Topotecan-Vincristine-Doxorubicin in Stage 4 High-Risk Neuroblastoma Patients Failing to Achieve a Complete Metastatic Response to Rapid COJEC: A SIOPEN Study.

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Amoroso, Loredana; Erminio, Giovanni; Makin, Guy; Pearson, Andrew D J; Brock, Penelope; Valteau-Couanet, Dominique; Castel, Victoria; Pasquet, Marlène; Laureys, Genevieve; Thomas, Caroline; Luksch, Roberto; Ladenstein, Ruth; Haupt, Riccardo; Garaventa, Alberto

2018-01-01

Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([ 123 I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate. Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m 2 /day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m 2 , and doxorubicin, 45 mg/m 2 . Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%). TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.

Ecdysteroids Sensitize MDR and Non-MDR Cancer Cell Lines to Doxorubicin, Paclitaxel, and Vincristine but Tend to Protect Them from Cisplatin

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Ana Martins

2015-01-01

Full Text Available Ecdysteroids, analogs of the insect molting hormone, are known for their various mild, nonhormonal bioactivities in mammals. Previously, we reported that less-polar ecdysteroids can modulate the doxorubicin resistance of a multidrug resistant (MDR mouse lymphoma cell line expressing the human ABCB1 transporter. Here, we describe the ability of 20-hydroxyecdysone (1 and its mono- (2 and diacetonide (3 derivatives to sensitize various MDR and non-MDR cancer cell lines towards doxorubicin, paclitaxel, vincristine, or cisplatin. Drug IC50 values with or without ecdysteroid were determined by MTT assay. Compound 3 significantly sensitized all cell lines to each chemotherapeutic except for cisplatin, whose activity was decreased. In order to overcome solubility and stability issues for the future in vivo administration of compound 3, liposomal formulations were developed. By means of their combination index values obtained via checkerboard microplate method, a formulation showed superior activity to that of compound 3 alone. Because ecdysteroids act also on non-ABCB1 expressing (sensitive cell lines, our results demonstrate that they do not or not exclusively exert their adjuvant anticancer activity as ABCB1 inhibitors, but other mechanisms must be involved, and they opened the way towards their in vivo bioactivity testing against various cancer xenografts.

Rituximab and new regimens for indolent lymphoma: a brief update from 2012 ASCO Annual Meeting

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Zhao Jiangning

2012-08-01

Full Text Available Abstract Indolent lymphoma (IL, the second most common lymphoma, remains incurable with chemotherapy alone. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone remains the standard frontline regimen for diffuse Large B –cell lymphoma, the optimal chemotherapy regimen for frontline therapy of advanced IL remains uncertain. FCR (fludarabine, cyclophosphamide, rituximab has been shown to be better than fludarabine alone and fludarabine plus cyclophosphamide for IL. In FOLL05 trial, R-CHOP was compared with R-CVP (cyclophosphamide, vincristine, prednisone and R-FM (fludarabine, mitoxantrone. The study showed that R-CHOP appears to have the best risk-benefit ratio for IL. The StiL NHL1 trial showed that BR (bendamustine, rituximab has longer progression free survival and is better tolerated than R-CHOP. Long-term complications with secondary malignancies between the two regimens appear to be comparable. In this review, new combination regimens reported at 2012 ASCO annual meeting were evaluated for frontline and salvage therapy of indolent lymphoma.

Gene trio signatures as molecular markers to predict response to doxorubicin cyclophosphamide neoadjuvant chemotherapy in breast cancerpatients

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M.C. Barros Filho

2010-12-01

Full Text Available In breast cancer patients submitted to neoadjuvant chemotherapy (4 cycles of doxorubicin and cyclophosphamide, AC, expression of groups of three genes (gene trio signatures could distinguish responsive from non-responsive tumors, as demonstrated by cDNA microarray profiling in a previous study by our group. In the current study, we determined if the expression of the same genes would retain the predictive strength, when analyzed by a more accessible technique (real-time RT-PCR. We evaluated 28 samples already analyzed by cDNA microarray, as a technical validation procedure, and 14 tumors, as an independent biological validation set. All patients received neoadjuvant chemotherapy (4 AC. Among five trio combinations previously identified, defined by nine genes individually investigated (BZRP, CLPTM1,MTSS1, NOTCH1, NUP210, PRSS11, RPL37A, SMYD2, and XLHSRF-1, the most accurate were established by RPL37A, XLHSRF-1based trios, with NOTCH1 or NUP210. Both trios correctly separated 86% of tumors (87% sensitivity and 80% specificity for predicting response, according to their response to chemotherapy (82% in a leave-one-out cross-validation method. Using the pre-established features obtained by linear discriminant analysis, 71% samples from the biological validation set were also correctly classified by both trios (72% sensitivity; 66% specificity. Furthermore, we explored other gene combinations to achieve a higher accuracy in the technical validation group (as a training set. A new trio, MTSS1, RPL37 and SMYD2, correctly classified 93% of samples from the technical validation group (95% sensitivity and 80% specificity; 86% accuracy by the cross-validation method and 79% from the biological validation group (72% sensitivity and 100% specificity. Therefore, the combined expression of MTSS1, RPL37 and SMYD2, as evaluated by real-time RT-PCR, is a potential candidate to predict response to neoadjuvant doxorubicin and cyclophosphamide in breast cancer

Malignant lymphoma of the vagina successfully treated with rituximab, adryamicin, cyclophosphamide, vincristine sulfate, and prednisolone.

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Nasu, K; Okamoto, M; Nishida, M; Takai, N; Narahara, H

2012-01-01

Primary malignant lymphoma of the vagina is extremely rare. The most common histologic subtype is diffuse large B-cell lymphoma (DLBCL). We report a case of vaginal DLBCL successfully treated with chemotherapy consisting of rituximab, adryamicin, cyclophosphamide, vincristine sulfate, and prednisolone (R-CHOP), followed by pelvic irradiation. A 44-year-old Japanese woman was admitted complaining of atypical genital bleeding and puruloid vaginal discharge. Gynecological examination showed an ulceration of the vaginal wall and a hard mass the size of a goose egg beneath the left vaginal wall, which had infiltrated to the left pelvic wall. The pathological diagnosis based on a punch biopsy taken from the vaginal tumor was non-Hodgkin's lymphoma. Based on immunohistochemical study, the tumor was subclassified as activated B-cell type DLBCL. The patient was diagnosed with Ann Arbor Stage IEA DLBCL and Stage III vaginal cancer, according to the International Federation of Gynecologists and Obstetricians (FIGO) classification system. She was successfully treated by six courses of R-CHOP, followed by radiation therapy. The patient is well without evidence of disease 13 months following the initial treatment. Little attention has been paid to the use of rituximab in addition to conventional chemotherapy and the importance of clinical and morphological subgrouping of DLBCL arising in the vagina. The present case indicates that the effects of rituximab on the prognosis of vaginal DLBCL must be evaluated, and that clinical use of immunophenotypic subgrouping should be considered for vaginal DLBCL.

Treatment of Children and Adolescents With Hodgkin Lymphoma Without Radiotherapy for Patients in Complete Remission After Chemotherapy

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Dörffel, Wolfgang; Rühl, Ursula; Lüders, Heike

2013-01-01

1995 and 2001, 925 patients with classical HL (cHL) were registered from seven European countries in German Society of Pediatric Oncology and Hematology Hodgkin Lymphoma Trial 95. Patients in treatment group 1 (TG1; early stages) received two cycles of vincristine, prednisone, procarbazine......, and doxorubicin or vincristine, prednisone, etoposide, and doxorubicin chemotherapy; additional two or four cycles of cyclophosphamide, vincristine, prednisone, and procarbazine were added in TG2 (intermediate stages) or TG3 (advanced stages), respectively. Patients in CR (assessed by computed tomography...... results in TG3 (82.6% ± 5.4% v 88.7% ± 2.0%, P = .259). Reduction of the standard radiation dose from 25 to 20 Gy did not increase failure rate. CONCLUSION: RT can be omitted in early stage HL in so defined CR following this chemotherapy. RT with 20(-35) Gy proved to be sufficient in patients...

Advanced neuroblastoma: improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26.

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Shafford, E A; Rogers, D W; Pritchard, J

1984-07-01

Forty-two children, all over one year of age, were given vincristine, cyclophosphamide, and sequentially timed cisplatin and VM-26 (OPEC) or OPEC and doxorubicin (OPEC-D) as initial treatment for newly diagnosed stage III or IV neuroblastoma. Good partial response was achieved in 31 patients (74%) overall and in 28 (78%) of 36 patients whose treatment adhered to the chemotherapy protocol, compared with a 65% response rate achieved in a previous series of children treated with pulsed cyclophosphamide and vincristine with or without doxorubicin. Only six patients, including two of the six children whose treatment did not adhere to protocol, failed to respond, but there were five early deaths from treatment-related complications. Tumor response to OPEC, which was the less toxic of the two regimens, was at least as good as tumor response to OPEC-D. Cisplatin-induced morbidity was clinically significant in only one patient and was avoided in others by careful monitoring of glomerular filtration rate and hearing. Other centers should test the efficacy of OPEC or equivalent regimens in the treatment of advanced neuroblastoma.

Chromonychia Secondary to Chemotherapy

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Marien Lopes

2013-06-01

Full Text Available Chemotherapy drugs can affect the skin and its appendages. Several clinical presentations can be observed, depending on the affected structure. The most common dermatological side effect is chromonychia. The main causative agents are: (1 cyclophosphamide, which can provoke a diffuse, black pigmentation, longitudinal striae and dark grey pigmentation located proximally on the nails; (2 doxorubicin, which promotes dark brown bands alternating with white striae and dark brown pigmentation in transverse bands, and (3 hydroxyurea, which produces a distal, diffuse, dark brown pigmentation. In the majority of cases, the effects are reversible after the suspension of the causative agent for a few months. We report a patient who developed chromonychia while undergoing treatment with cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine for acute lymphocytic leukemia.

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

International Nuclear Information System (INIS)

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

1983-01-01

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

Treatment for non-Hodgkin's lymphoma (stage I, II) of the elderly: usefulness of local and regional irradiation and reduced dose chemotherapy

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Oguchi, Masahiko; Izuno, Itaru; Takei, Kazuyoshi; Shikama, Naoto; Sasaki, Shigeru; Gomi, Koutarou; Sone, Shusuke

1997-01-01

Purpose: To examine the usefulness and safety of a new treatment regimen consisting of irradiation to the involved area and adjacent lymph node area, and reduced dose chemotherapy for elderly patients with non-Hodgkin's lymphoma. Methods and Materials: The core of this study was 38 elderly patients older than 65 years old with intermediate or high grade non-Hodgkin's lymphoma, and concomitantly suffering from some other geriatric disease. They received involved area irradiation (40 Gy), adjacent lymph node irradiation (30 Gy), and reduced dose chemotherapy (two cycles of 50-70% ACOP: Doxorubicin, Cyclophosphamide, Vincristine, Prednisone or 70% MACOP-B: Doxorubicin, Cyclophosphamide, Vincristine, Methotrexate, Bleomycin, Prednisone for 4 weeks). Results: The completion rate of the treatment regimen was 100%. The 5-year local control rate was 98%. The 5-year disease-free survival rate and the 5-year cause-specific survival rate for all patients were 70 and 82%, respectively. No treatment deaths were observed, and the rate of serious complications arising from the treatment was 3%. Conclusions: The newly conducted treatment regimen proved to be safe and useful for elderly patients with non-Hodgkin's lymphoma concomitantly suffering from some other geriatric disease

Single-Institution Experience in the Treatment of Primary Mediastinal B Cell Lymphoma Treated With Immunochemotherapy in the Setting of Response Assessment by {sup 18}Fluorodeoxyglucose Positron Emission Tomography

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Pinnix, Chelsea C. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Dabaja, Bouthaina, E-mail: bdabaja@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Ahmed, Mohamed Amin [Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Chuang, Hubert H. [Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Costelloe, Colleen [Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Wogan, Christine F.; Reed, Valerie [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Romaguera, Jorge E.; Neelapu, Sattva; Oki, Yasuhiro [Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Rodriguez, M. Alma [Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Office of Medical Affairs, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Fayad, Luis; Hagemeister, Frederick B.; Nastoupil, Loretta; Turturro, Francesco; Fowler, Nathan; Fanale, Michelle A. [Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Nieto, Yago; Khouri, Issa F.; Ahmed, Sairah [Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); and others

2015-05-01

Purpose: Excellent outcomes obtained after infusional dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (R-EPOCH) alone have led some to question the role of consolidative radiation therapy (RT) in the treatment of primary mediastinal B cell lymphoma (PMBL). We reviewed the outcomes in patients treated with 1 of 3 rituximab-containing regimens (cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]; hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone [R-HCVAD], or R-EPOCH) with or without RT. We also evaluated the ability of positron emission tomography–computed tomography (PET-CT) to identify patients at risk of relapse. Methods and Materials: We retrospectively identified 97 patients with diagnoses of stage I/II PMBCL treated at our institution between 2001 and 2013. The clinical characteristics, treatment outcomes, and toxicity were assessed. We analyzed whether postchemotherapy PET-CT could identify patients at risk for progressive disease according to a 5 point scale (5PS) Deauville score assigned. Results: Among 97 patients (median follow-up time, 57 months), the 5-year overall survival rate was 99%. Of patients treated with R-CHOP, 99% received RT; R-HCVAD, 82%; and R-EPOCH, 36%. Of 68 patients with evaluable end-of-chemotherapy PET-CT scans, 62% had a positive scan (avidity above that of the mediastinal blood pool [Deauville 5PS = 3]), but only 9 patients experienced relapse (n=1) or progressive disease (n=8), all with a 5PS of 4 to 5. Of the 25 patients who received R-EPOCH, 4 experienced progression, all with 5PS of 4 to 5; salvage therapy (RT and autologous stem cell transplantation) was successful in all cases. Conclusion: Combined modality immunochemotherapy and RT is well tolerated and effective for treatment of PMBCL. A postchemotherapy 5PS of 4 to 5, rather than 3 to 5, can identify patients at high risk of progression who should be considered for therapy beyond

Single-Institution Experience in the Treatment of Primary Mediastinal B Cell Lymphoma Treated With Immunochemotherapy in the Setting of Response Assessment by 18Fluorodeoxyglucose Positron Emission Tomography

International Nuclear Information System (INIS)

Pinnix, Chelsea C.; Dabaja, Bouthaina; Ahmed, Mohamed Amin; Chuang, Hubert H.; Costelloe, Colleen; Wogan, Christine F.; Reed, Valerie; Romaguera, Jorge E.; Neelapu, Sattva; Oki, Yasuhiro; Rodriguez, M. Alma; Fayad, Luis; Hagemeister, Frederick B.; Nastoupil, Loretta; Turturro, Francesco; Fowler, Nathan; Fanale, Michelle A.; Nieto, Yago; Khouri, Issa F.; Ahmed, Sairah

2015-01-01

Purpose: Excellent outcomes obtained after infusional dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (R-EPOCH) alone have led some to question the role of consolidative radiation therapy (RT) in the treatment of primary mediastinal B cell lymphoma (PMBL). We reviewed the outcomes in patients treated with 1 of 3 rituximab-containing regimens (cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]; hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone [R-HCVAD], or R-EPOCH) with or without RT. We also evaluated the ability of positron emission tomography–computed tomography (PET-CT) to identify patients at risk of relapse. Methods and Materials: We retrospectively identified 97 patients with diagnoses of stage I/II PMBCL treated at our institution between 2001 and 2013. The clinical characteristics, treatment outcomes, and toxicity were assessed. We analyzed whether postchemotherapy PET-CT could identify patients at risk for progressive disease according to a 5 point scale (5PS) Deauville score assigned. Results: Among 97 patients (median follow-up time, 57 months), the 5-year overall survival rate was 99%. Of patients treated with R-CHOP, 99% received RT; R-HCVAD, 82%; and R-EPOCH, 36%. Of 68 patients with evaluable end-of-chemotherapy PET-CT scans, 62% had a positive scan (avidity above that of the mediastinal blood pool [Deauville 5PS = 3]), but only 9 patients experienced relapse (n=1) or progressive disease (n=8), all with a 5PS of 4 to 5. Of the 25 patients who received R-EPOCH, 4 experienced progression, all with 5PS of 4 to 5; salvage therapy (RT and autologous stem cell transplantation) was successful in all cases. Conclusion: Combined modality immunochemotherapy and RT is well tolerated and effective for treatment of PMBCL. A postchemotherapy 5PS of 4 to 5, rather than 3 to 5, can identify patients at high risk of progression who should be considered for therapy beyond

A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer.

Science.gov (United States)

Tu, Yifan; Hershman, Dawn L; Bhalla, Kapil; Fiskus, Warren; Pellegrino, Christine M; Andreopoulou, Eleni; Makower, Della; Kalinsky, Kevin; Fehn, Karen; Fineberg, Susan; Negassa, Abdissa; Montgomery, Leslie L; Wiechmann, Lisa S; Alpaugh, R Katherine; Huang, Min; Sparano, Joseph A

2014-07-01

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m(2) every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo.

Acute toxicity of adjuvant doxorubicin and cyclophosphamide for early breast cancer - a retrospective review of Chinese patients and comparison with an historic Western series

International Nuclear Information System (INIS)

Ma, Brigette; Yeo, Winnie; Hui, Pun; Ho, Wing M.; Johnson, Philip J.

2002-01-01

A cohort of 85 Chinese breast cancer patients who received adjuvant chemotherapy with doxorubicin and cyclophosphamide was found to have a significantly higher incidence of grade 3 (n=44, 52%) and grade 4 (n=21, 25%) neutropenia when compared with an historic Western cohort. Also noted was a higher incidence of hepatotoxicity (n=8, 9%). When compared to Caucasian patients, the higher myelotoxicity in our patients may be related to ethnic variation in susceptibility to chemotherapy-related toxicity, lower body mass index with higher percentage of body fat composition, and the popular practice of concurrent alternative medicine during chemotherapy. The higher incidence of hepatoxicity was possibly associated with endemic chronic hepatitis B infection in this geographical area

Ewing sarcoma

International Nuclear Information System (INIS)

Hamanoue, Satoshi; Makimoto, Atsushi

2007-01-01

Ewing sarcoma is the second most frequent primary bone cancer affecting children or young adults. Advances in molecular biology have revealed common chromosomal translocations such as EWS-FLI1 among Ewing sarcoma and related diseases such as primitive neuroectodermal tumor (PNET), so these are considered as Ewing sarcoma family tumor (ESFT). Although fewer than 10% of patients with ESFT survived before establishment of modern multiagent chemotherapy, the multimodal therapeutic regimens including combination chemotherapy, radiotherapy, and surgery can cure 60% of patients with localized disease, due to the collaborative research in European-American or the international trials. The standard chemotherapy for localized ESFT now comprises vincristine, actinomycin D, cyclophosphamide and doxorubicin (VACD) in Europe or vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC-IE) in North America. Meanwhile, those with metastatic disease have a much worse outcome with an approximately 10-30% 5-year event-free survival rate. New American-European collaborative trials such as EURO-E.W.I.N.G. 99 are in progress for further improvement of the cure rate in localized and metastatic ESFT. In Japan, Japan Ewing Sarcoma Study Group (JESS) phase II clinical trial for localized ESFT, and some clinical trials including new drugs are ongoing and waiting for results. (author)

Muscular pseudotumor of the breast following doxorubicin and radiation therapy for oat cell carcinoma of the lung

International Nuclear Information System (INIS)

Wergowske, G.; Chang, J.C.; Marger, D.

1982-01-01

Two male patients developed muscular pseudotumor of the breast following combined treatment of radiation and chemotherapy with cyclophosphamide, doxorubicin, methotrexate and procarbazine for oat cell carcinoma of the lung. The pathologic findings of the biopsy specimens revealed muscle and capillary changes similar to previously reported myocardiotoxicity from doxorubicin and radiation therapy. Discussed is a possible additive or synergistic toxic effect of doxorubicin and radiation therapy in the development of muscular pseudotumor of the breast

Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

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Tan, A R; Johannes, H; Rastogi, P; Jacobs, S A; Robidoux, A; Flynn, P J; Thirlwell, M P; Fehrenbacher, L; Stella, P J; Goel, R; Julian, T B; Provencher, L; Bury, M J; Bhatt, K; Geyer, C E; Swain, S M; Mamounas, E P; Wolmark, N

2015-01-01

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer

Science.gov (United States)

Tabchy, Adel; Valero, Vicente; Vidaurre, Tatiana; Lluch, Ana; Gomez, Henry; Martin, Miguel; Qi, Yuan; Barajas-Figueroa, Luis Javier; Souchon, Eduardo; Coutant, Charles; Doimi, Franco D; Ibrahim, Nuhad K; Gong, Yun; Hortobagyi, Gabriel N; Hess, Kenneth R; Symmans, W Fraser; Pusztai, Lajos

2010-01-01

Purpose We examined in a prospective, randomized, international clinical trial the performance of a previously defined 30-gene predictor (DLDA-30) of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil, doxorubicin, cyclophosphamide (T/FAC) chemotherapy, and assessed if DLDA-30 also predicts increased sensitivity to FAC-only chemotherapy. We compared the pCR rates after T/FAC versus FAC×6 preoperative chemotherapy. We also performed an exploratory analysis to identify novel candidate genes that differentially predict response in the two treatment arms. Experimental Design 273 patients were randomly assigned to receive either weekly paclitaxel × 12 followed by FAC × 4 (T/FAC, n=138), or FAC × 6 (n=135) neoadjuvant chemotherapy. All patients underwent a pretreatment FNA biopsy of the tumor for gene expression profiling and treatment response prediction. Results The pCR rates were 19% and 9% in the T/FAC and FAC arms, respectively (pcancers. PMID:20829329

Diagnosis and management of lymphoma in a green iguana (Iguana iguana).

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Folland, Douglas W; Johnston, Matthew S; Thamm, Douglas H; Reavill, Drury

2011-10-01

CASE DESCRIPTION-A 2-year-old female green iguana was examined for anorexia and swelling and pain on palpation in the cranial cervical area. CLINICAL FINDINGS-Marked soft tissue swelling in the cranial cervical area with corresponding cystic swellings in the pharynx were noted. The iguana was considered to be 50% under the expected body weight, given diet and husbandry conditions. The WBC count was markedly elevated, characterized by heterophilia and lymphocytosis. Surgical exploration of the cranial cervical area and histologic and microbial testing identified lymphoma with secondary infection as the cause of the swelling. TREATMENT AND OUTCOME-The tumor was initially treated with a single 10-Gy fraction of radiation directed at the masses in the neck. A vascular access port was placed in the ventral abdominal vein, and a canine chemotherapy protocol was modified for use in the iguana. During the course of treatment, the protocol was modified twice. At 1,008 days from the initiation of treatment, the iguana appeared to be in remission. CLINICAL RELEVANCE-To our knowledge, this is the first reported use of radiation with doxorubicin, vincristine, cyclophosphamide, and prednisone to successfully manage lymphoma in a reptile. A vascular access port was used effectively for drug administration for an extended period. The doxorubicin, vincristine, cyclophosphamide, and prednisone protocol appeared to be safe and effective in this iguana for the management of lymphoma.

Pegylated liposomal doxorubicin (Lipo-Dox®) combined with cyclophosphamide and 5-fluorouracil is effective and safe as salvage chemotherapy in taxane-treated metastatic breast cancer: an open-label, multi-center, non-comparative phase II study

International Nuclear Information System (INIS)

Rau, Kun-Ming; Lin, Yung-Chang; Chen, Yen-Yang; Chen, Jen-Shi; Lee, Kuan-Der; Wang, Cheng-Hsu; Chang, Hsien-Kun

2015-01-01

Anthracycline and taxane are classes of drugs that are frequently used in the adjuvant and palliative settings of metastatic breast cancer (MBC); however, treatment failure occurs in most cases. Limited data demonstrated favorable response in MBC after previous taxane-based treatment. The aim of this study was to evaluate the efficacy and safety of pegylated liposomal doxorubicin (Lipo-Dox®) used as part of a combination salvage therapy for patients with MBC whose tumors progressed during or after taxane-based treatment. Patients with MBC who failed to respond to previous taxane-based treatments were recruited. Treatment with pegylated liposomal doxorubicin (40 mg/m 2 ), cyclophosphamide (500 mg/m 2 ), and 5-fluorouracil (500 mg/m 2 ) was administered every 3 weeks. Tumor response to treatment was determined by using the Response Evaluation Criteria in Solid Tumor criteria version 1.0, and left ventricular ejection fraction was measured before and after treatment using echocardiography. Each patient was followed for 30 days after the last dose of study medication or until resolution/stabilization of any drug-related adverse event. Forty-five patients were recruited. As of December 2012, the median follow-up duration was 29.8 months, the overall response rate was 41.9 %, the median progression-free survival was 8.2 months, and the median overall survival was 36.6 months for all treated patients. Grade 3/4 neutropenia, leucopenia, and neutropenic fever were observed in 14 %, 9 %, and 1 % of the cycles, respectively. Other non-hematologic adverse effects were mild to moderate and were manageable. No decrease in left ventricular ejection function was noted. This regimen of combined of pegylated liposomal doxorubicin, cyclophosphamide, and 5-fluorouracil exhibited a promising overall response rate, progression-free survival rate, and overall survival rate, with a safe cardiac toxicity profile and manageable adverse effects. This regimen could be considered as a

Outcomes of autologous transplantation for multiple myeloma according to different induction regimens

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Edvan de Queiroz Crusoe

2014-01-01

Full Text Available Background: Induction therapy followed by high-dose chemotherapy and autologous transplantation is the standard treatment for suitable patients with multiple myeloma. Objective: The aim of this study was to assess whether induction therapy with thalidomidecontaining regimens was associated with improved results compared to vincristine, doxorubicin, and dexamethasone, and whether cyclophosphamide, thalidomide, and dexamethasone were associated with better results than thalidomide and dexamethasone. Methods: The records of 152 patients who underwent autologous transplantation at this institution from August of 2004 to January of 2012 were reviewed, selecting those with at least partial response to a maximum of eight cycles of induction therapy and sufficient follow-up information for analysis. Results: This study included 89 patients; 44 were female, with a mean age of 55 years (there was a significant trend for increasing age over the years of the study.The median number of induction therapy cycles was four, again with a trend of increase over the years.At least a very good partial response to induction therapy was achieved more often in the cyclophosphamide, thalidomide, and dexamethasone group (61.1% and in the thalidomide and dexamethasone group (59.2% than in the vincristine, doxorubicin, and dexamethasone group (16.2%. The overall median progression-free survival was 34 months, with no statistically significant difference between the three groups. The overall median survival was not reached, and there was no significant difference between the three groups; the estimated five-year overall survival was 55%. Conclusion: Although the quality of responses appeared to be better with thalidomidecontaining regimens, these improvements did not translate into improved long-term outcomes. Given its track record, cyclophosphamide, thalidomide, and dexamethasone is currently considered the preferred regimen for first-line induction therapy in the

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

Science.gov (United States)

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

1993-03-01

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

Cyclophosphamide

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... Cyclophosphamide is in a class of medications called alkylating agents. When cyclophosphamide is used to treat cancer, it ... pharmacist if you are allergic to cyclophosphamide, other alkylating agents such as bendamustine (Treanda®), busulfan (Myerlan®, Busulfex®), carmustine ( ...

Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.

Science.gov (United States)

Loi, Sherene; Sirtaine, Nicolas; Piette, Fanny; Salgado, Roberto; Viale, Giuseppe; Van Eenoo, Françoise; Rouas, Ghizlane; Francis, Prudence; Crown, John P A; Hitre, Erika; de Azambuja, Evandro; Quinaux, Emmanuel; Di Leo, Angelo; Michiels, Stefan; Piccart, Martine J; Sotiriou, Christos

2013-03-01

Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes. We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. There was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor

Analysis of treatment outcomes for primary tonsillar lymphoma

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Lee, Yun Hee [Dept. of Radiation Oncology, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju (Korea, Republic of); Cho, Seok Goo; Jung, Seung Eun; Kim, Sung Hoon; O, Joo Hyun; Park, Gyeong Sin; Yang, Suk Woo; Lee, In Seok; Rhee, Chin; Kook; Choi, Byung Ock [Catholic University Lymphoma Group (CULG), Seoul St. Mary' s Hospital, College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of)

2016-12-15

Although each Waldeyer’s ring sub-site is considered an independent prognostic factor, few studies have assessed the prognosis and treatment of tonsillar lymphoma. Treatment outcomes were analyzed in patients with primary tonsillar lymphoma who were treated with chemotherapy and radiotherapy (RT). Nineteen patients with diffuse large B-cell lymphoma were evaluated, with a median follow-up of 53 months. Age, sex, and histology, amongst other factors, were reviewed. Progression-free survival (PFS) and overall survival (OS) rates were analyzed. Most patients had Ann Arbor stage I-II (94.7%), IPI score of 0 (89.5%), and complete remission after chemotherapy (89.5%). The 5-year PFS and OS rates were 74.6% and 80%, respectively. In univariate analysis, the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen resulted in a better PFS than the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen (88.9% vs. 50.0%; p = 0.053). RT dose was related to the survival outcome (p = 0.010 for PFS, p = 0.044 for OS). Patients were classified into the CHOP + RT (>40 Gy) group and R-CHOP + RT (≤40 Gy) group. The 5-year PFS rates were 50% in the CHOP + RT group, and 100 % in the R-CHOP + RT group (p = 0.018). The 5-year OS rates were 66.7% and 100%, respectively (p = 0.087). Primary tonsillar lymphoma patients typically have favorable outcomes. Chemotherapy (R-CHOP) combined with relatively lower dose consolidative RT may be safe and effective for primary tonsillar lymphoma.

[Diffuse large B-cell lymphoma complicated with drug-induced vasculitis during administration of pegfilgrastim].

Science.gov (United States)

Ito, Yuta; Noda, Kentaro; Aiba, Keisuke; Yano, Shingo; Fujii, Tsunehiro

A 59-year-old female with diffuse large B-cell lymphoma was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen. In addition, we administered pegfilgrastim for treating chemotherapy-induced febrile neutropenia. She complained of fever and neck and chest pain a few days after pegfilgrastim administration during the third and fourth courses of R-CHOP. Radiological imaging revealed an inflammation of large vessels, which led to the diagnosis of drug-associated vasculitis. We confirmed that vasculitis observed in this case was caused by pegfilgrastim administration because similar symptoms appeared with both injections of pegfilgrastim.

Diffuse large B-cell lymphoma of the oral cavity

International Nuclear Information System (INIS)

Carlos Bortoluzzi, Marcelo

2010-01-01

The authors report a case of diffuse large B-cell lymphoma (DLBL) of the oral cavity. The patient was a 73-year-old white man who first presented at the Division of Stomatology with a large nodular mass in the hard palate and a nodular lesion in the upper lip, which were diagnosed as DLBL. The patient was treated with eight cycles of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone), but the disease recurred 22 months after the end of the therapy. Both primary sites hard palate and upper lip were involved again and the patient was resubmitted to chemotherapy. (author)

Cyclophosphamide Injection

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... Cyclophosphamide is in a class of medications called alkylating agents. When cyclophosphamide is used to treat cancer, it ... pharmacist if you are allergic to cyclophosphamide, other alkylating agents such as bendamustine (Treanda®), busulfan (Myerlan®), Busulfex®), carumustine ( ...

Extraskeletal ewing's sarcoma family of tumors in adults. Prognostic factors and clinical outcome

International Nuclear Information System (INIS)

Tural, D.; Molinas Mandel, N.; Dervisoglu, S.

2012-01-01

The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with extraskeletal Ewing's sarcoma. Data of patients with extraskeletal Ewing's sarcoma followed up at our center between 1997 and 2010 were retrospectively analyzed. The median age of 27 patients was 24 years (range, 16-54 years). The median follow-up was 31.8 months (range, 6-144 months). Tumor size was between 1.5 and 14 cm (median: 8 cm). Eighty-five percent of patients had localized disease at presentation and 15% had metastatic disease. Local therapy was surgery alone in 16% of patients, surgery combined with radiotherapy in 42% and radiotherapy alone in 27%. All patients were treated with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, alternating with ifosfamide and etoposide every 3 weeks. In patients with localized disease at presentation, the 5-year event-free survival and overall survival were 59.7 and 64.5%, respectively. At univariate analysis, patients with tumor size ≥8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size 8≥ cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. Prognostic factors were similar to primary osseous Ewing's sarcomas. Adequate surgical resection, aggressive chemotherapy (vincristine, doxorubicin, cyclophosphamide and actinomycin-D alternating with ifosfamide and etoposide) and radiotherapy if indicated are the recommended therapy for patients with extraskeletal Ewing's sarcoma. (author)

Extraskeletal Ewing's sarcoma family of tumors in adults: prognostic factors and clinical outcome.

Science.gov (United States)

Tural, Deniz; Molinas Mandel, Nil; Dervisoglu, Sergulen; Oner Dincbas, Fazilet; Koca, Sedat; Colpan Oksuz, Didem; Kantarci, Fatih; Turna, Hande; Selcukbiricik, Fatih; Hiz, Murat

2012-05-01

The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with extraskeletal Ewing's sarcoma. Data of patients with extraskeletal Ewing's sarcoma followed up at our center between 1997 and 2010 were retrospectively analyzed. The median age of 27 patients was 24 years (range, 16-54 years). The median follow-up was 31.8 months (range, 6-144 months). Tumor size was between 1.5 and 14 cm (median: 8 cm). Eighty-five percent of patients had localized disease at presentation and 15% had metastatic disease. Local therapy was surgery alone in 16% of patients, surgery combined with radiotherapy in 42% and radiotherapy alone in 27%. All patients were treated with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, alternating with ifosfamide and etoposide every 3 weeks. In patients with localized disease at presentation, the 5-year event-free survival and overall survival were 59.7 and 64.5%, respectively. At univariate analysis, patients with tumor size ≥ 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size 8 ≥ cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. Prognostic factors were similar to primary osseous Ewing's sarcomas. Adequate surgical resection, aggressive chemotherapy (vincristine, doxorubicin, cyclophosphamide and actinomycin-D alternating with ifosfamide and etoposide) and radiotherapy if indicated are the recommended therapy for patients with extraskeletal Ewing's sarcoma.

Vincristine-induced blindness: a case report and review of literature.

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Adhikari, Subodh; Dongol, Raj Man; Hewett, Yvonne; Shah, Binay Kumar

2014-11-01

Neurotoxicity is a dose-limiting side-effect of vincristine therapy. Blindness is a rare central neurotoxicity of vincristine with few case reports. In the present article, we report a rare case of vincristine-induced blindness in a patient with diffuse large B cell lymphoma. Literature search identified eleven published cases of vincristine-induced blindness. We reviewed patient characteristics, chemotherapy used and type of blindness. Vincristine-induced blindness is rare and unpredictable. Prompt recognition and discontinuation of vincristine may lead to recovery of vision. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

R-hyper-CVAD versus R-CHOP/cytarabine with high-dose therapy and autologous haematopoietic stem cell support in fit patients with mantle cell lymphoma: 20 years of single-center experience.

Science.gov (United States)

Widmer, Fabienne; Balabanov, Stefan; Soldini, Davide; Samaras, Panagiotis; Gerber, Bernhard; Manz, Markus G; Goede, Jeroen S

2018-02-01

Standard of care for untreated mantle cell lymphoma (MCL) is still debated. At the University Hospital Zurich, advanced MCL in physically fit patients is treated either with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone induction followed by consolidating high-dose chemotherapy and autologous stem cell support (R-CHOP/HD-ASCT), or with rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate-cytarabine (R-hyper-CVAD/MTX-AraC) without consolidating HD-ASCT upon physicians' and patients' choice. We retrospectively analysed the outcome and therapy tolerance in patients with MCL treated with R-CHOP/HD-ASCT or R-hyper-CVAD/MTX-AraC at the University Hospital Zurich between January 1996 and January 2016. Forty-three patients were included; 29 patients received R-CHOP/HD-ASCT and 14 patients R-hyper-CVAD/MTX-AraC. Mean age at diagnosis was 54.4 years (range 38-68 years). Thirty-five patients (81.4%) completed the entire first-line therapy (n = 24 in the R-CHOP/HD-ASCT group, n = 11 in the R-hyper-CVAD group). Of those, all patients responded and 97% achieved a complete remission (CR). With a mean follow-up of 5.7 years 10-year progression-free survival (PFS) for all patients was 32% and overall survival (OS) was 76%, with no difference between the two therapy groups. Complication-induced hospitalisation rate, haematological toxicity and economic burden were significantly higher in the R-hyper-CVAD therapy group. In contrast, quality of life and global health state were better in the R-hyper-CVAD therapy group. Both first-line therapies showed similar outcome with a median OS longer than 10 years. Due to significantly lower haematological toxicity and lower economic burden, we recommend R-CHOP/HD-ASCT as first-line therapy in fit adult patients with advanced MCL.

Positive response to neoadjuvant cyclophosphamide and doxorubicin in topoisomerase II nonamplified/HER2/neu negative/polysomy 17 absent breast cancer patients

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Henry G Kaplan

2010-08-01

Full Text Available Henry G Kaplan1, Judith A Malmgren2,3, Mary Atwood1, Lynn C Goldstein41Swedish Cancer Institute at Swedish Medical Center, Seattle, Washington, USA; 2HealthStat Consulting Inc., Seattle, Washington, USA; 3School of Public Health and Community Medicine, Department of Epidemiology, University of Washington, Seattle, Washington, USA; 4PhenoPath Laboratories, Seattle, Washington, USAPurpose: Human epidermal growth factor receptor 2 (HER2/neu, topoisomerase II alpha (TOP2A, and polysomy 17 may predict tumor responsiveness to doxorubicin (DOX therapy.Methods: We identified neoadjuvant DOX/cyclophosphamide treated breast cancer patients in our registry from 1997 to 2008 with sufficient tissue for testing (n = 34. Fluorescence in situ hybridization (FISH testing was done on deparaffinized tissue sections pretreated using vendor’s standard protocol modification, and incubated with US Food and Drug Administration approved Abbott Diagnostics Vysis PathVysion™ probe set, including Spectrum-Green-conjugated probe to a-satellite DNA located at the centromere of chromosome 17 (17p11.1–q11.1 and a Spectrum-Orange-conjugated probe to the TOP2A gene. Morphometric analysis was performed using a MetaSystems image analysis system. Manual counting was performed on all samples in which autofluorescence and/or artifact prevented the counting of sufficient numbers of cells. A ratio >2.0 was considered positive for TOP2A amplification. Polysomy 17 (PS17 presence was defined as signals of ≥2.5. Outcomes were pathological complete response (pCR, partial response (PR, and nonresponse (NR.Results: Of 34 patients tested, one was TOP2A amplified (hormone receptor negative/HER2 ­negative, partial responder. The subset of TOP2A nonamplified, HER2 negative, and PS17 absent (n = 23 patients had treatment response: pCR = 2 (9%, PR = 14 (61%, and NR = 7 (30%. Including the two PS17 present and HER2-positive patients (n = 33, 76% of TOP2A nonamplified patients had pCR or PR

[Treatment of non-Hodgkin's lymphoma associated with acquired immnodeficiency syndrome (AIDS) at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán].

Science.gov (United States)

Uriarte-Duque, Juan; Hernández-Riverab, Gabriela

2006-01-01

Survival in patients with acquired immunodeficiency syndrome (AIDS) related non-Hodgkin's Lymphoma has improved with the use of High Active Antiretroviral Therapy (HAART) and less toxic chemotherapy. Clinical characteristics and outcome among patients treated for AIDS related non-Hodgkin's Lymphoma are described. Nine patients were studied retrospectively. Overall survival (OS) and Free Disease Survival (FDS) using a Kaplan-Meier model were analyzed. Patients received (DA-EPOCH) etoposide, prednisone, vincristine, doxorubicin and cyclophosphamide. The overall Survival was 18 months and 13 month Free Disease Survival with a median follow-up of 16 months showing full response in 8/9 patients was observed. A very satisfactory treatment response in this group of patients expressed as an increased Overall Survival was noted.

Vincristine induced cortical blindness: An alarming but reversible side effect

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Sidharth Totadri

2016-10-01

Full Text Available Vincristine is one of the commonest chemotherapeutic agents in the practice of pediatric oncology. Although peripheral neuropathy is a dose limiting adverse event, blindness secondary to vincristine is seldom reported. We describe a child with Wilms tumor who developed transient visual loss after administration of vincristine. The child underwent early surgery and vincristine was re-introduced at reduced doses and gradually escalated to full dose while closely monitoring for recurrence. Blindness is a distressing adverse event, and re-exposure to the offending agent involves a conscientious decision.

Primary Hepatic Lymphoma Mimicking Cholangiocarcinoma

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Foroogh Forghani1,

2017-07-01

Full Text Available Primary hepatic lymphoma (PHL presenting with obstructive jaundice is rare and can mimic a preoperative diagnosis of cholangiocarcinoma. We should consider PHL in patients with radiological hepatic disease with normal serum alpha-fetoprotein and carcinoembryonic antigen levels, and elevated lactate dehydrogenase. We present the case of a 67-year-old male with no significant medical history presented with abdominal pain, jaundice, fever, and abnormal liver function tests. Abdominal sonography and computed tomography scan suggested a diagnosis of obstructive jaundice and cholangitis due to cholangiocarcinoma (Klatskin tumor. A subsequent liver biopsy diagnosed PHL, and the patient was treated with combination chemotherapy, including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP. PHL should be considered in patients presenting with biliary obstruction.

Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma

DEFF Research Database (Denmark)

Czuczman, Myron S; Hess, Georg; Gadeberg, Ole V

2012-01-01

An international, Phase II trial was conducted to assess two doses of ofatumumab, a human CD20 monoclonal antibody, combined with cyclophosphamide (750 mg/m(2) ), doxorubicin (50 mg/m(2) ), prednisone (100 mg days 3-7) and vincristine (1·4 mg/m(2) ) (O-CHOP), as frontline treatment for follicular...... lymphoma (FL). 59 patients with previously untreated FL were randomized to ofatumumab 500 mg (n = 29) or 1000 mg (n = 30) day 1, with CHOP on day 3 every 3 weeks for six cycles. Median duration of FL was 0·1 years for both dose groups; 34% and 38% of patients had high-risk Follicular Lymphoma International...

Leuconostoc sp. Meningitis in a Patient Treated with Rituximab for Mantle Cell Lymphoma

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Hrvoje Holik

2015-09-01

Full Text Available We present a 64-year-old man who was treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone chemoimmunotherapy for mantle cell lymphoma and developed purulent meningitis, probably caused by Leuconostoc sp. The patient had severe hypogammaglobulinemia, which is a possible complication of rituximab therapy. To our knowledge and after reviewing the available medical literature, this is the first described case of purulent meningitis caused by Leuconostoc sp. in a patient with mantle cell lymphoma that appeared after treatment with the R-CHOP protocol. The diagnosis of purulent meningitis was based on clinical, laboratory and cytological cerebrospinal fluid findings, in addition to blood culture results in which we isolated Leuconostoc sp. The patient was treated with meropenem with full recovery.

Vincristine-induced peripheral neuropathy in pediatric cancer patients

Science.gov (United States)

Mora, Erika; Smith, Ellen M Lavoie; Donohoe, Clare; Hertz, Daniel L

2016-01-01

Vincristine is a chemotherapeutic agent that is a component of many combination regimens for a variety of malignancies, including several common pediatric tumors. Vincristine treatment is limited by a progressive sensorimotor peripheral neuropathy. Vincristine-induced peripheral neuropathy (VIPN) is particularly challenging to detect and monitor in pediatric patients, in whom the side effect can diminish long term quality of life. This review summarizes the current state of knowledge regarding VIPN, focusing on its description, assessment, prediction, prevention, and treatment. Significant progress has been made in our knowledge about VIPN incidence and progression, and tools have been developed that enable clinicians to reliably measure VIPN in pediatric patients. Despite these successes, little progress has been made in identifying clinically useful predictors of VIPN or in developing effective approaches for VIPN prevention or treatment in either pediatric or adult patients. Further research is needed to predict, prevent, and treat VIPN to maximize therapeutic benefit and avoid unnecessary toxicity from vincristine treatment. PMID:27904761

Procarbazine-induced hepatotoxicity: case report and review of the literature.

Science.gov (United States)

Fesler, Mark J; Becker-Koepke, Stephanie; Di Bisceglie, Adrian M; Petruska, Paul J

2010-05-01

Procarbazine hydrochloride is an oral alkylating agent primarily used as a component of chemotherapy regimens for Hodgkin's lymphoma, as well as in regimens for primary central nervous system lymphoma and high-grade gliomas. Although the prescribing information for procarbazine lists hepatic dysfunction as a potential adverse reaction, we found only one published report with a probable link between procarbazine and liver injury. We describe a 65-year-old man who developed liver injury due to procarbazine during salvage chemotherapy for non-Hodgkin's lymphoma. The patient had no preexisting liver disease, his lymphoma was without hepatic involvement, and no liver injury developed after initial chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Due to relapse of his non-Hodgkin's lymphoma, salvage chemotherapy with C-MOPP-R (cyclophosphamide, vincristine, procarbazine, prednisone, and rituximab) was administered, and the patient developed fever and aminotransferase level elevation during the second cycle. After discontinuation of all drug therapy, exclusion of other potential etiologies, and resolution of hepatic injury, the patient was rechallenged with procarbazine and again experienced fever with aminotransferase level elevation. His aminotransferase levels promptly returned to normal after discontinuation of procarbazine, and he experienced no further evidence of liver disease. Use of validated scoring systems of drug-induced liver injury indicated a definitive association between the patient's hepatic injury and procarbazine. Based on our experience with this patient, periodic assessment of hepatic function, as suggested in the package insert, is recommended in patients receiving procarbazine.

Vincristine delays gastric emptying and gastrointestinal transit of liquid in awake rats

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A.A. Peixoto Júnior

2009-06-01

Full Text Available We evaluated the effects of vincristine on the gastrointestinal (GI motility of awake rats and correlated them with the course of vincristine-induced peripheral neuropathy. Vincristine or saline was injected into the tail vein of male Wistar rats (180-250 g on alternate days: 50 µg/kg (5 doses, N = 10, 100 µg/kg (2, 3, 4 and 5 doses, N = 49 or 150 µg/kg (1, 2, or 5 doses, N = 37. Weight and stool output were measured daily for each animal. One day after completing the vincristine treatment, the animals were fasted for 24 h, gavage-fed with a test meal and sacrificed 10 min later to measure gastric emptying (GE, GI transit and colon weight. Sensory peripheral neuropathy was evaluated by hot plate testing. Chronic vincristine treatments with total cumulative doses of at least 250 µg/kg significantly decreased GE by 31-59% and GI transit by 55-93%. The effect of 5 doses of vincristine (150 µg/kg on GE did not persist for more than 1 week. Colon weight increased after 2 and 5 doses of vincristine (150 µg/kg. Fecal output decreased up to 48 h after the fifth dose of vincristine (150 µg/kg. Vincristine decreased the heat pain threshold 1 day after 5 doses of 50-100 µg/kg or after 3-5 doses of 150 µg/kg. This effect lasted for at least 2 weeks after the fifth dose. Chronic intravenous vincristine treatment delayed GE and GI transit of liquid. This effect correlated with the peak increase in colon weight but not with the pain threshold changes.

Compound list: cyclophosphamide [Open TG-GATEs

Lifescience Database Archive (English)

Full Text Available cyclophosphamide CPA 00024 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/H...uman/in_vitro/cyclophosphamide.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATE...ST/Rat/in_vitro/cyclophosphamide.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATE...ST/Rat/in_vivo/Liver/Single/cyclophosphamide.Rat.in_vivo.Liver.Single.zip ftp://f...tp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/cyclophosphamide.Rat.in_vivo.Liver.

Fludarabine-based versus CHOP-like regimens with or without rituximab in patients with previously untreated indolent lymphoma: a retrospective analysis of safety and efficacy

Directory of Open Access Journals (Sweden)

Xu XX

2013-10-01

Full Text Available Xiao-xiao Xu,1 Bei Yan,2 Zhen-xing Wang,3 Yong Yu,1 Xiao-xiong Wu,2 Yi-zhuo Zhang11Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, 2Department of Hematology, First Affiliated Hospital of Chinese People's Liberation Army General Hospital, Beijing, 3Department of Stomach Oncology, TianJin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of ChinaAbstract: Fludarabine-based regimens and CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone-like regimens with or without rituximab are the most common treatment modalities for indolent lymphoma. However, there is no clear evidence to date about which chemotherapy regimen should be the proper initial treatment of indolent lymphoma. More recently, the use of fludarabine has raised concerns due to its high number of toxicities, especially hematological toxicity and infectious complications. The present study aimed to retrospectively evaluate both the efficacy and the potential toxicities of the two main regimens (fludarabine-based and CHOP-like regimens in patients with previously untreated indolent lymphoma. Among a total of 107 patients assessed, 54 patients received fludarabine-based regimens (FLU arm and 53 received CHOP or CHOPE (doxorubicin, cyclophosphamide, vincristine, prednisone, or plus etoposide regimens (CHOP arm. The results demonstrated that fludarabine-based regimens could induce significantly improved progression-free survival (PFS compared with CHOP-like regimens. However, the FLU arm showed overall survival, complete response, and overall response rates similar to those of the CHOP arm. Grade 3–4 neutropenia occurred in 42.6% of the FLU arm and 7.5% of the CHOP arm (P 60 years and presentation of grade 3–4 myelosuppression were the independent factors to infection, and the FLU arm had significantly

Primary testicular diffuse large B-cell lymphoma: A case report

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Muhammad Sadiq

2017-12-01

Full Text Available Primary testicular diffuse large-B cell lymphoma (DLBCL is an uncommon and aggressive disease with predominant manifestation in the older age. Herein, we report a case of 47-year-old male patient who presented with three months history of left testis swelling. The patient underwent unilateral (left radical orchiectomy. Histopathological examination revealed extensive involvement and replacement of testicular parenchyma by a tumor composed of large discohesive sheets of cells with pleomorphic, hyperchromatic nuclei and prominent nucleoli. Immunohistochemical (IHC staining showed reactivity for LCA & Pan B (CD20 and negativity for OCT 3/4, SALL4 and Inhibin. Moreover, Pan T (CD3 highlighted reactive T-cells. These features rendered the diagnosis of DLBCL of testis. The hybrid 2-[fluorine-18] fluoro-2-deoxy-d-glucose (FDG positron emission tomography/computed tomography (PET/CT demonstrated two para-aortic FDG avid lymph nodes on the left side at the level of L2 vertebra. Presently, the patient has been planned for doxorubicin-based chemotherapy (i.e., cyclophosphamide, doxorubicin, vincristine and prednisone; CHOP along with intrathecal Methroxate (MTX, which would presumably improve the prognosis. Our study would expand the pool of this uncommon tumor towards its better understanding. Keywords: Primary testicular lymphoma, Diffuse large-B cell lymphoma, Orchiectomy, Doxorubicin-based chemotherapy

Involvement of Cannabinoid Signaling in Vincristine-Induced Gastrointestinal Dysmotility in the Rat

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Vera, Gema; López-Pérez, Ana E.; Uranga, José A.; Girón, Rocío; Martín-Fontelles, Ma Isabel; Abalo, Raquel

2017-01-01

Background: In different models of paralytic ileus, cannabinoid receptors are overexpressed and endogenous cannabinoids are massively released, contributing to gastrointestinal dysmotility. The antitumoral drug vincristine depresses gastrointestinal motility and a similar mechanism could participate in this effect. Therefore, our aim was to determine, using CB1 and CB2 antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus. Methods: First, we confirmed the effects of vincristine on the gut mucosa, by conventional histological techniques, and characterized its effects on motility, by radiographic means. Conscious male Wistar rats received an intraperitoneal injection of vincristine (0.1–0.5 mg/kg), and barium sulfate (2.5 ml; 2 g/ml) was intragastrically administered 0, 24, or 48 h later. Serial X-rays were obtained at different time-points (0–8 h) after contrast. X-rays were used to build motility curves for each gastrointestinal region and determine the size of stomach and caecum. Tissue samples were taken for histology 48 h after saline or vincristine (0.5 mg/kg). Second, AM251 (a CB1 receptor antagonist) and AM630 (a CB2 receptor antagonist) were used to determine if CB1 and/or CB2 receptors are involved in vincristine-induced gastrointestinal dysmotility. Key results: Vincristine induced damage to the mucosa of ileum and colon and reduced gastrointestinal motor function at 0.5 mg/kg. The effect on motor function was particularly evident when the study started 24 h after administration. AM251, but not AM630, significantly prevented vincristine effect, particularly in the small intestine, when administered thrice. AM251 alone did not significantly alter gastrointestinal motility. Conclusions: The fact that AM251, but not AM630, is capable of reducing the effect of vincristine suggests that, like in other experimental models of paralytic ileus, an increased cannabinoid tone develops and is at least

Reduced expression of TRIM21/Ro52 predicts poor prognosis in diffuse large B-cell lymphoma patients with and without rheumatic disease

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Brauner, S; Zhou, W; Backlin, C

2015-01-01

OBJECTIVE: TRIM21 (also known as Ro52) is an autoantigen in rheumatic disease and is predominantly expressed in leucocytes. Overexpression is associated with decreased proliferation, and the TRIM21 gene maps to a tumour suppressor locus. We therefore investigated the expression of TRIM21...... in patients with diffuse large B-cell lymphoma (DLBCL) and its potential usefulness as a prognostic biomarker. MATERIALS AND METHODS: TRIM21 expression levels were assessed by immunohistochemistry in lymphoma biopsies from three cohorts of patients with DLBCL: 42 patients with rheumatic disease treated...... with a cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP)-like regimen, 76 CHOP-treated and 196 rituximab-CHOP-treated nonrheumatic patients. Expression was correlated with clinical and biomedical parameters. TRIM21 expression was assessed in relation to lymphocyte proliferation by quantitative PCR...

Neurolymphomatosis of Brachial Plexus in Patients with Non-Hodgkin's Lymphoma

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Yong Jun Choi

2013-01-01

Full Text Available Neurolymphomatosis (NL is a rare clinical disease where neoplastic cells invade the cranial nerves and peripheral nerve roots, plexus, or other nerves in patients with hematologic malignancy. Most NL cases are caused by B-cell non-Hodgkin’s lymphoma (NHL. Diagnosis can be made by imaging with positron emission tomography (PET and magnetic resonance imaging (MRI. We experienced two cases of NL involving the brachial plexus in patients with NHL. One patient, who had NHL with central nervous system (CNS involvement, experienced complete remission after 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy but relapsed into NL of the brachial plexus 5 months later. The other patient, who suffered from primary central nervous system lymphoma (PCNSL, had been undergoing chemoradiotherapy but progressed to NL of the brachial plexus.

Spinal MRI of vincristine neuropathy mimicking Guillain-Barre syndrome

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Chang, Yun Woo; Yoon, Hye-Kyung; Cho, Jae Min [Department of Radiology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Kangnam-gu, Seoul 135-710 (Korea); Sung, Ki Woong [Department of Paediatrics, Samsung Medical Centre, Seoul 135-710 (Korea)

2003-11-01

A 4.3-year-old girl with acute leukaemia, who was being treated with chemotherapy (including vincristine), developed paraplegia. Spinal MRI showed diffusely enhancing nerve roots on contrast-enhanced images. Spinal fluid analysis showed a normal protein level. Vincristine neuropathy mimicking Guillain-Barre syndrome is thought to be the cause of the MRI abnormalities. (orig.)

Spinal MRI of vincristine neuropathy mimicking Guillain-Barre syndrome

International Nuclear Information System (INIS)

Chang, Yun Woo; Yoon, Hye-Kyung; Cho, Jae Min; Sung, Ki Woong

2003-01-01

A 4.3-year-old girl with acute leukaemia, who was being treated with chemotherapy (including vincristine), developed paraplegia. Spinal MRI showed diffusely enhancing nerve roots on contrast-enhanced images. Spinal fluid analysis showed a normal protein level. Vincristine neuropathy mimicking Guillain-Barre syndrome is thought to be the cause of the MRI abnormalities. (orig.)

Effectiveness of modified hyper-CVAD chemotherapy regimen in the treatment of adult acute lymphoblastic leukemia: a retrospective experience.

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Jalaeikhoo, Hasan; Rajaeinejad, Mohsen; Keyhani, Manoutchehr; Zokaasadi, Mohammad; Dehghani Firoozabadi, Mohammad Mehdi

2018-03-01

Several chemotherapy regimens have been developed for the treatment of acute lymphoblastic leukemia (ALL), but relapse still presents the most common obstacles to attaining long-term survival. The hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and prednisolone)/HD MTX and Ara-C (high-dose methotrexate and cytarabine) chemotherapy regimen was first started in the MD Anderson Cancer Center as an intensive regimen for adult patients with ALL. The purpose of this study was to evaluate the effectiveness of a modified hyper-CVAD protocol. We used hyper-CVAD as consolidation/maintenance after remission induction with daunorubicin, vincristine, and prednisolone (and cyclophosphamide for T-cell ALL only) rather than standard hyper-CVAD in order to reduce treatment complications. This study was conducted as a retrospective review of medical records of ALL patients at 501 army hospital, Tehran, Iran, from 2005 to 2015. Three hundred and one patients underwent modified hyper-CVAD chemotherapy regimen. Complete remission and overall survival (OS) rates were measured as primary endpoints. Two hundred and forty-six (81.7%) reached complete remission (CR) during the first 6 months of treatment, and 55 patients (18.3%) did not reach CR. The 5-year OS rate was 51.8% (95% CI (confidence interval): 45.1-57.8%). Modified hyper-CVAD regimen is an efficient intensive chemotherapy regimen for consolidation/maintenance of adults with newly diagnosed ALL and has an acceptable 5-year overall that is comparable to standard hyper-CVAD regimen. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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

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Kevin Shee

2016-12-01

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.

TREATMENT OF PRIMARY PLASMA CELL LEUKAEMIA

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Peter Černelč

2003-04-01

Full Text Available Background. The author describes long-term survival in 3 patients with primary plasma cell leukaemia (PL after different therapeutic regimen and maintenance treatment with interferon alpha (INF.Patients and treatment. In a 52-year-old male patient, a partial remission of PL was achieved after 6 months of treatment with melphalan and prednisone. The patient did not consent to stem cell transplantation (SCT. An 86-year-old female patient with PL achieved a complete remission after 6 months of treatment with vincristine, doxorubicin and dexamethasone. A 31-year-old male patient experienced a complete remission of PL after 6 months of treatment with cyclophosphamide, vincristine, doxorubicin, methilprednisone, followed by autologous SCT. All three patients were placed on maintenance therapy with INF-2b (Intron A 3 × 106 IU given subcutaneously on two days per week. In the 52-year-old man, the remission lasted 9 months and in the woman 23 months, whereupon they developed a relapse with signs of disseminated plasmacytoma. In both patients the former chemotherapy was applied again, resulting in a slight improvement. The man died 37 months and the woman 43 months after the diagnosis of PL, while the youngest patient has been in complete remission for 82 months.Conclusions. Long remission achieved in our patients confirmed the favourable effect of INF in terms of prolongation of the remission duration in this patients. The effect of maintenance treatment with INF is usually directly dependent on the degree of remission induced by different therapeutic regimen.

Effect of curcumin in mice model of vincristine-induced neuropathy.

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Babu, Anand; Prasanth, K G; Balaji, Bhaskar

2015-06-01

Curcumin exhibits a wide spectrum of biological activities which include neuroprotective, antinociceptive, anti-inflammatory, and antioxidant activity. The present study evaluates the effect of curcumin in vincristine-induced neuropathy in a mice model. Vincristine sulfate (0.1 mg/kg, i.p. for 10 consecutive days) was administered to mice to induce neuropathy. Pain behavior was assessed at different days, i.e., 0, 7, 10, and 14 d. Sciatic nerve total calcium, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), nitric oxide (NO), and lipid peroxidation (LPO) were also estimated after the 14th day of study. Pregabalin (10 mg/kg, p.o.) and curcumin (15, 30, and 60 mg/kg, p.o.) were administered for 14 consecutive days. Curcumin at 60 mg/kg significantly attenuated the vincristine-induced neuropathic pain manifestations in terms of thermal hyperalgesia (p Curcumin at 30 and 60 mg/kg exhibited significant changes (p Curcumin at 30 and 60 mg/kg dose levels significantly attenuated vincristine-induced neuropathy which may be due to its multiple actions including antinociceptive, calcium inhibitory, and antioxidant effect.

Treatment-related risk factors for premature menopause following Hodgkin lymphoma

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De Bruin, Marie L; Huisbrink, Jeannine; Hauptmann, Michael

2008-01-01

We conducted a cohort-study among 518 female 5-year Hodgkin lymphoma (HL) survivors, aged 14 to 40 years (median: 25 years) at treatment (1965-1995). Multivariable Cox regression was used to quantify treatment effects on risk of premature menopause, defined as cessation of menses before age 40...... years. After a median follow up of 9.4 years, 97 women had reached menopause before age 40 years. Chemotherapy was associated with a 12.3-fold increased risk of premature menopause compared with radiotherapy alone. Treatment with MOPP (mechlorethamine, vincristine, procarbazine, prednisone......)/ABV (doxorubicine, bleomycine, vinblastine) significantly increased the risk of premature menopause (hazard ratio [HR]: 2.9), although to a lesser extent than MOPP treatment (HR: 5.7). Alkylating agents, especially procarbazine (HR: 8.1) and cyclophosphamide (HR: 3.5), showed the strongest associations. Ten years...

FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas

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Brown, P J; Wong, K K; Felce, S L

2016-01-01

The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II......) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes......, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (PABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone...

TRPM4 expression is associated with activated B cell subtype and poor survival in diffuse large B cell lymphoma

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Loo, Suet K; Ch'ng, Ewe S; Md Salleh, Md Salzihan

2017-01-01

to investigate TRPM4 protein expression pattern in non-malignant tissues and DLBCL cases, and its association with clinico-demographic parameters and survival in DLBCL. METHODS AND RESULTS: Analysis of publicly available DLBCL microarray data sets showed that TRPM4 transcripts were up-regulated in DLBCL compared...... to normal germinal centre B (GCB) cells, were expressed more highly in the activated B cell-like DLBCL (ABC-DLBCL) subtype and higher TRPM4 transcripts conferred worse overall survival (OS) in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL cases (P ... immunohistochemical analysis showed that TRPM4 was expressed in various human tissues but not in normal B cells within lymphoid tissues (reactive tonsil, lymph node and appendix). TRPM4 protein was present in 26% (n = 49 of 189) of our cohort of R-CHOP-treated DLBCL cases and this was associated significantly...

Effect of pentoxifylline on P-glycoprotein mediated vincristine resistance of L1210 mouse leukemic cell line

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Breier, A.; Uhrik, B.; Barancik, M.; Stefankova, Z.; Tribulova, N.

