) is a member of the anthracycline class of chemotherapeutic agents that are used for the treatment of many common human cancers. A self-assembled functionalized metal-organic nanotubes, SWMONTs could be loaded with the anticancer drug DOX. Via the modification of SWMONTs, DOX/SWMONTs-SiO2, DOX/SWMONTs-SiO2-NH2, DOX/SWMONTs-SiO2-NH2-FA samples could be obtained. The SEM characterization of the samples indicated that the particle size of DOX/SWMONTs-SiO2NH2 samples were smaller than 200 nm. Drug-release experiments implied that DOX from the DOX/SWMONTs-SiO2-NH2-FA samples could be released faster at acidic tumor tissue than at normal body fluid (pH7.4). DOX has strong cytotoxicity, and at 20 μg/mL dosage of DOX large amount of apoptotic cells could be seen. Cellular uptaking experiments were used to study the apoptotic mechanism, while for DOX/SWMONTs-SiO2-NH2-FA samples, the strong drug fluorescence was found in the cytoplasm rather than in the nucleus.

  18. Prognostic significance of Epstein-Barr virus DNA detection in pretreatment serum in diffuse large B-cell lymphoma. (United States)

    Okamoto, Akinao; Yanada, Masamitsu; Miura, Hiroki; Inaguma, Yoko; Tokuda, Masutaka; Morishima, Satoko; Kanie, Tadaharu; Yamamoto, Yukiya; Mizuta, Shuichi; Akatsuka, Yoshiki; Yoshikawa, Tetsushi; Mizoguchi, Yoshikazu; Nakamura, Shigeo; Okamoto, Masataka; Emi, Nobuhiko


    It is still a matter of debate whether detection of Epstein-Barr virus (EBV) DNA in pretreatment serum has clinical implications for diffuse large B-cell lymphoma. For this study, we measured EBV DNA load in pretreatment serum from 127 diffuse large B-cell lymphoma patients without any underlying immunodeficiency to evaluate its effects on clinical manifestations and prognosis. Anthracycline-based chemotherapy in combination with rituximab was given as initial therapy for 119 patients (94%). Epstein-Barr virus DNA was detected in 15 patients (12%), who were older (P = 0.005) and tended to be at a more advanced disease stage (P = 0.053). They showed significantly worse progression-free survival (PFS) and overall survival (OS) than other patients (P EBV-encoded small RNA in situ hybridization was known for 123 patients; 6 of 8 positive patients (75%) and 9 of 115 negative patients (8%) had detectable EBV DNA in pretreatment serum. While patients positive for EBV-encoded small RNA had significantly worse PFS and OS than negative patients (P = 0.001 and P = 0.029, respectively), EBV DNA detection in pretreatment serum was associated with poorer PFS and OS even for the 115 patients negative for EBV-encoded small RNA (P EBV DNA detection in pretreatment serum may have an adverse prognostic impact for patients with diffuse large B-cell lymphoma.

  19. Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial. (United States)

    Pluta, Agnieszka; Robak, Tadeusz; Wrzesien-Kus, Agata; Katarzyna Budziszewska, Bozena; Sulek, Kazimierz; Wawrzyniak, Ewa; Czemerska, Magdalena; Zwolinska, Malgorzata; Golos, Aleksandra; Holowiecka-Goral, Aleksandra; Kyrcz-Krzemien, Slawomira; Piszcz, Jaroslaw; Kloczko, Janusz; Mordak-Domagala, Monika; Lange, Andrzej; Razny, Małgorzata; Madry, Krzysztof; Wiktor-Jedrzejczak, Wieslaw; Grosicki, Sebastian; Butrym, Aleksandra; Kuliczkowski, Kazimierz; Warzocha, Krzysztof; Holowiecki, Jerzy; Giebel, Sebastian; Szydlo, Richard; Wierzbowska, Agnieszka


    Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.

  20. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence. (United States)

    Ghosh, Asish K; Rai, Rahul; Park, Kitae E; Eren, Mesut; Miyata, Toshio; Wilsbacher, Lisa D; Vaughan, Douglas E


    Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition. Results show that TM5441, a potent small molecule inhibitor of PAI-1, effectively prevents Doxorubicin-induced senescence in cardiomyocytes, fibroblasts and endothelial cells. TM5441 exerts its inhibitory effect on Doxorubicin-induced cellular senescence by decreasing reactive oxygen species generation, induction of antioxidants like catalase and suppression of stress-induced senescence cadre p53, p21, p16, PAI-1 and IGFBP3. Importantly, TM5441 also reduces replicative senescence of fibroblasts. Together these results for the first time demonstrate the efficacy of PAI-1 inhibitor in prevention of Doxorubicin-induced and replicative senescence in normal cells. Thus PAI-1 inhibitor may form an important adjuvant component of chemotherapy regimens, limiting not only Doxorubicin-induced cardiac senescence but also ameliorating the prothrombotic profile.

  1. Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion (United States)

    Luthra, Priya; Aguirre, Sebastian; Yen, Benjamin C.; Pietzsch, Colette A.; Sanchez-Aparicio, Maria T.; Tigabu, Bersabeh; Morlock, Lorraine K.; García-Sastre, Adolfo; Leung, Daisy W.; Williams, Noelle S.; Fernandez-Sesma, Ana; Bukreyev, Alexander


    ABSTRACT Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication. PMID:28377530

  2. Two Streptomyces species producing antibiotic, antitumor, and anti-inflammatory compounds are widespread among intertidal macroalgae and deep-sea coral reef invertebrates from the central Cantabrian Sea. (United States)

    Braña, Alfredo F; Braña, Afredo F; Fiedler, Hans-Peter; Nava, Herminio; González, Verónica; Sarmiento-Vizcaíno, Aida; Molina, Axayacatl; Acuña, José L; García, Luis A; Blanco, Gloria


    Streptomycetes are widely distributed in the marine environment, although only a few studies on their associations to algae and coral ecosystems have been reported. Using a culture-dependent approach, we have isolated antibiotic-active Streptomyces species associated to diverse intertidal marine macroalgae (Phyllum Heterokontophyta, Rhodophyta, and Chlorophyta), from the central Cantabrian Sea. Two strains, with diverse antibiotic and cytotoxic activities, were found to inhabit these coastal environments, being widespread and persistent over a 3-year observation time frame. Based on 16S rRNA sequence analysis, the strains were identified as Streptomyces cyaneofuscatus M-27 and Streptomyces carnosus M-40. Similar isolates to these two strains were also associated to corals and other invertebrates from deep-sea coral reef ecosystem (Phyllum Cnidaria, Echinodermata, Arthropoda, Sipuncula, and Anelida) living up to 4.700-m depth in the submarine Avilés Canyon, thus revealing their barotolerant feature. These two strains were also found to colonize terrestrial lichens and have been repeatedly isolated from precipitations from tropospheric clouds. Compounds with antibiotic and cytotoxic activities produced by these strains were identified by high-performance liquid chromatography (HPLC) and database comparison. Antitumor compounds with antibacterial activities and members of the anthracycline family (daunomycin, cosmomycin B, galtamycin B), antifungals (maltophilins), anti-inflamatory molecules also with antituberculosis properties (lobophorins) were identified in this work. Many other compounds produced by the studied strains still remain unidentified, suggesting that Streptomyces associated to algae and coral ecosystems might represent an underexplored promising source for pharmaceutical drug discovery.

  3. Emerging intravesical therapies for management of nonmuscle invasive bladder cancer

    Directory of Open Access Journals (Sweden)

    Jeffrey J Tomaszewski


    Full Text Available Jeffrey J Tomaszewski, Marc C SmaldoneDepartment of Urology, University of Pittsburgh School of Medicine, Pennsylvania, USAAbstract: Transitional cell carcinoma (TCC is the second most common urologic malignancy, and 70% of patients present with superficial or nonmuscle invasive bladder cancer (NMIBC. Intravesical bacillus Calmette-Guerin (BCG is the most effective agent for preventing disease recurrence, and the only therapy able to inhibit disease progression. However, recurrence rates as high as 30% and significant local and systemic toxicity have led to increased interest in alternative intravesical therapies. In patients refractory or intolerant to BCG, BCG-interferon α2b, gemcitabine, and anthracyclines (doxorubicin, epirubicin, valrubicin have demonstrated durable clinical responses. Phase I trials investigating alternative cytotoxic agents, such as apaziquone, taxanes (docetaxel, paclitaxel, and suramin are reporting promising data. Novel immunomodulating agents have demonstrated promise as efficacious alternatives in patients refractory to BCG. Optimization of existing chemotherapeutic regimens using hyperthermia, photodynamic therapy, magnetically-targeted carriers, and liposomes remains an area of active investigation. Despite enthusiasm for new intravesical agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy and selected patients with naïve T1 tumors and aggressive features. This report provides a comprehensive review of contemporary intravesical therapy for NMIBC and refractory NMIBC, with an emphasis on emerging agents and novel treatment modalities.Keywords: transitional cell carcinoma, nonmuscle, invasive, intravesical therapy, BCG

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

    Directory of Open Access Journals (Sweden)

    Hallett Robin M


    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.

  5. Treatment of acute promyelocytic leukemia during pregnancy. (United States)

    Yang, Daisy; Hladnik, Lindsay


    Management of the pregnant patient with acute promyelocytic leukemia (APL) is a challenge. Immediate treatment of APL is critical, as it is an oncologic emergency, with a high risk of morbidity and mortality associated with disseminated intravascular coagulation. However, administration of chemotherapy and differentiating agents in pregnancy is controversial because of potential teratogenic effects. In addition, complications associated with APL, including retinoic acid syndrome, add to the complexity of management. To better understand how to manage this complex patient care situation, we searched the PubMed database (January 1972-May 2008) for English-language articles about maternal and fetal outcomes resulting from APL treatment during pregnancy. A total of 42 cases from 35 articles were identified: 12 first-trimester, 21 second-trimester, and 9 third-trimester cases. The most commonly administered agents were all-trans-retinoic acid (ATRA), anthracyclines, and antimetabolites. Complete remission was reported in 35 (83%) of 42 patients. Administration of ATRA or chemotherapy in the first trimester was associated with an increased risk of fetal malformations and spontaneous abortion, whereas administration in the second and third trimesters was associated with relatively favorable fetal outcomes. The overall treatment of the pregnant patient with APL should include a discussion about pregnancy termination, especially if APL is diagnosed in the first trimester. If the pregnancy is to continue, then the appropriate chemotherapy regimen needs to be determined. Frequent fetal monitoring, along with aggressive management of potential APL-related complications, is necessary to allow for optimal maternal and fetal outcomes.

  6. New approaches in the management of advanced breast cancer – role of combination treatment with liposomal doxorubicin

    Directory of Open Access Journals (Sweden)

    Iain RJ Macpherson


    Full Text Available Iain RJ Macpherson, TR Jeffry EvansBeatson West of Scotland Cancer Centre, Glasgow, United KingdomAbstract: Metastatic breast cancer (MBC remains a major cause of morbidity and mortality in women worldwide. For three decades doxorubicin, alone or in combination with other cytotoxic agents, has been a mainstay of systemic therapy for MBC. However, its use is limited by cumulative cardiotoxicity. More recently liposomal formulations of doxorubicin have been developed which exhibit equal efficacy but reduced cardiotoxicity in comparison to conventional doxorubicin. The novel toxicity profile of liposomal doxorubicins has prompted their evaluation with various cytotoxic agents in patients with MBC. In addition, their favorable cardiac safety profile has prompted re-evaluation of concomitant therapy with doxorubicin and trastuzumab, a regimen of proven efficacy in MBC but previously considered to be associated with significant cardiotoxicity. We review clinical trial data addressing combination therapy with both pegylated and non-pegylated liposomal doxorubicin in patients with MBC.Keywords: breast cancer, anthracycline, liposome-encapsulated doxorubicin, pegylated liposomal doxorubicin, cardiotoxicity

  7. Altered balance between proteolysis and antiproteolysis in oncohematologic diseases

    Directory of Open Access Journals (Sweden)

    O. E. Shaul’ska


    Full Text Available Destruction of malignant cell clones and search for markers of the effectiveness of chemotherapy in patients with hematologic malignancies is an urgent direction of research. The purpose of this paper was to study plasma of patients with various forms of blood tumor, the activity of trypsin-like enzymes, matrix metalloproteinases MMP2 and MMP9, content of α1-proteinase inhibitor and α2-macroglobulin before and after the cytotoxic therapy by anthracycline antibiotics, doxorubicin and daunorubicin. It was established that concentration of inhibitors and activity of trypsin-like enzymes increased in patients with acute myeloid leukemia and multiple myeloma against the backdrop of multidirectional changes of proMMP9. Activity of the latter enzyme was reduced to 0,03±0,01 rel. u. in acute myeloid leukemia, and after chemotherapy it increased 7 times. Reducing level of inhibitors and increasing activity of MMP9 were found in chronic lymphocytic leukemia. The presence of the correlation between the α2-macroglobulin and gelatinase activity in the treatment indicates that the inhibitor is an important mechanism for storing of gelatinоlytic potential. Balance between proteolysis and antiproteolysis depends on the type of proliferating cells and the course of the disease. Indicators of tissue destruction may be an additional criterion for monitoring the stage of blood tumors and efficacy of treatment.

  8. Benefit risk assessment and update on the use of docetaxel in the management of breast cancer

    Directory of Open Access Journals (Sweden)

    Alken S


    Full Text Available Scheryll Alken, Catherine M KellyDepartment of Medical Oncology, Mater Misericordiae University Hospital, Dublin, IrelandAbstract: The objective of this paper is to review the data supporting the use of docetaxel in the treatment of breast cancer, focusing on pharmacokinetics, efficacy in adjuvant and metastatic trials alone and in combination with chemotherapeutic and targeted agents, and the toxicity of docetaxel in comparison to paclitaxel. Docetaxel is a semisynthetic product derived from the European yew tree Taxus baccata L. It promotes the assembly of microtubules, stabilizes them, and thereby prevents their depolymerization. Docetaxel has been incorporated into neo-adjuvant chemotherapy regimens, both with and without anthracyclines. The inclusion of taxanes such as docetaxel in polychemotherapy regimens in early breast cancer is associated with a statistically significant reduction in mortality. As a single agent, docetaxel is highly active in the treatment of metastatic breast cancer. In first-line treatment of metastatic breast cancer, the combination of docetaxel and capecitabine was associated with an improvement in overall survival; however, toxicity was higher. The toxicity profile of docetaxel has been well documented and is predictable; the most frequent adverse effects are neutropenia and febrile neutropenia. Taxane-specific adverse effects, such as peripheral neuropathy, are also expected but are manageable with appropriate dosing and scheduling.Keywords: taxanes, docetaxel, clinical trial, adverse effects, peripheral neuropathy, neutropenia

  9. Phase III trial of casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of nausea and vomiting in patients receiving moderately emetogenic chemotherapy

    DEFF Research Database (Denmark)

    Herrstedt, Jørn; Apornwirat, Wichit; Shaharyar, Ahmed;


    PURPOSE: The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemo...... proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms. CONCLUSION: All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.......PURPOSE: The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic...... chemotherapy (MEC). PATIENTS AND METHODS: Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) -based regimen were enrolled onto this multinational, randomized, double-blind, parallel...

  10. Glutamine: A novel approach to chemotherapy-induced toxicity

    Directory of Open Access Journals (Sweden)

    Kumar Gaurav


    Full Text Available Treatment of cancer is associated with short- and long-term side-effects. Cancer produces a state of glutamine deficiency, which is further aggravated by toxic effects of chemotherapeutic agents leading to increased tolerance of tumor to chemotherapy as well as reduced tolerance of normal tissues to the side-effects of chemotherapy. This article reviews the possible role of glutamine supplementation in reducing the serious adverse events in patients treated with anticancer drugs. The literature related to the possible role of glutamine in humans with cancer and the supportive evidence from animal studies was reviewed. Searches were made and the literature was retrieved using PUBMED, MEDLINE, COCHRANE LIBRARY, CENAHL and EMBASE, with a greater emphasis on the recent advances and clinical trials. Glutamine supplementation was found to protect against radiation-induced mucositis, anthracycline-induced cardiotoxicity and paclitaxel-related myalgias/arthralgias. Glutamine may prevent neurotoxicity of paclitaxel, cisplatin, oxaplatin bortezomib and lenolidamide, and is beneficial in the reduction of the dose-limiting gastrointestinal toxic effects of irinotecan and 5-FU-induced mucositis and stomatitis. Dietary glutamine reduces the severity of the immunosuppressive effect induced by methotrexate and improves the immune status of rats recovering from chemotherapy. In patients with acute myeloid leukemia requiring parenteral nutrition, glycyl-glutamine supplementation could hasten neutrophil recovery after intensive myelosuppressive chemotherapy. Current data supports the usefulness of glutamine supplementation in reducing complications of chemotherapy; however, paucity of clinical trials weakens the clear interpretation of these findings.

  11. Quality of life and quality-adjusted survival (Q-TWiST) in patients receiving dose-intensive or standard dose chemotherapy for high-risk primary breast cancer. (United States)

    Bernhard, J; Zahrieh, D; Zhang, J J; Martinelli, G; Basser, R; Hürny, C; Forbes, J F; Aebi, S; Yeo, W; Thürlimann, B; Green, M D; Colleoni, M; Gelber, R D; Castiglione-Gertsch, M; Price, K N; Goldhirsch, A; Coates, A S


    Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: PQ-TWiST was 1.8 months longer for patients receiving DI-EC (95% CI, -2.5 to 6.1). Q-TWiST favoured DI-EC for most values of utilities attached to TOX and REL. Despite greater initial toxicity, quality-adjusted survival was similar or better with dose-intensive treatment as compared to standard treatment. Thus, QL considerations should not be prohibitive if future intensive therapies show superior efficacy.

  12. Targeting topoisomerase IIa in endometrial adenocarcinoma: a combined chromogenic in situ hybridization and immunohistochemistry study based on tissue microarrays. (United States)

    Tsiambas, E; Alexopoulou, D; Lambropoulou, S; Gerontopoulos, K; Karakitsos, P; Karameris, A


    Topoisomerase IIa is a nucleic enzyme that affects the topological structure of DNA and also is a target for chemotherapy (ie, anthracyclines). In this study, we coevaluated its protein expression with chromosome 17 and gene status. Using tissue microarrays, 40 cases of sporadic, primary endometrial adenocarcinomas, 5 cases of atypical hyperplasia, and 5 cases of benign hyperplasia were obtained and reembedded into two paraffin blocks with a core diameter of 1 mm. Immunohistochemistry combined with chromogenic in situ hybridization was performed in 2 and 5 microm sections, respectively. Finally using a semiautomated Image Analysis System, we evaluated the levels of Nuclear labeling index of topoisomerase IIa expression. Statistical analysis was performed by SPSS version 11.0 software. The results indicate that chromosome 17 instability (aneuploidy in 7/40 cases) and Topo IIa gene deregulation (amplification in 3/40 and deletion in 1/40 cases) are significant genetic events correlated with biologic behavior in endometrial adenocarcinoma. Because protein overexpression was observed in a significant proportion of the tumors (18/40), detection of the specific gene deregulation mechanism is a crucial process for application of targeted chemotherapies, which are characterized by different levels of cardiotoxicity and other serious effects.

  13. Targeting ABCB1-mediated tumor multidrug resistance by CRISPR/Cas9-based genome editing (United States)

    Yang, Yang; Qiu, Jian-Ge; Li, Yong; Di, Jin-Ming; Zhang, Wen-Ji; Jiang, Qi-Wei; Zheng, Di-Wei; Chen, Yao; Wei, Meng-Ning; Huang, Jia-Rong; Wang, Kun; Shi, Zhi


    The RNA-guided clustered regularly interspaced short palindromic (CRISPR) in combination with a CRISPR-associated nuclease 9 (Cas9) nuclease system is a new rapid and precise technology for genome editing. In the present study, we applied the CRISPR/Cas9 system to target ABCB1 (also named MDR1) gene which encodes a 170 kDa transmembrane glycoprotein (P-glycoprotein/P-gp) transporting multiple types of chemotherapeutic drugs including taxanes, epipodophyllotoxins, vinca alkaloids and anthracyclines out of cells to contribute multidrug resistance (MDR) in cancer cells. Our data showed that knockout of ABCB1 by CRISPR/Cas9 system was succesfully archieved with two target sgRNAs in two MDR cancer cells due to the alteration of genome sequences. Knockout of ABCB1 by CRISPR/Cas9 system significantly enhances the sensitivity of ABCB1 substrate chemotherapeutic agents and the intracellular accumulation of rhodamine 123 and doxorubicin in MDR cancer cells. Although now there are lots of limitations to the application of CRISPR/Cas9 for editing cancer genes in human patients, our study provides valuable clues for the use of the CRISPR/Cas9 technology in the investigation and conquest of cancer MDR. PMID:27725879

  14. Phase I dose intensification study of 2-weekly epirubicin with GM-CSF in advanced cancer. (United States)

    Michael, M; Toner, G C; Olver, I N; Fenessy, A; Bishop, J F


    This study investigated dose intensification of epirubicin administered as a 2-weekly regimen with granulocyte-macrophage colony-stimulating factor (GM-CSF) support. The aim was to define the maximally tolerated dose of epirubicin and to assess the efficacy of GM-CSF to ameliorate its toxicity. Patients with anthracycline-responsive advanced malignancies were eligible. Six dose levels, commencing at 90 mg/m2, of epirubicin administered every 2 weeks for four courses were planned with GM-CSF 10 micrograms/kg/day administered for 10 days from the second day of each course. Six patients were to be entered at each dose level, and escalation to the next level was based upon toxicity criteria. Twelve patients were entered, six at dose level 1 (90 mg/m2) and six at dose level 2 (120 mg/m2). Prospectively defined haematological dose-limiting toxicities were noted in one patient at dose level 1 and in five patients at dose level 2. Further dose escalation was not attempted. Significant nonhaematological toxicities included febrile neutropenia in two and four patients at dose levels 1 and 2, respectively. This study has demonstrated that epirubicin can be safely administered at 2 week intervals with GM-CSF at a dose of 90 mg/m2, equivalent to the previously reported maximum tolerated dose intensity of 45 mg/m2/week. Neutropenia was dose-limiting despite the use of GM-CSF.

  15. DNA topoisomerase II-dependent control of the cell cycle progression in root meristems of Allium cepa. (United States)

    Zabka, Aneta; Polit, Justyna Teresa; Bernasińska, Joanna; Maszewski, Janusz


    The catalytic ability of DNA topoisomerases (Topo) to generate short-term DNA breaks allow these enzymes to play crucial functions in managing DNA topology during S-phase replication, transcription, and chromatin-remodelling processes required to achieve commitment for the onset and transition through mitosis. Our experiments on root meristem cells of onion (Allium cepa) were designed to gain insight into the contribution of Topo II to plant-specific progression throughout interphase and mitosis. Irrespective of the position of the cell in interphase, the immunofluorescence of Topo II revealed similar nuclear labelling pattern with well defined signals dispersed in the nucleoplasm and the cortical zone of the nucleolus. Only weak labelling was detected in metaphase and anaphase chromosomes. Experiments with two potent anti-Topo II agents, doxorubicin (DOX, an anthracycline) and a bisdioxopiperazine derivative, ICRF-193, suggest that the inhibition-mediated increase in Topo II immunofluorescence may represent a compensatory mechanism, by which an up-regulated expression of the enzyme tends to counteract the drug-induced loss of indispensable catalytic and relaxation functions. γ-H2AX immunolabelling seems to indicate that both DOX- and ICRF-193-induced alterations in cell cycle progression reflect primarily the activity of the G2/M DNA damage checkpoint. Our findings provide evidence for the plant-specific cell cycle control mechanism induced by Topo II inhibitors under DNA stress conditions.

  16. Isorhamnetin protects against doxorubicin-induced cardiotoxicity in vivo and in vitro.

    Directory of Open Access Journals (Sweden)

    Jing Sun

    Full Text Available Doxorubicin (Dox is an anthracycline antibiotic for cancer therapy with limited usage due to cardiotoxicity. Isorhamnetin is a nature antioxidant with obvious cardiac protective effect. The aim of this study is going to investigate the possible protective effect of isorhamnetin against Dox-induced cardiotoxicity and its underlying mechanisms. In an in vivo investigation, rats were intraperitoneally (i.p. administered with Dox to duplicate the model of Dox-induced chronic cardiotoxicity. Daily pretreatment with isorhamnetin (5 mg/kg, i.p. for 7 days was found to reduce Dox-induced myocardial damage significantly, including the decline of cardiac index, decrease in the release of serum cardiac enzymes and amelioration of heart vacuolation. In vitro studies on H9c2 cardiomyocytes, isorhamnetin was effective to reduce Dox-induced cell toxicity. A further mechanism study indicated that isorhamnetin pretreatment can counteract Dox-induced oxidative stress and suppress the activation of mitochondrion apoptotic pathway and mitogen-activated protein kinase pathway. Isorhamnetin also potentiated the anti-cancer activity of Dox in MCF-7, HepG2 and Hep2 cells. These findings indicated that isorhamnetin can be used as an adjuvant therapy for the long-term clinical use of Dox.

  17. Isorhamnetin protects against doxorubicin-induced cardiotoxicity in vivo and in vitro. (United States)

    Sun, Jing; Sun, Guibo; Meng, Xiangbao; Wang, Hongwei; Luo, Yun; Qin, Meng; Ma, Bo; Wang, Min; Cai, Dayong; Guo, Peng; Sun, Xiaobo


    Doxorubicin (Dox) is an anthracycline antibiotic for cancer therapy with limited usage due to cardiotoxicity. Isorhamnetin is a nature antioxidant with obvious cardiac protective effect. The aim of this study is going to investigate the possible protective effect of isorhamnetin against Dox-induced cardiotoxicity and its underlying mechanisms. In an in vivo investigation, rats were intraperitoneally (i.p.) administered with Dox to duplicate the model of Dox-induced chronic cardiotoxicity. Daily pretreatment with isorhamnetin (5 mg/kg, i.p.) for 7 days was found to reduce Dox-induced myocardial damage significantly, including the decline of cardiac index, decrease in the release of serum cardiac enzymes and amelioration of heart vacuolation. In vitro studies on H9c2 cardiomyocytes, isorhamnetin was effective to reduce Dox-induced cell toxicity. A further mechanism study indicated that isorhamnetin pretreatment can counteract Dox-induced oxidative stress and suppress the activation of mitochondrion apoptotic pathway and mitogen-activated protein kinase pathway. Isorhamnetin also potentiated the anti-cancer activity of Dox in MCF-7, HepG2 and Hep2 cells. These findings indicated that isorhamnetin can be used as an adjuvant therapy for the long-term clinical use of Dox.