1994-01-01

Effect of pentoxifylline (PTX) on vincristine (VCR) resistance of multidrug resistant L1210/VCR mouse leukemic cell line was studied. Reversal effect of PTX (in concentration 50-150 mg dm -3 ) on vincristine resistance, i.e. potentiation of vincristine cytotoxicity on L1210/VCR cells by PTX was found. PTX alone in the above concentration did not exert any significant effect on sensitive or resistant cell lines in the absence of vincristine. Resistance of L1210/VCR cell line was found previously to be accompanied with overexpression of drug transporting P-glycoprotein. Indeed, lower level of 3 H-vincristine accumulation by resistant L1210/VCR cell line in comparison with sensitive L1210 cell line was observed. Accumulation of 3 H-vincristine by L1210/VCR cell line was significantly increased in the presence of PTX. PTX in the same condition did not exert any considerable effect on accumulation of 3 H-vincristine by nonresistant L1210 cells. Observable morphological damage was observed in 1210/VCR cells cultivated in medium containing vincristine (0.2 mg dm -3 ) and pentoxifylline (100 mg dm -3 ) in comparison with the non-damaged cells in the presence of vincristine or pentoxifylline alone. The results obtained indicate that pentoxifylline may be considered as a reversal agent in multidrug resistance. (author)

Measuring Vincristine-Induced Peripheral Neuropathy in Children with Acute Lymphoblastic Leukemia

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Lavoie Smith, Ellen M.; Li, Lang; Hutchinson, Raymond J.; Ho, Richard; Burnette, W. Bryan; Wells, Elizabeth; Bridges, Celia; Renbarger, Jamie

2014-01-01

Background Vincristine-induced peripheral neuropathy (VIPN) is difficult to quantify in children. Objective The study objective was to examine the reliability, validity, and clinical feasibility of several VIPN measures for use in children with acute lymphoblastic leukemia. Interventions/Methods Children (N = 65) aged 1–18 years receiving vincristine at four academic centers participated in the study. Baseline and pre-vincristine VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS-PV), the National Cancer Institute Common Terminology Criteria for Adverse Events, the Balis grading scale, and the FACES pain scale. TNS-PV scores (n = 806) were obtained over 15 weeks. Blood was obtained at several time-points to quantify pharmacokinetic parameters. Results Cronbach’s alpha for a reduced TNS-PV scale was 0.84. TNS-PV scores correlated with cumulative vincristine dosage (r = 0.53, p = 0.01), pharmacokinetic parameters (r = 0.41, p = 0.05), and grading scale scores (r = 0.46 – 0.52; p = 0.01). FACES scores correlated with the TNS-PV neuropathic pain item (r = 0.48; p = 0.01), and were attainable in all ages. A 2-item V-Rex score (vibration and reflex items) was the most responsive to change (es 0.65, p < 0.001). TNS-PV scores were attainable in 95% of children ≥ 6 years. Conclusions The TNS-PV is reliable and valid for measuring VIPN. It is sensitive to change over time (15 weeks) and feasible for use in children ≥ 6 years of age. Implications for Practice The TNS-PV may be a useful tool for assessing vincristine toxicity in children with acute lymphoblastic leukemia. PMID:23842524

Cyclophosphamide-hydroxycamptothecin as second-line chemotherapy for advanced Ewing's sarcoma: experience of a single institution.

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Han, Kun; Sun, Yuanjue; Zhang, Jianjun; He, Aina; Zheng, Shui'er; Shen, Zan; Yao, Yang

2014-06-01

To investigate the feasibility and efficacy of cyclophosphamide (CTX)-hydroxycamptothecin (HCPT) as second-line chemotherapy on advanced Ewing's sarcoma. From April 2009 to November 2010, 27 patients with advanced Ewing's sarcoma who had progressive disease after the first-line chemotherapy regimen of vincristine, dactinomycin and cyclophosphamide and ifosfamide and etoposide were retrospectively reviewed in this analysis. CTX was given (0.6 g/m(2), i.v. push day 1) and HCPT (6 mg/m(2), i.v. drip days 1-5) as second-line chemotherapy every 3 weeks. The primary end-point was overall response rate, the secondary end-point included progression-free, overall survival, disease control rate and toxicities. A total of 134 cycles were given, median four cycles per patient (range 2-6). Overall response rate was 30% and disease control rate was 82%, with two complete response (8%), six partial remission (22%) and 14 stable disease (52%). The median time to progression and overall survival time were 7 months (95% CI 3-10) and 11 months (95% CI 5-18), respectively. Major severe toxicities (grade 3 and 4) were: nausea/vomiting (17%), alopecia (17%); leukopenia (27%) in total cycles. Mild toxicities (grade 1 or 2) were leukopenia (73%), nausea/vomiting (83%), hepatic lesion (14%) and anemia (44%). A CTX-HCPT regimen can control disease progression effectively and the side effects can be tolerable for Chinese advanced Ewing's sarcoma patients. Further assessment is necessary to confirm the safety and efficacy of this treatment. © 2012 Wiley Publishing Asia Pty Ltd.

Secondary cutaneous Epstein-Barr virus-associated diffuse large B-cell lymphoma in a patient with angioimmunoblastic T-cell lymphoma: a case report and review of literature

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Yang Qing-Xu

2012-01-01

Full Text Available Abstract Only a few cases of extranodal Epstein-Barr virus (EBV-associated B-cell lymphomas arising from patients with angioimmunoblastic T-cell lymphoma (AITL have been described. We report a case of AITL of which secondary cutaneous EBV-associated diffuse large B-cell lymphoma (DLBCL developed after the initial diagnosis of AITL. A 65-year-old Chinese male patient was diagnosed as AITL based on typical histological and immunohistochemical characteristics in biopsy of the enlarged right inguinal lymph nodes. The patient initially received 6 cycles of chemotherapy with CHOP regimen (cyclophosphamide, vincristine, adriamycin, prednisone, but his symptoms did not disappear. Nineteen months after initial diagnosis of AITL, the patient was hospitalized again because of multiple plaques and nodules on the skin. The skin biopsy was performed, but this time the tumor was composed of large, polymorphous population of lymphocytes with CD20 and CD79a positive on immunohistochemical staining. The tumor cells were strong positive for EBER by in situ hybridization. The findings of skin biopsy were compatible with EBV-associated DLBCL. CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab was then administered, resulting in partial response of the disease with pancytopenia and suppression of cellular immunity. To our knowledge, this is the first case of cutaneous EBV-associated DLBCL originated from AITL in Chinese pepole. We suggest the patients with AITL should perform lymph node and skin biopsies regularly in the course of the disease to detect the progression of secondary lymphomas. Virtual slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1197421158639299

Treatment of small cell carcinoma of lung with combined high dose mediastinal irradiation, whole brain prophylaxis and chemotherapy

International Nuclear Information System (INIS)

Shank, B.; Natale, R.B.; Hilaris, B.S.; Wittes, R.E.

1981-01-01

Survival of patients with small cell carcinoma of lung, treated on a new combined radiotherapy-chemotherapy protocol, compares favorably with other regimens in the literature and our own previous combined approaches. Radiation, given after induction chemotherapy, consisted of whole brain prophylaxis in all 44 evaluable patients. Patients with limited disease were also treated to the primary and mediastinum to a high dose (5000 rad equivalent) using multiple fields. The new chemotherapy regimen consisted of induction with cyclophosphamide, doxorubicin, and vincristine alternated with cis-platinum and VP-16 (an epipodophyllotoxin) for two cycles, followed by consolidation with low dose cyclophosphamide and vincristine concurrent with irradiation. Patients with limited disease who achieved less than complete response, and all patients with extensive disease were not continued on maintenance chemotherapy. Out of 24 evaluable patients with limited disease, there was 73% survival at 1 year by life-table analysis, measured from treatment initiation. After induction, 16/24 of these limited disease patients were CR (complete responders): 20/24 were CR at completion of their irradiation. Out of 20 evaluable patients with extensive disease, there was 59% survival at 1 year by life-table analysis. Only 4/44 (9%) brain parenchymal relapses occurred, one at 3 months and one at 6 months after local failure and two in patients who did not become CRs, implicating a possible re-seeding mechanism. Five patients had central nervous system relapses outside of brain parenchyma (spinal epidural and leptomeningeal); in three patients this was the initial site of failure. Significant complications included leukopenia (50%) and thrombocytopenia (24%) primarily during induction, and chronic pulmonary fibrosis (25%), possibly contributing to two deaths

Pegylated niosomal nanoparticles loaded with vincristine ...

African Journals Online (AJOL)

Purpose: To investigate the effect of pegylated niosomal vincristine (VCR) on enhanced performance, drug resistance and prolonged blood circulation time. Methods: Pegylated niosomal VCR was synthesized by reverse phase evaporation. The mean diameter, size distribution, and zeta potential of pegylated niosomal ...

Long-term maintenance combination chemotherapy with OPEC/MPEC (vincristine or methotrexate, prednisolone, etoposide and cyclophosphamide) or with daily oral etoposide and prednisolone can improve survival and quality of life in adult T-cell leukemia/lymphoma.

Science.gov (United States)

Matsushita, K; Matsumoto, T; Ohtsubo, H; Fujiwara, H; Imamura, N; Hidaka, S; Kukita, T; Tei, C; Matsumoto, M; Arima, N

1999-12-01

Acute leukemia and lymphoma varieties of adult T-cell leukemia/lymphoma (ATL) usually carry a poor prognosis. While etoposide is generally useful for treating ATL, especially as a daily oral maintenance regimen, etoposide has not proven effective in severe types of ATL efficient in some patients. Of 87 ATL patients whom we have treated, 51 had acute leukemia, 22 lymphoma and 14 progressive chronic leukemia. Seventy-nine patients were treated with a long term maintenance combination protocol, OPEC/MPEC (weekly doses of vincristine, 0.7 mg/m2 or methotrexate, 14 mg/m2; prednisolone, 20 mg/m2; etoposide, 70 mg/m2 and cyclophosphamide, 200 mg/m2). The other 8 patients, 3 with acute leukemia, 2 with lymphoma and 3 with progressive chronic leukemia, were treated with daily oral administration of 25 mg of etoposide and 10 mg of prednisolone (DOEP). The dose administered was modified in individual cases to maintain the granulocyte count and reduce the number of ATL cells. Considering both protocols, a complete response and a partial response were achieved in 31.0% and 58.6% patients, respectively. Median survival times (MST) of all patients and, acute leukemia, lymphoma and progressive chronic leukemia types were 7.5, 6.7, 9.6 and 12.4 months, respectively. Respective MST of patients treated with OPEC/MPEC or DOEP protocols were 7.1 and 18.0 months. Relatively normal WBC counts, lower lactate dehydrogenase concentration and normal calcium concentration, limited numbers of anatomic sites involved, good performance status and good response to chemotherapy were significantly associated with long survival time. Drug toxicity was not apparent, and about half of patients were treated in an outpatient setting.

Introduction of vincristine mini-bags and an assessment of the subsequent risk of extravasation.

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Nurgat, Z A; Smythe, M; Al-Jedai, A; Ewing, S; Rasheed, W; Belgaumi, A; Ahmed, S O; Ashour, M; Al Agil, A; Siddiqui, K; Aljurf, M

2015-10-01

Numerous international organisations have advocated the preparation of vincristine in small volume intravenous bags in order to eliminate inadvertent intrathecal administration. However, the risk of extravasation is a significant deterrent, and adoption of this practice has been variable and only hesitantly accepted in the clinical setting. We carried out a study with the aims of establishing the incidence of reported extravasation of vincristine administration to paediatric and adult patients in mini-bags; here we describe motivating factors and barriers faced by clinical staff. The secondary aim was to support the need for change and implementation of the international recommendations. Chemotherapy-certified nurses completed a survey spanning August 2009 to August 2011, to ascertain the incidence of extravasation associated with the administration of vincristine in mini-bags. This period captured 421 occasions of vincristine administration in 25-ml or 50-ml mini-bags (in 0.9% sodium chloride). The median age of patients was 13 years (range 2.5 months to 99 years). Vincristine was administered through peripheral lines (26.4%), portacath (52.0%), PICC line (15.9%) and Hickman line (5.7%). The majority of infusions were over at least 10 minutes (50.1%). There were no cases of extravasation reported. The administration of vincristine in small volume intravenous bags was safe, practical, and feasible in all patient groups. The successful implementation of the international recommendations for vincristine administration in mini-bags to eliminate potential inadvertent intrathecal administration was dependent on stakeholder buy-in. © The Author(s) 2014.

Clinical pharmacokinetics and effects of vincristine sulfate in dogs with transmissible venereal tumor (TVT).

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Hantrakul, Supannika; Klangkaew, Narumol; Kunakornsawat, Sunee; Tansatit, Tawewan; Poapolathep, Ammart; Kumagai, Susumu; Poapolathep, Saranya

2014-12-01

This study was conducted to evaluate the pharmacokinetic characteristics of vincristine and their correlation with its clinical effects in dogs with transmissible venereal tumor (TVT). Dogs with TVT were intravenously administered vincristine sulfate at a dose of 0.7 mg/m(2) of body surface area. Blood samples were collected starting from 5 min to 48 hr after drug administration. The plasma concentration of vincristine was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of vincristine were characterized using a two-compartmental pharmacokinetic model. The volume of distribution, distribution half-life, elimination half-life and plasma clearance were 0.660 ± 0.210 l/kg, 21.5 ± 6.90 min, 47.6 ± 14.2 min and 0.010 ± 0.001 l/min/kg, respectively. Tumor regression was determined at weekly interval by a physical examination and histopathological analysis. In our study, three to eight administrations of vincristine at a dose of 0.7 mg/m(2) were able to induce a complete tumor regression without any evidence of gross lesion of disease. Therefore, this investigation provides the pharmacokinetic characteristics of vincristine in dogs with TVT, which may be used as an integration tool to gain a better understanding of the disposition properties of the drug and the correlation of these properties with the drug's clinical effects. In addition, we validated the LC-MS/MS method and found that it is suitable for the pharmacokinetic study of vincristine in dog plasma.

Treatment toxicities in long-term survivors of limited small cell lung cancer

International Nuclear Information System (INIS)

Frytak, S.; Shaw, J.N.; Lee, R.E.; Eagan, R.T.; Shaw, E.G.; Richardson, R.L.; Creagan, E.T.; Coles, D.T.; Jett, J.R.

1988-01-01

A total of 211 patients with limited small cell lung cancer were assessed retrospectively for long-term toxicities, treatment-related deaths, and second primaries. All had received treatment with various combinations of doxorubicin, vincristine, cisplatin, lomustine, cyclophosphamide, and etoposide with or without split-course thoracic radiotherapy (4,000 cGy/10 fractions) and/or split-course prophylactic cranial irradiation (3,600 cGy/10 fractions). Sixty-eight (32%) of the patients survived longer than 1.5 years and formed the basis of this study. Debilitating pulmonary, cardiac, and neurologic toxicity was noted in 12%, 14%, and 15%, respectively, of long-term survivors. These complications were the result of aggressive combined modality therapy. Certain drugs appeared to cause additive toxicity when combined with radiation. Three patients developed new primary tumors of squamous cell origin. Attention must be directed to defining the safest way to employ aggressive combined modality treatment for these patients

Influence of chemotherapy for lymphoma in canine parvovirus DNA distribution and specific humoral immunity.

Science.gov (United States)

Elias, M A; Duarte, A; Nunes, T; Lourenço, A M; Braz, B S; Vicente, G; Henriques, J; Tavares, L

2014-12-01

In man, the combination of cancer and its treatment increases patients' susceptibility to opportunistic infections, due to immune system impairment. In veterinary medicine little information is available concerning this issue. In order to evaluate if a similar dysfunction is induced in small animals undergoing chemotherapy, we assessed the complete blood count, leukocytic, plasma and fecal canine parvovirus (CPV) viral load, and anti-CPV protective antibody titers, in dogs with lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) protocol, before and during chemotherapy. There was no evidence of decreased immune response, either at admission or after two chemotherapy cycles, indicating that the previously established immunity against CPV was not significantly impaired, supporting the idea that immunosuppression as a result of hematopoietic neoplasms and their treatment in dogs requires further investigation and conclusions cannot be extrapolated from human literature. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of paclitaxel and carboplatin versus combination chemotherapy with fluorouracil doxorubicin and cyclophosphamide as a neoadjuvant therapy in patients with inoperable breast cancer

International Nuclear Information System (INIS)

Akhtar, M.S.; Kausar, F.

2010-01-01

To compare the results of patients with locally advanced breast cancer receiving two different regimens Fluorouracil, Doxorubicin and Cyclophosphamide (FAC) and Paclitaxel and Carboplatin. Study Design: Comparative study. Place and Duration of Study: The Oncology Department, Institute of Nuclear Medicine and Oncology (INMOL), Lahore, from March 2007 to September 2008. Methodology: Patients with inoperable locally advanced breast cancer of stage were included. Sixteen patients were given FAC regimen and 9 patients were given Paclitaxel and Carboplatin, each combination was cycled after 21 days for four times. Before enrollment, detailed medical histories, physical examinations and performance status assessments were done as well as post chemotherapy evaluation with regular follow-up visits was done. Complete Response (CR, 100%) is defined as the disappearance of all known disease parameter i.e. disappearance in detectable tumour size, node free disease and surgery is possible. Paratial Response (PR, > 50%) was defined by 50% or greater decrease in the sum of the areas of bidimensionally measured lesions i.e. change of N2 to N1 or no status and some surgical procedure is possible to down stage the disease. Minor Response (MR) was defined as a decrease in the tumour insufficient to quality for partial resp once. Static disease or no evaluable reflected no significant change in disease and no evidence of new disease. Progression of disease (> 25%) was defined as a 25% or greater increase in the area of any lesion > 2 cm or in the sum of the products of the individual lesions or the appearance of new malignant lesions, surgery not possible. Results: Twenty five patients completed neoadjuvant chemotherapy. Sixteen (66%) patients received FAC and 9 (37%) patients received PC chemotherapy. Overall CR (breast and axilla) was 54%, PR was 16% and minor response (MR) was 8%. FAC treatment induced more emesis, mucositis, alopecia and cardiotoxicity. No death occurred

Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukaemia

NARCIS (Netherlands)

Schie, R.M. van; Bruggemann, R.J.M.; Hoogerbrugge, P.M.; Loo, D.M. te

2011-01-01

BACKGROUND: Vincristine is one of the cornerstones of the treatment of children with acute lymphoblastic leukaemia (ALL). Constipation, and peripheral and central neurotoxicities are the most common side effects. A comparative study exploring vincristine toxicity in individual patients receiving

Control of nausea with palonosetron versus granisetron, both combined with dexamethasone, in patients receiving cisplatin- or anthracycline plus cyclophosphamide-based regimens.

Science.gov (United States)

Kubota, Kaoru; Saito, Mitsue; Aogi, Kenjiro; Sekine, Ikuo; Yoshizawa, Hirohisa; Yanagita, Yasuhiro; Sakai, Hiroshi; Inoue, Kenichi; Kitagawa, Chiyoe; Ogura, Takashi

2016-09-01

In a comparative phase 3 study involving 1114 Japanese patients receiving highly emetogenic chemotherapy (HEC), palonosetron (PALO) was found to be superior to granisetron (GRA) for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in the delayed phase. This post hoc analysis of the phase 3 study evaluated the efficacy of PALO for the control of nausea. The proportion of patients without nausea was assessed at 24-h intervals during the acute phase (0-24 h), delayed phase (24-120 h), and overall (0-120 h). No nausea rates were also evaluated by sex, type of chemotherapy (cisplatin or doxorubicin/epirubicin plus cyclophosphamide [AC/EC]), and age (<55 vs. ≥55 years). Nausea severity was categorized using a 4-point Likert scale (0 = no nausea to 3 = severe nausea). The proportion of patients without nausea was significantly higher in the PALO arm than in the GRA arm in the delayed phase (37.8 % vs. 27.2 %; p = 0.002) and overall (31.9 % vs. 25.0 %; p = 0.0117). When analyzed by stratification factors, the proportion of patients without nausea was significantly higher in the PALO arm in the delayed phase and overall in patients who were female, younger, or treated with cisplatin and in the delayed phase in patients who were older or treated with doxorubicin or epirubicin plus cyclophosphamide (all p < 0.05). PALO was more effective than GRA in prophylaxis of HEC-induced nausea in the delayed phase and overall. In addition, PALO was more effective than GRA in young and female patients, who are at high risk of CINV, both in the delayed phase and overall.

Compound list: doxorubicin [Open TG-GATEs

Lifescience Database Archive (English)

Full Text Available doxorubicin DOX 00149 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/...in_vitro/doxorubicin.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_...vitro/doxorubicin.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/...Liver/Single/doxorubicin.Rat.in_vivo.Liver.Single.zip ftp://ftp.biosciencedbc.jp/...archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/doxorubicin.Rat.in_vivo.Liver.Repeat.zip ftp://ftp.bios

Vincristine-induced bystander effect in human lymphocytes

International Nuclear Information System (INIS)

Testi, Serena; Azzarà, Alessia; Giovannini, Caterina; Lombardi, Sara; Piaggi, Simona; Facioni, Maria Sole; Scarpato, Roberto

2016-01-01

Highlights: • We studied whether or not vincristine induced a bystander response in human lymphocytes. • Vincristine significantly increased MN frequencies in mononucleated recipient cells. • ROS or soluble proteins (IL-32 and TGF-β) may account for the observed response. - Abstract: Bystander effect is a known radiobiological effect, widely described using ionizing radiations and which, more recently, has also been related to chemical mutagens. In this study, we aimed to assess whether or not a bystander response can be induced in cultured human peripheral lymphocytes by vincristine, a chemotherapeutic mutagen acting as spindle poison, and by mitomycin-C, an alkylating agent already known to induce this response in human lymphoblastoid cells. Designing a modified ad hoc protocol for the cytokinesis blocked micronucleus (MN) assay, we detected the presence of a dose-dependent bystander response in untreated cultures receiving the conditioned medium (CM) from mitomycin-C (MMC) or vincristine (VCR) treated cultures. In the case of MMC, MN frequencies, expressed as micronucleated binucleates, were: 13.5 ± 1.41 at 6 μM, 22 ± 2.12 at 12 μM or 28.25 ± 5.13 at 15 μM vs. a control value of 4.75 ± 1.59. MN levels for VCR, expressed as micronucleated mononucleates were: 2.75 ± 0.88 at 0.0 μM, 27.25 ± 2.30 at 0.4 μM, 46.25 ± 1.94 at 0.8 μM, 98.25 ± 7.25 at 1.6 μM. To verify that no mutagen residual was transferred to recipient cultures together with the CM, we evaluated MN levels in cultures receiving the medium immediately after three washings following the chemical treatment (unconditioned medium). We further confirmed these results using a cell-mixing approach where untreated lymphocytes were co-cultured with donor cells treated with an effect-inducing dose of MMC or VCR. A distinct production pattern of both reactive oxygen species and soluble mediator proteins by treated cells may account for the differences observed in the manifestation of the

Vincristine-induced bystander effect in human lymphocytes

Energy Technology Data Exchange (ETDEWEB)

Testi, Serena; Azzarà, Alessia; Giovannini, Caterina; Lombardi, Sara [Unità di Genetica, Dipartimento di Biologia, Pisa University, Via Derna 1, 56126 Pisa (Italy); Piaggi, Simona [Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Pisa University, Via Savi 10, 56126 Pisa (Italy); Facioni, Maria Sole [Unità di Genetica, Dipartimento di Biologia, Pisa University, Via Derna 1, 56126 Pisa (Italy); Scarpato, Roberto, E-mail: roberto.scarpato@unipi.it [Unità di Genetica, Dipartimento di Biologia, Pisa University, Via Derna 1, 56126 Pisa (Italy); Research Center of Nutraceuticals and Food for Health, University of Pisa, Pisa (Italy)

2016-07-15

Highlights: • We studied whether or not vincristine induced a bystander response in human lymphocytes. • Vincristine significantly increased MN frequencies in mononucleated recipient cells. • ROS or soluble proteins (IL-32 and TGF-β) may account for the observed response. - Abstract: Bystander effect is a known radiobiological effect, widely described using ionizing radiations and which, more recently, has also been related to chemical mutagens. In this study, we aimed to assess whether or not a bystander response can be induced in cultured human peripheral lymphocytes by vincristine, a chemotherapeutic mutagen acting as spindle poison, and by mitomycin-C, an alkylating agent already known to induce this response in human lymphoblastoid cells. Designing a modified ad hoc protocol for the cytokinesis blocked micronucleus (MN) assay, we detected the presence of a dose-dependent bystander response in untreated cultures receiving the conditioned medium (CM) from mitomycin-C (MMC) or vincristine (VCR) treated cultures. In the case of MMC, MN frequencies, expressed as micronucleated binucleates, were: 13.5 ± 1.41 at 6 μM, 22 ± 2.12 at 12 μM or 28.25 ± 5.13 at 15 μM vs. a control value of 4.75 ± 1.59. MN levels for VCR, expressed as micronucleated mononucleates were: 2.75 ± 0.88 at 0.0 μM, 27.25 ± 2.30 at 0.4 μM, 46.25 ± 1.94 at 0.8 μM, 98.25 ± 7.25 at 1.6 μM. To verify that no mutagen residual was transferred to recipient cultures together with the CM, we evaluated MN levels in cultures receiving the medium immediately after three washings following the chemical treatment (unconditioned medium). We further confirmed these results using a cell-mixing approach where untreated lymphocytes were co-cultured with donor cells treated with an effect-inducing dose of MMC or VCR. A distinct production pattern of both reactive oxygen species and soluble mediator proteins by treated cells may account for the differences observed in the manifestation of the

Induction of micronuclei in the mouse. Revised timing of the final stage of erythropoiesis

International Nuclear Information System (INIS)

Hart, J.W.; Hartley-Asp, B.

1983-01-01

the early effects of X-rays, vincristine, cyclophosphamide, quinacrine dihydrochloride, cycloheximide, actinomycin D and hydroxyurea on the induction of micronuclei in mouse bone-marrow erythrocytes were studied. A significant increase in the incidence of micronuclei in polychromatic erythrocytes was seen as early as 5 h after a single treatment with vincristine, 6 h after treatment with X-rays and 10 h after treatment with cyclophosphamide. The cell kinetics of the mouse erythropoietic system described by Cole et al. (1981) can be modified to fit these results. According to this revised model, the final mitosis takes place only 5 h before the expulsion of the nucleus. (orig.)

Induction of micronuclei in the mouse. Revised timing of the final stage of erythropoiesis

Energy Technology Data Exchange (ETDEWEB)

Hart, J.W. (Leo Pharmaceutical Products Ltd., Ballerup (Denmark)); Hartley-Asp, B. (AB Leo, Helsingborg (Sweden))

1983-05-01

the early effects of X-rays, vincristine, cyclophosphamide, quinacrine dihydrochloride, cycloheximide, actinomycin D and hydroxyurea on the induction of micronuclei in mouse bone-marrow erythrocytes were studied. A significant increase in the incidence of micronuclei in polychromatic erythrocytes was seen as early as 5 h after a single treatment with vincristine, 6 h after treatment with X-rays and 10 h after treatment with cyclophosphamide. The cell kinetics of the mouse erythropoietic system described by Cole et al. (1981) can be modified to fit these results. According to this revised model, the final mitosis takes place only 5 h before the expulsion of the nucleus.

The prognostic value of biological markers in paediatric Hodgkin lymphoma.

Science.gov (United States)

Farruggia, Piero; Puccio, Giuseppe; Sala, Alessandra; Todesco, Alessandra; Buffardi, Salvatore; Garaventa, Alberto; Bottigliero, Gaetano; Bianchi, Maurizio; Zecca, Marco; Locatelli, Franco; Pession, Andrea; Pillon, Marta; Favre, Claudio; D'Amico, Salvatore; Provenzi, Massimo; Trizzino, Angela; Zanazzo, Giulio Andrea; Sau, Antonella; Santoro, Nicola; Murgia, Giulio; Casini, Tommaso; Mascarin, Maurizio; Burnelli, Roberta

2016-01-01

Many biological and inflammatory markers have been proposed as having a prognostic value at diagnosis of Hodgkin lymphoma (HL), but very few have been validated in paediatric patients. We explored the significance of these markers in a large population of 769 affected children. By using the database of patients enrolled in A.I.E.O.P. (Associazione Italiana di Emato-Oncologia Pediatrica) trial LH2004 for paediatric HL, we identified 769 consecutive patients treated with curative intent from 1st June 2004 to 1st April 2014 with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or hybrid COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin and vinblastine) regimens. On multivariate analysis with categorical forms, the 5-year freedom from progression survival was significantly lower in patients with stage IV or elevated value of platelets, eosinophils and ferritin at diagnosis. Furthermore, stage IV and eosinophils seem to maintain their predictive value independently of interim (after IV cycles of chemotherapy) positron emission tomography. Using the combination of four simple markers such as stage IV and elevated levels of platelets, ferritin and eosinophils, it is possible to classify the patients into subgroups with very different outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization

International Nuclear Information System (INIS)

Heibein, Allan D; Guo, Baoqing; Sprowl, Jason A; MacLean, David A; Parissenti, Amadeo M

2012-01-01

Since proteins involved in chemotherapy drug pharmacokinetics and pharmacodynamics have a strong impact on the uptake, metabolism, and efflux of such drugs, they likely play critical roles in resistance to chemotherapy drugs in cancer patients. To investigate this hypothesis, we conducted a whole genome microarray study to identify difference in the expression of genes between isogenic doxorubicin-sensitive and doxorubicin-resistant MCF-7 breast tumour cells. We then assessed the degree of over-representation of doxorubicin pharmacokinetic and pharmacodynamic genes in the dataset of doxorubicin resistance genes. Of 27,958 Entrez genes on the array, 7.4 per cent or 2,063 genes were differentially expressed by ≥ 2-fold between wildtype and doxorubicin-resistant cells. The false discovery rate was set at 0.01 and the minimum p value for significance for any gene within the “hit list” was 0.01. Seventeen and 43 per cent of doxorubicin pharmacokinetic genes were over-represented in the hit list, depending upon whether the gene name was identical or within the same gene family, respectively. The most over-represented genes were within the 1C and 1B families of aldo-keto reductases (AKRs), which convert doxorubicin to doxorubicinol. Other genes convert doxorubicin to other metabolites or affect the influx, efflux, or cytotoxicity of the drug. In further support of the role of AKRs in doxorubicin resistance, we observed that, in comparison to doxorubicin, doxorubincol exhibited dramatically reduced cytotoxicity, reduced DNA-binding activity, and strong localization to extra nuclear lysosomes. Pharmacologic inhibition of the above AKRs in doxorubicin-resistant cells increased cellular doxorubicin levels, restored doxorubicin cytotoxicity and re-established doxorubicin localization to the nucleus. The properties of doxorubicinol were unaffected. These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledge bases to identify

EFFECT OF AUXIN AND CYTOKININ ON VINCRISTINE PRODUCTION BY CALLUS CULTURES OF CATHARANTHUS ROSEUS L. (APOCYNACEAE

Directory of Open Access Journals (Sweden)

Chinnamadasamy Kalidass

2009-11-01

Full Text Available Callus cultures of Catharanthus roseus L. were established to verify whether they produce vincristine as the intact plant. Different growth regulator combinations were applied to Murashige and Skoog (MS medium to influence the level of production of vincristine. The effects of various combinations (0.5 µM to 3.0 µM of auxin and cytokinin on the growth and accumulation of vincristine were investigated. MS medium supplemented with 2,4-Dichlorophenoxy acetic acid (2,4-D 1.0 µM and 6-furfurylaminopurine (Kinetin 1.0 µM was used to support the growth of callus cultures and the maximum amount of dry biomass (598.04 mg was produced after seven weeks of culture. High performance liquid chromatographic (HPLC analysis of methanol extracts from callus cultures of C. roseus revealed that the cultures produced vincristine. The concentrations of the growth regulators alpha-naphthalene acetic acid (NAA and kinetin played a critical role in the production of vincristine.

Rituximab and chemotherapy in diffuse large B-cell lymphoma.

Science.gov (United States)

Sonet, Anne; Bosly, André

2009-06-01

Rituximab is an anti-CD20 chimeric monoclonal antibody with activity in nearly all subtypes of B-cell lymphomas. Association of rituximab with chemotherapy (mostly the cyclophosphamide, doxorubicin, vincristine and prednisolone [CHOP] regimen) in diffuse large B-cell lymphoma (DLBCL) represents an extraordinary revolution in the prognosis of DLBCL, and is the new standard of therapy in elderly and young, low-risk patients. Despite the lack of randomized, clinical trials in younger patients with high risk, rituximab is also a standard of care in these patients in clinical practice, at least in North America. The practice is based on observational trials (e.g., the British Columbia Registry) and the missing logic in classifying patients as 'younger' or 'older': 60 years old or 65 years old. In Europe, trials are ongoing to establish the best treatment for young, high-risk patients. Association of rituximab and chemotherapy deeply modifies prognostic factors defined before the rituximab era.

Extraskeletal presentation of Ewing's Sarcoma.

Science.gov (United States)

Mangual, Danny; Bisbal-Matos, Luis A; Jiménez-Lee, Ricardo; Vélez, Román; Noy, Miguel

2018-03-01

The case of a 27-year-old Hispanic female who presented with an occipito-parietal tumor after suffering trauma to the area. A physical examination revealed no tenderness to palpation and with evidence of healing ulcerations. The biopsy was consistent with a synovial sarcoma. A wide excision of the mass (15cm x 14cm x 6cm) followed by a pericranial flap was performed. A follow-up CT showed recurrence involving the parietal sagittal sinus. After a second biopsy the mass was determined to be a small-cell sarcoma, consistent with Ewing's sarcoma. Chemotherapy included 8 cycles of doxorubicin, vincristine, and cyclophosphamide, with alternating cycles of etoposide and ifosfamide. A year later, a second wide excision of the mass was performed, followed by bilaminate skin substitute and skin graft placement for reconstruction of the soft-tissue defect. After chemotherapy, a follow-up PET scan showed no signs of re-uptake in any soft tissue or skeletal structures. After 2 years, the patient remains in complete remission.

A Rare Case of Metastatic Desmoplastic Small Round Cell Tumour: Diagnosis and Management

Directory of Open Access Journals (Sweden)

Shahzaib Nabi

2015-01-01

Full Text Available A 26-year-old male without any significant past medical history presented to the hospital with shortness of breath, cough, pleuritic chest pain, and weight loss for the past 3 months. On chest CT, he was found to have extensive mediastinal and hilar lymphadenopathy and multiple pulmonary nodules. On physical examination, a right groin mass was noted which had been slowly growing for the past 2 years. Ultrasound of the groin showed complex solid mass with internal vascular channels. CT guided biopsy of the mass showed desmoplastic small round cell tumour. His hospital course was complicated by hypoxic respiratory failure requiring emergent intubation and ICU admission where he completed one cycle of vincristine, cyclophosphamide, and doxorubicin with subsequent improvement, followed by extubation. His condition continued to improve after second cycle of chemotherapy and he was ultimately discharged in a stable condition to continue outpatient chemotherapy after a 2-month inpatient stay.

Early Chemotherapy Intensification With Escalated BEACOPP in Patients With Advanced-Stage Hodgkin Lymphoma With a Positive Interim Positron Emission Tomography/Computed Tomography Scan After Two ABVD Cycles: Long-Term Results of the GITIL/FIL HD 0607 Trial.

Science.gov (United States)

Gallamini, Andrea; Tarella, Corrado; Viviani, Simonetta; Rossi, Andrea; Patti, Caterina; Mulé, Antonino; Picardi, Marco; Romano, Alessandra; Cantonetti, Maria; La Nasa, Giorgio; Trentin, Livio; Bolis, Silvia; Rapezzi, Davide; Battistini, Roberta; Gottardi, Daniela; Gavarotti, Paolo; Corradini, Paolo; Cimminiello, Michele; Schiavotto, Corrado; Parvis, Guido; Zanotti, Roberta; Gini, Guido; Ferreri, Andrés J M; Viero, Piera; Miglino, Maurizio; Billio, Atto; Avigdor, Abraham; Biggi, Alberto; Fallanca, Federico; Ficola, Umberto; Gregianin, Michele; Chiaravalloti, Agostino; Prosperini, Giuseppe; Bergesio, Fabrizio; Chauvie, Stephane; Pavoni, Chiara; Gianni, Alessandro Massimo; Rambaldi, Alessandro

2018-02-10

Purpose To investigate the progression-free survival (PFS) of patients with advanced Hodgkin lymphoma (HL) after a risk-adapted treatment strategy that was based on a positive positron emission tomography scan performed after two doxorubicin, vinblastine, vincristine, and dacarbazine (ABVD) cycles (PET2). Patients and Methods Patients with advanced-stage (IIB to IVB) HL were consecutively enrolled. After two ABVD cycles, PET2 was performed and centrally reviewed according to the Deauville five-point scale. Patients with a positive PET2 were randomly assigned to four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) followed by four cycles of standard BEACOPP with or without rituximab. Patients with a negative PET2 continued ABVD, and those with a large nodal mass at diagnosis (≥ 5 cm) in complete remission with a negative PET at the end of chemotherapy were randomly assigned to radiotherapy or no further treatment. The primary end point was 3-year PFS. Results Of 782 enrolled patients, 150 (19%) had a positive and 630 (81%) a negative PET2. The 3-year PFS of all patients was 82%. The 3-year PFS of those with a positive and negative PET2 was 60% and 87%, respectively ( P < .001). The 3-year PFS of patients with a positive PET2 assigned to BEACOPP with or without rituximab was 63% versus 57% ( P = .53). In 296 patients with both interim and post-ABVD-negative PET who had a large nodal mass at diagnosis, radiotherapy was randomly added after chemotherapy without a significant PFS improvement (97% v 93%, respectively; P = .29). The 3-year overall survival of all 782 patients was 97% (99% and 89% for PET2 negative and positive, respectively). Conclusion The PET-driven switch from ABVD to escalated BEACOPP is feasible and effective in high-risk patients with advanced-stage HL.

An elevated serum beta-2-microglobulin level is an adverse prognostic factor for overall survival in patients with early-stage Hodgkin disease.

Science.gov (United States)

Chronowski, Gregory M; Wilder, Richard B; Tucker, Susan L; Ha, Chul S; Sarris, Andreas H; Hagemeister, Fredrick B; Barista, Ibrahim; Hess, Mark A; Cabanillas, Fernando; Cox, James D

2002-12-15

The relative importance of prognostic factors in patients with early-stage Hodgkin disease remains controversial. The purpose of this study was to evaluate prognostic factors among patients who received chemotherapy before radiotherapy. From 1987 to 1995, 217 consecutive patients ranging in age from 16 to 88 years (median, 28 years) with Ann Arbor Stage I (n = 55) or II (n = 162) Hodgkin disease underwent chemotherapy before radiotherapy at a single center. Most were treated on prospective studies. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone (NOVP), doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), cyclophosphamide, vinblastine, procarbazine, prednisone, doxorubicin, bleomycin, dacarbazine, and CCNU (CVPP/ABDIC), or other chemotherapeutic regimens were given to 160, 18, 15, 10, and 14 patients, respectively. The median radiotherapy dose was 40 Gy. Serum beta-2-microglobulin (beta-2M) levels ranged from 1.0 to 4.1 mg/L (median, 1.7 mg/L; upper limit of normal, 2.0 mg/L). We studied univariate and multivariate associations between survival and the following clinical features: serum beta-2M level above 1.25 times the upper limit of normal (n = 12), male gender (n = 113), hypoalbuminemia (n = 11), and bulky mediastinal disease (n = 94). Follow-up of surviving patients ranged from 0.9 to 13.4 years (median, 6.6 years) and 92% were observed for 3.0 or more years. Nineteen patients have died. Only elevation of the serum beta-2M level was an independent adverse prognostic factor for overall survival (P = 0.0009). The prognostic significance of a simple, widely available, and inexpensive blood test, beta-2M, has not been studied routinely in patients with Hodgkin disease and should be tested prospectively in large, cooperative group trials. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10998

Doxorubicin-induced second degree and complete atrioventricular block.

Science.gov (United States)

Kilickap, Saadettin; Akgul, Ebru; Aksoy, Sercan; Aytemir, Kudret; Barista, Ibrahim

2005-05-01

Doxorubicin is one of the most effective chemotherapeutic agents used in the treatment of malignancies. Cardiotoxicity is the most important dose-limiting toxicity of doxorubicin. Although cardiomyopathy is the most well known side effect of doxorubicin, it usually occurs many years after the treatment and relates to cumulative doxorubicin dosage. Another form of doxorubicin cardiotoxicity is arrhythmia which may occur at any time and after any dosage. However, doxorubicin-induced arrhythmia is rarely a life-threatening side effect. In this report, we present a case in which there were doxorubicin-induced life-threatening arrhythmias.

Exploring the potential effect of Ocimum sanctum in vincristine-induced neuropathic pain in rats

Directory of Open Access Journals (Sweden)

Jaggi Amteshwar

2010-01-01

Full Text Available Abstract The present study was designed to investigate the ameliorative potential of Ocimum sanctum and its saponin rich fraction in vincristine-induced peripheral neuropathic pain in rats. Peripheral neuropathy was induced in rats by administration of vincristine sulfate (50 μg/kg i.p. for 10 consecutive days. The mechanical hyperalgesia, cold allodynia, paw heat hyperalgesia and cold tail hyperalgesia were assessed by performing the pinprick, acetone, hot plate and cold tail immersion tests, respectively. Biochemically, the tissue thio-barbituric acid reactive species (TBARS, super-oxide anion content (markers of oxidative stress and total calcium levels were measured. Vincristine administration was associated with the development of mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia. Furthermore, vincristine administration was also associated with an increase in oxidative stress and calcium levels. However, administration of Ocimum sanctum (100 and 200 mg/kg p.o. and its saponin rich fraction (100 and 200 mg/kg p.o. for 14 days significantly attenuated vincristine-induced neuropathic pain along with decrease in oxidative stress and calcium levels. It may be concluded that Ocimum sanctum has ameliorative potential in attenuating chemotherapy induced-painful neuropathic state, which may be attributed to decrease in oxidative stress and calcium levels. Furthermore, saponin rich fraction of Ocimum sanctum may be responsible for its noted beneficial effect in neuropathic pain in rats.

Validated assay for the simultaneous quantification of total vincristine and actinomycin-D concentrations in human EDTA plasma and of vincristine concentrations in human plasma ultrafiltrate by high-performance liquid chromatography coupled with tandem mass spectrometry

NARCIS (Netherlands)

Damen, Carola W. N.; Israëls, Trijn; Caron, Huib N.; Schellens, Jan H. M.; Rosing, Hilde; Beijnen, Jos H.

2009-01-01

A sensitive, specific and efficient high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) assay for the simultaneous determination of total vincristine and actinomycin-D concentrations in human plasma and an assay for the determination of unbound vincristine are presented.

Cyclophosphamide administration routine in autoimmune rheumatic diseases: a review

Directory of Open Access Journals (Sweden)

Kaian Amorim Teles

Full Text Available Abstract Cyclophosphamide is an alkylating agent widely used for the treatment of malignant neoplasia and which can be used in the treatment of multiple rheumatic diseases. Medication administration errors may lead to its reduced efficacy or increased drug toxicity. Many errors occur in the administration of injectable drugs. The present study aimed at structuring a routine for cyclophosphamide use, as well as creating a document with pharmacotherapeutic guidelines for the patient. The routine is schematized in three phases: pre-chemotherapy, administration of cyclophosphamide, and post-chemotherapy, taking into account the drugs to be administered before and after cyclophosphamide in order to prevent adverse effects, including nausea and hemorrhagic cystitis. Adverse reactions can alter laboratory tests; thus, this routine included clinical management for changes in white blood cells, platelets, neutrophils, and sodium, including cyclophosphamide dose adjustment in the case of kidney disease. Cyclophosphamide is responsible for other rare - but serious - side effects, for instance, hepatotoxicity, severe hyponatremia and heart failure. Other adverse reactions include hair loss, amenorrhea and menopause. In this routine, we also entered guidelines to post-chemotherapy patients. The compatibility of injectable drugs with the vehicle used has been described, as well as stability and infusion times. The routine aimed at the rational use of cyclophosphamide, with prevention of adverse events and relapse episodes, factors that may burden the health care system.

Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer

DEFF Research Database (Denmark)

Ejlertsen, Bent Laursen; Mouridsen, Henning T; Jensen, Maj-Britt

2010-01-01

BACKGROUND: The Danish Breast Cancer Cooperative Group (DBCG) 77B trial examined the relative efficacy of levamisole, single-agent oral cyclophosphamide, and the classic combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) against no adjuvant systemic therapy in high-risk breast...... cancer patients. The authors report the results from that trial after a potential follow-up of 25 years. METHODS: Between 1977 and 1983, 1146 premenopausal patients who had tumors >5 cm or positive axillary lymph nodes were assigned randomly to 1 of 4 options: no systemic therapy, levamisole 5 mg weekly...... for 48 weeks (the levamisole arm), oral cyclophosphamide 130 mg/m(2) on Days 1 through 14 every 4 weeks for 12 cycles (the C arm), or oral cyclophosphamide 80 mg/m(2) on Days 1 through 14 plus methotrexate 30 mg/m(2) and fluorouracil 500 mg/m(2) intravenously on Days 1 and 8 every 4 weeks for 12 cycles...

Vinorelbine-Cyclophosphamide compared to cyclophosphamide in peripheral blood stem cell mobilization for multiple myeloma.

Science.gov (United States)

de Mel, Sanjay; Chen, Yunxin; Lin, Adeline; Soh, Teck Guan; Ooi, Melissa; Yap, Eng Soo; Donato, Lara Kristina Sioco; Halim, Nurul Aidah Abdul; Mah, Joanna; Lim, Karen; Poon, Li Mei; Tan, Belinda; Yelly; Lim, Hui Li; Koh, Liang Piu; Tai, Bee Choo; Chen, Zhaojin; Chng, Wee Joo; Gopalakrishnan, Satish Kumar; Tan, Lip Kun

2018-04-23

High dose Cyclophosphamide (Cy) and Vinorelbine Cyclophosphamide (Vino-Cy) are stem cell (SC) mobilisation options for patients with multiple myeloma (MM). We present a comparison of mobilisation outcomes using these regimens. Vino-Cy patients received Vinorelbine 25 mg/m 2 on day 1, cyclophosphamide 1500 mg/m 2 on day 2, and pegylated GCSF on day 4 or GCSF 10 mcg/kg/day from day 4 onwards. Cy patients were given cyclophosphamide 4000 mg/m 2 on day 1 and GCSF10 mcg/kg/day from day 5 onwards. The target CD34 + SC collection was 5 × 10 6  per kg/BW. 149 patients were included. SC collection was lower in the Vino-Cy group (8.20 × 10 6 /Kg BW) compared to the Cy group (11.43 × 10 6 /Kg BW), with adjusted geometric mean ratio of 0.59 (95% CI 0.41 to 0.86, p = 0.006). Time taken to achieve an adequate PB SC count was shorter for Vino-Cy (9 ± 1 day compared to 12 ± 2 days for Cy, adjusted absolute mean difference -3.95, 95% CI -4.85 to -3.06, P < .001). Mobilisation related toxicities (in particular, neutropaenic fever) were greater for Cy. Vino-Cy is a potential alternative to Cy given the need for effective mobilisation protocols with acceptable toxicity. Copyright © 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal and solution formulations of doxorubicin.

Science.gov (United States)

Ryan, Gemma M; Kaminskas, Lisa M; Bulitta, Jürgen B; McIntosh, Michelle P; Owen, David J; Porter, Christopher J H

2013-11-28

Improved delivery of chemotherapeutic drugs to the lymphatic system has the potential to augment outcomes for cancer therapy by enhancing activity against lymph node metastases. Uptake of small molecule chemotherapeutics into the lymphatic system, however, is limited. Nano-sized drug carriers have the potential to promote access to the lymphatics, but to this point, this has not been examined in detail. The current study therefore evaluated the lymphatic exposure of doxorubicin after subcutaneous and intravenous administration as a simple solution formulation or when formulated as a doxorubicin loaded PEGylated poly-lysine dendrimer (hydrodynamic diameter 12 nm), a PEGylated liposome (100 nm) and various pluronic micellar formulations (~5 nm) to thoracic lymph duct cannulated rats. Plasma and lymph pharmacokinetics were analysed by compartmental pharmacokinetic modelling in S-ADAPT, and Berkeley Madonna software was used to predict the lymphatic exposure of doxorubicin over an extended period of time. The micelle formulations displayed poor in vivo stability, resulting in doxorubicin profiles that were similar to that observed after administration of the doxorubicin solution formulation. In contrast, the dendrimer formulation significantly increased the recovery of doxorubicin in the thoracic lymph after both intravenous and subcutaneous dosing when compared to the solution or micellar formulation. Dendrimer-doxorubicin also resulted in increases in lymphatic doxorubicin concentrations when compared to the liposome formulation, although liposomal doxorubicin did increase lymphatic transport when compared to the solution formulation. Specifically, the dendrimer formulation increased the recovery of doxorubicin in the lymph up to 30 h post dose by up to 685 fold and 3.7 fold when compared to the solution and liposomal formulations respectively. Using the compartmental model to predict lymphatic exposure to longer time periods suggested that doxorubicin exposure to

Preparation, quality control and biological characterization of 99mTc-vincristine

International Nuclear Information System (INIS)

Saira Hina; Muhammad Ibrahim Rajoka; Asma Haque

2015-01-01

In present study it is aimed to radiolabel vincristine with 99m Tc and to evaluate bioaffinity of 99m Tc labeled vinc. The optimum conditions required to obtain 99.6 ± 0.4 %, (n = 5) radiolabeling yield of 99m Tc-vincristine ( 99m Tc-vinc) were as follows: pH 4, 5 µg of vincristine sulphate, 6 µg SnCl 2 ·2H 2 O as a reducing agent and 10 min incubation time at room temperature. Quality control of 99m Tc-vinc was done by using paper electrophoresis and thin layer chromatography. The radiolabeling yield was confirmed by High performance liquid chromatography using radioactive and UV detector operating at 230 nm. 99m Tc-vinc was stable in vitro for 5 h. Biodistribution and scintigraphy of 99m Tc-vinc was performed in mice and rabbits respectively and that 99m Tc-vinc showed high uptake of it in liver and spleen. Finally 99m Tc-vinc may be the potential imaging agent for liver and spleen. (author)

1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitizes neuroblastoma cells for taxol and vincristine

NARCIS (Netherlands)

Sietsma, H; Veldman, Robert; Ausema, B; Nijhof, W; Kamps, W; Vellenga, E; Kok, JW

In this study, we show that an inhibitor of glycosphingolipid biosynthesis, D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), increases the chemosensitivity of neuroblastoma tumor cells for Taxol and vincristine. At noneffective low doses of Taxol or vincristine, the addition of a

Adjuvant endocrine and chemotherapy for early breast cancer

International Nuclear Information System (INIS)

Henderson, I. Craig

1996-01-01

Objective: Present the results of the 1995 World Overview which will be held in Oxford England two weeks before ASTRO. Discuss the interpretation and application of these results. Review current research topics on the use of adjuvant endocrine and chemotherapy for early breast cancer. The survival benefits from adjuvant chemotherapy in premenopausal women and adjuvant tamoxifen in postmenopausal women are well established. Each will reduce the annual odds of death by about 25% resulting in a 10 year survival difference of 8-10%. By the time of this presentation, the results of the 1995 Adjuvant Therapy Overview should be with 10+ years of follow-up, and if possible these will be summarized. Current efforts to improve on previous results are focused on the following areas: Optimal chemotherapy dose. Decreasing dose will compromise patient survival. It is not as certain that increasing dose will have as much impact in improving survival. The NSABP was unable to demonstrate an improvement in survival by modestly increasing the dose of cyclophosphamide alone. However, recent results of a Canadian study of CEF (cyclophosphamide, epidoxorubicin, and 5-fluorouracil) and an Intergroup trial of an intense 16 week polychemotherapy program keep alive the possibility that dose escalation is still a very important question. An NSABP trial evaluating even greater cyclophosphamide dose escalation, an Intergroup evaluation of different doxorubicin doses, and two Intergroup trials evaluating very high dose chemotherapy and bone marrow transplantation should provide definitive evidence regarding the importance of dose. Drug sequence. A study from Milan suggests that initial treatment with single agent doxorubicin followed by CMF will be superior to alternating doxorubicin and CMF. This has not been confirmed yet, and the reason for increased benefit from such a sequence is not entirely clear. This concept is being explored further in an Intergroup trial comparing four cycles of

Severe vincristine-induced polyneuropathy in a teenager with anaplastic medulloblastoma and undiagnosed Charcot-Marie-Tooth disease.

Science.gov (United States)

Aghajan, Yasmin; Yoon, Janet M; Crawford, John Ross

2017-04-24

Severe neuropathy is a known adverse effect of vincristine in patients with Charcot-Marie-Tooth disease (CMT). We present the case of a 16-year-old girl with anaplastic medulloblastoma treated with gross total resection and high-dose craniospinal radiation with adjuvant vincristine chemotherapy who developed acute-onset severe quadriplegia and vocal cord paralysis. Vincristine and radiation therapy were discontinued. Although her neuropathy slowly improved over several weeks, she developed metastatic extraneural medulloblastoma and died 5 months after diagnosis. Subsequent genetic testing revealed previously asymptomatic and undiagnosed CMT1A. Our case highlights the importance of early recognition of acute vincristine neurotoxicity that should raise suspicion of an underlying hereditary neuropathy. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Aerobic activated sludge transformation of vincristine and identification of the transformation products.

Science.gov (United States)

Kosjek, Tina; Negreira, Noelia; Heath, Ester; López de Alda, Miren; Barceló, Damià

2018-01-01

This study aims to identify (bio)transformation products of vincristine, a plant alkaloid chemotherapy drug. A batch biotransformation experiment was set-up using activated sludge at two concentration levels with and without the addition of a carbon source. Sample analysis was performed on an ultra-high performance liquid chromatograph coupled to a high-resolution hybrid quadrupole-Orbitrap tandem mass spectrometer. To identify molecular ions of vincristine transformation products and to propose molecular and chemical structures, we performed data-dependent acquisition experiments combining full-scan mass spectrometry data with product ion spectra. In addition, the use of non-commercial detection and prediction algorithms such as MZmine 2 and EAWAG-BBD Pathway Prediction System, was proven to be proficient for screening for transformation products in complex wastewater matrix total ion chromatograms. In this study eleven vincristine transformation products were detected, nine of which were tentatively identified. Copyright © 2017 Elsevier B.V. All rights reserved.

Mitochondrial Dynamics Decrease Prior to Axon Degeneration Induced by Vincristine and are Partially Rescued by Overexpressed cytNmnat1.

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Gregory Berbusse

2016-07-01

Full Text Available Axon degeneration is a prominent feature of various neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, and is often characterized by aberrant mitochondrial dynamics. Mitochondrial fission, fusion, and motility have been shown to be particularly important in progressive neurodegeneration. Thus we investigated these imperative dynamics, as well as mitochondrial fragmentation in vincristine induced axon degradation in cultured DRG neurons. CytNmnat1 inhibits axon degeneration in various paradigms including vincristine toxicity. The mechanism of its protection is not yet fully understood; therefore, we also investigated the effect of cytNmnat1 on mitochondrial dynamics in vincristine treated neurons. We observed that vincristine treatment decreases the rate of mitochondrial fission, fusion and motility and induces mitochondrial fragmentation. These mitochondrial events precede visible axon degeneration. Overexpression of cytNmnat1 inhibits axon degeneration and preserves the normal mitochondrial dynamics and motility in vincristine treated neurons. We suggest the alterations in mitochondrial structure and dynamics are early events which lead to axon degeneration and cytNmnat1 blocks axon degeneration by halting the vincristine induced changes to mitochondrial structure and dynamics.

Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy

Directory of Open Access Journals (Sweden)

Kim Dong-Wan

2007-04-01

Full Text Available Abstract Background Bcl-2 is positively regulated by hormonal receptor pathways in breast cancer. A study was conducted to assess the prognostic significances of clinico-pathologic variables and of ER, PR, p53, c-erbB2, bcl-2, or Ki-67 as markers of relapse in breast cancer patients who had received the identical adjuvant therapy at a single institution. Methods A cohort of 151 curatively resected stage III breast cancer patients (M:F = 3:148, median age 46 years who had 4 or more positive lymph nodes and received doxorubicin and cyclophosphamide followed by paclitaxel (AC/T as adjuvant chemotherapy was analyzed for clinico-pathologic characteristics including disease-free survival (DFS and overall survival (OS. Patients with positive ER and/or PR expression received 5 years of tamoxifen following AC/T. The protein expressions of biomarkers were assessed immunohistochemically. Results The median follow-up duration was 36 months, and 37 patients (24.5% experienced a recurrence. Univariate analyses indicated that the tumor size (P = 0.038 and the number of involved lymph nodes (P P = 0.013, bcl-2 positivity (P = 0.002 and low p53 expression (P = 0.032 were found to be significantly associated with a prolonged DFS. Furthermore, multivariate analysis identified 10 or more involved lymph nodes (HR 7.366; P P = 0.030, and c-erbB2 over-expression (HR 3.535; P = 0.001 as independent indicators of poorer DFS. In addition, bcl-2 expression was found to be significantly correlated with the expressions of ER and PR, and inversely correlated with the expressions of p53, c-erbB2 and Ki-67. Patients with bcl-2 expression had a significantly longer DFS than those without, even in the ER (+ subgroup. Moreover, OS was significantly affected by ER, bcl-2 and c-erbB2. Conclusion Bcl-2 is an independent prognostic factor of DFS in curatively resected stage III breast cancer patients and appears to be a useful prognostic factor in combination with c-erbB2 and the

Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma

DEFF Research Database (Denmark)

Judson, Ian; Verweij, Jaap; Gelderblom, Hans

2014-01-01

BACKGROUND: Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used...

Comparison between types of cancer chemotherapies used in a private and a government-based hospital in Mexico.

Science.gov (United States)

Calderón Guzmán, David; Juarez Olguín, Hugo; Guevara Zempoalteca, Angeles; Juárez Jacobo, Arturo; Segura Abarca, Lourdes; Barragán Mejía, Gerardo; Hernández García, Ernestina

2009-01-01

We have compared the frequency and types of cancer chemotherapies used in a private hospital and in a government-based hospital in Mexico City. A retrospective study was conducted from January 2005 to December 2007, and therapeutic management determined in 415 cases reviewed by the attending physicians of the oncology service. In the government-based hospital, 60 different types of cancer were found among 273 patients diagnosed. Acute lymphoblastic leukemia (ALL) had the greatest incidence (30%), followed by Hodgkin's lymphoma (9%), retinoblastoma (7%), neuroblastoma (6%), and osteosarcoma (6%). The entire number of chemotherapy sessions was 7575. Drugs most frequently employed included etoposide (577), followed by methotrexate (575), vincristine (483), cyclophosphamide (312), and cytarabine (277). The economic status among these patients was mainly of limited resources and represented 80% of the total number of patients. The types of cancer found in the private hospital were similar, however the drugs used were predominantly cyclophosphamide (416), doxorubicin (382), 5-fluorouracil (368), paclitaxel (237) and cisplatin (128). The types of cancer were similar in both hospitals and reflected the incidence among the entire population in Mexico, since acute lymphoblastic leukemia, Hodgkin's lymphoma and retinoblastoma, were the types most represented. However, the treatment schemes differed; the chemotherapeutic agents used in the private hospital were rather more specific but significantly more expensive than those employed in the government hospital.

Novel Combination Chemotherapy for Localized Ewing Sarcoma

Science.gov (United States)

In this clinical trial, researchers will test whether the addition of the drug combination vincristine, topotecan, and cyclophosphamide to a standard chemotherapy regimen improves overall survival in patients with extracranial Ewing

Metastatic Angiosarcoma with Kasabach-Merritt Syndrome Responsive to Gemcitabine and Vinorelbine after Failure of Liposomal Doxorubicin and Paclitaxel: A Case Report

Directory of Open Access Journals (Sweden)

William L. Read

2016-03-01

Full Text Available Kasabach-Merritt syndrome (KMS describes a consumptive coagulopathy associated with certain vascular tumors. It is thought that platelets are destroyed as they circulate through the aberrant endothelial surfaces associated with these tumors. Most published literature describes infants with kaposiform hemangioendothelioma, but a similar syndrome can complicate angiosarcoma in adults. This report describes a man with metastatic angiosarcoma arising in the scalp in whom disease progression was complicated by profound thrombocytopenia consistent with KMS. His disease and associated KMS had progressed previously through paclitaxel and then through liposomal doxorubicin. It did not respond to paclitaxel and bevacizumab, but responded almost completely to chemotherapy with gemcitabine and vinorelbine. Six months later, progression through ongoing chemotherapy then responded to chemotherapy with cyclophosphamide and sirolimus.

Effects of quercetin on kidney injury induced by doxorubicin.

Science.gov (United States)

Yagmurca, M; Yasar, Z; Bas, O

2015-01-01

The anthracycline antitumor drug doxorubicine causes severe nephrotoxicity in a variety of experimental animals and may be nephrotoxic to humans. The aim of present study was to determine the protective effects of quercetin against doxorubicin-induced kidney injury with light microscopy. Forty male Wistar albino rats were divided into four groups: control, doxorubicin, doxorubicin+quercetin and quercetin. A single dose of 20 mg/kg/ i.p. doxorubicin was used to induce injury. Quercetin was administrated orally against doxorubicin toxicity. The kidneys were examined under light microscopy after H-E (hematoxylin-eosin) staining and the changes were scored. Significant tissue injury was observed in doxorubicin-administered group. Among these injuries, renal tubular dilatation, tubular vacuolar changes, glomerular vacuolization, decrease in bowman space, bowman capsule thickening, and interstitial infiltration were evident. However, the injury induced by doxorubicin was attenuated with quercetin administration. Quercetin decreased doxorubicin-induced kidney damage (Tab. 1, Fig. 4, Ref. 27).

Cyclophosphamide for connective tissue disease-associated interstitial lung disease.