  18. Aggressive lymphoma in the elderly. (United States)

    Lichtman, S M


    Persons 65 years of age and older are the fastest growing segment of the United States population. Over the next 30 years they will comprise approximately 20% of the population. There will be a parallel rise in the number of patients with non-Hodgkin's lymphoma. Age has long been known to be an adverse prognostic factor. Clinical trials of older patients are complicated by the effect of comorbid illness, particularly its effect on overall survival. CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) remains the standard therapy for all patients with aggressive non-Hodgkin's lymphoma. There are a number of regimens which may be beneficial for older patients with significant comorbidity and poor performance status. The randomized trials in the elderly has reaffirmed CHOP and emphasize the need for adequate dosing, maintaining schedule and anthracyclines. Relapsed patients have a poor prognosis but selected fit older patients may benefit from aggressive reinduction regimens and possibly bone marrow transplantation. Future research should include defining the role of comorbidity, measurement of organ dysfunction and assessment of performance status with geriatric functional scales. New drug treatments should also be explored.

  19. Azacitidine. Poor-prognosis myelodysplasia: promising, but more data needed. (United States)


    Some myelodysplastic syndromes carry a poor prognosis. This is also the case for chronic myelomonocytic leukaemia (related to myelodysplastic syndromes), and acute myeloblastic leukaemia, a frequent complication of myelodysplasia. The only treatment capable of providing long-term remission (in about 1 in 2 patients on average) is haematopoietic stem cell transplantation, but this burdensome treatment can only be used in a minority of cases. Azacitidine (Vidaza, Celgene), an agent that blocks DNA synthesis, is the first drug to receive EU marketing authorisation in these settings. Its clinical evaluation is based on an unblinded trial that included 358 patients comparable to those discussed in the marketing authorisation. In addition to individually tailored symptomatic care, they were randomised to receive either azacitidine or conventional care regimens chosen by their physician (no treatment, low-dose cytarabine, or an anthracycline plus cytarabine). The median overall survival time was significantly longer with azacitidine (24.5 versus 15 months), and transfusion requirements were also reduced. Another comparative trial versus symptomatic treatment alone in 191 patients with various prognoses also showed an increase in survival time with azacitidine, but this study suffered from methodological flaws. The main adverse effects of azacitidine are potentially severe toxicity for various blood cells, gastrointestinal disorders, and reactions at the injection site. In practice, when haematopoietic stem cell transplantation is not feasible for poor-prognosis patients with myelodysplastic syndromes or related disorders, azacitidine can be used instead of disappointing standard treatments, even though more clinical evaluation is needed.

  20. Methods for Elucidation of DNA-Anticancer Drug Interactions and their Applications in the Development of New Drugs. (United States)

    Misiak, Majus; Mantegazza, Francesco; Beretta, Giovanni L


    DNA damaging agents including anthracyclines, camptothecins and platinum drugs are among most frequently used drugs in the chemotherapeutic routine. Due to their relatively low selectivity for cancer cells, administration of these drugs is associated with adverse side effects, inherent genotoxicity with risk of developing secondary cancers. Development of new drugs, which could be spared of these drawbacks and characterize by improved antitumor efficacy, remains challenging yet vitally important task. These properties are in large part dictated by the selectivity of interaction between the drug and DNA and in this way the studies aimed at elucidating the complex interactions between ligand and DNA represent a key step in the drug development. Studies of the drug-DNA interactions encompass determination of DNA sequence specificity and mode of DNA binding as well as kinetic, dynamic and structural parameters of binding. Here, we consider the types of interactions between small molecule ligands and polynucleotides, how they are affected by DNA sequence and structure, and what is their significance for the antitumor activity. Based on this knowledge, we discuss the wide array of experimental techniques available to researchers for studying drug-DNA interactions, which include absorption and emission spectroscopies, NMR, magnetic and optical tweezers or atomic force microscopy. We show, using the clinical and experimental anticancer drugs as examples, how these methods provide various types of information and at the same time complement each other to provide full picture of drug- DNA interaction and aid in the development of new drugs.

  1. Synthesis of marmycin A and investigation into its cellular activity (United States)

    Cañeque, Tatiana; Gomes, Filipe; Mai, Trang Thi; Maestri, Giovanni; Malacria, Max; Rodriguez, Raphaël


    Anthracyclines such as doxorubicin are used extensively in the treatment of cancers. Anthraquinone-related angucyclines also exhibit antiproliferative properties and have been proposed to operate via similar mechanisms, including direct genome targeting. Here, we report the chemical synthesis of marmycin A and the study of its cellular activity. The aromatic core was constructed by means of a one-pot multistep reaction comprising a regioselective Diels-Alder cycloaddition, and the complex sugar backbone was introduced through a copper-catalysed Ullmann cross-coupling, followed by a challenging Friedel-Crafts cyclization. Remarkably, fluorescence microscopy revealed that marmycin A does not target the nucleus but instead accumulates in lysosomes, thereby promoting cell death independently of genome targeting. Furthermore, a synthetic dimer of marmycin A and the lysosome-targeting agent artesunate exhibited a synergistic activity against the invasive MDA-MB-231 cancer cell line. These findings shed light on the elusive pathways through which anthraquinone derivatives act in cells, pointing towards unanticipated biological and therapeutic applications.

  2. Late effects of breast cancer treatment and potentials for rehabilitation

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    Ewertz, Marianne (Dept. of Oncology, Odense Univ. Hospital, Odense (Denmark)); Bonde Jensen, Anders (Inst. of Clinical Research, Univ. of Southern Denmark (Denmark))


    Background. Breast cancer is the most frequent malignant disease among women world wide. Survival has been improving leading to an increasing number of breast cancer survivors, in the US estimated to about 2.6 million. Material and methods. The literature was reviewed with focus on data from the Nordic countries. Results. Local therapies such as breast cancer surgery and radiotherapy may cause persistent pain in the breast area, arm, and shoulder reported by 30-50% of patients after three to five years, lymphedema in 15-25% of patients, and restrictions of arm and shoulder movement in 35%. Physiotherapy is the standard treatment for the latter while no pain intervention trials have been published. Chemotherapy may cause infertility and premature menopause, resulting in vasomotor symptoms, sexual dysfunction, and osteoporosis, which are similar to the side effects of endocrine treatment in postmenopausal women. Awareness of cardiotoxicity is needed since anthracyclines, trastuzumab, and radiotherapy can damage the heart. Breast cancer survivors have an increased risk of a major depression and far from all receive adequate anti-depressive treatment. Other psychological symptoms include fear of recurrence, sleep disturbances, cognitive problems, fatigue, and sexual problems. Discussion. To improve rehabilitation, specific goals have to be formulated into national guidelines and high priority directed towards research into developing and testing new interventions for alleviating symptoms and side effects experienced by breast cancer survivors

  3. Clinical utility of trabectedin for the treatment of ovarian cancer: current evidence

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    Mascilini F


    Full Text Available Floriana Mascilini,* Giulia Amadio,* Maria Grazia Di Stefano, Manuela Ludovisi, Alessia Di Legge, Carmine Conte, Rosa De Vincenzo, Caterina Ricci, Valeria Masciullo, Vanda Salutari, Giovanni Scambia, Gabriella FerrandinaGynecologic Oncology Unit, Department of Oncology, Catholic University of Rome, Italy  *These authors contributed equally to this work Abstract: Among the pharmaceutical options available for treatment of ovarian cancer, attention has been increasingly focused on trabectedin (ET-743, a drug which displays a unique mechanism of action and has been shown to be active in several human malignancies. Currently, single agent trabectedin is approved for treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, and in association with pegylated liposomal doxorubicin for treatment of patients with relapsed partially platinum-sensitive ovarian cancer. This review aims at summarizing the available evidence about the clinical role of trabectedin in the management of patients with epithelial ovarian cancer. Novel perspectives coming from a better understanding of trabectedin mechanisms of action and definition of patients subgroups likely susceptible to benefit of trabectedin treatment are also presented. Keywords: ET-743, ovarian cancer, clinical trials

  4. DNA sequence-dependent fluorescence of doxorubicin for turn-on detection of biothiols in human serum. (United States)

    Chen, Xing; Jiang, Guimei; Wang, Zhili; Hong, Shanni; Zhang, Yuanyuan; Guo, Yahui; Cheng, Hui; Wang, Jine; Pei, Renjun


    Doxorubicin (Dox) is a DNA-targeting anthracycline antibiotic active against a wide spectrum of cancers. The interaction between Dox and double-stranded DNA (dsDNA) was used to load Dox using DNA duplexes as carriers. More importantly, the interesting DNA sequence-dependent fluorescence response of Dox could be exploited in the design of efficient Dox release systems and efficient fluorescence sensors. In this work, we demonstrated that separate introduction of G and C bases into T-rich single-stranded DNA (ssDNA) sequences afforded the best discrimination of Dox binding between dsDNA and ssDNA. For the first time, we successfully utilized this interesting DNA sequence-dependent fluorescence response of Dox as a signal transduction mechanism for the sensitive detection of biothiols in human serum. Cysteine, homocysteine, and glutathione were detected at as low as 26 nM, 37 nM, and 29 nM, respectively. The biosensors exhibited not only good selectivity, stability, and sensitivity in aqueous solutions but also a sensitive response in human serum, demonstrating their potential for diagnosis.

  5. Radiation-associated valvular heart disease. (United States)

    Ong, Daniel S; Aertker, Robert A; Clark, Alexandra N; Kiefer, Todd; Hughes, G Chad; Harrison, J Kevin; Bashore, Thomas M


    Therapeutic ionizing radiation, such as that used in the treatment of Hodgkin's lymphoma, can cause cardiac valvular damage that may take several years to manifest as radiation-associated valvular heart disease. Treatment can be complicated by comorbid radiation injury to other cardiac and mediastinal structures that lead to traditional surgical valve replacement or repair becoming high-risk. A representative case is presented that demonstrates the complexity of radiation-associated valvular heart disease and its successful treatment with percutaneous transcatheter valve replacement. The prevalence and pathophysiologic mechanism of radiation-associated valvular injury are reviewed. Anthracycline adjuvant therapy appears to increase the risk of valvular fibrosis. Left-sided heart valves are more commonly affected than right-sided heart valves. A particular pattern of calcification has been noted in some patients, and experimental data suggest that radiation induction of an osteogenic phenotype may be responsible. A renewed appreciation of the cardiac valvular effects of therapeutic ionizing radiation for mediastinal malignancies is important, and the treatment of such patients may be assisted by the development of novel, less-invasive approaches.

  6. Progress in adjuvant chemotherapy for breast cancer: an overview. (United States)

    Anampa, Jesus; Makower, Della; Sparano, Joseph A


    Breast cancer is the most common cause of cancer and cancer death worldwide. Although most patients present with localized breast cancer and may be rendered disease-free with local therapy, distant recurrence is common and is the primary cause of death from the disease. Adjuvant systemic therapies are effective in reducing the risk of distant and local recurrence, including endocrine therapy, anti-HER2 therapy, and chemotherapy, even in patients at low risk of recurrence. The widespread use of adjuvant systemic therapy has contributed to reduced breast cancer mortality rates. Adjuvant cytotoxic chemotherapy regimens have evolved from single alkylating agents to polychemotherapy regimens incorporating anthracyclines and/or taxanes. This review summarizes key milestones in the evolution of adjuvant systemic therapy in general, and adjuvant chemotherapy in particular. Although adjuvant treatments are routinely guided by predictive factors for endocrine therapy (hormone receptor expression) and anti-HER2 therapy (HER2 overexpression), predicting benefit from chemotherapy has been more challenging. Randomized studies are now in progress utilizing multiparameter gene expression assays that may more accurately select patients most likely to benefit from adjuvant chemotherapy.

  7. Eribulin for the treatment of metastatic breast cancer: an update on its safety and efficacy

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    Doherty MK


    Full Text Available Mark K Doherty, Patrick G Morris Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland Abstract: Breast cancer remains a leading cause of cancer-related death internationally. Treatment approaches for metastatic breast cancer have evolved in recent years; however chemotherapy remains a core component for the majority of patients. Agents such as anthracyclines and taxanes have been extensively studied and form standard treatment. Eribulin mesylate is a novel synthetic microtubule-directed chemotherapy, based on a naturally-occurring compound. Through phase I studies, eribulin was found to be tolerable and activity was seen in patients with metastatic breast cancer. Phase II studies in metastatic breast cancer further demonstrated its efficacy, with responses and survival which compare favorably with other studied chemotherapy agents. The phase III EMBRACE study showed superior survival for patients treated with eribulin compared with those who received a physician’s choice control. This led to its approval for use in many countries in this setting. Its toxicity profile is well established and manageable for the most part, with the commonest reported toxicities being alopecia, fatigue, neutropenia and peripheral neuropathy. A second reported phase III study comparing eribulin to capecitabine failed to show an improvement in survival in pretreated patients. This article reviews the clinical pharmacology and mechanism of action of eribulin, and summarizes the results of the major preclinical and clinical studies of eribulin in metastatic breast cancer. Keywords: eribulin, breast cancer, metastatic breast cancer, review, new treatments, chemotherapy


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    Ramzi Jeddi


    Full Text Available In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens combining ATRA and an anthracycline with cytarabine (APL93, and without cytarabine (LPA99. From 2004, 51 patients with confirmed APL either by t(15;17 or PML/RARA were treated according to the PETHEMA LPA 99 trial. Forty three patients achieved CR (86%. The remaining seven patients had early death (one died before treatment onset: four caused by differentiation syndrome (DS and three died from central nervous system hemorrhage. Multivariate analysis revealed that female gender (P=0.045, baseline WBC> 10 G/L ( P=0.041 and serum creatinine > 1.4mg/dl ( P=0.021 were predictive of mortality during induction. DS was observed in 16 patients (32% after a median onset time of 15 days from treatment onset (range, 2–29. Body mass index ≥ 30 (P=0.01 was the only independent predictor of DS. Occurrence of hypertensive peaks significantly predicted occurrence of DS (P=0.011 and was significantly associated with high BMI (p=0.003. With a median follow-up of 50 months, 5 year cumulative incidence of relapse, event free and overall survival were 4.7%, 74% and 78%, respectively.

  9. Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs. (United States)

    Fanciullino, Raphaelle; Ciccolini, Joseph; Milano, Gérard


    Improving the efficacy-toxicity balance of anticancer agents remains an ongoing challenge in oncology. Beside the ever-growing development of innovative drugs addressing newly discovered molecular targets, nanotechnologies provide today a promising and exciting strategy to achieve this goal. The idea of carrying active compounds to their respective targets so as to improve their efficacy while sparing healthy tissue and reducing side-effects is not new. However, this area of research is in constant rise, and benefits from the latest advances in the field of biopharmaceutics, medicinal chemistry and nanomedicine. In addition to anthracyclines already widely present as liposomal drugs on the shelves, a variety of anticancer drugs can be now encapsulated into different chemical of structures so as to enhance their specificity toward malignant cells, mainly through improved pharmacokinetics profiles. Indeed, the recent advances in chemistry allow now a wide variety of scaffolds to be used as drug-carriers, so as optimize the delivery of cytotoxics. Even more recently, conjugated-drugs such as nanoalbumin (Nab) conjugates have emerged as a new promising alternative to improve both anticancer drugs distribution in the body and efficacy/toxicity balance eventually. This review covers the achievements and current limits of nanoparticles in oncology, with a special focus on nab-paclitaxel as a paradigmatic drug for this new generation of conjugated entities.

  10. Anti-Müllerian hormone in breast cancer patients treated with chemotherapy: a retrospective evaluation of subsequent pregnancies. (United States)

    Hamy, Anne-Sophie; Porcher, Raphaël; Eskenazi, Sarah; Cuvier, Caroline; Giacchetti, Sylvie; Coussy, Florence; Hocini, Hamid; Tournant, Bertrand; Perret, Francine; Bonfils, Sylvie; Charvériat, Patrick; Lacorte, Jean-Marc; Espie, Marc


    Few studies have reported reproductive outcomes after breast cancer chemotherapy. The relationship between anti-Müllerian hormone (AMH) concentrations and the occurrence of subsequent pregnancies in women after chemotherapy for breast cancer was investigated. Women aged 18-43 years treated with chemotherapy for invasive breast cancer between May 2005 and January 2011 were retrospectively identified. Exclusion criteria were previous gonadotoxic treatment, oophorectomy or hysterectomy. Measurement of AMH took place before, during chemotherapy and at distant time points after the end of chemotherapy (4 months to 5.5 years). Seventeen out of 134 patients experienced 28 spontaneous pregnancies (median follow-up: 59 months). Neither baseline AMH (divided into quartiles) nor end-of-chemotherapy AMH (detectable versus undetectable) were significantly associated with the occurrence of pregnancy. Chemotherapy regimen with anthracyclines was associated with a greater probability of pregnancy compared with a taxane-containing regimen (hazard ratio 4.75; (95% CI 1.76 to 12.8); P = 0.002). Five-year disease-free survival and overall survival rates were 60% (95% CI: 51 to 70; relapse, n = 48) and 88% (95% CI 82 to 95; deaths, n = 21), respectively. AMH did not predict the occurrence of pregnancy. Additional studies assessing ovarian reserve and reproductive outcomes after breast cancer are required.

  11. Clinical outcomes of HER2-positive metastatic breast cancer patients with brain metastasis treated with lapatinib and capecitabine: an open-label expanded access study in Korea

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    Ro Jungsil


    Full Text Available Abstract Background To evaluate efficacy in patients with brain metastasis (BM on entry into the lapatinib expanded access program (LEAP. Methods LEAP is a worldwide, single-arm, open-label study. HER2-positive, locally-advanced or metastatic breast cancer patients with progression after an anthracycline, taxane, and trastuzumab were eligible. Patients received capecitabine 2000 mg/m2 daily in two divided doses, days 1–14, every 21 days and lapatinib 1250 mg once daily. Results Among 186 patients enrolled in 6 Korean centers, 58 had BM. Progression-free survival (PFS was 18.7 weeks in patients with BM and 19.4 weeks without BM (P = 0.88. In patients with BM, brain response was synchronized with systemic responses (P = 0.0001. Overall survival (OS was 48.9 weeks in patients with BM and 64.6 weeks without BM (P = 0.23. Multivariable analysis found hormone receptor positivity (P = 0.003 and clinical benefit rate (CBR of combined systemic and brain disease (P  Conclusion Lapatinib plus capecitabine is equally effective in patients with or without BM. Trial registration (NCT00338247

  12. Angioimmunoblastic T-Cell Lymphoma: A Diagnostic Challenge (United States)

    Ocampo-Garza, Jorge; Herz-Ruelas, Maira Elizabeth; González-Lopez, Elias Eugenio; Mendoza-Oviedo, Eric Eduardo; Garza-Chapa, Juana Irma; Ocampo-Garza, Sonia Sofía; Vázquez-Herrera, Norma Elizabeth; Miranda-Maldonado, Ivett; Ocampo-Candiani, Jorge


    Angioimmunoblastic T-cell lymphoma (AITL) accounts for 15–20% of all peripheral T-cell lymphomas. It is a rare subtype of CD4 T-cell peripheral lymphoma that affects aged individuals, causing B symptoms, generalized lymphadenopathy and hepatosplenomegaly. Its pathogenesis is still unclear, but in some cases it has been associated with infection, allergic reaction or drug exposure. The majority of patients are diagnosed in an advanced stage and anthracycline based regimen is considered the first-line therapy. Skin involvement is not well characterized, occurring in up to 50% of patients and presenting as nonspecific rash, macules, papules, petechiae, purpura, nodules and urticaria. We present the illustrative case of a 55-year-old woman with an AITL who presented prominent skin findings, arthritis, lymphadenopathy and hypereosinophilia. Skin biopsy reported a T-cell lymphoma and the diagnosis of AITL was confirmed by an axillary lymph node biopsy, which was also positive for Epstein-Barr virus. Chemotherapy with CHOP-21 and thalidomide was given, accomplishing complete remission after six cycles. PMID:25685133

  13. Multifunctional materials for bone cancer treatment

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    Marques C


    Full Text Available Catarina Marques,1 José MF Ferreira,1 Ecaterina Andronescu,2 Denisa Ficai,2 Maria Sonmez,3 Anton Ficai21Department of Materials and Ceramics Engineering, Centre for Research in Ceramics and Composite Materials, University of Aveiro, Aveiro, Portugal; 2Faculty of Applied Chemistry and Material Science, University Politehnica of Bucharest, Bucharest, Romania; 3National Research and Development Institute for Textiles and Leather, Bucharest, RomaniaAbstract: The purpose of this review is to present the most recent findings in bone tissue engineering. Special attention is given to multifunctional materials based on collagen and collagen–hydroxyapatite composites used for skin and bone cancer treatments. The multifunctionality of these materials was obtained by adding to the base regenerative grafts proper components, such as ferrites (magnetite being the most important representative, cytostatics (cisplatin, carboplatin, vincristine, methotrexate, paclitaxel, doxorubicin, silver nanoparticles, antibiotics (anthracyclines, geldanamycin, and/or analgesics (ibuprofen, fentanyl. The suitability of complex systems for the intended applications was systematically analyzed. The developmental possibilities of multifunctional materials with regenerative and curative roles (antitumoral as well as pain management in the field of skin and bone cancer treatment are discussed. It is worth mentioning that better materials are likely to be developed by combining conventional and unconventional experimental strategies.Keywords: bone graft, cancer, collagen, magnetite, cytostatics, silver

  14. Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin. (United States)

    Ikezoe, Takayuki


    Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia characterized by the proliferation of blasts with distinct morphology, a specific balanced reciprocal translocation t(15;17), and life-threatening hemorrhage caused mainly by enhanced fibrinolytic-type disseminated intravascular coagulation (DIC). The introduction of all-trans retinoic acid (ATRA) into anthracycline-based induction chemotherapy regimens has dramatically improved overall survival of individuals with APL, although hemorrhage-related death during the early phase of therapy remains a serious problem. Moreover, population-based studies have shown that the incidence of early death during induction chemotherapy is nearly 30 %, and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required. Recombinant human soluble thrombomodulin (rTM) comprises the active extracellular domain of TM, and has been used for treatment of DIC since 2008 in Japan. Use of rTM in combination with remission induction chemotherapy, including ATRA, produces potent resolution of DIC without exacerbation of bleeding tendency in individuals with APL. This review article discusses the pathogenesis and features of DIC caused by APL, as well as the possible anticoagulant and anti-leukemic action of rTM in APL patients.

  15. Combination of Cladribine plus Topotecan for Relapsed or Refractory Pediatric Acute Myeloid Leukemia (United States)

    Inaba, Hiroto; Stewart, Clinton F.; Crews, Kristine R.; Yang, Shengping; Pounds, Stanley; Pui, Ching-Hon; Rubnitz, Jeffrey E.; Razzouk, Bassem I.; Ribeiro, Raul C.


    BACKGROUND The prognosis after relapse of pediatric acute myeloid leukemia (AML) is poor and effective salvage regimens are urgently needed. METHODS In Phase I and pilot studies, we evaluated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a 5-day course of cladribine (2-CDA) followed by topotecan in pediatric patients with relapsed/refractory AML. The 2-CDA dose was escalated as follows: 9.1, 13.6, 16.3, and 19.5 mg/m2 per day (8.9 mg/m2 per day in the pilot study). Outcome was analyzed according to the absence (stratum 1) vs. presence (stratum 2) of previous allogeneic hematopoietic stem cell transplantation. Twenty-six patients (20 in stratum 1, 6 in stratum 2) were treated. RESULTS The MTD was not reached in stratum 1, but DLT occurred at the lowest 2-CDA dosage (9.1 mg/m2 per day) in stratum 2. Febrile neutropenia was common in both strata. Nine (34.6%) of 26 patients experienced a complete response and 7 (30.4%) had a partial response; 5 (19.2%) are long-term survivors. Clinical outcome was not associated with 2-CDA or topotecan systemic exposure. CONCLUSION The combination was well tolerated in stratum 1, and the response rate is encouraging. This regimen offers a post-relapse treatment alternative for patients, especially those who have received anthracycline-containing chemotherapy. PMID:19885837

  16. Bayesian network meta-analysis comparing five contemporary treatment strategies for newly diagnosed acute promyelocytic leukaemia. (United States)

    Wu, Fenfang; Wu, Di; Ren, Yong; Duan, Chongyang; Chen, Shangwu; Xu, Anlong


    Acute promyelocytic leukemia (APL) is a curable subtype of acute myeloid leukemia. The optimum regimen for newly diagnosed APL remains inconclusive. In this Bayesian network meta-analysis, we compared the effectiveness of five regimens-arsenic trioxide (ATO) + all-trans retinoic acid (ATRA), realgar-indigo naturalis formula (RIF) which contains arsenic tetrasulfide + ATRA, ATRA + anthracycline-based chemotherapy (CT), ATO alone and ATRA alone, based on fourteen randomized controlled trials (RCTs), which included 1407 newly diagnosed APL patients. According to the results, the ranking efficacy of the treatment, including early death and complete remission in the induction stage, was the following: 1. ATO/RIF + ATRA; 2. ATRA + CT; 3. ATO, and 4. ATRA. For long-term benefit, ATO/RIF + ATRA significantly improved overall survival (OS) (hazard ratio = 0.35, 95%CI 0.15-0.82, p = 0.02) and event-free survival (EFS) (hazard ratio = 0.32, 95%CI 0.16-0.61, p = 0.001) over ATRA + CT regimen for the low-to-intermediate-risk patients. Thus, ATO + ATRA and RIF + ATRA might be considered the optimum treatments for the newly diagnosed APL and should be recommended as the standard care for frontline therapy.

  17. Dose- and Time-Dependent Response of Human Leukemia (HL-60 Cells to Arsenic Trioxide Treatment

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    Paul B. Tchounwou


    Full Text Available The treatment of acute promyelocytic leukemia (APL has been based on the administration of all-trans retinoic acid plus anthracycline chemotherapy, which is very effective as first line therapy; however 25 to 30% of patients will relapse with their disease becoming refractory to conventional therapy. Recently, studies have shown arsenic trioxide to be effective in the treatment of acute promyelocytic leukemia. In this study, we used the human leukemia (HL-60 cell line as a model to evaluate the cytoxicity of arsenic trioxide based on the MTT assay. Data obtained from this assay indicated that arsenic trioxide significantly reduced the viability of HL-60 cells, showing LD50 values of 14.26 + 0.5μg/mL, 12.54 + 0.3μg/mL, and 6.4 + 0.6μg/mL upon 6, 12, and 24 hours of exposure, respectively; indicating a dose- and time-dependent response relationship. Findings from the present study indicate that arsenic trioxide is highly cytotoxic to human leukemia (HL-60 cells, supporting its use as an effective therapeutic agent in the management of acute promyelocytic leukemia.

  18. High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia. (United States)

    Lucena-Araujo, Antonio R; Kim, Haesook T; Thomé, Carolina; Jacomo, Rafael H; Melo, Raul A; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Glória, Ana Beatriz F; Chauffaille, Maria de Lourdes; Athayde, Melina; Chiattone, Carlos S; Mito, Ingrid; Bendlin, Rodrigo; Souza, Carmino; Bortolheiro, Cristina; Coelho-Silva, Juan L; Schrier, Stanley L; Tallman, Martin S; Grimwade, David; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C; Lo-Coco, Francesco; Löwenberg, Bob; Sanz, Miguel A; Rego, Eduardo M


    The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.

  19. Cross-resistance of an amsacrine-resistant human leukemia line to topoisomerase II reactive DNA intercalating agents. Evidence for two topoisomerase II directed drug actions

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    Zwelling, L.A.; Mayes, J.; Hinds, M.; Chan, D.; Altschuler, E.; Carroll, B.; Parker, E.; Deisseroth, K.; Radcliffe, A.; Seligman, M.; Li, Li; Farquhar, D. (Univ. of Texas M.D. Anderson Cancer Center, Houston (USA))


    HL-60/AMSA is a human leukemia cell line that is 50-100-fold more resistant than its drug-sensitive HL-60 parent line to the cytotoxic actions of the DNA intercalator amsacrine (m-AMSA). HL-60/AMSA topoisomerase II is also resistant to the inhibitory actions of m-AMSA. HL-60/AMSA cells and topoisomerase II are cross-resistant to anthracycline and ellipticine intercalators but relatively sensitive to the nonintercalating topoisomerase II reactive epipodophyllotoxin etoposide. The authors now demonstrate that HL-60/AMSA and its topoisomerase II are cross-resistant to the DNA intercalators mitoxantrone and amonafide, thus strongly indicating that HL-60/AMSA and its topoisomerase II are resistant to topoisomerase II reactive intercalators but not to nonintercalators. At high concentrations, mitoxantrone and amonafide were also found to inhibit their own, m-AMSA's, and etoposide's abilities to stabilize topoisomerase II-DNA complexes. These results suggest that the cytotoxicity of m-AMSA and etoposide is initiated primarily by the stabilization of the topoisomerase II-DNA complex. Other topoisomerase II reactive drugs may inhibit the enzyme at other steps in the topoisomerization cycle, particularly at elevated concentrations. Under these conditions, these latter drugs may not produce protein-associated DNA cleavage while still inhibiting topoisomerase II function as well as the actions of other topoisomerase II reactive drugs.

  20. Applications of ultrasound to veterinary diagnostics in a veterinary teaching hospital. (United States)

    Miller, C W; Wingfield, W E; Boon, J A


    Animal patients at Colorado State University's Veterinary Teaching Hospital as well as beagles at the Collaborative Radiological Health Laboratory (CRHL) have been routinely evaluated using a variety of ultrasonic procedures that are commonplace in human medicine. The results from these clinical investigations have provided diagnostic information which in many cases has not been available using other clinical testing methods. Dogs, cats, horses, and cattle have been the primary animals evaluated, but more exotic subjects such as rabbits, ferrets, goats, and armadillos have also been examined. Standard M mode echocardiographic and classic contact scanning have been used to evaluate the heart and abdominal-pelvic areas respectively. Recently, real time scanning has been added to our capabilities for evaluating animal subjects. These clinical studies, while obviously adding to veterinary diagnostics have also become an exciting new area in the veterinary teaching program. Ultrasound has shown potential in a variety of studies employing animal models, i.e., aging effects on the heart in beagles and anthracycline-induced myocardial dysfunction in rabbits.

  1. Costs Associated with Intravenous Cancer Therapy Administration in Patients with Metastatic Soft Tissue Sarcoma in a US Population

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    Mei Sheng Duh


    Full Text Available Background. The most common chemotherapies in metastatic soft tissue sarcoma (mSTS require intravenous (IV administration. This often requires patients to make multiple outpatient visits per chemotherapy cycle, possibly impeding patients’ daily activities and increasing caregiver burden and medical costs. This study investigated costs associated with IV cancer therapy administration in mSTS from the payer perspective of the health care system. Patients and Methods. From the Experian Healthcare database, 1,228 mSTS patients were selected. Data were analyzed on outpatient visits during 2005–2012 involving IV cancer therapy administration. Costs were estimated on a per patient per visit (PPPV and per patient per month (PPPM basis. Results. The mean (median cost of IV therapy was $2,427 ($1,532 PPPV and $5,468 ($4,310 PPPM, of which approximately 60% was IV drug costs. IV administration costs averaged $399 PPPV and $900 PPPM, representing 16.5% of total visit costs. Anthracycline and alkylating-agents-based therapies had the highest PPPV and PPPM IV administration costs, respectively (mean $479 and $1,336, resp.. Patients with managed care insurance had the highest IV administration costs (mean $504 PPPV; $1,120 PPPM. Conclusions. IV administration costs constitute a considerable proportion of the total costs of receiving an IV cancer therapy to treat mSTS.

  2. A novel method to load topotecan into liposomes driven by a transmembrane NH₄EDTA gradient. (United States)

    Yang, Yuehui; Ma, Yanling; Wang, Shaoning


    Antitumor drugs not only cause cytocidal effect on cancer cells, but also damage on normal healthy tissues, resulting in side effects. Liposome encapsulation can result in reduced systematic distribution due to the enhanced permeability and retention (EPR) effect, accompanied by drug accumulation in liver, spleen, and other immune organs, which can cause damage to those organs. It has been demonstrated that EDTA, frequently used as a chelator, possesses a synergistic antitumor effect. Indeed, our previous study showed that EDTA could reduce the toxicity of anthracyclines to the heart and immune organs. In this study, we intended to encapsulate topotecan within liposome adopting transmembrane NH(4)EDTA gradient in order to increase the antitumor activity and decrease the toxicity against normal immune organs. Regarding the encapsulation efficiency of topotecan liposomes, both the pH value of the buffer and the cholesterol content showed significant effects on encapsulation and drug retention. Liposome encapsulation dramatically increased the antitumor activity of topotecan compared to free drug (pgradient or a (NH(4))(2)SO(4) gradient (tumor inhibition ratios were 85.6% and 84.1%, respectively). However, a significant decrease in toxicity against the immune organs was found in liposomes prepared by a NH(4)EDTA gradient compared to those prepared by a (NH(4))(2)SO(4) gradient. These results suggest the superiority of the proposed gradient for topotecan encapsulation in decreasing its toxicity on immune systems.

  3. Apoptosis-based therapy to treat pulmonary arterial hypertension (United States)

    Suzuki, Yuichiro J.; Ibrahim, Yasmine F.; Shults, Nataliia V.


    Pulmonary arterial hypertension (PAH) is rare, but patients who are diagnosed with this disease still suffer from a lack of satisfactory treatment strategies to prolong survival. While currently approved drugs for PAH have some benefits, these vasodilators only have limited efficacy for eliminating pulmonary vascular remodeling and reducing mortality. Thus, our laboratory has been exploring the use of aggressive drugs, which are capable of causing apoptotic cell death, to treat PAH. We have so far found that three classes of anti-tumor agents, including anthracyclines, taxanes, and proteasome inhibitors, are capable of reducing pulmonary vascular thickness in rats with PAH. These drugs kill cells in remodeled pulmonary vessels without affecting the normal, healthy pulmonary vasculature, revealing that proliferating vascular cells in PAH patients are more sensitive to drug-induced apoptosis compared to the differentiated phenotype that is physiologically important for smooth muscle contraction. Since many apoptosis-inducing drugs cause cardiotoxicity in cancer patients, and because PAH patients already have a weakened heart, we focus on finding biological mechanisms that may reverse pulmonary vascular remodeling without promoting cardiotoxicity. We found two agents, dexrazoxane and pifithrin-α, that selectively inhibit cardiac muscle apoptosis without affecting the drug-induced apoptosis of the proliferating pulmonary vascular cells. Thus, we propose that the addition of apoptosis-inducing drugs and cardioprotectants to PAH therapies may be effective in treating patients and preventing right heart failure.

  4. Low-density lipoprotein peptide-combined DNA nanocomplex as an efficient anticancer drug delivery vehicle. (United States)

    Zhang, Nan; Tao, Jun; Hua, Haiying; Sun, Pengchao; Zhao, Yongxing


    DNA is a type of potential biomaterials for drug delivery due to its nanoscale geometry, loading capacity of therapeutics, biocompatibility, and biodegradability. Unfortunately, DNA is easily degraded by DNases in the body circulation and has low intracellular uptake. In the present study, we selected three cationic polymers polyethylenimine (PEI), hexadecyl trimethyl ammonium bromide (CTAB), and low-density lipoprotein (LDL) receptor targeted peptide (RLT), to modify DNA and improve the issues. A potent anti-tumor anthracycline-doxorubicin (DOX) was intercalated into DNA non-covalently and the DOX/DNA was then combined with PEI, CTAB, and RLT, respectively. Compact nanocomplexes were formed by electrostatic interaction and could potentially protect DNA from DNases. More importantly, RLT had the potential to enhance intracellular uptake by LDL receptor mediated endocytosis. In a series of in vitro experiments, RLT complexed DNA enhanced intracellular delivery of DOX, increased tumor cell death and intracellular ROS production, and reduced intracellular elimination of DOX. All results suggested that the easily prepared and targeted RLT/DNA nanocomplexes had great potential to be developed into a formulation for doxorubicin with enhanced anti-tumor activity.

  5. Therapeutic uses of topotecan for thoracic malignancies

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    Saoirse O. Dolly


    Full Text Available Topotecan, a topoisomerase 1 inhibitor (topo1-i, is a semi-synthetic derivative of camptothecan with wellestablished cytotoxic properties. It is licensed for the treatment of relapsed, sensitive small cell lung cancer (SCLC and for second line treatment in ovarian cancer. Studies have also shown this drug to be an effective first line treatment for SCLC with either cisplatin or in combination with a topoisomerase 2 inhibitor (topo2-i, etoposide; both combinations have shown similar efficacy. Oral and parenteral formulations of topotecan have proven to be equivocal in relapsed SCLC patients. The parenteral form showed reduced rates of severe haematological toxicities and better symptom control than an anthracycline combination (CAV. In relapsed SCLC, a randomised phase III trial of oral topotecan versus best supportive care showed a statistically significant increase in overall survival. In the second line treatment of non-small cell lung cancer (NSCLC, oral topotecan was not inferior to the current standard iv docetaxel for 1 year survival rates. Worthwhile potential investigations include combining oral topotecan with other oral agents to design treatments for different lines of therapy. The new oral formulation of topotecan also lends itself to testing with small molecule tyrosine kinase inhibitors. The myelosuppressive toxicity profile needs to be vigorously monitored and managed. The trials with oral topotecan have also highlighted the need to reassess the utility of the terms ‘sensitive’ and ‘resistant’ in the selection of patients with relapsed small cell lung cancer.

  6. 3D collagen type I matrix inhibits the antimigratory effect of doxorubicin

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    Millerot-Serrurot Emilie


    Full Text Available Abstract Background The cell microenvironment, especially extracellular matrix proteins, plays an important role in tumor cell response to chemotherapeutic drugs. The present study was designed to investigate whether this microenvironment can influence the antimigratory effect of an anthracycline drug, doxorubicin, when tumor cells are grown in a matrix of type I collagen, a three-dimensional (3D context which simulates a natural microenvironment. Methods To this purpose, we studied the migratory parameters, the integrin expression, and the activation state of focal adhesion kinase (FAK and GTPase RhoA involved in the formation of focal adhesions and cell movement. These parameters were evaluated at non toxic concentrations which did not affect HT1080 cell proliferation. Results We show that while doxorubicin decreased cell migration properties by 70% in conventional two-dimensional (2D culture, this effect was completely abolished in a 3D one. Regarding the impact of doxorubicin on the focal adhesion complexes, unlike in 2D systems, the data indicated that the drug neither affected β1 integrin expression nor the state of phosphorylation of FAK and RhoA. Conclusion This study suggests the lack of antiinvasive effect of doxorubicin in a 3D environment which is generally considered to better mimic the phenotypic behaviour of cells in vivo. Consistent with the previously shown resistance to the cytotoxic effect in a 3D context, our results highlight the importance of the matrix configuration on the tumor cell response to antiinvasive drugs.

  7. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. (United States)

    Apetoh, Lionel; Ghiringhelli, François; Tesniere, Antoine; Criollo, Alfredo; Ortiz, Carla; Lidereau, Rosette; Mariette, Christophe; Chaput, Nathalie; Mira, Jean-Paul; Delaloge, Suzette; André, Fabrice; Tursz, Thomas; Kroemer, Guido; Zitvogel, Laurence


    For the last four decades, the treatment of cancer has relied on four treatment modalities, namely surgery, radiotherapy, cytotoxic chemotherapy, and hormonotherapy. Most of these therapies are believed to directly attack and eradicate tumor cells. The emerging concept that cancer is not just a disease of a tissue or an organ but also a host disease relies on evidence of tumor-induced immunosuppression and polymorphisms in genes involved in host protection against tumors. This theory is now gaining new impetus, based on our recent data showing that optimal therapeutic effects require the immunoadjuvant effect of tumor cell death induced by cytotoxic anticancer agents. Here, we show that the release of the high mobility group box 1 protein (HMGB1) by dying tumor cells is mandatory to license host dendritic cells (DCs) to process and present tumor antigens. HMGB1 interacts with Toll-like receptor 4 (TLR4) on DCs, which are selectively involved in the cross-priming of anti-tumor T lymphocytes in vivo. A TLR4 polymorphism that affects the binding of HMGB1 to TLR4 predicts early relapse after anthracycline-based chemotherapy in breast cancer patients. This knowledge may be clinically exploited to predict the immunogenicity and hence the efficacy of chemotherapeutic regimens.

  8. Meta-Analysis of Therapeutic Efficacy and Safety of Capecitabine plus Docetaxel and Epirubicin plus Docetaxel in Treatment of Metastatic Breast Cancer%卡培他滨或表柔比星联合多西他赛治疗转移性乳腺癌的疗效与安全性Meta分析

    Institute of Scientific and Technical Information of China (English)

    高靓; 郑晓辉; 赵振营; 史桂玲; 张惠娟


    Objective To systematically evaluate the clinical effect and safety of capecitabine plus docetaxel in the treatment of the pa-tients with anthracycline-failed metastatic breast cancer. Methods The English databases of Medline, Embase, Pubmed, Cochrane library and the Chinese databases of CNKI, VIP, Wanfang were retrieved by computer. The randomized controlled trials ( RCTs ) on the combina-tion therapy of capecitabine plus docetaxel in the anthracycline-failed patients with metastatic breast cancer were included. The retrieval cut-off date was up to December 2013. The retrieval was limited to English and Chinese languages. The methodological quality of the included RCTs was evaluated by the Cochrane system evaluation method. After extracting the effective data, the RevMan 5. 0 software was applied for conducting the meta-analysis on the objective response rate ( ORR ) , stable disease ( SD ) , time to progression ( TTP ) and adverse events. Results 4 RCTs involving 419 patients were included. The meta-analysis results showed that capecitabine plus docetaxel and epirubicin plus docetaxel for treating anthracycline-failed metastatic breast cancer had no obvious differences in ORR [ RR=1. 17, 95% CI(0. 98, 1. 39),P=0. 08], SD[ RR=0. 79,95% CI(0. 58,1. 08),P=0. 14] and TTP[ RR=1. 11,95% CI(0. 92, 1. 33),P<0. 28], indicating that the efficacy of the two regimens was similar. The meta-analysis showed that the adverse reactions of capecitabine were hand-foot syndrome, anemia, nausea, vomiting as well as myalgia with statistical significance ( P<0. 01 );in which the RR value revealed that the occurrence rate of the hand-foot syndrome in the capecitabine group was greater than that in the non-capecitabine group, but the RR< 1 in anemia, vomiting, nausea and myalgia, which revealing that their occurrence rates in the epirubicin group were greater;other adverse reactions had no statistical significance. Conclusion Capecitabine plus docetaxel and epirubicin plus docetaxel have

  9. Mitoxantrone-Surfactant Interactions: A Physicochemical Overview

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    Mirela Enache


    Full Text Available Mitoxantrone is a synthetic anticancer drug used clinically in the treatment of different types of cancer. It was developed as a doxorubicin analogue in a program to find drugs with improved antitumor activity and decreased cardiotoxicity compared with the anthracyclines. As the cell membrane is the first barrier encountered by anticancer drugs before reaching the DNA sites inside the cells and as surfactant micelles are known as simple model systems for biological membranes, the drugs-surfactant interaction has been the subject of great research interest. Further, quantitative understanding of the interactions of drugs with biomimicking structures like surfactant micelles may provide helpful information for the control of physicochemical properties and bioactivities of encapsulated drugs in order to design better delivery systems with possible biomedical applications. The present review describes the physicochemical aspects of the interactions between the anticancer drug mitoxantrone and different surfactants. Mitoxantrone-micelle binding constants, partitions coefficient of the drug between aqueous and micellar phases and the corresponding Gibbs free energy for the above processes, and the probable location of drug molecules in the micelles are discussed.

  10. Phytochemicals that counteract the cardiotoxic side effects of cancer chemotherapy

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    Anita Piasek


    Full Text Available Almost all clinically used antitumor drugs exhibit toxic side effects affecting heart function. Because of cardiotoxicity during anticancer chemotherapy, effective doses of cytostatics have to be limited, which may worsen antitumor efficacy. The cardiotoxicity induced by cytostatics of the anthracycline group in particular results, among others, from massive stimulation of ROS. It has therefore been suggested that some phytochemicals with high antioxidant potential, when administered together with antitumor agents, could decrease the toxic side effects of chemotherapy and reduce the risk of heart failure. This review summarizes findings of studies undertaken to identify edible plants or phytochemicals isolated from them displaying cardioprotective properties during chemotherapy. Such properties have been shown for such foods as grapes, garlic, tomato, spinach, and beetroot. A protective role on the heart is also displayed by melatonin (a hormone synthesized by the pineal gland, but also present in many edible plants, chalcones (precursors of all known flavonoids, some herbal dietary supplements, vitamins A, C, and E, selenium, and semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER. Although to date only a limited number of investigations have been carried out, their results suggest that dietary intervention with antioxidants found in edible plants may be a safe and effective way of alleviating the toxicity of anticancer chemotherapy and preventing heart failure.

  11. Antivasoconstrictor effect of the neuroprotective agent dexrazoxane in rat aorta. (United States)

    Vidrio, Horacio; Carrasco, Omar F; Rodríguez, Rodolfo


    Dexrazoxane is used clinically to reduce the cardiotoxicity of anthracycline cancer chemotherapeutic agents, acting by an iron-chelating antioxidant mechanism. In a study designed to explore the possible mechanism of the recently described neuroprotective effect of the drug in cerebral ischemia, its influence on vascular reactivity was determined in rat aortic rings. Dexrazoxane was found to be devoid of direct contractile or relaxant activity and to have no influence on responses to acetylcholine or histamine (relaxation), or to angiotensin or serotonin (contraction). In contrast, it decreased contractions to norepinephrine, as evidenced by rightward displacement of the concentration-response curves. The effect was prevented by the removal of the endothelium and by the alpha(2)-adrenoceptor antagonist yohimbine; it was partially antagonized by the endothelium-derived depolarizing factor inhibitor clotrimazole, but was not affected by L-NAME or indomethacin, inhibitors of endothelial nitric oxide and prostacyclin production. The anti-contractile effect did not occur in rings stimulated with the alpha(1)-adrenoceptor agonist phenylephrine. It was concluded that dexrazoxane opposes norepinephrine vascular contraction by enhancing endothelial alpha(2)-adrenoceptor-mediated release of relaxing factor(s). The drug could thus offset the deleterious vasoconstriction elicited by the increased circulating catecholamines present during cerebral ischemia, and by this mechanism produce neuroprotection.

  12. Impairments that Influence Physical Function among Survivors of Childhood Cancer

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    Carmen L. Wilson


    Full Text Available Children treated for cancer are at increased risk of developing chronic health conditions, some of which may manifest during or soon after treatment while others emerge many years after therapy. These health problems may limit physical performance and functional capacity, interfering with participation in work, social, and recreational activities. In this review, we discuss treatment-induced impairments in the endocrine, musculoskeletal, neurological, and cardiopulmonary systems and their influence on mobility and physical function. We found that cranial radiation at a young age was associated with a broad range of chronic conditions including obesity, short stature, low bone mineral density and neuromotor impairments. Anthracyclines and chest radiation are associated with both short and long-term cardiotoxicity. Although numerous chronic conditions are documented among individuals treated for childhood cancer, the impact of these conditions on mobility and function are not well characterized, with most studies limited to survivors of acute lymphoblastic leukemia and brain tumors. Moving forward, further research assessing the impact of chronic conditions on participation in work and social activities is required. Moreover, interventions to prevent or ameliorate the loss of physical function among children treated for cancer are likely to become an important area of survivorship research.

  13. Management of malignant phyllode tumors of the breast: the experience of the Institut Curie; Prise en charge des tumeurs phyllodes malignes du sein: l'experience de l'Institut Curie

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    Haberer, S.; Kirova, Y.M.; Dendale, R.; Campana, F.; Miranda, O.; Fourquet, A.; Bollet, M.A. [Institut Curie, Dept. de Radiotherapie Oncologique, 75 - Paris (France); Lae, M. [Institut Curie, Dept. de Biologie des Tumeurs, 75 - Paris (France); Seegers, V. [Institut Curie, Dept. de Biostatistiques, 75 - Paris (France); Pierga, J.Y. [Institut Curie, Dept. d' Oncologie Medicale, 75 - Paris (France); Salmon, R.; Reyal, F. [Institut Curie, Dept. de Chirurgie, 75 - Paris (France)


    Purpose Given the scarcity of malignant phyllode tumours of the breast and the absence of consensus regarding their management justify the need for institutional retrospective evaluations of clinical practices. Patients and methods Retrospective study with central pathology review of the 25 consecutive patients treated at the Institut Curie (Paris, France) between 1969 and 2006 for non metastatic malignant phyllodes tumors of the breast. The median follow-up was 65 months (7-257 months). Results Median age at diagnosis was 52 years (20-64 years). Breast surgery was conservative in five patients (20%). Surgical margins were wide (> 10 mm), narrow, involved or unknown in respectively 17 (68%), three (12%), three (12%) and two (8%) patients. Median tumour size was 65 mm (12-250 mm). Adjuvant radiotherapy was delivered in seven (28%) patients (two patients, post tumor-ectomy; five patients, post mastectomy) and 13 patients (52%) received anthracycline-based adjuvant chemotherapy. Five-year overall survival rate was 91% (95% CI, 80-100%). Five patients (20%) developed distant metastases (one after chemotherapy) and three (12%) locoregional relapse (one after tumor-ectomy and unknown margin without radiotherapy, two after mastectomy and involved margins with radiotherapy). Conclusion Wide breast surgery (that can be conservative in selected patients) is the mainstay of the treatment of non metastatic malignant phyllodes tumors of the breast. To better determine the respective roles of adjuvant systemic treatment and radiotherapy, further clinical studies and the search for new prognostic and predictive factors remain necessary. (authors)

  14. The Effect of Mangiferin Against Brain Damage Caused by Oxidative Stress and Inflammation Induced by Doxorubicin

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    Soni Siswanto


    Full Text Available Doxorubicin (DOX is an anthracycline antibiotic used for anticancer therapy. However, this agent can cause various systemic side effects including cognitive impairments in chronic use. Brain damage due to DOX is caused by an increase of tumor necrosis factor-alpha (TNF-α level in the brain. Increased TNF-α can further lead to chronic inflammation which can lead to neuronal deaths or neurodegenerative diseases. Mangiferin (MAG, a compound extracted from Mangifera indica, has been found neuroprotective activities, but its effect on DOX-induced brain damage is unknown. This study aims to determine the effect of MAG on brain damage induced by DOX. Male Sprague-Dawley rats were induced by DOX intraperitoneally. MAG was given orally at the doses of 30 and 60 mg/kg bw for 7 consecutive weeks. The parameters measured were inflammatory and oxidative stress markers in brain tissue. Coadministration of MAG with DOX reduced inflammation which was marked by the reduction of TNF-α mRNA expression, decreased TNF-α level and reduction of oxidative stress marked by increase of superoxide dismutase level and decrease of malondialdehyde level. In conclusion, MAG was shown to have a neuroprotective effect on brain damage induced by DOX, partly due to inhibition of inflammation and oxidative stress.