Science.gov (United States)

Barnes, Hayley; Holland, Anne E; Westall, Glen P; Goh, Nicole Sl; Glaspole, Ian N

2018-01-03

Approximately one-third of individuals with interstitial lung disease (ILD) have associated connective tissue disease (CTD). The connective tissue disorders most commonly associated with ILD include scleroderma/systemic sclerosis (SSc), rheumatoid arthritis, polymyositis/dermatomyositis, and Sjögren's syndrome. Although many people with CTD-ILD do not develop progressive lung disease, a significant proportion do progress, leading to reduced physical function, decreased quality of life, and death. ILD is now the major cause of death amongst individuals with systemic sclerosis.Cyclophosphamide is a highly potent immunosuppressant that has demonstrated efficacy in inducing and maintaining remission in autoimmune and inflammatory illnesses. However this comes with potential toxicities, including nausea, haemorrhagic cystitis, bladder cancer, bone marrow suppression, increased risk of opportunistic infections, and haematological and solid organ malignancies.Decision-making in the treatment of individuals with CTD-ILD is difficult; the clinician needs to identify those who will develop progressive disease, and to weigh up the balance between a high level of need for therapy in a severely unwell patient population against the potential for adverse effects from highly toxic therapy, for which only relatively limited data on efficacy can be found. Similarly, it is not clear whether histological subtype, disease duration, or disease extent can be used to predict treatment responsiveness. To assess the efficacy and adverse effects of cyclophosphamide in the treatment of individuals with CTD-ILD. We performed searches on CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science up to May 2017. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles. We included randomised controlled parallel-group trials that compared cyclophosphamide in any form, used individually or concomitantly with other immunomodulating therapies, versus non-cyclophosphamide

Progressive myelopathy, a consequence of intra‑thecal chemotherapy

African Journals Online (AJOL)

2014-09-09

splenomegally ... Protocol consisting of intravenous cyclophosphamide, vincristine (oncovin) ... to the National guideline for cancer chemotherapy.[6]. The pathology ... Vitamin B12 in our patient because of lack of this facility, although our ...

Proteomic changes in a childhood acute lymphoblastic leukemia cell line during the adaptation to vincristine.

Science.gov (United States)

Guzmán-Ortiz, Ana Laura; Aparicio-Ozores, Gerardo; Valle-Rios, Ricardo; Medina-Contreras, Oscar; Patiño-López, Genaro; Quezada, Héctor

Relapse occurs in approximately 20% of Mexican patients with childhood acute lymphoblastic leukemia (ALL). In this group, chemoresistance may be one of the biggest challenges. An overview of complex cellular processes like drug tolerance can be achieved with proteomic studies. The B-lineage pediatric ALL cell line CCRF-SB was gradually exposed to the chemotherapeutic vincristine until proliferation was observed at 6nM, control cells were cultured in the absence of vincristine. The proteome from each group was analyzed by nanoHPLC coupled to an ESI-ion trap mass spectrometer. The identified proteins were grouped into overrepresented functional categories with the PANTHER classification system. We found 135 proteins exclusively expressed in the presence of vincristine. The most represented functional categories were: Toll receptor signaling pathway, Ras Pathway, B and T cell activation, CCKR signaling map, cytokine-mediated signaling pathway, and oxidative phosphorylation. Our study indicates that signal transduction and mitochondrial ATP production are essential during adaptation of leukemic cells to vincristine, these processes represent potential therapeutic targets. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

The Use of Vincristine in Refractory Auto-immune Thrombocytopenic ...

African Journals Online (AJOL)

Two patients with auto-immune thrombocytopenic purpura are reported who continued to bleed despite high doses of corticosteroids, immunosuppressive therapy and splenec- tomy. The addition of vincristine to their therapeutic regimen produced a response in each case and both patients are now off all therapy without ...

Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study.

Science.gov (United States)

Rosiñol, Laura; Oriol, Albert; Teruel, Ana Isabel; Hernández, Dolores; López-Jiménez, Javier; de la Rubia, Javier; Granell, Miquel; Besalduch, Joan; Palomera, Luis; González, Yolanda; Etxebeste, María Asunción; Díaz-Mediavilla, Joaquín; Hernández, Miguel T; de Arriba, Felipe; Gutiérrez, Norma C; Martín-Ramos, María Luisa; Cibeira, María Teresa; Mateos, María Victoria; Martínez, Joaquín; Alegre, Adrián; Lahuerta, Juan José; San Miguel, Jesús; Bladé, Joan

2012-08-23

The Spanish Myeloma Group conducted a trial to compare bortezomib/thalidomide/dexamethasone (VTD) versus thalidomide/dexamethasone (TD) versus vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib (VBMCP/VBAD/B) in patients aged 65 years or younger with multiple myeloma. The primary endpoint was complete response (CR) rate postinduction and post-autologous stem cell transplantation (ASCT). Three hundred eighty-six patients were allocated to VTD (130), TD (127), or VBMCP/VBAD/B (129). The CR rate was significantly higher with VTD than with TD (35% vs 14%, P = .001) or with VBMCP/VBAD/B (35% vs 21%, P = .01). The median progression-free survival (PFS) was significantly longer with VTD (56.2 vs 28.2 vs 35.5 months, P = .01). In an intention-to-treat analysis, the post-ASCT CR rate was higher with VTD than with TD (46% vs 24%, P = .004) or with VBMCP/VBAD/B (46% vs 38%, P = .1). Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups. In conclusion, VTD resulted in a higher pre- and posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. Our results support the use of VTD as a highly effective induction regimen prior to ASCT. The study was registered with http://www.clinicaltrials.gov (NCT00461747) and Eudra CT (no. 2005-001110-41).

[Pharmacogenetic aspects of the immunodepressive action of cyclophosphamide].

Science.gov (United States)

Telegin, L Iu

1979-03-01

The alkylating and immunodepressive activity of the serum of CBA, BALB/c and DBA/2 mice was studied after the cyclophosphamide administration. The interstrain differences between the indices under study were revealed; no direct correlation was shown between them. DBA/2 mice were found to be the most sensitive to the immunodepressive action of cyclophosphamide, and had the highest blood serum immunodepressive activity.

Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats

International Nuclear Information System (INIS)

Kalender, Yusuf; Yel, Mustafa; Kalender, Suna

2005-01-01

Doxorubicin (DXR) is an anthracycline antibiotic, broady used in tumor therapy. In the present study we investigated whether vitamin E and catechin can reduce the toxic effects of doxorubicin. Vitamin E (200 IU/kg/week), catechin (200 mg/kg/week), doxorubicin (5 mg/kg/week), doxorubicin + vitamin E (200 IU/kg/week), doxorubicin + catechin (200 mg/kg/week) combinations were given to rats weighing 210-230 g (n = 6/group). Changes in major enzymes participating in free radical metabolism superoxide dismutase (Cu,Zn-SOD), glutathione peroxidase (GSHPx), catalase (CAT) and malondialdehyde (MDA) were evaluated in the livers of all animals. Superoxide dismutase and catalase activity increased in the doxorubicin-treated group compared to control (P 0.05). Electron microscopic studies supported biochemical findings. We conclude that vitamin E and catechin significantly reduce doxorubicin-induced hepatotoxicity in rats

Tripeptide tyroserleutide plus doxorubicin: therapeutic synergy and side effect attenuation

International Nuclear Information System (INIS)

Zhu, Zhi-feng; Yao, Zhi; Chen, Li-juan; Lu, Rong; Jia, Jing; Liang, Yu; Xu, Qiong; Zhou, Chun-lei; Wang, Li; Wang, Song

2008-01-01

Tripeptide tyroserleutide (YSL) is a novel small molecule anti-tumor polypeptide that has been shown to inhibit the growth of human liver cancer cells. In this study, we investigated the effects of YSL plus doxorubicin on the growth of human hepatocellular carcinoma BEL-7402 cells that had been transplanted into nude mice. Nude mice bearing human hepatocellular carcinoma BEL-7402 tumors were treated with successive intraperitoneal injections of saline; low-, mid-, or high-dose doxorubicin; or low-, mid-, or high-dose doxorubicin plus YSL. Effects on the weight and volume of the tumors were evaluated. Co-administration of YSL and high-dose doxorubicin (6 mg/kg every other day) prolonged the survival time of tumor-bearing mice as compared to high-dose doxorubicin alone. As well, the anti-tumor effects of mid- and low-dose doxorubicin (2 and 0.7 mg/kg every other day, respectively) were enhanced when supplemented with YSL; the tumor growth inhibition rates for YSL plus doxorubicin were greater than the inhibition rates for the same dosages of doxorubicin alone. The combination of YSL and doxorubicin decreased chemotherapy-associated weight loss, leukocyte depression, and heart, liver, and kidney damage as compared to doxorubicin alone. The combination of YSL plus doxorubicin enhances the anti-tumor effect and reduces the side effects associated with doxorubicin chemotherapy

Conservative multimodal management of a primitive neuroectodermal tumor of the thyroid

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Juliette Haudebourg

2013-04-01

Full Text Available Primitive neuroectodermal tumors (PNET represent 1% of sarcomas. Head and neck peripheral PNETs have an intermediate prognosis between abdominopelvic disease and extremities. We here report the case of a 40-year old male who presented with primitive neuroectodermal tumor of the thyroid and was treated by multimodal treatment, including surgery, chemotherapy and intermediate dose radiotherapy. The patient is alive and fit with a functional larynx at 27 months. Multimodal treatments yield five-year survival rates of about 60%. Major drug regimens use vincristine, doxorubicin, ifosfamide or cyclophosphamide, dactinomycin and/or etoposide. Complete surgical excision is undertaken whenever possible to improve long-term survival. However, the relative radiosensitivity of tumors of the Ewing family, suggest multimodal treatment including adjuvant conformal radiotherapy in case of positive margins or poor response to chemotherapy rather than resection with 2-3 cm margins, which would imply laryngeal sacrifice for thyroid tumors. The role of expert rare tumor networks is crucial for optimal decision-making and management of such rare tumors on a case by case basis.

Treatment of feline lymphoma using a 12-week, maintenance-free combination chemotherapy protocol in 26 cats.

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Limmer, S; Eberle, N; Nerschbach, V; Nolte, I; Betz, D

2016-08-01

The aim of this prospective clinical trial was to investigate the efficacy and toxicity of a short-term, maintenance-free chemotherapy protocol in feline lymphoma. Twenty-six cats with confirmed diagnosis of high-/intermediate-grade lymphoma were treated with a 12-week protocol consisting of cyclic administration of l-asparaginase, vincristine, cyclophosphamide, doxorubicin and prednisolone. Complete (CR) and partial remission (PR) rates were 46 and 27%, respectively. Median duration of first CR was 394 days compared with a median PR duration of 41 days. No factor was identified to significantly influence the likelihood to reach CR. Overall survival amounted to 78 days (range: 9-2230 days). Median survival in CR cats was 454 days and in PR cats was 82 days. Toxicosis was mainly low grade with anorexia seen most frequently. In cats achieving CR, maintenance-free chemotherapy may be sufficient to attain long-term remission and survival. Factors aiding in prognosticating the likelihood for CR, strategies enhancing response and targeting chemotherapy-induced anorexia need to be identified in future. © 2014 John Wiley & Sons Ltd.

Peripheral T-cell lymphoma with unusual clinical presentation of rhabdomyolysis.

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Liu, Zhiyu; Medeiros, L Jeffrey; Young, Ken H

2017-03-01

Primary extranodal lymphoma is known to occur in nose, gastrointestinal tract, skin, bone, and central nervous system. However, it is extremely rare for primary lymphoma to arise in skeletal muscle. We report a case of a 32-year-old man who presented initially with fever and fatigue. He had a history of alcohol abuse. Laboratory studies and computerized tomography scan showed results consistent with rhabdomyolysis, but the cause of the rhabdomyolysis was undetermined. After biopsy of abdominal skeletal muscle with histologic examination and T-cell receptor gamma chain gene rearrangement analysis, the diagnosis of peripheral T-cell lymphoma was established. After two cycles of the cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide regimen, the patient's symptoms greatly improved. This is the third reported case of peripheral T-cell lymphoma arising in skeletal muscle reported in the literature and which presented clinically with rhabdomyolysis. The alcohol abuse during the clinical course likely worsens the pathologic process of the rhabdomyolysis. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Long-term survival in an adolescent with widely metastatic renal cell carcinoma with rhabdoid features.

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Ettinger, L J; Goodell, L A; Javidian, P; Hsieh, Y; Amenta, P

2000-01-01

Renal cell carcinoma is rarely seen in children and adolescents. Patients with widespread disease at diagnosis have a particularly poor survival rate. Currently, all known chemotherapy has been ineffective in improving the median survival in patients with advanced disease. A 13-year-old black boy with stage IV renal cell carcinoma with rhabdoid features is a long-term disease-free survivor after aggressive multiagent chemotherapy. After the initial evaluation and histologic diagnosis of renal cell carcinoma, the patient received three courses of an aggressive chemotherapy regimen consisting of vincristine, doxorubicin, cyclophosphamide with mesna uroprotection, granulocyte colony-stimulating factor and erythropoietin (Epogen). After an almost complete response, a radical nephrectomy was performed and results demonstrated a solitary small nodule with viable tumor. After surgery, he received floxuridine infusion for 14 days by circadian schedule at 28-day intervals for a total of 1 year. The patient is well and free of disease 5 years after initial presentation. The dramatic response to treatment and long-term disease-free survival of this patient suggest this chemotherapeutic approach warrants additional investigation.

Rituximab-Based Treatment, HCV Replication, and Hepatic Flares

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Evangelista Sagnelli

2012-01-01

Full Text Available Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only a few small studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases.

Rituximab-based treatment, HCV replication, and hepatic flares.

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Sagnelli, Evangelista; Pisaturo, Mariantonietta; Sagnelli, Caterina; Coppola, Nicola

2012-01-01

Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only a few small studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases.

A Case of Renal Primitive Neuroectodermal Tumor Confirmed by Fluorescence in situ Hybridization

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Toshiki Etani

2015-04-01

Full Text Available Primitive neuroectodermal tumor (PNET is a member of the Ewing's sarcoma family of tumors (ESFT. We report a case of PNET in a 66-year-old male who presented with a large solid tumor within the parenchyma of the middle pole of the left kidney with metastases to the left adrenal gland and right ischium. A fine-needle biopsy was performed and showed a small round cell tumor. Results of immunohistochemical staining suggested this tumor belonged to ESFT. Preoperative VDC-IE (combined vincristine, doxorubicin and cyclophosphamide followed by another combination of ifosfamide and etoposide chemotherapy and left radical nephrectomy and adrenalectomy were performed. The histopathological findings of the resected tumor were similar to those in the biopsy specimen, but the results of AE1/AE3 were different. For the diagnosis, fluorescence in situ hybridization was performed. Split signals of the EWSR1 gene were detected, and transmission electron microscopy showed neuroendocrine granules and microtubules. The final diagnosis of this tumor was PNET of the kidney.

Total body irradiation in a patient with fragile X syndrome for acute lymphoblastic leukemia in preparation for stem cell transplantation: A case report and literature review.

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Collins, D T; Mannina, E M; Mendonca, M

2015-10-01

Fragile X syndrome (FXS) is a congenital disorder caused by expansion of CGG trinucleotide repeat at the 5' end of the fragile X mental retardation gene 1 (FMR1) on the X chromosome that leads to chromosomal instability and diminished serum levels of fragile X mental retardation protein (FMRP). Afflicted individuals often have elongated features, marfanoid habitus, macroorchidism and intellectual impairment. Evolving literature suggests the condition may actually protect from malignancy while chromosomal instability would presumably elevate the risk. Increased sensitivity to ionizing radiation should also be predicted by unstable sites within the DNA. Interestingly, in this report, we detail a patient with FXS diagnosed with acute lymphoblastic leukemia treated with induction followed by subsequent cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with a complete response who then was recommended to undergo peripheral stem cell transplantation. The patient underwent total body irradiation (TBI) as a component of his conditioning regimen and despite the concern of his clinicians, developed minimal acute toxicity and successful engraftment. The pertinent literature regarding irradiation of patients with FXS is also reviewed. © 2015 Wiley Periodicals, Inc.

Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy

International Nuclear Information System (INIS)

Lee, Kyung-Hun; Noh, Dong-Young; Heo, Dae Seog; Ha, Sung Whan; Bang, Yung-Jue; Im, Seock-Ah; Oh, Do-Youn; Lee, Se-Hoon; Chie, Eui Kyu; Han, Wonshik; Kim, Dong-Wan; Kim, Tae-You; Park, In Ae

2007-01-01

Bcl-2 is positively regulated by hormonal receptor pathways in breast cancer. A study was conducted to assess the prognostic significances of clinico-pathologic variables and of ER, PR, p53, c-erbB2, bcl-2, or Ki-67 as markers of relapse in breast cancer patients who had received the identical adjuvant therapy at a single institution. A cohort of 151 curatively resected stage III breast cancer patients (M:F = 3:148, median age 46 years) who had 4 or more positive lymph nodes and received doxorubicin and cyclophosphamide followed by paclitaxel (AC/T) as adjuvant chemotherapy was analyzed for clinico-pathologic characteristics including disease-free survival (DFS) and overall survival (OS). Patients with positive ER and/or PR expression received 5 years of tamoxifen following AC/T. The protein expressions of biomarkers were assessed immunohistochemically. The median follow-up duration was 36 months, and 37 patients (24.5%) experienced a recurrence. Univariate analyses indicated that the tumor size (P = 0.038) and the number of involved lymph nodes (P < 0.001) significantly affected the recurrences. However, the type of surgery, the histology, histologic grade, the presence of endolymphatic emboli, and a close resection margin did not. Moreover, ER positivity (P = 0.013), bcl-2 positivity (P = 0.002) and low p53 expression (P = 0.032) were found to be significantly associated with a prolonged DFS. Furthermore, multivariate analysis identified 10 or more involved lymph nodes (HR 7.366; P < 0.001), negative bcl-2 expression (HR 2.895; P = 0.030), and c-erbB2 over-expression (HR 3.535; P = 0.001) as independent indicators of poorer DFS. In addition, bcl-2 expression was found to be significantly correlated with the expressions of ER and PR, and inversely correlated with the expressions of p53, c-erbB2 and Ki-67. Patients with bcl-2 expression had a significantly longer DFS than those without, even in the ER (+) subgroup. Moreover, OS was significantly affected by ER, bcl

Response rate of fibrosarcoma cells to cytotoxic drugs on the expression level correlates to the therapeutic response rate of fibrosarcomas and is mediated by regulation of apoptotic pathways

International Nuclear Information System (INIS)

Lehnhardt, Marcus; Mueller, Oliver; Klein-Hitpass, Ludger; Kuhnen, Cornelius; Homann, Heinz Herbert; Daigeler, Adrien; Steinau, Hans Ulrich; Roehrs, Sonja; Schnoor, Laura; Steinstraesser, Lars

2005-01-01

Because of the high resistance rate of fibrosarcomas against cytotoxic agents clinical chemotherapy of these tumors is not established. A better understanding of the diverse modes of tumor cell death following cytotoxic therapies will provide a molecular basis for new chemotherapeutic strategies. In this study we elucidated the response of a fibrosarcoma cell line to clinically used cytostatic agents on the level of gene expression. HT1080 fibrosarcoma cells were exposed to the chemotherapeutic agents doxorubicin, actinomycin D or vincristine. Total RNA was isolated and the gene expression patterns were analyzed by microarray analysis. Expression levels for 46 selected candidate genes were validated by quantitative real-time PCR. The analysis of the microarray data resulted in 3.309 (actinomycin D), 1.019 (doxorubicin) and 134 (vincristine) probesets that showed significant expression changes. For the RNA synthesis blocker actinomycin D, 99.4% of all differentially expressed probesets were under-represented. In comparison, probesets down-regulated by doxorubicin comprised only 37.4% of all genes effected by this agent. Closer analysis of the differentially regulated genes revealed that doxorubicin induced cell death of HT1080 fibrosarcoma cells mainly by regulating the abundance of factors mediating the mitochondrial (intrinsic) apoptosis pathway. Furthermore doxorubicin influences other pathways and crosstalk to other pathways (including to the death receptor pathway) at multiple levels. We found increased levels of cytochrome c, APAF-1 and members of the STAT-family (STAT1, STAT3), while Bcl-2 expression was decreased. Caspase-1, -3, -6, -8, and -9 were increased indicating that these proteases are key factors in the execution of doxorubicin mediated apoptosis. This study demonstrates that chemotherapy regulates the expression of apoptosis-related factors in fibrosarcoma cells. The number and the specific pattern of the genes depend on the used cytotoxic drug

Effects of anthracycline, cyclophosphamide and taxane chemotherapy on QTc measurements in patients with breast cancer.

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Veronese, Pedro; Hachul, Denise Tessariol; Scanavacca, Mauricio Ibrahim; Hajjar, Ludhmila Abrahão; Wu, Tan Chen; Sacilotto, Luciana; Veronese, Carolina; Darrieux, Francisco Carlos da Costa

2018-01-01

Acute and subacute cardiotoxicity are characterized by prolongation of the corrected QT interval (QTc) and other measures derived from the QTc interval, such as QTc dispersion (QTdc) and transmural dispersion of repolarization (DTpTe). Although anthracyclines prolong the QTc interval, it is unclear whether breast cancer patients who undergo the ACT chemotherapy regimen of anthracycline (doxorubicin: A), cyclophosphamide (C) and taxane (T) may present with QTc, QTdc and DTpTe prolongation. Twenty-three consecutive patients with breast cancer were followed prospectively during ACT chemotherapy and were analyzed according to their QT measurements. QTc, QTdc and DTpTe measurements were determined by a 12-lead electrocardiogram (EKG) prior to chemotherapy (baseline), immediately after the first phase of anthracycline and cyclophosphamide (AC) treatment, and immediately after T treatment. Serum troponin and B-type natriuretic peptide (BNP) levels were also measured. Compared to baseline values, the QTc interval was significantly prolonged after the AC phase (439.7 ± 33.2 ms vs. 472.5 ± 36.3 ms, p = 0.001) and after T treatment (439.7 ± 33.2 ms vs. 467.9 ± 42.6 ms, p < 0.001). Troponin levels were elevated after the AC phase (23.0 pg/mL [min-max: 6.0-85.0] vs. 6.0 pg/mL [min-max: 6.0-22.0], p < 0.001) and after T treatment (25.0 pg/mL [min-max: 6.0-80.0] vs. 6.0 pg/mL [min-max: 6.0-22.0], p < 0.001) compared to baseline values. In this prospective study of patients with non-metastatic breast cancer who underwent ACT chemotherapy, significant QTc prolongation and an elevation in serum troponin levels were observed.

Charcot-Marie-Tooth Disease in a Child with Acute Lymphoblastic ...

African Journals Online (AJOL)

Alasia Datonye

38.6 C) with generalised non tender lymphadenopathy. His weight was 22kg ... intravenous (iv) cyclophosphamide, iv vincristine, and oral ... anti-cancer regimen and vitamin B complex was added to his .... Cancer 1996; 77: 1356-. 1362. 10.

A Novel Insight into the Cardiotoxicity of Antineoplastic Drug Doxorubicin

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Zbynek Heger

2013-10-01

Full Text Available Doxorubicin is a commonly used antineoplastic agent in the treatment of many types of cancer. Little is known about the interactions of doxorubicin with cardiac biomolecules. Serious cardiotoxicity including dilated cardiomyopathy often resulting in a fatal congestive heart failure may occur as a consequence of chemotherapy with doxorubicin. The purpose of this study was to determine the effect of exposure to doxorubicin on the changes in major amino acids in tissue of cardiac muscle (proline, taurine, glutamic acid, arginine, aspartic acid, leucine, glycine, valine, alanine, isoleucine, threonine, lysine and serine. An in vitro interaction study was performed as a comparison of amino acid profiles in heart tissue before and after application of doxorubicin. We found that doxorubicin directly influences myocardial amino acid representation even at low concentrations. In addition, we performed an interaction study that resulted in the determination of breaking points for each of analyzed amino acids. Lysine, arginine, β-alanine, valine and serine were determined as the most sensitive amino acids. Additionally we compared amino acid profiles of myocardium before and after exposure to doxorubicin. The amount of amino acids after interaction with doxorubicin was significantly reduced (p = 0.05. This fact points at an ability of doxorubicin to induce changes in quantitative composition of amino acids in myocardium. Moreover, this confirms that the interactions between doxorubicin and amino acids may act as another factor most likely responsible for adverse effects of doxorubicin on myocardium.

PROTECTIVE PROPERTIES OF DIARYLHEPTANOID OREGONIN WITH ADMINISTRATION OF CYCLOPHOSPHAMIDE TO ANIMALS

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Sheibak V. M.

2018-03-01

Full Text Available Background. Diarylheptanoids administration increases the efficacy of cyclophosphamide and reduces the activity of lipid peroxidation processes, allowing to decrease the dose of a cytostatic agent and reduce its side effects. The purpose of the study was to determine the protective properties of diarylheptanoid oregonin against the toxic effects of cyclophosphamide on the leukocyte count and the concentration of free amino acids in the blood plasma and spleen tissue. Material and methods. Male rats treated with cyclophosphamide (160 mg/kg body weight and oregonin (5 mg/kg body weight were used in the study. The determination of free amino acids was performed by the reversed-phase HPLC. Results. It has been established that the administration of a course of oregonin together with cyclophosphamide increases the content of amino acids and their derivatives in blood plasma as well as the availability of proteinogenic amino acids in spleen cells. Conclusion. Administration of a course of oregonin together with cyclophosphamide has a protective effect against the amino acid imbalance in the blood plasma and spleen tissue.

Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model.

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Wada, Satoshi; Yoshimura, Kiyoshi; Hipkiss, Edward L; Harris, Tim J; Yen, Hung-Rong; Goldberg, Monica V; Grosso, Joseph F; Getnet, Derese; Demarzo, Angelo M; Netto, George J; Anders, Robert; Pardoll, Drew M; Drake, Charles G

2009-05-15

To study the immune response to prostate cancer, we developed an autochthonous animal model based on the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse in which spontaneously developing tumors express influenza hemagglutinin as a unique, tumor-associated antigen. Our prior studies in these animals showed immunologic tolerance to hemagglutinin, mirroring the clinical situation in patients with cancer who are generally nonresponsive to their disease. We used this physiologically relevant animal model to assess the immunomodulatory effects of cyclophosphamide when administered in combination with an allogeneic, cell-based granulocyte-macrophage colony-stimulating factor-secreting cancer immunotherapy. Through adoptive transfer of prostate/prostate cancer-specific CD8 T cells as well as through studies of the endogenous T-cell repertoire, we found that cyclophosphamide induced a marked augmentation of the antitumor immune response. This effect was strongly dependent on both the dose and the timing of cyclophosphamide administration. Mechanistic studies showed that immune augmentation by cyclophosphamide was associated with a transient depletion of regulatory T cells in the tumor draining lymph nodes but not in the peripheral circulation. Interestingly, we also noted effects on dendritic cell phenotype; low-dose cyclophosphamide was associated with increased expression of dendritic cell maturation markers. Taken together, these data clarify the dose, timing, and mechanism of action by which immunomodulatory cyclophosphamide can be translated to a clinical setting in a combinatorial cancer treatment strategy.

Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat.

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Yarmohmmadi, Fatemeh; Rahimi, Nastaran; Faghir-Ghanesefat, Hedyeh; Javadian, Nina; Abdollahi, Alireza; Pasalar, Parvin; Jazayeri, Farahnaz; Ejtemaeemehr, Shahram; Dehpour, Ahmad Reza

2017-02-05

The detrimental cardio-toxic effect of doxorubicin, an effective chemotherapeutic agent, limited its clinical use. It has been claimed that doxorubicin cardio-toxicity occurs through calcium ions (Ca 2+ ) overload and reactive oxygen species production. Agmatine, an endogenous imidazoline receptor agonist, induce uptake of cytosolic Ca 2+ and cause an increase in activity of calcium pumps, including Ca 2+ -ATPase. Also it shows self-scavenging effect against reactive oxygen species production. Therefore, present study was designed to investigate the effects of agmatine against chronic cardio-toxicity of doxorubicin in rats. Male wistar rats were intraperitoneally injected with doxorubicin and agmatine four times a week for a month. Agmatine significantly alleviate the adverse effect of doxorubicin on left ventricular papillary muscle stimulation threshold and contractibility. Chronic co-administration of agmatine with doxorubicin blocked electrocardiographic changes induced by doxorubicin. In addition, agmatine improved body weight and decreased the mortality rate of animals by doxorubicin. Moreover, reversing the doxorubicin induced myocardial lesions was observed in animals treated by agmatine. A significant rise in the total antioxidant capacity of rat plasma was achieved in agmatine-treated animals in comparison to doxorubicin. To conclude, agmatine may improve therapeutic outcomes of doxorubicin since it exerts protective effects against doxorubicin-induced chronic cardiotoxicity in rats. Copyright © 2016 Elsevier B.V. All rights reserved.

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification.

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Li, Dan L; Wang, Zhao V; Ding, Guanqiao; Tan, Wei; Luo, Xiang; Criollo, Alfredo; Xie, Min; Jiang, Nan; May, Herman; Kyrychenko, Viktoriia; Schneider, Jay W; Gillette, Thomas G; Hill, Joseph A

2016-04-26

The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1. Beclin 1(+/-) mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response. Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity. © 2016 American Heart Association, Inc.

Cyclophosphamide-induced symptomatic hyponatremia, a rare but severe side effect: a case report

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Elazzazy S

2014-09-01

Full Text Available Shereen Elazzazy,1 Asmaa Elhassan Mohamed,2 Amaal Gulied1 1Pharmacy Department, 2Oncology Hematology Department, National Center for Cancer Care and Research (NCCCR, Hamad Medical Corporation, Doha, QatarAbstract: Cyclophosphamide is commonly used in the treatment of malignant diseases. Symptomatic severe hyponatremia induced by low-dose cyclophosphamide is very uncommon worldwide. We report a case of severe symptomatic hyponatremia that developed in a female breast cancer patient following the first cycle of chemotherapy containing low-dose cyclophosphamide. Her laboratory test showed serum Na of 112 mmol/L. Her hyponatremia was initially treated with sodium bicarbonate. She completely recovered without neurological deficits after slow correction of the serum Na concentration. Although hyponatremia is a rare toxicity it should always be considered during the usage of cyclophosphamide, even if the dosage is low, especially with concurrent use of other medications that impair water excretion, like chlorthalidone. This report describes the first reported case of cyclophosphamide-induced hyponatremia in Qatar.Keywords: AC protocol, adjuvant chemotherapy, breast cancer, cyclophosphamide, hyponatremia, thiazides

Role of fibronectin under conditions of doxorubicin action

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A. I. Shevtsova

2015-02-01

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.

PHARMACOKINETICS OF VINCRISTINE IN CHILDREN AND ADOLESCENTS WITH ACUTE LYMPHOCYTIC-LEUKEMIA

NARCIS (Netherlands)

CROM, WR; DEGRAAF, SSN; SYNOLD, T; UGES, DRA; BLOEMHOF, H; RIVERA, G; CHRISTENSEN, ML; MAHMOUD, H; EVANS, WE

1994-01-01

We studied the pharmacokinetics of vincristine in children with acute lymphocytic leukemia by means of a specific high-performance liquid chromatographic assay with ultraviolet and electrochemical detection and a limited sampling strategy. Our objectives were to characterize the disposition of

Early and late arrhythmogenic effects of doxorubicin.

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Kilickap, Saadettin; Barista, Ibrahim; Akgul, Ebru; Aytemir, Kudret; Aksoy, Sercan; Tekuzman, Gulten

2007-03-01

To determine the incidence of early and late arrhythmogenic effects of doxorubicin-containing chemotherapy regimens. A prospective study including 29 patients who were treated with doxorubicin-containing regimens. Cardiac evaluation was based on 24-hour electrocardiographic monitorization (Holter), which was performed during the first cycle of doxorubicin-containing regimens, as well as after the last cycle of chemotherapy. The mean age of the patients was 45.8 +/- 15.1 (range 18-69). Holter records obtained during the first cycle of treatment revealed varying arrhythmias in 19 patients (65.5%) and in 18 (62.1%) patients after completion of therapy. One patient presented with syncope and both Mobitz Type 2 atrioventricular block and complete atrioventricular block were demonstrated. The patient subsequently underwent permanent pacemaker implantation. Doxorubicin may result in arrhythmias both in early and late periods of treatment. These arrhythmias are rarely life threatening.

Pro: Cyclophosphamide in lupus nephritis

NARCIS (Netherlands)

Kallenberg, Cees G. M.

Based on efficacy and toxicity considerations, both low-dose pulse cyclophosphamide as part of the Euro-Lupus Nephritis protocol and mycophenolate mofetil (MMF) with corticosteroids may be considered for induction of remission in patients with proliferative lupus nephritis. The long-term follow-up

The co-presence of deletion 7q, 20q and inversion 16 in therapy-related acute myeloid leukemia developed secondary to treatment of breast cancer with cyclophosphamide, doxorubicin, and radiotherapy: a case report

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Yonal Ipek

2012-02-01

Full Text Available Abstract Introduction Therapy-related acute myeloid leukemia occurs as a complication of treatment with chemotherapy, radiotherapy, immunosuppressive agents or exposure to environmental carcinogens. Case presentation We report a case of therapy-related acute myeloid leukemia in a 37-year-old Turkish woman in complete remission from breast cancer. Our patient presented to our facility with fatigue, fever, sore throat, peripheral lymphadenopathy, and moderate hepatosplenomegaly. On peripheral blood and bone marrow aspirate smears, monoblasts were present. Immunophenotypic analysis of the bone marrow showed expression of CD11b, CD13, CD14, CD15, CD33, CD34, CD45 and human leukocyte antigen-DR, findings compatible with the diagnosis of acute monoblastic leukemia (French-American-British classification M5a. Therapy-related acute myeloid leukemia developed three years after adjuvant chemotherapy consisting of an alkylating agent, cyclophosphamide and DNA topoisomerase II inhibitor, doxorubicin and adjuvant radiotherapy. Cytogenetic analysis revealed a 46, XX, deletion 7 (q22q34, deletion 20 (q11.2q13.1 karyotype in five out of 20 metaphases and inversion 16 was detected by fluorescence in situhybridization. There was no response to chemotherapy (cytarabine and idarubicin, FLAG-IDA protocol, azacitidine and our patient died in the 11th month after diagnosis. Conclusions The median survival in therapy-related acute myeloid leukemia is shorter compared to de novoacute myeloid leukemia. Also, the response to therapy is poor. In therapy-related acute myeloid leukemia, complex karyotypes have been associated with abnormalities of chromosome 5, rather than 7. To the best of our knowledge, this is the first case of therapy-related acute myeloid leukemia showing the co-presence of deletion 7q, 20q and the inversion 16 signal.

Effects on quality of life, anti-cancer responses, breast conserving surgery and survival with neoadjuvant docetaxel: a randomised study of sequential weekly versus three-weekly docetaxel following neoadjuvant doxorubicin and cyclophosphamide in women with primary breast cancer

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Wiseman Janice

2011-05-01

Full Text Available Abstract Background Weekly docetaxel has occasionally been used in the neoadjuvant to downstage breast cancer to reduce toxicity and possibly enhance quality of life. However, no studies have compared the standard three weekly regimen to the weekly regimen in terms of quality of life. The primary aim of our study was to compare the effects on QoL of weekly versus 3-weekly sequential neoadjuvant docetaxel. Secondary aims were to determine the clinical and pathological responses, incidence of Breast Conserving Surgery (BCS, Disease Free Survival (DFS and Overall Survival (OS. Methods Eighty-nine patients receiving four cycles of doxorubicin and cyclophosphamide were randomised to receive twelve cycles of weekly docetaxel (33 mg/m2 or four cycles of 3-weekly docetaxel (100 mg/m2. The Functional Assessment of Cancer Therapy-Breast and psychosocial questionnaires were completed. Results At a median follow-up of 71.5 months, there was no difference in the Trial Outcome Index scores between treatment groups. During weekly docetaxel, patients experienced less constipation, nail problems, neuropathy, tiredness, distress, depressed mood, and unhappiness. There were no differences in overall clinical response (93% vs. 90%, pathological complete response (20% vs. 27%, and breast-conserving surgery (BCS rates (49% vs. 42%. Disease-free survival and overall survival were similar between treatment groups. Conclusions Weekly docetaxel is well-tolerated and has less distressing side-effects, without compromising therapeutic responses, Breast Conserving Surgery (BCS or survival outcomes in the neoadjuvant setting. Trial registration ISRCTN: ISRCTN09184069

Cardanol: toxicogenetic assessment and its effects when combined with cyclophosphamide

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Beatriz Ursinos Catelan Schneider

2016-06-01

Full Text Available Abstract Cardanol is an effective antioxidant and is a compound with antimutagenic and antitumoral activity. Here, we evaluated the genotoxic and mutagenic potential of saturated side chain cardanol and its effects in combination with cyclophosphamide in preventing DNA damage, apoptosis, and immunomodulation. Swiss mice were treated with cardanol (2.5, 5 and 10 mg/kg alone or in combination with cyclophosphamide (100 mg/kg. The results showed that cardanol is an effective chemopreventive compound, with damage reduction percentages that ranged from 18.9 to 31.76% in the comet assay and from 45 to 97% in the micronucleus assay. Moreover, cardanol has the ability to reduce the frequency of apoptosis induced by cyclophosphamide. The compound did not show immunomodulatory activity. A final interpretation of the data showed that, despite its chemoprotective capacity, cardanol has a tendency to induce DNA damage. Hence, caution is needed if this compound is used as a chemopreventive agent. Also, this compound is likely not suitable as an adjuvant in chemotherapy treatments that use cyclophosphamide.

Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models

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Yingjen Jeffrey Wu

2009-02-01

Full Text Available The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally 24 hours before human ovarian carcinoma (SKOV3, small cell lung carcinoma (LX-1 SCLC, and glioma (UW28, U87MG, and U251 tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0% of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.

Protective effect of Zingiber officinale extract on rat testis after cyclophosphamide treatment.

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Mohammadi, F; Nikzad, H; Taghizadeh, M; Taherian, A; Azami-Tameh, A; Hosseini, S M; Moravveji, A

2014-08-01

Decreasing the side effects of chemotherapy in testis has been the subjects of many studies. In this study, the protective effects of Zingiber officinale extract on rat testis were investigated after chemotherapy with cyclophosphamide. Histological and biochemical parameters were compared in cyclophosphamide-treated rats with or without ginger extract intake. Wistar male rats were randomly divided into four groups each 10. The control group received a single injection of 1 ml isotonic saline intraperitoneally. The Cyclophosphamide (CP) group received a single dose of cyclophosphamide (100 mg kg(-1) BW) intraperitoneally. CP + 300 and CP + 600 groups received orally 300 or 600 mg of ginger extract, respectively, for a period of 6 weeks after cyclophosphamide injection. The morphologic and histological structure of the testis was compared in different groups of the rats. Also, factors like malondialdehyde, reactive oxygen species, total antioxidant capacity and testosterone level were assessed in blood serum as well. Our results showed that although ginger extract could not change testis weight, malondialdehyde (MDA) and ROS, but antioxidant and testosterone levels in serum were increased significantly. Also, an obvious improved histological change was seen in CP + 300 and CP + 600 groups in comparison with CP group. These protective effects of ginger on rat testis after cyclophosphamide treatment could be attributed to the higher serum level of antioxidants. © 2013 Blackwell Verlag GmbH.

Reversal of progressive necrotizing vasculitis with intravenous pulse cyclophosphamide and methylprednisolone.

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Fort, J G; Abruzzo, J L

1988-09-01

We describe a patient with polyarteritis nodosa who, despite therapy with daily doses of oral prednisone and cyclophosphamide, developed acute renal failure. Renal histopathologic examination demonstrated crescentic glomerulonephritis. Treatment with intravenous pulse cyclophosphamide and methylprednisolone resulted in clinical improvement and significant recovery of renal function.

Neoadjuvant chemotherapy and pathologic response: a retrospective cohort

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Andrade, Diocésio Alves Pinto de [Instituto Oncológico de Ribeirão Preto, Ribeirão Preto, SP (Brazil); Zucca-Matthes, Gustavo; Vieira, René Aloísio da Costa [Hospital de Câncer de Barretos, Barretos, SP (Brazil); Andrade, Cristiane Thomaz de Aquino Exel de [Instituto Oncológico de Ribeirão Preto, Ribeirão Preto, SP (Brazil); Costa, Allini Mafra da [Hospital de Câncer de Barretos, Barretos, SP (Brazil); Monteiro, Aurélio Julião de Castro [Instituto Oncológico de Ribeirão Preto, Ribeirão Preto, SP (Brazil); Lago, Lissandra Dal [Institut Jules Bordet, Brussels (Belgium); Nunes, João Soares [Hospital de Câncer de Barretos, Barretos, SP (Brazil)

2013-07-01

To evaluate the complete pathologic response attained by patients diagnosed with locally advanced breast cancer submitted to neoadjuvant chemotherapy based on the doxorubicin/ cyclophosphamide regimen followed by paclitaxel. A retrospective cohort of patients with locally advanced breast cancer, admitted to the Hospital de Câncer de Barretos between 2006 and 2008 submitted to the doxorubicin/cyclophosphamide protocol followed by paclitaxel (4 cycles of doxorubicin 60mg/m{sup 2} and cyclophosphamide 600mg/m{sup 2} every 21 days; 4 cycles of paclitaxel 175mg/m{sup 2} every 21 days). The following variables were assessed: age, menopause, performance status, initial clinical staging, anthropometric data, chemotherapy (dose – duration), toxicity profile, post-treatment staging, surgery, pathologic complete response rate, disease-free survival, and pathological characteristics (type and histological degree, hormonal profile and lymph node involvement). Statistical analysis was performed using a 5% level of significance. Of the 434 patients evaluated, 136 were excluded due to error in staging or because they had received another type of chemotherapy. Median age was 50 years, all with performance status 0-1. Median initial clinical size of tumor was 65mm and the median final clinical size of the tumor was 22mm. Fifty-one (17.1%) patients experienced a pathologic complete response. Those with a negative hormonal profile or who were triple-negative (negative Her-2 and hormonal profile) experienced a favorable impact on the pathologic complete response. Neoadjuvant chemotherapy with doxorubicin/ cyclophosphamide followed by paclitaxel provided a pathologic complete response in the population studied in accordance with that observed in the literature. Triple-negative patients had a greater chance of attaining this response.

Doxorubicin and vincristine affect undifferentiated rat spermatogonia

NARCIS (Netherlands)

Beaud, Hermance; van Pelt, Ans; Delbes, Geraldine

2017-01-01

Anticancer drugs, such as alkylating agents, can affect male fertility by targeting the DNA of proliferative spermatogonial stem cells (SSC). Therefore, to reduce such side effects, other chemotherapeutics are used. However, less is known about their potential genotoxicity on SSC. Moreover, DNA

Cyclophosphamide and TNI in aplastic anemias

International Nuclear Information System (INIS)

Scotti, G.; Rigon, A.; Polico, C.

1987-01-01

Personal experience is outlined with a preparative regimen consisting of total nodal irradiation (TNI) and cyclophosphamide in patients with severe aplastic anemia undergoing bone marrow transplantation (BMT). Nine patients (median age 23) previously having blood transfusions received BMT at the BMT Center in Pesaro. All patients were prepared for transplantation with cyclophosphamide 50 mg/kg/day (day -6, -5, -4, -3), and 7,5 Gy total nodal irradiation day -1, with a dose rate of 26 cGy/m. Six out of eight evaluable transplanted patients are still surviving 3 to 23 months with a median follow-up of 16,5 months. This preoperative regimen is extremely effective in decreasing rejection following transplantation for severe aplastic anemia. Future investigation must be aimed at the elimination of graft-versus-host-disease and control of fatal infections

The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

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Henninger, Christian; Huelsenbeck, Johannes; Huelsenbeck, Stefanie; Grösch, Sabine; Schad, Arno; Lackner, Karl J.; Kaina, Bernd; Fritz, Gerhard

2012-01-01

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

The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

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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: fritz@uni-duesseldorf.de [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)

2012-05-15

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

Molecular Effects of Doxorubicin on Choline Metabolism in Breast Cancer

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Menglin Cheng

2017-08-01

Full Text Available Abnormal choline phospholipid metabolism is a hallmark of cancer. The magnetic resonance spectroscopy (MRS detected total choline (tCho signal can serve as an early noninvasive imaging biomarker of chemotherapy response in breast cancer. We have quantified the individual components of the tCho signal, glycerophosphocholine (GPC, phosphocholine (PC and free choline (Cho, before and after treatment with the commonly used chemotherapeutic drug doxorubicin in weakly metastatic human MCF7 and triple-negative human MDA-MB-231 breast cancer cells. While the tCho concentration did not change following doxorubicin treatment, GPC significantly increased and PC decreased. Of the two phosphatidylcholine-specific PLD enzymes, only PLD1, but not PLD2, mRNA was down-regulated by doxorubicin treatment. For the two reported genes encoding GPC phosphodiesterase, the mRNA of GDPD6, but not GDPD5, decreased following doxorubicin treatment. mRNA levels of choline kinase α (ChKα, which converts Cho to PC, were reduced following doxorubicin treatment. PLD1 and ChKα protein levels decreased following doxorubicin treatment in a concentration dependent manner. Treatment with the PLD1 specific inhibitor VU0155069 sensitized MCF7 and MDA-MB-231 breast cancer cells to doxorubicin-induced cytotoxicity. Low concentrations of 100 nM of doxorubicin increased MDA-MB-231 cell migration. GDPD6, but not PLD1 or ChKα, silencing by siRNA abolished doxorubicin-induced breast cancer cell migration. Doxorubicin induced GPC increase and PC decrease are caused by reductions in PLD1, GDPD6, and ChKα mRNA and protein expression. We have shown that silencing or inhibiting these genes/proteins can promote drug effectiveness and reduce adverse drug effects. Our findings emphasize the importance of detecting PC and GPC individually.

Transarterial chemoembolization using gelatin sponges or microspheres plus lipiodol-doxorubicin versus doxorubicin-loaded beads for the treatment of hepatocellular carcinoma

International Nuclear Information System (INIS)

Liu, Yi Sheng; Ou, Ming Ching; Tsai, Yi Shan; Lin, Xi Zhang; Wang, Chien Kuo; Tsai, Hong Ming; Chuang, Ming Tsung

2015-01-01

To retrospectively compare treatment of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) using gelatin sponges or microspheres plus lipiodol-doxorubicin vs. doxorubicin-loaded drug-eluting beads (DEB). A total of 158 patients with HCC received TACE from November 2010 to November 2011 were enrolled in this study, including 64 (40.5%) received TACE with lipiodol-doxorubicin and gelatin sponges (group A), 41 (25.9%) received TACE with lipiodol-doxorubicin and microspheres (group B), and 53 (33.5%) received TACE with doxorubicin-loaded DEB (group C). Tumor response and adverse events (AEs) were evaluated. No significant difference was found at baseline among the three groups. The doxorubicin dosage in group C was significantly (p < 0.001) higher compared to the dose used in groups A or B (median, 50 mg vs. 31 mg or 25 mg). Significantly (p < 0.001) more patients in group C achieved complete response compared to those in groups A or B (32.1% vs. 6.3% or 2.4%). Significantly (p < 0.001) less patients in group C had progressive disease compared to those in groups A or B (34.0% vs. 57.8% or 68.3%). Minor AEs were more common in groups A and B compared to group C, with rates of 54.7%, 34.1%, and 5.7%, respectively. In patients with HCC, TACE with DEB offers better safety and efficacy profiles compared to either TACE with gelatin sponges or TACE with microspheres.

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.

Science.gov (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

2015-07-01

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.

INFLUENCE OF DOXORUBICIN ON ADHESIVE PROPERTIES OF E.COLI

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O.G. Shapoval

2008-09-01

Full Text Available Influence ofantineoplastic drug doxorubicin and amikacin, the aminoglycoside family on adhesive activity of Escherichia coli was studied. Antimicrobialactivity(minimum inhibitory concentration-MIC ofboth drugs against experimental strains using serial two-fold dilution method was determined. Susceptibility of E.coli to amikacin in the presence of Sand j MIC doxorubicin was studied. After 10 passages in beef-extract broth with constant and increasing doxorubicin concentrations in the presence of Sand j MIC doxorubicin, the adhesive activity of initial and passage variants according to theirability to absorb human erythrocytes 1(0 Rh+ was determined. Itwas observed that experimental strains were susceptible to amikacin (MIC 1,5-6,2 mkg/ml butwere resistantto doxorubicin (MIC 1000 mkg/ml. Subinhibitory concentrations of this cytostatic (S and j MIC raised the sensitivity of experimental strains to amikacin and differently effected on adhesive activity of passage variants of E.coli.

Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy.

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Moruno-Manchon, Jose F; Uzor, Ndidi-Ese; Kesler, Shelli R; Wefel, Jeffrey S; Townley, Debra M; Nagaraja, Archana Sidalaghatta; Pradeep, Sunila; Mangala, Lingegowda S; Sood, Anil K; Tsvetkov, Andrey S

2018-01-01

Doxorubicin, a commonly used anti-neoplastic agent, causes severe neurotoxicity. Doxorubicin promotes thinning of the brain cortex and accelerates brain aging, leading to cognitive impairment. Oxidative stress induced by doxorubicin contributes to cellular damage. In addition to mitochondria, peroxisomes also generate reactive oxygen species (ROS) and promote cell senescence. Here, we investigated if doxorubicin affects peroxisomal homeostasis in neurons. We demonstrate that the number of peroxisomes is increased in doxorubicin-treated neurons and in the brains of mice which underwent doxorubicin-based chemotherapy. Pexophagy, the specific autophagy of peroxisomes, is downregulated in neurons, and peroxisomes produce more ROS. 2-hydroxypropyl-β-cyclodextrin (HPβCD), an activator of the transcription factor TFEB, which regulates expression of genes involved in autophagy and lysosome function, mitigates damage of pexophagy and decreases ROS production induced by doxorubicin. We conclude that peroxisome-associated oxidative stress induced by doxorubicin may contribute to neurotoxicity, cognitive dysfunction, and accelerated brain aging in cancer patients and survivors. Peroxisomes might be a valuable new target for mitigating neuronal damage caused by chemotherapy drugs and for slowing down brain aging in general. Copyright © 2017 Elsevier Inc. All rights reserved.

Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes.

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Karagiannis, Tom C; Lin, Ann J E; Ververis, Katherine; Chang, Lisa; Tang, Michelle M; Okabe, Jun; El-Osta, Assam

2010-10-01

Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubicin-induced hypertrophy to examine the effects of the prototypical histone deacetylase inhibitor, Trichostatin A. Our findings indicate that doxorubicin modulates the expression of the hypertrophy-associated genes, ventricular myosin light chain-2, the alpha isoform of myosin heavy chain and atrial natriuretic peptide, an effect which is augmented by Trichostatin A. Furthermore, we show that Trichostatin A amplifies doxorubicin-induced DNA double strand breaks, as assessed by γH2AX formation. More generally, our findings highlight the importance of investigating potential side effects that may be associated with emerging combination therapies for cancer.

Structural and molecular alterations of primary afferent fibres in the spinal dorsal horn in vincristine-induced neuropathy in rat.

Science.gov (United States)

Thibault, Karine; Rivals, Isabelle; M'Dahoma, Saïd; Dubacq, Sophie; Pezet, Sophie; Calvino, Bernard

2013-11-01

Vincristine is one of the most common anti-cancer drug therapies administered for the treatment of many types of cancer. Its dose-limiting side effect is the emergence of peripheral neuropathy, resulting in chronic neuropathic pain in many patients. This study sought to understand the mechanisms underlying the development of neuropathic pain by vincristine-induced neurotoxicity. We focused on signs of functional changes and revealed that deep layers of the spinal cord (III-IV) experience increased neuronal activity both in the absence of peripheral stimulation and, as a result of tactile mechanical stimulations. These laminae and superficial laminae I-II were also subject to structural changes as evidenced by an increase in immunoreactivity of Piccolo, a marker of active presynaptic elements. Further investigations performed, using DNA microarray technology, describe a large number of genes differentially expressed in dorsal root ganglions and in the spinal dorsal horn after vincristine treatment. Our study describes an important list of genes differentially regulated by vincristine treatment that will be useful for future studies and brings forward evidence for molecular and anatomical modifications of large diameter sensory neurons terminating in deep dorsal horn laminae, which could participate in the development of tactile allodynia.

Increased Dietary Leucine Reduces Doxorubicin-Associated Cardiac Dysfunction in Rats

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Thiago M. Fidale

2018-01-01

Full Text Available Cardiotoxicity is one of the most significant adverse effects of the oncologic treatment with doxorubicin, which is responsible for a substantial morbid and mortality. The occurrence of heart failure with ventricular dysfunction may lead to severe cardiomyopathy and ultimately to death. Studies have focused on the effects of leucine supplementation as a strategy to minimize or revert the clinical condition of induced proteolysis by several clinical onsets. However, the impact of leucine supplementation in heart failure induced by doxorubicin is unknown. Therefore, the objective of this work is to evaluate the effects of leucine supplementation on the cardiotoxicity in the heart of rats treated with doxorubicin. Rats treated with a 7.5 mg/kg cumulative dose of doxorubicin for 14 days presented a dilatation of the left ventricle (LV, and a reduction of the ejection fraction (FE. The 5% supplementation of leucine in the rats' food prevented the malfunctioning of the LV when administered with doxorubicin. Some alterations in the extracellular matrix remodeling were confirmed by the increase of collagen fibers in the doxorubicin group, which did not increase when the treatment was associated with leucine supplementation. Leucine attenuates heart failure in this experimental model with doxorubicin. Such protection is followed by the maintenance of interstitial collagen fibers.

Primary immunodeficiencies and B-cell lymphomas.

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Martín-Mateos, María Anunciación; Piquer Gibert, Mónica

In primary immunodeficiencies there is a failure in the anti-tumor defense. Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies characterized by an alteration in the differentiation of B lymphocytes (BL). Epstein-Barr virus (EBV) is an ubiquitous virus that selectively infects the BL. In patients with immunodeficiency, uncontrolled proliferation of infected BL and the action of viral proteins promote the development of lymphomas. At the University Hospital Sant Joan de Deu, Barcelona, 28 patients were diagnosed with CVID from 2000 to 2013. This paper describes four patients who developed non-Hodgkin's lymphoma (NHL). The lymphoma was associated with EBV in two of the cases. Patients were<18 years old, diagnosed with lymphoma between 4 and 13 years old. Two patients were treated with rituximab as monotherapy and achieved complete remission. Two patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and radiotherapy or rituximab and achieved complete remission. Early detection of EBV infections and NHL in all patients diagnosed with CVID is recommended, regardless of age at diagnosis. Copyright © 2016 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Clinical and Cost Comparison Evaluation of Inpatient Versus Outpatient Administration of EPOCH-Containing Regimens in Non-Hodgkin Lymphoma.

Science.gov (United States)

Evans, Sarah S; Gandhi, Arpita S; Clemmons, Amber B; DeRemer, David L

2017-08-01

Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-containing regimens are frequently utilized in non-Hodgkin's lymphoma, however, the incidence of febrile neutropenia (FN) in patients receiving inpatient versus outpatient EPOCH has not been described. Additionally, no comparisons have been made regarding financial implications of EPOCH administration in either setting. This study's primary objective was to compare hospital admissions for FN in patients receiving inpatient or outpatient EPOCH. A single-center, institutional review board-approved review was conducted for adults receiving EPOCH beginning January 2010. Clinical and financial data were collected through chart review and the institution's financial department. Descriptive statistics were utilized for analysis. A total of 25 patients received 86 cycles of an EPOCH-containing regimen (61 [70.9%] inpatient). Five (8.2%) inpatient cycles resulted in an admission for FN compared to 4 (16%) outpatient cycles. Prophylactic antifungal and antiviral agents were prescribed more often after inpatient cycles (>80%) compared to outpatient cycles (cost savings of approximately US$141 116 for both chemotherapy costs and hospital day avoidance. EPOCH-containing regimens can be safely administered in the outpatient setting, which may result in cost savings for healthcare institutions.

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

International Nuclear Information System (INIS)

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

1986-01-01

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

Classification of malignant lymphomas

International Nuclear Information System (INIS)

Schneider, M.; Thyss, A.

1986-01-01

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

Spinal intradural extraosseous Ewing’s sarcoma

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Daniel Lachance

2011-03-01

Full Text Available Extraosseous Ewing’s sarcoma (EES involving the central nervous system is rare, but can be diagnosed and distinguished from other primitive neuroectodermal tumors (PNET by identification of the chromosomal translocation (11;22(q24;q12. We report EES arising from the spinal intradural extramedullary space, based on imaging, histopathological, and molecular data in two men, ages 50 and 60 years old and a review of the literature using PubMed (1970-2009. Reverse transcriptase polymerase chain reaction (RT-PCR identified the fusion product FL1-EWS. Multimodal therapy, including radiation and alternating chemotherapy including vincristine, cyclophosphamide, doxorubicin and ifosfamide and etoposide led to local tumor control and an initial, favorable therapeutic response. No systemic involvement was seen from the time of diagnosis to the time of last follow-up (26 months or death (4 years. This report confirms that EES is not confined to the earliest decades of life, and like its rare occurrence as an extra-axial meningeal based mass intracranially, can occasionally present as an intradural mass in the spinal canal without evidence of systemic tumor. Gross total resection followed by multimodal therapy may provide for extended progression free and overall survival.

Ab initio computational study of vincristine as a biological active compound: NMR and NBO analyses

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Shiva Joohari

2015-06-01

Full Text Available Vincristine is a biological active alkaloid that has been used clinically against a variety of neoplasms. In the current study we have theoretically investigated the magnetic properties of titled compound to predict physical and chemical properties of vincristine as a biological inhibitor. Ab initio computation using HF and B3LYP with 3-21G(d and 6-31G(d level of theory have been performed and then magnetic shielding tensor (, ppm, shielding asymmetry (, magnetic shielding anisotropy (aniso, ppm, the skew of a tensor (K, chemical shift anisotropy ( and chemical shift ( were calculated to indicate the details of the interaction mechanism between microtubules and vincristine. Moreover, EHOMO, ELUMO and Ebg were evaluated. The maximum and minimum values of Ebg were found in HF/3-21g and B3LYP/3-21g respectively. It was also uggested that O24, O37, O49 and O55 with minimum values of iso, are active sites of titled compound. Furthermore the calculated chemical shifts were compared with experimental data in DMSO and CDCl3 solvents.

Visible-light system for detecting doxorubicin contamination on skin and surfaces.

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Van Raalte, J; Rice, C; Moss, C E

1990-05-01

A portable system that uses fluorescence stimulated by visible light to identify doxorubicin contamination on skin and surfaces was studied. When activated by violet-blue light in the 465-nm range, doxorubicin fluoresces, emitting orange-red light in the 580-nm range. The light source to stimulate fluorescence was a slide projector with a filter to selectively pass short-wave (blue) visible light. Fluorescence was both observed visually with viewing spectacles and photographed. Solutions of doxorubicin in sterile 0.9% sodium chloride injection were prepared in nine standard concentrations ranging from 2 to 0.001 mg/mL. Droplets of each admixture were placed on stainless steel, laboratory coat cloth, pieces of latex examination glove, bench-top absorbent padding, and other materials on which antineoplastics might spill or leak. These materials then were stored for up to eight weeks and photographed weekly. The relative ability of water, household bleach, hydrogen peroxide solution, and soap solution to deactivate doxorubicin was also measured. Finally, this system was used to inspect the antineoplastic-drug preparation and administration areas of three outpatient cancer clinics for doxorubicin contamination. Doxorubicin fluorescence was easily detectable with viewing spectacles when a slide projector was used as the light source. The photographic method was sensitive for doxorubicin concentrations from 2.0 to 0.001 mg/mL. Immersion of study materials in bleach for one minute eliminated detectable fluorescence. Doxorubicin contamination is detectable for at least eight weeks in the ambient environment. Probable doxorubicin contamination was detected in two of the three clinics surveyed. A safe, portable system that uses fluorescence stimulated by visible light is a sensitive method for detecting doxorubicin on skin and surfaces.

Overcoming of P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cells could be induced by pentoxifylline but not by theophylline and caffeine

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Stefankova, Z.; Barancik, M.; Breier, A.

1996-01-01

Effects of xanthine derivatives (pentoxifylline (PTX), caffeine, theophylline, 1-methyl-3-isobutylxanthine) on P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cell sub-line were studied. From the applied xanthines only PTX was found to reverse the vincristine resistance of the above cells. Moreover, only PTX, but not other xanthine, increased the accumulation of [ 3 H]vincristine by L1210/VCR cells. Thus it may be concluded that PTX-induced reversal of vincristine (VCR) resistance could not be explained from the point of known pharmacological effects of PTX that are common for other xanthines such as inhibition of phosphodiesterase activity, calcium mobilizing effect, inhibition of tumor necrosis factor α (TNF), etc. (author)

Low-Dose Cyclophosphamide Synergizes with Dendritic Cell-Based Immunotherapy in Antitumor Activity

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Joris D. Veltman

2010-01-01

Full Text Available Clinical immunotherapy trials like dendritic cell-based vaccinations are hampered by the tumor's offensive repertoire that suppresses the incoming effector cells. Regulatory T cells are instrumental in suppressing the function of cytotoxic T cells. We studied the effect of low-dose cyclophosphamide on the suppressive function of regulatory T cells and investigated if the success rate of dendritic cell immunotherapy could be improved. For this, mesothelioma tumor-bearing mice were treated with dendritic cell-based immunotherapy alone or in combination with low-dose of cyclophosphamide. Proportions of regulatory T cells and the cytotoxic T cell functions at different stages of disease were analyzed. We found that low-dose cyclophosphamide induced beneficial immunomodulatory effects by preventing the induction of Tregs, and as a consequence, cytotoxic T cell function was no longer affected. Addition of cyclophosphamide improved immunotherapy leading to an increased median and overall survival. Future studies are needed to address the usefulness of this combination treatment for mesothelioma patients.

Modifications on the Basic Skeletons of Vinblastine and Vincristine

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Csaba Szántay

2012-05-01

Full Text Available The synthetic investigation of biologically active natural compounds serves two main purposes: (i the total synthesis of alkaloids and their analogues; (ii modification of the structures for producing more selective, more effective, or less toxic derivatives. In the chemistry of dimeric Vinca alkaloids enormous efforts have been directed towards synthesizing new derivatives of the antitumor agents vinblastine and vincristine so as to obtain novel compounds with improved therapeutic properties.

Doxorubicin Action on Mitochondria: Relevance to Osteosarcoma Therapy?

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Armstrong, Jo; Dass, Crispin R

2018-01-01

The mitochondria may very well determine the final commitment of the cell to death, particularly in times of energy stress. Cancer chemotherapeutics such as the anthracycline doxorubicin perturb mitochondrial structure and function in tumour cells, as evidenced in osteosarcoma, for which doxorubicin is used clinically as frontline therapy. This same mechanism of cell inhibition is also pertinent to doxorubicin's primary cause of side-effects, that to the cardiac tissue, culminating in such dire events as congestive heart failure. Reactive oxygen species are partly to blame for this effect on the mitochondria, which impact the electron transport chain. As this review highlights that, there is much more to be learnt about the mitochondria and how it is affected by such effective but toxic drugs as doxorubicin. Such information will aid researchers who search for cancer treatment able to preserve mitochondrial number and function in normal cells. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Histopathological effects of doxorubicin on kidneys in rats

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I.A. Ali

2014-06-01

Full Text Available The aim of this study was to investigate the histolopathological effect of doxorubicin on rat kidney tissue. The drug was administrated by rats at the dose of (1, 2, 3, 4, 5 mg/kg intrapertonial every (84 hr for the three weeks and the doses of (1, 2, 3 mg/kg intrapertonial every 84 hrs for six weeks. The animals were scarified after 48 hr. of last injection. The study revealed congestion, thrombus, blood vessels hemorrhage, vaculation in the cells of glomerular tuft and tubular, tubuo-interstitial degeneration, tubular casts. The injury score revealed significantly increasing in the degree of injury in glomerules in the animals that received 5 mg/kg of doxorubicin for three weeks and also significantly increasing in the degree of injury in glomerules of the animals that received 3 mg/kg of doxorubicin for six weeks as compared with control animals. We concluded that the doxorubicin has histopathological effect on kidney.

Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome.

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Bray Denard

Full Text Available Doxorubicin has been shown to inhibit proliferation of cancer cells through proteolytic activation of CREB3L1 (cAMP response element binding protein 3-like 1, a transcription factor synthesized as a membrane-bound precursor. Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation. These results suggest that the level of CREB3L1 in cancer cells may determine their sensitivity to doxorubicin.Mice transplanted with 6 lines of renal cell carcinoma (RCC were injected with doxorubicin to observe the effect of the chemotherapy on tumor growth. Immunohistochemistry and bioinformatics analyses were performed to compare CREB3L1 levels in types of cancer known to respond to doxorubicin versus those resistant to doxorubicin.Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis. From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin. Doxorubicin is used as the standard treatment for cancers that express the highest levels of CREB3L1 such as osteosarcoma and malignant fibrous histiocytoma but is not generally used to treat those that express the lowest levels of CREB3L1 such as RCC.Identification of CREB3L1 as the biomarker for doxorubicin sensitivity may markedly improve the doxorubicin response rate by applying doxorubicin only to patients with cancers expressing CREB3L1.

Vincristine, Irinotecan, and Bevacizumab in Relapsed Wilms Tumor With Diffuse Anaplasia.

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Schiavetti, Amalia; Varrasso, Giulia; Collini, Paola; Clerico, Anna

2018-05-01

The prognosis of relapsed Wilms tumor (WT) with diffuse anaplasia is dismal, therefore, novel therapeutic strategies need to be explored. We reported on 2 consecutive cases with relapsed anaplastic WT who presented a partial response after 2 courses of vincristine, irinotecan, and bevacizumab association. This regimen may have a role in the treatment of patients with anaplastic advanced WT.

Propofol ameliorates doxorubicin-induced oxidative stress and cellular apoptosis in rat cardiomyocytes

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Lai, H.C. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine and Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Yeh, Y.C. [Graduate Institute of Natural Healing Sciences, Nanhua University, Chiayi, Taiwan (China); Wang, L.C. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Ting, C.T.; Lee, W.L. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine and Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Lee, H.W. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Wang, K.Y. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine, Chung-Shan Medical University, Taichung, Taiwan (China); Wu, A. [College of Biological Science, University of California, Davis (United States); Su, C.S. [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine and Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Liu, T.J., E-mail: trliu@vghtc.gov.tw [Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Medicine and Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan (China)

2011-12-15

Background: Propofol is an anesthetic with pluripotent cytoprotective properties against various extrinsic insults. This study was designed to examine whether this agent could also ameliorate the infamous toxicity of doxorubicin, a widely-used chemotherapeutic agent against a variety of cancer diseases, on myocardial cells. Methods: Cultured neonatal rat cardiomyocytes were administrated with vehicle, doxorubicin (1 {mu}M), propofol (1 {mu}M), or propofol plus doxorubicin (given 1 h post propofol). After 24 h, cells were harvested and specific analyses regarding oxidative/nitrative stress and cellular apoptosis were conducted. Results: Trypan blue exclusion and MTT assays disclosed that viability of cardiomyocytes was significantly reduced by doxorubicin. Contents of reactive oxygen and nitrogen species were increased and antioxidant enzymes SOD1, SOD2, and GPx were decreased in these doxorubicin-treated cells. Mitochondrial dehydrogenase activity and membrane potential were also depressed, along with activation of key effectors downstream of mitochondrion-dependent apoptotic signaling. Besides, abundance of p53 was elevated and cleavage of PKC-{delta} was induced in these myocardial cells. In contrast, all of the above oxidative, nitrative and pro-apoptotic events could be suppressed by propofol pretreatment. Conclusions: Propofol could extensively counteract oxidative/nitrative and multiple apoptotic effects of doxorubicin in the heart; hence, this anesthetic may serve as an adjuvant agent to assuage the untoward cardiac effects of doxorubicin in clinical application. -- Highlights: Black-Right-Pointing-Pointer We evaluate how propofol prevents doxorubicin-induced toxicity in cardiomyocytes. Black-Right-Pointing-Pointer Propofol reduces doxorubicin-imposed nitrative and oxidative stress. Black-Right-Pointing-Pointer Propofol suppresses mitochondrion-, p53- and PKC-related apoptotic signaling. Black-Right-Pointing-Pointer Propofol ameliorates apoptosis and

Oenothera paradoxa defatted seeds extract containing pentagalloylglucose and procyanidins potentiates the cytotoxicity of vincristine.

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Jaszewska, E; Kosmider, A; Kiss, A K; Naruszewicz, M

2010-10-01

The purpose of the study was a comparison of Oenothera paradoxa Hudziok defatted seeds extract (EPE) effect with the activity of individual constituents of the extract: pentagalloylglucose (PGG), gallic acid, (+)-catechin and the procyanidin fraction, as well as an assessment of the combined effect of EPE and vincristine (VCR) in the absence or presence of MRP1 (indomethacin) and P-glycoprotein (verapamil) inhibitors, on two human cancer cell lines, metastatic melanoma (HTB-140) and hepatoma (HepG2). The presence of EPE, PGG and procyanidins caused a marked reduction in viability (MTT assay) and rise in mortality (LDH release assay) of HTB-140 cells. The combined use of EPE (25 μg/mL) and VCR (1 μM) in HTB-140 and HepG2 cells produced an increased cytotoxicity as compared to vincristine alone - by more than 4 and 1.5 times, respectively. In HTB-140 cells, the level of intracellular ATP (measured by bioluminescence) was lowered over 7-fold as a result of exposure to the combination of EPE and VCR, while the addition of MRP-1 inhibitor did not cause an increased cytotoxicity or further lowering of the ATP level. Our results demonstrate that EPE, containing PGG and procyanidins, significantly increased the sensitivity of cancer cells, particularly the melanoma cells, to the action of vincristine.

Cyclophosphamide Alters the Gene Expression Profile in Patients Treated with High Doses Prior to Stem Cell Transplantation

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El-Serafi, Ibrahim; Abedi-Valugerdi, Manuchehr; Potácová, Zuzana; Afsharian, Parvaneh; Mattsson, Jonas; Moshfegh, Ali; Hassan, Moustapha

2014-01-01

Background Hematopoietic stem cell transplantation is a curative treatment for several haematological malignancies. However, treatment related morbidity and mortality still is a limiting factor. Cyclophosphamide is widely used in condition regimens either in combination with other chemotherapy or with total body irradiation. Methods We present the gene expression profile during cyclophosphamide treatment in 11 patients conditioned with cyclophosphamide for 2 days followed by total body irradiation prior to hematopoietic stem cell transplantation. 299 genes were identified as specific for cyclophosphamide treatment and were arranged into 4 clusters highly down-regulated genes, highly up-regulated genes, early up-regulated but later normalized genes and moderately up-regulated genes. Results Cyclophosphamide treatment down-regulated expression of several genes mapped to immune/autoimmune activation and graft rejection including CD3, CD28, CTLA4, MHC II, PRF1, GZMB and IL-2R, and up-regulated immune-related receptor genes, e.g. IL1R2, IL18R1, and FLT3. Moreover, a high and significant expression of ANGPTL1 and c-JUN genes was observed independent of cyclophosphamide treatment. Conclusion This is the first investigation to provide significant information about alterations in gene expression following cyclophosphamide treatment that may increase our understanding of the cyclophosphamide mechanism of action and hence, in part, avoid its toxicity. Furthermore, ANGPTL1 remained highly expressed throughout the treatment and, in contrast to several other alkylating agents, cyclophosphamide did not influence c-JUN expression. PMID:24466173

An atypical case of Wegener's granulomatosis complicated by sepsis and coxitis

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Makowski, A.; Faflik, J.

1993-01-01

There is presented an atypical case Wegener's granulomatosis of maxillo-nasal region without bony destruction. The case is unusual because of sepsis and purulent coxitis. The patient responded well to treatment with vincristine and cyclophosphamide. ANCA (anti-neutrophil cytoplasmic antibodies) assays have very good sensitivity and specificity for Wegener's granulomatosis. (author)

Postoperative Chemotherapy for Medulloblastoma

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J Gordon Millichap

2005-03-01

Full Text Available The survival rate and cognitive function of 43 children, age <3 years, with medulloblastoma treated with intensive postoperative chemotherapy alone, without radiotherapy, were determined at the University of Wurzburg and other centers in Germany Chemotherapy consisted of three two-month cycles of cyclophosphamide, methotrexate, vincristine, carboplatin, and etoposide.

The Protective effect of Ellagic acid on rats’ ovarian fetus toxicity induced by cyclophosphamide

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M Mousavi M

2015-10-01

Full Text Available Background & aim: Cyclophosphamide, an alkylating agent used in the treatment of cancer that has many side effects on different organs, including the gonads .The purpose of this study was to investigate the effects of an antioxidant Ellagic acid on cyclophosphamide -induced toxicity in rat fetal ovarian tissue. Methods: Forty two pregnant  female Wistar rats weighing 250-200 gr were randomly divided into seven groups.The first, second, third, fourth, fifth and sixth 5 mg/ kg cyclophosphamide on days 1, 13 and 18 were given intraperitoneal remote pregnancy .The fourth, fifth and sixth groups hour after receiving cyclophosphamide, Ellagic acid (10 mg/kg has received in the course of pregnancy.Control groups and seven group (normal during pregnancy daily orally received 0.5 mL of saline. After postpartum, Neonatal rats were anesthetized with ether. Animals were dissects, then Ovaries were removed and transferred to 10% formalin solution. After tissue processing, tissue sections were prepared and H&E stained.Data were analyzed by SPSSsoftware and One- way ANOVA test. Results: The groups that were exposed to cyclophosphamide ovarian mean of diameter, primordial follicle diameter and number of follicular cell of primordialin control group compared to ellagic acid treatments showed a significant decrease. Conclusion: The results showed that Ellagic acid due to its antioxidant properties could reduce the harmful effects caused by cyclophosphamide in the fetal ovary.

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

NARCIS (Netherlands)

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

2008-01-01

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

Antioxidant activities of celery and parsley juices in rats treated with doxorubicin.

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Kolarovic, Jovanka; Popovic, Mira; Zlinská, Janka; Trivic, Svetlana; Vojnovic, Matilda

2010-09-03

We have examined the influence of diluted pure celery and parsley leaf and root juices and their combinations with doxorubicin on the antioxidant status [as measured by the content of reduced glutathione (GSH) and ferric reducing antioxidant power (FRAP)] in liver homogenate and hemolysate and on the contents of cytochrome P450 in liver homogenate. It was found that doxorubicin significantly decreased the content of reduced glutathione and the total antioxidative status (FRAP) in liver homogenate and hemolysate, while celery and parsley juices alone and in combination with doxorubicin had different actions. Doxorubicin and celery juice had no effect on content of cytochrome P450. However, in combination with doxorubicin, parsley root juice significant increased, and parsley leaves juice decreased the cytochrome P450 content (compared to doxorubicin treated animals). Only parsley root juice significantly increased the content of cytochrome P450.

No adverse effect of vincristine on handwriting in children after completion of therapy

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Hartman, A.; van den Bos, C.; van Dartel, N.; Stijnen, Th; Pieters, R.

2007-01-01

Long-term writing difficulties in children after treatment with vincristine for acute lymphoblastic leukemia, Wilms tumor, B non-Hodgkin lymphoma, and malignant mesenchymal tumors, were investigated. Handwriting of 33 survivors and 33 controls matched for age, sex, and grade, was assessed with the

Progressive outer retinal necrosis after rituximab and cyclophosphamide therapy.

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Dogra, Mohit; Bajgai, Priya; Kumar, Ashok; Sharma, Aman

2018-04-01

We report a case of progressive outer retinal necrosis (PORN) in a patient of microscopic polyangitis (MPA), being treated with immunosuppressive drugs such as cyclophosphamide and rituximab. Her aqueous tap was positive for Varicella Zoster virus and she was treated with oral and intravitreal antivirals, along with discontinuation of one of the immunosuppressive agents, i.e. rituximab, which might have led to reactivation of the virus causing necrotizing retinitis lesions. Rituximab and cyclophosphamide are extremely potent drugs, which are necessary to manage immunological disorders such as MPA. However, they may predispose the patient to serious complications like viral infections, including PORN.

Late effects on gonadal function of cyclophosphamide, total-body irradiation, and marrow transplantation

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Sanders, J.E.; Buckner, C.D.; Leonard, J.M.; Sullivan, K.M.; Witherspoon, R.P.; Deeg, H.J.; Storb, R.; Thomas, E.D.

1983-01-01

One hundred thirty-seven patients had gonadal function evaluated 1-11 years after marrow transplantation. All 15 women less than age 26 and three of nine older than age 26 who were treated with 200 mg/kg cyclophosphamide recovered normal gonadotropin levels and menstruation. Five have had five pregnancies resulting in three live births, one spontaneous abortion, and one elective abortion. Three of 38 women who were prepared with 120 mg/kg cyclophosphamide and 920-1200 rad total-body irradiation had normal gonadotropin levels and menstruation. Two had pregnancies resulting in one spontaneous and one elective abortion. Of 31 men prepared with 200 mg/kg cyclophosphamide, 30 had normal luteinizing hormone levels, 20 had normal follicle-stimulating hormone levels, and 10 of 15 had spermatogenesis. Four have fathered five normal children. Thirty-six of 41 men prepared with 120 mg/kg cyclophosphamide and 920-1750 rad total-body irradiation had normal luteinizing hormone levels, ten had normal follicle-stimulating hormone levels, and 2 of 32 studied had spermatogenesis. One has fathered two normal children. It was concluded that cyclophosphamide does not prevent return of normal gonadal function in younger women and in most men. Total-body irradiation prevents return of normal gonadal function in the majority of patients

TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin

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Moruno Manchon, Jose Felix; Uzor, Ndidi-Ese; Kesler, Shelli R.; Wefel, Jeffrey S.; Townley, Debra M.; Nagaraja, Archana Sidalaghatta; Pradeep, Sunila; Mangala, Lingegowda S.; Sood, Anil K.; Tsvetkov, Andrey S.

2016-01-01

Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin. PMID:27992857

The same drug but a different mechanism of action: comparison of free doxorubicin with two different N-(2-hydroxypropyl)methacrylamide copolymer-bound doxorubicin conjugates in EL-4 cancer cell line.

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Kovár, Lubomír; Strohalm, Jirí; Chytil, Petr; Mrkvan, Tomás; Kovár, Marek; Hovorka, Ondrej; Ulbrich, Karel; Ríhová, Blanka

2007-01-01

Doxorubicin is one of the most potent anti-tumor drugs with a broad spectrum of use. To reduce its toxic effect and improve its pharmacokinetics, we conjugated it to an HPMA copolymer carrier that enhances its passive accumulation within solid tumors via the EPR effect and decreases its cytotoxicity to normal, noncancer cells. In this study, we compared the antiproliferative, pro-survival, and death signals triggered in EL-4 cancer cells exposed to free doxorubicin and doxorubicin conjugated to a HPMA copolymer carrier via either enzymatically (PK1) or hydrolytically (HYD) degradable bonds. We have previously shown that the intracellular distribution of free doxorubicin, HYD, and PK1 is markedly different. Here, we demonstrated that these three agents greatly differ also in the antiproliferative effect and cell death signals they trigger. JNK phosphorylation sharply increased in cells treated with HYD, while treatment with free doxorubicin moderately decreased and treatment with PK1 even strongly decreased it. On the other hand, treatment with free doxorubicin greatly increased p38 phosphorylation, while PK1 and HYD increased it slightly. PK1 also significantly increased ERK phosphorylation, while both the free doxorubicin and HYD conjugate slightly decreased it. Long-term inhibition of JNK significantly increased both proliferation and viability of EL-4 cells treated with free doxorubicin, showing that the JNK signaling pathway could be critical for mediating cell death in EL-4 cells exposed to free doxorubicin. Both activation of caspase 3 and decreased binding activity of the p50 subunit of NFkappaB were observed in cells treated with free doxorubicin and HYD, while no such effects were seen in cells incubated with PK1. Analysis of the expression of genes involved in apoptosis and regulation of the cell cycle demonstrated that free doxorubicin and HYD have very similar mechanisms of action, while PK1 has very different characteristics.

Antioxidant Activities of Celery and Parsley Juices in Rats Treated with Doxorubicin

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Svetlana Trivic

2010-09-01

Full Text Available We have examined the influence of diluted pure celery and parsley leaf and root juices and their combinations with doxorubicin on the antioxidant status [as measured by the content of reduced glutathione (GSH and ferric reducing antioxidant power (FRAP] in liver homogenate and hemolysate and on the contents of cytochrome P450 in liver homogenate. It was found that doxorubicin significantly decreased the content of reduced glutathione and the total antioxidative status (FRAP in liver homogenate and hemolysate, while celery and parsley juices alone and in combination with doxorubicin had different actions. Doxorubicin and celery juice had no effect on content of cytochrome P450. However, in combination with doxorubicin, parsley root juice significant increased, and parsley leaves juice decreased the cytochrome P450 content (compared to doxorubicin treated animals. Only parsley root juice significantly increased the content of cytochrome P450.

Effect of chemoradiotherapy using ACNU, vincristine, and nicardipine with high-dose irradiation on malignant astrocytomas

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Genka, Shigeru; Shitara, Nobuyuki; Nakamura, Hirohiko; Takakura, Kintomo [Tokyo Univ. (Japan). Hospital

1993-05-01

Fifty-two patients with malignant astrocytoma were treated with cellular synchronization radiation therapy at the University of Tokyo Hospital between 1977 and 1989. Twenty-five patients (Group 1) received 1 - (4-amino-2-methyl-5-pyrimidinyl)methyl - 3 - (2-chloroethyl) - 3 - nitrosourea hydrochloride (ACNU), vincristine, and 60 Gy of irradiation, and 27 patients (Group 2) ACNU, vincristine, the Ca-channel blocker nicardipine, and 72 Gy of irradiation. Median survival times for Groups 1 and 2 were 15 and 30 months, respectively. Although there was no significant difference, Group 2 achieved longer survival with 1-, 2-, and 3-year survival rates of 85.2, 65.8, and 46.9% compared to rates of 66.7, 40.0, and 26.7%, respectively, for Group 1. (author).

Effect of chemoradiotherapy using ACNU, vincristine, and nicardipine with high-dose irradiation on malignant astrocytomas

International Nuclear Information System (INIS)

Genka, Shigeru; Shitara, Nobuyuki; Nakamura, Hirohiko; Takakura, Kintomo

1993-01-01

Fifty-two patients with malignant astrocytoma were treated with cellular synchronization radiation therapy at the University of Tokyo Hospital between 1977 and 1989. Twenty-five patients (Group 1) received 1 - (4-amino-2-methyl-5-pyrimidinyl)methyl - 3 - (2-chloroethyl) - 3 - nitrosourea hydrochloride (ACNU), vincristine, and 60 Gy of irradiation, and 27 patients (Group 2) ACNU, vincristine, the Ca-channel blocker nicardipine, and 72 Gy of irradiation. Median survival times for Groups 1 and 2 were 15 and 30 months, respectively. Although there was no significant difference, Group 2 achieved longer survival with 1-, 2-, and 3-year survival rates of 85.2, 65.8, and 46.9% compared to rates of 66.7, 40.0, and 26.7%, respectively, for Group 1. (author)

Modulator effect of watercress against cyclophosphamide-induced oxidative stress in mice

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Natalia A. Casanova

2017-06-01

Full Text Available Watercress (Nasturtium officinale, Cruciferae; W. Aiton is a vegetable widely consumed in our country, with nutritional and potentially chemopreventive properties. Previous reports from our laboratory demonstrated the protective effect of watercress juice against DNA damage induced by cyclophosphamide in vivo. In this study, we evaluated the in vivo effect of cress plant on the oxidative stress in mice. Animals were treated by gavage with different doses of watercress juice (0.5 and 1g/kg body weight for 15 consecutive days before intraperitoneal injection of cyclophosphamide (100 mg/kg body weight. After 24 h, mice were killed by cervical dislocation. The effect of watercress was investigated by assessing the following oxidative stress biomarkers: catalase activity, superoxide dismutase activity, lipid peroxidation, and glutathione balance. Intake of watercress prior to cyclophosphamide administration enhanced superoxide dismutase activity in erythrocytes with no effect on catalase activity. In bone marrow and liver tissues, watercress juice counteracted the effect of cyclophosphamide. Glutathione balance rose by watercress supplementation and lipid oxidation diminished in all matrixes when compared to the respective control groups. Our results support the role of watercress as a diet component with promising properties to be used as health promoter or protective agent against oxidative damage

Chemical denervation of the renal artery with vincristine for the treatment of resistant arterial hypertension: first-in-man application.

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Stefanadis, Christodoulos; Toutouzas, Konstantinos; Vlachopoulos, Charalambos; Tsioufis, Costas; Synetos, Andreas; Pietri, Panagiota; Tousoulis, Dimitris; Tsiamis, Eleftherios

2013-01-01

Renal artery denervation has recently emerged as a novel therapy for patients with resistant hypertension. Clinical results from renal sympathetic denervation support the safety and efficacy of this method over a period of 18 months. However, several limitations have been reported. Previous studies have shown that chemical denervation by vincristine is safe and effective in an experimental model. We describe the first-in-man application of chemical denervation with vincristine in a 74-year-old male patient with resistant arterial hypertension.

Post-induction residual leukemia in childhood acute lymphoblastic leukemia quantified by PCR correlates with in vitro prednisolone resistance

DEFF Research Database (Denmark)

Schmiegelow, K; Nyvold, C; Seyfarth, J

2001-01-01

Most prognostic factors in childhood acute lymphoblastic leukemia (ALL) are informative for groups of patients, whereas new approaches are needed to predict the efficacy of chemotherapy for the individual patient. The residual leukemia following 4 weeks of induction therapy with prednisolone......, vincristine, doxorubicin and i.t. methotrexate and the in vitro resistance to prednisolone, vincristine, and doxorubicin were measured in 30 boys and 12 girls with B (n = 34) or T lineage (n = 8) ALL. The residual leukemia was quantified after 2 (MRD-D15, n = 29) and 4 weeks (MRD-PI, n = 42) of induction...... pronounced when B cell precursor and T cell leukemia were analyzed separately (B cell precursor ALL: MRD-PI vs prednisolone LC50: n = 33, rs = 0.47, P = 0.006; T cell ALL: MRD-PI vs prednisolone resistance: n = 8, rs = 0.84, P = 0.009). After a median follow-up of 5.0 years (75% range 3.2-6.9) eight patients...

Progressive outer retinal necrosis after rituximab and cyclophosphamide therapy

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Mohit Dogra

2018-01-01

Full Text Available We report a case of progressive outer retinal necrosis (PORN in a patient of microscopic polyangitis (MPA, being treated with immunosuppressive drugs such as cyclophosphamide and rituximab. Her aqueous tap was positive for Varicella Zoster virus and she was treated with oral and intravitreal antivirals, along with discontinuation of one of the immunosuppressive agents, i.e. rituximab, which might have led to reactivation of the virus causing necrotizing retinitis lesions. Rituximab and cyclophosphamide are extremely potent drugs, which are necessary to manage immunological disorders such as MPA. However, they may predispose the patient to serious complications like viral infections, including PORN.

Cyclophosphamide induced Haemorrhagic Cystitis; a review of ...

African Journals Online (AJOL)

Cyclophosphamide is an akylating agent widely used in the management of both malignant and non neoplastic disorders. We undertook this review to assess the advancement in knowledge regarding the aetiopathogenesis and current management approaches of haemorrhagic cystitis resulting from the use of ...

Long-term follow-up of cardiac function in patients with Hodgkin's disease treated with mediastinal irradiation and combination chemotherapy including doxorubicin

International Nuclear Information System (INIS)

LaMonte, C.S.; Yeh, S.D.; Straus, D.J.

1986-01-01

Among 41 evaluable patients whose first treatment for advanced Hodgkin's disease had consisted of alternating cycles of mechlorethamine, vincristine, prednisone, and procarbazine (MOPP), and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), in addition to low-dose mediastinal irradiation, 19 underwent retrospective cardiac evaluation by routine posteroanterior and lateral chest x-ray, 12-lead ECG, M-mode echocardiogram, and ECG-gated left ventricular blood pool scan at rest and during exercise. Fifteen patients had unequivocally normal left ventricular function by all these parameters. Two patients had minimally reduced left ventricular ejection fraction (LVEF) at rest with a normal increment with exercise. In two other patients with high normal resting LVEF and subnormal increment with exercise, the elevated resting values implied initial measurement in a nonbasal state. A twentieth patient (the oldest; one of two with active Hodgkin's disease at the time of evaluation and the stimulus for this study) had markedly reduced LVEF as determined by radionuclide cardiac angiography and had developed clinical congestive heart failure shortly before evaluation. Despite this patient, the study indicates that treatment with MOPP/ABVD and low-dose mediastinal irradiation entails low risk for cardiac complications

Ovarian protection in cyclophosphamide-treated mice by fennel

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Azam Hassanpour

Full Text Available Evaluation of protective effect of fennel on mouse ovary against the destructive effects of cyclophosphamide (CP was the aim of this study. Adult female NMARI mice were randomly divided into six groups (n = 8: (A negative control, (B CP200 mg/kg, (C fennel 400 mg/kg/day, (E, F, and D that received fennel 200, 400 and 100 mg/kg/day respectively + CP200 mg/kg. Their ovary weight, volume, and diameter (WVD were measured. Five micron sections were stained using the H&E method. The serum levels of oestrogen and progesterone were measured using ELISA kit. The results showed that WVD significantly reduced in the CP-treated groups in comparison with the A and C, but WVD increased after treatment of the mice with fennel extract, in comparison with B group. A significant decrease of serum in terms of oestrogen and progesterone levels among CP-treated groups in comparison with the A group was observed. In the CP-treated groups a reduction in the number of different ovarian follicles in comparison with the A and C groups was observed. However, in the treated animals with fennel extract, these parameters significantly increased in comparison with the B group. Finally, it is concluded that fennel can protect ovary from cyclophosphamide side effects. Keywords: Cyclophosphamide, Fennel, Mice, Ovary

Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma

International Nuclear Information System (INIS)

Susa, Michiro; Iyer, Arun K; Ryu, Keinosuke; Hornicek, Francis J; Mankin, Henry; Amiji, Mansoor M; Duan, Zhenfeng

2009-01-01

Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy. Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOS R2 , U-2OS, and U-2OS R2 cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed. Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone. Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma

Effects of cyclophosphamide and irradiation singly and in combination upon SaI growth in A/J mice

International Nuclear Information System (INIS)

Anderson, R.E.; Williams, W.L.; Tokuda, S.

1987-01-01

The effects of various doses of cyclophosphamide and low-dose (15 rads) radiation upon the size of tumors caused by 10(4) Sarcoma I (SaI) cells was determined. In intact A/Jax (A/J) recipients, the effect of the two agents singly and in combination was found to be dependent especially upon the dosage of cyclophosphamide and the time of its administration in relation to tumor inoculation. In cell transfer experiments to adult thymectomized, lethally irradiated, bone-marrow-restored (ATxXBM) mice, the effects of cyclophosphamide and irradiation appeared to be either overlapping (low dosages of cyclophosphamide) or additive (dosages of cyclophosphamide greater than or equal to 50 mg/kg), suggesting that the two agents exert their influence in dissimilar fashion, perhaps by injuring different cell types with the same basic function. The most pronounced conjoint effects are seen when low dosages of cyclophosphamide are given 3 days after the adoptive transfer of spleen cells from mice pretreated with low-dose irradiation. The implications of this observation with respect to immunotherapy are discussed

Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart

International Nuclear Information System (INIS)

Montaigne, David; Marechal, Xavier; Baccouch, Riadh; Modine, Thomas; Preau, Sebastien; Zannis, Konstantinos; Marchetti, Philippe; Lancel, Steve; Neviere, Remi

2010-01-01

The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 μM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt max of 105 ± 8 mN/s in control hearts vs. 49 ± 7 mN/s in doxorubicin-treated hearts; *p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 ± 0.2 in control hearts vs. 2.2 ± 0.2 in doxorubicin-treated hearts; *p < 0.05) and cytochrome c oxidase kinetic activity (24 ± 1 μM cytochrome c/min/mg in control hearts vs. 14 ± 3 μM cytochrome c/min/mg in doxorubicin-treated hearts; *p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity.

INFLUENCE OF METRONIDAZOLE ON BIOLOGICAL ACTION OF DOXORUBICIN

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S. A. Yagubov

2017-01-01

Full Text Available Purpose. Investigation of the effect of the Metronizatol on the biological effect of Doxirubicin.Materials and methods. The studies were performed in the CBA/Lac males and C57Bl/6 females mice grafted with melanoma B16 and mucinous ovarian cancer CaO‑1. Metronidazole and Doxorubicin were used in the work. The antitumor effect was assessed by tumor volume and inhibition of tumor growth.Results. The data obtained indicate that Metronidazole used in oncologic practice for the treatment and prevention of infectious complications, and as a radiosensitizer, can enhance the antitumor effect of Doxorubicin, but this effect is accompanied by a significant increase of the cytostatic toxicity. These effects are leveled by increasing the interval between injections of Metronidazole and Doxorubicin up to 4 hours.Conclusion. The enhancement of the antitumor activity of Doxorubicin under the influence of Metronidazole depends on the interval between the administration of these drugs. When Metronidazole is used in cancer patients, the possibility of enhancing the toxic effect of cytostatics should be considered when they are simultaneously exposed. Patients receiving chemotherapy should be administered antitumor drugs no earlier than 4 hours after exposure to Metronidazole. 

Poly-L-arginine: Enhancing Cytotoxicity and Cellular Uptake of Doxorubicin and Necrotic Cell Death.

Science.gov (United States)

Movafegh, Bahareh; Jalal, Razieh; Mohammadi, Zobeideh; Aldaghi, Seyyede Araste

2018-04-11

Cell resistance to doxorubicin and its toxicity to healthy tissue reduce its efficiency. The use of cell penetrating peptides as drug delivery system along with doxorubicin is a strategy to reduce its side effects. In this study, the influence of poly-L-arginine on doxorubicin cytotoxicity, its cellular uptake and doxorubicin-induced apoptosis on human prostate cancer DU145 cells are assessed. The cytotoxicity of doxorubicin and poly-L-arginine, alone and in combination, in DU145 cells was evaluated at different exposure times using MTT assay. The influence of poly-L-arginine on doxorubicin delivery into cells was evaluated by fluorescence microscopy and ultraviolet spectroscopy. DAPI and ethidium bromide-acridine orange stainings, flow cytometry using annexin V/propidium iodide, western blot analysis with anti-p21 antibody and caspase-3 activity were used to examine the influence of poly-L-arginine on doxorubicin-induced cell death. Poly-L-arginine had no cytotoxicity at low concentrations and short exposure times. Poly-L-arginine increased the cytotoxic effect of doxorubicin in DU145 cells in a time-dependent manner. But no significant reduction was found in HFF cell viability. Poly-L-arginine seems to facilitate doxorubicin uptake and increase its intracellular concentration. 24 h combined treatment of cells with doxorubicin (0.5 μM) and poly-L-arginine (1 μg ml-1) caused a small increase in doxorubicin-induced apoptosis and significant elevated necrosis in DU145 cells as compared to each agent alone. Conlusion: Our results indicate that poly-L-arginine at lowest and highest concentrations act as proliferation-inducing and antiproliferative agents, respectively. Between these concentrations, poly-L-arginine increases the cellular uptake of doxorubicin and its cytotoxicity through induction of necrosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Doxorubicin, mesenchymal stem cell toxicity and antitumour activity: implications for clinical use.

Science.gov (United States)

Baxter-Holland, Mia; Dass, Crispin R

2018-03-01

The use of doxorubicin, an antineoplastic medication used for the treatment of cancers via mechanisms that prevent replication of cells or lead to their death, can result in damage to healthy cells as well as malignant. Among the affected cells are mesenchymal stem cells (MSCs), which are involved in the maintenance and repair of tissues in the body. This review explores the mechanisms of biological effects and damage attributed to doxorubicin on MSCs. The PubMed database was used as a source of literature for this review. Doxorubicin has the potential to lead to significant and irreversible damage to the human bone marrow environment, including MSCs. The primary known mechanism of these changes is through free radical damage and activation of apoptotic pathways. The presence of MSCs in culture or in vivo appears to either suppress or promote tumour growth. Interactions between doxorubicin and MSCs have the potential to increase chemotherapy resistance. Doxorubicin-induced damage to MSCs is of concern clinically. However, MSCs also have been associated with resistance of tumour cells to drugs including doxorubicin. Further studies, particularly in vivo, are needed to provide consistent results of how the doxorubicin-induced changes to MSCs affect treatment and patient health. © 2018 Royal Pharmaceutical Society.

Cyclophosphamide-induced pulmonary toxicity

International Nuclear Information System (INIS)

Siemann, D.W.; Macler, L.; Penney, D.P.

1986-01-01

Unlike radiation effects, pulmonary toxicity following drug treatments may develop soon after exposure. The dose-response relationship between Cyclophosphamide and lung toxicity was investigated using increased breathing frequency assays used successfully for radiation induced injury. The data indicate that release of protein into the alveolus may play a significant role in Cy induced pulmonary toxicity. Although the mechanism responsible for the increased alveolar protein is as yet not identified, the present findings suggest that therapeutic intervention to inhibit protein release may be an approach to protect the lungs from toxic effects. (UK)

Managing AIDS-related Kaposi's sarcoma and pregnancy

African Journals Online (AJOL)

additional 14 cycles of chemotherapy, which was discontinued when her KS lesions demonstrated a good clinical response. She returned 6 months later with KS progression and was re-challenged with the ABV regime (doxorubicin, bleomycin and vincristine) for 6 cycles. She reached the tolerance dose of bleomycin, and ...

Effects of cyclophosphamide on laser immunotherapy for the treatment of metastatic cancer

Science.gov (United States)

Bahavar, Cody F.; Acquaviva, Joseph T.; Rabei, Sheyla; Sikes, Allie; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

2014-02-01

Laser immunotherapy (LIT) is an innovative cancer modality that uses laser irradiation and immunological stimulation to treat late-stage, metastatic cancers. The current mode of operation in LIT is through interstitial laser irradiation. Although LIT is still in development, recent clinical trials have shown that it can be used to successfully treat patients with late-stage breast cancer and melanoma. Cyclophosphamide is a chemotherapy drug that suppresses regulatory T cells when used in low doses. In this study tumor-bearing rats were treated with LIT using an 805-nm laser with a power of 2.0 W and low-dose cyclophosphamide. Glycated chitosan was used as an immunological stimulant. The goal was to observe the effects of different doses of cyclophosphamide in addition to LIT on the survival of the tumor-bearing rats.

Radiotherapy using bleomycin, ACNU, and vincristine for malignant brain tumors

Energy Technology Data Exchange (ETDEWEB)

Tanaka, Ryuichi; Murakami, Naoto; Suzuki, Yasuo; Takeda, Norio; Arai, Hiroyuki; Konno, Kimikazu; Tanimura, Ken-ichi

1984-08-01

Radiotherapy combined with bleomycin, ACNU, and vincristine was performed on 106 patients with malignant brain tumors. The treatment protocol was based on the concept of combination chemotherapy or chemoradiotherapy and synchronized chemoradiotherapy. For the purpose of synchronized chemoradiotherapy, bleomycin, ACNU, and vincristine were used as G/sub 2/M cell cycle phase accumulator, and radiation and bleomycin were used as agents to which G/sub 2/M or G/sub 2/ phase cells are sensitive. The short-term results of the chemoradiotherapy were evaluated by measuring tumor regression by computerized tomography (CT) in 80 patients with evaluable CT lesions. The response rate was 67% (6/9) for astrocytoma, 29% (7/24) for anaplastic glioma, 67% (4/6) for pontine glioma, 100%(5/5) for malignant lymphoma, 100% (8/8) for germ cell tumors and 65% (15/23) for metastatic tumors. A control study was performed using radiation alone on another 18 patients with metastatic tumors, and the response rate was 50% (9/18). Among the 106 patients treated with chemoradiotherapy, the major side effects observed were as follows: leukopenia in 33 patients (31%), thrombocytopenia in 14 (13%), paralytic ileus in 2 (2%), peripheral neuropathy in 2 (2%), and lung fibrosis in 1 (1%). Contrary to expectation, low-grade astrocytomas responded much better to the chemoradiotherapy than high-grade astrocytomas.

Metronomic cyclophosphamide-induced long-term remission after recurrent high-grade serous ovarian cancer: A case study.

Science.gov (United States)

de Boo, Leonora Wijnandina; Vulink, Annelie Johanna Elisabeth; Bos, Monique Elisabeth Martina Maria

2017-12-01

Metronomic oral cyclophosphamide has gained increasing interest in recent years as a promising maintenance therapy in advanced, platinum-sensitive, high-grade serous ovarian cancer (HGSOC). Metronomic treatment with cyclophosphamide refers to the frequent, usually daily, administration of a low (oral) dose of cyclophosphamide with no prolonged drug-free breaks. Main advantages of this treatment are the effective reduction of tumour activity, oral administration in an outpatient setting, low cost and the low toxicity profile. Metronomic oral cyclophosphamide can benefit patients suffering from types of cancer known to be sensitive to alkylating agents, such as platinum-sensitive HGSOC. In recent years, several publications have underlined the advantage of this regimen and possible explanations were explored. We here present a patient with multiple recurrences of metastasized HGSOC, platinum-sensitive, with an on-going complete response to monotherapy with oral cyclophosphamide. This observation supports that patients with relapsing HGSOC who responded to platinum-based chemotherapy and cannot continue platinum-based chemotherapy because of toxicity, can be offered a course of metronomic cyclophosphamide. This case may serve as a reminder that old drugs can be used successfully even in the age of new upcoming therapy such as anti-angiogenic agents (VEGF inhibitors) and poly-ADP-ribose polymerase (PARP) inhibitors.

Direct effects of doxorubicin on skeletal muscle contribute to fatigue

NARCIS (Netherlands)

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

2009-01-01

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

Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast

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Jana S. Miles

2018-01-01

Full Text Available Anthracyclines are frequently used to treat many cancers including triple negative breast cancer, which is commonly observed in African-American women (AA, and tend to be more aggressive, carry worse prognoses, and are harder to manage because they lack molecular targets. Although effective, anthracyclines use can be limited by serious side effects and eventually the development of drug resistance. In S. cerevisiae, mutants of HOM6 display hypersensitivity to doxorubicin. HOM6 is required for synthesis of threonine and interruption of the pathway leads to accumulation of the threonine intermediate L-aspartate-semialdehyde. This intermediate may synergize with doxorubicin to kill the cell. In fact, deleting HOM3 in the first step, preventing the pathway to reach the HOM6 step, rescues the sensitivity of the hom6 strain to doxorubicin. Using several S. cerevisiae strains (wild type, hom6, hom3, hom3hom6, ydj1, siz1, and msh2, we determined their sensitivity to aldehydes and to their combination with doxorubicin, cisplatin, and etoposide. Combination of formaldehyde and doxorubicin was most effective at reducing cell survival by 31-fold–39-fold (in wild type cells relative to doxorubicin and formaldehyde alone. This effect was dose dependent on doxorubicin. Cotreatment with formaldehyde and doxorubicin also showed increased toxicity in anthracycline-resistant strains siz1 and msh2. The hom6 mutant also showed sensitivity to menadione with a 2.5-fold reduction in cell survival. The potential use of a combination of aldehydes and cytotoxic drugs could potentially lead to applications intended to enhance anthracycline-based therapy.

Successful treatment of idiopathic pulmonary capillaritis with intravenous cyclophosphamide.

LENUS (Irish Health Repository)

Flanagan, Frances

2013-03-01

Idiopathic pulmonary hemosiderosis (IPH), a subtype of diffuse alveolar hemorrhage is a rare condition, first described by Virchow in 1864. Historically, it manifests in children in the first decade of life with the combination of hemoptysis, iron deficiency anemia, and alveolar infiltrates on chest radiograph. More recently, diffuse alveolar hemorrhage has been classified by the absence or presence of pulmonary capillaritis (PC), the latter carrying a potential for a poorer outcome. While systemic corticosteroids remain the first line treatment option, other immune modulators have been trailed including hydroxychloroquine, azathioprine, 6-mercaptopurine, and cyclophosphamide with varying results. Our case demonstrates for the first time, the successful use of intravenous cyclophosphamide in the management of chronic idiopathic PC.

Ovarian toxicity of cyclophosphamide alone and in combination with ovarian irradiation in the rat

International Nuclear Information System (INIS)

Jarrell, J.; Lai, E.V.; Barr, R.; McMahon, A.; Belbeck, L.; O'Connell, G.

1987-01-01

The effects of radiation and chemotherapy on gonadal function are relevant to the morbidity induced by such treatments. Cyclophosphamide given i.p. to rats on Day 30 of age delayed vaginal opening, prevented vaginal cyclicity, and caused a reduction in serum estradiol and progesterone. Antral follicular atresia increased in a dose-dependent fashion in response to cyclophosphamide (0 mg/kg, 53.5%; 1 mg/kg, 67.3%; 50 mg/kg, 65.7%; 100 mg/kg, 73.9%; 150 mg/kg, 92.2%). Despite such alterations in ovarian function, serum gonadotrophins did not rise. The concurrent administration of 0, 20, 30, 40, 50, and 60 Gy of radiation to the exteriorized ovaries in rats receiving 50 mg/kg cyclophosphamide induced widespread loss of primordial, preantral, and healthy antral follicles associated with reduction in serum progesterone and estradiol. Such irradiation induced dose-related increases in serum follicle-stimulating hormone and luteinizing hormone. Parenteral cyclophosphamide and local irradiation appear to induce ovarian toxicity by different mechanisms

Molecularly imprinted fluorescent probe based on FRET for selective and sensitive detection of doxorubicin

Energy Technology Data Exchange (ETDEWEB)

Xu, Zhifeng, E-mail: 897061147@qq.com [College of Chemistry and Materials Science, Hengyang Normal University, Key Laboratory of Functional Organometallic Materials of Hunan Province University, Hengyang 421008 (China); Deng, Peihong; Li, Junhua [College of Chemistry and Materials Science, Hengyang Normal University, Key Laboratory of Functional Organometallic Materials of Hunan Province University, Hengyang 421008 (China); Xu, Li [Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou 510642 (China); Tang, Siping [College of Chemistry and Materials Science, Hengyang Normal University, Key Laboratory of Functional Organometallic Materials of Hunan Province University, Hengyang 421008 (China)

2017-04-15

Highlights: • FRET-based molecularly imprinted probe for detection of doxorubicin was prepared. • The detection limit of the probe was 13.8 nM for doxorubicin. • The FRET-based probe had a higher selectivity for the template than ordinary MIMs. - Abstract: In this work, a new type of fluorescent probe for detection of doxorubicin has been constructed by the combined use of fluorescence resonance energy transfer (FRET) technology and molecular imprinting technique (MIT). Using doxorubicin as the template, the molecularly imprinted polymer thin layer was fabricated on the surfaces of carbon dot (CD) modified silica by sol-gel polymerization. The excitation energy of the fluorescent donor (CDs) could be transferred to the fluorescent acceptor (doxorubicin). The FRET based fluorescent probe demonstrated high sensitivity and selectivity for doxorubicin. The detection limit was 13.8 nM. The fluorescent probe was successfully applied for detecting doxorubicin in doxorubicin-spiked plasmas with a recovery of 96.8–103.8%, a relative standard deviation (RSD) of 1.3–2.8%. The strategy for construction of FRET-based molecularly imprinted materials developed in this work is very promising for analytical applications.

Delivery of vincristine sulfate-conjugated gold nanoparticles using liposomes: a light-responsive nanocarrier with enhanced antitumor efficiency

Directory of Open Access Journals (Sweden)

Liu Y

2015-04-01

Full Text Available Ying Liu,1,* Man He,1,* Mengmeng Niu,1 Yiqing Zhao,1 Yuanzhang Zhu,1 Zhenhua Li,2 Nianping Feng1 1Department of Pharmaceutical Sciences, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Cedars-Sinai Medical Center, Los Angeles, CA, USA *These authors contributed equally to this work Abstract: Rapid drug release at the specific site of action is still a challenge for antitumor therapy. Development of stimuli-responsive hybrid nanocarriers provides a promising strategy to enhance therapeutic effects by combining the unique features of each component. The present study explored the use of drug–gold nanoparticle conjugates incorporated into liposomes to enhance antitumor efficiency. A model drug, vincristine sulfate, was physically conjugated with gold nanoparticles and verified by UV-visible and fourier transform infrared spectroscopy, and differential scanning calorimetry. The conjugates were incorporated into liposomes by film dispersion to yield nanoparticles (113.4 nm with light-responsive release properties, as shown by in vitro release studies. Intracellular uptake and distribution was studied in HeLa cells using transmission electron microscopy and confocal laser scanning microscopy. This demonstrated liposome internalization and localization in endosomal–lysosomal vesicles. Fluorescence intensity increased in cells exposed to UV light, indicating that this stimulated intracellular drug release; this finding was confirmed by quantitative analyses using flow cytometry. Antitumor efficacy was evaluated in HeLa cells, both in culture and in implants in vivo in nude mice. HeLa cell viability assays showed that light exposure enhanced liposome cytotoxicity and induction of apoptosis. Furthermore, treatment with the prepared liposomes coupled with UV light exposure produced greater antitumor effects in nude mice and reduced side effects, as compared with free vincristine sulfate

Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells.

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Reenu Punia

Full Text Available Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients.In this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC cells.During this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin.The effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR.The results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin-doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on

Effect of Chromium on Antioxidant Potential of Catharanthus roseus Varieties and Production of Their Anticancer Alkaloids: Vincristine and Vinblastine

Science.gov (United States)

Tandon, Pramod Kumar; Khatoon, Sayyada

2014-01-01

Catharanthus roseus (L.) G. Don, a medicinal plant, has a very important place in the traditional as well as modern pharmaceutical industry. Two common varieties of this plant rosea and alba are named so because of pink and white coloured flowers, respectively. This plant comprises of about 130 terpenoid indole alkaloids and two of them, vincristine and vinblastine, are common anticancer drugs. The effect of chromium (Cr) on enzymatic and non-enzymatic antioxidant components and on secondary metabolites vincristine and vinblastine was studied under pot culture conditions of both varieties of C. roseus. Antioxidant responses of these varieties were analyzed under 0, 10, 50, and 100 μM chromium (Cr) level in order to investigate the plant's protective mechanisms against Cr induced oxidative stress. The results indicated that Cr affects all the studied parameters and decreases growth performance. However, vincristine and vinblastine contents were increased under Cr stress. Results are quite encouraging, as this plant shows good antioxidant potential and increased the level of active constituents under Cr stress. PMID:24734252

Effect of Chromium on Antioxidant Potential of Catharanthus roseus Varieties and Production of Their Anticancer Alkaloids: Vincristine and Vinblastine

Directory of Open Access Journals (Sweden)

Vartika Rai

2014-01-01

Full Text Available Catharanthus roseus (L. G. Don, a medicinal plant, has a very important place in the traditional as well as modern pharmaceutical industry. Two common varieties of this plant rosea and alba are named so because of pink and white coloured flowers, respectively. This plant comprises of about 130 terpenoid indole alkaloids and two of them, vincristine and vinblastine, are common anticancer drugs. The effect of chromium (Cr on enzymatic and non-enzymatic antioxidant components and on secondary metabolites vincristine and vinblastine was studied under pot culture conditions of both varieties of C. roseus. Antioxidant responses of these varieties were analyzed under 0, 10, 50, and 100 μM chromium (Cr level in order to investigate the plant’s protective mechanisms against Cr induced oxidative stress. The results indicated that Cr affects all the studied parameters and decreases growth performance. However, vincristine and vinblastine contents were increased under Cr stress. Results are quite encouraging, as this plant shows good antioxidant potential and increased the level of active constituents under Cr stress.

Abatement by Naringenin of Doxorubicin-Induced Cardiac Toxicity in Rats

International Nuclear Information System (INIS)

Arafa, H.M.; Abd-Ellah, M.F.; Hafez, H.F.

2005-01-01

Doxorubicin is one of the most active cytotoxic agents in current use. It has proven efficacy in various malignancies either alone or combined with other cytocidal agents. The clinical usefulness of the anthracycline drug has been precluded by cardiac toxicity. Many therapeutic interventions have been attempted to improve the therapeutic benefits of the drug. Few, however, have been efficacious in this setting. Purpose: We have addressed in the current study the possible protective effects of naringenin, a flavonoid known to have anti-oxidant properties, on doxorubicin induced cardiac toxicity in male Swiss albino rats. Methods: Forty male Swiss albino rats were used in this study. Naringenin (25 mg/kg body weight) was administered daily by gavage for 7 consecutive days before a cumulative single dose of doxorubicin (15 mg/kg body weight, ip). Doxorubicin induced marked biochemical alterations characteristic of cardiac toxicity including, elevated activities of serum total lactate dehydrogenase (LDH) and creatine phosphokinase (CPK), enhanced lipid peroxidation measured as malonaldehyde (MDA). The anthracycline drug has also reduced the cardiac enzymatic activities of superoxide dismutase (SOD), glutathione-Stransferase (GST) and catalase (CAT). Besides, it reduced significantly the reduced glutathione (GSH) level, but it increased the total NO content in heart tissue. Prior administration of naringenin ahead of doxorubicin challenge ameliorated all these biochemical markers. Taken together, one could conclude that naringenin has a protective role in the abatement of doxorubicin-induced cardiac toxicity that resides, at least in part, on its anti-radical effects and regulatory role on NO production

High Dose Cyclophosphamide without Stem Cell Rescue in 207 Patients with Aplastic anemia and other Autoimmune Diseases

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DeZern, Amy E.; Petri, Michelle; Drachman, Daniel B.; Kerr, Doug; Hammond, Edward R.; Kowalski, Jeanne; Tsai, Hua-Ling; Loeb, David M.; Anhalt, Grant; Wigley, Fredrick; Jones, Richard J.; Brodsky, Robert A.

2011-01-01

High-dose cyclophosphamide has long been used an anticancer agent, a conditioning regimen for hematopoietic stem cell transplantation and as potent immunosuppressive agent in autoimmune diseases including aplastic anemia. High-dose cyclophosphamide is highly toxic to lymphocytes but spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase, the major mechanism of cyclophosphamide inactivation. High dose cyclophosphamide therapy induces durable remissions in most patients with acquired aplastic anemia. Moreover, high-dose cyclophosphamide without hematopoietic stem cell rescue has shown activity in a variety of other severe autoimmune diseases. Here we review the history of cyclophosphamide as is applies to aplastic anemia (AA) and other autoimmune diseases. Included here are the historical data from early patients treated for AA as well as an observational retrospective study in a single tertiary care hospital. This latter component was designed to assess the safety and efficacy of high-dose cyclophosphamide therapy without stem cell rescue in patients with refractory autoimmune diseases. We analyzed fully the 140 patients with severe, progressive autoimmune diseases treated. All patients discussed here received cyclophosphamide, 50 mg/kg per day for 4 consecutive days. Response, relapse and overall survival were measured. Response was defined as a decrease in disease activity in conjunction with a decrease or elimination of immune modulating drugs. Relapse was defined as worsening disease activity and/or a requirement of an increase in dose of, or administration of new, immunosuppressive medications. Hematologic recovery occurred in all patients. The overall response rate of the was 95%, and 44% of those patients remain progression-free with a median follow up time of 36 (range 1–120) months for the 140 patients analyzed together. The overall actuarial and event free survival across all diseases at 60 months is 90.7% and 20

Histone deacetylase inhibitors augment doxorubicin-induced DNA damage in cardiomyocytes.

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Ververis, Katherine; Rodd, Annabelle L; Tang, Michelle M; El-Osta, Assam; Karagiannis, Tom C

2011-12-01

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid (Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies, involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes. Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum histone deacetylase inhibitors tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination therapies for cancer.

A retrospective comparison of cyclophosphamide plus antithymocyte globulin with cyclophosphamide plus busulfan as the conditioning regimen for severe aplastic anemia

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L.V.M. Ommati

2009-03-01

Full Text Available Allogeneic hematopoietic stem cell transplantation (AHSCT is the treatment of choice for young patients with severe aplastic anemia (SAA. The association of antithymocyte globulin (ATG and cyclophosphamide (CY is the most frequently used conditioning regimen for this disease. We performed this retrospective study in order to compare the outcomes of HLA-matched sibling donor AHSCT in 41 patients with SAA receiving cyclophosphamide plus ATG (ATG-CY, N = 17 or cyclophosphamide plus busulfan (BU-CY, N = 24. The substitution of BU for ATG was motivated by the high cost of ATG. There were no differences in the clinical features between the two groups, including age, gender, cytomegalovirus status, ABO match, interval between diagnosis and transplant, and number of total nucleated cells infused. No differences were observed in the time to neutrophil and platelet engraftment, or in the risk of veno-occlusive disease and hemorrhage. However, there was a higher risk of mucositis in the BU-CY group (71 vs 24%, P = 0.004. There were no differences in the incidence of neutrophil and platelet engraftment, acute and chronic graft-versus-host disease, and transplant-related mortality. There was a higher incidence of late rejection in the ATG-CY group (41 vs 4%, P = 0.009. Although the ATG-CY group had a longer follow-up (101 months than the BU-CY group (67 months, P = 0.04, overall survival was similar between the groups (69 vs 58%, respectively, P = 0.32. We conclude that the association BU-CY is a feasible option to the conventional ATG-CY regimen in this population.

Optimization of doxorubicin loading for superabsorbent polymer microspheres: in vitro analysis.

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Liu, David M; Kos, Sebastian; Buczkowski, Andrzej; Kee, Stephen; Munk, Peter L; Klass, Darren; Wasan, Ellen

2012-04-01

This study was designed to establish the ability of super-absorbent polymer microspheres (SAP) to actively uptake doxorubicin and to establish the proof of principle of SAP's ability to phase transfer doxorubicin onto the polymer matrix and to elute into buffer with a loading method that optimizes physical handling and elution characteristics. Phase I: 50-100 μm SAP subject to various prehydration methods (normal saline 10 cc, hypertonic saline 4 cc, iodinated contrast 10 cc) or left in their dry state, and combined with 50 mg of clinical grade lyophilized doxorubicin reconstituted with various methods (normal saline 10 cc and 25 cc, sterile water 4 cc, iodinated contrast 5 cc) were placed in buffer and assessed based on loading, handling, and elution utilizing high-performance liquid chromatography (HPLC). Phase II: top two performing methods were subject to loading of doxorubicin (50, 75, 100 mg) in a single bolus (group A) or as a serial loading method (group B) followed by measurement of loading vs. time and elution vs. time. Phase I revealed the most effective loading mechanisms and easiest handling to be dry (group A) vs. normal saline prehydrated (group B) SAP with normal saline reconstituted doxorubicin (10 mg/mL) with loading efficiencies of 83.1% and 88.4%. Phase II results revealed unstable behavior of SAP with 100 mg of doxorubicin and similar loading/elution profiles of dry and prehydrated SAP, with superior handling characteristics of group B SAP at 50 and 75 mg. SAP demonstrates the ability to load and bulk phase transfer doxorubicin at 50 and 75 mg with ease of handling and optimal efficiency through dry loading of SAP.

Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial.

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Bear, Harry D; Tang, Gong; Rastogi, Priya; Geyer, Charles E; Liu, Qing; Robidoux, André; Baez-Diaz, Luis; Brufsky, Adam M; Mehta, Rita S; Fehrenbacher, Louis; Young, James A; Senecal, Francis M; Gaur, Rakesh; Margolese, Richard G; Adams, Paul T; Gross, Howard M; Costantino, Joseph P; Paik, Soonmyung; Swain, Sandra M; Mamounas, Eleftherios P; Wolmark, Norman

2015-09-01

NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m(2)) with addition of capecitabine (825 mg/m(2) oral twice daily days 1-14, 75 mg/m(2) docetaxel) or with addition of gemcitabine (1000 mg/m(2) days 1 and 8 intravenously, 75 mg/m(2) docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m(2) and 600 mg/m(2) intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and

Intestinal diffuse large B-cell lymphoma: an evaluation of different staging systems.

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Hwang, Hee Sang; Yoon, Dok Hyun; Suh, Cheolwon; Park, Chan-Sik; Huh, Jooryung

2014-01-01

The gastrointestinal tract is the most common primary extranodal site for diffuse large B-cell lymphoma (DLBCL). However, there is no consensus on the most appropriate staging system for intestinal DLBCL. We evaluated the utility of the modified Ann Arbor system, the Lugano system, and the Paris staging system (a modification of the Tumor, Node, Metastases [TNM] staging for epithelial tumors) in 66 cases of resected intestinal DLBCL. The cases were treated with surgery, plus either cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy alone (n=26) or with the addition of rituximab immunotherapy (n=40). Median follow-up time was 40.4 months (range, 2.1-171.6 months). Fifty-six patients (84.8%) achieved complete remission. The overall 5-yr survival rate was 86.4% (57/66). Of the stage categories defined for each staging system, only the T stage of the Paris classification showed prognostic significance for overall survival by univariate analysis. However, none of the stage parameters was significantly correlated with patient survival on multivariate analysis. In conclusion, the results suggest that the T stage of the Paris classification system may be a prognostic indicator in intestinal DLBCL. The results also imply that in surgically resected intestinal DLBCL, the addition of rituximab to the CHOP regimen does not confer significant survival advantage.

Plasmablastic lymphoma of the upper gingiva in an HIV-negative elderly patient

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Tomohiro Yamada, DDS, PhD

2015-06-01

Full Text Available Plasmablastic lymphoma (PBL is a highly aggressive variant of diffuse large B-cell lymphoma and is usually treated by chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP or CHOP-like regimens. However, elderly patients tend to have difficulty with the chemotherapy. We successfully treated an HIV-negative elderly PBL patient with surgery alone. An 87-year-old Japanese man was referred to our hospital because of gingival swelling of the left maxilla. After several examinations, a multilobular 3-cm tumor of the left maxilla and lymph node swelling on the left side of the neck were revealed. The patient was HIV negative and human T-cell leukemia virus negative. He was diagnosed with PBL, or undifferentiated carcinoma/sarcoma, and we performed surgical therapy, radical neck dissection, and a partial maxillectomy. The surgical margin of the resected specimen was negative for tumor cells, and 6 of 27 lymph nodes contained tumor cells. Histologically, the tumor consisted of basophilic large cells with deviated nuclei. Together with the immunohistochemical findings, the final diagnosis was PBL. The patient and his family did not agree to chemotherapy. Nineteen months after surgery, he is fine and no signs of recurrence were observed. Surgery-only therapy may be a reasonable alternative for elderly PBL patients.

Primary Diffuse Large B-Cell Lymphoma of the Liver in a Patient with Sjogren Syndrome

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Vadim Gorodetskiy

2016-01-01

Full Text Available Sjögren’s syndrome (SS has the highest incidence of malignant lymphoproliferative disorders transformation among autoimmune diseases. We present a case of extranodal high grade lymphoma of the liver in a 52-year-old patient with long history of SS. Lymphoma manifested with sharp significant pain in the right hypochondrium, weakness, and profuse night sweats. Contrast-enhanced computed tomography scan (CT-scan of the abdomen revealed multiple low density foci with homogeneous structure and clear contours in both lobes of the liver. Histologically, proliferation of medium sized lymphoma cells with round-oval and slightly irregular nuclei with fine chromatin was shown. Immunohistochemical and molecular features of the tumors allowed diagnosis of diffuse large B-cell lymphoma (DLBCL. To exclude secondary liver lesion by non-Hodgkin lymphoma, chest and small pelvis CT-scan, endoscopy of upper and lower gastrointestinal tract and study of bone marrow were performed. After 8 cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, the complete remission was achieved, which persists after 45 months of follow-up. Primary hepatic lymphomas are extremely rare, and previously only low-grade hepatic lymphomas have been described in SS. To our knowledge, the patient described here represents the first reported case of DLBCL with primary liver involvement in SS.

Impact on Medical Cost, Cumulative Survival, and Cost-Effectiveness of Adding Rituximab to First-Line Chemotherapy for Follicular Lymphoma in Elderly Patients: An Observational Cohort Study Based on SEER-Medicare

International Nuclear Information System (INIS)

Griffiths, R. I.; Gleeson, M. L.; Danese, M. D.; Griffiths, R. I.; Mikhael, J.

2012-01-01

Rituximab improves survival in follicular lymphoma (FL), but is considerably more expensive than conventional chemotherapy. We estimated the total direct medical costs, cumulative survival, and cost-effectiveness of adding rituximab to first-line chemotherapy for FL, based on a single source of data representing routine practice in the elderly. Using surveillance, epidemiology, and end results (SEER) registry data plus Medicare claims, we identified 1,117 FL patients who received first-line CHOP (cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P)) or CVP +/− rituximab. Multivariate regression was used to estimate adjusted cumulative cost and survival differences between the two groups over four years after beginning treatment. The median age was 73 years (minimum 66 years), 56% had stage III-IV disease, and 67% received rituximab. Adding rituximab to first-line chemotherapy was associated with higher adjusted incremental total cost ($18,695; 95% Confidence Interval (CI) $9,302-$28,643) and longer adjusted cumulative survival (0.18 years; 95% CI 0.10-0.27) over four years of followup. The expected cost-effectiveness was $102,142 (95% CI $34,531-296,337) per life-year gained. In routine clinical practice, adding rituximab to first-line chemotherapy for elderly patients with FL results in higher direct medical costs to Medicare and longer cumulative survival after four years.

Gastric Lymphoma with Secondary Trigeminal Nerve Lymphoma: A Case Report

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Warissara Rongthong

2017-05-01

Full Text Available Data supporting the role of radiotherapy in secondary trigeminal nerve lymphoma is scarce. Here, I report the case of 64-year-old Thai male diagnosed as gastric diffuse large B cell lymphoma with secondary trigeminal nerve lymphoma. He had previously received one cycle of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP, followed by five cycles of rituximab plus CHOP (R-CHOP with intrathecal methotrexate (MTX and cytarabine (Ara-C. One month after the last cycle of R-CHOP, he developed a headache and numbness on the left side of his face. MRI revealed thickening of the left trigeminal nerve. He received one intrathecal injection of MTX and Ara-C, followed by systemic chemotherapy. After receiving intrathecal chemotherapy, his symptoms disappeared. Clinical response and MRI studies suggested secondary trigeminal nerve lymphoma. Two months later, our patient’s secondary trigeminal nerve lymphoma had progressed. Salvage whole brain irradiation (36 Gy with boost dose (50 Gy along the left trigeminal nerve was given. Unfortunately, our patient developed heart failure and expired during the radiotherapy session. In conclusion and specific to secondary central nervous system lymphoma (SCNSL, radiotherapy may benefit patients who fail to respond to systemic chemotherapy and palliative treatment. The results this report fail to support the role of radiotherapy in secondary trigeminal nerve lymphoma.