  15. Rationale and efficacy of proteasome inhibitor combined with arsenic trioxide in the treatment of acute promyelocytic leukemia (United States)

    Ganesan, S; Alex, A A; Chendamarai, E; Balasundaram, N; Palani, H K; David, S; Kulkarni, U; Aiyaz, M; Mugasimangalam, R; Korula, A; Abraham, A; Srivastava, A; Padua, R A; Chomienne, C; George, B; Balasubramanian, P; Mathews, V


    Arsenic trioxide (ATO) mediates PML-RARA (promyelocytic leukemia–retinoic acid receptor-α) oncoprotein degradation via the proteasome pathway and this degradation appears to be critical for achieving cure in acute promyeloytic leukemia (APL). We have previously demonstrated significant micro-environment-mediated drug resistance (EMDR) to ATO in APL. Here we demonstrate that this EMDR could be effectively overcome by combining a proteasome inhibitor (bortezomib) with ATO. A synergistic effect on combining these two agents in vitro was noted in both ATO-sensitive and ATO-resistant APL cell lines. The mechanism of this synergy involved downregulation of the nuclear factor-κB pathway, increase in unfolded protein response (UPR) and an increase in reactive oxygen species generation in the malignant cell. We also noted that PML-RARA oncoprotein is effectively cleared with this combination in spite of proteasome inhibition by bortezomib, and that this clearance is mediated through a p62-dependent autophagy pathway. We further demonstrated that proteasome inhibition along with ATO had an additive effect in inducing autophagy. The beneficial effect of this combination was further validated in an animal model and in an on-going clinical trial. This study raises the potential of a non-myelotoxic proteasome inhibitor replacing anthracyclines in the management of high-risk and relapsed APL. PMID:27560113

  16. [Effect of aclacinomycin A on bone marrow (author's transl)]. (United States)

    Ohmori, K; Shirai, M; Kiyosaki, T; Hori, S; Tone, H


    Japan White rabbits were treated with aclacinomycin A, a new anthracycline antitumor antibiotic, at a dose of 6.25 or 25.0 mg/kg by single intravenous, or 12.5 or 50.0 mg/kg by single oral administration, respectively. Beagle dogs were treated at a dose of 3.0 or 6.0 mg/kg by single intravenous injection. In rabbits in higher dose groups, RBC and WBC counts as well as lymphocyte ratio in peripheral blood decreased on day 1. Nucleated cell counts and erythroid elements in bone marrow decreased to raise M/E ratio (Myeloid/Erythroid ratio) on day 3. In a dog given at 6.0 mg/kg, WBC and platelet counts, lymphocyte and neutrocyte per cents in peripheral blood and also nucleated cells, particularly erythroid elements in bone marrow remarkably decreased on day 3 accompanied with an increase in M/E ratio. These changes were almost completely recovered by day 14 in both animals. No abnormalities were found in lower dose groups. Male Wistar rats, treated with the drug at a dose of 1.5 mg/kg by daily intraperitoneal injection for 30 days, showed slight decreases in peripheral WBC and RBC counts and M/E ratio in bone marrow. No change was observed in rats treated at 0.75 mg/kg and less for 30 days.

  17. [Acute myeloid leukemia originating from the same leukemia clone after the complete remission of acute lymphoid leukemia]. (United States)

    Matsuda, Isao; Nakamaki, Tsuyoshi; Amaya, Hiroshi; Kiyosaki, Masanobu; Kawakami, Keiichiro; Yamada, Kazunari; Yokoyama, Akihiro; Hino, Ken-ichiro; Tomoyasu, Shigeru


    A 22-year-old female was diagnosed as having acute lymphoid leukemia (ALL) in February 1995, from the findings of peroxidase negative, CD10+, CD19+, TdT+ and rearrangement of IgH and TCR beta. AdVP (doxorubicin, vincristine and prednisolone) therapy achieved a complete remission (CR). Bone marrow transplantation had to be abandoned because of the lack of an HLA-identical donor. Intensification therapy was thus carried out repeatedly. In June 1998, myeloblast with Auer rods, peroxidase positive, CD13+, CD33+ and HLA-DR+, appeared. The patient was diagnosed as having lineage switch acute myeloid leukemia (AML) from ALL. Though A-DMP (cytosine arabinoside, daunorubicin, 6-mercaptopurine) therapy was resistant, AdVP therapy led to a CR. The patient died of cardiotoxicity from anthracyclines in February 1999. From the results of the Ramasamy method using the clonal rearrangements of the Ig heavy chain gene locus, the origin of the pathological cells of ALL and AML was indicated to be the same leukemia clone.

  18. Pharmacokinetics and disposition of (2''R)-4'-O-tetrahydropyranyladriamycin in dogs. (United States)

    Iguchi, H; Tone, H; Kiyosaki, T; Ishikura, T; Takeuchi, T; Umezawa, H


    The pharmacokinetics and physiological disposition of a novel anthracyclines, (2''R)-4'-O-tetrahydropyranyladriamycin (THP) were studied in dogs by an HPLC analysis. The THP administered intravenously (1.5 mg/kg) disappeared rapidly from the plasma immediately after an injection of the drug. The plasma level of THP was lowered in a triphasic pattern up to 24 hours and was simulated by a three-compartment open model in which the half-lives of alpha-, beta- and gamma-phase were calculated to be 0.0116 hour, 0.152 hour and 7.02 hours, respectively. The blood cell level of THP was about 10 times as high as the plasma level during the observation. In the study of tissue distribution of THP 2 and 8 hours after the administration, the highest concentration of THP was found in the spleen and lung and these concentrations were diminished quickly. However, in the lymph nodes and bone marrow concentrations of THP increased with a lapse of time. THP and its metabolites were excreted in the bile by 2.7% of dose during 8 hours in the bile-cannulated dogs. Urinary recovery of THP and its metabolites was about 1.3% of the dose up to 72 hours. In these experiment, THP was metabolized to THP-OH and ADM, and to aglycones which were excreted in conjugated forms. The results obtained from a similar study on ADM were compared and discussed.

  19. Cardiac complications after haploidentical HLA-mismatched hematopoietic stem cell transplantation using in vivo alemtuzumab. (United States)

    Oshima, K; Sakata-Yanagimoto, M; Asano-Mori, Y; Izutsu, K; Watanabe, T; Shoda, E; Ogawa, S; Motokura, T; Chiba, S; Kurokawa, M; Hirai, H; Kanda, Y


    Alemtuzumab is a humanized monoclonal antibody directed against human CD52 with a strong lympholytic effect. We have performed unmanipulated hematopoietic stem cell transplantation (HSCT) from 2- or 3-locus-mismatched family donors in 14 patients using in vivo alemtuzumab. All achieved complete donor cell engraftment and grade III-IV acute graft-versus-host disease was observed in only one patient. However, eight of the 14 patients developed grade II-IV cardiac complications according to Bearman's criteria. Next, we retrospectively analyzed the records of 142 adult patients who underwent allogeneic HSCT from 1995 to 2004 to evaluate whether the use of alemtuzumab was an independent risk factor for cardiac complications. Among several factors that increased the incidence of grade II-IV cardiac complications with at least borderline significance, a multivariate analysis identified the cumulative dose of anthracyclines (P=0.0016) and the use of alemtuzumab (P=0.0001) as independent significant risk factors. All of the cardiac complications in the alemtuzumab group were successfully treated with diuretics and/or catecholamines. Patient selection and close monitoring of cardiac function may be important in HLA-mismatched HSCT using in vivo alemtuzumab.

  20. Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast.

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    Zoey Tay

    Full Text Available Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance.

  1. [Biodegradable polyhydroxyalkanoates as carriers for antitumor agents]. (United States)

    Shishatskaia, E I; Zhemchugova, A V; Volova, T G


    The possible use of biodegradable polyethers of microbial origin (polyhydroxyalkanoates) as matrices for deposition of daunorubicin (rubomycin), an antitumor anthracycline, was studied. The tablet dosage form of various rubomycin load (from 1 to 60% w/w) was prepared by cold compaction under pressure. The in vitro kinetics of the rubomycin release from the polymer matrix was investigated. It was shown that the rubomycin release to the medium resulted from the drug solution and diffusion within various periods, from tens hours to several weeks and months depending on the load. When the rubomycin load was under 20% w/w the drug release was prolonged and directly proportional to the observation time. When the rubomycin concentration was under 5%, the drug release kinetics corresponded to the type of the zero order reaction with prolonged release without sharp efflux at the initial stage of the observation. The findings showed that the polyhydroxyalkanoates were applicable as matrices for deposition of rubomycin and preparation of drugs with prolonged action.

  2. Clinical efficacy of capecitabine and cyclophosphamide (XC) in patients with metastatic breast cancer. (United States)

    Shien, Tadahiko; Doihara, Hiroyoshi; Nishiyama, Keiko; Masuda, Hiroko; Nogami, Tomohiro; Ikeda, Hirokuni; Taira, Naruto


    Combined low-dose therapy of oral capecitabine (Xeloda) and cyclophosphamide (XC) has been demonstrated to be useful for long-term control of lesions in patients with metastatic breast cancer (MBC) and is aimed at symptomatic alleviation and prolongation of survival. Here, a retrospective review was conducted of MBC patients administered XC at the Okayama University Hospital (OUH), to evaluate responses to XC, adverse events and time to progression (TTP). Twenty patients with MBC received XC between 2006 and 2009. With the exception of 2 elderly patients who were over the age of 70 at the initial examination, all of the patients had received prior treatment with an anthracycline and/or a taxane. No complete response (CR) cases were observed, but partial response (PR) was achieved in 6 patients (30%) and SD in 9 (45%), of whom 5 (20%) sustained SD status for >12 months. The median TTP was 6 months (range:3-27 mo.). Three patients developed Grade 3 adverse events (diarrhea, nausea and stomatitis), but no other patients developed adverse reactions causing interruption of the therapy. XC was safe even in previously treated and elderly MBC patients;moreover, it yielded remarkable clinical responses.

  3. Phylogenetic conservation of the preapoptotic calreticulin exposure pathway from yeast to mammals. (United States)

    Madeo, Frank; Durchschlag, Michael; Kepp, Oliver; Panaretakis, Theocharis; Zitvogel, Laurence; Fröhlich, Kai-Uwe; Kroemer, Guido


    The pre-apoptotic exposure of calreticulin (CRT) on the cell surface determines the efficient engulfment of mouse or human tumor cells by antigen-presenting dendritic cells. CRT exposure is rapidly induced by anthracyclins and ionizing irradiation and follows a complex signal transduction pathway that is interrupted by depletion of PERK, caspase-8, BAP31, Bax, Bak or SNAREs, as well as by knock-in mutation of eIF2alpha (to make it non-phosphorylable by PERK) or BAP31 (to render it uncleavable by caspase-8). Here, we show that yeast (Saccharomyces cerevisiae) can expose the CRT orthologue CNE1 on the surface in response to cell death induced by the anthracylin mitoxantrone (MTX). This MTX-triggered CNE1 translocation is abolished by knockout of the yeast orthologues of PERK (Gcn2), BAP31 (Yet3) and SNAREs (Nyv1, Sso1). Altogether, our data point to the existence of an ancestral and cell death-related CRT exposure pathway with conserved elements shared between unicellular fungi and mammals.

  4. Five year retrospective survival analysis of triple negative breast cancer in North-West India

    Directory of Open Access Journals (Sweden)

    B Sharma


    Full Text Available Background: In our institute, about 10% of total cancer is female breast cancer. This analysis was performed to check triple negativity among these patients with their survival strength up to 5 years in relation to different age groups, stage and chemotherapy protocols. Materials and Methods: 208 immunohistochemistry proved triple negative breast cancer patients registered and treated until 2008 were retrospectively selected for the study. Overall survival up to 5 years was observed on the basis of stage, different age groups and chemotherapy regimens. All patients had undergone surgery, conventional external beam radiation therapy and adjuvant chemotherapy. The survival analyses were performed using the Kaplan-Meier method. Results: The majority of patients (41% were in the age group 21-30 years. Stage IV was seen in 18% of the patients at diagnosis and mainly in 21-40 years age group. Only 3% of females were >70 years age and were of Stage I and II. Overall 5 year survival in Stage I in Cyclophosphamide, Adriamycin/Epirubicin, 5-Flurouracil group was 37.5% as compared with Docetaxel/Paclitaxel, Epirubicin group 93% (P < 0.0001. Conclusion: Triple negativity in North-West India is about 11.8%. We observed it in younger patients mainly with highly aggressive behaviors. Taxane based chemotherapy gives better result as compared with anthracycline based regimens in all stages.

  5. Substance P Receptor Signaling Mediates Doxorubicin-Induced Cardiomyocyte Apoptosis and Triple-Negative Breast Cancer Chemoresistance. (United States)

    Robinson, Prema; Kasembeli, Moses; Bharadwaj, Uddalak; Engineer, Nikita; Eckols, Kris T; Tweardy, David J


    Doxorubicin (DOX), an anthracycline, is broadly considered the most active single agent available for treating breast cancer but has been known to induce cardiotoxicity. Although DOX is highly effective in treating triple-negative breast cancer (TNBC), DOX can have poor outcomes owing to induction of chemoresistance. There is an urgent need to develop new therapies for TNBC aimed at improving DOX outcome and DOX-induced cardiotoxicity. Substance P (SP), a neuropeptide involved in pain transmission is known to stimulate production of reactive oxygen species (ROS). Elevated cardiac ROS is linked with heart injury and failure. We investigated the role of SP in chemotherapy-associated death of cardiomyocytes and chemoresistance. We showed that pretreating a cardiomyocyte cell line (H9C2) and a TNBC cell line (MDA-MB 231) with aprepitant, a SP receptor antagonist that is routinely used to treat chemotherapy-associated associated nausea, decreased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in cardiomyocytes and increased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in TNBC cells compared with cells treated with DOX alone. Our findings demonstrate the ability of aprepitant to decrease DOX-induced killing of cardiomyocytes and to increase cancer cell sensitivity to DOX, which has tremendous clinical significance.

  6. Substance P Receptor Signaling Mediates Doxorubicin-Induced Cardiomyocyte Apoptosis and Triple-Negative Breast Cancer Chemoresistance

    Directory of Open Access Journals (Sweden)

    Prema Robinson


    Full Text Available Doxorubicin (DOX, an anthracycline, is broadly considered the most active single agent available for treating breast cancer but has been known to induce cardiotoxicity. Although DOX is highly effective in treating triple-negative breast cancer (TNBC, DOX can have poor outcomes owing to induction of chemoresistance. There is an urgent need to develop new therapies for TNBC aimed at improving DOX outcome and DOX-induced cardiotoxicity. Substance P (SP, a neuropeptide involved in pain transmission is known to stimulate production of reactive oxygen species (ROS. Elevated cardiac ROS is linked with heart injury and failure. We investigated the role of SP in chemotherapy-associated death of cardiomyocytes and chemoresistance. We showed that pretreating a cardiomyocyte cell line (H9C2 and a TNBC cell line (MDA-MB 231 with aprepitant, a SP receptor antagonist that is routinely used to treat chemotherapy-associated associated nausea, decreased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in cardiomyocytes and increased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in TNBC cells compared with cells treated with DOX alone. Our findings demonstrate the ability of aprepitant to decrease DOX-induced killing of cardiomyocytes and to increase cancer cell sensitivity to DOX, which has tremendous clinical significance.

  7. Exposure of CD34+ precursors to cytostatic anthraquinone-derivatives induces rapid dendritic cell differentiation: implications for cancer immunotherapy. (United States)

    van de Ven, Rieneke; Reurs, Anneke W; Wijnands, Pepijn G J T B; van Wetering, Sandra; Kruisbeek, Ada M; Hooijberg, Erik; Scheffer, George L; Scheper, Rik J; de Gruijl, Tanja D


    Appropriate activation of dendritic cells (DC) is essential for successful active vaccination and induction of cell-mediated immunity. The scarcity of precursor cells, as well as long culture methods, have hampered wide-scale application of DC vaccines derived from CD34(+) precursors, despite their suggested superior efficacy over the more commonly applied monocyte-derived DC (MoDC). Here, employing the CD34(+)/CD14(+) AML-derived human DC progenitor cell line MUTZ3, we show that cytostatic anthraquinone-derivatives (i.e., the anthracenedione mitoxantrone and the related anthracyclin doxorubicin) induce rapid differentiation of CD34(+) DC precursors into functional antigen-presenting cells (APC) in a three-day protocol. The drugs were found to act specifically on CD34(+), and not on CD14(+) DC precursors. Importantly, these observations were confirmed for primary CD34(+) and CD14(+) DC precursors from peripheral blood. Mitoxantrone-generated DC were fully differentiated within three days and after an additional 24 h of maturation, were as capable as standard 9-day differentiated and matured DC to migrate toward the lymph node-homing chemokines CCL19 and CCL21, to induce primary allogeneic T cell proliferation, and to prime functional MART1-specific CD8(+) T lymphocytes. Our finding that anthraquinone-derivatives like mitoxantrone support rapid high-efficiency differentiation of DC precursors may have consequences for in vitro production of DC vaccines as well as for novel immunochemotherapy strategies.

  8. Asian-variant intravascular lymphoma in the African race

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    Holly Geyer


    Full Text Available Intravascular large B-cell lymphoma (IVLBCL is an exceptionally rare form of non- Hodgkin lymphoma (NHL distinguished by the preferential growth of neoplastic cells within blood vessel lumen. Challenging to detect and deemed disseminated at diagnosis, this condition is characterized by a highly aggressive, inconspicuous course with a high mortality rate. We describe the case of a 48 year-old African-American female presenting with a two month history of low-grade fevers and malaise. Laboratory data was notable for anemia, thrombocytopenia, elevated liver function tests, and hematuria. An extensive workup for infectious, rheumatologic and malignant causes was negative. Her symptoms progressed and within two weeks, she was admitted for disseminated intravascular coagulation (DIC. Her course was complicated by diffuse pulmonary hemorrhage and ultimately, care was withdrawn. Autopsy identified widespread CD-20 positive intravascular large B-cell lymphoma with significant hepatosplenic involvement, characteristic of the Asian variant IVLBCL. This case uniquely highlights development of the Asian variant IVLBVL in a previously undescribed race. Identified by its intraluminal vascular growth pattern, IVLBCL generally spares lymphatic channels. Diagnosis and differentiation of this condition from other hematological malignancies via skin, visceral and bone marrow biopsy is imperative as anthracycline-containing chemotherapies may significantly improve clinical outcomes. This article outlines the common presentation, natural course, and treatment options of IVLBCL, along with the histopathology, immunohistochemistry, and chromosomal aberrations common to this condition.

  9. Clinical role of indium-111 antimyosin imaging

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    Bhattacharya, S.; Lahiri, A. (Northwich Park Hospital and Clinical Research Centre, Harrow (UK). Dept. of Cardiology Northwich Park Hospital and Clinical Research Centre, Harrow (UK). Div. of Cardiovascular Sciences)


    Myocyte necrosis occurs in ischaemic, inflammatory and toxic heart diseases and can be detected by indium 111 antimyosin imaging. This allows a non-invasive evaluation of the site, extent and quantitation of the severity of myocardial necrosis. Simultaneous imaging of perfusion in patients with myocardial infarction allows the differentiation of necrosed and perfused areas and the varying degrees of mismatch and overlap, which has prognostic significance. Indium 111 antimyosin imaging is useful in the assessment of patients with unstable angina and in those for whom the diagnosis of infarction or unstable angina is not clear. In suspected myocarditis, a positive scan indicates the necessity for endomyocardial biopsy to confirm inflammation, whereas a negative scan makes the diagnosis of myocarditis unlikely. Antimyosin imaging is not useful as a marker of rejection in the 1 year-post-transplant, but uptake after this period is associated with an increased rejection rate and is therefore an important tool in planning management strategies. Most patients on anthracycline treatment have demonstrable uptake, which is related to the cumulative dose and to the ejection fraction. Its role in this situation is as yet unclear. The use of new ligands and radioisotopes ({sup 99m}Tc) is likely to allow earlier imaging and produce improved quality. (orig.).

  10. A GINECO randomized phase II trial of two capecitabine and weekly paclitaxel schedules in metastatic breast cancer. (United States)

    Lortholary, Alain; Hardy-Bessard, Anne-Claire; Bachelot, Thomas; de Rauglaudre, Gaëtan; Alexandre, Jérôme; Bourgeois, Hugues; Jaubert, Dominique; Paraiso, Désiré; Largillier, Rémy


    To determine whether capecitabine schedule adaptation improves the tolerability of capecitabine-paclitaxel combination therapy for metastatic breast cancer (MBC), patients with anthracycline-pretreated HER2-negative MBC were randomized to either arm A (21-day cycles: capecitabine 1,000 mg/m(2) twice daily, days 1-14; paclitaxel 60 mg/m(2), days 1, 8, and 15) or arm B (28-day cycles: capecitabine 1,000 mg/m(2) twice daily, days 1-5, 8-12, and 15-19; paclitaxel 80 mg/m(2), days 1, 8, and 15). The primary endpoint was the incidence of dose reductions or delays >1 week for grade 3/4 toxicity. Secondary endpoints were efficacy and safety. All 130 randomized patients were evaluable for safety. Dose reduction or delay for grade 3/4 toxicity occurred in 39% of patients in arm A and 34% in arm B during cycles 1-6. In arm A, there were significantly more toxicity-related dose reductions (cycles 1-6: 82 vs. 67%, respectively; P = 0.05) and discontinuations (29 vs. 8%, respectively). Grade 3 diarrhea occurred in 12 and 0%, respectively, and grade 3 hand-foot syndrome in 12 versus 9%, respectively (grade 4 not applicable). There were no detectable differences in efficacy. Weekday capecitabine dosing with weekly paclitaxel may improve tolerability without a detrimental effect on efficacy, and merits further evaluation in patients suited to combination chemotherapy.

  11. Therapy-related acute myeloid leukemia with chromosomal abnormalities involving t(9;22(q34;q11 and t(3;21(q26;q22 during chemotherapy for follicular lymphoma

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    Ogasawara T


    Full Text Available This report describes a case of a patient who developed therapy-related acute myeloid leukemia five years after initiating chemotherapy for follicular lymphoma. The patient had been treated with multiple chemotherapeutic regimens, including anthracycline and etoposide (VP-16, as well as with radiation therapy for refractory follicular lymphoma over the preceding five years. The patient subsequently developed myelodysplastic syndrome (MDS with karyotypic abnormalities of monosomy 7 and del (q11; q13.3 followed by acute myeloid leukemia (AML with an additional balanced translocation of t(9;22(q34;q11 and t(3;21(q26;q22. Reverse transcription-polymerase chain reaction amplification of the patient’s RNA showed a fusion transcript of minor BCR-ABL but not EVI1-RUNX1 (AML1 genes. Imatinib therapy resulted in regression of AML, but the patient soon became refractory to chemotherapy and died. Therapy-related acute leukemia develops mostly as non-lymphoid leukemia with unbalanced aberrations of monosomy 7 and 5 or balanced aberrations involving 11q23 and 21q22, but Philadelphia chromosome is uncommon. In addition, simultaneous occurrence of both t(9;22(q34;q11 and t(3;21(q26;q22 balanced aberrations in t-MDS/t-AML is a very rare event. The balanced translocations detected in this case suggest another mechanism by which t-AML can develop after chemotherapy and radiation therapy for follicular lymphoma.

  12. A study from the EORTC new drug development group: open label phase II study of sabarubicin (MEN-10755) in patients with progressive hormone refractory prostate cancer. (United States)

    Fiedler, W; Tchen, N; Bloch, J; Fargeot, P; Sorio, R; Vermorken, J B; Collette, L; Lacombe, D; Twelves, C


    Sabarubicin (MEN-10755), a new synthetic anthracycline analogue, was evaluated for safety and efficacy in a multicentre phase II study in patients with advanced hormone refractory prostate cancer (HRPC). Thirty seven patients were included, of which 34 were evaluable for PSA response according to Bubley's criteria. Sabarubicin was administered as a short (30 min) intravenous infusion at a dose of 80 mg/m(2) every 3 weeks. The main toxicity consisted of grade 3/4 neutropenia in 24 patients (64.9%), with grade 3/4 febrile neutropenia occurring in one patient only. Grade 3/4 cardiotoxicity was observed in 4 patients including one ineligible. Other toxicities were mild. Nine patients achieved a PSA response (26.5%), 10 patients had stable disease (29.4%) and 14 patients disease progression (41.2%). One patient (2.9%) had a PSA response that was not confirmed by repeat PSA testing. The objective response rate according to RECIST criteria was 6.7% in 15 patients with measurable disease. The median duration of PSA responses was relatively long 7.1 months (95% CI 4.9-20.7) as was the median time to treatment progression in patients with stable disease. The median overall survival was 18.7 months (95% CI 9.1-N), comparable to results recently observed in taxotere-containing regimens. To confirm and extend these results, further testing of sabarubicin in larger trials is warranted.

  13. Synthesis and Biological Activities of a 3'-Azido Analogue of Doxorubicin Against Drug-Resistant Cancer Cells

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    Fengshan Wang


    Full Text Available Doxorubicin (DOX, an anthracycline antibiotic, is one of the most active anticancer chemotherapeutic agents. The clinical use of DOX, however, is limited by the dose-dependant P-glycoprotein (P-gp-mediated resistance. Herein, a 3′-azido analogue of DOX (ADOX was prepared from daunorubicin (DNR. ADOX exhibited potent antitumor activities in drug-sensitive (MCF-7 and K562 and drug-resistant cell lines (MCF-7/DNR, K562/DOX, respectively. The drug resistance index (DRI values of ADOX were much lower than that of DOX. The cytotoxicity experiments of ADOX or DOX against K562/DOX, with or without P-gp inhibitor, indicated that ADOX circumvents resistance by abolishing the P-gp recognition. This conclusion was further supported by drug influx/efflux flow cytometry experiments, as well as by molecular docking of ADOX to P-gp. In vivo animal tests, ADOX exhibited higher activity and less toxicity than DOX. The current data warranted ADOX for additional pre-clinical evaluations for new drug development.

  14. FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance. (United States)

    Nestal de Moraes, Gabriela; Delbue, Deborah; Silva, Karina L; Robaina, Marcela Cristina; Khongkow, Pasarat; Gomes, Ana R; Zona, Stefania; Crocamo, Susanne; Mencalha, André Luiz; Magalhães, Lídia M; Lam, Eric W-F; Maia, Raquel C


    Drug resistance is a major hurdle for successful treatment of breast cancer, the leading cause of deaths in women throughout the world. The FOXM1 transcription factor is a potent oncogene that transcriptionally regulates a wide range of target genes involved in DNA repair, metastasis, cell invasion, and migration. However, little is known about the role of FOXM1 in cell survival and the gene targets involved. Here, we show that FOXM1-overexpressing breast cancer cells display an apoptosis-resistant phenotype, which associates with the upregulation of expression of XIAP and Survivin antiapoptotic genes. Conversely, FOXM1 knockdown results in XIAP and Survivin downregulation as well as decreased binding of FOXM1 to the promoter regions of XIAP and Survivin. Consistently, FOXM1, XIAP, and Survivin expression levels were higher in taxane and anthracycline-resistant cell lines when compared to their sensitive counterparts and could not be downregulated in response to drug treatment. In agreement with our in vitro findings, we found that FOXM1 expression is significantly associated with Survivin and XIAP expression in samples from patients with IIIa stage breast invasive ductal carcinoma. Importantly, patients co-expressing FOXM1, Survivin, and nuclear XIAP had significantly worst overall survival, further confirming the physiological relevance of the regulation of Survivin and XIAP by FOXM1. Together, these findings suggest that the overexpression of FOXM1, XIAP, and Survivin contributes to the development of drug-resistance and is associated with poor clinical outcome in breast cancer patients.

  15. [Efficacy of Levofloxacin Hydrate in Febrile Neutropenia for Outpatient Chemotherapy]. (United States)

    Inagaki, Manato; Sato, Junya; Nihei, Satoru; Kashiwaba, Masahiro; Kudo, Kenzo


    Management of febrile neutropenia (FN) is important for the safety of patients undergoing outpatient chemotherapy. Oral antimicrobials are usually prescribed as the initial treatment for FN, and outpatients are instructed to begin medication prior to chemotherapy. However, the effectiveness and safety of the use of these oral antibiotics have not yet been established. In this study, we investigated the effectiveness and safety of levofloxacin hydrate (LVFX) for breast cancer patients with FN, and the factors associated with the onset of FN in 134 breast cancer patients who underwent chemotherapy including the anticancer drug anthracycline (total, 513 courses), in an outpatient chemotherapy department. The effectiveness and safety of LVFX were defined respectively as defervescence within 5 days, and the appearance of side effects such as diarrhea and rashes. Fever was observed in 89 (66%) of the 134 patients, and during 164 (32%) of 513 courses. Defervescence was observed with the LVFX medication in 149 (93%) of 160 courses. The primary side effect was the development of rashes, and only 2 (1%) of the 160 courses were discontinued. Onset of stomatitis during chemotherapy was observed as a factor of FN (odds ratio: 1.36, p<0.05). Our results suggest that the use of LVFX according to the patients' discretion might be an effective and safe option for the management of FN during outpatient chemotherapy.

  16. Effects of Traditional Chinese Medicine on Chemotherapy-Induced Myelosuppression and Febrile Neutropenia in Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Huan Tian


    Full Text Available Title. Chemotherapy-induced myelosuppression lowers the quality of life in breast cancer patients and causes many complications. Traditional Chinese Medicine (TCM is a widely used complementary and alternative medicine therapies. Objective. To study whether TCM can reduce the incidence of chemotherapy-induced leukopenia, neutropenia, and febrile neutropenia (FN in breast cancer patients. Methods. The data were analyzed retrospectively between patients who received TCM treatment (group 1, n=453 and patients who did not receive TCM treatment (group 2, n=359. Significant risk factors associated with the occurrence of chemotherapy-induced leukopenia, neutropenia, and FN were identified using multivariate analysis. Propensity score-matched patients were analyzed to adjust for any baseline differences. Results. Group 1 patients had a significantly lower rate of chemotherapy-induced severe leukopenia, neutropenia, and FN, compared with group 2 (43% versus 71%, P<0.0001, 72% versus 78%, P=0.005, 6% versus 24%, P<0.0001, resp.. Multivariate analysis revealed that chemotherapy regimens containing anthracyclines combined with paclitaxel or docetaxel were the most significant predictor. Subgroup analysis indicated that TCM treatment showed benefit in relieving chemotherapy-induced leukopenia and FN in most chemotherapy regimens. Conclusions. TCM treatment could lower the risk of severe chemotherapy-induced leukopenia, neutropenia, and FN in breast cancer patients.

  17. A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification

    DEFF Research Database (Denmark)

    Tarpgaard, Line S.; Qvortrup, Camilla; Nygård, Sune Boris;


    A gene amplification in their tumor cells. BACKGROUND: Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin...... normal tissue. The TOP2A gene is located on chromosome 17 and when the TOP2A/CEN-17 ratio was applied to identify tumors with gene loss or amplifications, 10.5 % had a ratio ≥ 1.5 consistent with gene amplification and 2.6 % had a ratio ≤ 0.8 suggesting gene deletions. Based on these observations......, investigating the efficacy of epirubicin in patients with oxaliplatin refractory mCRC and with a cancer cell TOP2A/CEN-17 ratio ≥ 1.5. TOP2A gene amplification measured by fluorescence in situ hybridization. A total of 25 evaluable patients (15 + 10 in two steps) will be included (Simon's two-stage minimax...

  18. Cardiac Function in Long-Term Survivors of Childhood Lymphoma

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    Mark K. Friedberg


    Full Text Available Objectives. We studied long-term effects of therapy for childhood lymphoma on cardiac function. Design and patients. We prospectively evaluated 45 survivors of childhood lymphoma, using clinical parameters, electrocardiography and echocardiography. Further comparisons were made between lymphoma subgroups and between males and females. Results. Mean age at diagnosis was 9.1 years. Mean followup duration was 10.9 years. The NYHA functional class was I in 43 patients and II in 2 patients. A prolonged QTc interval (>0.44 msec was found in 8 patients. Left ventricular (LV systolic function and compliance were normal (LV shortening fraction 40±5.6%; cardiac index 2.84±1.13 L/min/m2; E/A wave ratio 2.5±1.3; mean ± S.D., LV mass was normal (97±40 grams/m2, mean ± S.D.. Mitral regurgitation was observed in 7/45 patients (16%. Asymptomatic pericardial effusions were found in 3/45 (7% patients. Conclusions. Long-term follow-up shows that most parameters of cardiac function are normal in survivors of childhood lymphoma. This is likely due to relatively low doses of anthracyclines in modern protocol modalities. Abnormalities in mitral valve flow, QTc prolongation and in a small proportion of survivors, and functional capacity necessitate long-term cardiac follow-up of these patients.

  19. Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. (United States)

    Low, Siew-Kee; Chung, Suyoun; Takahashi, Atsushi; Zembutsu, Hitoshi; Mushiroda, Taisei; Kubo, Michiaki; Nakamura, Yusuke


    Chemotherapeutic agents are notoriously known to have a narrow therapeutic range that often results in life-threatening toxicity. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy through a pharmacogenomics approach. In this study, we carried out multiple genome-wide association studies (GWAS) of 13 122 cancer patients who received different chemotherapy regimens, including cyclophosphamide- and platinum-based (cisplatin and carboplatin), anthracycline-based (doxorubicin and epirubicin), and antimetabolite-based (5-fluorouracil and gemcitabine) treatment, antimicrotubule agents (paclitaxel and docetaxel), and topoisomerase inhibitors (camptothecin and etoposide), as well as combination therapy with paclitaxel and carboplatin, to identify genetic variants that are associated with the risk of severe neutropenia/leucopenia in the Japanese population. In addition, we used a weighted genetic risk scoring system to evaluate the cumulative effects of the suggestive genetic variants identified from GWAS in order to predict the risk levels of individuals who carry multiple risk alleles. Although we failed to identify genetic variants that surpassed the genome-wide significance level (P < 5.0 × 10(-8) ) through GWAS, probably due to insufficient statistical power and complex clinical features, we were able to shortlist some of the suggestive associated loci. The current study is at the relatively preliminary stage, but does highlight the complexity and problematic issues associated with retrospective pharmacogenomics studies. However, we hope that verification of these genetic variants through local and international collaborations could improve the clinical outcome for cancer patients.

  20. Is it time for cardiac innervation imaging?

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    Knuuti, J. [Turku Univ., Turku (Finland) Turku PET Center; Sipola, P. [Kuopio Univ., Kuopio (Finland)


    The autonomic nervous system plays an important role in the regulation of cardiac function and the regional distribution of cardiac nerve terminals can be visualized using scintigraphic techniques. The most commonly used tracer is iodine-123-metaiodobenzylguanidine (MIBG) but C-11-hydroxyephedrine has also been used with PET. When imaging with MIBG, the ratio of heart-to-mediastinal counts is used as an index of tracer uptake, and regional distribution is also assessed from tomographic images. The rate of clearance of the tracer can also be measured and indicates the function of the adrenergic system. Innervation imaging has been applied in patients with susceptibility to arrythmias, coronary artery disease, hypertrophic and dilated cardiomyopathy and anthracycline induced cardiotoxicity. Abnormal adrenergic innervation or function appear to exist in many pathophysiological conditions indicating that sympathetic neurons are very susceptible to damage. Abnormal findings in innervation imaging also appear to have significant prognostic value especially in patients with cardiomyopathy. Recently, it has also been shown that innervation imaging can monitor drug-induced changes in cardiac adrenergic activity. Although innervation imaging holds great promise for clinical use, the method has not received wider clinical acceptance. Larger randomized studies are required to confirm the value of innervation imaging in various specific indications.

  1. Identification of a functional antioxidant responsive element in the promoter of the Chinese hamster carbonyl reductase 3 (Chcr3) gene. (United States)

    Miura, Takeshi; Taketomi, Ayako; Nakabayashi, Toshikatsu; Nishinaka, Toru; Terada, Tomoyuki


    CHCR3, a member of the short-chain dehydrogenase/reductase superfamily, is a carbonyl reductase 3 enzyme in Chinese hamsters. Carbonyl reductase 3 in humans has been believed to involve the metabolism and/or pharmacokinetics of anthracycline drugs, and the mechanism underlying the gene regulation has been investigated. In this study, the nucleotide sequence of the Chcr3 promoter was originally determined, and its promoter activity was characterised. The proximal promoter region is TATA-less and GC-rich, similar to the promoter region of human carbonyl reductase 3. Cobalt stimulated the transcriptional activity of the Chcr3 gene. The results of a luciferase gene reporter assay demonstrated that cobalt-induced stimulation required an antioxidant responsive element. Forced expression of Nrf2, the transcription factor that binds to antioxidant responsive elements, enhanced the transcriptional activity of the Chcr3 gene. These results suggest that cobalt induces the expression of the Chcr3 gene via the Nrf2-antioxidant responsive element pathway.

  2. Targeting Nuclear Factor-kappa B to overcome resistance to chemotherapy.

    Directory of Open Access Journals (Sweden)

    Peter eGodwin


    Full Text Available Intrinsic or acquired resistance to chemotherapeutic agents is a common phenomenon and a major challenge to the treatment of cancer patients, especially those with progressive disease. Chemoresistance is defined by a complex network of factors including multi-drug resistance proteins, reduced cellular uptake of the drug, enhanced DNA repair, intracellular drug inactivation and evasion of apoptosis. Preclinical models have demonstrated activation of the NF-κB pathway by several chemotherapy drugs, including platinum based agents, anthracyclines and taxanes. NF-κB is a key transcription factor, playing a role in the development and progression of cancer as well as chemoresistance through the activation of anti-apoptotic genes. Consequently, NF-κB has emerged as a promising anticancer target. Here, we describe the role of NF-κB in the cancer cell and in resistance to chemotherapeutic agents, particularly cisplatin. Additionally, the potential benefits and disadvantages of targeting NF-κB signalling by pharmacological intervention will be addressed.

  3. Quantum-dot-conjugated graphene as a probe for simultaneous cancer-targeted fluorescent imaging, tracking, and monitoring drug delivery. (United States)

    Chen, Mei-Ling; He, Ye-Ju; Chen, Xu-Wei; Wang, Jian-Hua


    We report a novel quantum-dot-conjugated graphene, i.e., hybrid SiO2-coated quantum dots (HQDs)-conjugated graphene, for targeted cancer fluorescent imaging, tracking, and monitoring drug delivery, as well as cancer therapy. The hybrid SiO2 shells on the surface of QDs not only mitigate its toxicity, but also protect its fluorescence from being quenched by graphene. By functionalizing the surface of HQDs-conjugated graphene (graphene-HQDs) with transferrin (Trf), we developed a targeted imaging system capable of differential uptake and imaging of cancer cells that express the Trf receptor. The widely used fluorescent antineoplastic anthracycline drug, doxorubicin (DOX), is adsorbed on the surface of graphene and results in a large loading capacity of 1.4 mg mg(-1). It is advantageous that the new delivery system exhibits different fluorescence color in between graphene-HQDs and DOX in the aqueous core upon excitation at a same wavelength for the purpose of tracking and monitoring drug delivery. This simple multifunctional nanoparticle system can deliver DOX to the targeted cancer cells and enable us to localize the graphene-HQDs and monitor intracellular DOX release. The specificity and safety of the nanoparticle conjugate for cancer imaging, monitoring, and therapy has been demonstrated in vitro.

  4. Clinically relevant drug interactions between anticancer drugs and psychotropic agents. (United States)

    Yap, K Y-L; Tay, W L; Chui, W K; Chan, A


    Drug interactions are commonly seen in the treatment of cancer patients. Psychotropics are often indicated for these patients since they may also suffer from pre-existing psychological disorders or experience insomnia and anxiety associated with cancer therapy. Thus, the risk of anticancer drug (ACD)-psychotropic drug-drug interactions (DDIs) is high. Drug interactions were compiled from the British National Formulary (53rd edn), Lexi-Comp's Drug Information Handbook (15th edn), Micromedex (v5.1), Hansten & Horn's Drug Interactions (2000) and Drug Interaction Facts (2008 edn). Product information of the individual drugs, as well as documented literature on ACD-psychotropic interactions from PubMed and other databases was also incorporated. This paper identifies clinically important ACD-psychotropic DDIs that are frequently observed. Pharmacokinetic DDIs were observed for tyrosine kinase inhibitors, corticosteroids and antimicrotubule agents due to their inhibitory or inductive effects on cytochrome P450 isoenzymes. Pharmacodynamic DDIs were identified for thalidomide with central nervous system depressants, procarbazine with antidepressants, myelosuppressive ACDs with clozapine and anthracyclines with QT-prolonging psychotropics. Clinicians should be vigilant when psychotropics are prescribed concurrently with ACDs. Close monitoring of plasma drug levels should be carried out to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and psychotropic coverage.

  5. Paeoniflorin inhibits doxorubicin-induced cardiomyocyte apoptosis by downregulating microRNA-1 expression (United States)



    Doxorubicin (DOX) is an effective anthracycline anti-tumor antibiotic. Because of its cardiotoxicity, the clinical application of DOX is limited. Paeoniflorin (PEF), a monoterpene glucoside extracted from the dry root of Paeonia, is reported to exert multiple beneficial effects on the cardiovascular system. The present study was designed to explore the protective effect of PEF against DOX-induced cardiomyocyte apoptosis and the underlying mechanism. In cultured H9c2 cells, PEF (100 µmol/l) was added for 2 h prior to exposure to DOX (5 µmol/l) for 24 h. Cell viability, creatine kinase activity, cardiomyocyte apoptosis, intracellular reactive oxygen species (ROS) levels, and the expression of microRNA-1 (miR-1) and B-cell lymphoma 2 (Bcl-2) were measured following treatment with PEF and/or DOX. The results showed that treatment with DOX notably induced cardiomyocyte apoptosis, concomitantly with enhanced ROS generation, upregulated miR-1 expression and downregulated Bcl-2 expression. These effects of DOX were significantly inhibited by pretreatment of the cells with PEF. These results suggest that the inhibitory effect of PEF on DOX-induced cardiomyocyte apoptosis may be associated with downregulation of miR-1 expression via a reduction in ROS generation. PMID:27284328

  6. PI3K inhibition enhances doxorubicin-induced apoptosis in sarcoma cells.

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    Diana Marklein

    Full Text Available We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX. We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.

  7. 急性早幼粒细胞白血病诱导缓解及序贯治疗方案的临床观察%Clinical observation of acute promyelocytic leukemia remission induction and sequential treatment programs

    Institute of Scientific and Technical Information of China (English)

    宋丽丽; 孙玲


    目的 观察急性早幼粒细胞白血病(APL)诱导化疗及缓解后治疗方案.方法 将初诊的28例APL患者给予三氧化二砷(As2O3)、全反式维甲酸(ATRA)联合诱导治疗,白细胞>10×109/L时给予蒽环类化疗[柔红霉素(DNR) 40 mg×3 d].诱导缓解后给予蒽环类强化治疗3个疗程,初治高白细胞的患者加用标准剂量阿糖胞苷.强化治疗结束且患者血象、骨髓象恢复后开始予As2O3、ATRA、巯嘌呤(6-MP)+甲氨蝶呤(MTX)、化疗序贯治疗,观察患者治疗过程中复发率及不良反应.结果 28例患者除1例在治疗初期死于颅内出血外,其余27例均获得血液学缓解,PML/RARα融合基因均转阴.其中5例患者维持治疗结束2年后融合基因仍持续阴性.结论 As2O3、ATRA联合化疗治疗APL疗效确切,且可缩短血液学缓解时间;序贯治疗可以明显降低复发率,缩短患者住院时间,增加患者治疗依从性,提高患者生存质量.%Objective To observe efficacy of acute promyelocytic leukemia (APL) by chemotherapy induction and treatment programs after remission.Methods 28 cases of newly diagnosed APL were treated with combined arsenic trioxide and retinoic acid which was called induced program,the patients whose leukocytes >10×109/L would be given anthracycline chemotherapy (DNR 40 mg × 3 d).Remission induction anthracycline chemotherapy was given after three courses of intensive therapy,the standard-dose cytarabine was used to the patients with high white blood.After the intensive treatment and with the recorery of the patient' s blood,bone marrow sequential therapy was used [arsenic trioxide (As2O3),retinoic acid (ATRA),6-MP + MTX and chemotherapy],during which recurrence rate and adverse reactions in the patient' s course of treatment were observed.Results Except 1 was died of intracranial hemorrhage at the beginning of treatment,the remaining 27 patients had received hematologic remission with PML/RARα fusion gene negative

  8. Balancing activity and tolerability of neoadjuvant paclitaxel- and docetaxel-based chemotherapy for HER2-positive early stage breast cancer: sensitivity analysis of randomized trials. (United States)

    Carbognin, Luisa; Sperduti, Isabella; Nortilli, Rolando; Brunelli, Matteo; Vicentini, Cecilia; Pellini, Francesca; Pollini, Giovanni Paolo; Giannarelli, Diana; Tortora, Giampaolo; Bria, Emilio


    Paclitaxel and docetaxel represent the most adopted taxanes in the neoadjuvant treatment of HER2-positive breast cancer. Questions still remain with regard to their difference in terms of activity and tolerability. Events for pathological complete response (pCR), severe and febrile neutropenia (FN), and severe neurotoxicity were pooled by adopting a fixed- and random-effect model. A sensitivity analysis to test for the interaction between paclitaxel and docetaxel was accomplished. Absolute differences with 95% confidence intervals (CIs) and the number of patients needed to treat/harm (NNT/NNH) were calculated to derive the Likelihood of being Helped or Harmed (LHH). Data from 15 trials (3601 patients) were included. Paclitaxel significantly increases pCR rate by 6.8% in comparison with docetaxel (43.4%, 95% CI 41.1-45.7% versus 36.6%, 95% CI 34.3-39.0%, p=0.0001), regardless of the chemotherapy backbone, with an absolute difference of 9% and 9.2% for anthracycline-based or free-regimens. Paclitaxel significantly improves pCR versus docetaxel with a single HER2-inhibition by 6.7% (p=0.0012), with no difference if combined with a dual HER2-inhibition. Severe neutropenia and FN are significantly lower with paclitaxel, with an absolute difference of 32.4% (p<0.0001) and 2.5% (p=0.0059), respectively. Conversely, severe neurotoxicity is slightly higher with paclitaxel (3%, p=0.0001). The LHH ratio calculated for pCR and severe neutropenia is 2.0 and 0.7 for paclitaxel and docetaxel. Although the activity of neoadjuvant paclitaxel and docetaxel HER2-positive breast cancer is considered similar, the slight advantage in pCR, the significantly lower neutropenia and FN, do favor paclitaxel (in the weekly fashion) over docetaxel, despite the slightly worst neurotoxicity.

  9. Plasma membrane targeting by short chain sphingolipids inserted in liposomes improves anti-tumor activity of mitoxantrone in an orthotopic breast carcinoma xenograft model. (United States)

    Cordeiro Pedrosa, Lília R; van Tellingen, Olaf; Soullié, Thomas; Seynhaeve, Ann L; Eggermont, Alexander M M; Ten Hagen, Timo L M; Verheij, Marcel; Koning, Gerben A


    Mitoxantrone (MTO) is clinically used for treatment of various types of cancers providing an alternative for similarly active, but more toxic chemotherapeutic drugs such as anthracyclines. To further decrease its toxicity MTO was encapsulated into liposomes. Although liposomal drugs can accumulate in target tumor tissue, they still face the plasma membrane barrier for effective intracellular delivery. Aiming to improve MTO tumor cell availability, we used short chain lipids to target and modulate the tumor cell membrane, promoting MTO plasma membrane traversal. MTO was encapsulated in liposomes containing the short chain sphingolipid (SCS), C8-Glucosylceramide (C8-GluCer) or C8-Galactosylceramide (C8-GalCer) in their bilayer. These new SCS-liposomes containing MTO (SCS-MTOL) were tested in vivo for tolerability, pharmacokinetics, biodistribution, tumor drug delivery by intravital microscopy and efficacy, and compared to standard MTO liposomes (MTOL) and free MTO. Liposomal encapsulation decreased MTO toxicity and allowed administration of higher drug doses. SCS-MTOL displayed increased clearance and lower skin accumulation compared to standard MTOL. Intratumoral liposomal drug delivery was heterogeneous and rather limited in hypoxic tumor areas, yet SCS-MTOL improved intracellular drug uptake in comparison with MTOL. The increased MTO availability correlated well with the improved antitumor activity of SCS-MTOL in a MDAMB-231 breast carcinoma model. Multiple dosing of liposomal MTO strongly delayed tumor growth compared to free MTO and prolonged mouse survival, whereas among the liposomal MTO treatments, C8-GluCer-MTOL was most effective. Targeting plasma membranes with SCS improved MTO tumor availability and thereby therapeutic activity and represents a promising approach to improve MTO-based chemotherapy.

  10. Choice of study endpoint significantly impacts the results of breast cancer trials evaluating chemotherapy-induced nausea and vomiting. (United States)

    Ng, Terry; Mazzarello, Sasha; Wang, Zhou; Hutton, Brian; Dranitsaris, George; Vandermeer, Lisa; Smith, Stephanie; Clemons, Mark


    Multiple endpoints can be used to evaluate chemotherapy-induced nausea and vomiting (CINV). These endpoints reflect the various combinations of vomiting, nausea and rescue antiemetic use in the acute (0-24 h), delayed (>24-120 h) and overall (0-120 h) periods after chemotherapy. As the choice of outcome measure could potentially change the interpretation of clinical trial results, we evaluated CINV rates using different endpoints on a single dataset from a prospective cohort. Data from 177 breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy was used to calculate CINV control rates using the 15 most commonly reported CINV endpoints. As nausea remains such a significant symptom, we explored the frequency at which pharmaceutical and non-pharmaceutical company-funded studies included measures of nausea in their primary study endpoint. CINV control rates ranged from 12.5 %, 95 % (CI 7.6-17.4 %) for total control (no vomiting, no nausea and no rescue medication) in the overall period to 77.4 %, 95 % (CI 71.2-83.6 %) for no vomiting in the overall period. Similar differences were found in the acute and delayed periods. Non-pharmaceutical company-funded trials were more likely to include a measure of nausea in the primary study outcome (9/18, 50 %) than pharmaceutical-funded trials (1/12, 8.3 %). The choice of trial endpoint has an important impact on reported CINV control rates and could significantly impact on interpretation of the results. Primary endpoints of studies, including those mandated by regulatory bodies, should account for nausea to reflect patient experience. Reporting of endpoints should be more comprehensive to allow for cross-trial comparisons.