The changing landscape of peripheral T-cell lymphoma in the era of novel therapies.

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Karlin, Lionel; Coiffier, Bertrand

2014-01-01

Peripheral T-cell lymphomas (PTCLs) are the most common sub-entity of mature T-cell lymphomas, and apart from particular presentations, share a poor prognosis with frequent short-term, agressive, and chemorefractory relapses. Because of the rarity and also the heterogeneity of the disease, we lack randomized clinical trials. However, to date, neither intensification of frontline chemotherapy or autologous transplant has led to any improvement of survival, and the standard CHOP (cyclophosphamide, doxorubicine, vincristine, and prednisone) regimen remains the most employed as induction therapy. In the past few years, new chemotherapeutic agents, with the capability to encompass the resistance to conventional chemotherapy, such as pralatrexate or bendamustine, have been evaluated. Furthermore, identification of cell surface molecular markers (CD52, CD30, CCR4) has led to the development of new monoclonal antibodies. Similarly, the better comprehension of physiopathological mechanisms and detection of deregulated intracellular pathways encouraged the use of novel therapies such as histone deacetylase inhibitors or immunomodulatory drugs. Some of these compounds have been approved for relapse, and are currently evaluated upfront in ongoing clinical trials. Despite these efforts, the global prognosis still remains much inferior to those of B-cell lymphomas, highlighting the necessity of multicenter clinical trials. © 2013 Elsevier Inc. All rights reserved.

Dose critical in-vivo detection of anti-cancer drug levels in blood

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Miller, Holly H.; Hirschfeld, deceased, Tomas B.

1991-01-01

A method and apparatus are disclosed for the in vivo and in vitro detection and measurement of dose critical levels of DNA-binding anti-cancer drug levels in biological fluids. The apparatus comprises a laser based fiber optic sensor (optrode) which utilizes the secondary interactions between the drug and an intercalating fluorochrome bound to a probe DNA, which in turn is attached to the fiber tip at one end thereof. The other end of the optical fiber is attached to an illumination source, detector and recorder. The fluorescence intensity is measured as a function of the drug concentration and its binding constant to the probe DNA. Anticancer drugs which lend themselves to analysis by the use of the method and the optrode of the present invention include doxorubicin, daunorubicin, carminomycin, aclacinomycin, chlorambucil, cyclophosphamide, methotrexate, 5-uracil, arabinosyl cytosine, mitomycin, cis-platinum 11 diamine dichloride procarbazine, vinblastine vincristine and the like. The present method and device are suitable for the continuous monitoring of the levels of these and other anticancer drugs in biological fluids such as blood, serum, urine and the like. The optrode of the instant invention also enables the measurement of the levels of these drugs from a remote location and from multiple samples.

A Case of Cutaneous Plasmablastic Lymphoma in HIV/AIDS with Disseminated Cryptococcus

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Jun Gong

2013-01-01

Full Text Available We present a case of a patient with HIV/AIDS who presented with a tender left lower extremity cutaneous mass over a site of previous cryptococcal infection and was found to have plasmablastic lymphoma (PBL. The incidence of PBL is estimated to account for less than 5% of all cases of non-Hodgkin lymphoma (NHL in HIV-positive individuals. In fact, there were only two reports of extraoral PBL at the time of a 2003 review. PBL in HIV-positive individuals is an aggressive malignancy that tends to occur in middle-aged males with low CD4 counts, high viral loads, and chronic HIV infection. The definitive diagnosis can be made with biopsy which typically shows malignant lymphoid cells that stain positive for plasma cell markers and negative for B-cell markers. The most common treatment is chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP or CHOP-like regimens, but the overall survival rate is poor despite its relative responsiveness to chemotherapy. This case highlights the challenges that remain in improving clinical outcomes, the importance of antiretroviral therapy and HIV disease control, and a potential association between a chronic inflammatory state caused by disseminated Cryptococcus and tumorigenesis in individuals with PBL.

Primary cutaneous large B-cell lymphoma of scalp: Case report of a rare variant

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Yasmeen Khatib

2017-01-01

Full Text Available Primary cutaneous large B-cell lymphoma (Bcl is defined as a lymphoma composed of large cells constituting more than 80% of the infiltrate and absence of extracutaneous involvement after staging investigations. In the new World Health Organization/European Organization for Research and Treatment of Cancer classification, cutaneous Bcls with large cells are of three types - primary cutaneous large Bcl leg type (PCLBCLLT, primary cutaneous follicle center lymphoma diffuse type (PCFCLDT, and primary cutaneous large Bcls other (PCLBCLO. These three different types are distinct in terms of their clinicopathological features and survival. The PCLBCLO has intermediate features between those of PCLBCLLT and PCFCLDT. We present a case of PCLBCLO in a 57-year-old male who presented with a scalp swelling. Ultrasonography examination was suggestive of a sebaceous cyst. Computed tomography scan revealed the presence of an ill-defined hyperdense region in the soft tissue of the scalp region extending into the deeper layers of the scalp. Fine-needle aspiration cytology (FNAC revealed the presence of atypical lymphoid cells. Diagnosis was confirmed by biopsy and immunohistochemistry. Patient received rituximab combined with doxorubicin, vincristine, cyclophosphamide, and prednisolone regimen with complete resolution of the lesion. We present this case for its rarity, the utility of FNAC in early diagnosis, and to discuss the differential diagnosis.

Primary Ewing’s Sarcoma of the Sinonasal Tract: A Case Report

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Tomoharu Suzuki

2017-01-01

Full Text Available A 23-year-old male presented with a 3-month history of left purulent rhinorrhea, progressive nasal obstruction, and intermittent epistaxis. A fiberoptic examination revealed a large vascular polypoid mass completely filling the left nasal cavity. CT and MRI scans showed a large hypervascular mass involving the left nasal airway, maxillary antrum, and the anterior ethmoid cells. There was no bony erosion or contiguous spread, and the remaining sinuses, orbit, and cranial fossa were uninvolved. The patient underwent complete removal of the mass via an external lateral rhinotomy approach. The soft mass was large and vascular. A microscopic analysis revealed an undifferentiated tumor consisting of a solid sheet of small, round blue cells. Mitotic figures were also present. Immunohistochemically, the tumor cells were strongly positive for CD99. Molecular studies using a PCR confirmed the chromosomal translocation of FLI1 (exon 6. These findings were considered diagnostic for Ewing’s sarcoma. Postoperatively, the patient was treated with combined chemotherapy and radiotherapy. Adjuvant chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (total: 7 cycles was commenced. He also received radiation therapy for local control (total dose: 50.4 Gy. The patient is currently alive without any evidence of recurrence or metastasis.

Evaluation of the lung function in cancer patients undergoing to chemotherapy

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Caroline Heemann Vione

2016-10-01

Full Text Available Background and Objective: Some neoplastic agents used in cancer treatment cause pulmonary toxicity and other important adverse effects, therefore, the present study aimed to evaluate the presence of obstructive lung disease (OLD, restrictive lung disease (RLD or mixed in patients 2 with cancer undergoing chemotherapy. Method: This is a cross-sectional and descriptive study that evaluated patients diagnosed with cancer and undergoing chemotherapy using Doxorubicin, Bleomycin, Vinblastine, Dacarbazine, Cyclophosphamide, Fluorouracil and Vincristine, being excluded those diagnosed with lung cancer. Realized pulmonary function test byspirometric analysis (EasyOne®, Switzerland in patients who started chemotherapy for over 30 days, it was evaluated the Forced Vital Capacity (FVC, forced expiratory volume in one second FVC (FEV1, forced expiratory flow between 25-75% of FVC (FEF25-75 % and the FEV1 / FVC Relation before the chemotherapy session. Results: Sample (n = 18 composed of cancer patients with average age of 49.28±9.90 years and 26.49±5.67 kg/m2 on which 44.4% had normal spirometry standard, 27.8% had OLD, 16.7% presented RLD and 11.1% presented mixed respiratory disorder. Conclusion: Thechemotherapy resulted in obstructive pulmonary disease, restrictive and mixedin patients with leukemia, breast cancer and Hodgkin's lymphoma not specific evaluated.

Rapid-infusion rituximab in lymphoma treatment: 2-year experience in a single institution.

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Atay, Sevcan; Barista, Ibrahim; Gundogdu, Fatma; Akgedik, Kiymet; Arpaci, Afey

2012-05-01

Rituximab is a chimeric anti-CD20 monoclonal antibody. We aimed to explore the safety and tolerability of rapid infusion rituximab, (over 90 minutes) in patients with non-Hodgkin's lymphoma at Hacettepe University Department of Medical Oncology. Adult patients diagnosed with non-Hodgkin's lymphoma who were to receive rituximab were included in the study. The schedule of administration for cycle 1 was unaltered and delivered according to the product monograph. All subsequent cycles were administered over a total infusion time of 90 minutes (20% of the dose in the first 30 minutes, then the remaining 80% over 60 minutes, total dose delivered in 500 mL). All patients were observed for infusion-related reactions during the rituximab infusion, and vital signs were recorded every 15 minutes. From July 2006 to December 2008, 75 patients with non-Hodgkin's lymphoma were treated with rituximab-based chemotherapy. A total of 372 infusions were administered. The majority of patients were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, or rituximab only. The 90-minute rituximab infusion schedule was well tolerated, with no grade 3 or 4 infusion-related adverse events observed. A rapid infusion rituximab over 90 minutes is well tolerated and safe when administered as the second and subsequent infusions in the course of therapy.

Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing - A surrogate marker of brain penetration

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Kellie, SJ; Barbaric, D; Koopmans, P; Earl, J; Carr, DJ

2002-01-01

BACKGROUND. Vincristine (VCR) is used widely in oncology practice, and regular dosing is commonly associated with the development of sensorimotor or autonomic neuropathies. However, the incidence of VCR-related central nervous system (CNS) toxicity is comparatively low, suggesting that the

Successful hematopoietic stem cell transplantation following a cyclophosphamide-containing preparative regimen with concomitant phenobarbital administration.

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Weber, Catherine; Kasberg, Heather; Copelan, Edward

2012-01-01

Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial.

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Tap, William D; Papai, Zsuzsanna; Van Tine, Brian A; Attia, Steven; Ganjoo, Kristen N; Jones, Robin L; Schuetze, Scott; Reed, Damon; Chawla, Sant P; Riedel, Richard F; Krarup-Hansen, Anders; Toulmonde, Maud; Ray-Coquard, Isabelle; Hohenberger, Peter; Grignani, Giovanni; Cranmer, Lee D; Okuno, Scott; Agulnik, Mark; Read, William; Ryan, Christopher W; Alcindor, Thierry; Del Muro, Xavier F Garcia; Budd, G Thomas; Tawbi, Hussein; Pearce, Tillman; Kroll, Stew; Reinke, Denise K; Schöffski, Patrick

2017-08-01

Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m 2 via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m 2 intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to

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

International Nuclear Information System (INIS)

Reynolds, Joseph G.; Geretti, Elena; Hendriks, Bart S.; Lee, Helen; Leonard, Shannon C.; Klinz, Stephan G.; Noble, Charles O.; Lücker, Petra B.; Zandstra, Peter W.; Drummond, Daryl C.; Olivier, Kenneth J.; Nielsen, Ulrik B.; Niyikiza, Clet; Agresta, Samuel V.; Wickham, Thomas J.

2012-01-01

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

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: twickham@merrimackpharma.com [Merrimack Pharmaceuticals, 1 Kendall Square, Suite B7201, Cambridge, MA 02139 (United States)

2012-07-01

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

Echocardiographic changes in dogs long term treated with doxorubicin

International Nuclear Information System (INIS)

Silva, C.E.V.

2005-01-01

The doxorubicin's cardiotoxity was evaluated in seven clinically healthy adult dogs by means of intravenously injections of 30 mg/m2 of doxorubicin chloridate (Adriblastina), every 21 days, for 168 days (group A), performing a total cumulative dose of 240 mg/m2. Seven other dogs received 5 ml of 0.9% saline sterile solution intravenously (group B), following the protocol described above

The effects of Vitamin C on sperm quality parameters in laboratory rats following long-term exposure to cyclophosphamide.

Science.gov (United States)

Shabanian, Sheida; Farahbod, Farnoosh; Rafieian, Mahmoud; Ganji, Forouzan; Adib, Afshin

2017-01-01

Cyclophosphamide is a widely used medication and can cause oxidative stress. This study was conducted to investigate the effects of Vitamin C on reproductive organs' weight and the quality of sperm parameters in laboratory rats. In this experimental study, 40 rats were randomly assigned into five groups of eight each. Distilled water (DW) group received only food and water, Group 2 was administered with drug solvent (DW) by gavage, Group 3 intraperitoneally administered with 1.6 mg/kg cyclophosphamide, Group 4 gavaged Vitamin C at 0.88 mg/kg, and Group 5 administered with effective doses of Vitamin C and cyclophosphamide by gavage with 1-h intervals. Sperm parameters of the samples were taken from distal epididymis and tissues were studied, and the data were analyzed by SPSS version 22. The lowest weight of testicles and epididymis was seen in cyclophosphamide-exposed rats and the highest weight of testicles and epididymis in Vitamin C-exposed rats ( P < 0.05). The highest motility, progression, viability, and count of sperm were seen in the Vitamin C-treated group and the lowest in the cyclophosphamide-exposed group. The highest proportion of sperm anomalies was seen in the cyclophosphamide-exposed group. Vitamin C, as an antioxidant, can be effective on some of the sperm parameters and can reduce cyclophosphamide-induced complications in animal model.

The effects of Vitamin C on sperm quality parameters in laboratory rats following long-term exposure to cyclophosphamide

Directory of Open Access Journals (Sweden)

Sheida Shabanian

2017-01-01

Full Text Available Cyclophosphamide is a widely used medication and can cause oxidative stress. This study was conducted to investigate the effects of Vitamin C on reproductive organs' weight and the quality of sperm parameters in laboratory rats. In this experimental study, 40 rats were randomly assigned into five groups of eight each. Distilled water (DW group received only food and water, Group 2 was administered with drug solvent (DW by gavage, Group 3 intraperitoneally administered with 1.6 mg/kg cyclophosphamide, Group 4 gavaged Vitamin C at 0.88 mg/kg, and Group 5 administered with effective doses of Vitamin C and cyclophosphamide by gavage with 1-h intervals. Sperm parameters of the samples were taken from distal epididymis and tissues were studied, and the data were analyzed by SPSS version 22. The lowest weight of testicles and epididymis was seen in cyclophosphamide-exposed rats and the highest weight of testicles and epididymis in Vitamin C-exposed rats (P < 0.05. The highest motility, progression, viability, and count of sperm were seen in the Vitamin C-treated group and the lowest in the cyclophosphamide-exposed group. The highest proportion of sperm anomalies was seen in the cyclophosphamide-exposed group. Vitamin C, as an antioxidant, can be effective on some of the sperm parameters and can reduce cyclophosphamide-induced complications in animal model.

[Immunosuppressant effect of cyclophosphamide activated in vitro by liver microsomes from different strains of mice].

Science.gov (United States)

Telegin, L Iu; Zhirnov, G F; Mazurov, A V; Pevnitskiĭ, L A

1981-07-01

The paper is concerned with activation of cyclophosphamide by mouse liver microsomes in vitro. Liver microsomes from BALB/c mice metabolize cyclophosphamide more effectively as compared with those from DBA/2 mice, which manifested by a more intense output of products having alkylating or immunodepressant properties. This seems likely to be a consequence of the increased P-450 cytochrome content in liver microsomes from BALB/c mice, as well as of its structural characteristics in the mouse. The relationship between the immunodepressant effect of cyclophosphamide in vivo and in vitro in mice of varied genotypes is discussed.

A Novel Submicron Emulsion System Loaded with Doxorubicin Overcome Multi-Drug Resistance in MCF-7/ADR Cells.

Science.gov (United States)

Zhou, W P; Hua, H Y; Sun, P C; Zhao, Y X

2015-01-01

The purpose of the present study was to develop the Solutol HS15-based doxorubicin submicron emulsion with good stability and overcoming multi-drug resistance. In this study, we prepared doxorubicin submicron emulsion, and examined the stability after autoclaving, the in vitro cytotoxic activity, the intracellular accumulation and apoptpsis of doxorubicin submicron emulsion in MCF-7/ADR cells. The physicochemical properties of doxorubicin submicron emulsion were not significantly affected after autoclaving. The doxorubicin submicron emulsion significantly increased the intracellular accumulation of doxorubicin submicron emulsion and enhanced cytotoxic activity and apoptotic effects of doxorubicin. These results may be correlated to doxorubicin submicron emulsion inhibitory effects on efflux pumps through the progressive release of intracellular free Solutol HS15 from doxorubicin submicron emulsion. Furthermore, these in vitro results suggest that the Solutol HS15-based submicron emulsion may be a potentially useful drug delivery system to circumvent multi-drug resistance of tumor cells.

Combination Therapy With Pulse Cyclophosphamide Plus Corticosteroids Improves Renal Outcome In Patients With Lupus Nephritis

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H. Mansouri Torghabeh

2005-08-01

Full Text Available Background: The prognosis of SLE is int1uenced by the onset of glomerulonephtitis. Clinical ttials in lupus nephritis have demonstrated that cyclophosphamide therapy is the superior regimen in the management oflupus nephritis for preserving renal function.Objective:The purpose of this study is to define the outcome of renal function with bolus pu lses of cyclophosphamide and steroid according to our protocol and also to determine an appropriate pattern of treatment of lupus nephritis. Methods: In this open-label clinical triaL to evaluate the results, the short-term prognosis and the rate of complications of an immunosuppressive regimen with corticosteroids and cyclophosphamide, twenty-five patients with biopsy-proven lupus nephritis were studied. Treatment was structured in 4 phases: I Induction with bolus methylprednisolone and cyclophosphamide. 2 Maintenance with oral prednisolone for 4 weeks and monthly cyclophosphamide pulses for 6 months. 3 Tapeting with reduction of prednisolone by 10% each month and continuing cyclophosphamide every other month till one year and for the second year every 3 months. 4 Discontinuation with oral prednisolone slowly tapered to the least effective daily dose and cyclophosphamide discontinued after 2 yr of therapy. We defined primary outcome measures according to these criteria: renal function return to normal limits or become stable, regression of systemic and local inflammatory symptoms. urine protein excretion h1lling below 0.3 gr/ elL or by at least SOo/c. RBC cast disappearance, C3, C4, Hb, and ESR return to notmallimits. Result: Twenty-three patients wi th lupus nephritis completed our therapeutic protocol. Renal biopsy was perfonned in 22 cases and indicated type IV in 20 patients (95.2%, and type V in 2 patients. After an average of 4+ 1.95 months 22 patients achieved remission (95.65% and only one case remained non-responsive. She became pregnant in her fourth month of therapy. Significant

Chemomodulation of Doxorubicin Pharmacodynamics

Science.gov (United States)

2002-10-01

doxorubicin in athymic nude mice with multidrug resistant MCF-7 human tumor xenografts. High pressure liquid chromatography ( HPLC ) will be utilized to measure...is a flavonoid that causes 50% growth tumor growth support by the host (42). The clinical efficacy of inhibition of tumor cells at 60 nM (57). It also

Optimization of Doxorubicin Loading for Superabsorbent Polymer Microspheres: in vitro Analysis

International Nuclear Information System (INIS)

Liu, David M.; Kos, Sebastian; Buczkowski, Andrzej; Kee, Stephen; Munk, Peter L.; Klass, Darren; Wasan, Ellen

2012-01-01

Purpose: This study was designed to establish the ability of super-absorbent polymer microspheres (SAP) to actively uptake doxorubicin and to establish the proof of principle of SAP’s ability to phase transfer doxorubicin onto the polymer matrix and to elute into buffer with a loading method that optimizes physical handling and elution characteristics. Methods: Phase I: 50–100 μm SAP subject to various prehydration methods (normal saline 10 cc, hypertonic saline 4 cc, iodinated contrast 10 cc) or left in their dry state, and combined with 50 mg of clinical grade lyophilized doxorubicin reconstituted with various methods (normal saline 10 cc and 25 cc, sterile water 4 cc, iodinated contrast 5 cc) were placed in buffer and assessed based on loading, handling, and elution utilizing high-performance liquid chromatography (HPLC). Phase II: top two performing methods were subject to loading of doxorubicin (50, 75, 100 mg) in a single bolus (group A) or as a serial loading method (group B) followed by measurement of loading vs. time and elution vs. time. Results: Phase I revealed the most effective loading mechanisms and easiest handling to be dry (group A) vs. normal saline prehydrated (group B) SAP with normal saline reconstituted doxorubicin (10 mg/mL) with loading efficiencies of 83.1% and 88.4%. Phase II results revealed unstable behavior of SAP with 100 mg of doxorubicin and similar loading/elution profiles of dry and prehydrated SAP, with superior handling characteristics of group B SAP at 50 and 75 mg. Conclusions: SAP demonstrates the ability to load and bulk phase transfer doxorubicin at 50 and 75 mg with ease of handling and optimal efficiency through dry loading of SAP.

Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial.

Science.gov (United States)

Brain, Etienne G C; Mertens, Cécile; Girre, Véronique; Rousseau, Frédérique; Blot, Emmanuel; Abadie, Sophie; Uwer, Lionel; Bourbouloux, Emmanuelle; Van Praagh-Doreau, Isabelle; Mourey, Loic; Kirscher, Sylvie; Laguerre, Brigitte; Fourme, Emmanuelle; Luneau, Sylvia; Genève, Jean; Debled, Marc

2011-10-01

Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients' autonomy. In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or "high risk" pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete. Forty patients (median age 75 [70-82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred. This study demonstrates the feasibility of an adjuvant chemotherapy

Successful Hematopoietic Stem Cell Transplantation Following a Cyclophosphamide-Containing Preparative Regimen with Concomitant Phenobarbital Administration

Directory of Open Access Journals (Sweden)

Catherine Weber

2012-01-01

Full Text Available Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG, and total body irradiation (TBI followed by an allogeneic hematopoietic stem cell transplant (HSCT for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Bone marrow transplantation in aplastic anaemia using cyclophosphamide and total lymphoid irradiation

International Nuclear Information System (INIS)

Jansen, J.; Zwaan, F.E.; Noordijk, E.M.

1980-01-01

Six patients with severe aplastic anaemia received a bone-marrow graft after conditioning with cyclophosphamide and total lymphoid irradiation (TLI). No rejections occurred. Acute graft-versus-host disease developed in 3 patients and was fatal in one. Another patient died from systemic aspergillus infection. Chronic GVHD of the skin developed in a patient who was grafted with bone marrow from her HLA-phenotypically identical father. These data suggest that conditioning with cyclophosphamide and TLI is a promising regimen. (orig.) [de

Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin

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Wang, Feng [Department of Gastroenterology, The Tenth People’s Hospital of Shanghai, Tongji University, Shanghai 200072 (China); Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Yang, Yong, E-mail: yyang@houstonmethodist.org [Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Department of Medicine, Weill Cornell Medical College, New York, NY 10065 (United States)

2014-11-21

Highlights: • Suppression of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. • Repression of PKM2 affects the glycolysis and decreases ATP production. • Downregulation of PKM2 increases the intracellular accumulation of doxorubicin. • Inhibition of PKM2 enhances the antitumor efficacy of doxorubicin in vivo. - Abstract: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, we examined the effects of combined treatment with doxorubicin and anti-PKM2 small interfering RNA (siRNA) on triple-negative breast cancer (TNBC). The suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP resulted in the intracellular accumulation of doxorubicin, consequently enhancing the therapeutic efficacy of this drug in several triple-negative breast cancer cell lines. Furthermore, the combined effect of PKM2 siRNA and doxorubicin was evaluated in an in vivo MDA-MB-231 orthotopic breast cancer model. The siRNA was systemically administered through a polyethylenimine (PEI)-based delivery system that has been extensively used. We demonstrate that the combination treatment showed superior anticancer efficacy as compared to doxorubicin alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with TNBC.

Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP

DEFF Research Database (Denmark)

Xu-Monette, Zijun Y; Wu, Lin; Visco, Carlo

2012-01-01

TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. ...... for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies....

Radiation plus adjuvant CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) vs CCNU, hydroxyurea and vincristine in the treatment of malignant glioma

International Nuclear Information System (INIS)

Costanza, M.; Buechler, M.; Munzenreider, J.

1979-01-01

Following maximal surgery, 25 patients with malignant glioma were randomized to receive either radiation therapy and CCNU or radiation therapy and CCNU, hydroxyurea, and vincristine. Radiation therapy included 4000 rad to whole brain followed by 1500 rad to the primary. Chemotherapy was either: CCNU alone 130 mg/m 2 PO every 6 weeks or triple drug chemotherapy given in 6 week cycles of CCNU 90 mg/m 2 PO (one dose), vincristine 1 mg/m 2 IV (one dose), and hydroxyurea 1.5 gm/m 2 PO every 3 days x 7 doses. Thirteen patients received CCNU alone. Of these, 8 are dead, 2 are alive with progressive disease and 3 are alive with stable disease at 10, 22, and 23 months. Median survival is 10 months. Twelve patients received CCNU, vincristine and hydroxyurea. Of these, 8 are dead, 1 is alive with progressive disease and 3 are stable. Median survival is 9.5 months +. Toxicity included nausea, which was common, leukopenia < 3000 in 7 patients and thrombocytopenia in 9 patients. There were no episodes of bleeding or infection attributable to chemotherapy. Although toxicity was tolerable, no additional benefit could be demonstrated for triple agent chemotherapy with CCNU, vincristine and hydroxyurea compared to CCNU alone. Median survival for both groups was similar at 42 to 44 weeks

Browse Title Index

African Journals Online (AJOL)

Vol 107, No 11 (2017), Kaposi's sarcoma: Good outcome with doxorubicin, bleomycin and vincristine sulphate (ABV) chemotherapy and highly active antiretroviral therapy, Abstract PDF. P.B. Hesseling, E Katayi, P Wharin, R Bardin, F Kouya, D Palmer, M Glenn, M Kruger. Vol 47, No ... P. Jacobs, J.D.M. Richards. Vol 91, No ...

Pericardial Effusion

Science.gov (United States)

... heart was within the field of radiation Chemotherapy treatment for cancer, such as doxorubicin (Doxil) and cyclophosphamide Waste products in the blood due to kidney failure (uremia) Underactive thyroid (hypothyroidism) Viral, bacterial, fungal or parasitic infections Trauma or ...

Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial

DEFF Research Database (Denmark)

de Groot, Kirsten; Harper, Lorraine; Jayne, David R W

2009-01-01

BACKGROUND: Current therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are limited by toxicity. OBJECTIVE: To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission. DESIGN: Randomized, controlled trial. Random assignments were...... outcome); change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes). RESULTS: Groups did not differ in time to remission (hazard ratio, 1.098 [95% CI, 0.78 to 1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs. 87...... regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia. PRIMARY FUNDING SOURCE: The European Union....

Influence of definitive radiation therapy for primary breast cancer on ability to deliver adjuvant chemotherapy

International Nuclear Information System (INIS)

Lippman, M.E.; Edwards, B.K.; Findlay, P.; Danforth, D.W. Jr.; MacDonald, H.; D'Angelo, T.; Gorrell, C.

1986-01-01

Primary radiotherapy as a means of managing stage I and II breast cancer is receiving increasing attention. In a prospectively randomized trial comparing modified radical mastectomy to lumpectomy followed by definitive radiotherapy, we evaluated whether radiotherapy has a deleterious effect on the ability to administer adjuvant doxorubicin and cyclophosphamide to patients with histologically positive axillary lymph nodes. All patients were treated with an identical regimen, and doses were escalated to the same degree until myelosuppression occurred. There were no significant differences in the amount of chemotherapy administered to either treatment group. Patients in both groups received approximately 100% of the predicted dose of doxorubicin and approximately 117% of the predicted dose of cyclophosphamide. At present, we have no evidence that there are differences in recurrence rates as a function of the quantity of drug received, although longer follow-up is required

Dasatinib and Doxorubicin Treatment of Sarcoma Initiating Cells: A Possible New Treatment Strategy

Directory of Open Access Journals (Sweden)

Ninna Aggerholm-Pedersen

2016-01-01

Full Text Available Background. One of the major challenges affecting sarcoma treatment outcome, particularly that of metastatic disease, is resistance to chemotherapy. Cancer-initiating cells are considered a major contributor to this resistance. Methods. An immortalised nontransformed human stromal (mesenchymal stem cell line hMSC-TERT4 and a transformed cell line hMSC-TERT20-CE8, known to form sarcoma-like tumours when implanted in immune-deficient mice, were used as models. Receptor tyrosine kinase (RTK activation was analysed by RTK arrays and cellular viability after tyrosine kinases inhibitor (TKI treatment with or without doxorubicin was assessed by MTS assay. Results. Initial results showed that the hMSC-TERT4 was more doxorubicin-sensitive while hMSC-TERT20-CE8 was less doxorubicin-sensitive evidenced by monitoring cell viability in the presence of doxorubicin at different doses. The epidermal growth factor receptor (EGFR was activated in both cell lines. However hMSC-TERT20-CE8 exhibited significantly higher expression of the EGFR ligands. EGFR inhibitors such as erlotinib and afatinib alone or in combination with doxorubicin failed to further decrease cell viability of hMSC-TERT20-CE8. However, inhibition with the TKI dasatinib in combination with doxorubicin decreased cell viability of the hMSC-TERT20-CE8 cell line. Conclusion. Our results demonstrate that dasatinib, but not EGFR-directed treatment, can decrease cell viability of stromal cancer stem cells less sensitive to doxorubicin.

Dasatinib and Doxorubicin Treatment of Sarcoma Initiating Cells: A Possible New Treatment Strategy.

Science.gov (United States)

Aggerholm-Pedersen, Ninna; Demuth, Christina; Safwat, Akmal; Meldgaard, Peter; Kassem, Moustapha; Sandahl Sorensen, Boe

2016-01-01

Background. One of the major challenges affecting sarcoma treatment outcome, particularly that of metastatic disease, is resistance to chemotherapy. Cancer-initiating cells are considered a major contributor to this resistance. Methods. An immortalised nontransformed human stromal (mesenchymal) stem cell line hMSC-TERT4 and a transformed cell line hMSC-TERT20-CE8, known to form sarcoma-like tumours when implanted in immune-deficient mice, were used as models. Receptor tyrosine kinase (RTK) activation was analysed by RTK arrays and cellular viability after tyrosine kinases inhibitor (TKI) treatment with or without doxorubicin was assessed by MTS assay. Results. Initial results showed that the hMSC-TERT4 was more doxorubicin-sensitive while hMSC-TERT20-CE8 was less doxorubicin-sensitive evidenced by monitoring cell viability in the presence of doxorubicin at different doses. The epidermal growth factor receptor (EGFR) was activated in both cell lines. However hMSC-TERT20-CE8 exhibited significantly higher expression of the EGFR ligands. EGFR inhibitors such as erlotinib and afatinib alone or in combination with doxorubicin failed to further decrease cell viability of hMSC-TERT20-CE8. However, inhibition with the TKI dasatinib in combination with doxorubicin decreased cell viability of the hMSC-TERT20-CE8 cell line. Conclusion. Our results demonstrate that dasatinib, but not EGFR-directed treatment, can decrease cell viability of stromal cancer stem cells less sensitive to doxorubicin.

Multicenter study of environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in 48 Canadian hospitals.

Science.gov (United States)

Poupeau, Céline; Tanguay, Cynthia; Caron, Nicolas J; Bussières, Jean-François

2018-01-01

Context Oncology workers are occupationally exposed to antineoplastic drugs. This exposure can induce adverse health effects. In order to reduce their exposure, contamination on surfaces should be kept as low as possible. Objectives To monitor environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in oncology pharmacy and patient care areas in Canadian hospitals. To describe the impact of some factors that may limit contamination. Methods This is a descriptive study. Twelve standardized sites were sampled in each participating center (six in the pharmacy and six in patient care areas). Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography tandem mass spectrometry technology. Descriptive statistical analyses were done and results were compared with a Kolmogorov-Smirnov test for independent samples. Results In 2015, 48 hospitals participated in this study (48/202, 24%). Overall, 34% (181/525) of the samples were positive for cyclophosphamide, 8% (41/525) for ifosfamide, and 6% (31/525) for methotrexate. The 75th percentile value of cyclophosphamide surface concentration was 6.9 pg/cm 2 . For ifosfamide and methotrexate, they were lower than the limit of detection. Centers who prepared more antineoplastic drugs per year and centers who used more cyclophosphamide per year showed significantly higher surface contamination ( p contamination. Conclusion In comparison with other multicenter studies that were conducted in Canada, the concentration of antineoplastic drugs measured on surfaces is decreasing. Regular environmental monitoring is a good practice in order to maintain contamination as low as reasonably achievable.

Medicinal therapy of malignant lymphomas; Medikamentoese Therapie maligner Lymphome

Energy Technology Data Exchange (ETDEWEB)

Aul, C.; Schroeder, M.; Giagounidis, A. [Medizinische Klinik II, St.-Johannes-Hospital Duisburg (Germany)

2002-12-01

Chemotherapy represents the most important therapeutic option in malignant lymphomas. Low to intermediate risk Hodgkin's disease is treated by a combination of chemotherapy and radiation. The new chemotherapy protocol BEACOPP has improved the outcome of advanced stages in comparison with the internationally accepted standard protocol COPP/ABVD. Dependent on the initial staging, cure rates between 50 and 95% can be achieved. Indolent non-Hodgkin's lymphomas usually present in advanced stages of disease. Chemotherapy in these cases has palliative character and aims at improving patients'quality of life and at avoiding complications due to the disease. In aggressive and very aggressive non-Hodgkin's lymphoma chemotherapy is curative and must be initiated immediately irrespective of the staging results. The efficacy of the standard protocol CHOP (cyclophosphamide,doxorubicin, vincristine and prednisone), that was established in the 1970s, has recently been improved by shortening of the therapy interval (CHOP-14 vs.CHOP-21),addition of etoposide (CHOEP) and combination with the monoclonal antibody rituximab (R-CHOP). The value of high dose chemotherapy with stem cell transplantation has been shown unequivocally only for aggressive non-Hodgkin lymphoma and relapsed Hodgkin's disease responsive to chemotherapy. The therapeutic strategy of malignant lymphomas is likely to be improved within the next years due to the introduction of novel cytostatic agents, the broadening application of monoclonal antibodies,upcoming new transplantation procedures and the development of substances with molecular targets.To rapidly increase our current knowledge on the topic it is mandatory to include patients into the large national and international multicenter studies. (orig.) [German] Die Chemotherapie stellt die wichtigste Behandlungsoption maligner Lymphome dar. Bei Hodgkin-Lymphomen niedrigen bzw. intermediaeren Risikoprofils wird eine kombinierte Behandlung

Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore

Energy Technology Data Exchange (ETDEWEB)

Gharanei, M.; Hussain, A. [Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB (United Kingdom); Janneh, O. [Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB (United Kingdom); Pharmacology Research Laboratories, 70, Pembroke Place, The University of Liverpool, Liverpool. L69 3GF (United Kingdom); Maddock, H.L., E-mail: h.maddock@coventry.ac.uk [Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB (United Kingdom)

2013-04-15

Chemotherapeutic agents such as doxorubicin are known to cause or exacerbate cardiovascular cell death when an underlying heart condition is present. However, the mechanism of doxorubicin-induced cardiotoxicity is unclear. Here we assess the cardiotoxic effects of doxorubicin in conditions of myocardial ischaemia reperfusion and the mechanistic basis of protection, in particular the role of the mitochondrial permeability transition pore (mPTP) in such protection. The effects of doxorubicin (1 μM) ± cyclosporine A (CsA, 0.2 μM; inhibits mPTP) were investigated in isolated male Sprague–Dawley rats using Langendorff heart and papillary muscle contraction models subjected to simulated ischaemia and reperfusion injury. Isolated rat cardiac myocytes were used in an oxidative stress model to study the effects of drug treatment on mPTP by confocal microscopy. Western blot analysis evaluated the effects of drug treatment on p-Akt and p-Erk 1/2 levels. Langendorff and the isometric contraction models showed a detrimental effect of doxorubicin throughout reperfusion/reoxygenation as well as increased p-Akt and p-Erk levels. Interestingly, CsA not only reversed the detrimental effects of doxorubicin, but also reduced p-Akt and p-Erk levels. In the sustained oxidative stress assay to study mPTP opening, doxorubicin decreased the time taken to depolarization and hypercontracture, but these effects were delayed in the presence of CsA. Collectively, our data suggest for the first that doxorubicin exacerbates myocardial injury in an ischaemia reperfusion model. If the inhibition of mPTP ameliorates the cardiotoxic effects of doxorubicin, then more selective inhibitors of mPTP should be further investigated for their utility in patients receiving doxorubicin. - Highlights: ► Doxorubicin exacerbates myocardial ischaemia reperfusion injury. ► Co-treatment with CsA protects against doxorubicin induced myocardial injury. ► CsA delays doxorubicin induced mPTP opening in laser

Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore

International Nuclear Information System (INIS)

Gharanei, M.; Hussain, A.; Janneh, O.; Maddock, H.L.

2013-01-01

Chemotherapeutic agents such as doxorubicin are known to cause or exacerbate cardiovascular cell death when an underlying heart condition is present. However, the mechanism of doxorubicin-induced cardiotoxicity is unclear. Here we assess the cardiotoxic effects of doxorubicin in conditions of myocardial ischaemia reperfusion and the mechanistic basis of protection, in particular the role of the mitochondrial permeability transition pore (mPTP) in such protection. The effects of doxorubicin (1 μM) ± cyclosporine A (CsA, 0.2 μM; inhibits mPTP) were investigated in isolated male Sprague–Dawley rats using Langendorff heart and papillary muscle contraction models subjected to simulated ischaemia and reperfusion injury. Isolated rat cardiac myocytes were used in an oxidative stress model to study the effects of drug treatment on mPTP by confocal microscopy. Western blot analysis evaluated the effects of drug treatment on p-Akt and p-Erk 1/2 levels. Langendorff and the isometric contraction models showed a detrimental effect of doxorubicin throughout reperfusion/reoxygenation as well as increased p-Akt and p-Erk levels. Interestingly, CsA not only reversed the detrimental effects of doxorubicin, but also reduced p-Akt and p-Erk levels. In the sustained oxidative stress assay to study mPTP opening, doxorubicin decreased the time taken to depolarization and hypercontracture, but these effects were delayed in the presence of CsA. Collectively, our data suggest for the first that doxorubicin exacerbates myocardial injury in an ischaemia reperfusion model. If the inhibition of mPTP ameliorates the cardiotoxic effects of doxorubicin, then more selective inhibitors of mPTP should be further investigated for their utility in patients receiving doxorubicin. - Highlights: ► Doxorubicin exacerbates myocardial ischaemia reperfusion injury. ► Co-treatment with CsA protects against doxorubicin induced myocardial injury. ► CsA delays doxorubicin induced mPTP opening in laser

Bortezomib interactions with chemotherapy agents in acute leukemia in vitro.

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Horton, Terzah M; Gannavarapu, Anurhadha; Blaney, Susan M; D'Argenio, David Z; Plon, Sharon E; Berg, Stacey L

2006-07-01

Although there is effective chemotherapy for many patients with leukemia, 20% of children and up to 65% of adults relapse. Novel therapies are needed to treat these patients. Leukemia cells are very sensitive to the proteasome inhibitor bortezomib (VELCADE(R), PS-341), which enhances the in vitro cytotoxic effects of dexamethasone and doxorubicin in multiple myeloma. To determine if bortezomib enhances the cytotoxicity of agents used in leukemia, we employed an in vitro tetrazolium-based colorimetric assay (MTT) to evaluate the cytotoxic effects of bortezomib alone and in combination with dexamethasone, vincristine, doxorubicin, cytarabine, asparaginase, geldanamycin, trichostatin A, and the bcl-2 inhibitor HA14.1. We demonstrated that primary leukemia lymphoblasts and leukemia cell lines are sensitive to bortezomib, with an average IC(50) of 12 nM. Qualitative and quantitative bortezomib-drug interactions were evaluated using the universal response surface approach (URSA). Bortezomib was synergistic with dexamethasone in dexamethasone-sensitive leukemia cells, and additive with vincristine, asparaginase, cytarabine, and doxorubicin. The anti-leukemic activity of bortezomib was also additive with geldanamycin and HA14.1, and additive or synergistic with trichostatin A. These results were compared to analysis using the median-dose effect method, which generated complex drug interactions due to differences in dose-response curve sigmoidicities. These data suggest bortezomib could potentiate the cytotoxic effects of combination chemotherapy in patients with leukemia.

Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes

OpenAIRE

Karagiannis, Tom C; Lin, Ann JE; Ververis, Katherine; Chang, Lisa; Tang, Michelle M; Okabe, Jun; El-Osta, Assam

2010-01-01

Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubic...

Schedule-dependency of doxorubicin and vinblastine in EAT tumours in mice

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Auersperg, M.; Pogacnik, A.; Kloboves-Prevodnik, V.; Sersa, G.; Cemazar, M.

2006-01-01

Background. Antitumour schedule-dependency of the doxorubicin and vinblastine combination was explored. Materials and methods. Intraperitoneal Ehrlich ascites tumours (EAT) syngeneic to CBA mice were treated with vinblastine or doxorubicin alone, or in combined treatment schedules. Results. Combinations of doxorubicin and vinblastine administered at 48-h, but not at 24-h interval, regardless of the sequence of drugs, significantly reduced the number of tumour cells in the ascites in comparison with all other treatments. In the combined treatment schedules, the predominant morphological changes as well as DNA distribution pattern were dependent on the first drug applied. Regardless of the sequence of the drugs, median survival times of animals did not significantly differ between the treatment groups. Conclusions. The effect of combination of vinblastine and doxorubicin is schedule-dependent. The time interval, but not the sequence of drugs seems to be crucial for the observed effect. The data from preclinical studies are important for planning combined treatment schedules in clinical setting. (author)

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.

High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity

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Mitra, Mayurranjan S.; Donthamsetty, Shashikiran; White, Brent; Mehendale, Harihara M.

2008-01-01

Often, chemotherapy by doxorubicin (Adriamycin) is limited due to life threatening cardiotoxicity in patients during and posttherapy. Recently, we have shown that moderate diet restriction remarkably protects against doxorubicin-induced cardiotoxicity. This cardioprotection is accompanied by decreased cardiac oxidative stress and triglycerides and increased cardiac fatty-acid oxidation, ATP synthesis, and upregulated JAK/STAT3 pathway. In the current study, we investigated whether a physiological intervention by feeding 40% high fat diet (HFD), which induces obesity in male Sprague-Dawley rats (250-275 g), sensitizes to doxorubicin-induced cardiotoxicity. A LD 10 dose (8 mg doxorubicin/kg, ip) administered on day 43 of the HFD feeding regimen led to higher cardiotoxicity, cardiac dysfunction, lipid peroxidation, and 80% mortality in the obese (OB) rats in the absence of any significant renal or hepatic toxicity. Doxorubicin toxicokinetics studies revealed no change in accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the normal diet-fed (ND) and OB hearts. Mechanistic studies revealed that OB rats are sensitized due to: (1) higher oxyradical stress leading to upregulation of uncoupling proteins 2 and 3, (2) downregulation of cardiac peroxisome proliferators activated receptor-α, (3) decreased plasma adiponectin levels, (4) decreased cardiac fatty-acid oxidation (666.9 ± 14.0 nmol/min/g heart in ND versus 400.2 ± 11.8 nmol/min/g heart in OB), (5) decreased mitochondrial AMP-α2 protein kinase, and (6) 86% drop in cardiac ATP levels accompanied by decreased ATP/ADP ratio after doxorubicin administration. Decreased cardiac erythropoietin and increased SOCS3 further downregulated the cardioprotective JAK/STAT3 pathway. In conclusion, HFD-induced obese rats are highly sensitized to doxorubicin-induced cardiotoxicity by substantially downregulating cardiac mitochondrial ATP generation, increasing oxidative stress and downregulating the JAK/STAT3

Transcriptional profiling provides insights into metronomic cyclophosphamide-activated, innate immune-dependent regression of brain tumor xenografts

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Doloff, Joshua C; Waxman, David J

2015-01-01

Cyclophosphamide treatment on a six-day repeating metronomic schedule induces a dramatic, innate immune cell-dependent regression of implanted gliomas. However, little is known about the underlying mechanisms whereby metronomic cyclophosphamide induces innate immune cell mobilization and recruitment, or about the role of DNA damage and cell stress response pathways in eliciting the immune responses linked to tumor regression. Untreated and metronomic cyclophosphamide-treated human U251 glioblastoma xenografts were analyzed on human microarrays at two treatment time points to identify responsive tumor cell-specific factors and their upstream regulators. Mouse microarray analysis across two glioma models (human U251, rat 9L) was used to identify host factors and gene networks that contribute to the observed immune and tumor regression responses. Metronomic cyclophosphamide increased expression of tumor cell-derived DNA damage, cell stress, and cell death genes, which may facilitate innate immune activation. Increased expression of many host (mouse) immune networks was also seen in both tumor models, including complement components, toll-like receptors, interferons, and cytolysis pathways. Key upstream regulators activated by metronomic cyclophosphamide include members of the interferon, toll-like receptor, inflammatory response, and PPAR signaling pathways, whose activation may contribute to anti-tumor immunity. Many upstream regulators inhibited by metronomic cyclophosphamide, including hypoxia-inducible factors and MAP kinases, have glioma-promoting activity; their inhibition may contribute to the therapeutic effectiveness of the six-day repeating metronomic cyclophosphamide schedule. Large numbers of responsive cytokines, chemokines and immune regulatory genes linked to innate immune cell recruitment and tumor regression were identified, as were several immunosuppressive factors that may contribute to the observed escape of some tumors from metronomic CPA

Seven-Year Follow-Up Assessment of Cardiac Function in NSABP B-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab As Adjuvant Therapy for Patients With Node-Positive, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

Science.gov (United States)

Romond, Edward H.; Jeong, Jong-Hyeon; Rastogi, Priya; Swain, Sandra M.; Geyer, Charles E.; Ewer, Michael S.; Rathi, Vikas; Fehrenbacher, Louis; Brufsky, Adam; Azar, Catherine A.; Flynn, Patrick J.; Zapas, John L.; Polikoff, Jonathan; Gross, Howard M.; Biggs, David D.; Atkins, James N.; Tan-Chiu, Elizabeth; Zheng, Ping; Yothers, Greg; Mamounas, Eleftherios P.; Wolmark, Norman

2012-01-01

Purpose Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. Patients and Methods In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified. Results At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. Conclusion The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab. PMID:22987084

Sialic acid changes in Dalton's lymphoma-bearing mice after cyclophosphamide and cisplatin treatment

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Nicol B.M.

2002-01-01

Full Text Available Sialic acid changes in Dalton's lymphoma cells and other tissues of 10-12-week-old Swiss albino mice were investigated in relation to tumour growth in vivo and following cyclophosphamide (ip, 200 mg/kg body weight or cisplatin (ip, 8 mg/kg body weight treatment. Three to four animals of both sexes were used in each experimental group. The sialic acid level of tumour cells (0.88 µmol/g increased with tumour progression (1.44-1.59 µmol/g; P<=0.05 in mice. Sialic acid concentration in other tissues (liver, kidney, testes and brain also increased (~40, 10, 30 and 58%, respectively in the tumour-bearing hosts as compared with that in the respective tissues of normal mice. In vivo cyclophosphamide or cisplatin treatment resulted in an overall decrease of sialic acid contents in the tissues. Cyclophosphamide was more efficient in lowering tissue sialic acid than cisplatin (P<=0.01, ANOVA. It is suggested that sialic acid residues could be an important factor contributing to the manifestation of malignant properties in cancer cells in general and Dalton's lymphoma cells in particular. A significant decrease in the sialic acid content of Dalton's lymphoma cells after cisplatin or cyclophosphamide treatment may bring about specific changes in tumour cells which could be associated with tumour regression.

Amifostine reduces the seminiferous epithelium damage in doxorubicin-treated prepubertal rats without improving the fertility status

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Miraglia Sandra M

2010-01-01

Full Text Available Abstract Background Amifostine is an efficient cytoprotector against toxicity caused by some chemotherapeutic drugs. Doxorubicin, a potent anticancer anthracycline, is known to produce spermatogenic damage even in low doses. Although some studies have suggested that amifostine does not confer protection to doxorubicin-induced testicular damage, schedules and age of treatment have different approach depending on the protocol. Thus, we proposed to investigate the potential cytoprotective action of amifostine against the damage provoked by doxorubicin to prepubertal rat testes (30-day-old by assessing some macro and microscopic morphometric parameters 15, 30 and 60 days after the treatment; for fertility evaluation, quantitative analyses of sperm parameters and reproductive competence in the adult phase were also carried out. Methods Thirty-day-old male rats were distributed into four groups: Doxorubicin (5 mg/kg, Amifostine (400 mg/kg, Amifostine/Doxorubicin (amifostine 15 minutes before doxorubicin and Sham Control (0.9% saline solution. "Standard One Way Anova" parametric and "Anova on Ranks" non-parametric tests were applied according to the behavior of the obtained data; significant differences were considered when p Results The rats killed 30 and 60 days after doxorubicin treatment showed diminution of seminiferous epithelium height and reduction on the frequency of tubular sections containing at least one type of differentiated spermatogonia; reduction of sperm concentration and motility and an increase of sperm anomalous forms where observed in doxorubicin-treated animals. All these parameters were improved in the Amifostine/Doxorubicin group only when compared to Doxorubicin group. Such reduction, however, still remained below the values obtained from the Sham Control group. Nevertheless, the reproductive competence of doxorubicin-treated rats was not improved by amifostine pre-administration. Conclusions These results suggest that

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.

2009-01-01

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

New approaches in the management of advanced breast cancer – role of combination treatment with liposomal doxorubicin

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Iain RJ Macpherson

2009-08-01

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

[Cytogenetic effect of cyclophosphamide in a culture of human lymphocytes following its activation in the bodies of mice].

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Chebotarev, A N; Telegin, L I; Derzhavets, E M

1976-01-01

Cytogenetic effect of cyclophosphamide in cultured human lymphocytes after its activation in C57BL/6 mice in vivo was investigated. Cyclophosphamide was injected intraperitoneally in mice for 30 min. at doses of 200, 400, 600, 800 and 1000 mg/kg. Blood serum with activated metabolites of cyclophosphamide was added to human lymphocyte culture. The dependence of the part of aberrant metaphases on the concentration of cyclophosphamide after the activation can be presented as equation rho==1-e-(KC+alpha)2 and the total number of breaks as X=e(KC+alpha)2-1, where rho is a part of aberrant metaphases, X is a number of breaks of chromosomes per cell, C is the concentration, K and alpha are coefficients. The part of chromatid breaks from the total number of chromosome damages is constant for all concentrations and the comprises on the average 79,11%. Only the chromatid type of exchanges are observed. Distribution of chromosome breaks in cells corresponds to geometrical, but not to Poisson's distribution. Cyclophosphamide belongs to the group of one-sited mutagens in its cytogenetic chatacteristics. The alkylating activity of cyclophosphamide metabolites, estimated by means of NBP test, increases up to the dose 400 mg/kg and then remains constant for the strain of mice studied, cytogenetic activity increasing. Cyclophosphamide does not produce cytogenetic activity without activation. To test chemical substances for mutagenic activity, it is suggested to activate them in the mouse organism with the following administrating blood serum of these animals with the metabolites of tested (or with primary) substances in the study of their mutagenic activity on human lymphocyte culture.

Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

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Lee, Kwang-Hun; Liapi, Eleni A; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A; Ventura, Veronica Prieto; Geschwind, Jean-Francois H

2010-06-01

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

International Nuclear Information System (INIS)

Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A.; Ventura, Veronica Prieto; Geschwind, Jean-Francois H.

2010-01-01

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

Role of metabolites of cyclophosphamide in cardiotoxicity

OpenAIRE

Kurauchi, Koichiro; Nishikawa, Takuro; Miyahara, Emiko; Okamoto, Yasuhiro; Kawano, Yoshifumi

2017-01-01

Background The dose-limiting toxic effect of cyclophosphamide (CY) is cardiotoxicity. The pathogenesis of myocardial damage is poorly understood, and there is no established means of prevention. In previous studies, we suggested that for CY-induced cardiotoxicity, whereas acrolein is the key toxic metabolite, carboxyethylphosphoramide mustard (CEPM) is protective. We sought to verify that acrolein is the main cause of cardiotoxicity and to investigate whether aldehyde dehydrogenase (ALDH), wh...

Partial splenic embolization combined with vincristine infusion for the treatment of refractory idiopathic thrombocytopenic purpura and Evans syndrome: observation of its long-term efficacy

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Chen Shibing

2011-01-01

Objective: To observe the long-term efficacy of partial spleen embolization combined with vincristine infusion in treating refractory idiopathic thrombocytopenic purpura (ITP) and Evans syndrome. Methods: During the period of 2000-2007, partial spleen embolization together with vincristine infusion was carried out in 30 patients with refractory idiopathic thrombocytopenic purpura (n=24) or Evans syndrome (n=6). Vincristine infusion (2 mg) via splenic artery was performed before partial spleen embolization procedure. The long-term effectiveness was observed and analyzed. Results: One week after the treatment, the platelet count was increased from preoperative (10.23±8.28) × 10 9 /L to (140.28±85.45) × 10 9 /L in patients with ITP, while the platelet count was increased from preoperative (12±8) × 10 9 /L to (210±60) × 10 9 /L in patients with Evans syndrome. Meanwhile, the hemoglobin level showed an increase in different degrees, from preoperative (63.00±13.62) g/L to postoperative (123.00±13.14) g/L. The therapeutic effectiveness was 100%. During the follow-up time lasting for 3-5 years, recurrence was seen in 11 patients (36.7%) and the overall efficacy rate was 63.3%. Conclusion: For the treatment of refractory idiopathic thrombocytopenic purpura and Evans syndrome, partial spleen embolization combined with vincristine infusion carries reliable long-term efficacy. (author)

Impact of lymphoma treatments on spermatogenesis and sperm deoxyribonucleic acid: a multicenter prospective study from the CECOS network.

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Bujan, Louis; Walschaerts, Marie; Brugnon, Florence; Daudin, Myriam; Berthaut, Isabelle; Auger, Jacques; Saias, Jacqueline; Szerman, Ethel; Moinard, Nathalie; Rives, Nathalie; Hennebicq, Sylvianne

2014-09-01

To determine consequences of lymphoma treatments on sperm characteristics and sperm DNA, and to evaluate predictors of sperm recovery. Multicenter prospective longitudinal study of patients analyzed before treatment and after 3, 6, 12, and 24 months. University hospitals. Seventy-five Hodgkin lymphoma and non-Hodgkin lymphoma patients and a control group of 257 fertile men. Semen analyses, and sperm DNA and chromatin assessments. Comparisons of sperm characteristics before and after treatment. Patients already had altered sperm characteristics before lymphoma treatment, with no identified risk factor. Sperm count, total sperm count, motility, and vitality decreased after treatment, with lowest values at 3 and 6 months. Twelve months after treatment, mean sperm count recovered to pretreatment values after doxorubicin, bleomycin, vinblastine, darcarbacine (ABVD) or ABVD+radiotherapy, but not after doxorubicin, cyclophosphamide, vincristine, prednisone (CHOP) or mechlorethamine, oncovin, procarbazine, prednisone (MOPP) chemotherapies. It was noteworthy that 7% of patients remained azoospermic at 24 months. After 24 months, Kaplan-Meier estimates showed that more than 90% of patients will recover normal sperm count after ABVD or ABVD+radiotherapy vs. 61% for CHOP chemotherapies. In multivariate analyses including diagnosis and treatment protocol, only pretreatment total sperm count was related to recovery. Compared with a control group, lymphoma patients had higher sperm chromatin alterations and DNA fragmentation before any treatment. After treatment, DNA fragmentation assessed by TUNEL assay and sperm chromatin structure assay decreased from 3 and 6 months, respectively, while remaining higher than in the control group during follow-up. Lymphoma patients had altered sperm DNA and chromatin before treatment. Lymphoma treatment had damaging effects on spermatogenesis. These data on both the recovery period according to treatment modalities and the pre- and post

Adult T-cell leukemia/lymphoma treatment in Bahia, Brazil

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Pedro Dantas Oliveira

Full Text Available Abstract Background: Adult T-cell leukemia/lymphoma is a peripheral disease associated with human T-cell lymphotropic virus type 1. Treatment is carried out according to clinical type with watchful waiting being recommended for less aggressive types. Aggressive adult T-cell leukemia/lymphoma is generally treated with chemotherapy and/or antivirals. The objective of this study was to correlate the survival of patients diagnosed in Bahia, Brazil, with the therapeutic approaches employed and to evaluate what issues existed in their treatment processes. Methods: Eighty-three adult T-cell leukemia/lymphoma patients (26 smoldering, 23 chronic, 16 acute, 13 lymphoma and five primary cutaneous tumoral with available data were included in this study. Results: Complete response was achieved in seven smoldering patients with symptomatic treatment, in two with chronic disease using antivirals/chemotherapy, in one with acute disease using antivirals and in one lymphoma using the LSG15 regimen [vincristine, cyclophosphamide, doxorubicin, and prednisolone (VCAP; doxorubicin, ranimustine, and prednisolone (AMP; and vindesine, etoposide, carboplatin, and prednisolone (VECP]. Smoldering patients who received symptomatic treatment presented longer survival. Favorable chronic patients treated with antivirals presented longer survival compared to the unfavorable subtype. However, for the acute form, first-line chemotherapy was better, albeit without significance, than antivirals. Only one of the patients with lymphoma and primary cutaneous tumors responded. Conclusions: Watchful waiting associated with phototherapy represents the best option for smoldering adult T-cell leukemia/lymphoma with survival in Bahia being superior to that described in Japan. There was a trend of better results with zidovudine/interferon-alpha in favorable chronic disease. Excellent results were achieved in the lymphoma type treated with the LSG15 protocol. Patients are diagnosed late

Microarray based comparative genome-wide expression profiling of ...

African Journals Online (AJOL)

pg

2014-03-05

Mar 5, 2014 ... 45/F. ALL. 18/M. Fever, anaemia, enlarge lymph glands in children. Child having >50-60% blast cells in. TLC, TLC >20,000/cm mm. Vincristine (1.5 mg/m2), doxorubicin (25 mg/m2), prednisone. (40 mg/m2),. L-asparaginase (10,000 units iv/ alternate day), methotrexate. (12 mg/m2intrathecal). ALL. 6/M. ALL.

Effect of citral on the cytotoxicity of doxorubicin in human B-lymphoma cells.

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Dangkong, Darinee; Limpanasithikul, Wacharee

2015-02-01

Doxorubicin is a chemotherapy agent used in non-Hodgkin's lymphoma but side effects limit its use. Citral is a mixture of neral and geranial found in essential oils of lemon grass. We evaluated the activity of citral, doxorubicin, and combination on cytotoxicity, apoptosis, and anti-proliferative effects using human lymphoma Ramos cells. Cells were treated with doxorubicin alone or in combination with citral (10, 20, and 40 μM). Cytotoxic and apoptosis studies were done after 24 and 18 h incubations, respectively. Cytotoxic effects of citral on normal human peripheral blood mononuclear cells (PBMCs) were also investigated for its safety. Changes in the expression of BCL-2 family genes were analyzed by quantitative RT-PCR. Citral had cytotoxicity on cells with an IC50 value of 77.19 ± 4.95 µM. Citral at concentrations of 10, 20, and 40 µM additively increased the cytotoxic and apoptotic effects of doxorubicin, leading to decreased IC50 (µM) of the drug from 2.50 ± 0.01 to 2.16 ± 0.03, 1.90 ± 0.04, and 1.23 ± 0.04, respectively. Enhanced cytotoxicity was not observed in normal human PBMCs. Citral (40 µM) in combination with doxorubicin (1.5 µM) increased the expression of pro-apoptotic protein BAK but significantly decreased the expression of anti-apoptotic protein BCL-XL to 5.26-fold compared with doxorubicin-treated cells. It did not change the anti-proliferative activity of drug. Citral potentiated cytotoxicity of doxorubicin by increasing apoptotic effects. We conclude that citral may have beneficial effects in patients with B cell lymphoma treated with chemotherapy.

The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors

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Patel, Krupa J; Tannock, Ian F

2009-01-01

Anti-cancer drugs access solid tumors via blood vessels, and must penetrate tumor tissue to reach all cancer cells. Previous studies have demonstrated steep gradients of decreasing doxorubicin fluorescence with increasing distance from blood vessels, such that many tumor cells are not exposed to drug. Studies using multilayered cell cultures show that increased P-glycoprotein (PgP) is associated with better penetration of doxorubicin, while PgP inhibitors decrease drug penetration in tumor tissue. Here we evaluate the effect of PgP expression on doxorubicin distribution in vivo. Mice bearing tumor sublines with either high or low expression of PgP were treated with doxorubicin, with or without pre-treatment with the PgP inhibitors verapamil or PSC 833. The distribution of doxorubicin in relation to tumor blood vessels was quantified using immunofluorescence. Our results indicate greater uptake of doxorubicin by cells near blood vessels in wild type as compared to PgP-overexpressing tumors, and pre-treatment with verapamil or PSC 833 increased uptake in PgP-overexpressing tumors. However, there were steeper gradients of decreasing doxorubicin fluorescence in wild-type tumors compared to PgP overexpressing tumors, and treatment of PgP overexpressing tumors with PgP inhibitors led to steeper gradients and greater heterogeneity in the distribution of doxorubicin. PgP inhibitors increase uptake of doxorubicin in cells close to blood vessels, have little effect on drug uptake into cells at intermediate distances, and might have a paradoxical effect to decrease doxorubicin uptake into distal cells. This effect probably contributes to the limited success of PgP inhibitors in clinical trials

OS7.7 Feasibility and toxicity of concomitant radiochemotherapy with vincristine in adult patients with medulloblastoma - results from the NOA-07 trial

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Seidel, C.; Reimers, C.; Beier, D.; Pietsch, T.; Warmuth-Metz, M.; Bogdahn, U.; Kortmann, R.; Hau, P.