  11. Fabrication and characterization of a rapid prototyped tissue engineering scaffold with embedded multicomponent matrix for controlled drug release

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    Chen M


    Full Text Available Muwan Chen,1,2 Dang QS Le,1,2 San Hein,2 Pengcheng Li,1 Jens V Nygaard,2 Moustapha Kassem,3 Jørgen Kjems,2 Flemming Besenbacher,2 Cody Bünger11Orthopaedic Research Lab, Aarhus University Hospital, Aarhus C, Denmark; 2Interdisciplinary Nanoscience Center (iNANO, Aarhus University, Aarhus C, Denmark; 3Department of Endocrinology and Metabolism, Odense University Hospital, Odense C, DenmarkAbstract: Bone tissue engineering implants with sustained local drug delivery provide an opportunity for better postoperative care for bone tumor patients because these implants offer sustained drug release at the tumor site and reduce systemic side effects. A rapid prototyped macroporous polycaprolactone scaffold was embedded with a porous matrix composed of chitosan, nanoclay, and β-tricalcium phosphate by freeze-drying. This composite scaffold was evaluated on its ability to deliver an anthracycline antibiotic and to promote formation of mineralized matrix in vitro. Scanning electronic microscopy, confocal imaging, and DNA quantification confirmed that immortalized human bone marrow-derived mesenchymal stem cells (hMSC-TERT cultured in the scaffold showed high cell viability and growth, and good cell infiltration to the pores of the scaffold. Alkaline phosphatase activity and osteocalcin staining showed that the scaffold was osteoinductive. The drug-release kinetics was investigated by loading doxorubicin into the scaffold. The scaffolds comprising nanoclay released up to 45% of the drug for up to 2 months, while the scaffold without nanoclay released 95% of the drug within 4 days. Therefore, this scaffold can fulfill the requirements for both bone tissue engineering and local sustained release of an anticancer drug in vitro. These results suggest that the scaffold can be used clinically in reconstructive surgery after bone tumor resection. Moreover, by changing the composition and amount of individual components, the scaffold can find application in other

  12. Final results of a phase I/II pilot study of capecitabine with or without vinorelbine after sequential dose-dense epirubicin and paclitaxel in high-risk early breast cancer

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    Müller Volkmar


    Full Text Available Abstract Background The integration of the non-cross-resistant chemotherapeutic agents capecitabine and vinorelbine into an intensified dose-dense sequential anthracycline- and taxane-containing regimen in high-risk early breast cancer (EBC could improve efficacy, but this combination was not examined in this context so far. Methods Patients with stage II/IIIA EBC (four or more positive lymph nodes received post-operative intensified dose-dense sequential epirubicin (150 mg/m² every 2 weeks and paclitaxel (225 mg/m² every 2 weeks with filgrastim and darbepoetin alfa, followed by capecitabine alone (dose levels 1 and 3 or with vinorelbine (dose levels 2 and 4. Capecitabine was given on days 1-14 every 21 days at 1000 or 1250 mg/m2 twice daily (dose levels 1/2 and 3/4, respectively. Vinorelbine 25 mg/m2 was given on days 1 and 8 of each 21-day course (dose levels 2 and 4. Results Fifty-one patients were treated. There was one dose-limiting toxicity (DLT at dose level 1. At dose level 2 (capecitabine and vinorelbine, five of 10 patients experienced DLTs. Therefore evaluation of vinorelbine was abandoned and dose level 3 (capecitabine monotherapy was expanded. Hand-foot syndrome and diarrhoea were dose limiting with capecitabine 1250 mg/m2 twice daily. At 35.2 months' median follow-up, the estimated 3-year relapse-free and overall survival rates were 82% and 91%, respectively. Conclusions Administration of capecitabine monotherapy after sequential dose-dense epirubicin and paclitaxel is feasible in node-positive EBC, while the combination of capecitabine and vinorelbine as used here caused more DLTs. Trial registration Current Controlled Trials ISRCTN38983527.

  13. An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice (United States)

    Montgomery, Megan D.; Chan, Trevor; Swigart, Philip M.; Myagmar, Bat-erdene; Dash, Rajesh; Simpson, Paul C.


    Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35–40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies. PMID:28081170

  14. Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel.

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    Ranjan Chrisanthar

    Full Text Available BACKGROUND: TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy. EXPERIMENTAL DESIGN: Each patient was randomly assigned to treatment with epirubicin 90 mg/m(2 (n = 109 or paclitaxel 200 mg/m(2 (n = 114 every 3rd week as monotherapy for 4-6 cycles. Patients obtaining a suboptimal response on first-line treatment requiring further chemotherapy received the opposite regimen. Time from last patient inclusion to follow-up censoring was 69 months. Each patient had snap-frozen tumor tissue specimens collected prior to commencing chemotherapy. PRINCIPAL FINDINGS: While TP53 and CHEK2 mutations predicted resistance to epirubicin, MDM2 status did not. Neither TP53/CHEK2 mutations nor MDM2 status was associated with paclitaxel response. Remarkably, TP53 mutations (p = 0.007 but also MDM2 309TG/GG genotype status (p = 0.012 were associated with a poor disease-specific survival among patients having paclitaxel but not patients having epirubicin first-line. The effect of MDM2 status was observed among individuals harbouring wild-type TP53 (p = 0.039 but not among individuals with TP53 mutated tumors (p>0.5. CONCLUSION: TP53 and CHEK2 mutations were associated with lack of response to epirubicin monotherapy. In contrast, TP53 mutations and MDM2 309G allele status conferred poor disease-specific survival among patients treated with primary paclitaxel but not epirubicin monotherapy.

  15. The stress granule protein Vgl1 and poly(A)-binding protein Pab1 are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe

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    Morita, Takahiro [Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Kowakae 3-4-1, Higashi-Osaka 577-8502 (Japan); Satoh, Ryosuke [Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Kowakae 3-4-1, Higashi-Osaka 577-8502 (Japan); Japan Society for the Promotion of Science, 1-8 Chiyoda-ku, Tokyo 102-8472 (Japan); Umeda, Nanae; Kita, Ayako [Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Kowakae 3-4-1, Higashi-Osaka 577-8502 (Japan); Sugiura, Reiko, E-mail: [Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Kowakae 3-4-1, Higashi-Osaka 577-8502 (Japan)


    Highlights: Black-Right-Pointing-Pointer Stress granules (SGs) as a mechanism of doxorubicin tolerance. Black-Right-Pointing-Pointer We characterize the role of stress granules in doxorubicin tolerance. Black-Right-Pointing-Pointer Deletion of components of SGs enhances doxorubicin sensitivity in fission yeast. Black-Right-Pointing-Pointer Doxorubicin promotes SG formation when combined with heat shock. Black-Right-Pointing-Pointer Doxorubicin regulates stress granule assembly independent of eIF2{alpha} phosphorylation. -- Abstract: Doxorubicin is an anthracycline antibiotic widely used for chemotherapy. Although doxorubicin is effective in the treatment of several cancers, including solid tumors and leukemias, the basis of its mechanism of action is not completely understood. Here, we describe the effects of doxorubicin and its relationship with stress granules formation in the fission yeast, Schizosaccharomyces pombe. We show that disruption of genes encoding the components of stress granules, including vgl1{sup +}, which encodes a multi-KH type RNA-binding protein, and pab1{sup +}, which encodes a poly(A)-binding protein, resulted in greater sensitivity to doxorubicin than seen in wild-type cells. Disruption of the vgl1{sup +} and pab1{sup +} genes did not confer sensitivity to other anti-cancer drugs such as cisplatin, 5-fluorouracil, and paclitaxel. We also showed that doxorubicin treatment promoted stress granule formation when combined with heat shock. Notably, doxorubicin treatment did not induce hyperphosphorylation of eIF2{alpha}, suggesting that doxorubicin is involved in stress granule assembly independent of eIF2{alpha} phosphorylation. Our results demonstrate the usefulness of fission yeast for elucidating the molecular targets of doxorubicin toxicity and suggest a novel drug-resistance mechanism involving stress granule assembly.

  16. Host genetic variants in the interleukin-6 promoter predict poor outcome in patients with estrogen receptor-positive, node-positive breast cancer. (United States)

    DeMichele, Angela; Gray, Robert; Horn, Michelle; Chen, Jinbo; Aplenc, Richard; Vaughan, William P; Tallman, Martin S


    Interleukin-6 modulates immune response, estrogen production, and growth pathways in breast cancer. We evaluated the effect of several common, functional interleukin-6 promoter variants in node-positive breast cancer patients enrolled on a multicenter, cooperative group, adjuvant chemotherapy trial to determine whether these variants were associated with clinical outcome overall and by estrogen receptor tumor phenotype. Genomic DNA and clinical data were collected from a clinical trial of adjuvant anthracycline-based chemotherapy followed by randomization to high-dose cyclophosphamide/thiotepa or observation (Intergroup Trial 0121). Genotyping for -174G>C (rs1800795), -597G>A (rs1800797), and -572G>C (rs1800796) was done by site-specific PCR and PyroSequencing, whereas the -373A(n)T(n) repeat was directly sequenced. Log-rank tests and Cox modeling were used to compare outcomes by genotype/haplotype and other factors. Three hundred forty-six patients (64% of trial) had corresponding genotype/clinical data available and did not differ from overall trial participants. After adjustment, patients with estrogen receptor-positive tumors and genotypes 597 GG or 174 GG had significantly worse disease-free survival [hazard ratio (HR), 1.6; P = 0.02 and HR, 1.71; P = 0.007, respectively], whereas the 373 8A12T repeat appeared to be protective (HR, 0.62; P = 0.02). The presence of at least one copy of the haplotype ([-597G, -572G, -373[10A/11T], -174G]) was associated with worse disease-free survival (HR, 1.46; P = 0.04). Kaplan-Meier plots show that all patients in this group relapsed by 24 months from diagnosis. This poor-risk haplotype was quite common overall (estimated frequency, 0.20) and twice as frequent among Blacks (estimated frequency, 0.41).

  17. Current data of targeted therapies for the treatment of triple-negative advanced breast cancer: empiricism or evidence-based? (United States)

    Petrelli, Fausto; Cabiddu, Mary; Ghilardi, Mara; Barni, Sandro


    Approximately 10 - 15% of breast carcinomas (BCs) are known to be 'triple-negative (TN) receptor' (i.e., not expressing ER or PR and not exhibiting overexpression and/or gene amplification of HER2-neu). Triple-negative BCs comprise approximately 85% of all basal-type tumours. Classically, basal-like BCs have been characterised by low expression of ER, PR, and HER2 neu and high expression of CK5, CK14, caveolin-1, CAIX, p63, and EGFR (HER1), which reflects the mammary gland basal/myoepithelial cell component. Although there is no standard first-line chemotherapy regimen for metastatic TN BCs, anthracycline- and taxane-containing regimens are acceptable treatments. A large number of agents, including DNA-damaging agents, EGFR inhibitors, antiangiogenic agents and novel taxane formulations are currently being tested in clinical trials for first-line and pretreated patients. Limited experiences with platinum salts, poly(ADP-ribose) polymerase (PARP) inhibitors, cetuximab, bevacizumab and ixabepilone have been published in recent years and will be reported. Novel immunohistochemistry analysis for identification of basal like/TN phenotype are awaited to correctly select this population. The clinical trials investigating new agents have to be designed for a specific (and possibly large) subset of patients with BC. In the future, a gene array platform with greater sensitivity for distinguishing the various BC subtypes, as well as having the power to predict the molecular biology of the disease, will be an indispensible tool for treatment selection. Currently, treatment of TN BC is more empirical than evidence-based. The cornerstone of treatment is chemotherapy, but in the near future, novel target agents will emerge as possible partners.

  18. Modulation of doxorubicin cytotoxicity by resveratrol in a human breast cancer cell line

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    Osman Abdel-Moneim M


    Full Text Available Abstract Background Breast cancer is the most common cancer in the Arab world and it ranked first among Saudi females. Doxorubicin (DOX, an anthracycline antibiotic is one of the most effective anticancer agents used to treat breast cancer. chronic cardiotoxicity is a major limiting factor of the use of doxorubicin. Therefore, our study was designed to assess the role of a natural product resveratrol (RSVL on sensitization of human breast cancer cells (MCF-7 to the action of DOX in an attempt to minimize doxorubicin effective dose and thereby its side effects. Methods Human breast cancer cell line MCF-7, was used in this study. Cytotoxic activity of DOX was determined using (sulforhodamine SRB method. Apoptotic cells were quantified after treatment by annexin V-FITC- propidium iodide (PI double staining using flow-cytometer. Cell cycle disturbance and doxorubicin uptake were determined after RSVL or DOX treatment. Results Treatment of MCF-7 cells with 15 μg/ml RSVL either simultaneously or 24 h before DOX increased the cytotoxicity of DOX, with IC50 were 0.056 and 0.035 μg/ml, respectively compared to DOX alone IC50 (0.417 μg/ml. Moreover, flow cytometric analysis of the MCF-7 cells treated simultaneously with DOX (0.5 μg/ml and RSVL showed enhanced arrest of the cells in G0 (80%. On the other hand, when RSVL is given 24 h before DOX although there was more increased in the cytotoxic effect of DOX against the growth of the cells, however, there was decreased in percentage arrest of cells in G0, less inhibition of DOX-induced apoptosis and reduced DOX cellular uptake into the cells. Conclusion RSVL treatment increased the cytotoxic activity of DOX against the growth of human breast cancer cells when given either simultaneously or 24 h before DOX.

  19. Computational prediction of state anxiety in Asian patients with cancer susceptible to chemotherapy-induced nausea and vomiting. (United States)

    Yap, Kevin Yi-Lwern; Low, Xiu Hui; Chui, Wai Keung; Chan, Alexandre


    State anxiety, a risk factor for chemotherapy-induced nausea and vomiting (CINV), is a subjective symptom and difficult to quantify. Clinicians need appropriate anxiety measures to assess patients' risks of CINV. This study aimed to determine the anxiety characteristics that can predict CINV based on computational analysis of an objective assessment tool. A single-center, prospective, observational study was carried out between January 2007 and July 2010. Patients with breast, head and neck, and gastrointestinal cancers were recruited and treated with a variety of chemotherapy protocols and appropriate antiemetics. Chemotherapy-induced nausea and vomiting characteristics and antiemetic use were recorded using a standardized diary, whereas patients' anxiety characteristics were evaluated using the Beck Anxiety Inventory. Principal component (PC) analysis was performed to analyze the anxiety characteristics. A subset known as principal variables, which had the highest PC weightings, was identified for patients with and without complete response, complete protection, and complete control. Chemotherapy-induced nausea and vomiting events and anxiety characteristics of 710 patients were collated; 51%, 30%, and 20% were on anthracycline-, oxaliplatin-, and cisplatin-based therapies, respectively. Most patients suffered from delayed CINV, with decreasing proportions achieving complete response (58%), complete protection (42%), and complete control (27%). Seven symptoms (fear of dying, fear of the worst, unable to relax, hot/cold sweats, nervousness, faintness, numbness) were identified as potential CINV predictors. This study demonstrates the usefulness of PC analysis, an unsupervised machine learning technique, to identify 7 anxiety characteristics that are useful as clinical CINV predictors. Clinicians should be aware of these characteristics when assessing CINV in patients on emetogenic chemotherapies.

  20. PET measurements of cAMP-mediated phosphodiesterase-4 with (R)-[11C]rolipram. (United States)

    Kenk, Miran; Thomas, Adam; Lortie, Mireille; Dekemp, Rob; Beanlands, Rob S; Dasilva, Jean N


    Cyclic adenosine monophosphate (cAMP) is the common second messenger in signal-transduction cascades originating at a number of monoamine receptors involved in neurotransmission, cardiac function and smooth muscle contraction. Altered regulation of cAMP synthesis (at receptors, G-protein subunits or adenylyl cyclase) and breakdown by phosphodiesterase (PDE) enzymes have been implicated in a number of pathologies. The PDE4 inhibitor (R)-rolipram, and the less active (S)- enantiomer, have been labeled with carbon-11 and characterized by in vivo and in vitro experiments for use in the evaluation of altered PDE4 levels in the brain and cardiac tissues. (R)-[11C]Rolipram has been shown to bind selectively to PDE4 over other PDE isozymes, with specific binding reflecting approximately 80 and 40% of the total detected radioactivity in the rat brain and the heart, respectively. Tracer retention in PDE4-rich tissues is increased by cAMP-elevating treatments, as detected by in vivo PET studies and ex vivo biodistribution experiments. In vivo PET imaging studies display strong region-specific signal in the brain and heart, as evaluated in rats, pigs, monkeys and humans. Impaired cAMP-mediated signaling was observed in animal models of aging, obesity, anthracycline-induced cardiotoxicity and myocardial infarction using (R)-[11C]rolipram. Given the critical role of cAMP in multiple hormonal pathways, the good safety profile and well-characterized pharmacokinetics, (R)-[11C]rolipram PET imaging provides a novel tool for serial monitoring of cAMP-mediated signaling at the PDE4 level, yielding insight into pathological progression with potential for directing therapy.

  1. Personalized risk prediction for event-free survival at 24 months in patients with diffuse large B-cell lymphoma (United States)

    Maurer, Matthew J.; Jais, Jean-Philippe; Ghesquières, Hervé; Witzig, Thomas E.; Hong, Fangxin; Haioun, Corinne; Thompson, Carrie A.; Thieblemont, Catherine; Micallef, Ivana N.; Porrata, Luis F.; Ribrag, Vincent; Nowakowski, Gregorz S.; Casanovas, Olivier; Bologna, Serge; Morschhauser, Franck; Morrison, Vicki A.; Peterson, Bruce A.; Macon, William R.; Copie-Bergman, Christiane; Feldman, Andrew L.; Syrbu, Sergei I.; Kurtin, Paul J.; Gascoyne, Randy D.; Li, Hailun; Allmer, Cristine; Kahl, Brad S.; Ansell, Stephen M.; Slager, Susan L.; Link, Brian K.; Salles, Gilles; Habermann, Thomas M.; Tilly, Hervé; Cerhan, James R.


    We recently defined event-free survival at 24 months (EFS24) as a clinically relevant outcome for patients with DLBCL. Patients who fail EFS24 have very poor overall survival, while those who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. Here, we develop and validate a clinical risk calculator (IPI24) for EFS24. Model building was performed on a discovery dataset of 1,348 patients with DLBCL and treated with anthracycline-based immunochemotherapy. A multivariable model containing age, Ann Arbor stage, normalized serum LDH, ALC, ECOG performance status, bulky disease, and sex was identified. The model was then applied to an independent validation dataset of 1,177 DLBCL patients. The IPI24 score estimates the probability of failing to achieve the EFS24 endpoint for an individual patient. The IPI24 model showed superior discriminatory ability (c-statistic = 0.671) in the validation dataset compared to the IPI (c-statistic = 0.649) or the NCCN-IPI (c-statistic = 0.657). After recalibration of the model on the combined dataset, the median predicted probability of failing to achieve EFS24 was 36% (range, 12–88%), and the IPI24 showed an EFS24 gradient in all IPI groups. The IPI24 also identified a significant percentage of patients with high risk disease, with over 20% of patients having a 50% or higher risk of failing to achieve EFS24. The IPI24 provides an individual patient level probability of achieving the clinically relevant EFS24 endpoint. It can be used via electronic apps. PMID:26492520

  2. Transcriptional shift identifies a set of genes driving breast cancer chemoresistance.

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    Laura Vera-Ramirez

    Full Text Available BACKGROUND: Distant recurrences after antineoplastic treatment remain a serious problem for breast cancer clinical management, which threats patients' life. Systemic therapy is administered to eradicate cancer cells from the organism, both at the site of the primary tumor and at any other potential location. Despite this intervention, a significant proportion of breast cancer patients relapse even many years after their primary tumor has been successfully treated according to current clinical standards, evidencing the existence of a chemoresistant cell subpopulation originating from the primary tumor. METHODS/FINDINGS: To identify key molecules and signaling pathways which drive breast cancer chemoresistance we performed gene expression analysis before and after anthracycline and taxane-based chemotherapy and compared the results between different histopathological response groups (good-, mid- and bad-response, established according to the Miller & Payne grading system. Two cohorts of 33 and 73 breast cancer patients receiving neoadjuvant chemotherapy were recruited for whole-genome expression analysis and validation assay, respectively. Identified genes were subjected to a bioinformatic analysis in order to ascertain the molecular function of the proteins they encode and the signaling in which they participate. High throughput technologies identified 65 gene sequences which were over-expressed in all groups (P ≤ 0·05 Bonferroni test. Notably we found that, after chemotherapy, a significant proportion of these genes were over-expressed in the good responders group, making their tumors indistinguishable from those of the bad responders in their expression profile (P ≤ 0.05 Benjamini-Hochgerg`s method. CONCLUSIONS: These data identify a set of key molecular pathways selectively up-regulated in post-chemotherapy cancer cells, which may become appropriate targets for the development of future directed therapies against breast cancer.

  3. Transcriptional Shift Identifies a Set of Genes Driving Breast Cancer Chemoresistance (United States)

    Vera-Ramirez, Laura; Sanchez-Rovira, Pedro; Ramirez-Tortosa, Cesar L.; Quiles, Jose L.; Ramirez-Tortosa, MCarmen; Lorente, Jose A.


    Background Distant recurrences after antineoplastic treatment remain a serious problem for breast cancer clinical management, which threats patients’ life. Systemic therapy is administered to eradicate cancer cells from the organism, both at the site of the primary tumor and at any other potential location. Despite this intervention, a significant proportion of breast cancer patients relapse even many years after their primary tumor has been successfully treated according to current clinical standards, evidencing the existence of a chemoresistant cell subpopulation originating from the primary tumor. Methods/Findings To identify key molecules and signaling pathways which drive breast cancer chemoresistance we performed gene expression analysis before and after anthracycline and taxane-based chemotherapy and compared the results between different histopathological response groups (good-, mid- and bad-response), established according to the Miller & Payne grading system. Two cohorts of 33 and 73 breast cancer patients receiving neoadjuvant chemotherapy were recruited for whole-genome expression analysis and validation assay, respectively. Identified genes were subjected to a bioinformatic analysis in order to ascertain the molecular function of the proteins they encode and the signaling in which they participate. High throughput technologies identified 65 gene sequences which were over-expressed in all groups (P ≤ 0·05 Bonferroni test). Notably we found that, after chemotherapy, a significant proportion of these genes were over-expressed in the good responders group, making their tumors indistinguishable from those of the bad responders in their expression profile (P ≤ 0.05 Benjamini-Hochgerg`s method). Conclusions These data identify a set of key molecular pathways selectively up-regulated in post-chemotherapy cancer cells, which may become appropriate targets for the development of future directed therapies against breast cancer. PMID:23326553

  4. Schisandrin B prevents doxorubicin-induced chronic cardiotoxicity and enhances its anticancer activity in vivo.

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    Yang Xu

    Full Text Available BACKGROUND: To mitigate the cardiotoxicity of anthracycline antibiotics without compromising their anticancer activities is still an issue to be solved. We previously demonstrated that schisandrin B (Sch B could protect against doxorubicin (Dox-induced acute cardiotoxicity via enhancing cardiomyocytic glutathione redox cycling that could attenuate oxidative stress generated from Dox. In this study, we attempted to prove if Sch B could also protect against Dox-induced chronic cardiotoxicity, a more clinically relevant issue, without compromising its anticancer activity. METHODOLOGY: Rat was given intragastrically either vehicle or Sch B (50 mg/kg two hours prior to i.p. Dox (2.5 mg/kg weekly over a 5-week period with a cumulative dose of Dox 12.5 mg/kg. At the 6th and 12th week after last dosing, rats were subjected to cardiac function measurement, and left ventricles were processed for histological and ultrastructural examination. Dox anticancer activity enhanced by Sch B was evaluated by growth inhibition of 4T1, a breast cancer cell line, and S180, a sarcoma cell line, in vitro and in vivo. PRINCIPAL FINDINGS: Pretreatment with Sch B significantly attenuated Dox-induced loss of cardiac function and damage of cardiomyocytic structure. Sch B substantially enhanced Dox cytotoxicities toward S180 in vitro and in vivo in mice, and increased Dox cytotoxcity against 4T1 in vitro. Although we did not observe this enhancement against the implanted 4T1 primary tumor, the spontaneous metastasis to lung was significantly reduced in combined treatment group than Dox alone group. CONCLUSION: Sch B is capable of protecting Dox-induced chronic cardiotoxicity and enhancing its anticancer activity. To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a chemotherapeutic sensitizer, which is potentially applicable for cancer treatment.

  5. Risk of cardiovascular adverse events from trastuzumab (Herceptin(®)) in elderly persons with breast cancer: a population-based study. (United States)

    Tsai, H-T; Isaacs, C; Fu, A Z; Warren, J L; Freedman, A N; Barac, A; Huang, C-Y; Potosky, A L


    Randomized controlled trials have reported a 4-5 times increased risk of heart failure (HF) in breast cancer patients receiving trastuzumab (Herceptin (®) ) compared to patients who do not receive trastuzumab. However, data regarding the cardiac effects of trastuzumab on elderly patients treated in general practice remain very limited. Using the US surveillance, epidemiology, and end results (SEER)-Medicare database, we conducted a retrospective cohort study on the cardiac effects of trastuzumab use in all incident breast cancer patients diagnosed from 1998 to 2007 who were 66 years and older, had no prior recent claims for cardiomyopathy (CM) or HF, and were followed through 2009. We defined our outcome as the first CM/HF event after diagnosis. We performed Cox-proportional hazard models with propensity score adjustment to estimate CM/HF risk associated with trastuzumab use. A total of 6,829 out of 68,536 breast cancer patients (median age: 75) had an incident CM/HF event. Patients who received trastuzumab tended to be younger, non-white, diagnosed more recently, and had a stage IV diagnosis. Trastuzumab use was associated with an increased risk of CM/HF (HR = 2.08, 95 % CI 1.77-2.44, p < 0.001). The trastuzumab-associated CM/HF risk was stronger in patients who were younger (HR = 2.52 for 66-75 years and HR = 1.44 for 76 years and older, p < 0.001) and diagnosed in recent years (HR = 2.58 for 2006-2007 vs. 1.86 for 1998-2005, p = 0.01). The twofold risk of CM/HF associated with trastuzumab remained regardless of patients' diagnosis stage, presence of hypertension, cardiovascular comorbidities, or receipt of anthracyclines, taxanes, or radiation. Trastuzumab may double CM/HF risk among elderly breast cancer patients. Our findings reinforce the need to prevent and manage cardiac risk among elderly breast cancer patients receiving trastuzumab.