2016-01-01

Abstract Introduction: Medulloblastoma is a tumor of the cerebellum that is rare in adults with an incidence of about 0.6 cases per million per year. In children the introduction of chemotherapy with cisplatin, lomustine and vincristine in combination with craniospinal radiotherapy led to a significant improvement of overall survival. In adults, this regimen was never prospectively investigated in a clinical trial. Methods. The NOA-07 trial is a prospective single arm Phase II study to evaluate toxicity of craniospinal irradiation (1.6 Gy/35.2 Gy, posterior fossa boost 1.8 Gy/55.0 Gy) in combination with vincristine (1.5 mg/m2 weekly, ceiling dose 2.0 mg) followed by adjuvant chemotherapy with a maximum 8 of 6-weekly cycles of cisplatin (70 mg/m2, day 1), lomustine (75 mg/m2, day 1) and vincristine (1.5 g/m2, ceiling dose 2.0 mg, day 1, 8, 15) in adults with medulloblastoma. Here, we report on feasibility and toxicity of the concomitant radiochemotherapy. Results. 30 patients with medulloblastoma were recruited in 15 German centers. Radiotherapy was completed in all patients. Treatment interruptions occurred in 3/30 patients (toxicity related: 2, compliance: 1). Leukopenia was the major toxicity with grade 3 and 4 (CTC Version 3.0) occurring in 11 of 30 patients and 1 of 30 patients, respectively. Grade 3 to 4 thrombocytopenia occurred in 1 patient. Grade 3 to 4 infections occurred in 3 patients. Polyneuropathy due to vincristine was the most prevalent adverse event (Grade 1: 5, Grade 2: 4, Grade 3: 5 of 30 patients). Frequent but less severe toxicities involved sickness, dermatitis and alopecia. Conclusion. Concomitant radiochemotherapy with vincristine was feasible in adults with medulloblastoma. Leukopenia and polyneuropathy are major complications, pointing out that polyneuropathy occurs already early in treatment after application of only 1 to 6 doses in a substantial number of patients. Toxicity of the complete treatment protocol including

S-diclofenac Protects against Doxorubicin-Induced Cardiomyopathy in Mice via Ameliorating Cardiac Gap Junction Remodeling

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Zhang, Huili; Zhang, Alian; Guo, Changfa; Shi, Chunzhi; Zhang, Yang; Liu, Qing; Sparatore, Anna; Wang, Changqian

2011-01-01

Hydrogen sulfide (H2S), as a novel gaseous mediator, plays important roles in mammalian cardiovascular tissues. In the present study, we investigated the cardioprotective effect of S-diclofenac (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester), a novel H2S-releasing derivative of diclofenac, in a murine model of doxorubicin-induced cardiomyopathy. After a single dose injection of doxorubicin (15 mg/kg, i.p.), male C57BL/6J mice were given daily treatment of S-diclofenac (25 and 50 µmol/kg, i.p.), diclofenac (25 and 50 µmol/kg, i.p.), NaHS (50 µmol/kg, i.p.), or same volume of vehicle. The cardioprotective effect of S-diclofenac was observed after 14 days. It showed that S-diclofenac, but not diclofenac, dose-dependently inhibited the doxorubicin-induced downregulation of cardiac gap junction proteins (connexin 43 and connexin 45) and thus reversed the remodeling of gap junctions in hearts. It also dose-dependently suppressed doxorubicin-induced activation of JNK in hearts. Furthermore, S-diclofenac produced a dose-dependent anti-inflammatory and anti-oxidative effect in this model. As a result, S-diclofenac significantly attenuated doxorubicin-related cardiac injury and cardiac dysfunction, and improved the survival rate of mice with doxorubicin-induced cardiomyopathy. These effects of S-diclofenac were mimicked in large part by NaHS. Therefore, we propose that H2S released from S-diclofenac in vivo contributes to the protective effect in doxorubicin-induced cardiomyopathy. These data also provide evidence for a critical role of H2S in the pathogenesis of doxorubicin-induced cardiomyopathy. PMID:22039489

Interactions between N-acetyl-L-cysteine protected CdTe quantum dots and doxorubicin through spectroscopic method

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Yang, Xiupei, E-mail: xiupeiyang@163.com [Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, Nanchong 637000 (China); College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637000 (China); Lin, Jia; Liao, Xiulin; Zong, Yingying; Gao, Huanhuan [College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637000 (China)

2015-06-15

Highlights: • CdTe quantum dots with the diameter of 3–5 nm were synthesized in aqueous solution. • The modified CdTe quantum dots showed well fluorescence properties. • The interaction between the CdTe quantum dots and doxorubicin (DR) was investigated. - Abstract: N-acetyl-L-cysteine protected cadmium telluride quantum dots with a diameter of 3–5 nm were synthesized in aqueous solution. The interaction between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin was investigated by ultraviolet–visible absorption and fluorescence spectroscopy at physiological conditions (pH 7.2, 37 °C). The results indicate that electron transfer has occurred between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin under light illumination. The quantum dots react readily with doxorubicin to form a N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex via electrostatic attraction between the −NH{sub 3}{sup +} moiety of doxorubicin and the −COO{sup −} moiety of N-acetyl-L-cysteine/cadmium telluride quantum dots. The interaction of N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex with bovine serum albumin was studied as well, showing that the complex might induce the conformation change of bovine serum due to changes in microenvironment of bovine serum.

Interactions between N-acetyl-L-cysteine protected CdTe quantum dots and doxorubicin through spectroscopic method

International Nuclear Information System (INIS)

Yang, Xiupei; Lin, Jia; Liao, Xiulin; Zong, Yingying; Gao, Huanhuan

2015-01-01

Highlights: • CdTe quantum dots with the diameter of 3–5 nm were synthesized in aqueous solution. • The modified CdTe quantum dots showed well fluorescence properties. • The interaction between the CdTe quantum dots and doxorubicin (DR) was investigated. - Abstract: N-acetyl-L-cysteine protected cadmium telluride quantum dots with a diameter of 3–5 nm were synthesized in aqueous solution. The interaction between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin was investigated by ultraviolet–visible absorption and fluorescence spectroscopy at physiological conditions (pH 7.2, 37 °C). The results indicate that electron transfer has occurred between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin under light illumination. The quantum dots react readily with doxorubicin to form a N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex via electrostatic attraction between the −NH 3 + moiety of doxorubicin and the −COO − moiety of N-acetyl-L-cysteine/cadmium telluride quantum dots. The interaction of N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex with bovine serum albumin was studied as well, showing that the complex might induce the conformation change of bovine serum due to changes in microenvironment of bovine serum

Zinc-Modified Nanotransporter of Doxorubicin for Targeted Prostate Cancer Delivery

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Sylvie Skalickova

2017-12-01

Full Text Available This work investigated the preparation of chitosan nanoparticles used as carriers for doxorubicin for targeted cancer delivery. Prepared nanocarriers were stabilized and functionalized via zinc ions incorporated into the chitosan nanoparticle backbone. We took the advantage of high expression of sarcosine in the prostate cancer cells. The prostate cancer targeting was mediated by the AntiSar antibodies decorated surface of the nanocage. Formation of the chitosan nanoparticles was determined using a ninhydrin assay and differential pulse voltammetry. Obtained results showed the strong effect of tripolyphosphine on the nanoparticle formation. The zinc ions affected strong chitosan backbone coiling both in inner and outer chitosan nanoparticle structure. Zinc electrochemical signal depended on the level of the complex formation and the potential shift from −960 to −950 mV. Formed complex is suitable for doxorubicin delivery. It was observed the 20% entrapment efficiency of doxorubicin and strong dependence of drug release after 120 min in the blood environment. The functionality of the designed nanotransporter was proven. The purposed determination showed linear dependence in the concentration range of Anti-sarcosine IgG labeled gold nanoparticles from 0 to 1000 µg/mL and the regression equation was found to be y = 3.8x − 66.7 and R2 = 0.99. Performed ELISA confirmed the ability of Anti-sarcosine IgG labeled chitosan nanoparticles with loaded doxorubicin to bind to the sarcosine molecule. Observed hemolytic activity of the nanotransporter was 40%. Inhibition activity of our proposed nanotransporter was evaluated to be 0% on the experimental model of S. cerevisiae. Anti-sarcosine IgG labeled chitosan nanoparticles, with loaded doxorubicin stabilized by Zn ions, are a perspective type of nanocarrier for targeted drug therapy managed by specific interaction with sarcosine and metallothionein for prostate cancer.

Significance of tumor size and radiation dose to local control in stage I-III diffuse large cell lymphoma treated with CHOP-Bleo and radiation

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Fuller, Lillian M.; Krasin, Matthew J.; Velasquez, William S.; Allen, Pamela K.; McLaughlin, Peter; Rodriguez, M. Alma; Hagemeister, Fredrick B.; Swan, Forrest; Cabanillas, Fernando; Palmer, Judy L.; Cox, James D.

1995-01-01

Purpose: The purpose of this study was to evaluate the possible effect of adjunctive involved field (IF) radiotherapy on long-term local control for patients with Ann Arbor Stage I-III diffuse large cell lymphoma (DLCL) who achieved a complete remission on a combined modality program which included cyclophosphamide, doxorubicin, vincristine, prednisone, and Bleomycin (CHOP-Bleo). Methods and Materials: One hundred and ninety patients with Ann Arbor Stage I-III DLCL were treated with CHOP-Bleo and radiotherapy. Analyses were undertaken to determine (a) response to treatment according to stage, extent of maximum local disease, and irradiation dose either < 40 Gy or ≥ 40 Gy and (b) relapse patterns. Results: A complete remission (CR) was achieved in 162 patients. Among patients who achieved a CR, local control was better for those who received tumor doses of ≥ 40 Gy (97%) than for those who received < 40 Gy (83%) (p = 0.002.) Among those with extensive local disease, the corresponding control rates were 88% and 71%, respectively. A study of distant relapse patterns following a CR showed that the first relapse usually involved an extranodal site. Conclusion: Radiotherapy was an effective adjunctive treatment to CHOP-Bleo for patients with stage I-III DLCL who achieved a CR. Patterns of relapse suggested that total nodal irradiation (TNI) possibly could have benefited a small subset of patients

Secondary pancreatic involvement by a diffuse large B-cell lymphoma presenting as acute pancreatitis

Institute of Scientific and Technical Information of China (English)

M Wasif Saif; Sapna Khubchandani; Marek Walczak

2007-01-01

Diffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma. More than 50% of patients have some site of extra-nodal involvement at diagnosis,including the gastrointestinal tract and bone marrow.However, a diffuse large B-cell lymphoma presenting as acute pancreatitis is rare. A 57-year-old female presented with abdominal pain and matted lymph nodes in her axilla. She was admitted with a diagnosis of acute pancreatitis. Abdominal computed tomography (CT) scan showed diffusely enlarged pancreas due to infiltrative neoplasm and peripancreatic lymphadenopathy. Biopsy of the axillary mass revealed a large B-cell lymphoma.The patient was classified as stage Ⅳ, based on the Ann Arbor Classification, and as having a high-risk lymphoma,based on the International Prognostic Index. She was started on chemotherapy with CHOP (cyclophosphamide,doxorubicin, vincristine and prednisone). Within a week after chemotherapy, the patient's abdominal pain resolved. Follow-up CT scan of the abdomen revealed a marked decrease in the size of the pancreas and peripancreatic lymphadenopathy. A literature search revealed only seven cases of primary involvement of the pancreas in B-cell lymphoma presenting as acute pancreatitis. However, only one case of secondary pancreatic involvement by B-cell lymphoma presenting as acute pancreatitis has been published. Our case appears to be the second report of such a manifestation.Both cases responded well to chemotherapy.

Impact on Medical Cost, Cumulative Survival, and Cost-Effectiveness of Adding Rituximab to First-Line Chemotherapy for Follicular Lymphoma in Elderly Patients: An Observational Cohort Study Based on SEER-Medicare

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Robert I. Griffiths

2012-01-01

Full Text Available Rituximab improves survival in follicular lymphoma (FL, but is considerably more expensive than conventional chemotherapy. We estimated the total direct medical costs, cumulative survival, and cost-effectiveness of adding rituximab to first-line chemotherapy for FL, based on a single source of data representing routine practice in the elderly. Using surveillance, epidemiology, and end results (SEER registry data plus Medicare claims, we identified 1,117 FL patients who received first-line CHOP (cyclophosphamide (C, doxorubicin, vincristine (V, and prednisone (P or CVP +/− rituximab. Multivariate regression was used to estimate adjusted cumulative cost and survival differences between the two groups over four years after beginning treatment. The median age was 73 years (minimum 66 years, 56% had stage III-IV disease, and 67% received rituximab. Adding rituximab to first-line chemotherapy was associated with higher adjusted incremental total cost ($18,695; 95% Confidence Interval (CI $9,302–$28,643 and longer adjusted cumulative survival (0.18 years; 95% CI 0.10–0.27 over four years of followup. The expected cost-effectiveness was $102,142 (95% CI $34,531–296,337 per life-year gained. In routine clinical practice, adding rituximab to first-line chemotherapy for elderly patients with FL results in higher direct medical costs to Medicare and longer cumulative survival after four years.

Determination of the external contamination and cross-contamination by cytotoxic drugs on the surfaces of vials available on the Swiss market.

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Fleury-Souverain, Sandrine; Nussbaumer, Susanne; Mattiuzzo, Marc; Bonnabry, Pascal

2014-04-01

The external contamination and cross-contamination by cytotoxic drugs on the surface (outside and septum) of 133 vials from various manufacturers and available on the Swiss market were evaluated. All of the tested vials contained one of the following active ingredients: cyclophosphamide, cytarabine, doxorubicin, epirubicin, etoposide phosphate, gemcitabine, ifosfamide, irinotecan, methotrexate or vincristine. The validated wiping liquid chromatography-mass spectrometry method used in this study allowed for the simultaneous determination of these 10 cytotoxic drugs in less than 30 min. External contamination by cytotoxic drugs was detected on 63% of tested vials (outside and septum). The highest contamination level was observed on etoposide phosphate vials with 1896.66 ng of active ingredient on the outside of the vial. Approximately 20% of the contaminated vials had greater than 10 ng of cytotoxic drugs. Chemical contamination on the septum was detected on 38% of the vials. No contamination or very low levels of cytotoxic drugs, less than 1 ng per vial, were detected on the vials protected by plastic shrink-wrap. Traces of cytotoxic drugs different from the active ingredient were detected on 35% of the tested vials. Handling cytotoxic vials with gloves and having a procedure for the decontamination of vials are of the utmost importance for reducing exposure to cytotoxic drugs. Moreover, manufacturers must improve their procedures to provide products free from any contamination.

The Impact of Drug Metabolism Gene Polymorphisms on Therapeutic Response and Survival in Diffuse Large B-Cell Lymphoma Patients.

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Pál, Ildikó; Illés, Árpád; Gergely, Lajos; Pál, Tibor; Radnay, Zita; Szekanecz, Zoltán; Zilahi, Erika; Váróczy, László

2018-04-01

Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of all non-Hodgkin lymphomas (NHL) and 80% of agressive lymphomas. Besides the traditional International Prognostic Index (IPI), some other factors may also influence the prognosis of DLBCL patients. To study how the genetic polymorphisms in the metabolic pathway influence the event-free and overall survivals and therapeutic responses in DLBCL. The study was comprised of 51 patients (32 men, 19 women). The average age was 53.1 years. DLBCL was diagnosed between 2011 and 2016 and the average follow-up time was 3.78 years. These patients received 1-8 cycles (an average of 6.2 cycles) of rituximab, cyclophosphamide, doxorubicin, vincristin, prednisolon (R-CHOP) immunochemotherapy. Real-time polymerase chain reaction was used to determine the genetic polymorphisms of CYP2E1, GSTP1, NAT1, and NAT2 genes. Our results showed that the polymorphisms of CYP2E1, GSTP1, and NAT1 genes did not influence the prognosis of DLBCL patients significantly. In terms of the NAT2 gene, GG homozygous patients showed slightly better therapeutic response and survival results compared to those bearing an A allele; however, the differences were not statistically significant. Our results could not confirm that genetic polymorphism in metabolic pathways has any predictive role in DLBCL.

Primary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations

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Luis Alberto de Pádua Covas Lage

2015-08-01

Full Text Available Nodal peripheral T-cell lymphomas are a rare group of neoplasms derived from post-thymic and activated T lymphocytes. A review of scientific articles listed in PubMed, Lilacs, and the Cochrane Library databases was performed using the term "peripheral T-cell lymphomas". According to the World Health Organization classification of hematopoietic tissue tumors, this group of neoplasms consists of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, angioimmunoblastic T-cell lymphoma (AITL, anaplastic large cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK+, and a provisional entity called anaplastic large cell lymphoma-anaplastic lymphoma kinase negative (ALCL-ALK-. Because the treatment and prognoses of these neoplasms involve different principles, it is essential to distinguish each one by its clinical, immunophenotypic, genetic, and molecular features. Except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, which has no adverse international prognostic index, the prognosis of nodal peripheral T-cell lymphomas is worse than that of aggressive B-cell lymphomas. Chemotherapy based on anthracyclines provides poor outcomes because these neoplasms frequently have multidrug-resistant phenotypes. Based on this, the current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP regimens with the addition of new drugs, and autologous hematopoietic stem cell transplantation. This paper describes the clinical features and diagnostic methods, and proposes a therapeutic algorithm for nodal peripheral T-cell lymphoma patients.

Salmonella Immunotherapy Improves the Outcome of CHOP Chemotherapy in Non-Hodgkin Lymphoma-Bearing Mice

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Bascuas, Thais; Moreno, María; Grille, Sofía; Chabalgoity, José A.

2018-01-01

We have previously shown that Salmonella immunotherapy is effective to treat B-cell non-Hodgkin lymphoma (B-NHL) in mice. However, this model involves animals with high tumor burden, whereas in the clinics B-NHL patients are usually treated with chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line therapy prior to immunotherapy. Recently, we have described a NHL-B preclinical model using CHOP chemotherapy to achieve MRD in immunocompetent animals that closely resemble patients’ conditions. In this work, we assessed the efficacy of Salmonella immunotherapy in B-NHL-bearing mice undergoing chemotherapy. Salmonella administration significantly delayed tumor growth and prolonged survival of chemotherapy-treated NHL-bearing animals. Mice receiving the CHOP–Salmonella combined therapy showed increased numbers of tumor-infiltrating leukocytes and a different profile of cytokines and chemokines expressed in the tumor microenvironment. Further, Salmonella immunotherapy in CHOP-treated animals also enhanced NK cells cytotoxic activity as well as induced systemic lymphoma-specific humoral and cellular responses. Chemotherapy treatment profoundly impacted on the general health status of recipient animals, but those receiving Salmonella showed significantly better overall body condition. Altogether, the results clearly demonstrated that Salmonella immunotherapy could be safely used in individuals under CHOP treatment, resulting in a better prognosis. These results give strong support to consider Salmonella as a neoadjuvant therapy in a clinical setting. PMID:29410666

Rapid-Infusion Rituximab in Lymphoma Treatment: 2-Year Experience in a Single Institution

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Atay, Sevcan; Barista, Ibrahim; Gundogdu, Fatma; Akgedik, Kiymet; Arpaci, Afey

2012-01-01

Purpose: Rituximab is a chimeric anti-CD20 monoclonal antibody. We aimed to explore the safety and tolerability of rapid infusion rituximab, (over 90 minutes) in patients with non-Hodgkin's lymphoma at Hacettepe University Department of Medical Oncology. Patients and Methods: Adult patients diagnosed with non-Hodgkin's lymphoma who were to receive rituximab were included in the study. The schedule of administration for cycle 1 was unaltered and delivered according to the product monograph. All subsequent cycles were administered over a total infusion time of 90 minutes (20% of the dose in the first 30 minutes, then the remaining 80% over 60 minutes, total dose delivered in 500 mL). All patients were observed for infusion-related reactions during the rituximab infusion, and vital signs were recorded every 15 minutes. Results: From July 2006 to December 2008, 75 patients with non-Hodgkin's lymphoma were treated with rituximab-based chemotherapy. A total of 372 infusions were administered. The majority of patients were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, or rituximab only. The 90-minute rituximab infusion schedule was well tolerated, with no grade 3 or 4 infusion-related adverse events observed. Conclusion: A rapid infusion rituximab over 90 minutes is well tolerated and safe when administered as the second and subsequent infusions in the course of therapy. PMID:22942806

Is there an increased rate of additional malignancies in patients with mantle cell lymphoma?

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Barista, I; Cabanillas, F; Romaguera, J E; Khouri, I F; Yang, Y; Smith, T L; Strom, S S; Medeiros, L J; Hagemeister, F B

2002-02-01

To examine the frequency of additional neoplasms preceding and following the diagnosis of mantle cell lymphoma (MCL). A total of 156 patients with MCL treated on the hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternated with methotrexate and cytosine arabinoside (Hyper-CVAD/M-A) program with or without rituximab from 1994 to 2000 were the subjects of this report. These patients were followed for a median time of 26 months, and a total of 32 (21%) additional neoplasms were diagnosed, 21 preceding the diagnosis of MCL and 11 following MCL. After excluding certain types of non-invasive neoplasms, including basal cell carcinoma, meningioma and cervical intraepithelial neoplasia, we observed seven second malignancies after the diagnosis of MCL, and the 5-year cumulative incidence rate of second malignancy was 11%. The observed-to-expected (O/E) ratio was 7/0.07 = 100 [95% confidence interval (CI) 49.3 to 186.6; P <0.0001]. Of the 21 malignancies diagnosed prior to MCL, 16 were invasive and five non-invasive. There were a total of 10 urologic malignancies occurring before or after the diagnosis of MCL was established. Our findings suggest that there is an increased incidence of second malignancies in patients with MCL. In addition, the high number of cases with urinary tract cancer in our series may substantiate prior reports describing a possible association between lymphoma and urologic malignancies.

Successful Hematopoietic Stem Cell Transplantation Following a Cyclophosphamide-Containing Preparative Regimen with Concomitant Phenobarbital Administration

OpenAIRE

Weber, Catherine; Kasberg, Heather; Copelan, Edward

2012-01-01

Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TB...

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

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Berdichevski, Alexandra; Meiry, Gideon; Milman, Felix; Reiter, Irena; Sedan, Oshra; Eliyahu, Sivan; Duffy, Heather S.; Youdim, Moussa B.; Binah, Ofer

2010-01-01

Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administration-approved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptotic-inducing stimuli. Studies on structure-activity relationship revealed that their neuroprotective effect is associated with the propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and protein kinase C-ε and by down-regulating the proapoptotic protein Bax. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives, as well as on our recent study showing that TVP1022 attenuates serum starvation-induced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that TVP1022 will also provide protection against doxorubicin-induced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 μM, 24 h) prevented doxorubicin (0.5 μM, 24 h)-induced elevation of diastolic [Ca2+]i, the slowing of [Ca2+]i relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca2+) ATPase, Na+/Ca2+ exchanger 1, and total connexin 43. Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means of Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/dtmax) measured by the Micro-Electrode-Array system. In summary, our results indicate that TVP1022 acts as a novel cardioprotective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, the inistered with doxorubicin in the treatment of malignancies in humans. PMID:19915070

Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

International Nuclear Information System (INIS)

Huijts, Charlotte M; Santegoets, Saskia J; Eertwegh, Alfons J van den; Pijpers, Laura S; Haanen, John B; Gruijl, Tanja D de; Verheul, Henk M; Vliet, Hans J van der

2011-01-01

For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell

Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

Directory of Open Access Journals (Sweden)

Huijts Charlotte M

2011-11-01

Full Text Available Abstract Background For patients with metastatic renal cell cancer (mRCC who progressed on vascular endothelial growth factor (VEGF receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. Methods/design This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part. In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. Discussion This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus

SIRT1 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the Oxidative Stress and p38MAPK Pathways

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Yang Ruan

2015-02-01

Full Text Available Background: SIRT1, which belongs to the Sirtuin family of NAD-dependent enzymes, plays diverse roles in aging, metabolism, and disease biology. It could regulate cell survival and has been shown to be a protective factor in heart function. Hence, we verified the mechanism by which SIRT1 regulates doxorubicin induced cardiomyocyte injury in vivo and in vitro. Methods: We analyzed SIRT1 expression in doxorubicin-induced neonatal rat cardiomyocyte injury model and adult mouse heart failure model. SIRT1 was over-expressed in cultured neonatal rat cardiomyocyte by adenovirus mediated gene transfer. SIRT1 agonist resveratrol was used to treat the doxorubicin-induced heart failure mouse model. Echocardiography, reactive oxygen species (ROS production, TUNEL, qRT-PCR, and Western blotting were performed to analyze cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes. Results: SIRT1 expression was down-regulated in doxorubicin induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis. SIRT1 over-expression reduced doxorubicin induced cardiomyocyte apoptosis with the attenuated ROS production. SIRT1 also reduced cell apoptosis by inhibition of p38MAPK phosphorylation and caspase-3 activation. The SIRT1 agonist resveratrol was able to prevent doxorubicin-induced heart function loss. Moreover, the SIRT1 inhibitor niacinamide could reverse SIRT1's protective effect in cultured neonatal rat cardiomyocytes. Conclusions: These results support the role of SIRT1 as an important regulator of cardiomyocyte apoptosis during doxorubicin-induced heart injury, which may represent a potential therapeutic target for doxorubicin-induced cardiomyopathy.

Surface contamination of counting tools after mock dispensing of cyclophosphamide in a simulated outpatient pharmacy.

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Chaffee, Bruce W; Lander, Michael J; Christen, Catherine; Redic, Kimberly A

2018-01-01

Purpose The primary aim was to determine if dispensing of cyclophosphamide tablets resulted in accumulated residue on pharmacy counting tools during a simulated outpatient dispensing process. Secondary objectives included determining if cyclophosphamide contamination exceeded a defined threshold level of 1 ng/cm 2 and if a larger number of prescriptions dispensed resulted in increased contamination. Methods Mock prescriptions of 40 cyclophosphamide 50 mg tablets were counted on clean trays in three scenarios using a simulated outpatient pharmacy after assaying five cleaned trays as controls. The three scenarios consisted of five simulated dispensings of one, three, or six prescriptions dispensed per scenario. Wipe samples of trays and spatulas were collected and assayed for all trays, including the five clean trays used as controls. Contamination was defined as an assayed cyclophosphamide level at or above 0.001 ng/cm 2 and levels above 1 ng/cm 2 were considered sufficient to cause risk of human uptake. Mean contamination for each scenario was calculated and compared using one-way analysis of variance. P-values of contamination on trays used to count one, three, and six cyclophosphamide prescriptions was 0.51 ± 0.10 (p=0.0003), 1.02 ± 0.10 (p contamination. Increasing the number of prescriptions dispensed from 1 to 3, 1 to 6, and 3 to 6 counts increased contamination by 0.51 ± 0.15 (p = 0.0140), 1.31 + 0.15 (p contaminates pharmacy counting tools, and an increased number of prescriptions dispensed correlates with increased level of contamination. Counting out three or more prescriptions leads to trays having contamination that surpasses the threshold at which worker exposure may be increased. Pharmacies should consider devoting a separate tray to cyclophosphamide tablets, as cross-contamination could occur with other drugs and the efficacy of decontamination methods is unclear. Employee exposure could be minimized with the use

Human colon cancer HT-29 cell death responses to doxorubicin and Morus Alba leaves flavonoid extract.

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Fallah, S; Karimi, A; Panahi, G; Gerayesh Nejad, S; Fadaei, R; Seifi, M

2016-03-31

The mechanistic basis for the biological properties of Morus alba flavonoid extract (MFE) and chemotherapy drug of doxorubicin on human colon cancer HT-29 cell line death are unknown. The effect of doxorubicin and flavonoid extract on colon cancer HT-29 cell line death and identification of APC gene expression and PARP concentration of HT-29 cell line were investigated. The results showed that flavonoid extract and doxorubicin induce a dose dependent cell death in HT-29 cell line. MFE and doxorubicin exert a cytotoxic effect on human colon cancer HT-29 cell line by probably promoting or induction of apoptosis.

Doxorubicin-Induced Gut Toxicity in Piglets fed Bovine Milk and Colostrum

DEFF Research Database (Denmark)

Shen, René Liang; Rathe, Mathias; Jiang, Pingping

2016-01-01

OBJECTIVE: Chemotherapy-induced intestinal toxicity is a common adverse effect of cancer treatment. We hypothesized that a milk diet containing bovine colostrum (BC) would reduce intestinal toxicity in doxorubicin-treated piglets. METHODS: Study 1 investigated intestinal parameters nine days after...... Colostrum supplementation had limited effects on doxorubicin-induced toxicity in milk-fed piglets suggesting that colostrum and a bovine milk diet enriched with whey protein provided similar...

Early detection of doxorubicin-induced cariotoxocity and its prevention by alpha-tocopherol

International Nuclear Information System (INIS)

Ajmal, K.; Khan, B.T.

2014-01-01

To detect doxorubicin-induced myocardial injury by quantitative estimation of cardiospecific protein, Cardiac Troponin I (cTnI) at early stage and to evaluate the cardioprotective effects of Tocopherol. Study Design: Labbased randomized controlled in-vivo study in rabbits. Place and Duration of Study: Department of Pharmacology in collaboration with Pathology department, Army Medical College Rawalpindi, Pakistan from Jan 2012 to Dec 2012. Material and Methods: Eighteen healthy male adult rabbits were used. Cardiotoxicity was induced by single intravenous injection of 12 mg /kg of doxorubicin in a group of rabbits, control group was treated with normal saline only and the rabbits of third group were pretreated with Tocopherol 200 mg/kg of body weight for ten days before injection of doxorubicin 12mg/kg. Results: Doxorubicin produced severe cardiotoxicity confirmed by markedly raised serum levels of cTnI, CK-MB, LDH and grade 3 necrosis of the heart issue in rabbits. The pre-treatment with Tocopherol resulted in improved serum levels of cTnI and the histological picture of heart tissue. Conclusions: The quantitative cTnI estimation for detection of cardiotoxicity at subclinical level can lead to significant economic impact in management of cancer patients because the troponin-negative subjects can be excluded from long term cardiac monitoring programs, which require high cost imaging techniques. Furthermore, the outcome of most potent and widely used doxorubicin chemotherapy can be made successful with the concurrent use of alpha-Tocopherol. (author)

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.

Oxygen radical detoxification enzymes in doxorubicin-sensitive and -resistant P388 murine leukemia cells

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Ramu, A.; Cohen, L.; Glaubiger, D.

1984-01-01

One of the proposed mechanisms for the cytotoxic effects of anthracycline compounds suggests that the effect is mediated through the formation of intracellular superoxide radicals. It is therefore possible that doxorubicin resistance is associated with increased intracellular enzyme capacity to convert these superoxide radicals to inactive metabolites. We have measured the relative activities of superoxide dismutase, glutathione peroxidase, and catalase in P388 mouse leukemia cells and in a doxorubicin-resistant subline. Since oxygen-reactive metabolites also play a role in mediating the cytotoxicity of ionizing radiation, the radiosensitivity of both cell lines was also studied. No significant differences in superoxide dismutase activity between these cell lines was observed, indicating that they have a similar capacity to convert superoxide anion radicals to hydrogen peroxide. P388 cells that are resistant to doxorubicin have 1.5 times the glutathione content and 1.5 times the activity of glutathione peroxidase measured in drug-sensitive P388 cells. However, incubation with 1-chloro-2,4-dinitrobenzene, which covalently binds glutathione, had no effect on the sensitivity of either cell line to doxorubicin. Measured catalase activity in drug-resistant P388 cells was one-third of the activity measured in doxorubicin-sensitive P388 cells. The activity of this enzyme was much higher than that of glutathione peroxidase in terms of H 2 O 2 deactivation in both cell lines. It is therefore unlikely that doxorubicin-resistant P388 cells have an increased ability to detoxify reactive oxygen metabolites when compared to drug-sensitive cells. Doxorubicin-resistant P388 cells were significantly more sensitive to X-irradiation than were drug-sensitive P388 cells. These observations suggest that the difference in catalase activity in these cell lines may be associated with the observed differences in radiosensitivity

Effects of Streptococcus thermophilus TH-4 in a rat model of doxorubicin-induced mucositis.

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Wang, Hanru; Brook, Caitlin L; Whittaker, Alexandra L; Lawrence, Andrew; Yazbeck, Roger; Howarth, Gordon S

2013-08-01

Mucositis is a debilitating intestinal side effect of chemotherapeutic regimens. Probiotics have been considered a possible preventative treatment for mucositis. Streptococcus thermophilus TH-4 (TH-4), a newly identified probiotic, has been shown to partially alleviate mucositis induced by administration of the antimetabolite chemotherapy drug, methotrexate in rats; likely mediated through a mechanism of folate production. However, its effects against other classes of chemotherapy drug have yet to be determined. The authors investigated the effects of TH-4 in a rat model of mucositis induced by the anthracycline chemotherapy drug, doxorubicin. Gastrointestinal damage was induced in female Dark Agouti rats (148.3 ± 1.5 g) by intraperitoneal injection of doxorubicin (20 mg/kg). Animals recieved a daily oral gavage of TH-4 at 10(9) cfu/ml or skim milk (vehicle) from days 0 to 8. At day 6, rats were injected with either saline or doxorubicin. At kill, small intestinal tissues were collected for determination of sucrase and myeloperoxidase (MPO) activities and histological assessment. Body weight was significantly decreased by doxorubicin compared with normal controls (p TH-4 partially prevented the loss of body weight induced by doxorubicin (2.3% compared with 4%), but provided no further therapeutic benefit. The minimal amelioration of doxorubicin-induced mucositis by TH-4 further supports folate production as a likely mechanism of TH-4 action against methotrexate-induced mucositis. Further studies into TH-4 are required to confirm its applicability to other conventional chemotherapy regimens.

Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy.

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Izabela Piotrowska

Full Text Available Doxorubicin is a potent chemotherapeutic agent that is widely-used to treat a variety of cancers but causes acute and chronic cardiac injury, severely limiting its use. Clinically, the acute side effects of doxorubicin are mostly manageable, whereas the delayed consequences can lead to life-threatening heart failure, even decades after cancer treatment. The cardiotoxicity of doxorubicin is subject to a critical cumulative dose and so dosage limitation is considered to be the best way to reduce these effects. Hence, a number of studies have defined a "safe dose" of the drug, both in animal models and clinical settings, with the aim of avoiding long-term cardiac effects. Here we show that a dose generally considered as safe in a mouse model can induce harmful changes in the myocardium, as early as 2 weeks after infusion. The adverse changes include the development of fibrotic lesions, disarray of cardiomyocytes and a major transcription dysregulation. Importantly, low-dose doxorubicin caused specific changes in the transcriptional profile of several histone deacetylases (HDACs which are epigenetic regulators of cardiac remodelling. This suggests that cardioprotective therapies, aimed at modulating HDACs during doxorubicin treatment, deserve further exploration.

Protective effects of D-Trp6-luteinising hormone-releasing hormone microcapsules against cyclophosphamide-induced gonadotoxicity in female rats.

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Bokser, L; Szende, B; Schally, A V

1990-06-01

The possible protective effect of an agonist of luteinising hormone-releasing hormone (LH-RH) against the ovarian damage caused by cyclophosphamide was investigated in rats. D-Trp6-LH-RH microcapsules were injected once a month for 3 months, in a dose calculated to release 25 micrograms day-1. Control animals received the injection vehicle. Sixty days after the first injection of microcapsules, cyclophosphamide was given at a loading dose of 50 mg kg-1 followed by 5 mg kg-1 day-1 for 30 days, while the treatment with D-Trp6-LH-RH was continued. When the ovaries were examined 3 months and 5 months after discontinuation of treatment, a significant reduction in the total number of follicles (P less than 0.01) was found in non-pretreated animals given cyclophosphamide. This reduction affected mainly follicles larger than 100 microns. An irreversible disintegration and destruction of granulosa cells was also observed in this group. In animals pretreated with D-Trp6-LH-RH, administration of cyclophosphamide caused no reduction in the number and diameter of follicles. Thus, the treatment with D-Trp6-LH-RH microcapsules before and during chemotherapy prevented the ovarian injury inflicted by cyclophosphamide. The suppression of gonadal function by LH-RH analogues could be possibly utilised for the protection of the ovaries against damage caused by cytotoxic drugs.

Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors.

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Yu, Man; Lee, Carol; Wang, Marina; Tannock, Ian F

2015-10-01

Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Hemorrhagic cystitis in children treated with alkylating agent cyclophosphamide: The experience of a medical center in Taiwan

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Ching-Chia Wang

2015-08-01

Conclusion: Alteration serum uric acid level and BMT could be indicators for severe hemorrhagic cystitis. The elevated levels of urinary nitrite/nitrate and 8-iso-prostaglandin F2α may indicate the essential roles played by nitric oxide syntheses and reactive oxidative stress in cyclophosphamide-induced hemorrhagic cystitis. These findings may help clinicians formulate a better strategy for treating cyclophosphamide-induced hemorrhagic cystitis.

Preparation and characteristics of lipid nanoemulsion formulations loaded with doxorubicin

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Jiang SP

2013-08-01

Full Text Available Sai-Ping Jiang,1,2,* Sai-Nan He,3,* Yun-Long Li,2,3 Da-Lin Feng,2 Xiao-Yang Lu,1 Yong-Zhong Du,2 He-Yong Yu,3 Fu-Qiang Hu,2 Hong Yuan2 1Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 2College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 3Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China *These authors contributed equally to this work Purpose: Safe and effective lipid nanoemulsion (LNE formulations for the antitumor delivery of doxorubicin is designed. Methods: LNEs composed of medium-chain triglyceride, soybean oil, lecithin, and doxorubicin are prepared by a solvent-diffusion method in an aqueous system. The effects of lipid material composition and polyethylene glycol (PEGylation on the size, drug encapsulation efficiency, and stability of LNEs are investigated. Based on in-vitro cytotoxicity and cellular uptake tests of A549 (human lung carcinoma cells, in-vivo biodistribution, antitumor activity, and cardiac toxicity are further examined using nude mouse bearing A549 tumor. Results: The LNE size decreases from 126.4 ± 8.7 nm to 44.5 ± 9.3 nm with increased weight ratio of medium-chain triglyceride to soybean oil from 1:4 to 3:2, whereas the encapsulation efficiency of doxorubicin is slightly reduced from 79.2% ± 2.1% to 71.2% ± 2.9%. The PEGylation of LNE by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(PEG2000] (DSPE-PEG 2000 does not significantly change the size and drug encapsulation efficiency. Three-month storage at room temperature and lyophilization process does not affect the drug encapsulation efficiency, whereas the size slightly increases to almost 100 nm. The in-vitro drug-release profiles of LNEs suggest that the present formulation can prolong drug release for 48 hours. LNEs can be internalized into tumor cells in vitro and efficiently accumulate in tumor tissues in vivo by passive targeting

Prospective study of cyclophosphamide, thiotepa, carboplatin combined with adoptive DC-CIK followed by metronomic cyclophosphamide therapy as salvage treatment for triple negative metastatic breast cancers patients (aged <45).

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Wang, X; Ren, J; Zhang, J; Yan, Y; Jiang, N; Yu, J; Di, L; Song, G; Che, L; Jia, J; Zhou, X; Yang, H; Lyerly, H K

2016-01-01

The recent immunotherapy treatment on triple-negative breast cancer (TNBC) leads to the breakthrough assignation. In this study, we have tried the new combinations of specific chemo with DC-CIKs immunotherapy to treat those patients. Twenty-three metastatic anthracyclines and taxanes pretreated TNBC younger (mean 41.5 years) patients were initially mobilized with cyclophosphamide (3 g/m(2)) for the preparation of CD34(+) peripheral blood mononuclear cells as the resources for generating DC/CIKs and marrow function supports. All cases were subsequently experienced 2 cycles of chemotherapy with cyclophosphamide 3 g/m(2), thiotepa 150 mg/m(2), and carboplatin AUC = 6, Q4w. The patients then received 3 infusions of DC-CIKs at the chemo intervals and followed by maintenance therapy with oral cyclophosphamide 50 mg daily. The endpoints were progression-free survival and overall survival. The partial response rate was 13.0 %, stable and progressive disease rates were 56.5 and 30.4 %, respectively. The median PFS was 13.5 months (95 % confidence interval (CI) 10.1-16.9 months) and OS was 15.2 months (95 % CI 12.5-18.1 months). The most common serious adverse events were neutropenia (100.0 %) and anemia (69.7 %) but without treatment-related mortality. These data suggested that such combination therapy model be effective and safe for younger metastatic TNBC exposure to previous anthracyclines and taxanes based adjuvant chemotherapy.

Studies of radiation effects on allopathic formulations for cancer management

International Nuclear Information System (INIS)

Varshney, L.; Choughule, S.V.; Dodke, P.B.; Jothish, P.K.

2005-01-01

In the present study, two anticancer drugs, Cyclophosphamide and Doxorubucin Hydrochloride have been investigated. The results of various physico-chemical tests on unirradiated and irradiated drugs indicate possibility of use of lower radiation doses and cryo-irradiation in case of sterilization of Cyclophosphamide. Doxorubcin Hydrochloride could be sterilized at 25 kGy without any significant changes in its physico-chemical properties. HPLC studies reveal formation of several trace level degradation products in irradiated cyclophosphamide. HPLC/MS studies revealed that higher and lower molecular weight products of the original molecules are formed on irradiation. Although, no significant changes are observed in absolute purity values, a little discolouration and formation of degradation products in Cyclophosphamide are the main impediments in acceptability of radiation sterilization. On the other hand, orange-red coloured Doxorubicin Hydrochloride did not show any such changes and could be radiation sterilized at normal sterilization dose of 25 kGy. (author)

Studies of radiation effects on allopathic formulations for cancer management

Energy Technology Data Exchange (ETDEWEB)

Varshney, L; Choughule, S V; Dodke, P B; Jothish, P K [International Standard Orthopedic Measurements Education and Development (ISOMED), Bhabha Atomic Research Centre, Mumbai (India)

2005-07-01

In the present study, two anticancer drugs, Cyclophosphamide and Doxorubucin Hydrochloride have been investigated. The results of various physico-chemical tests on unirradiated and irradiated drugs indicate possibility of use of lower radiation doses and cryo-irradiation in case of sterilization of Cyclophosphamide. Doxorubcin Hydrochloride could be sterilized at 25 kGy without any significant changes in its physico-chemical properties. HPLC studies reveal formation of several trace level degradation products in irradiated cyclophosphamide. HPLC/MS studies revealed that higher and lower molecular weight products of the original molecules are formed on irradiation. Although, no significant changes are observed in absolute purity values, a little discolouration and formation of degradation products in Cyclophosphamide are the main impediments in acceptability of radiation sterilization. On the other hand, orange-red coloured Doxorubicin Hydrochloride did not show any such changes and could be radiation sterilized at normal sterilization dose of 25 kGy. (author)

A sensitive high performance liquid chromatography assay for the quantification of doxorubicin associated with DNA in tumor and tissues.

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Lucas, Andrew T; O'Neal, Sara K; Santos, Charlene M; White, Taylor F; Zamboni, William C

2016-02-05

Doxorubicin, a widely used anticancer agent, exhibits antitumor activity against a wide variety of malignancies. The drug exerts its cytotoxic effects by binding to and intercalating within the DNA of tumor and tissue cells. However, current assays are unable to accurately determine the concentration of the intracellular active form of doxorubicin. Thus, the development of a sample processing method and a high-performance liquid chromatography (HPLC) methodology was performed in order to quantify doxorubicin that is associated with DNA in tumors and tissues, which provided an intracellular cytotoxic measure of doxorubicin exposure after administration of small molecule and nanoparticle formulations of doxorubicin. The assay uses daunorubicin as an internal standard; liquid-liquid phase extraction to isolate drug associated with DNA; a Shimadzu HPLC with fluorescence detection equipped with a Phenomenex Luna C18 (2μm, 2.0×100mm) analytical column and a gradient mobile phase of 0.1% formic acid in water or acetonitrile for separation and quantification. The assay has a lower limit of detection (LLOQ) of 10ng/mL and is shown to be linear up to 3000ng/mL. The intra- and inter-day precision of the assay expressed as a coefficient of variation (CV%) ranged from 4.01 to 8.81%. Furthermore, the suitability of this assay for measuring doxorubicin associated with DNA in vivo was demonstrated by using it to quantify the doxorubicin concentration within tumor samples from SKOV3 and HEC1A mice obtained 72h after administration of PEGylated liposomal doxorubicin (Doxil(®); PLD) at 6mg/kg IV x 1. This HPLC assay allows for sensitive intracellular quantification of doxorubicin and will be an important tool for future studies evaluating intracellular pharmacokinetics of doxorubicin and various nanoparticle formulations of doxorubicin. Copyright © 2015 Elsevier B.V. All rights reserved.

Essential Oil from Myrica rubra Leaves Potentiated Antiproliferative and Prooxidative Effect of Doxorubicin and its Accumulation in Intestinal Cancer Cells.

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Ambrož, Martin; Hanušová, Veronika; Skarka, Adam; Boušová, Iva; Králová, Věra; Langhasová, Lenka; Skálová, Lenka

2016-01-01

Essential oil from the leaves of Myrica rubra, a subtropical Asian fruit tree traditionally used in folk medicines, has a significant antiproliferative effect in several intestinal cancer cell lines. Doxorubicin belongs to the most important cytostatics used in cancer therapy. The present study was designed to evaluate the effects of defined essential oil from M. rubra leaves on efficacy, prooxidative effect, and accumulation of doxorubicin in cancer cell lines and in non-cancerous cells. For this purpose, intestinal adenocarcinoma CaCo2 cells were used. Human fibroblasts (periodontal ligament) and a primary culture of rat hepatocytes served as models of non-cancerous cells. The results showed that the sole essential oil from M. rubra has a strong prooxidative effect in cancer cells while it acts as a mild antioxidant in hepatocytes. Combined with doxorubicin, the essential oil enhanced the antiproliferative and prooxidative effects of doxorubicin in cancer cells. At higher concentrations, synergism of doxorubicin and essential oil from M. rubra was proved. In non-cancerous cells, the essential oil did not affect the toxicity of doxorubicin and the doxorubicin-mediated reactive oxygen species formation. The essential oil increased the intracellular concentration of doxorubicin and enhanced selectively the doxorubicin accumulation in nuclei of cancer cells. Taken together, essential oil from M. rubra leaves could be able to improve the doxorubicin efficacy in cancer cells due to an increased reactive oxygen species production, and the doxorubicin accumulation in nuclei of cancer cells. Georg Thieme Verlag KG Stuttgart · New York.

Minoxidil (Mx) as a prophylaxis of doxorubicin--induced alopecia.

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Rodriguez, R; Machiavelli, M; Leone, B; Romero, A; Cuevas, M A; Langhi, M; Romero Acuña, L; Romero Acuña, J; Amato, S; Barbieri, M

1994-10-01

Minoxidil (Mx) is known to induce hair growth in men with male-pattern baldness. Based on this potential, the effectiveness of Mx 2% topical solution was evaluated in cancer patients (pts) to prevent doxorubicin-induced alopecia. 48 female pts with different types of solid tumors treated with doxorubicin-based chemotherapy in a dose range of 50-60 mg/m2/cycle were randomly assigned to receive Mx 2% topical solution or placebo. 88% and 92% of pts in both arms showed severe alopecia (p = ns). No adverse effects were observed. In this study Mx 2% topical solution was non-toxic but was not effective in the prevention of chemotherapy-induced alopecia.

Effect of Hydro Alcoholic Ginger Extracts on the Body Weight, Testis Weight and Spermatogenesis in Male Rats Undergoing Chemotherapy with Cyclophosphamide

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E Sharifi

2010-03-01

Full Text Available Introduction: Cyclophosphamide is used as an anti cancer medicine in chemotherapy. This is an alkalizing medicine and causes the binding of DNA strands, breaking of DNA and control of protein synthesis and RNA. The side effects of this medicine include lack of appetite, nausea, reduction in activity of sexual lymph nodes, causing amenorrhea, azoospermia and oligospermia. Ginger includes many compounds, some of which are shogaols, gingerols, pyrogallols and sesquiterpenes. Ginger has anti nauseating, anti cancer, anti oxidant effects and eliminates free radicals. This medicine is used along with cyclophosphamide to reduce its destructive side effects in the body. Methods: For 21 days, the rats were fed with ginger and cyclophosphamide. After 21 days, the animals were weighed and rendered unconscious. Their testes were removed and tissue samples were provided from their testes. Results: The results showed that cyclophosphamide alone reduces body weight, testes weight and spermatogenesis as compared to the control group. In other experimental groups that were fed with ginger and cyclophosphamide, increased dosage of ginger increased the body weight, the testes weight and spermatogenesis in comparison to the other experimental groups. Conclusion: It seems that compounds present in ginger are anti tumoral and control the production of active metabolites. Therefore, if administered together with Cyclophosphamide, it can be useful and effective in patients undergoing chemotherapy.

Cell-cycle alterations underline cyclophosphamide-induced teratogenesis in the chick embryo

Czech Academy of Sciences Publication Activity Database

Heringová, L.; Jelínek, R.; Dostál, Miroslav

č. 67 (2003), s. 438-443 ISSN 1542-0752 R&D Projects: GA ČR GA304/98/P296 Institutional research plan: CEZ:AV0Z5039906 Keywords : embryotoxicity * cyclophosphamide * flow cytometry Subject RIV: EB - Genetics ; Molecular Biology

Cisplatin and doxorubicin induce distinct mechanisms of ovarian follicle loss; imatinib provides selective protection only against cisplatin.

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Stephanie Morgan

Full Text Available Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001 and doxorubicin (3 fold, p<0.01. TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01 but not against doxorubicin treatment.Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s the patient is exposed to.

Antitumor activity of doxorubicine-loaded nanoemulsion against ...

African Journals Online (AJOL)

Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights ... Keywords: Doxorubicine, Anti-tumor activity, Mean survival time, Heart histology, Nanoemulsion, Lipid profile .... the standard kit methods using fully Automated ..... effects of this new formulation in human patients.

Extensive preclinical investigation of polymersomal formulation of doxorubicin versus Doxil-mimic formulation.

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Alibolandi, Mona; Abnous, Khalil; Mohammadi, Marzieh; Hadizadeh, Farzin; Sadeghi, Fatemeh; Taghavi, Sahar; Jaafari, Mahmoud Reza; Ramezani, Mohammad

2017-10-28

Due to the severe cardiotoxicity of doxorubicin, its usage is limited. This shortcoming could be overcome by modifying pharmacokinetics of the drugs via preparation of various nanoplatforms. Doxil, a well-known FDA-approved nanoplatform of doxorubicin as antineoplastic agent, is frequently used in clinics in order to reduce cardiotoxicity of doxorubicin. Since Doxil shows some shortcomings in clinics including hand and food syndrome and very slow release pattern thus, there is a demand for the development and preparation of new doxorubicin nanoformulation with fewer side effects. The new formulation of the doxorubicin, synthesized previously by our group was extensively examined in the current study. This new formulation is doxorubicin encapsulated in PEG-PLGA polymersomes (PolyDOX). The main aim of the study was to compare the distribution and treatment efficacy of a new doxorubicin-polymersomal formulation (PolyDOX) with regular liposomal formulation (Doxil-mimic) in murine colon adenocarcinoma model. Additionally, the pathological, hematological changes, pharmacodynamics, biodistribution, tolerated dose and survival rate in vivo were evaluated and compared. Murine colon cancer model was induced by subcutaneous inoculation of BALB/c mice with C26 cells. Afterwards, either Doxil-mimic or PolyDOX was administered intravenously. The obtained results from biodistribution study showed a remarkable difference in the distribution of drugs in murine organs. In this regard, Doxil-mimic exhibited prolonged (48h) presence within liver tissues while PolyDOX preferentially accumulate in tumor and the presence in liver 48h post-treatment was significantly lower than that of Doxil-mimic. Obtained results demonstrated comparable final length of life for mice receiving either Doxil-mimic or PolyDOX formulations whereas tolerated dose of mice receiving Doxil-mimic was remarkably higher than those receiving PolyDOX. Therapeutic efficacy of formulation in term of tumor growth rate

Circumvention of acquired resistance to doxorubicin in K562 human leukemia cells by oxatomide.

Science.gov (United States)

Ishikawa, M; Fujita, R; Furusawa, S; Takayanagi, M; Sasaki, K; Satoh, S

2001-10-01

We studied the effect of oxatomide, an antiallergic drug, on the resistance of K562 cells to doxorubicin. Oxatomide synergistically potentiated the cytotoxicity of doxorubicin in doxorubicin-resistant K562 cells (K562/DXR) at a concentration of 1-10 microM, but had hardly any synergistic effect on the parental cell line (K562) at the same concentration. Oxatomide inhibit P-glycoprotein pump-efflux activity and the binding of [3H]-azidopine to the cell-surface protein P-glycoprotein, in a dose-related manner. These results indicate that oxatomide reverses the multidrug-resistance phenotype through direct interaction with P-glycoprotein.

Targeting doxorubicin encapsulated in stealth liposomes to solid tumors by non thermal diode laser.

Science.gov (United States)

Ghannam, Magdy M; El Gebaly, Reem; Fadel, Maha

2016-04-05

The use of liposomes as drug delivery systems is the most promising technique for targeting drug especially for anticancer therapy. In this study sterically stabilized liposomes was prepared from DPPC/Cholesterol/PEG-PE encapsulated doxorubicin. The effect of lyophilization on liposomal stability and hence expiration date were studied. Moreover, the effect of diode laser on the drug released from liposomesin vitro and in vivo in mice carrying implanted solid tumor were also studied. The results indicated that lyophilization of the prepared liposomes encapsulating doxorubicin led to marked stability when stored at 5 °C and it is possible to use the re-hydrated lyophilized liposomes within 12 days post reconstitution. Moreover, the use of low energy diode laser for targeting anticancer drug to the tumor cells is a promising method in cancer therapy. We can conclude that lyophilization of the liposomes encapsulating doxorubicin lead to marked stability for the liposomes when stored at 5 °C. Moreover, the use of low energy diode laser for targeting anticancer drug to the tumor cells through the use of photosensitive sterically stabilized liposomes loaded with doxorubicin is a promising method. It proved to be applicable and successful for treatment of Ehrlich solid tumors implanted in mice and eliminated toxic side effects of doxorubicin.

High-Performance Liquid Chromatography (HPLC) Quantification of Liposome-Delivered Doxorubicin in Arthritic Joints of Collagen-Induced Arthritis Rats.

Science.gov (United States)

Niu, Hongqing; Xu, Menghua; Li, Shuangtian; Chen, Junwei; Luo, Jing; Zhao, Xiangcong; Gao, Chong; Li, Xiaofeng

2017-04-14

BACKGROUND Neoangiogenesis occurring in inflamed articular synovium in early rheumatoid arthritis (RA) is characterized by enhanced vascular permeability that allows nanoparticle agents, including liposomes, to deliver encapsulated drugs to arthritic joints and subsequently improve therapeutic efficacy and reduce adverse effects. However, the targeting distribution of liposomes in arthritic joints during RA has not been quantitatively demonstrated. We performed this study to evaluate the targeting distribution of PEGylated doxorubicin liposomes in the arthritic joints of collagen-induced arthritis (CIA) rats by high-performance liquid chromatography (HPLC). MATERIAL AND METHODS Two doxorubicin formulations were administered to CIA rats via tail intravenous injection at a single dose (50 mg/m²). CIA rats were sacrificed and the tissues of the inflamed ankle joints were collected. The content of doxorubicin in the arthritic joints was analyzed by a validated and reproducible HPLC method. A two-way ANOVA for 2×5 factorial design was used for statistical analysis. RESULTS The developed HPLC method was sensitive, precise, and reproducible. The method was successfully applied to quantify doxorubicin content in arthritic tissues. At each time point (6, 12, 24, 48, and 72 h), doxorubicin content in the arthritic joints of the doxorubicin liposome group (DOX-LIP group) was higher than in the free doxorubicin group (DOX group) (P<0.05). In the DOX-LIP group, doxorubicin levels in the arthritic joints increased gradually and significantly in the interval of 6-72 h post-administration. CONCLUSIONS PEGylated doxorubicin liposomes were targeted to, accumulated, and retained in the arthritic joints of CIA rats. The present study indicates that liposome encapsulation increases the therapeutic efficacy of antirheumatic drugs, presenting a promising therapeutic strategy for RA.

Simultaneous hyperthermia and doxorubicin delivery from polymer-coated magnetite nanoparticles

Energy Technology Data Exchange (ETDEWEB)

Iglesias, G.R., E-mail: iglesias@ugr.es [Department of Applied Physics, University of Granada, Granada 18071 (Spain); Delgado, A.V.; González-Caballero, F. [Department of Applied Physics, University of Granada, Granada 18071 (Spain); Ramos-Tejada, M.M. [Department of Physics, University of Jaén, Linares 23700 (Spain)

2017-06-01

In this work, the hyperthermia response, (i.e., heating induced by an externally applied alternating magnetic field) and the simultaneous release of an anti-cancer drug (doxorubicin) by polymer-coated magnetite nanoparticles have been investigated. After describing the setup for hyperthermia measurements in suspensions of magnetic nanoparticles, the hyperthermia (represented by the rate of suspension heating and, ultimately, by the specific absorption rate or SAR) of magnetite nanoparticles (both bare and polymer-coated as drug nanocarriers) is discussed. The effect of the applied ac magnetic field on doxorubicin release is also studied, and it is concluded that the field does not interfere with the release process, demonstrating the double functionality of the investigated particles. - Highlights: • Magnetite NPs coated with polymers are used for drug delivery and hyperthermia. • The SAR of polyelectrolyte-coated NPs is larger because of their improved stability. • The antitumor drug doxorubicin is adsorbed on the coated particles. • The release rate of the drug is not affected by the ac magnetic field used in hyperthermia.

Micronucleus formation in cultured human keratinocytes following exposure to mitomycin C and cyclophosphamide.

Science.gov (United States)

van Pelt, F N; Haring, R M; Overkamp, M J; Weterings, P J

1991-02-01

A method is described to investigate the induction of micronuclei in cultured human keratinocytes after short-term exposure to known clastogenic agents. The cytokinesis-block method was applied to facilitate the scoring of micronucleated cells. Mitomycin C, a direct-acting compound, caused a 5-20-fold increase in micronuclei over the controls at the highest concentration tested (1 microgram/ml). Cyclophosphamide, an agent requiring metabolic activation, did not induce the formation of micronuclei in cultured keratinocytes. However, after pretreatment of the keratinocyte cultures with Aroclor 1254 for 72 h, exposure to cyclophosphamide resulted in a 3-fold increase in micronucleus frequency over the controls. No cytogenetic effect of Aroclor 1254 was observed in control experiments.

Spatiotemporal Control of Doxorubicin Delivery from “Stealth-Like” Prodrug Micelles

Science.gov (United States)

Kong, Li; Schneider, Gregory F.; Campbell, Frederick

2017-01-01

In the treatment of cancer, targeting of anticancer drugs to the tumor microenvironment is highly desirable. Not only does this imply accurate tumor targeting but also minimal drug release en route to the tumor and maximal drug release once there. Here we describe high-loading, “stealth-like” doxorubicin micelles as a pro-drug delivery system, which upon light activation, leads to burst-like doxorbicin release. Through this approach, we show precise spatiotemporal control of doxorubicin delivery to cells in vitro. PMID:28937592

Activity of trypsin-like enzymes and gelatinases in rats with doxorubicin cardiomyopathy

OpenAIRE

Iu. А. Gordiienko; Ya. V. Babets; А. О. Kulinich; А. І. Shevtsova; G. О. Ushakova

2014-01-01

Activity of trypsin-like enzymes (ATLE) and gelatinases A and B were studied in the blood plasma and extracts from cardiac muscle, cerebral cortex and cerebellum of rats with cardiomyopathy caused by anthracycline antibiotic doxorubicin against the background of preventive application of corvitin and α-ketoglutarate. ATLE significantly increased in blood plasma and extracts from cerebral cortex but decreased in extracts from cardiac muscle and cerebellum in doxorubicin cardiomyopathy (DCMP). ...

OPEC chemotherapy (vincristine, prednisolone, etoposide and chlorambucil) for refractory and recurrent Hodgkin's disease.

Science.gov (United States)

Barnett, M J; Man, A M; Richards, M A; Waxman, J H; Wrigley, P F; Lister, T A

1987-01-01

Fifteen adults with refractory or recurrent Hodgkin's disease were treated with a combination of: vincristine, prednisolone, etoposide and chlorambucil (OPEC). All had previously received mustine, vinblastine, procarbazine and prednisolone (MVPP) and seven had subsequently been treated with alternative regimens. Responses were achieved in four, but complete remission in only one. Toxicity was considerable and five died of treatment related complications. Only two are alive (one in complete remission) more than three years after therapy. The toxicity of the OPEC regimen outweighed its benefit in this group of poor prognosis patients.

Hypothalamic energy metabolism is impaired by doxorubicin independently of inflammation in non-tumour-bearing rats.

Science.gov (United States)

Antunes, Barbara M M; Lira, Fabio Santos; Pimentel, Gustavo Duarte; Rosa Neto, José Cesar; Esteves, Andrea Maculano; Oyama, Lila Missae; de Souza, Cláudio Teodoro; Gonçalves, Cinara Ludvig; Streck, Emilio Luiz; Rodrigues, Bruno; dos Santos, Ronaldo Vagner; de Mello, Marco Túlio

2015-08-01

We sought to explore the effects of doxorubicin on inflammatory profiles and energy metabolism in the hypothalamus of rats. To investigate these effects, we formed two groups: a control (C) group and a Doxorubicin (DOXO) group. Sixteen rats were randomly assigned to either the control (C) or DOXO groups. The hypothalamus was collected. The levels of interleukin (IL)-1β, IL-6, IL-10, TNF-α and energy metabolism (malate dehydrogenase, complex I and III activities) were analysed in the hypothalamus. The DOXO group exhibited a decreased body weight (p hypothalamus is a central organ that regulates a great number of functions, such as food intake, temperature and energy expenditure, among others. Doxorubicin can lead to deep anorexia and metabolic chaos; thus, we observed the effect of this chemotherapeutic drug on the inflammation and metabolism in rats after the administration of doxorubicin in order to understand the central effect in the hypothalamus. Drug treatment by doxorubicin is used as a cancer therapy; however the use of this drug may cause harmful alterations to the metabolism. Thus, further investigations are needed on the impact of drug therapy over the long term. Copyright © 2015 John Wiley & Sons, Ltd.

Thermo-sensitive liposomes loaded with doxorubicin and lysine modified single-walled carbon nanotubes as tumor-targeting drug delivery system.