  6. Influence of mitochondrion-toxic agents on the cardiovascular system. (United States)

    Finsterer, Josef; Ohnsorge, Peter


    Cardiovascular disease may be induced or worsened by mitochondrion-toxic agents. Mitochondrion-toxic agents may be classified as those with or without a clinical effect, those which induce cardiac disease only in humans or animals or both, as prescribed drugs, illicit drugs, exotoxins, or nutritiants, as those which affect the heart exclusively or also other organs, as those which are effective only in patients with a mitochondrial disorder or cardiac disease or also in healthy subjects, or as solid, liquid, or volatile agents. In humans, cardiotoxic agents due to mitochondrial dysfunction include anthracyclines (particularly doxorubicin), mitoxantrone, cyclophosphamide, cisplatin, fluorouracil, imatinib, bortezomib, trastuzumab, arsenic trioxide, cyclosporine-A, zidovudine, lamotrigine, glycosides, lidocain, isoproterenol, nitroprusside, pivalic acid, alcohol, cocaine, pesticides, cadmium, mycotoxins, cyanotoxins, meat meal, or carbon monoxide. Even more agents exhibit cardiac abnormalities due to mitochondrion-toxicity only in animals or tissue cultures. The mitochondrion-toxic effect results from impairment of the respiratory chain, the oxidative phosphorylation, the Krebs cycle, or the β-oxidation, from decrease of the mitochondrion-membrane potential, from increased oxidative stress, reduced anti-oxidative capacity, or from induction of apoptosis. Cardiac abnormalities induced via these mechanisms include cardiomyopathy, myocarditis, coronary heart disease, arrhythmias, heart failure, or Takotsubo syndrome. Discontinuation of the cardiotoxic agent results in complete recovery in the majority of the cases. Antioxidants and nutritiants may be of additional help. Particularly coenzyme-Q, riboflavin, vitamin-E, vitamin-C, L-carnitine, vitamin-D, thiamin, folic acid, omega-3 fatty acids, and D-ribose may alleviate mitochondrial cardiotoxic effects.

  7. Identification of Personalized Chemoresistance Genes in Subtypes of Basal-Like Breast Cancer Based on Functional Differences Using Pathway Analysis.

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    Tong Wu

    Full Text Available Breast cancer is a highly heterogeneous disease that is clinically classified into several subtypes. Among these subtypes, basal-like breast cancer largely overlaps with triple-negative breast cancer (TNBC, and these two groups are generally studied together as a single entity. Differences in the molecular makeup of breast cancers can result in different treatment strategies and prognoses for patients with different breast cancer subtypes. Compared with other subtypes, basal-like and other ER+ breast cancer subtypes exhibit marked differences in etiologic factors, clinical characteristics and therapeutic potential. Anthracycline drugs are typically used as the first-line clinical treatment for basal-like breast cancer subtypes. However, certain patients develop drug resistance following chemotherapy, which can lead to disease relapse and death. Even among patients with basal-like breast cancer, there can be significant molecular differences, and it is difficult to identify specific drug resistance proteins in any given patient using conventional variance testing methods. Therefore, we designed a new method for identifying drug resistance genes. Subgroups, personalized biomarkers, and therapy targets were identified using cluster analysis of differentially expressed genes. We found that basal-like breast cancer could be further divided into at least four distinct subgroups, including two groups at risk for drug resistance and two groups characterized by sensitivity to pharmacotherapy. Based on functional differences among these subgroups, we identified nine biomarkers related to drug resistance: SYK, LCK, GAB2, PAWR, PPARG, MDFI, ZAP70, CIITA and ACTA1. Finally, based on the deviation scores of the examined pathways, 16 pathways were shown to exhibit varying degrees of abnormality in the various subgroups, indicating that patients with different subtypes of basal-like breast cancer can be characterized by differences in the functional status of

  8. Triple-negative breast cancer: treatment challenges and solutions

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    Collignon J


    Full Text Available Joëlle Collignon,1 Laurence Lousberg,1 Hélène Schroeder,1 Guy Jerusalem,1,21Medical Oncology Department, CHU Sart Tilman Liege, Domaine Universitaire du Sart Tilman, Liege, Belgium; 2University of Liege, Liege, Belgium Abstract: Triple-negative breast cancers (TNBCs are defined by the absence of estrogen and progesterone receptors and the absence of HER2 overexpression. These cancers represent a heterogeneous breast cancer subtype with a poor prognosis. Few systemic treatment options exist besides the use of chemotherapy (CT. The heterogeneity of the disease has limited the successful development of targeted therapy in unselected patient populations. Currently, there are no approved targeted therapies for TNBC. However, intense research is ongoing to identify specific targets and develop additional and better systemic treatment options. Standard adjuvant and neoadjuvant regimens include anthracyclines, cyclophosphamide, and taxanes. Platinum-based CT has been proposed as another CT option of interest in TNBC. We review the role of this therapy in general, and particularly in patients carrying BRCA germ-line mutations. Available data concerning the role of platinum-based CT in TNBC were acquired primarily in the neoadjuvant setting. The routine use of platinum-based CT is not yet recommended by available guidelines. Many studies have reported the molecular characterization of TNBCs. Several actionable targets have been identified. Novel therapeutic strategies are currently being tested in clinical trials based on promising results observed in preclinical studies. These targets include androgen receptor, EGFR, PARP, FGFR, and the angiogenic pathway. We review the recent data on experimental drugs in this field. We also discuss the recent data concerning immunologic checkpoint inhibitors. Keywords: triple-negative breast cancer, molecular subtype, platinum-based chemotherapy, targeted therapy, androgen receptor, BRCA1/2 mutation

  9. Molecular Modification of Metadherin/MTDH Impacts the Sensitivity of Breast Cancer to Doxorubicin.

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    Zhenchuan Song

    Full Text Available Breast cancer is a leading cause of death in women and with an increasing worldwide incidence. Doxorubicin, as a first-line anthracycline-based drug is conventional used on breast cancer clinical chemotherapy. However, the drug resistances limited the curative effect of the doxorubicin therapy in breast cancer patients, but the molecular mechanism determinants of breast cancer resistance to doxorubicin chemotherapy are not fully understood. In order to explore the association between metadherin (MTDH and doxorubicin sensitivity, the differential expressions of MTDH in breast cancer cell lines and the sensitivity to doxorubicin of breast cancer cell lines were investigated.The mRNA and protein expression of MTDH were determined by real-time PCR and Western blot in breast cancer cells such as MDA-MB-231, MCF-7, MDA-MB-435S, MCF-7/ADR cells. Once MTDH gene was knocked down by siRNA in MCF-7/ADR cells and overexpressed by MTDH plasmid transfection in MDA-MB-231 cells, the cell growth and therapeutic sensitivity of doxorubicin were evaluated using MTT and the Cell cycle assay and apoptosis rate was determined by flow cytometry.MCF-7/ADR cells revealed highly expressed MTDH and MDA-MB-231 cells had the lowest expression of MTDH. After MTDH gene was knocked down, the cell proliferation was inhibited, and the inhibitory rate of cell growth and apoptosis rate were enhanced, and the cell cycle arrest during the G0/G1 phase in the presence of doxorubicin treatment. On the other hand, the opposite results were observed in MDA-MB-231 cells with overexpressed MTDH gene.MTDH gene plays a promoting role in the proliferation of breast cancer cells and its high expression may be associated with doxorubicin sensitivity of breast cancer.

  10. Fabrication of doxorubicin nanoparticles by controlled antisolvent precipitation for enhanced intracellular delivery. (United States)

    Tam, Yu Tong; To, Kenneth Kin Wah; Chow, Albert Hee Lum


    Over-expression of ATP-binding cassette transporters is one of the most important mechanisms responsible for multidrug resistance. Here, we aimed to develop a stable polymeric nanoparticle system by flash nanoprecipitation (FNP) for enhanced anticancer drug delivery into drug resistant cancer cells. As an antisolvent precipitation process, FNP works best for highly lipophilic solutes (logP>6). Thus we also aimed to evaluate the applicability of FNP to drugs with relatively low lipophilicity (logP=1-2). To this end, doxorubicin (DOX), an anthracycline anticancer agent and a P-gp substrate with a logP of 1.3, was selected as a model drug for the assessment. DOX was successfully incorporated into the amphiphilic diblock copolymer, polyethylene glycol-b-polylactic acid (PEG-b-PLA), by FNP using a four-stream multi-inlet vortex mixer. Optimization of key processing parameters and co-formulation with the co-stabilizer, polyvinylpyrrolidone, yielded highly stable, roughly spherical DOX-loaded PEG-b-PLA nanoparticles (DOX.NP) with mean particle size below 100nm, drug loading up to 14%, and drug encapsulation efficiency up to 49%. DOX.NP exhibited a pH-dependent drug release profile with higher cumulative release rate at acidic pHs. Surface analysis of DOX.NP by XPS revealed an absence of DOX on the particle surface, indicative of complete drug encapsulation. While there were no significant differences in cytotoxic effect on P-gp over-expressing LCC6/MDR cell line between DOX.NP and free DOX in buffered aqueous media, DOX.NP exhibited a considerably higher cellular uptake and intracellular retention after efflux. The apparent lack of cytotoxicity enhancement with DOX.NP may be attributable to its slow DOX release inside the cells.

  11. Recent advances in small organic molecules as DNA intercalating agents: synthesis, activity, and modeling. (United States)

    Rescifina, Antonio; Zagni, Chiara; Varrica, Maria Giulia; Pistarà, Venerando; Corsaro, Antonino


    The interaction of small molecules with DNA plays an essential role in many biological processes. As DNA is often the target for majority of anticancer and antibiotic drugs, study about the interaction of drug and DNA has a key role in pharmacology. Moreover, understanding the interactions of small molecules with DNA is of prime significance in the rational design of more powerful and selective anticancer agents. Two of the most important and promising targets in cancer chemotherapy include DNA alkylating agents and DNA intercalators. For these last the DNA recognition is a critical step in their anti-tumor action and the intercalation is not only one kind of the interactions in DNA recognition but also a pivotal step of several clinically used anti-tumor drugs such as anthracyclines, acridines and anthraquinones. To push clinical cancer therapy, the discovery of new DNA intercalators has been considered a practical approach and a number of intercalators have been recently reported. The intercalative binding properties of such molecules can also be harnessed as diagnostic probes for DNA structure in addition to DNA-directed therapeutics. Moreover, the problem of intercalation site formation in the undistorted B-DNA of different length and sequence is matter of tremendous importance in molecular modeling studies and, nowadays, three models of DNA intercalation targets have been proposed that account for the binding features of intercalators. Finally, despite DNA being an important target for several drugs, most of the docking programs are validated only for proteins and their ligands. Therefore, a default protocol to identify DNA binding modes which uses a modified canonical DNA as receptor is needed.

  12. Addition of Arsenic Trioxide into Induction Regimens Could Not Accelerate Recovery of Abnormality of Coagulation and Fibrinolysis in Patients with Acute Promyelocytic Leukemia.

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    Ye Zhang

    Full Text Available All-trans retinoic acid combined to anthracycline-based chemotherapy is the standard regimen of acute promyelocytic leukemia. The advent of arsenic trioxide has contributed to improve the anti-leukemic efficacy in acute promyelocytic leukemia. The objectives of the current study were to evaluate if dual induction by all-trans retinoic acid and arsenic trioxide could accelerate the recovery of abnormality of coagulation and fibrinolysis in patients with acute promyelocytic leukemia.Retrospective analysis was performed in 103 newly-diagnosed patients with acute promyelocytic leukemia. Hemostatic variables and the consumption of component blood were comparably analyzed among patients treated by different induction regimen with or without arsenic trioxide.Compared to patients with other subtypes of de novo acute myeloid leukemia, patients with acute promyelocytic leukemia had lower platelet counts and fibrinogen levels, significantly prolonged prothrombin time and elevated D-dimers (P<0.001. Acute promyelocytic leukemia patients with high or intermediate risk prognostic stratification presented lower initial fibrinogen level than that of low-risk group (P<0.05. After induction treatment, abnormal coagulation and fibrinolysis of patients with acute promyelocytic leukemia was significantly improved before day 10. The recovery of abnormal hemostatic variables (platelet, prothrombin time, fibrinogen and D-dimer was not significantly accelerated after adding arsenic trioxide in induction regimens; and the consumption of transfused component blood (platelet and plasma did not dramatically change either. Acute promyelocytic leukemia patients with high or intermediate risk prognostic stratification had higher platelet transfusion demands than that of low-risk group (P<0.05.Unexpectedly, adding arsenic trioxide could not accelerate the recovery of abnormality of coagulation and fibrinolysis in acute promyelocytic leukemia patients who received all

  13. New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: Part I--Formulation development and in-vitro characterization. (United States)

    Tinkov, Steliyan; Winter, Gerhard; Coester, Conrad; Bekeredjian, Raffi


    Despite high antitumor efficacy and a broad application spectrum, clinical treatment with anthracycline chemotherapeutics is often limited by severe adverse effects such as cardiotoxicity and myelosupression. In recent years, tumor drug targeting has evolved as a promising strategy to increase local drug concentration and reduce systemic side effects. One recent approach for targeting solid tumors is the application of microbubbles, loaded with chemotherapeutic drugs. These advanced drug carriers can be safely administered to the patient by intravenous infusion, and will circulate through the entire vasculature. Their drug load can be locally released by ultrasound targeted microbubble destruction. In addition, tumors can be precisely localized by diagnostic ultrasound since microbubbles act as contrast agents. In the present work a novel microbubble carrier for doxorubicin has been developed and characterized in-vitro. In contrast to many recent tumor-targeting MB designs the newly developed doxorubicin-loaded microbubbles possess a soft but stable phospholipid monolayer shell. Importantly, the active drug is embedded in the microbubble shell and is complexed to the phospholipids by both electrostatic and hydrophobic interactions. Despite their drug load, these novel microbubbles retained all important physical characteristics for ultrasound targeted microbubble destruction, comparable with the commercially available ultrasound contrast agents. In cell culture studies doxorubicin-loaded microbubbles in combination with ultrasound demonstrated an about 3 fold increase of the anti-proliferative activity compared to free doxorubicin and doxorubicin-loaded liposomes. For the first time in the literature the intracellular partition of free doxorubicin and phospholipid-complexed doxorubicin were compared. In conclusion, new doxorubicin-loaded microbubbles with ideal physical characteristics were developed. In-vitro studies show enhanced cytotoxic activity compared to

  14. Development and validation of a UHPLC-MS/MS method for simultaneous quantitation the plasma concentration of Sabarubicin and its alcohol metabolite M3 in Chinese small cell lung cancer patients. (United States)

    Zhang, Yan; Liu, Peng; Li, Ning; Wu, Di; Feng, Yun; Song, Yuanyuan; Shi, Yuankai; Han, Xiaohong


    To support a novel anthracycline agent - Sabarubicin's pharmacokinetics study in Chinese small cell lung cancer patients, a rapid, sensitive, and high throughput ultra-performance liquid chromatography tandem mass spectrometry method using Doxorubicin hydrochloride as internal standard (IS) was developed and validated for simultaneously quantifying Sabarubicin and its alcohol metabolite M3 in human plasma. Plasma samples were pre-extracted with n-hexane to remove hydrophobic interferences and the target compounds were extracted into a 1ml mixture of chloroform and isopropanol (1:1, v/v) and separated on an ACQUITY UPLC BEH Shield RP18 (100mm×2.1mm, 1.7μm) column with gradient mobile phase composed of acetonitrile and water containing 0.1% formic acid. Detection was performed by electrospray ionization in the positive ionization mode under multiple reaction monitoring of the transitions at m/z 644→130 for Sabarubicin, m/z 646→333.2 for M3, and m/z 544→360 for IS. For Sabarubicin and M3, calibration curves over 2-400ng/ml and 0.5-100ng/ml could achieve excellent linearity respectively(r>0.99). Intra- and inter-day precisions were 1.5%-9.1% and 2.2%-12.8%, and accuracy were -9.6% to 0.7% and -4.8% to 5.9% for Sabarubicin and M3 respectively at four concentration levels. The mean recovery for Sabarubicin was 62.4%, 71.9% for M3, and 58.8% for IS. This method was completely validated and successfully applied in the pharmacokinetics study of Sabarubicin and M3 in Chinese small cell lung cancer patients.

  15. Doxorubicin inhibits E. coli division by interacting at a novel site in FtsZ. (United States)

    Panda, Pragnya; Taviti, Ashoka Chary; Satpati, Suresh; Kar, Mitali Madhusmita; Dixit, Anshuman; Beuria, Tushar Kant


    The increase in antibiotic resistance has become a major health concern in recent times. It is therefore essential to identify novel antibacterial targets as well as discover and develop new antibacterial agents. FtsZ, a highly conserved bacterial protein, is responsible for the initiation of cell division in bacteria. The functions of FtsZ inside cells are tightly regulated and any perturbation in its functions leads to inhibition of bacterial division. Recent reports indicate that small molecules targeting the functions of FtsZ may be used as leads to develop new antibacterial agents. To identify small molecules targeting FtsZ and inhibiting bacterial division, we screened a U.S. FDA (Food and Drug Administration)-approved drug library of 800 molecules using an independent computational, biochemical and microbial approach. From this screen, we identified doxorubicin, an anthracycline molecule that inhibits Escherichia coli division and forms filamentous cells. A fluorescence-binding assay shows that doxorubicin interacts strongly with FtsZ. A detailed biochemical analysis demonstrated that doxorubicin inhibits FtsZ assembly and its GTPase activity through binding to a site other than the GTP-binding site. Furthermore, using molecular docking, we identified a probable doxorubicin-binding site in FtsZ. A number of single amino acid mutations at the identified binding site in FtsZ resulted in a severalfold decrease in the affinity of FtsZ for doxorubicin, indicating the importance of this site for doxorubicin interaction. The present study suggests the presence of a novel binding site in FtsZ that interacts with the small molecules and can be targeted for the screening and development of new antibacterial agents.

  16. Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma. (United States)

    Schütt, P; Ebeling, P; Buttkereit, U; Brandhorst, D; Opalka, B; Hoiczyk, M; Flasshove, M; Hense, J; Bojko, P; Metz, K; Moritz, T; Seeber, S; Nowrousian, M R


    The present study aimed to evaluate the side-effects and efficacy of thalidomide in combination with an anthracycline-containing chemotherapy regimen in previously untreated myeloma patients. Thalidomide (400 mg/d) was combined with bolus injections of vincristine and epirubicin and oral dexamethasone (VED). Chemotherapy cycles were repeated every 3 wk until no further reduction in myeloma protein was observed, whereas the treatment with thalidomide was continued until disease progression. Thirty-one patients were enrolled, 12 patients were exclusively treated with thalidomide in combination with VED and 19 patients additionally received high-dose melphalan, for consolidation. Adverse events and response to therapy were assessed prior to treatment with high-dose chemotherapy. Response to thalidomide combined with VED was complete remission in six patients (19%), partial remission in 19 patients (61%), stable disease in five patients (16%), and progressive disease in one patient (3.2%). Grade 3 and 4 adverse events consisted of leukocytopenia in 10 patients (32%), and thrombocytopenia and anemia in one patient each (3.2%). Neutropenic infections grade 3 and 4 occurred in seven (23%) and three patients (9.7%), respectively, including two patients (6.5%) who died from septic shock. Deep vein thrombosis occurred in eight patients (26%), constipation in 20 patients (65%), and polyneuropathy in 20 patients (65%). The probability of event-free survival and overall survival in the whole group of patients at 36 months were 26 and 62%, respectively. In conclusion, the combination of thalidomide with VED appears to be highly effective in previously untreated patients with multiple myeloma, but it is associated with a high rate of thrombotic events, polyneuropathy, and neutropenic infections.

  17. Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9. (United States)

    Abraham, Jame; Robidoux, André; Tan, Antoinette R; Limentani, Steven; Sturtz, Keren; Shalaby, Ibrahim; Alcorn, Hope; Buyse, Marc E; Wolmark, Norman; Jacobs, Samuel A


    Locally advanced breast cancer (LABC) is a good setting in which to monitor response to neoadjuvant chemotherapy, to downsize the tumor (which facilitates breast-conserving surgery), and to test newer agents in untreated patients. Eribulin (E) has shown activity in patients who have undergone previous taxane, anthracycline, and capecitabine treatment. We aimed to evaluate the neoadjuvant use of E followed by doxorubicin and cyclophosphamide (AC) in patients with HER2-negative LABC, using as a control a randomized group of women who received weekly paclitaxel (WP). Fifty women with LABC were accrued January-August 2013. Patients were randomized (1:2) to receive either WP (N = 19) for 12 treatments or E (N = 31) every 3 weeks for 4 cycles followed by AC every 3 weeks for 4 cycles before surgery. 17/19 patients who took WP and 25/30 who took E completed all cycles. Patients were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. Surgical pCR in breast and lymph nodes was determined by a local pathologist following chemotherapy. Forty-nine patients received ≥1 dose of neoadjuvant chemotherapy and are included in this analysis. Forty-eight underwent surgery; one had disease that was inoperable (on E) and is included as no-pCR patient. 17/19 of these patients who took WP completed 12 doses; 28/30 on E completed 4 cycles. Six discontinued treatment on WP, E, or AC. Both treatments were well tolerated. pCR on WP = 5/19(26 %) and on E = 5/30(17 %). Both regimens were equally well tolerated with no unexpected toxicities. pCR did not suggest higher activity with E than with other standard regimens in these LABC patients.

  18. Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes. (United States)

    Kotoula, Vassiliki; Karavasilis, Vasilios; Zagouri, Flora; Kouvatseas, George; Giannoulatou, Eleni; Gogas, Helen; Lakis, Sotiris; Pentheroudakis, George; Bobos, Mattheos; Papadopoulou, Kyriaki; Tsolaki, Eleftheria; Pectasides, Dimitrios; Lazaridis, Georgios; Koutras, Angelos; Aravantinos, Gerasimos; Christodoulou, Christos; Papakostas, Pavlos; Markopoulos, Christos; Zografos, George; Papandreou, Christos; Fountzilas, George


    The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p TP53-PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44-0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47-0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07-2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.

  19. Topoisomerase II alpha gene copy loss has adverse prognostic significance in ERBB2-amplified breast cancer: a retrospective study of paraffin-embedded tumor specimens and medical charts

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    Zhu April


    Full Text Available Abstract Background Amplification of the ERBB2 (Her-2/neu oncogene, which occurs in approximately 25% of breast carcinomas, is a known negative prognostic factor. Available data indicate that a variable number of nearby genes on chromosome 17q may be co-amplified or deleted, forming a continuous amplicon of variable size. In approximately 25% of these patients, the amplicon extends to the gene for topoisomerase II alpha (TOP2A, a target for anthracyclines. We sought to understand the significance of these associated genomic changes for breast cancer prognosis and predicting response to therapy. Methods and patients Archival tissue samples from 63 breast cancer patients with ERBB2 amplification, stages 0–IV, were previously analyzed with FISH probes for genes located near ERBB2. In the present study, the clinical outcome data were determined for all patients presenting at stages I–III for whom adequate clinical follow up was available. Results Four amplicon patterns (Classes were identified. These were significantly associated with the clinical outcome, specifically, recurrence of breast cancer. The Amplicon class IV with deleted TOP2A had 67% (6/9 cases with recurrence, whereas the other three classes combined had only 12% (3/25 cases (p-value = 0.004 at the time of last follow-up. TOP2A deletion was also significantly associated with time to recurrence (p-value = 0.0002. After adjusting for age in Cox regression analysis, the association between TOP2A deletion and time to recurrence remains strongly significant (p-value = 0.002 whereas the association with survival is marginally significant (p-value = 0.06. Conclusion TOP2A deletion is associated with poor prognosis in ERBB2-amplified breast carcinomas. Clarification of the mechanism of this association will require additional study.

  20. Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. (United States)

    Castellino, Sharon M; Geiger, Ann M; Mertens, Ann C; Leisenring, Wendy M; Tooze, Janet A; Goodman, Pam; Stovall, Marilyn; Robison, Leslie L; Hudson, Melissa M


    The contribution of specific cancer therapies, comorbid medical conditions, and host factors to mortality risk after pediatric Hodgkin lymphoma (HL) is unclear. We assessed leading morbidities, overall and cause-specific mortality, and mortality risks among 2742 survivors of HL in the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study of survivors diagnosed from 1970 to 1986. Excess absolute risk for leading causes of death and cumulative incidence and standardized incidence ratios of key medical morbidities were calculated. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of risks for overall and cause-specific mortality. Substantial excess absolute risk of mortality per 10,000 person-years was identified: overall 95.5; death due to HL 38.3, second malignant neoplasms 23.9, and cardiovascular disease 13.1. Risks for overall mortality included radiation dose ≥ 3000 rad ( ≥ 30 Gy; supra-diaphragm: HR, 3.8; 95% CI, 1.1-12.6; infradiaphragm + supradiaphragm: HR, 7.8; 95% CI, 2.4-25.1), exposure to anthracycline (HR, 2.6; 95% CI, 1.6-4.3) or alkylating agents (HR, 1.7; 95% CI, 1.2-2.5), non-breast second malignant neoplasm (HR, 2.6; 95% CI 1.4-5.1), or a serious cardiovascular condition (HR, 4.4; 95% CI 2.7-7.3). Excess mortality from second neoplasms and cardiovascular disease vary by sex and persist > 20 years of follow-up in childhood HL survivors.

  1. Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients. (United States)

    Testa, Ugo; Lo-Coco, Francesco


    All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 10(9)/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease.

  2. Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.

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    Caterina Vacchi-Suzzi

    Full Text Available Anti-cancer therapy based on anthracyclines (DNA intercalating Topoisomerase II inhibitors is limited by adverse effects of these compounds on the cardiovascular system, ultimately causing heart failure. Despite extensive investigations into the effects of doxorubicin on the cardiovascular system, the molecular mechanisms of toxicity remain largely unknown. MicroRNAs are endogenously transcribed non-coding 22 nucleotide long RNAs that regulate gene expression by decreasing mRNA stability and translation and play key roles in cardiac physiology and pathologies. Increasing doses of doxorubicin, but not etoposide (a Topoisomerase II inhibitor devoid of cardiovascular toxicity, specifically induced the up-regulation of miR-208b, miR-216b, miR-215, miR-34c and miR-367 in rat hearts. Furthermore, the lowest dosing regime (1 mg/kg/week for 2 weeks led to a detectable increase of miR-216b in the absence of histopathological findings or alteration of classical cardiac stress biomarkers. In silico microRNA target predictions suggested that a number of doxorubicin-responsive microRNAs may regulate mRNAs involved in cardiac tissue remodeling. In particular miR-34c was able to mediate the DOX-induced changes of Sipa1 mRNA (a mitogen-induced Rap/Ran GTPase activating protein at the post-transcriptional level and in a seed sequence dependent manner. Our results show that integrated heart tissue microRNA and mRNA profiling can provide valuable early genomic biomarkers of drug-induced cardiac injury as well as novel mechanistic insight into the underlying molecular pathways.