Science.gov (United States)

Zhu, Xiali; Xie, Yingxia; Zhang, Yingjie; Huang, Heqing; Huang, Shengnan; Hou, Lin; Zhang, Huijuan; Li, Zhi; Shi, Jinjin; Zhang, Zhenzhong

2014-11-01

This report focuses on the thermo-sensitive liposomes loaded with doxorubicin and lysine-modified single-walled carbon nanotube drug delivery system, which was designed to enhance the anti-tumor effect and reduce the side effects of doxorubicin. Doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes was prepared by reverse-phase evaporation method, the mean particle size was 232.0 ± 5.6 nm, and drug entrapment efficiency was 86.5 ± 3.7%. The drug release test showed that doxorubicin released more quickly at 42℃ than at 37℃. Compared with free doxorubicin, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes could efficiently cross the cell membranes and afford higher anti-tumor efficacy on the human hepatic carcinoma cell line (SMMC-7721) cells in vitro. For in vivo experiments, the relative tumor volumes of the sarcomaia 180-bearing mice in thermo-sensitive liposomes group and doxorubicin group were significantly smaller than those of N.S. group. Meanwhile, the combination of near-infrared laser irradiation at 808 nm significantly enhanced the tumor growth inhibition both on SMMC-7721 cells and the sarcomaia 180-bearing mice. The quality of life such as body weight, mental state, food and water intake of sarcomaia 180 tumor-bearing mice treated with doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes were much higher than those treated with doxorubicin. In conclusion, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes combined with near-infrared laser irradiation at 808 nm may potentially provide viable clinical strategies for targeting delivery of anti-cancer drugs. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Metastatic primary duodenal adeno-carcinoma responding to metronomic oral cyclophosphamide chemotherapy

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Anis Bandyopadhyay

2014-01-01

Full Text Available Primary adenocarcinoma of duodenum is a very rare tumour with a prevalence of only 0.3 to 1% of among all the tumours of gastrointestinal tracts. Localised tumours, if resected have good prognosis but those with metastates entails a poor prognosis, where generally palliation may be the only feasible option. Low dose continous cytotoxic treatment or metronomic chemotherapy prevents neoangiogenesis and chemoresistance thereby, provides excellent symptom relief and palliation in many advanced heavily pretreated solid malignancies. It offers as an affordable, less toxic therapy with moderate to good efficacy. Here we report a case of a 52 year female who, presented with history of maleana, pallor and pedal edema for last 2 months. Her performance status was poor (KPS 40 and she had enlarged left supraclavicular lymph node, palpable liver and vague mass in paraumbilical region. Upper GI endoscopy revealed large ulceroproliferative growth in the D2 segment and HPE showed moderately differentiated adenocarcinoma. CT scan revealed paratracheal and retroperitoneal lymphadenopathy and bone scan revealed vertebral metastasis. Patient received oral cyclophosphamide and hematinic and vitamin support, along with radiation to spine. There was near complete clinical response, and progression free period of about 32 weeks. Thus, single agent cyclophosphamide in the present case provided near total clinical response and prolonged period of freedom from disease progression with excellent palliation of symptoms. Hence in patient of advanced and metastatic small bowel cancer, with poor performance status metronomic therapy with single agent cyclophosphamide may provide viable option both for treatment and palliation.

Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2-M cell cycle arrest and enhanced vincristine sensitivity in Ewing's sarcoma.

Science.gov (United States)

Zöllner, Stefan K; Selvanathan, Saravana P; Graham, Garrett T; Commins, Ryan M T; Hong, Sung Hyeok; Moseley, Eric; Parks, Sydney; Haladyna, Jessica N; Erkizan, Hayriye V; Dirksen, Uta; Hogarty, Michael D; Üren, Aykut; Toretsky, Jeffrey A

2017-10-03

Ewing's sarcoma (ES) is a rare and highly malignant cancer that grows in the bones or surrounding tissues mostly affecting adolescents and young adults. A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), which is generated from a chromosomal translocation, is implicated in driving most ES cases by modulation of transcription and alternative splicing. The small-molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis in ES cells. We aimed to identify both the underlying mechanism of the drug and potential combination therapies that might enhance its antitumor activity. We tested 69 anticancer drugs in combination with YK-4-279 and found that vinca alkaloids exhibited synergy with YK-4-279 in five ES cell lines. The combination of YK-4-279 and vincristine reduced tumor burden and increased survival in mice bearing ES xenografts. We determined that independent drug-induced events converged to cause this synergistic therapeutic effect. YK-4-279 rapidly induced G 2 -M arrest, increased the abundance of cyclin B1, and decreased EWS-FLI1-mediated generation of microtubule-associated proteins, which rendered cells more susceptible to microtubule depolymerization by vincristine. YK-4-279 reduced the expression of the EWS-FLI1 target gene encoding the ubiquitin ligase UBE2C, which, in part, contributed to the increase in cyclin B1. YK-4-279 also increased the abundance of proapoptotic isoforms of MCL1 and BCL2, presumably through inhibition of alternative splicing by EWS-FLI1, thus promoting cell death in response to vincristine. Thus, a combination of vincristine and YK-4-279 might be therapeutically effective in ES patients. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity

Energy Technology Data Exchange (ETDEWEB)

Pecoraro, Michela; Del Pizzo, Mariagiovanna; Marzocco, Stefania; Sorrentino, Rosalinda [Department of Pharmacy, University of Salerno, Fisciano, SA (Italy); Ciccarelli, Michele; Iaccarino, Guido [Department of Medicine and Surgery, University of Salerno, Baronissi, SA (Italy); Pinto, Aldo [Department of Pharmacy, University of Salerno, Fisciano, SA (Italy); Popolo, Ada, E-mail: apopolo@unisa.it [Department of Pharmacy, University of Salerno, Fisciano, SA (Italy)

2016-02-15

Doxorubicin (DOXO) is commonly used to treat a wide range of malignant tumors, but its clinical use is limited by acute and chronic cardiotoxicity. The precise mechanism underlying DOXO-induced cardiotoxicity is still not completely elucidated, but cardiac inflammation seems to be involved. Effects of DOXO on proinflammatory cytokines, inflammatory cell infiltration, and necrosis have been proven only when a functional impairment has already occurred, so this study aimed to investigate the acute effect of DOXO administration in mouse heart. The results of our study demonstrated alterations in cardiac function parameters assessed by ultrasound within 24 h after a single injection of DOXO, with a cumulative effect along the increase of the dose and the number of DOXO administrations. At the same time, DOXO causes a significant production of proinflammatory cytokines (such as TNF-α and IL-6) with a concomitant reduction of IL-10, a well-known antiinflammatory cytokine. Furthermore, overexpression of inducible nitric oxide synthase (iNOS) in heart tissue and increased levels of serum nitrite in DOXO-treated mice were detected. Notably, DOXO administration significantly increased nitrotyrosine expression in mouse heart. Our data support the hypothesis that these early events, could be responsible for the later onset of more severe deleterious remodeling leading to DOXO induced cardiomyopathy. - Highlights: • Doxorubicin induces echocardiographic alterations of the main cardiac functional parameters. • Doxorubicin induces increase of TNF-α and IL-6 production and iNOS expression. • Doxorubicin causes a significant reduction of the antiinflammatory cytokine IL-10. • The doses are lower than that used in human. • Doxorubicin administration significantly increased nitrotyrosine expression.

Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts

International Nuclear Information System (INIS)

El-Zawahry, Ahmed; McKillop, John; Voelkel-Johnson, Christina

2005-01-01

Prostate cancer is a significant health problem among American men. Treatment strategies for androgen-independent cancer are currently not available. Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a death receptor ligand that can induce apoptosis in a variety of cancer cell lines, including androgen-independent PC3 prostate carcinoma cells. In vitro, TRAIL-mediated apoptosis of prostate cancer cell lines can be enhanced by doxorubicin and correlates with the downregulation of the anti-apoptotic protein c-FLIP. This study evaluated the effects of doxorubicin on c-FLIP expression and tumor growth in combination with Apo2L/TRAIL in a xenograft model. In vitro cytotoxic effects of TRAIL were measured using a MTS-based viability assay. For in vivo studies, PC3 prostate carcinoma cells were grown subcutaneously in athymic nude mice and tumor growth was measured following treatment with doxorubicin and/or Apo2L/TRAIL. c-FLIP expression was determined by western blot analysis. Apoptosis in xenografts was detected using TUNEL. Statistical analysis was performed using the student t-test. In vitro experiments show that PC3 cells are partially susceptible to Apo2L/TRAIL and that susceptibility is enhanced by doxorubicin. In mice, doxorubicin did not significantly affect the growth of PC3 xenografts but reduced c-FLIP expression in tumors. Expression of c-FLIP in mouse heart was decreased only at the high doxorubicin concentration (8 mg/kg). Combination of doxorubicin with Apo2L/TRAIL resulted in more apoptotic cell death and tumor growth inhibition than Apo2L/TRAIL alone. Combination of doxorubicin and Apo2L/TRAIL is more effective in growth inhibition of PC3 xenografts in vivo than either agent alone and could present a novel treatment strategy against hormone-refractory prostate cancer. The intracellular mechanism by which doxorubicin enhances the effect of Apo2L/TRAIL on PC3 xenografts may be by reducing expression of c-FLIP

Tween 20 increases intestinal transport of doxorubicin in vitro but not in vivo

DEFF Research Database (Denmark)

Al-Sharaf, Amal; Holm, Rene; Nielsen, Carsten Uhd

2016-01-01

co-administered with P-gp inhibitors (non-ionic surfactants) in vitro and in vivo . The aim of the present study was thus to investigate if different non-ionic surfactants would have a similar effect on the in vitro and in vivo absorption of doxorubicin. This was investigated in vitro in Caco-2 cells...... and by oral co-administration of doxorubicin together with tween 20 to male Sprague Dawley rats. 200 μM (0.025%) tween 20 increased the intestinal absorptive permeability of doxorubicin in vitro by 48 ± 4% from 8.8 × 10(-6)cm/s to 13.0 × 10(-6)cm/s. Further, the efflux ratio was reduced from 2.2 ± 0.06 to 1.2...

Radiation nephritis following total-body irradiation and cyclophosphamide in preparation for bone marrow transplantation

International Nuclear Information System (INIS)

Bergstein, J.; Andreoli, S.P.; Provisor, A.J.; Yum, M.

1986-01-01

Two children prepared for bone marrow transplantation with total-body irradiation and cyclophosphamide developed hypertension, microscopic hematuria, proteinuria, diminished renal function, and anemia six months after transplantation. Light microscopy of the kidneys revealed mesangial expansion, glomerular capillary wall thickening, and lumenal thrombosis. Electron microscopy demonstrated widening of the subendothelial space due to the deposition of amorphous fluffy material. In one patient, immunofluorescence microscopy revealed glomerular capillary wall deposition of fibrin and immunoglobulins. The clinical and histologic findings support the diagnosis of radiation nephritis. Patients prepared for bone marrow transplantation with total-body irradiation and cyclophosphamide should be followed closely after transplantation for the development of hypertension, proteinuria, and renal insufficiency

The role of Nardostachys jatamansi against doxorubicin-induced ...

African Journals Online (AJOL)

SUBASHINI

2013-12-04

Dec 4, 2013 ... Key words: Nardostachys jatamansi, doxorubicin, cytokine, glutathione, .... hoc test LSD, *P < 0.05, (Comparisons: control vs DOX induced group; DOX induced group vs NJ ... Figure 2 A-D shows the histological pictures of the.

Antiemetic therapy for non-anthracycline and cyclophosphamide moderately emetogenic chemotherapy.

Science.gov (United States)

Inui, Naoki

2017-05-01

Although antiemetic management in cancer therapy has improved, chemotherapy-induced nausea and vomiting remain common and troubling adverse events. Chemotherapeutic agents are classified based on their emetogenic effects, and appropriate antiemetics are recommended according to this categorization. Chemotherapy categorized as moderately emetogenic is associated with a wide spectrum of emetic risks. Combined anthracycline and cyclophosphamide regimens have been recently reclassified as highly emetogenic chemotherapy regimen. This review focuses on antiemetic pharmacotherapy in patients receiving non-anthracycline and cyclophosphamide-based moderately emetogenic chemotherapy regimens. Combination therapy with a 5-hydroxytryptamine-3 receptor agonist, preferably palonosetron, and dexamethasone is the standard therapy in moderately emetogenic chemotherapy, although triple therapy with add-on neurokinin-1 receptor antagonist is used as an alternative treatment strategy. Among moderately emetogenic chemotherapy regimens, carboplatin-containing chemotherapy has considerable emetic potential, particularly during the delayed phase. However, the additional of a neurokinin-1 receptor antagonist to the standard antiemetic therapy prevents carboplatin-induced nausea and vomiting. For regimens including oxaliplatin, the benefit of adding neurokinin-1 receptor antagonist requires further clarification.

A phase I study of Triapine in combination with doxorubicin in patients with advanced solid tumors.

Science.gov (United States)

Schelman, William R; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M; Ivy, Percy; Wilding, George; Traynor, Anne M

2009-05-01

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine administered in combination with doxorubicin. Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m(2) and Triapine 25 mg/m(2). PK analysis was performed at various time-points before and after treatment. Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m(2), Triapine 45 mg/m(2)), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m(2)) with Triapine 45 mg/m(2). The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine were reduced to 45 and 25 mg/m(2), respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Pretreated patients with advanced malignancies can tolerate the combination of Triapine and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m(2) on day 1 and Triapine 25 mg/m(2) on days 1-4 of a 21-day cycle.

The effect of vorinostat on the development of resistance to doxorubicin in neuroblastoma.

Directory of Open Access Journals (Sweden)

Timothy B Lautz

Full Text Available Histone deacetylase (HDAC inhibitors, especially vorinostat, are currently under investigation as potential adjuncts in the treatment of neuroblastoma. The effect of vorinostat co-treatment on the development of resistance to other chemotherapeutic agents is unknown. In the present study, we treated two human neuroblastoma cell lines [SK-N-SH and SK-N-Be(2C] with progressively increasing doses of doxorubicin under two conditions: with and without vorinsotat co-therapy. The resultant doxorubicin-resistant (DoxR and vorinostat-treated doxorubicin resistant (DoxR-v cells were equally resistant to doxorubicin despite significantly lower P-glycoprotein expression in the DoxR-v cells. Whole genome analysis was performed using the Ilumina Human HT-12 v4 Expression Beadchip to identify genes with differential expression unique to the DoxR-v cells. We uncovered a number of genes whose differential expression in the DoxR-v cells might contribute to their resistant phenotype, including hypoxia inducible factor-2. Finally, we used Gene Ontology to categorize the biological functions of the differentially expressed genes unique to the DoxR-v cells and found that genes involved in cellular metabolism were especially affected.

Is biopsy required prior to cyclophosphamide in steroid-sensitive nephrotic syndrome?

NARCIS (Netherlands)

Stadermann, M.B.; Lilien, M.R.; Kar, N.C.A.J. van de; Monnens, L.A.H.; Schröder, C.H.

2003-01-01

AIM: The present studywas designed to retrospectively evaluate the use of renal biopsies prior to cyclophosphamide therapy. The aim of the study was to determine in how many cases histological outcome of the biopsies had subsequently changed the decision to treat or refrain from treatment. PATIENTS

Iron distribution in cancer cells following doxorubicin exposure using proton and X-ray synchrotron radiation microprobes

International Nuclear Information System (INIS)

Ortega, R.; Deves, G.; Bohic, S.; Simionovici, A.; Menez, B.; Bonnin-Mosbah, M.

2001-01-01

Chemical studies have shown that doxorubicin, a well-established anticancer agent, is a powerful iron chelator and the resultant iron-drug complex is an efficient catalyst of the conversion of hydrogen peroxide to the highly reactive hydroxyl radical. However, the intracellular complexation of doxorubicin with iron is still debated. Using nuclear microprobe analysis (NMPA), we previously observed in human ovarian cancer cells exposed to 20 μM iodo-doxorubicin (IDX) that iodine and iron cellular distributions were spatially correlated, suggesting a mechanism of intracellular iron chelation by the anthracycline compound. Because maximal plasma drug concentrations in patients are expected to be around 5 μM, NMPA and X-ray absorption near edge spectroscopy (XANES) experiments for iron speciation analysis were performed on cultured cells exposed to pharmacological doses of 2 μM IDX or doxorubicin

miR-193b Modulates Resistance to Doxorubicin in Human Breast Cancer Cells by Downregulating MCL-1

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Jingpei Long

2015-01-01

Full Text Available MicroRNAs (miRNAs family, which is involved in cancer development, proliferation, apoptosis, and drug resistance, is a group of noncoding RNAs that modulate the expression of oncogenes and antioncogenes. Doxorubicin is an active cytotoxic agent for breast cancer treatment, but the acquisition of doxorubicin resistance is a common and critical limitation to cancer therapy. The aim of this study was to investigate whether miR-193b mediated the resistance of breast cancer cells to doxorubicin by targeting myeloid cell leukemia-1 (MCL-1. In this study, we found that miR-193b levels were significantly lower in doxorubicin-resistant MCF-7 (MCF-7/DOXR cells than in the parental MCF-7 cells. We observed that exogenous miR-193b significantly suppressed the ability of MCF-7/DOXR cells to resist doxorubicin. It demonstrated that miR-193b directly targeted MCL-1 3′-UTR (3′-Untranslated Regions. Further studies indicated that miR-193b sensitized MCF-7/DOXR cells to doxorubicin through a mechanism involving the downregulation of MCL-1. Together, our findings provide evidence that the modulation of miR-193b may represent a novel therapeutic target for the treatment of breast cancer.

Anti-cancer effect of oncolytic adenovirus-armed shRNA targeting MYCN gene on doxorubicin-resistant neuroblastoma cells.

Science.gov (United States)

Li, Yuan; Zhuo, Baobiao; Yin, Yiyu; Han, Tao; Li, Shixian; Li, Zhengwei; Wang, Jian

2017-09-09

Chemotherapy is one of the few effective choices for patients with neuroblastoma. However, the development of muti-drug resistance (MDR) to chemotherapy is a major obstacle to the effective treatment of advanced or recurrent neuroblastoma. The muti-drug resistance-associated protein (MRP), which encodes a transmembrane glycoprotein, is a key regulator of MDR. The expression of MRP is a close correlation with MYCN oncogene in neuroblastoma. We have recently shown ZD55-shMYCN (oncolytic virus armed with shRNA against MYCN) can down-regulate MYCN to inhibit tumor cells proliferation and induce apoptosis in neuroblastoma. Here we further report ZD55-shMYCN re-sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis, and inhibited cell migration), and reduced the in vivo growth rate of neuroblastoma xenografts by down-regulation of MRP expression. Sequential therapy with doxorubicin did not affect the replication of ZD55-shMYCN in doxorubicin-resistant neuroblastoma cells, but decreased the expression of Bcl-2, Bcl-X L , MMP-1. Thus, this synergistic effect of ZD55-shMYCN in combination with doxorubicin provides a novel therapy strategy for doxorubicin-resistant neuroblastoma, and is a promising approach for further clinical development. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of doxorubicin and daunorubicin on the activity of acetylcholinesterase in acute lymphoblastic leukamia

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Din, I.U.; Ali, A.

2011-01-01

Background: Our study was based on the alteration in the Michaelis Mentin parameters Apparent Michaelis Constant (aKm) and Apparent Maximum Velocity (aVm), which reflects activity of actyl cholinesterase (AChE). This activity decreases in Acute Lymphoblastic Leukaemia (ALL). This decrease in aKm and aVm values shows bad prognosis. Similarly the anticancer drugs like Daunorubicin and Doxorubicin further decreases the aKm and aVm values which worsen the prognosis. The objective of this study was to determine and compare the extent of inhibition of Acetylcholine Esterase by Daunorubicin and Doxorubicin in ALL. Methods: Study of 100 patients including both male and female children who's age ranged from 4 to 8 years and were advised doxorubicin and daunorubicin separately were tested by Ellman's method using acetylcholine iodide as substrate and 5,5-dithiobis 2-nitrobenzine as a colour reagent regardless of dose regimen i.e. (once in 3 week, small dose per week or a continuous infusion for 72 to 96 hours. Results: In this study the Michaelis Mentin parameters Apparent Michaelis Constant (aKm) and Apparent Maximum Velocity (aVm) of the enzyme were estimated both in normal individuals and in the patients and also during treatment with daunorubicin and doxorubicin. The value of Michaelis Mentin parameters, aKm, aVm and percentage activity of the enzyme in normal individual are 23, 70, and 100 respectively. The values of aKm, aVm and percentage activity of the enzyme were also estimated in the patients before and after treatment. The values of aKm and aVm in patients of acute lymphoblastic leukaemia and percentage activity of enzyme is decreased. After the treatment with daunorubicin and doxorubicin the values and activity is further decreased. Conclusion: We conclude that the drugs under study both decrease the enzyme activity but daunorubicin inhibits the enzyme more than doxorubicin. (author)

Toxicity of Doxorubicin on Pig Liver After Chemoembolization with Doxorubicin-loaded Microspheres: A Pilot DNA-microarrays and Histology Study

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Verret, Valentin, E-mail: valentin.verret@archimmed.com; Namur, Julien; Ghegediban, Saieda Homayra [ArchimMed (France); Wassef, Michel [University of Paris 7-Denis Diderot, Department of Pathology, Faculty of Medicine, AP-HP Hopital Lariboisiere (France); Moine, Laurence [Universite Paris Sud, Faculte de Pharmacie, UMR CNRS 8612, IFR 141-ITFM (France); Bonneau, Michel [AP-HP/INRA, Centre de Recherche En Imagerie Interventionnelle (France); Pelage, Jean-Pierre [AP-HP Hopital Ambroise Pare, Department of Interventional Radiology (France); Laurent, Alexandre [AP-HP/INRA, Centre de Recherche En Imagerie Interventionnelle (France)

2013-02-15

The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques.The left hepatic arteries of two pigs were embolized with 1 mL of doxorubicin-loaded (25 mg; (DoxMS)) or non-loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1 week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p < 0.01; fold-change > 2) between two groups were classified by biological process. At 1 week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 and 38 % of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up-regulated genes following embolization with DoxMS (vs. BlandMS, n = 353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down-regulated genes (n = 120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration. DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models.

Reverting doxorubicin resistance in colon cancer by targeting a key signaling protein, steroid receptor coactivator.

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Xiong, Sang; Xiao, Gong-Wei

2018-04-01

Although there have been notable improvements in treatments against cancer, further research is required. In colon cancer, nearly all patients eventually experience drug resistance and stop responding to the approved drugs, making treatment difficult. Steroid receptor coactivator (SRC) is an oncogenic nuclear receptor coactivator that serves an important role in drug resistance. The present study generated a doxorubicin-resistant colon cancer cell line, in which the upregulation/activation of SRC was responsible for drug resistance, which in turn activated AKT. Overexpression of receptor tyrosine kinase-like epidermal growth factor receptor and insulin-like growth factor 1 receptor also induced SRC expression. It was observed that doxorubicin resistance in colon cancer also induced epithelial to mesenchymal transition, a decrease in expression of epithelial marker E-cadherin and an increase in the expression of mesenchymal markers, including N-cadherin and vimentin. Additionally, the present study indicated that SRC acts as a common signaling node, and inhibiting SRC in combination with doxorubicin treatment in doxorubicin-resistant cells aids in reversing the resistance. Thus, the present study suggests that activation of SRC is responsible for doxorubicin resistance in colon cancer. However, further research is required to understand the complete mechanism of how drug resistance occurs and how it may be tackled to treat patients.

[The therapeutic effect of HSV1-hGM-CSF combined with doxorubicin on the mouse breast cancer model].

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Zhuang, X F; Zhang, S R; Liu, B L; Wu, J L; Li, X Q; Gu, H G; Shu, Y

2018-03-23

Objective: To evaluate the oncolytic effect of herpes simplex virus type 1 which carried recombined human granulocyte-macrophage colony-stimulating factor (HSV1-hGM-CSF) on the mouse breast cancer cell line 4T1 and compare the anticancer effects of HSV1-hGM-CSF, doxorubicin alone or combination on the breast cancer in mice. Methods: We investigated the cytotoxic effect on 4T1 cells in vitro, the cell growth, cell apoptosis and cell cycle of 4T1 cells treated with oncolytic HSV1-hGM-CSF at different MOIs (0, 0.5, 1 and 2) and doxorubicin at different concentrations (0, 2, 4 and 8 μg/ml). The effects of oncolytic HSV1-hGM-CSF and doxorubicin on the tumor growth, survival time and their side effects on the mouse breast cancer model were observed. Results: Both oncolytic HSV1-hGM-CSF and doxorubicin significantly inhibited the proliferation of 4T1 cells in vitro . Doxorubicin induced the G(2)/M phase arrest of 4T1 cells, while the cytotoxicity of oncolytic HSV1-hGM-CSF was no cell cycle-dependent.At day 16 after treatment with doxorubicin and HSV1-hGM-CSF, the tumor volume of 4T1 tumor bearing mice were (144.40±27.68)mm(3,) (216.80±57.18)mm(3,) (246.10±21.90)mm(3,) (327.50±44.24)mm(3,) (213.30±32.31)mm(3) and (495.80±75.87)mm(3) in the groups of doxorubicin combined with high dose HSV1-hGM-CSF, doxorubicin combined with low dose HSV1-hGM-CSF, doxorubicin alone, high dose HSV1-hGM-CSF alone, low dose HSV1-hGM-CSF alone and control, respectively.Compared with the control group, both doxorubicin and HSV1-hGM-CSF treatment exhibited significant reduction of primary tumor volume in vivo ( P CSF alone and low dose HSV1-hGM-CSF alone were significantly longer than that of control ( P CSF is observed in 4T1 mouse breast cancer.

Prophylaxis of invasive aspergillosis with caspofungin during construction works in patient with acute lymphoblasic leukemia treated with vincristin

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Mojca Modic

2012-12-01

Case presentation: A 59-year old woman with common ALL relapsed after 22 years (normal cytogenetics. She was treated according to the UKALL XII regimen and achieved complete second remission. She received four cycles of vincristine 2 mg i.v. In a retrospective cohort study, prolonged neutropenia, use of steroids, nursing unit without laminar air flow during a period of construction works were associated with an increased incidence of invasive aspergillosis in patients who did not receive primary antifungal prophylaxis. Intravenous caspofungin was administered to the patient as primary aspergillosis prophylaxis on the first day of chemotherapy. Galactomannan antigen tests were negative during the period of neutropenia. There was no infection in the period of prolonged neutropenia. Conclusions: The author discusses primary prophylaxis of invasive aspergillosis with caspofungin during construction works in patients with acute lymphoblastic leukemia treated with vincristine. Because of non-conventional unit without laminar air flow during induction chemotherapy treatment, which leads to an increased risk of invasive fungal infection with Aspergillus, caspofungin prophylaxis is recommended at least until upgrade to laminar flow or cessation of construction works.

The stress granule protein Vgl1 and poly(A)-binding protein Pab1 are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe

International Nuclear Information System (INIS)

Morita, Takahiro; Satoh, Ryosuke; Umeda, Nanae; Kita, Ayako; Sugiura, Reiko

2012-01-01

Highlights: ► Stress granules (SGs) as a mechanism of doxorubicin tolerance. ► We characterize the role of stress granules in doxorubicin tolerance. ► Deletion of components of SGs enhances doxorubicin sensitivity in fission yeast. ► Doxorubicin promotes SG formation when combined with heat shock. ► Doxorubicin regulates stress granule assembly independent of eIF2α 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 + , which encodes a multi-KH type RNA-binding protein, and pab1 + , which encodes a poly(A)-binding protein, resulted in greater sensitivity to doxorubicin than seen in wild-type cells. Disruption of the vgl1 + and pab1 + 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 eIF2α, suggesting that doxorubicin is involved in stress granule assembly independent of eIF2α 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.

siRNA inhibition of telomerase enhances the anti-cancer effect of doxorubicin in breast cancer cells

International Nuclear Information System (INIS)

Dong, Xuejun; Liu, Anding; Zer, Cindy; Feng, Jianguo; Zhen, Zhuan; Yang, Mingfeng; Zhong, Li

2009-01-01

Doxorubicin is an effective breast cancer drug but is hampered by a severe, dose-dependent toxicity. Concomitant administration of doxorubicin and another cancer drug may be able to sensitize tumor cells to the cytotoxicity of doxorubicin and lowers the therapeutic dosage. In this study, we examined the combined effect of low-dose doxorubicin and siRNA inhibition of telomerase on breast cancer cells. We found that when used individually, both treatments were rapid and potent apoptosis inducers; and when the two treatments were combined, we observed an enhanced and sustained apoptosis induction in breast cancer cells. siRNA targeting the mRNA of the protein component of telomerase, the telomerase reverse transcriptase (hTERT), was transfected into two breast cancer cell lines. The siRNA inhibition was confirmed by RT-PCR and western blot on hTERT mRNA and protein levels, respectively, and by measuring the activity level of telomerase using the TRAP assay. The effect of the hTERT siRNA on the tumorigenicity of the breast cancer cells was also studied in vivo by injection of the siRNA-transfected breast cancer cells into nude mice. The effects on cell viability, apoptosis and senescence of cells treated with hTERT siRNA, doxorubicin, and the combined treatment of doxorubicin and hTERT siRNA, were examined in vitro by MTT assay, FACS and SA-β-galactosidase staining. The hTERT siRNA effectively knocked down the mRNA and protein levels of hTERT, and reduced the telomerase activity to 30% of the untreated control. In vivo, the tumors induced by the hTERT siRNA-transfected cells were of reduced sizes, indicating that the hTERT siRNA also reduced the tumorigenic potential of the breast cancer cells. The siRNA treatment reduced cell viability by 50% in breast cancer cells within two days after transfection, while 0.5 μM doxorubicin treatment had a comparable effect but with a slower kinetics. The combination of hTERT siRNA and 0.5 μM doxorubicin killed twice as many

Leiomyosarcoma of the bladder in a 16-year-old girl with a history of cyclophosphamide therapy for bilateral retinoblastoma during infancy

International Nuclear Information System (INIS)

Al-Zahrani, Ali A.; Kamal, Baher A.; Eldarawani, Hamed M.; Hashim, Tariq M.

2006-01-01

A 16-year-old female with bladder leiomyosarcoma had a history of bilateral retinoblastoma at 6 months of life. She received cyclophosphamide chemotherapy after surgical enucleation. In this report, we discussed the possible role of retinoblastoma or cyclophosphamide as a target for development of bladder leiomyosarcoma. (author)

Can propolis and caffeic acid phenethyl ester (CAPE be promising agents against cyclophosphamide toxicity?

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Sumeyya Akyol

2016-03-01

Full Text Available Propolis is a mixture having hundreds of polyphenols including caffeic acid phenethyl ester (CAPE. They have been using in several medical conditions/diseases in both in vitro and in vivo experimental setup. Cyclophosphamide has been used to treat a broad of malignancies including Hodgkin’s and non-Hodgking’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, Ewing’s sarcoma, breast cancer, testicular cancer, etc. It may cause several side effects after treatment. In this mini review, the protective effects of propolis and CAPE were compared each other in terms of effectiveness against cyclophosphamide-induced injuries. [J Complement Med Res 2016; 5(1.000: 105-107

Real time in vitro studies of doxorubicin release from PHEMA nanoparticles

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Bajpai AK

2009-10-01

Full Text Available Abstract Background Many anticancer agents have poor water solubility and therefore the development of novel delivery systems for such molecules has received significant attention. Nanocarriers show great potential in delivering therapeutic agents into the targeted organs or cells and have recently emerged as a promising approach to cancer treatments. The aim of this study was to prepare and use poly-2-hydroxyethyl methacrylate (PHEMA nanoparticles for the controlled release of the anticancer drug doxorubicin. Results PHEMA nanoparticles have been synthesized and characterized using FTIR and scanning electron microscopy (SEM, particle size analysis and surface charge measurements. We also studied the effects of various parameters such as percent loading of drugs, chemical architecture of the nanocarriers, pH, temperature and nature of the release media on the release profiles of the drug. The chemical stability of doxorubicin in PBS was assessed at a range of pH. Conclusion Suspension polymerization of 2-hydroxyethyl methacrylate (HEMA results in the formation of swellable nanoparticles of defined composition. PHEMA nanoparticles can potentially be used for the controlled release of the anticancer drug doxorubicin.

Proteomic Differences in Feline Fibrosarcomas Grown Using Doxorubicin-Sensitive and -Resistant Cell Lines in the Chick Embryo Model

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Katarzyna Zabielska-Koczywąs

2018-02-01

Full Text Available Proteomic analyses are rapid and powerful tools that are used to increase the understanding of cancer pathogenesis, discover cancer biomarkers and predictive markers, and select and monitor novel targets for cancer therapy. Feline injection-site sarcomas (FISS are aggressive skin tumours with high recurrence rates, despite treatment with surgery, radiotherapy, and chemotherapy. Doxorubicin is a drug of choice for soft tissue sarcomas, including FISS. However, multidrug resistance is one of the major causes of chemotherapy failure. The main aim of the present study was to identify proteins that differentiate doxorubicin-resistant from doxorubicin-sensitive FISS using two-dimensional gel electrophoresis (2DE, followed by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS analysis. Using the three-dimensional (3D preclinical in ovo model, which resembles features of spontaneous fibrosarcomas, three significantly (p ≤ 0.05 differentially expressed proteins were identified in tumours grown from doxorubicin-resistant fibrosarcoma cell lines (FFS1 and FFS3 in comparison to the doxorubicin-sensitive one (FFS5: Annexin A5 (ANXA5, Annexin A3 (ANXA3, and meiosis-specific nuclear structural protein 1 (MNS1. Moreover, nine other proteins were significantly differentially expressed in tumours grown from the high doxorubicin-resistant cell line (FFS1 in comparison to sensitive one (FFS5. This study may be the first proteomic fingerprinting of FISS reported, identifying potential candidates for specific predictive biomarkers and research targets for doxorubicin-resistant FISS.

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: sugiurar@phar.kindai.ac.jp [Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Kowakae 3-4-1, Higashi-Osaka 577-8502 (Japan)

2012-01-06

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.

Effects of co-medicated drugs on cyclophosphamide bioactivation in human liver microsomes

NARCIS (Netherlands)

de Jonge, Milly E.; Huitema, Alwin D. R.; van Dam, Selma M.; Rodenhuis, Sjoerd; Beijnen, Jos H.

2005-01-01

The alkylating agent cyclophosphamide (CP) is a prodrug requiring cytochrome P-450-mediated bioactivation to form the active 4-hydroxycyclophosphamide (4OHCP). Modifications in the rate of CP bioactivation may have implications for the effectiveness of CP therapy, especially in high-dose regimens.

Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression

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Takahiro Ebata

2017-01-01

Full Text Available The physical properties of the extracellular matrix (ECM, such as stiffness, are involved in the determination of the characteristics of cancer cells, including chemotherapy sensitivity. Resistance to chemotherapy is often linked to dysfunction of tumor suppressor p53; however, it remains elusive whether the ECM microenvironment interferes with p53 activation in cancer cells. Here, we show that, in MCF-7 breast cancer cells, extracellular stiffness influences p53 activation induced by the antitumor drug doxorubicin. Cell growth inhibition by doxorubicin was increased in response to ECM rigidity in a p53-dependent manner. The expression of Rho-associated coiled coil-containing protein kinase (ROCK 2, which induces the activation of myosin II, was significantly higher when cells were cultured on stiffer ECM substrates. Knockdown of ROCK2 expression or pharmacological inhibition of ROCK decreased doxorubicin-induced p53 activation. Our results suggest that a soft ECM causes downregulation of ROCK2 expression, which drives resistance to chemotherapy by repressing p53 activation.

Efficient chemotherapy of rat glioblastoma using doxorubicin-loaded PLGA nanoparticles with different stabilizers.

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Stefanie Wohlfart

Full Text Available BACKGROUND: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid (PLGA nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. METHODOLOGY: The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA or human serum albumin (PLGA/HSA as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3 × 2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. CONCLUSION: The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.

Multicenter study of environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in 66 Canadian hospitals: A 2016 follow-up study.

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Roland, C; Caron, N; Bussières, J F

2017-08-01

Oncology workers are occupationally exposed to antineoplastic drugs. This exposure can induce adverse health effects. To reduce their exposure, contamination on surfaces should be kept as low as possible. The main objective of this study was to monitor environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in oncology pharmacy and patient care areas in Canadian centers. The secondary objective was to describe the impact of some factors that may limit contamination. This is a descriptive study. Twelve standardized sites were sampled in each participating center (six in the pharmacy and six in patient care areas). Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography-tandem mass spectrometry technology. Descriptive statistical analyses were done and results were compared with a Kolmogorov-Smirnov test for independent samples. In 2016, 66 centers participated in this study (66/202, 32.7%). Overall, 43.4% (326/752) of the samples were positive for cyclophosphamide, 13.2% (99/752) for ifosfamide and 6.9% (52/752) for methotrexate. The 75th percentile value of cyclophosphamide surface concentration was 6.8 pg/cm 2 and lower than the limit of detection for ifosfamide and methotrexate. Centers who prepared more antineoplastic drugs per year (p contamination to cyclophosphamide. Environmental surveillance is one part of a comprehensive approach for minimizing hazardous exposures in healthcare. This study highlights a low level of contamination of three hazardous drugs amongst 66 Canadian centers. Regular environmental monitoring is a good practice to maintain contamination as low as reasonably achievable.

An inflammation-based cumulative prognostic score system in patients with diffuse large B cell lymphoma in rituximab era.

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Sun, Feifei; Zhu, Jia; Lu, Suying; Zhen, Zijun; Wang, Juan; Huang, Junting; Ding, Zonghui; Zeng, Musheng; Sun, Xiaofei

2018-01-02

Systemic inflammatory parameters are associated with poor outcomes in malignant patients. Several inflammation-based cumulative prognostic score systems were established for various solid tumors. However, there is few inflammation based cumulative prognostic score system for patients with diffuse large B cell lymphoma (DLBCL). We retrospectively reviewed 564 adult DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy between Nov 1 2006 and Dec 30 2013 and assessed the prognostic significance of six systemic inflammatory parameters evaluated in previous studies by univariate and multivariate analysis:C-reactive protein(CRP), albumin levels, the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio(NLR), the platelet-lymphocyte ratio(PLR)and fibrinogen levels. Multivariate analysis identified CRP, albumin levels and the LMR are three independent prognostic parameters for overall survival (OS). Based on these three factors, we constructed a novel inflammation-based cumulative prognostic score (ICPS) system. Four risk groups were formed: group ICPS = 0, ICPS = 1, ICPS = 2 and ICPS = 3. Advanced multivariate analysis indicated that the ICPS model is a prognostic score system independent of International Prognostic Index (IPI) for both progression-free survival (PFS) (p systemic inflammatory status was associated with clinical outcomes of patients with DLBCL in rituximab era. The ICPS model was shown to classify risk groups more accurately than any single inflammatory prognostic parameters. These findings may be useful for identifying candidates for further inflammation-related mechanism research or novel anti-inflammation target therapies.

Prognostic Value of the Pretreatment Advanced Lung Cancer Inflammation Index (ALI) in Diffuse Large B Cell Lymphoma Patients Treated with R-CHOP Chemotherapy.

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Park, Young Hoon; Yi, Hyeon Gyu; Lee, Moon Hee; Kim, Chul Soo; Lim, Joo Han

2017-01-01

The Advanced Lung Cancer Inflammation Index (ALI, body mass index × albumin/neutrophil-to-lymphocyte ratio) has been demonstrated to be a prognostic factor of survival in some solid cancers. We retrospectively investigated the usefulness of the ALI to predict chemotherapy response and survival in 212 patients with diffuse large B cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. Patients were allocated to a low ALI group (n = 82, 38.7%) or a high ALI group (n = 130, 61.3%) according to an optimal pretreatment ALI cut-off value of 15.5 as determined by receiver operating curve analysis. The low ALI group displayed more adverse clinical characteristics, lower rates of complete remission (54.9 vs. 75.4%, p = 0.008), and poorer 5-year progression-free (PFS, 58.1 vs. 77.3%, p = 0.006) and overall (OS, 64.2 vs. 80.2%, p = 0.008) survival. Multivariate analysis showed that low ALI was found to independently predict shorter PFS and OS. Interestingly, a low ALI reverted to a high ALI during treatment in 58 patients (27.4%), and the 5-year OS of these patients was better than that of patients whose ALI remained low (n = 24, 72.5 vs. 24%, p ALI might be an easily available marker for predicting clinical outcomes in DLBCL patients treated with R-CHOP chemotherapy. © 2017 S. Karger AG, Basel.

Prognostic significances of overexpression MYC and/or BCL2 in R-CHOP-treated diffuse large B-cell lymphoma: A Systematic review and meta-analysis.

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Li, Lu; Li, Yanyan; Que, Ximei; Gao, Xue; Gao, Qian; Yu, Mingxing; Ma, Kaili; Xi, Yanfeng; Wang, Tong

2018-04-19

Numerous studies have investigated the prognostic values of MYC and/or BCL2 protein overexpression in diffuse large B-cell lymphoma (DLBCL). However, the results still demonstrate discrepancies among different studies. We aimed to do a systematic review and meta-analysis on the relationships between overexpression MYC and/or BCL2 and DLBCLs treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This study followed the guidelines of PRISMA and Cochrane handbook. The hazard ratios (HRs) for overall survival (OS) were pooled to estimate the main effect size. Twenty studies recruited a total of 5576 patients were available for this meta-analysis. The results showed that MYC (HR = 1.96, 95%CI (confidence interval) = 1.69-2.27)without heterogeneity(I 2  = 17.2%, P = 0.280), BCL2 (HR = 1.65, 95%CI = 1.43-1.89, I 2  = 20.7%, P = 0.234) protein overexpression, and co-overexpression (HR = 2.58, 95%CI = 2.19-3.04, I 2  = 17.2%, P = 0.275) had a poor prognosis in R-CHOP treated DLBCL patients, respectively. The current analysis indicated that MYC and/or BCL2 protein overexpression, and particularly co-overexpression was related to short overall survival in R-CHOP treated DLBCL patients, showing that application of the two new biomarkers can help to better stratify DLBCL patients and guide targeted treatment.

Two thymus-related autoimmune disorders: a case report and review of the literature

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Mirtavoos-Mahyari H

2014-05-01

Full Text Available Mirtavoos-Mahyari Hanifeh,1 Adnan Khosravi,2 Esfahani-Monfared Zahra,1 Shadmehr Mohammad Behgam31Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Tobacco Prevention and Control Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 3Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, IranAbstract: Thymoma is the most common tumor in the anterior mediastinum. A 56-year-old man presented unremitting and periodic chronic diarrhea of 9 weeks duration, and clinical examination revealed a huge nonhomogeneous mass lesion in the right lung and leukocytosis. He was treated with CHOP regimen (cyclophosphamide 1,200 mg/m2, doxorubicin 50 mg/m2, vincristine 1.5 mg/m2 and prednisolone 75 mg/m2 × 5 days based on lung mass computed tomography-guided biopsy, but he was reevaluated because neither symptom improved. Surprisingly, celiac disease was documented with increased titer of immunoglobulin antibodies to gliadin and tissue transglutaminase. Lung mass rebiopsy and thymectomy demonstrated thymoma. After surgery, the patient showed aplastic anemia that responded well to cyclosporine. At 2-year follow-up, the patient’s hematologic status and diarrhea were completely recovered and no symptom and/or sign of thymoma recurrence was seen.Keywords: thymus, thymoma, celiac, aplastic anemia, autoimmune disorder

Twenty-seven years of phase III trials for patients with extensive disease small-cell lung cancer: disappointing results.

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Isao Oze

Full Text Available BACKGROUND: Few studies have formally assessed whether treatment outcomes have improved substantially over the years for patients with extensive disease small-cell lung cancer (ED-SCLC enrolled in phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials. METHODS AND FINDINGS: We searched for trials that were reported between January 1981 and August 2008. Phase III randomized controlled trials were eligible if they compared first-line, systemic chemotherapy for ED-SCLC. Data were evaluated by using a linear regression analysis. RESULTS: In total, 52 trials were identified that had been initiated between 1980 and 2006; these studies involved 10,262 patients with 110 chemotherapy arms. The number of randomized patients and the proportion of patients with good performance status (PS increased over time. Cisplatin-based regimens, especially cisplatin and etoposide (PE regimen, have increasingly been studied, whereas cyclophosphamide, doxorubicin, and vincristine-based regimens have been less investigated. Multiple regression analysis showed no significant improvement in survival over the years. Additionally, the use of a PE regimen did not affect survival, whereas the proportion of patients with good PS and the trial design of assigning prophylactic cranial irradiation were significantly associated with favorable outcome. CONCLUSIONS AND SIGNIFICANCE: The survival of patients with ED-SCLC enrolled in phase III trials did not improve significantly over the years, suggesting the need for further development of novel targets, newer agents, and comprehensive patient care.

Usefulness of 18F-fluorodeoxyglucose positron emission tomography in follicular lymphoma management

International Nuclear Information System (INIS)

Le Dortz, L.; Devillers, A.; Prigent, F.; Bahri, H.; Hervouet, T.; Garin, E.; Guibert, S. de.; Lamy, T.; Rolland, Y.; Bayat, S.

2009-01-01

Purpose To assess the usefulness of positron emission tomography/computed tomography in staging, prognosis evaluation and re staging of patients with follicular lymphoma. Patients and methods a retrospective study was performed on 45 patients with untreated biopsy-proven follicular lymphoma who underwent F.D.G.-PET/CT and CT before and after chemo-immunotherapy induction treatment (rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone). Results PET/CT detected more nodal (+51%) and extra nodal (+89%) lesions than CT. PET/CT changed Ann Arbor stage in eight patients (18%). Five patients (11%) initially considered with early stage (I/II) were finally managed as advanced stage (III/IV). In this study, initial PET/CT was significantly more accurate to identify patients with poor prognosis than F.L.I.P.I.. Poor prognosis was defined as incomplete therapeutic response or early relapse. Accuracy of PET/CT for therapeutic response assessment was significantly higher than that of CT (0.97 vs 0.64), especially because of its ability to identify inactive residual masses. Beside, post-treatment PET/CT was able to predict patients outcome. The median progression free survival (P.F.S.) was 48 months in the PET/CT negative group as compared to 17.2 months for the group with residual uptake (P < 10-4). Conclusion F.D.G.-PET/CT is a very useful tool for staging, assessing prognosis and therapeutic response of patients with follicular lymphoma. (authors)

Diagnostic and prognostic impact of 18F-FDG PET/CT in follicular lymphoma

International Nuclear Information System (INIS)

Le Dortz, Ludovic; Garin, Etienne; Guibert, Sophie de; Houot, Roch; Bayat, Sahar; Cuggia, Marc; Devillers, Anne; Le Jeune, Florence; Bahri, Haifa; Barge, Marie-Luce; Rolland, Yan; Lamy, Thierry

2010-01-01

The aim of this study was to assess the usefulness of positron emission tomography/computed tomography in staging, prognosis evaluation and restaging of patients with follicular lymphoma. A retrospective study was performed on 45 patients with untreated biopsy-proven follicular lymphoma who underwent 18 F-fluorodeoxyglucose PET/CT (FDG PET/CT) and CT before and after chemoimmunotherapy induction treatment (rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone). PET/CT detected more nodal (+51%) and extranodal (+89%) lesions than CT. PET/CT modified Ann Arbor staging in eight patients (18%). Five patients (11%) initially considered as being early stage (I/II) were eventually treated as advanced stage (III/IV). In this study, an initial PET/CT prognostic score was significantly more accurate than the Follicular Lymphoma International Prognostic Index score in identifying patients with poor prognosis (i.e. patients with incomplete therapeutic response or early relapse). The accuracy of PET/CT for therapeutic response assessment was higher than that of CT (0.97 vs 0.64), especially due to its ability to identify inactive residual masses. In addition, post-treatment PET/CT was able to predict patients' outcomes. The median progression-free survival was 48 months in the PET/CT-negative group as compared with 17.2 months for the group with residual uptake (p -4 ). FDG PET/CT is useful for staging and assessing the prognosis and therapeutic response of patients with follicular lymphoma. (orig.)

CHOEP-21 chemotherapy for newly diagnosed nodal peripheral T-cell lymphomas (PTCLs) in Maharaj Nakorn Chiang Mai Hospital.

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Rattarittamrong, Ekarat; Norasetthada, Lalita; Tantiworawit, Adisak; Chai-Adisaksopha, Chatree; Nawarawong, Weerasak

2013-11-01

To determine the effectiveness and tolerability of the combination of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with the addition of etoposide (CHOEP-21) for newly diagnosed nodal peripheral T-cell lymphomas (PTCLs). Between January 2009 and October 2011, patients aged 18 to 60 years with newly diagnosed nodal PTCLs at the Maharaj Nakorn Chiang Mai Hospital were enrolled to receive CHOEP-21 every three weeks for eight cycles. G-CSF prophylaxis was given to all patients. Twenty-four patients were enrolled. Twenty of them were male with a median age of 49 years. The majority of patients (66.7%) had PTCL, not otherwise specified (PTCL, NOS), and 95.8% of the patients were in stage III or IV. The overall response rate was 58% with 42% having complete response. The response rates were better among patients with ALK-negative anaplastic large cell lymphoma (ALCL; 100%) and angioimmunoblastic T-cell lymphoma (AITL; 85%) than those with PTCL, NOS (44%). With a median follow-up of 21 months, the patients had an estimated 2-year event-free survival, and an overall survival rate of 37.6% and 54.4%, respectively. The most common adverse effects were infection and hematologic toxicities that was manageable. Although CHOEP-21 induced favorable responses in patients with ALK-negative ALCL and AITL, the responses were not durable and further therapy is mandated in management of patients with nodal PTCL.

Human T cell leukemia virus reactivation with progression of adult T-cell leukemia-lymphoma.

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Lee Ratner

Full Text Available Human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma (ATLL has a very poor prognosis, despite trials of a variety of different treatment regimens. Virus expression has been reported to be limited or absent when ATLL is diagnosed, and this has suggested that secondary genetic or epigenetic changes are important in disease pathogenesis.We prospectively investigated combination chemotherapy followed by antiretroviral therapy for this disorder. Nineteen patients were prospectively enrolled between 2002 and 2006 at five medical centers in a phase II clinical trial of infusional chemotherapy with etoposide, doxorubicin, and vincristine, daily prednisone, and bolus cyclophosphamide (EPOCH given for two to six cycles until maximal clinical response, and followed by antiviral therapy with daily zidovudine, lamivudine, and alpha interferon-2a for up to one year. Seven patients were on study for less than one month due to progressive disease or chemotherapy toxicity. Eleven patients achieved an objective response with median duration of response of thirteen months, and two complete remissions. During chemotherapy induction, viral RNA expression increased (median 190-fold, and virus replication occurred, coincident with development of disease progression.EPOCH chemotherapy followed by antiretroviral therapy is an active therapeutic regimen for adult T-cell leukemia-lymphoma, but viral reactivation during induction chemotherapy may contribute to treatment failure. Alternative therapies are sorely needed in this disease that simultaneously prevent virus expression, and are cytocidal for malignant cells.

Ewing sarcoma of the adrenal gland: a case report and review of the literature.

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Eddaoualline, Hanane; Mazouz, Khadija; Rafiq, Bouchra; El Mghari Tabib, Ghizlane; El Ansari, Nawal; Belbaraka, Rhizlane; El Omrani, Abdelhamid; Khouchani, Mouna

2018-03-16

Ewing sarcoma/primitive neuroectodermal tumor is a family of highly malignant proliferation of neuroectodermal origin, most often skeletal, adrenal localization is extremely rare. Only few cases have been reported in the literature. Classical management includes radical surgery with adjuvant chemotherapy or radiotherapy or both. This case report is the only one where recurrence was surgically removed, and it confirms the importance of adjuvant treatment, and the efficacy of neoadjuvant chemotherapy. We report the case of a 23-year-old Moroccan woman presenting with flank pain. An abdominal computed tomography scan showed a large and enhancing left suprarenal mass. After radical nephrectomy, histologic examination revealed a small round cell proliferation. The diagnosis of Ewing sarcoma was confirmed by molecular analysis; time to final diagnosis was 5 months due to financial and coordination issues. Computed tomography (on an asymptomatic patient) revealed a locoregional recurrence, our patient received 12 cycles of the vincristine, doxorubicin and cyclophosphamide/ifosfamide and etoposide protocol used in an alternating schedule, with partial radiologic response (62%) and pathologic complete response, then underwent adjuvant radiotherapy of 45 Gy. The young women is still in remission after 36 months of follow-up. Our patient had an early recurrence due to absence of adjuvant treatment, but did respond well to neoadjuvant chemotherapy with a pathologic complete response. Management of adrenal Ewing sarcoma could be extrapolated from skeletal one with good outcomes even in locoregional recurrence.

Treatment results in localized primary gastric lymphoma: data of patients registered within the German multicenter study (GIT NHL 02/96).

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Koch, Peter; Probst, Andreas; Berdel, Wolfgang E; Willich, Normann A; Reinartz, Gabriele; Brockmann, Jens; Liersch, Rüdiger; del Valle, Francisco; Clasen, Hermann; Hirt, Carsten; Breitsprecher, Regine; Schmits, Rudolf; Freund, Mathias; Fietkau, Rainer; Ketterer, Peter; Freitag, Eva-Maria; Hinkelbein, Margit; Heinecke, Achim; Parwaresch, Reza; Tiemann, Markus

2005-10-01

In the prospective study 02/96 on primary GI lymphoma, we have collected data on histology, clinical features, and treatment results. In particular, in stages I and II localized primary gastric lymphoma (PGL), our objectives were to reduce treatment intensity and to confirm our hypothesis from study 01/92, which maintained that an organ-preserving approach is not inferior to primary surgery. Patients receiving radiotherapy and/or chemotherapy were stratified for histologic grade, stage, and whether surgery had been carried out or not (as decided by each participating center). Patients with aggressive PGL received six cycles of CHOP-14 (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by involved-field radiotherapy (40 Gy). Patients with indolent PGL (including patients experiencing treatment failure with antibiotic therapy for Helicobacter pylori) were treated with extended-field radiotherapy. The volume depended on stage. The irradiation dose was 30 Gy, followed by a boost of 10 Gy (the latter omitted after complete resection) to the tumor region. Seven hundred forty-seven patients were accrued. Of these patients, 393 with localized PGL were treated with radiotherapy and/or chemotherapy only or additional surgery between December 1996 and December 2003. The survival rate at 42 months for patients treated with surgery was 86% compared with 91.0% for patients without surgery. In this nonrandomized study (02/96), we reproduced the previous results of study 01/92 showing no disadvantage for an organ-preserving treatment. Therefore, primary stomach resection should be questioned.

Management of mantle cell lymphoma in the elderly: current and potential strategies.

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Vignon, Marguerite; Venon, Marie-Dominique; Hermine, Olivier; Delarue, Richard

2013-12-01

Mantle cell lymphoma is a distinct subtype of B-cell non-Hodgkin lymphoma, accounting for 3-10 % of all non-Hodgkin lymphoma cases. The median age at diagnosis is nearly 70 years. The prognosis of patients is based on the Mantle Cell Lymphoma International Prognostic Index, which is calculated on the basis of four independent prognostic factors (age, performance status, serum lactate dehydrogenase and leukocyte count). Treatment of elderly patients with de novo untreated mantle cell lymphoma is based on rituximab combined with chemotherapy. The most commonly used regimen is the classical CHOP21 (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen. Bendamustine is also an option, especially for patients with cardiac comorbidities. In elderly patients who are relatively young and fit, an approach based on treatment usually used for younger patients, with cytarabine-based induction followed by autologous stem cell transplantation, should be discussed. Treatment of relapsing patients is based on the use of newer effective drugs, including bortezomib, lenalidomide and thalidomide, and mammalian target of rapamycin (mTOR) inhibitors, such as temsirolimus. These drugs are often combined with rituximab and can be prescribed in combination with chemotherapy. Promising new drugs are Bruton tyrosine kinase inhibitors and other inhibitors of the phosphoinositide 3-kinase (PI3K)-mTOR-protein kinase B (AKT) pathway. Despite these new advances, mantle cell lymphoma remains an incurable disease, and further basic and clinical research is warranted.

Radiotherapy Does Not Influence the Severe Pulmonary Toxicity Observed With the Administration of Gemcitabine and Bleomycin in Patients With Advanced-Stage Hodgkin's Lymphoma Treated With the BAGCOPP Regimen: A Report by the German Hodgkin's Lymphoma Study Group

International Nuclear Information System (INIS)

Macann, Andrew; Bredenfeld, Henning; Mueller, Rolf-Peter; Diehl, Volker; Engert, Andreas; Eich, Hans Theodor

2008-01-01

Purpose: To evaluate the effect of radiotherapy on the severe pulmonary toxicity observed in the pilot study of BAGCOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine) for advanced-stage Hodgkin's lymphoma. Methods and Materials: Patients with Stage III or IV Hodgkin's lymphoma or Stage IIB with risk factors participated in this single-arm, multicenter pilot study. Results: Twenty-seven patients were enrolled on the study before its premature closure as a result of the development of serious pulmonary toxicity in 8 patients. The pulmonary toxicity occurred either during or immediately after the BAGCOPP chemotherapy course. Pulmonary toxicity contributed to one early fatality but resolved in the other 7 patients after cessation of gemcitabine and bleomycin, allowing continuation of therapy. Fifteen patients received consolidative radiotherapy, including 4 who previously had pulmonary toxicity. There were no reported cases of radiation pneumonitis and no exacerbation of pulmonary symptoms in the 4 patients who had had previous pulmonary toxicity. Conclusions: The severe pulmonary toxicity observed in this study has been attributed to an interaction between gemcitabine and bleomycin. Gemcitabine (when administered without bleomycin) remains of interest in Hodgkin's lymphoma and is being incorporated into a new German Hodgkin's Lymphoma Study Group protocol that also includes consolidative radiotherapy. This study supports the concept of the integration of radiotherapy in gemcitabine-containing regimens in Hodgkin's lymphoma if there is an interval of at least 4 weeks between the two modalities and with a schedule whereby radiotherapy follows the chemotherapy

Effect of doxorubicin on cell survival and micronuclei formation in HeLa cells exposed to different doses of gamma-radiation

International Nuclear Information System (INIS)

Jagetia, G.C.; Nayak, V.

2000-01-01

Purpose: The present study was undertaken to obtain an insight into the combined effects of doxorubicin with radiation on the cell survival and micronuclei induction in HeLa cells. Material and Methods: HeLa S3 cells were allowed to grow till they reached plateau phase, inoculated with 10 μg/ml doxorubicin hydrochloride and then exposed to 0, 0.5, 1, 2 and 3 Gy γ-radiation. Clonogenicity of cell was measured using the colony forming assay, micronuclei formation using the micronucleus assay. Results: The treatment of HeLa cells with doxorubicin (adriamycin) for 2 hours before exposure to different doses of γ-radiation resulted in a significant and dose-dependent decline in the cell survival and cell proliferation when compared to the PBS+irradiation group. Conversely, the frequency of micronuclei increased in a dose-related manner in both the PBS+irradiation and doxorubicin+irradiation groups. The pretreatment of HeLa cells with doxorubicin before irradiation to various doses of γ-rays resulted in a significant elevation in the frequency of micronuclei when compared with the concurrent PBS+irradiation group. The dose-response relationship for both PBS+irradiation and doxorubicin+irradiation groups was linear. The correlation between cell survival and micronuclei induction was also determined for PBS or doxorubicin+irradiation group, where the clonogenicity of cells declined with the increase in micronuclei formation. The correlation between cell survical and micronuclei induction was linear quadratic for both PBS+irradiation and doxorubicin+irradiation groups. Conclusion: From our study it can be concluded that combination treatment with doxorubicin and radiation increased the genotoxic effect of the either treatment given alone. (orig.) [de

Selective Killing of Breast Cancer Cells by Doxorubicin-Loaded Fluorescent Gold Nanoclusters: Confocal Microscopy and FRET.

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Chattoraj, Shyamtanu; Amin, Asif; Jana, Batakrishna; Mohapatra, Saswat; Ghosh, Surajit; Bhattacharyya, Kankan

2016-01-18

Fluorescent gold nanoclusters (AuNCs) capped with lysozymes are used to deliver the anticancer drug doxorubicin to cancer and noncancer cells. Doxorubicin-loaded AuNCs cause the highly selective and efficient killing (90 %) of breast cancer cells (MCF7) (IC50 =155 nm). In contrast, the killing of the noncancer breast cells (MCF10A) by doxorubicin-loaded AuNCs is only 40 % (IC50 =4500 nm). By using a confocal microscope, the fluorescence spectrum and decay of the AuNCs were recorded inside the cell. The fluorescence maxima (at ≈490-515 nm) and lifetime (≈2 ns), of the AuNCs inside the cells correspond to Au10-13 . The intracellular release of doxorubicin from AuNCs is monitored by Förster resonance energy transfer (FRET) imaging. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Long-term follow-up of cyclophosphamide compared with azathioprine for initial maintenance therapy in ANCA-associated vasculitis

DEFF Research Database (Denmark)

Walsh, M.; Faurschou, M.; Berden, A.

2014-01-01

BACKGROUND AND OBJECTIVES: Treatment with azathioprine within 3 months of remission induction with cyclophosphamide is a common treatment strategy for patients with ANCA-associated vasculitis. This study comprised patients undergoing long-term follow-up who were randomly allocated to azathioprine...... after 3-6 months or after 12 months of cyclophosphamide treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients from 39 European centers between 1995 and 1997 with a new diagnosis of ANCA-associated vasculitis that involved the kidneys or another vital organ were eligible. At the time...

Eleutheroside E inhibits doxorubicin-induced inflammation and ...

African Journals Online (AJOL)

Purpose: To identify the effects of eleutheroside E (EE) on apoptosis and inflammation induced by doxorubicin (DOX) in H9c2 cells and to investigate the underlying mechanisms. Methods: The effect of EE on H9c2 cell viability was determined using Cell Counting Kit-8 (CCK8). EE effect on DOX-induced apoptosis and ...

Age-related effect of aerobic exercise training on antioxidant and oxidative markers in the liver challenged by doxorubicin in rats.

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Ahmadian, Mehdi; Dabidi Roshan, Valiollah; Leicht, Anthony S

2018-05-16

The aims of the current study were to investigate the oxidant and antioxidant status of liver tissue challenged by doxorubicin and to examine the possible protective effects of aerobic exercise on doxorubicin-induced oxidative stress. Seventy-two rats were divided into three age groups (Young, Adult, and Elderly) with three treatment subgroups consisting of eight rats per age group: doxorubicin, aerobic exercise + doxorubicin, and aerobic exercise + saline. The experimental groups performed regular treadmill running for 3 weeks. Doxorubicin was administered by i.p. injection at a dosage of 20 mg kg -1 while the aerobic exercise + saline group received saline of a comparable volume. Heat shock protein 70, malondialdehyde, glutathione peroxidase, and protein carbonyl were determined from the liver homogenates following the intervention period. Treatment with doxorubicin induced hepatotoxicity in all groups with lower values of oxidative stress in young compared with the older groups. The inclusion of aerobic exercise training significantly increased heat shock protein 70 and antioxidant enzyme levels (glutathione peroxidase) whereas it decreased oxidative stress biomarkers (malondialdehyde and protein carbonyl) for all age groups. These results suggest that aerobic exercise training may be a potential, non-drug strategy to modulate doxorubicin-induced hepatotoxicity through its positive impact on antioxidant levels and oxidative stress biomarkers.