  3. Cardiotoxicity of cancer therapeutics: current issues in screening, prevention and therapy

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    Richard Joseph Sheppard


    Full Text Available In the context of modern cancer chemotherapeutics, cancer survivors are living longer and being exposed to potential comorbidities related to non-cancer side effects of such treatments. With close monitoring of cancer patients receiving potentially cardiotoxic medical therapies, oncologists and cardiologists alike are identifying patients in both clinical and subclinical phases of cardiovascular disease related to such chemotherapies. Specifically, cardiotoxicity at the level of the myocardium and potential for the development of heart failure are becoming a growing concern with increasing survival of cancer patients.Traditional chemotherapeutic agents used commonly in the treatment of breast cancer and hematologic malignancies, such as anthracyclines and HER-2 antagonists, are well known to be associated with cardiovascular sequelae. Patients often present without symptoms and an abnormal cardiac imaging study performed as part of routine evaluation of patients receiving cardiotoxic therapies. Additionally, patients can present with signs and symptoms of cardiovascular disease months to years after receiving the chemotherapies. As the understanding of the physiology underlying the various cancers has grown, therapies have been developed that target specific molecules that represent key aspects of physiologic pathways responsible for cancer growth. Inhibition of these pathways, such as those involving tyrosine kinases, has lead to the potential for cardiotoxicity as well. In view of the potential cardiotoxicity of specific chemotherapies, there is a growing interest in identifying patients who are at risk of cardiotoxicity prior to becoming symptomatic or developing cardiotoxicity that may limit the use of potentially life-saving chemotherapy agents. Serological markers and novel cardiac imaging techniques have become the source of many investigations with the goal of screening patients for pre-clinical cardiotoxicity. Additionally, studies have

  4. Ultrafast Electron Transfer in Complexes of Doxorubicin with Human Telomeric G-Quadruplexes and GC Duplexes Probed by Femtosecond Fluorescence Spectroscopy. (United States)

    Changenet-Barret, Pascale; Gustavsson, Thomas; Markovitsi, Dimitra; Manet, Ilse


    Doxorubicin (DOX) is a natural anthracycline widely used in chemotherapy; its combined application as a chemotherapeutic and photodynamic agent has been recently proposed. In this context, understanding the photoinduced properties of DOX complexes with nucleic acids is crucial. Herein, the study of photoinduced electron transfer in DOX-DNA complexes by femtosecond fluorescence spectroscopy is reported. The behaviour of complexes with two model DNA structures, a G-quadruplex (G4) formed by the human telomeric sequence (Tel21) and a d(GC) duplex, is compared. The DOX affinity for these two sequences is similar. Although both 1:1 and 2:1 stoichiometries have been reported for DOX-G4 complexes, only 1:1 complexes form with the duplex. The steady-state absorption indicates a strong binding interaction with the duplex due to drug intercalation between the GC base pairs. In contrast, the interaction of DOX with Tel21 is much weaker and arises from drug binding on the G4 external faces at two independent binding sites. As observed for DOX-d(GC) complexes, fluorescence of the drug in the first binding site of Tel21 exhibits decays within a few picoseconds following a biphasic pattern; this is attributed to the existence of two drug conformations. The fluorescence of the drug in the second binding site of Tel21 shows slower decays within 150 ps. These timescales are consistent with electron transfer from the guanines to the excited drug, as favoured by the lower oxidation potential of the stacked guanines of G4 with respect to those in the duplex.

  5. Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval

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    Iwase H


    Full Text Available Yutaka Yamamoto1, Ichiro Kawano2, Hirotaka Iwase11Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Surgery, Asahino General Hospital, Kumamoto, JapanAbstract: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel. nab-paclitaxel displays greater antitumor activity and less toxicity than solvent-base paclitaxel. In a phase I trial of single nab-paclitaxel, the maximum tolerated dose was 300 mg/m2 with the dose limiting toxicities being sensory neuropathy, stomatitis, and superficial keratopathy. In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m2 over 30 minutes infusion without premedication every 3 weeks mediated a superior objective response rate and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m2 over a 3-hour injection with standard premedication. The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Weekly administration of nab-paclitaxel was also more active and displayed less toxicity compared with 100 mg/m2 docetaxel given triweekly. Nab-paclitaxel has already been approved in 42 countries for the treatment of metastatic breast cancer previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting. This review summarizes the most relevant knowledge on nab-paclitaxel for treating breast cancer

  6. Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers

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    Berge Elisabet


    Full Text Available Abstract Background The tumor suppressor pRb plays a key role regulating cell cycle arrest, and disturbances in the RB1 gene have been reported in different cancer forms. However, the literature reports contradictory findings with respect to a pro - versus anti - apoptotic role of pRb, and the consequence of alterations in RB1 to chemotherapy sensitivity remains unclear. This study is part of a project investigating alterations in pivotal genes as predictive factors to chemotherapy sensitivity in breast cancer. Results Analyzing 73 locally advanced (stage III breast cancers, we identified two somatic and one germline single nucleotide changes, each leading to amino acid substitution in the pRb protein (Leu607Ile, Arg698Trp, and Arg621Cys, respectively. This is the first study reporting point mutations affecting RB1 in breast cancer tissue. In addition, MLPA analysis revealed two large multiexon deletions (exons 13 to 27 and exons 21 to 23 with the exons 21-23 deletion occurring in the tumor also harboring the Leu607Ile mutation. Interestingly, Leu607Ile and Arg621Cys point mutations both localize to the spacer region of the pRb protein, a region previously shown to harbor somatic and germline mutations. Multiple sequence alignment across species indicates the spacer to be evolutionary conserved. All three RB1 point mutations encoded nuclear proteins with impaired ability to induce apoptosis compared to wild-type pRb in vitro. Notably, three out of four tumors harboring RB1 mutations displayed primary resistance to treatment with either 5-FU/mitomycin or doxorubicin while only 14 out of 64 tumors without mutations were resistant (p = 0.046. Conclusions Although rare, our findings suggest RB1 mutations to be of pathological importance potentially affecting sensitivity to mitomycin/anthracycline treatment in breast cancer.

  7. Effects of vitamin D on kidney histology and trpv1 channels in doxorubicin-induced nephropathy. (United States)

    Gurel, Ali; Atli, Hasan; Kaya, Nalan; Onalan, Ebru; Kuloglu, Tuncay; Aygen, Bilge


    Doxorubicin (DXR) is an antineoplastic agent of the anthracycline group, and may show nephrotoxic effects in animal models and humans. We investigated changes in kidney tissue following doxorubicin treatment and the effects of vitamin D on kidney tissue and TRPV1 channels. In this study, 24 adult male Wistar Albino rats were used. The animals were divided into four groups of six animals. During the 14-day experiment period, Group I did not have any application. 200 IU/day cholecalciferol was administered orally to Group II. Group III received 10 mg/kg single dose of DXR intraperitoneally (IP); and Group IV had a single 10 mg/kg dose of IP DXR and 200 IU/day of oral cholecalciferol. At the end of the experiment, the rats were decapitated, and their kidney tissues were removed. TRPV1 expression and apoptosis were detected in the tissue section by using immunohistochemical, TUNEL and real time-PCR (RT-PCR) techniques. The findings were examined and photographed with BH2 Olympus photomicroscope. As result of immunohistochemical staining, RT-PCR and examination with light microscope, it was found that the TRPV 1 immunoreactivity of the DXR group decreased in comparison with the control group, and the vitamin D application did not reverse this effect. Apoptosis detected by the TUNEL method tended to increase in the doxorubicin group and was relatively reversed with the administration of vitamin D. Tissue malondialdehyde (MDA) levels were observed to correlate with the findings of apoptosis. This study showed that vitamin D has anti- apoptotic and antioxidant effects on kidney tissue after DXR-induced injury.

  8. Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies. (United States)

    Herold, Nikolas; Rudd, Sean G; Ljungblad, Linda; Sanjiv, Kumar; Myrberg, Ida Hed; Paulin, Cynthia B J; Heshmati, Yaser; Hagenkort, Anna; Kutzner, Juliane; Page, Brent D G; Calderón-Montaño, José M; Loseva, Olga; Jemth, Ann-Sofie; Bulli, Lorenzo; Axelsson, Hanna; Tesi, Bianca; Valerie, Nicholas C K; Höglund, Andreas; Bladh, Julia; Wiita, Elisée; Sundin, Mikael; Uhlin, Michael; Rassidakis, Georgios; Heyman, Mats; Tamm, Katja Pokrovskaja; Warpman-Berglund, Ulrika; Walfridsson, Julian; Lehmann, Sören; Grandér, Dan; Lundbäck, Thomas; Kogner, Per; Henter, Jan-Inge; Helleday, Thomas; Schaller, Torsten


    The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP), which causes DNA damage through perturbation of DNA synthesis. Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment. Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient-derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.

  9. Pediatric heart failure therapy with beta-adrenoceptor antagonists. (United States)

    Foerster, Susan R; Canter, Charles E


    Management of chronic heart failure in pediatrics has been altered by the adult literature showing improvements in mortality and hospitalization rates with the use of beta-adrenoceptor antagonists (beta-blockers) for routine therapy of all classes of ischemic and non-ischemic heart failure. Many pediatric heart failure specialists have incorporated these agents into their routine management of pediatric heart failure related to dilated cardiomyopathy or ventricular dysfunction in association with congenital heart disease. Retrospective and small prospective case series have shown encouraging improvements in cardiac function and symptoms, but interpretation has been complicated by the high rate of spontaneous recovery in pediatric patients. A recently completed pediatric double-blind, randomized, placebo-controlled clinical trial showed no difference between placebo and two doses of carvedilol over a 6-month period of follow-up, with significant improvement of all three groups over the course of evaluation. Experience with adults has suggested that only certain beta-blockers, including carvedilol, bisoprolol, nebivolol, and metoprolol succinate, should be used in the treatment of heart failure and that patients with high-grade heart failure may derive the most benefit. Other studies surmise that early or prophylactic use of these medications may alter the risk of disease progression in some high-risk subsets, such as patients receiving anthracyclines or those with muscular dystrophy. This article reviews these topics using experience as well as data from all the recent pediatric studies on the use of beta-blockers to treat congestive heart failure, especially when related to systolic ventricular dysfunction.

  10. Biochemical characterization of the interactions between doxorubicin and lipidic GM1 micelles with or without paclitaxel loading (United States)

    Leonhard, Victoria; Alasino, Roxana V; Bianco, Ismael D; Garro, Ariel G; Heredia, Valeria; Beltramo, Dante M


    Doxorubicin (Dox) is an anthracycline anticancer drug with high water solubility, whose use is limited primarily due to significant side effects. In this study it is shown that Dox interacts with monosialoglycosphingolipid (GM1) ganglioside micelles primarily through hydrophobic interactions independent of pH and ionic strength. In addition, Dox can be incorporated even into GM1 micelles already containing highly hydrophobic paclitaxel (Ptx). However, it was not possible to incorporate Ptx into Dox-containing GM1 micelles, suggesting that Dox could be occupying a more external position in the micelles. This result is in agreement with a higher hydrolysis of Dox than of Ptx when micelles were incubated at alkaline pH. The loading of Dox into GM1 micelles was observed over a broad range of temperature (4°C–55°C). Furthermore, Dox-loaded micelles were stable in aqueous solutions exhibiting no aggregation or precipitation for up to 2 months when kept at 4°C–25°C and even after freeze–thawing cycles. Upon exposure to blood components, Dox-containing micelles were observed to interact with human serum albumin. However, the amount of human serum albumin that ended up being associated to the micelles was inversely related to the amount of Dox, suggesting that both could share their binding sites. In vitro studies on Hep2 cells showed that the cellular uptake and cytotoxic activity of Dox and Ptx from the micellar complexes were similar to those of the free form of these drugs, even when the micelle was covered with albumin. These results support the idea of the existence of different nano-domains in a single micelle and the fact that this micellar model could be used as a platform for loading and delivering hydrophobic and hydrophilic active pharmaceutical ingredients. PMID:26005348

  11. The Impact of Skin-Sparing Mastectomy With Immediate Reconstruction in Patients With Stage III Breast Cancer Treated With Neoadjuvant Chemotherapy and Postmastectomy Radiation

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    Prabhu, Roshan; Godette, Karen [Department of Radiation Oncology, Emory University, Atlanta, GA (United States); Winship Cancer Institute, Emory University, Atlanta, GA (United States); Carlson, Grant; Losken, Albert; Gabram, Sheryl [Winship Cancer Institute, Emory University, Atlanta, GA (United States); Department of Surgery, Emory University, Atlanta, GA (United States); Fasola, Carolina [Department of Radiation Oncology, Emory University, Atlanta, GA (United States); Winship Cancer Institute, Emory University, Atlanta, GA (United States); O' Regan, Ruth; Zelnak, Amelia [Winship Cancer Institute, Emory University, Atlanta, GA (United States); Department of Hematology and Medical Oncology, Emory University, Atlanta, GA (United States); Torres, Mylin, E-mail: [Department of Radiation Oncology, Emory University, Atlanta, GA (United States); Winship Cancer Institute, Emory University, Atlanta, GA (United States)


    Purpose: The safety and efficacy of skin-sparing mastectomy (SSM) with immediate reconstruction (IR) in patients with locally advanced breast cancer are unclear. The purpose of this study is to compare the outcomes of women with noninflammatory Stage III SSM with IR vs. non-SSM-treated women who underwent neoadjuvant chemotherapy and adjuvant radiation therapy (XRT). Methods and Materials: Between October 1997 and March 2010, 100 consecutive patients (40 SSM with IR vs. 60 non-SSM) with Stage III breast cancer received anthracycline- and/or taxane-based neoadjuvant chemotherapy, mastectomy, and adjuvant XRT. Clinical stage (SSM with IR vs. for non-SSM) was IIIA (75% vs. 67%), IIIB (8% vs. 18%), and IIIC (8% vs. 8%). Tumors greater than 5 cm were found in 74% vs. 69%; 97% of patients in both groups were clinically node positive; and 8% vs. 18% had T4b disease. Results: The time from initial biopsy to XRT was prolonged for SSM-IR patients (274 vs. 254 days, p = 0.04), and there was a trend toward XRT delay of more than 8 weeks (52% vs. 31%, p = 0.07) after surgery. The rate of complications requiring surgical intervention was higher in the SSM-IR group (37.5% vs. 5%, p < 0.001). The 2-year actuarial locoregional control, breast cancer-specific survival, and overall survival rates for SSM with IR vs. non-SSM were 94.7% vs. 97.4%, 91.5% vs. 86.3%, and 87.4% vs. 84.8%, respectively (p = not significant). Conclusions: In our small study with limited follow-up, SSM with IR prolonged overall cancer treatment time and trended toward delaying XRT but did not impair oncologic outcomes. Complication rates were significantly higher in this group. Longer follow-up is needed.

  12. Role of fibronectin under conditions of doxorubicin action

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    A. I. Shevtsova


    Full Text Available There is no standard as to treatment of anthracycline chemotherapy complications. The reduction of cytotoxic drugs toxicity without weakening of their antitumor action remains relevant. The extracellular matrix which key component is fibronectin is present in all tissues and it continuously undergoes controlled remodeling. So, the purpose of our work was to study the level of fibronectin in the experimental model of doxorubicin-induced cardiomyopathy and effects of this cytostatic and its co-administration with antioxidants of different nature.The level of fibronectin was measured by ELISA using monospecific antibodies against fibronectin (Sigma, USA, secondary anti-IgG labeled with horseradish peroxidase (Sigma, USA and fibronectin standard (Sigma, USA. The study was conducted on Wistar male rats with weight of 210 ± 50 g which were divided into 4 groups by 8 animals in each group: 1 – control, rats receiving saline i/p; 2 – doxorubicin 1 mg/kg i/p once a week during 4 weeks; 3 – doxorubicin by the same scheme plus 1% 2-oxoglutarate in drinking water during 4 weeks;4 – doxorubicin by the same scheme and korvitin injection 30 min before doxorubicin application once a week during 4 weeks. Obtained data indicate the effect of doxorubicin to decrease in index mass heart in 38% of animals compared to control animals; decrease in total protein concentration by 8% (Р < 0,05 and increase of the level of fibronectin by 67% (P < 0,001 in blood plasma of rats and decrease in the level of fibronectin in the heart extract by 19% (Р < 0,05 under development of doxorubicin-induced cardiotoxicity. Increased fibronectin concentration in blood plasma had strong correlation with decreased total protein concentration in blood (r=0,80 and heart extract (r=0,59 in rats with doxorubicin-induced cardiomiophaty indicating the sensitive reaction of fibronectin to development of metabolic disorders under doxorubicin influence.

  13. A myeloablative conditioning regimen for patients with impaired cardiac function undergoing allogeneic stem cell transplantation: reduced cyclophosphamide combined with etoposide and total body irradiation. (United States)

    Yoshimi, Akihide; Nannya, Yasuhito; Sakata-Yanagimoto, Mamiko; Oshima, Kumi; Takahashi, Tsuyoshi; Kanda, Yoshinobu; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo


    To circumvent the cardiac toxicity of high-dose cyclophosphamide (CY) in the myeloablative conditioning for those with cardiac comorbidity, we developed a new cardiac sparing conditioning regimen (VP/rCY/TBI) composed of 12 Gy of total body irradiation (TBI), etoposide (VP-16) (40 mg/kg), and reduced CY (40 mg/kg). We assessed the feasibility of this regimen by retrospectively comparing the outcome of VP/rCY/TBI recipients (n = 18) with that of CY/TBI recipients (n = 140). VP/rCY/TBI recipients had significantly higher cumulative dose of anthracyclines, lower ejection fraction (EF), and poorer Karnofsky performance scales (KPS) than CY/TBI recipients. The cumulative incidences of disease progression were 34.9% in VP/rCY/TBI recipients and 19.0% in CY/TBI recipients (P = 0.33). Despite poorer KPS and more cardiac comorbidity in the VP/rCY/TBI recipients, no difference in the nonprogression mortality rates was observed among recipients of the two regimens (17.5 and 14.3%, respectively, P = 0.96). Severe cardiac toxicity within 28 days after transplantation occurred in 5.9 and 3.6% of VP/rCY/TBI and CY/TBI recipients, respectively (P = 0.64). Graft rejection was not observed in VP/rCY/TBI recipients. There is a possibility that VP/rCY/TBI regimen can be safely administered for patients with pretransplantation cardiac comorbidity while preserving antineoplastic effects. These observations merit further prospective study.

  14. Is there a role for consolidative radiotherapy in the treatment of aggressive and localized Non-Hodgkin Lymphoma? A systematic review with meta-analysis

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    dos Santos Lucas


    Full Text Available Abstract Background Chemotherapy is the mainstay of non-Hodgkin lymphoma (NHL treatment. Based on expert opinion, the use of radiotherapy (RT is currently preferred in some institutions as consolidative treatment for patients with localized disease. The lack of conclusive data coming from conflicting studies about the impact of treatment demands a systematic review, which could provide the most reliable assessment for clinical decision-making. We evaluate the addition of RT post-CT, for aggressive and localized NHL (ALNHL. Methods Randomized controlled trials (RCT that evaluated chemotherapy alone versus chemotherapy plus RT were searched in databases. The outcomes were overall survival (OS, progression-free survival (PFS, overall response rate (ORR and toxicity. Risk ratio (RR and hazard ratio (HR with their respective 95% confidence intervals (CI were calculated using a fized-effect model. Results Four trials (1,796 patients met the inclusion criteria. All trials tested the use of RT after systemic therapy comprising anthracycline-based chemotherapy. This systematic review showed that RT enhances PFS after chemotherapy (hazard ratio [HR] 0.81; 95% CI 0.67-0.98; p = 0.03, with no impact on ORR and OS. Some heterogeneity between trials could limit the conclusions about OS. Toxicity data could not be pooled due to differences in reporting adverse events. Conclusions This systematic review with meta-analysis shows no improvement in survival when adding RT to systemic therapy for ALNHL. Our conclusions are limited by the available data. Further evaluations of new RT technologies and its association with biologic agents are needed.

  15. Role of glutathione-s-transferase and CYP1A1FNx012A polymorphisms in the therapy outcome of south Indian acute lymphoblastic leukemia patients

    Directory of Open Access Journals (Sweden)

    K J Suneetha


    Full Text Available Background: Polymorphisms in the drug-metabolizing enzymes are found to be associated with the inter-individual variation in response to a particular drug. Glutathione S-transferases (GSTs are involved in the metabolism of several anticancer drugs, including alkylating agents, anthracyclines, and cyclophosphamides. Aim: The present study is aimed to examine the association of GST and CYP1A1FNx012A polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL and the prognostic significance. Materials and Methods: A total of 92 immunophenotyped patients and 150 cord blood controls were genotyped by PCR for GSTM1 and GSTT1, RQ-PCR allelic discrimination assay for GSTP1 and PCR-RFLP for CYP1A1FNx012A polymorphism. Results: We have previously reported the significant association of GSTM1 (null and combined GSTP1 {(Ile/Val/ (Val/Val} /GSTM1 (null genotype with the susceptibility to ALL. No significant association was observed with GSTT1 (P=0.75 and CYP1A1FNx012A (P=0.61 for +/- and P=0.86 for -/- respectively in the susceptibility to ALL. Survival analysis was performed in 50 of the 92 patients who were followed for three years. Kaplan-Meier survival analysis for three years showed significant lower event-free survival in patients harboring GSTP1 (Ile/Val and GSTP1 (Val/Val (P=0.038 and 0.0001, respectively genotype. Cox regression analysis revealed GSTP1 as an independent prognostic marker with 6-fold higher risk with Val/Val genotype (P=0.003. Conclusions: Our results show that GSTP1 (Ile/Val polymorphism has a role in the susceptibility to ALL and also influence treatment outcome.

  16. 血管免疫母细胞性T细胞淋巴瘤治疗进展%Advances of treatment for angioimmunoblastic T-cell lymphoma

    Institute of Scientific and Technical Information of China (English)

    周志远; 张明智


    Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of peripheral T-cell lymphoma (PTCL) with aggressive behaviour and poor prognosis.Due to the rarity of the disease,few prospective controlled randomized clinical trials were conducted,and the standard therapeutic option for AITL has not been established.Although conventional anthracycline-based chemotherapy achieves response rates of up to 50 %,most of the patients relapse,the median survival time and overall survival rate are unsatisfactory.Recent studies have demonstrated that hematopietic stem cell transplantation and cyclosporine show promising efficacy in the treatment of AITL.This current review mainly focused on the advance of treatment for AITL.%血管免疫母细胞性T细胞淋巴瘤(AITL)是一种罕见的侵袭性外周T细胞淋巴瘤,预后较差.AITL发病率较低,缺乏大样本的前瞻性临床随机对照试验,标准的治疗方案尚未明确.尽管以传统蒽环类药物为基础的化疗方案缓解率达50%,但大多数患者短期内复发,中位生存时间和总体生存率均不理想.最新研究发现造血干细胞移植、环孢素等治疗AITL显示出较好的临床疗效,义章介绍AITL的治疗进展.

  17. Clinical management of primary non-acute promyelocytic leukemia acute myeloid leukemia: Practice Guidelines by the Italian Society of Hematology, the Italian Society of Experimental Hematology, and the Italian Group for Bone Marrow Transplantation. (United States)

    Morra, Enrica; Barosi, Giovanni; Bosi, Alberto; Ferrara, Felicetto; Locatelli, Franco; Marchetti, Monia; Martinelli, Giovanni; Mecucci, Cristina; Vignetti, Marco; Tura, Sante


    As many options are now available to treat patients with de novo acute myeloid leukemia, the Italian Society of Hematology and two affiliated societies (SIES and GITMO) commissioned project to an Expert Panel aimed at developing clinical practice guidelines for acute myeloid leukemia treatment. After systematic comprehensive literature review, the Expert Panel formulated recommendations for the management of primary acute myeloid leukemia (with the exception of acute promyelocytic leukemia) and graded them according to the supporting evidence. When evidence was lacking, consensus-based statements have been added. First-line therapy for all newly diagnosed patients eligible for intensive treatment should include one cycle of induction with standard dose cytarabine and an anthracycline. After achieving complete remission, patients aged less than 60 years should receive consolidation therapy including high-dose cytarabine. Myeloablative allogeneic stem cell transplantation from an HLA-compatible sibling should be performed in first complete remission: 1) in children with intermediate-high risk cytogenetics or who achieved first complete remission after the second course of therapy; 2) in adults less than 40 years with an intermediate-risk; in those aged less than 55 years with either high-risk cytogenetics or who achieved first complete remission after the second course of therapy. Stem cell transplantation from an unrelated donor is recommended to be performed in first complete remission in adults 30 years old or younger, and in children with very high-risk disease lacking a sibling donor. Alternative donor stem cell transplantation is an option in high-risk patients without a matched donor who urgently need transplantation. Patients aged less than 60 years, who either are not candidate for allogeneic stem cell transplantation or lack a donor, are candidates for autologous stem cell transplantation. We describe the results of a systematic literature review and an

  18. [San Antonio Breast Cancer Symposium -- highlights 2004]. (United States)

    Rody, A; V Minckwitz, G; Loibl, S; Kaufmann, M


    The adjuvant therapy of postmenopausal, hormonereceptor positive breast cancer patients with aromatase inhibitors in ATAC, ABCSG 8/ ARNO 95 and IES trial revealed just a benefit in terms of disease-free survival, but not for over-all survival. Thus MA-17 trial is so far the only study which could demonstrate a survival benefit for node positive disease by "extended adjuvant" therapy with letrozole. Node- and receptorpositive, postmenopausal women show a higher benefit by anthracycline containing chemotherapy in combination with tamoxifen, than by endocrine therapy alone. But tamoxifen should given sequentially to chemotherapy (Intergroup 0100/ SWOG-8814 trial). Adjuvant chemotherapy with three cycles FEC followed by three cycles docetaxel reveals a survival benefit compared to six cycles FEC, especially in women older than 50 years (PACS 01 trial). Furthermore there is evolving evidence that dose-dense, interval shortened chemotherapy is superior to standard chemotherapy in adjuvant setting. The impaired survival of receptornegative, nodalpositive breast cancer patients seems to be convert