Doxorubicin-mediated bone loss in breast cancer bone metastases is driven by an interplay between oxidative stress and induction of TGFβ.

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Tapasi Rana

Full Text Available Breast cancer patients, who are already at increased risk of developing bone metastases and osteolytic bone damage, are often treated with doxorubicin. Unfortunately, doxorubicin has been reported to induce damage to bone. Moreover, we have previously reported that doxorubicin treatment increases circulating levels of TGFβ in murine pre-clinical models. TGFβ has been implicated in promoting osteolytic bone damage, a consequence of increased osteoclast-mediated resorption and suppression of osteoblast differentiation. Therefore, we hypothesized that in a preclinical breast cancer bone metastasis model, administration of doxorubicin would accelerate bone loss in a TGFβ-mediated manner. Administration of doxorubicin to 4T1 tumor-bearing mice produced an eightfold increase in osteolytic lesion areas compared untreated tumor-bearing mice (P = 0.002 and an almost 50% decrease in trabecular bone volume expressed in BV/TV (P = 0.0005, both of which were rescued by anti-TGFβ antibody (1D11. Doxorubicin, which is a known inducer of oxidative stress, decreased osteoblast survival and differentiation, which was rescued by N-acetyl cysteine (NAC. Furthermore, doxorubicin treatment decreased Cu-ZnSOD (SOD1 expression and enzyme activity in vitro, and treatment with anti-TGFβ antibody was able to rescue both. In conclusion, a combination therapy using doxorubicin and anti-TGFβ antibody might be beneficial for preventing therapy-related bone loss in cancer patients.

Pilot study of interaction of radiation therapy with doxorubicin by continuous infusion

International Nuclear Information System (INIS)

Rosenthal, C.J.; Rotman, M.

1988-01-01

Doxorubicin was initially administered alone by continuous infusion for 5 days every 3 weeks in escalating doses to 13 patients with advanced metastatic and/or recurrent malignancies. The maximum tolerable dosage was 13 mg/m2 per day for 5 days. Kinetic data showed a steady level of 60 ng/ml for 4 days and a biphasic disappearance curve. Radiation therapy (150-200 cGy per session) was then administered in 5-day cycles, every 3 weeks, concomitantly with continuous infusion of doxorubicin (12 mg/m2 per day) to 21 patients with various advanced unresectable recurrent or metastatic malignancies. Four of 9 patients with soft tissue sarcomas achieved complete response after a radiation dose of 2,206 +/- 590 (SD) cGy and 3 had partial response; the median durations of the response were 142 +/- 65 (SD) weeks for complete response and 28 +/- 10 weeks for partial response. Of 4 patients with primary hepatoma, 2 achieved partial response after 1,290 +/- 210 cGy. No response was seen in any of the 7 patients with adenocarcinoma of the gastrointestinal tract or breast. Complications of this regimen included moderate leukopenia and thrombocytopenia, mucositis, skin erythema, and decrease of the ventricular ejection fraction at a cumulative doxorubicin dose of 840 mg/m2. We conclude that doxorubicin given by protracted infusion can be safely administered with concomitant radiation and appears to enhance the effects of radiation on most soft tissue sarcomas and on some hepatocellular carcinomas

JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin.

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Qiu, Mingning; Ke, Longzhi; Zhang, Sai; Zeng, Xin; Fang, Zesong; Liu, Jianjun

2017-08-01

Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells. The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species. We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production. JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.

Targeted delivery of doxorubicin-utilizing chitosan nanoparticles surface-functionalized with anti-Her2 trastuzumab

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Yousefpour P

2011-09-01

Full Text Available Parisa Yousefpour1, Fatemeh Atyabi2, Ebrahim Vasheghani-Farahani3, Ali-Akbar Mousavi Movahedi1, Rassoul Dinarvand21Department of Biotechnology, Faculty of Science, University of Tehran, 2Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, 3Biotechnology Group, Department of Chemical Engineering, Faculty of Engineering, Tarbiat Modares University, Tehran, IranBackground: Targeting drugs to their sites of action to overcome the systemic side effects associated with most antineoplastic agents is still a major challenge in pharmaceutical research. In this study, the monoclonal antibody, trastuzumab, was used as a targeting agent in nanoparticles carrying the antitumor drug, doxorubicin, specifically to its site of action.Methods: Chitosan-doxorubicin conjugation was carried out using succinic anhydride as a crosslinker. Trastuzumab was conjugated to self-assembled chitosan-doxorubin conjugate (CS-DOX nanoparticles (particle size, 200 nm via thiolation of lysine residues and subsequent linking of the resulted thiols to chitosan. Conjugation was confirmed by gel permeation chromatography, differential scanning calorimetry, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance spectroscopy studies. Dynamic light scattering, transmission electron microscopy, and zeta potential determination were used to characterize the nanoparticles.Results: CS-DOX conjugated nanoparticles had a spherical shape and smooth surface with a narrow size distribution and core-shell structure. Increasing the ratio of doxorubicin to chitosan in the conjugation reaction gave rise to a higher doxorubicin content but lower conjugation efficiency. Trastuzumab-decorated nanoparticles (CS-DOX-mAb contained 47 µg/mg doxorubicin and 33.5 µg/mg trastuzumab. Binding of trastuzumab to the nanoparticles was further probed thermodynamically by isothermal titration calorimetry. Fluorescence microscopy demonstrated enhanced and

Mesenchymal Stem Cells Reduce Left Ventricular Mass in Rats with Doxorubicin-Induced Cardiomyopathy

OpenAIRE

Haydardedeoglu, Ali Evren; Boztok Özgermen, Deva Basak; Yavuz, Orhan

2018-01-01

SUMMARY: Doxorubicin is a drug that used by a majority in the treatment of carcinomas. The most obvious known side effect is cardiomyopathy. Many studies have been carried out to eliminate side effects of the doxorubicin, and stem cell studies have been added in recent years. In this study, it was aimed to investigate fetal-derived mesenchymal stem cells (F-MSCs) treatment of doxorubicininduced cardiomyopathy by morphological methods. A total of 24 rats which were divided into three separate ...

Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity

International Nuclear Information System (INIS)

Mitra, Mayurranjan S.; Donthamsetty, Shashikiran; White, Brent; Latendresse, John R.; Mehendale, Harihara M.

2007-01-01

Clinical use of doxorubicin (Adriamycin (registered) ), an antitumor agent, is limited by its oxyradical-mediated cardiotoxicity. We tested the hypothesis that moderate diet restriction protects against doxorubicin-induced cardiotoxicity by decreasing oxidative stress and inducing cardioprotective mechanisms. Male Sprague-Dawley rats (250-275 g) were maintained on diet restriction [35% less food than ad libitum]. Cardiotoxicity was estimated by measuring biomarkers of cardiotoxicity, cardiac function, lipid peroxidation, and histopathology. A LD 100 dose of doxorubicin (12 mg/kg, ip) administered on day 43 led to 100% mortality in ad libitum rats between 7 and 13 days due to higher cardiotoxicity and cardiac dysfunction, whereas all the diet restricted rats exhibited normal cardiac function and survived. Toxicokinetic analysis revealed equal accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the ad libitum and diet restricted hearts. Mechanistic studies revealed that diet restricted rats were protected due to (1) lower oxyradical stress from increased cardiac antioxidants leading to downregulation of uncoupling proteins 2 and 3, (2) induction of cardiac peroxisome proliferators activated receptor-α and plasma adiponectin increased cardiac fatty acid oxidation (666.9 ±14.0 nmol/min/g heart in ad libitum versus 1035.6 ± 32.3 nmol/min/g heart in diet restriction) and mitochondrial AMPα2 protein kinase. The changes led to 51% higher cardiac ATP levels (17.7 ± 2.1 μmol/g heart in ad libitum versus 26.7 ± 1.9 μmol/g heart in diet restriction), higher ATP/ADP ratio, and (3) increased cardiac erythropoietin and decreased suppressor of cytokine signaling 3, which upregulates cardioprotective JAK/STAT3 pathway. These findings collectively show that moderate diet restriction renders resiliency against doxorubicin cardiotoxicity by lowering oxidative stress, enhancing ATP synthesis, and inducing the JAK/STAT3 pathway

Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats

International Nuclear Information System (INIS)

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

2015-01-01

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 (3 mg/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 (P < 0.05 or 0.01) induced by doxorubicin. In rats treated with doxorubicin, taurine zinc dose-dependently increased liver superoxide dismutase activity and glutathione concentration, and decreased malondialdehyde level (P < 0.01). qBase + was used to evaluate the stability of eight candidate reference genes for real-time quantitative reverse-transcription PCR. Taurine zinc dose-dependently increased liver heme oxygenase-1 and UDP-glucuronyl transferase mRNA and protein expression (P < 0.01). Western blotting demonstrated that taurine zinc 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. - Highlights: �

Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats

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Wang, Yu; Mei, Xueting; Yuan, Jingquan; Lu, Wenping; Li, Binglong; Xu, Donghui, E-mail: Donghuixu007@163.com

2015-11-15

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 (3 mg/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{sup 2+} and albumin levels (P < 0.05 or 0.01) induced by doxorubicin. In rats treated with doxorubicin, taurine zinc dose-dependently increased liver superoxide dismutase activity and glutathione concentration, and decreased malondialdehyde level (P < 0.01). qBase{sup +} was used to evaluate the stability of eight candidate reference genes for real-time quantitative reverse-transcription PCR. Taurine zinc dose-dependently increased liver heme oxygenase-1 and UDP-glucuronyl transferase mRNA and protein expression (P < 0.01). Western blotting demonstrated that taurine zinc 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. - Highlights: �

Circumvention of inherent or acquired cytotoxic drug resistance in vitro using combinations of modulating agents.

Science.gov (United States)

Cadagan, David; Merry, Stephen

2013-10-01

Modulating agents are used to circumvent drug resistance in the clinical setting. However achievable serum concentrations are often lower than those which are optimal in vitro. Combination of modulating agents with non-overlapping toxicities may overcome this obstacle. We have investigated combinations of three modulating agents (quinine, verapamil, and cinnarizine) to circumvent inherent or acquired resistance to the cytotoxic drugs doxorubicin, vincristine and paclitaxel. Dose-response curves to cytotoxic drugs in the presence/absence of modulating agents were determined using colony formation and cell proliferation assays. Doxorubicin accumulation into cell monolayers was measured by fluorescence spectrophotometry. Greater (1.9-fold) sensitisation to particular cytotoxic drugs was observed for certain combinations of modulating agents compared to individual effects. The most effective combination was quinine-plus-verapamil with the cytotoxic drug doxorubicin. This increase in sensitivity was associated with increased doxorubicin accumulation. Such enhanced activity was, however, not observed for all combinations of modulating agents or for all studied cytotoxic drugs. The findings of the present study suggest certain combinations of modulating agents to have a clinical role in circumventing drug resistance. Particular combinations of modulating agents must be carefully chosen to suit particular cytotoxic drug treatments.

Hesperidin as a preventive resistance agent in MCF–7 breast cancer cells line resistance to doxorubicin

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Rifki Febriansah

2014-03-01

Conclusions: Hesperidin has cytotoxic effect on MCF-7/Dox cells with IC50 of 11 μmol/L. Hesperidin did not increased the apoptotic induction combined with doxorubicin. Co-chemotherapy application of doxorubicin and hesperidin on MCF-7/Dox cells showed synergism effect through inhibition of Pgp expression.

Studies on the effect of doxorubicin on MDA, NO2, NO3, Se-GSH ...

African Journals Online (AJOL)

SERVER

2007-10-18

Oct 18, 2007 ... Nitric oxide; NO2. - Nitric oxide; NO3- ... The lipid peroxides were determined by the TBA me- ... Effect of different doses of doxorubicin on rat serum nitrite (NO2 .... 2306. Afr. J. Biotechnol. 0. 5. 10. 15. 20. 25. 30. P e rc e n. t c h a n g e o v e ... Doxorubicin induced percent changes of rat serum Nitrate (NO3.

Gene expression profiling in chemoresistant variants of three cell lines of different origin

DEFF Research Database (Denmark)

Johnsson, Anders; Vallon-Christensson, Johan; Strand, Carina

2005-01-01

lines (K562 leukemia, MCF-7 breast cancer and S1 colon cancer) with acquired resistance against five cytostatic drugs; daunorubicin (DNR), doxorubicin (DOX), vincristine (VCR), etoposide (VP) and mitoxantrone (MX). RESULTS: The resistant cell lines clustered together based on their type of origin...... was also seen in, e.g., GSTs, topoisomerases, caveolins, annexins and CD44. CONCLUSION: These results will constitute a platform for further studies on specific pathways and biological processes involved in chemotherapy resistance....

Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of Ovarian Cancer

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Carmela Pisano

2013-01-01

Full Text Available Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD, whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent.

Preparation, quality control and biodistribution of [61Cu]-doxorubicin for PET imaging

International Nuclear Information System (INIS)

Jalilian, A.R.; Akhlaghi, M.; Zandi, H.; Yousefnia, H.; Faghihi, R.

2009-01-01

This work was conducted for radiolabeling of an anticancer antibiotic, i.e. doxorubicin with 61 Cu for production of possible tracer used in PET oncology. 61 Cu was prepared with natural zinc target and 22 MeV 150 μA protons via nat Zn(p, xn) 61 Cu reaction with a yield of 123.2 MBq·μA -1 ·h -1 . Optimization reactions were performed for pH, temperature and concentration. Biodistribution of the tracer was studied in normal and fibrosarcoma bearing mice. At the optimized conditions, ITLC showed that radiochemical purity was over 97% with a specific activity of 2.22 X 10 3 MBq·mmol -1 ·L -1 . This was kept unchanged even with presence of human serum as well as room temperature for 5 h. Biodistribution of the tracer in fibrosarcoma bearing mice demonstrated significant tumor uptake after 2 h. This tracer can be used in the detection of various tumors responding to doxorubicin chemotherapy using PET scan and/or determination of tumor therapy response to doxorubicin chemotherapy. (authors)

Ecotoxicity and genotoxicity of cyclophosphamide, ifosfamide, their metabolites/transformation products and their mixtures

International Nuclear Information System (INIS)

Česen, Marjeta; Eleršek, Tina; Novak, Matjaž; Žegura, Bojana; Kosjek, Tina; Filipič, Metka; Heath, Ester

2016-01-01

Cyclophosphamide (CP) and ifosfamide (IF) are commonly used cytostatic drugs that repress cell division by interaction with DNA. The present study investigates the ecotoxicity and genotoxicity of CP, IF, their human metabolites/transformation products (TPs) carboxy-cyclophosphamide (CPCOOH), keto-cyclophosphamide (ketoCP) and N-dechloroethyl-cyclophosphamide (NdCP) as individual compounds and as mixture. The two parent compounds (CP and IF), at concentrations up to 320 mg L −1 , were non-toxic towards the alga Pseudokirchneriella subcapitata and cyanobacterium Synecococcus leopoliensis. Further ecotoxicity studies of metabolites/TPs and a mixture of parent compounds and metabolites/TPs performed in cyanobacteria S. leopoliensis, showed that only CPCOOH (EC 50  = 17.1 mg L −1 ) was toxic. The measured toxicity (EC 50  = 11.5 mg L −1 ) of the mixture was lower from the toxicity predicted by concentration addition model (EC 50  = 21.1 mg L −1 ) indicating potentiating effects of the CPCOOH toxicity. The SOS/umuC assay with Salmonella typhimurium revealed genotoxic activity of CP, CPCOOH and the mixture in the presence of S9 metabolic activation. Only CPCOOH was genotoxic also in the absence of metabolic activation indicating that this compound is a direct acting genotoxin. This finding is of particular importance as in the environment such compounds can directly affect DNA of non-target organisms and also explains toxicity of CPCOOH against cyanobacteria S. leopoliensis. The degradation study with UV irradiation of samples containing CP and IF showed efficient degradation of both compounds and remained non-toxic towards S. leopoliensis, suggesting that no stable TPs with adverse effects were formed. To our knowledge, this is the first study describing the ecotoxicity and genotoxicity of the commonly used cytostatics CP and IF, their known metabolites/TPs and their mixture. The results indicate the importance of toxicological evaluation and

A Phase I Study of Triapine® in Combination with Doxorubicin in Patients with Advanced Solid Tumors

Science.gov (United States)

Schelman, William R.; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M.; Ivy, Percy; Wilding, George; Traynor, Anne M.

2011-01-01

Purpose To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine® administered in combination with doxorubicin. Study Design Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine® IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m2 and Triapine® 25 mg/m2. PK analysis was performed at various time-points before and after treatment. Results Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m2, Triapine® 45 mg/m2), 2 patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional 3 patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m2) with Triapine® 45 mg/m2. The 2 patients enrolled on this level had 2 DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine® were reduced to 45 mg/m2 and 25 mg/m2, respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Conclusions Pretreated patients with advanced malignancies can tolerate the combination of Triapine® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m2 on day 1 and Triapine® 25 mg/m2 on

Solid tumor models for the assessment of different treatment modalities. XIV. The evaluation of host and tumor response to cyclophosphamide and radiation

International Nuclear Information System (INIS)

Looney, W.B.; Hopkins, H.A.; MacLeod, M.S.; Ritenour, E.R.

1979-01-01

The effect of increasing doses of cyclophosphamide (50 to 250 mg/kg) on the time of occurrence of maximal and minimal tumor growth rates, tumor volume reduction, and linear doubling times (LDT) on the solid tumor model H-4-II-E has been determined. Tumor response to cyclophosphamide was classified as class I, tumor regression; class II, pseudo-regression; and class III, slow-down. The overall treatment efficiency (OTE) has been used to assess the magnitude of tumor volume changes after treatment. The maximum OTE occurred after 150 mg/kg of cyclophosphamide. Increasing the dose to 200 and 250 mg/kg of cyclophosphamide resulted in a decrease in OTE. Similar parameters were utilized to measure the effectiveness of increasing doses of local tumor radiation (750, 1500, 2000, 2500, 3000 and 3500R). The major increase in OTE occurs when the radiation dose is increased from 750R to 2000R. Increasing the dose further to 3500R results in smaller incremental increases in the OTE. Results of the study indicate that increasing the cyclophosphamide dose beyond a certain level (i.e., 150 mg/kg) increases mortality and morbidity without concomitant therapeutic benefit. The effects of increasing the dose of local tumor radiation on life span have given results which suggest that increasing the total radiation dose beyond a certain limit is less effective in increasing life span

Potentiation of apoptosis by histone deacetylase inhibitors and doxorubicin combination: cytoplasmic cathepsin B as a mediator of apoptosis in multiple myeloma.

Science.gov (United States)

Cheriyath, V; Kuhns, M A; Kalaycio, M E; Borden, E C

2011-03-15

Although inhibitors of histone deacetylase inhibitors (HDACis) in combination with genotoxins potentiate apoptosis, the role of proteases other than caspases in this process remained elusive. Therefore, we examined the potentiation of apoptosis and related mechanisms of HDACis and doxorubicin combination in a panel of myeloma cell lines and in 25 primary myelomas. At IC(50) concentrations, sodium butyrate (an HDACi) or doxorubicin alone caused little apoptosis. However, their combination potentiated apoptosis and synergistically reduced the viability of myeloma cells independent of p53 and caspase 3-7 activation. Potentiated apoptosis correlated with nuclear translocation of apoptosis-inducing factor, suggesting the induction of caspase 3- and 7-independent pathways. Consistent with this, butyrate and doxorubicin combination significantly increased the activity of cytoplasmic cathepsin B. Inhibition of cathepsin B either with a small-molecule inhibitor or downregulation with a siRNA reversed butyrate- and doxorubicin-potentiated apoptosis. Finally, ex vivo, clinically relevant concentrations of butyrate or SAHA (suberoylanilide hydroxamic acid, vorinostat, an HDACi in clinical testing) in combination with doxorubicin significantly (Pmediating apoptosis potentiated by HDACi and doxorubicin combinations in myeloma. Our results support a molecular model of lysosomal-mitochondrial crosstalk in HDACi- and doxorubicin-potentiated apoptosis through the activation of cathepsin B.

Mangifera indica L. leaf extract alleviates doxorubicin induced cardiac stress

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Laxit Bhatt

2017-09-01

Conclusion: The present findings clearly suggest the protective role of alcoholic leaf extract of M. indica against oxidative stress induced by doxorubicin. [J Complement Med Res 2017; 6(3.000: 284-289

Serial exercise gated radionuclide ventriculograms (RVG) in monitoring doxorubicin cardiotoxicity

International Nuclear Information System (INIS)

Goldstein, H.A.; Lahoda, J.; Fox, L.

1985-01-01

The resting RVG (Radionuclide Ventriculograms) are demonstrated to be an effective monitor of the cardiotoxicity of doxorubicin. The exercise RVG has not been as well studied to see if it yields additional information or detects toxicity effects earlier. Sixteen patients receiving doxorubicin for chemotherapy had 2-6 serial exercise studies with intervals between studies of 1 month to 15 months. The patients exercised varying amounts with cardiac work indicated by their double products (HR x Sys. BP). Although all patients started with a normal resting LVEF (>50%), 5 of the 16 did not have a normal response (≥5% increase in LVEF) with initial exercise study. Of the 11 patients with an initially normal response to exercise, on at least one subsequent study, 3 had an abnormal response to exercise. On a later follow up study 1 of these 3 patients again had a normal response to exercise. Six of these 11 patients had had RVG evidence of cardiotoxicity. Four of these 6 patients had continually normal exercise responses, while 2 of these 5 patients had had an abnormal exercise response. An initial exercise RVG may be reasonable to detect unsuspected CAD in cancer victims. These patients are reported to be more sensitive to the toxic effects of doxorubicin. Follow up exercise RVGs do not contribute useful information, do not predict cardiotoxicity, and may be misleading

Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide

DEFF Research Database (Denmark)

Ellebaek, Eva; Engell-Noerregaard, Lotte; Iversen, Trine Zeeberg

2012-01-01

Dendritic cells (DC) are the most potent antigen presenting cells and have proven effective in stimulation of specific immune responses in vivo. Competing immune inhibition could limit the clinical efficacy of DC vaccination. In this phase II trial, metronomic Cyclophosphamide and a Cox-2 inhibitor...... have been added to a DC vaccine with the intend to dampen immunosuppressive mechanisms. Twenty-eight patients with progressive metastatic melanoma were treated with autologous DCs pulsed with survivin, hTERT, and p53-derived peptides (HLA-A2(+)) or tumor lysate (HLA-A2(-)). Concomitantly the patients...... were treated with IL-2, Cyclophosphamide, and Celecoxib. The treatment was safe and tolerable. Sixteen patients (57 %) achieved stable disease (SD) at 1st evaluation and 8 patients had prolonged SD (7-13.7 months). The median OS was 9.4 months. Patients with SD had an OS of 10.5 months while patients...

C(60 fullerene prevents genotoxic effects of doxorubicin in human lymphocytes in vitro

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K. S. Afanasieva

2015-02-01

Full Text Available The self-ordering of C60 fullerene, doxorubicin and their mixture precipitated from aqueous solutions was investigated using atomic-force microscopy. The results suggest the complexation between the two compounds. The genotoxicity of doxorubicin in complex with C60 fullerene (С60+Dox was evaluated in vitro with comet assay using human lymphocytes. The obtained results show that the C60 fullerene prevents the toxic effect of Dox in normal cells and, thus, С60+Dox complex might be proposed for biomedical application.

Study on the Antiradiation role of Melatonin: An investigation on Induced Oxidative Stress Mice by Radiomimetic Drug Cyclophosphamide

Energy Technology Data Exchange (ETDEWEB)

Manda, K.; Bhatia, A. L.

2004-07-01

Clinical studies have demonstrated an altered pineal function in cancer patients. Owing to the document antineoplastic activity of the pineal gland, these anomalies could have a prognostic significance. This study was carried out to monitor the effect of higher blood levels of melatonin, the most important pineal hormone, which could be applied in relation to the response to chemotherapy in human neoplasms. Cyclophosphamide is a commonly used chemotherapeutic drug and well-known mutagen and clastogen. It is an alkylating agent, producing highly active carbonium ion, which the extremely electron-rich area of the nucleic acids and proteins. The present study aimed to investigate the protective effect of melatonin against cyclophosphamide induced oxidative stress in mice tissues. Lipid perioxidation. Reduced glutathione (GSH), Glutathione disulphide (GSSG), Glutathione peroxidase (GSH-Px) and serum phosphatase level taken as endpoints. Twenty days oral administration with melatonin (0.25 mg/Kg body weight) followed by an acute treatment with cyclophosphamide (75 mg/kg b. w.) inhibited the radiomimetic drug-induced augmented level of lipid peroxidation, Blood GSSG and acid phosphatase. Cyclophosphamide induced depletion in the level of GSH, GSH-Px and alkaline phosphatase is ameliorated significantly by melatonin administration. The findings support the results showing melatonin as a free radical scavenger, and singlet oxygen quencher. Results clearly indicate the antioxidative properties of melatonin against the radiomimetic drug which could be effectively used selectively for the protection of normal tissue during chemotherapy. (Author) 34 refs.

Study on the Antiradiation role of Melatonin: An investigation on Induced Oxidative Stress Mice by Radiomimetic Drug Cyclophosphamide

International Nuclear Information System (INIS)

Manda, K.; Bhatia, A. L.

2004-01-01

Clinical studies have demonstrated an altered pineal function in cancer patients. Owing to the document antineoplastic activity of the pineal gland, these anomalies could have a prognostic significance. This study was carried out to monitor the effect of higher blood levels of melatonin, the most important pineal hormone, which could be applied in relation to the response to chemotherapy in human neoplasms. Cyclophosphamide is a commonly used chemotherapeutic drug and well-known mutagen and clastogen. It is an alkylating agent, producing highly active carbonium ion, which the extremely electron-rich area of the nucleic acids and proteins. The present study aimed to investigate the protective effect of melatonin against cyclophosphamide induced oxidative stress in mice tissues. Lipid perioxidation. Reduced glutathione (GSH), Glutathione disulphide (GSSG), Glutathione peroxidase (GSH-Px) and serum phosphatase level taken as endpoints. Twenty days oral administration with melatonin (0.25 mg/Kg body weight) followed by an acute treatment with cyclophosphamide (75 mg/kg b. w.) inhibited the radiomimetic drug-induced augmented level of lipid peroxidation, Blood GSSG and acid phosphatase. Cyclophosphamide induced depletion in the level of GSH, GSH-Px and alkaline phosphatase is ameliorated significantly by melatonin administration. The findings support the results showing melatonin as a free radical scavenger, and singlet oxygen quencher. Results clearly indicate the antioxidative properties of melatonin against the radiomimetic drug which could be effectively used selectively for the protection of normal tissue during chemotherapy. (Author) 34 refs

Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer.

Science.gov (United States)

Greish, Khaled; Fateel, Maryam; Abdelghany, Sara; Rachel, Nanitha; Alimoradi, Houman; Bakhiet, Moiz; Alsaie, Ahmed

2017-11-21

Sildenafil is an approved drug for the treatment of erectile dysfunction. The drug exerts its action through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. In this work, we tested whether the aforementioned effects of sildenafil on tumour vasculatures could result in an improvement of anticancer drug concentration in tumour tissues and hence improves its anticancer effect. Sildenafil when added to doxorubicin showed synergistic anticancer activity against 4T1 breast cancer cells in vitro. Adding 1, 30 and 100 μM of Viagra to 1 μM of doxorubicin resulted in 1.8-fold, 6.2-fold and 21-fold statistically significant increases in its cytotoxic effect, respectively. As a result, 4T1 tumour-bearing mice showed up to 2.7-fold increase in drug concentrations of the fluorescent Dye DiI and doxorubicin in tumour tissues, as well as their nanoformulations. Animals treated with the combinations of both Sildenafil citrate and doxorubicin showed a statistically significant 4.7-fold reduction in tumour size compared to doxorubicin alone. This work highlights the effect of Sildenafil on tumour vasculatures and provides a rational for further testing the combination on breast cancer patients.

Histopathological effects of doxorubicin on pancreas in male albino rats

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I.A. Ali

2015-06-01

Full Text Available The aim of this study was to investigate the histopathological side effects of doxorubicin on pancreas tissue in male albino rats Rattus norvegicus. This study were used 55 adult rats (2.5-3.5 month of age. The rats divided into two groups, the first group include (35 rats. The second group were (20 rats. Microscopial examination of pancreas lesion demonstrated oedema around the acini, swelling of the epithelial cells of acini, occurance of cystic fibrosis (mucoviscidosis at the concentration of (4,5 mg/kg of body weight ,occurrence of small islets that form of few cells and exocrine-endocrine transformation. There were thickness in the walls of blood vessels, thrombus, congestion of blood vessels, we conclude, that doxorubicin had histopathological effect on pancreas in sub-acute doses more than chronic doses.

MicroRNA181a Is Overexpressed in T-Cell Leukemia/Lymphoma and Related to Chemoresistance

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Zi-Xun Yan

2015-01-01

Full Text Available MicroRNAs (miRs play an important role in tumorogenesis and chemoresistance in lymphoid malignancies. Comparing with reactive hyperplasia, miR181a was overexpressed in 130 patients with T-cell leukemia/lymphoma, including acute T-cell lymphoblastic leukemia (n=32, T-cell lymphoblastic lymphoma (n=16, peripheral T-cell lymphoma, not otherwise specified (n=45, anaplastic large cell lymphoma (n=15, and angioimmunoblastic T-cell lymphoma (n=22. Irrespective to histological subtypes, miR181a overexpression was associated with increased AKT phosphorylation. In vitro, ectopic expression of miR181a in HEK-293T cells significantly enhanced cell proliferation, activated AKT, and conferred cell resistance to doxorubicin. Meanwhile, miR181a expression was upregulated in Jurkat cells, along with AKT activation, during exposure to chemotherapeutic agents regularly applied to T-cell leukemia/lymphoma treatment, such as doxorubicin, cyclophosphamide, cytarabine, and cisplatin. Isogenic doxorubicin-resistant Jurkat and H9 cells were subsequently developed, which also presented with miR181a overexpression and cross-resistance to cyclophosphamide and cisplatin. Meanwhile, specific inhibition of miR181a enhanced Jurkat and H9 cell sensitivity to chemotherapeutic agents, further indicating that miR181a was involved in acquired chemoresistance. Collectively, miR181a functioned as a biomarker of T-cell leukemia/lymphoma through modulation of AKT pathway. Related to tumor cell chemoresistance, miR181a could be a potential therapeutic target in treating T-cell malignancies.

Concurrent inhibition of MYC and BCL2 is a potentially effective treatment strategy for double hit and triple hit B-cell lymphomas.

Science.gov (United States)

Cinar, Munevver; Rosenfelt, Fred; Rokhsar, Sepehr; Lopategui, Jean; Pillai, Raju; Cervania, Melissa; Pao, Andy; Cinar, Bekir; Alkan, Serhan

2015-07-01

Double hit lymphoma or triple hit lymphoma (DHL/THL) is a rare form of aggressive B-Cell Lymphoma. Overexpression of MYC, BCL2 or/and BCL6 due to genomic rearrangements are the key molecular features of DHL/THL. Patients with DHL/THL show very aggressive disease course and poor survival due to the lack of effective treatment modalities. Here, we established new THL cell model and assessed its in vitro growth characteristics along with the DHL cell line in response to potent MYC inhibitors, 10058-F4 and JQ-1, and a BCL2 inhibitor, ABT-199, with or without chemotherapeutic agent vincristine or doxorubicin. We found that 10058-F4, JQ-1 or ABT-199 exposure as a single agent inhibited the growth of DHL/THL cells in a dose-dependent manner. Combined exposure of 10058-F4 or JQ-1 and ABT-199 as well as vincristine or doxorubicin markedly suppressed the growth of DHL/THL cells compared with the single treatment. As assessed by multiple approaches, apoptosis induced by ABT-199, 10058-F4 or JQ-1 was underlying cause of the observed growth suppression. These findings suggest that co-inhibition of MYC and BCL2 signaling is a promising therapeutic strategy for patients with DHL/THL lymphomas. Copyright © 2015 Elsevier Ltd. All rights reserved.

The effect of HCV serological status on Doxorubicin based ...

African Journals Online (AJOL)

Background: Breast cancer and HCV are two frequent diseases in Egypt. There is a considerable probability of concurrent affection. This concurrence creates a subpopulation, which needs special evaluation and care. Objective: To evaluate a subset of Egyptian breast cancer patients receiving Doxorubicin based adjuvant ...

Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery

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Lee SJ

2015-08-01

Full Text Available Sang Joon Lee,1,* Young-Il Jeong,2,* Hyung-Kyu Park,3 Dae Hwan Kang,2,4 Jong-Suk Oh,3 Sam-Gyu Lee,5 Hyun Chul Lee31Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, 2Biomedical Research Institute, Pusan National University Hospital, Busan, 3Department of Microbiology, Chonnam National University Medical School, Gwangju, 4Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Gyeongnam, 5Department of Physical and Rehabilitation Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea*These authors contributed equally to this workBackground: Since cancer cells are normally over-expressed cathepsin B, we synthesized dendrimer-methoxy poly(ethylene glycol (MPEG-doxorubicin (DOX conjugates using a cathepsin B-cleavable peptide for anticancer drug targeting.Methods: Gly-Phe-Leu-Gly peptide was conjugated with the carboxylic acid end groups of a dendrimer, which was then conjugated with MPEG amine and doxorubicin by aid of carbodiimide chemistry (abbreviated as DendGDP. Dendrimer-MPEG-DOX conjugates without Gly-Phe-Leu-Gly peptide linkage was also synthesized for comparison (DendDP. Nanoparticles were then prepared using a dialysis procedure.Results: The synthesized DendGDP was confirmed with 1H nuclear magnetic resonance spectroscopy. The DendDP and DendGDP nanoparticles had a small particle size of less than 200 nm and had a spherical morphology. DendGDP had cathepsin B-sensitive drug release properties while DendDP did not show cathepsin B sensitivity. Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles. The DendGDP nanoparticles were found to be relatively concentrated in the tumor tissue and

Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells.

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Lulu Fan

Full Text Available BACKGROUND: Endoplasmic reticulum stress (ER stress is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. Paeonol (Pae, 2-hydroxy-4-methoxyacetophenone, is a natural product extracted from the root of Paeonia Suffruticosa Andrew. Although Pae displays anti-neoplastic activity and increases the efficacy of chemotherapeutic drugs in various cell lines and in animal models, studies related to the effect of Pae on ER stress-induced resistance to chemotherapeutic agents in hepatocellular carcinoma (HCC are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the effect of the endoplasmic reticulum (ER stress response during resistance of human hepatocellular carcinoma cells to doxorubicin. Treatment with the ER stress-inducer tunicamycin (TM before the addition of doxorubicin reduced the rate of apoptosis induced by doxorubicin. Interestingly, co-pretreatment with tunicamycin and Pae significantly increased apoptosis induced by doxorubicin. Furthermore, induction of ER stress resulted in increasing expression of COX-2 concomitant with inactivation of Akt and up-regulation of the pro-apoptotic transcription factor CHOP (GADD153 in HepG2 cells. These cellular changes in gene expression and Akt activation may be an important resistance mechanism against doxorubicin in hepatocellular carcinoma cells undergoing ER stress. However, co-pretreatment with tunicamycin and Pae decreased the expression of COX-2 and levels of activation of Akt as well as increasing the levels of CHOP in HCC cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that Pae reverses ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by targeting COX-2 mediated inactivation of PI3K/AKT/CHOP.

Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis

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Begoña Porteiro

2018-02-01

Full Text Available Objective: Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD and nonalcoholic steatohepatitis (NASH. Methods: We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45% and 60% kcal fat and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet. We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2. Results: The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability. Conclusion: These data provide new evidence for targeting p53 as a strategy to treat liver disease. Keywords: Obesity, Lipid metabolism, Inflammation

Bicontinuous cubic liquid crystalline nanoparticles for oral delivery of Doxorubicin

DEFF Research Database (Denmark)

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

2014-01-01

PURPOSE: The present study explores the potential of bicontinous cubic liquid crystalline nanoparticles (LCNPs) for improving therapeutic potential of doxorubicin. METHODS: Phytantriol based Dox-LCNPs were prepared using hydrotrope method, optimized for various formulation components, process...

Follow up study of malignant lymphoma after therapy

International Nuclear Information System (INIS)

Imanishi, Masami; Yuasa, Takashi; Iida, Noriyuki; Sakaki, Toshisuke; Tanikake, Tatsuo

1979-01-01

Changes in CT scan were followed in a case of malignant lymphoma during CVP (Cyclophosphamide, Vincristine, Predomine) therapy and Lineac irradiation. The 23-year-old male patient progressed well until June, 1979, when he developed clumsy action and right hemiparesis. Plain CT scan on admission revealed a midline shift from left to right, compression and deformity of the lateral ventricle, and on extensive iso-high-density area with perifocal low density. CT scan with contrast enhancement demonstrated multiple well-circumscribed high-density mass shadows in both the left temporal lobe and subcortical nuclei. Left parietal craniotomy was performed, but since no mass lesion was found in the surgical field, the brain tissue of the tip of the left temporal lobe was partially removed. The histologically confirmed diagnosis was intracranial malignant lymphoma. Initial postoperative treatment consisted of CVP administration (cyclophosphamide, vincristine, predonine). On the 30th day of hospitalization, CT scan showed the tumor mass to have decreased. Clinical symptoms and the right hemiparesis also improved. However, on the 80th day CT scan revealed recurrence of the tumor and on the 100th day a huge high-density area centered in the posterior part of the thalamus was found, indicating growth of the recurrent tumor. Lineac irradiation was started on the 100th day. As a result of irradiation (3400 rad irradiation) the tumor shadow decreased and the patient's general condition and neurological symptoms again improved. (author)

Protolichesterinic acid enhances doxorubicin-induced apoptosis in HeLa cells in vitro.

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Brisdelli, Fabrizia; Perilli, Mariagrazia; Sellitri, Doriana; Bellio, Pierangelo; Bozzi, Argante; Amicosante, Gianfranco; Nicoletti, Marcello; Piovano, Marisa; Celenza, Giuseppe

2016-08-01

The aim of this study was to investigate the effect of protolichesterinic acid, a lichen secondary metabolite, on anti-proliferative activity of doxorubicin in three human cancer cell lines, HeLa, SH-SY5Y and K562 cells. The data obtained from MTT assays, performed on cells treated with protolichesterinic acid and doxorubicin alone and in combination, were analysed by the median-effect method as proposed by Chou and Talalay and the Bliss independence model. Apoptosis rate was evaluated by fluorescence microscopy, caspase-3, 8 and 9 activities were detected by spectrofluorimetric analysis and protein expression of Bim, Bid, Bax and Mcl-2 was analysed by Western blotting. The interaction of protolichesterinic acid with thioesterase domain of human fatty acid synthase (hFAS) was investigated by a molecular docking study. The in vitro activity of doxorubicin against HeLa cancer cell line, but not against SH-SY5Y and K562 cells, was synergically increased by protolichesterinic acid. The increased cytotoxicity caused by protolichesterinic acid in HeLa cells was due to a pro-apoptotic effect and was associated to caspase-3, 8 and 9 activation. The simultaneous treatment for 24h with protolichesterinic acid plus doxorubicin caused an increase of Bim protein expression and the appearance of cleaved form of Bid protein. The molecular modelling analysis showed that protolichesterinic acid seemed to behave as a competitive inhibitor of hFAS. These results suggest that protolichesterinic acid could be envisaged as an useful tool against certain types of tumor cells in combination with anticancer drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

Rituximab Therapy for Severe Cutaneous Leukocytoclastic Angiitis Refractory to Corticosteroids, Cellcept and Cyclophosphamide

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Kamel El-Reshaid

2013-04-01

Full Text Available We report our clinical experience with rituximab in the treatment of 2 patients with idiopathic cutaneous angiitis who relapsed after treatment with high-dose corticosteroids and cyclophosphamide. A 39-year-old woman and a 51-year-old man presented with ulcerating maculopapular rash in both lower limbs which relapsed 6 months after treatment with a combination of high-dose corticosteroids and cyclophosphamide. After treatment with 2 g of rituximab, the first patient has still been in clinical remission for 32 months while the second has finished 28 months. Interestingly, CD19 which had dropped to 0.5% 8 months later in both patients. Despite that, our patients are still in clinical remission. No significant side effects were noted during infusions and up to the period of follow-up. In conclusion, rituximab is a useful and safe agent in the treatment of idiopathic cutaneous angiitis refractory to conventional therapy. Clinical remission persists years after improvement of B-cell suppression.

Involvement of HIF-1α activation in the doxorubicin resistance of human osteosarcoma cells.

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Roncuzzi, Laura; Pancotti, Fabia; Baldini, Nicola

2014-07-01

Osteosarcoma is the most common primary bone cancer in children and adolescents. Despite aggressive treatment regimens, survival outcomes remain unsatisfactory, particularly in patients with metastatic and/or recurrent disease. Unfortunately, treatment failure is commonly due to the development of chemoresistance, for which the underlying molecular mechanisms remain unclear. The aim of the present study was to investigate the role of hypoxia-inducible factor 1α (HIF‑1α) and its signalling pathways as mediators of drug-resistance in human osteosarcoma. Toward this aim, we established two osteosarcoma cell lines selected for resistance to doxorubicin, a drug of choice in the treatment of this tumour. Our results showed that the multidrug resistance (MDR) phenotype was also mediated by HIF-1α, the most important regulator of cell adaptation to hypoxia. Our data showed that this transcription factor promoted the outward transport of intracellular doxorubicin by activating the P-glycoprotein (P-gp) expression in osteosarcoma cells maintained in normoxic conditions. In addition, it hindered doxorubicin-induced apoptosis by regulating the expression of c-Myc and p21. Finally, we observed that the doxorubicin-resistant cells maintained for 2 months of continuous culture in a drug-free medium, lost their drug-resistance and this effect was associated with the absence of HIF-1α expression. The emerging role of HIF-1α in osteosarcoma biology indicates its use as a valuable therapeutic target.

Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer.

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Wesolowski, Robert; Duggan, Megan C; Stiff, Andrew; Markowitz, Joseph; Trikha, Prashant; Levine, Kala M; Schoenfield, Lynn; Abdel-Rasoul, Mahmoud; Layman, Rachel; Ramaswamy, Bhuvaneswari; Macrae, Erin R; Lustberg, Maryam B; Reinbolt, Raquel E; Mrozek, Ewa; Byrd, John C; Caligiuri, Michael A; Mace, Thomas A; Carson, William E

2017-11-01

This study sought to evaluate whether myeloid-derived suppressor cells (MDSC) could be affected by chemotherapy and correlate with pathologic complete response (pCR) in breast cancer patients receiving neo-adjuvant chemotherapy. Peripheral blood levels of granulocytic (G-MDSC) and monocytic (M-MDSC) MDSC were measured by flow cytometry prior to cycle 1 and 2 of doxorubicin and cyclophosphamide and 1st and last administration of paclitaxel or paclitaxel/anti-HER2 therapy. Of 24 patients, 11, 6 and 7 patients were triple negative, HER2+ and hormone receptor+, respectively. 45.8% had pCR. Mean M-MDSC% were types. G-MDSC levels at the last draw were numerically lower in patients with pCR (1.15; 95% CI 0.14-2.16) versus patients with no pCR (2.71; 95% CI 0-5.47). There was no significant rise in G-MDSC from draw 1 to 3 in African American patients, and at draw 3 G-MDSC levels were significantly lower in African Americans versus Caucasians (p < 0.05). It was concluded that G-MDSC% increased during doxorubicin and cyclophosphamide therapy, but did not significantly differ between patients based on pathologic complete response.

Antitumor Properties of Modified Detonation Nanodiamonds and Sorbed Doxorubicin on the Model of Ehrlich Ascites Carcinoma.

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Medvedeva, N N; Zhukov, E L; Inzhevatkin, E V; Bezzabotnov, V E

2016-01-01

We studied antitumor properties of modified detonation nanodiamonds loaded with doxorubicin on in vivo model of Ehrlich ascites carcinoma. The type of tumor development and morphological characteristics of the liver, kidneys, and spleen were evaluated in experimental animals. Modified nanodiamonds injected intraperitoneally produced no antitumor effect on Ehrlich carcinoma. However, doxorubicin did not lose antitumor activity after sorption on modified nanodiamonds.

Safety and efficacy of pegylated liposomal doxorubicin in HIV-associated Kaposi’s sarcoma

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Francesca Cainelli

2009-08-01

Full Text Available Francesca Cainelli1, Alfredo Vallone21Department of Internal Medicine, School of Medicine, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana; 2Infectious Diseases Unit, Annunziata Hospital, Cosenza, ItalyAbstract: Kaposi’s sarcoma is a vascular tumor linked to the presence of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus-8 and the incidence of which has increased considerably the world over after the onset of the human immunodeficiency virus (HIV pandemic. Antiretroviral therapy combined with cytotoxic agents has been established as the treatment of choice in the past 10 years. Among chemotherapeutic agents, pegylated liposomal doxorubicin has become the preferred one for patients with HIV-associated Kaposi’s sarcoma in Western countries. The drug in this formulation localizes better to the tumor and has higher efficacy. Skin toxicity, mucositis, and leukopenia/neutropenia are the main side effects. Hepatotoxicity and mild cardiotoxicity are observed less frequently. Pegylated liposomal doxorubicin impacts favorably on quality of life. Although cost effective in Western countries, the drug is less so in developing countries.Keywords: pegylated liposomal doxorubicin, Kaposi’s sarcoma, HIV infection

Transferrin targeted core-shell nanomedicine for combinatorial delivery of doxorubicin and sorafenib against hepatocellular carcinoma.

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Malarvizhi, Giridharan Loghanathan; Retnakumari, Archana Payickattu; Nair, Shantikumar; Koyakutty, Manzoor

2014-11-01

Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing >75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in ~92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer. Transferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques. Copyright © 2014 Elsevier Inc. All rights reserved.

Targeting PEPT1: a novel strategy to improve the antitumor efficacy of doxorubicin in human hepatocellular carcinoma therapy.

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Gong, Yanxia; Wu, Xiang; Wang, Tao; Zhao, Jia; Liu, Xi; Yao, Zhi; Zhang, Qingyu; Jian, Xu

2017-06-20

Proton coupled oligopeptide transporter 1 (PEPT1) is a member of the peptide transporter superfamily and plays important role in the absorption of oligopeptide and peptidomimetic drugs. Our previous research verified that PEPT1 expressed specifically in human Hepatocellular carcinoma (HCC) tissue and cell lines and showed potential transport activity to be a new candidate of the tumor therapeutic target. In this study, we aim to explore the feasibility of a novel tumor target therapeutic strategy: Targeting PEPT1 to improve the antitumor efficacy of Doxorubicin in human HCC therapy. First, Doxorubicin was conjugated with Glycylglycylglycine (Gly-Gly-Gly) - a tripeptide which was known as the substrate of PEPT1 and characterized by HPLC and MS successfully. Doxorubicin-tripeptide conjugate was then observed to clarify the target delivery by PEPT1 and the antitumor effect on human hepatocarcinoma in vivo and in vitro. Furthermore, the improvement of the toxic and side effect of Doxorubicin after conjugation was also evaluated by some biochemical tests. Our results reveal that targeting PEPT1 may contribute to the efficient delivery of Doxorubicin to hepatocarcinoma cells and the reduction of drug toxicity. PEPT1 has the prospect to be a novel target of HCC therapy.

Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes.

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Patrizia Fabbi

Full Text Available Insulin-like growth factor-1 (IGF-1 promotes the survival of cardiomyocytes by activating type 1 IGF receptor (IGF-1R. Within the myocardium, IGF-1 action is modulated by IGF binding protein-3 (IGFBP-3, which sequesters IGF-1 away from IGF-1R. Since cardiomyocyte apoptosis is implicated in anthracycline cardiotoxicity, we investigated the effects of the anthracycline, doxorubicin, on the IGF-1 system in H9c2 cardiomyocytes.Besides inducing apoptosis, concentrations of doxorubicin comparable to those observed in patients after bolus infusion (0.1-1 µM caused a progressive decrease in IGF-1R and increase in IGFBP-3 expression. Exogenous IGF-1 was capable to rescue cardiomyocytes from apoptosis triggered by 0.1 and 0.5 µM, but not 1 µM doxorubicin. The loss of response to IGF-1 was paralleled by a significant reduction in IGF-1 availability and signaling, as assessed by free hormone levels in conditioned media and Akt phosphorylation in cell lysates, respectively. Doxorubicin also dose-dependently induced p53, which is known to repress the transcription of IGF1R and induce that of IGFBP3. Pre-treatment with the p53 inhibitor, pifithrin-α, prevented apoptosis and the changes in IGF-1R and IGFBP-3 elicited by doxorubicin. The decrease in IGF-1R and increase in IGFBP-3, as well as apoptosis, were also antagonized by pre-treatment with the antioxidant agents, N-acetylcysteine, dexrazoxane, and carvedilol.Doxorubicin down-regulates IGF-1R and up-regulates IGFBP-3 via p53 and oxidative stress in H9c2 cells. This leads to resistance to IGF-1 that may contribute to doxorubicin-initiated apoptosis. Further studies are needed to confirm these findings in human cardiomyocytes and explore the possibility of manipulating the IGF-1 axis to protect against anthracycline cardiotoxicity.

Synergistic effect of pyrazoles derivatives and doxorubicin in claudin-low breast cancer subtype.

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Saueressig, Silvia; Tessmann, Josiane; Mastelari, Rosiane; da Silva, Liziane Pereira; Buss, Julieti; Segatto, Natalia Vieira; Begnini, Karine Rech; Pacheco, Bruna; de Pereira, Cláudio Martin Pereira; Collares, Tiago; Seixas, Fabiana Kömmling

2018-02-01

Breast cancer is a global public health problem. For some subtypes, such as Claudin-low, the prognosis is poorer and the treatment is still a challenge. Pyrazoles are an important class of heterocyclic compounds and are promising anticancer agents based on their chemical properties. The present study was aimed not only at testing pyrazoles previously prepared by our research group in two breast cancer cell lines characterized by intermediated response to conventional chemotherapy but also at analyzing the possible synergistic effect of these pyrazoles associated with doxorubicin. Four 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-1H pyrazoles were tested for the first time in MCF-7 and MDA-MB-231 culture cells. The pyrazoles with best results in cytotoxicity were used in combination with doxorubicin and compared with this drug alone as standard. The synergic effect was analyzed using Combination Index method. In addition, cell death and apoptosis assays were carried out. Two pyrazoles with cytotoxic effect in MCF-7 and especially in MDA-MB-231 were identified. This activity was markedly higher in pyrazoles containing bromine and chlorine substituents. The combination of these pyrazoles with doxorubicin had a significant synergic effect in both cells tested and mainly in MDA-MB-231. These data were confirmed with apoptosis and cell death analysis. The synergic effect observed with combination of these pyrazoles and doxorubicin deserves special attention in Claudin-low breast cancer subtype. This should be explored in order to improve treatment results and minimize side effects. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Cyclophosphamide/fludarabine nonmyeloablative allotransplant for acute myeloid leukemia.

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Khawaja, Muhammad Rizwan; Perkins, Susan M; Schwartz, Jennifer E; Robertson, Michael J; Kiel, Patrick J; Sayar, Hamid; Cox, Elizabeth A; Vance, Gail H; Farag, Sherif S; Cripe, Larry D; Nelson, Robert P

2015-02-01

We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165 patients with acute myelogenous leukemia (AML) in remission or without frank relapse. Patients who received NMAT were more likely to be older and have secondary AML and lower performance status. At a median follow-up of 61 months, median event-free survival and overall survival survival were not different between NMAT and MAT in univariate as well as multivariate analyses. Cy/Flu NMAT may provide similar disease control and survival when compared with MAT in patients with AML in remission or without frank relapse. © 2014 Wiley Periodicals, Inc.

Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients

NARCIS (Netherlands)

Mulder, Renée L.; Paulides, Marios; Langer, Thorsten; Kremer, Leontien C. M.; van Dalen, Elvira C.

2010-01-01

BACKGROUND: Alkylating agents, such as cyclophosphamide and ifosfamide, play a major role in the improved survival of children and young adults with bone and soft tissue sarcoma. However, there is still controversy as to their comparative anti-tumour efficacy and possible adverse effects.

Cordycepin enhances Epstein-Barr virus lytic infection and Epstein-Barr virus-positive tumor treatment efficacy by doxorubicin.

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Du, Yinping; Yu, Jieshi; Du, Li; Tang, Jun; Feng, Wen-Hai

2016-07-01

The consistent latent presence of Epstein-Barr virus (EBV) in tumor cells offers potential for virus-targeted therapies. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. In this study, we report that a natural small molecule compound, cordycepin, can induce lytic EBV infection in tumor cells. Subsequently, we demonstrate that cordycepin can enhance EBV reactivating capacity and EBV-positive tumor cell killing ability of low dose doxorubicin. The combination of cordycepin and doxorubicin phosphorylates CCAAT/enhancer binding protein β (C/EBPβ) through protein kinase C (PKC)-p38 mitogen activated protein kinases (p38 MAPK) signaling pathway, and C/EBPβ is required for the activation of lytic EBV infection. Most importantly, an in vivo experiment demonstrates that the combination of cordycepin and doxorubicin is more effective in inhibiting tumor growth in SCID mice than is doxorubicin alone. Our findings establish that cordycepin can enhance the efficacy of conventional chemotherapy for treatment of EBV-positive tumors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Combined doxorubicin and paclitaxel in advanced breast cancer

DEFF Research Database (Denmark)

Gehl, J; Boesgaard, M; Paaske, T

1996-01-01

-550). The main toxicities were neutropenia, parestesia, nausea/vomiting, alopecia, myalgia and cardiotoxicity. Fifteen patients (50%) had reductions of left ventricular ejection fraction of below normal levels and 6 of these patients (20%) developed congestive heart failure. CONCLUSION: The combination...... of doxorubicin and paclitaxel is highly active, but is accompanied by the dose-limiting toxic effects of neutropenia, neuropathy and cardiotoxicity....

pH-Switch Nanoprecipitation of Polymeric Nanoparticles for Multimodal Cancer Targeting and Intracellular Triggered Delivery of Doxorubicin.

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Herranz-Blanco, Bárbara; Shahbazi, Mohammad-Ali; Correia, Alexandra R; Balasubramanian, Vimalkumar; Kohout, Tomáš; Hirvonen, Jouni; Santos, Hélder A

2016-08-01

Theranostic nanoparticles are emerging as potent tools for noninvasive diagnosis, treatment, and monitoring of solid tumors. Herein, an advanced targeted and multistimuli responsive theranostic platform is presented for the intracellular triggered delivery of doxorubicin. The system consists of a polymeric-drug conjugate solid nanoparticle containing encapsulated superparamagnetic iron oxide nanoparticles (IO@PNP) and decorated with a tumor homing peptide, iRGD. The production of this nanosystem is based on a pH-switch nanoprecipitation method in organic-free solvents, making it ideal for biomedical applications. The nanosystem shows sufficient magnetization saturation for magnetically guided therapy along with reduced cytotoxicity and hemolytic effects. IO@PNP are largely internalized by endothelial and metastatic cancer cells and iRGD decorated IO@PNP moderately enhance their internalization into endothelial cells, while no enhancement is found for the metastatic cancer cells. Poly(ethylene glycol)-block-poly(histidine) with pH-responsive and proton-sponge properties promotes prompt lysosomal escape once the nanoparticles are endocyted. In addition, the polymer-doxorubicin conjugate solid nanoparticles show both intracellular lysosomal escape and efficient translocation of doxorubicin to the nuclei of the cells via cleavage of the amide bond. Overall, IO@PNP-doxorubicin and the iRGD decorated counterpart demonstrate to enhance the toxicity of doxorubicin in cancer cells by improving the intracellular delivery of the drug carried in the IO@PNP. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Early biomarkers of doxorubicin-induced heart injury in a mouse model

Energy Technology Data Exchange (ETDEWEB)

Desai, Varsha G., E-mail: varsha.desai@fda.hhs.gov [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Kwekel, Joshua C.; Vijay, Vikrant; Moland, Carrie L. [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Herman, Eugene H. [Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, The National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850-9734 (United States); Lee, Taewon [Department of Mathematics, Korea University, Sejong, Chungnam 339-700 (Korea, Republic of); Han, Tao [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Lewis, Sherry M. [Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Davis, Kelly J.; Muskhelishvili, Levan [Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Kerr, Susan [Arkansas Heart Hospital, Little Rock, AR 72211 (United States); Fuscoe, James C. [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States)

2014-12-01

Cardiac troponins, which are used as myocardial injury markers, are released in plasma only after tissue damage has occurred. Therefore, there is a need for identification of biomarkers of earlier events in cardiac injury to limit the extent of damage. To accomplish this, expression profiling of 1179 unique microRNAs (miRNAs) was performed in a chronic cardiotoxicity mouse model developed in our laboratory. Male B6C3F{sub 1} mice were injected intravenously with 3 mg/kg doxorubicin (DOX; an anti-cancer drug), or saline once a week for 2, 3, 4, 6, and 8 weeks, resulting in cumulative DOX doses of 6, 9, 12, 18, and 24 mg/kg, respectively. Mice were euthanized a week after the last dose. Cardiac injury was evidenced in mice exposed to 18 mg/kg and higher cumulative DOX dose whereas examination of hearts by light microscopy revealed cardiac lesions at 24 mg/kg DOX. Also, 24 miRNAs were differentially expressed in mouse hearts, with the expression of 1, 1, 2, 8, and 21 miRNAs altered at 6, 9, 12, 18, and 24 mg/kg DOX, respectively. A pro-apoptotic miR-34a was the only miRNA that was up-regulated at all cumulative DOX doses and showed a significant dose-related response. Up-regulation of miR-34a at 6 mg/kg DOX may suggest apoptosis as an early molecular change in the hearts of DOX-treated mice. At 12 mg/kg DOX, up-regulation of miR-34a was associated with down-regulation of hypertrophy-related miR-150; changes observed before cardiac injury. These findings may lead to the development of biomarkers of earlier events in DOX-induced cardiotoxicity that occur before the release of cardiac troponins. - Highlights: • Upregulation of miR-34a before doxorubicin-induced cardiac tissue injury • Apoptosis might be an early event in mouse heart during doxorubicin treatment. • Expression of miR-150 declined before doxorubicin-induced cardiac tissue injury.

Multimodal doxorubicin loaded magnetic nanoparticles for VEGF targeted theranostics of breast cancer.

Science.gov (United States)

Semkina, Alevtina S; Abakumov, Maxim A; Skorikov, Alexander S; Abakumova, Tatiana O; Melnikov, Pavel A; Grinenko, Nadejda F; Cherepanov, Sergey A; Vishnevskiy, Daniil A; Naumenko, Victor A; Ionova, Klavdiya P; Majouga, Alexander G; Chekhonin, Vladimir P

2018-05-03

In presented paper we have developed new system for cancer theranostics based on vascular endothelial growth factor (VEGF) targeted magnetic nanoparticles. Conjugation of anti-VEGF antibodies with bovine serum albumin coated PEGylated magnetic nanoparticles allows for improved binding with murine breast adenocarcinoma 4T1 cell line and facilitates doxorubicin delivery to tumor cells. It was shown that intravenous injection of doxorubicin loaded VEGF targeted nanoparticles increases median survival rate of mice bearing 4T1 tumors up to 50%. On the other hand magnetic resonance imaging (MRI) of 4T1 tumors 24 h after intravenous injection showed accumulation of nanoparticles in tumors, thus allowing simultaneous cancer therapy and diagnostics. Copyright © 2018. Published by Elsevier Inc.

Sleep pattern and locomotor activity are impaired by doxorubicin in non-tumor-bearing rats.

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Lira, Fabio Santos; Esteves, Andrea Maculano; Pimentel, Gustavo Duarte; Rosa, José Cesar; Frank, Miriam Kannebley; Mariano, Melise Oliveira; Budni, Josiane; Quevedo, João; Santos, Ronaldo Vagner Dos; de Mello, Marco Túlio

2016-01-01

We sought explore the effects of doxorubicin on sleep patterns and locomotor activity. To investigate these effects, two groups were formed: a control group and a Doxorubicin (DOXO) group. Sixteen rats were randomly assigned to either the control or DOXO groups. The sleep patterns were examined by polysomnographic recording and locomotor activity was evaluated in an open-field test. In the light period, the total sleep time and slow wave sleep were decreased, while the wake after sleep onset and arousal were increased in the DOXO group compared with the control group (plocomotor activity.

Comparison between Antiemetic Effects of Palonosetron and Granisetron on Chemotherapy-Induced Nausea and Vomiting in Japanese Patients Treated with R-CHOP.

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Uchida, Mayako; Mori, Yasuo; Nakamura, Tsutomu; Kato, Koji; Kamezaki, Kenjiro; Takenaka, Katsuto; Shiratsuchi, Motoaki; Kadoyama, Kaori; Miyamoto, Toshihiro; Akashi, Koichi

2017-01-01

In the present study, the antiemetic effect of palonosetron, not combined with dexamethasone and aprepitant, on chemotherapy-induced nausea and vomiting was evaluated in patients with malignant lymphoma receiving first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, and was compared to that of granisetron. A total of 74 patients with non-Hodgkin lymphoma were included in this study (April 2007 to December 2015). Palonosetron (0.75 mg) or granisetron (3 mg) was intravenously administered before R-CHOP therapy. The proportions of patients with complete response (CR) during the overall (0-120 h after the start of R-CHOP therapy), acute (0-24 h) and delayed (24-120 h) phases were evaluated. CR was defined as no vomiting and no use of antiemetic rescue medication. A total of 32 and 42 patients were treated with palonosetron and granisetron, respectively. The CR rate in the palonosetron group was significantly higher than that in the granisetron group during the delayed phase (90.6 and 61.9%, respectively; p=0.007). Logistic regression analysis showed that use of palonosetron improved the CR rate during the delayed phase, compared to use of granisetron. Female sex, age less than 60 years, no habitual alcohol intake, and Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 1 were significant risk factors associated with non-CR. The findings of this study suggested the superiority of palonosetron to granisetron, without accompanying dexamethasone and aprepitant, for chemotherapy-induced nausea and vomiting in patients with malignant lymphoma.

Epstein-Barr Virus-positive T-cell Lymphoproliferative Disease Following Umbilical Cord Blood Transplantation for Acute Myeloid Leukemia.

Science.gov (United States)

Yui, Shunsuke; Yamaguchi, Hiroki; Imadome, Ken-ichi; Arai, Ayako; Takahashi, Mikiko; Ohashi, Ryuji; Tamai, Hayato; Moriya, Keiichi; Nakayama, Kazutaka; Shimizu, Akira; Inokuchi, Koiti

2016-01-01

We report a case of the extremely rare condition Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (LPD) which occurred after umbilical cord blood transplantation. A 25-year-old Japanese man underwent cord blood transplantation from a male human leukocyte antigen 4/6-matched donor due to acute myeloid leukemia with trisomy 8. Bone marrow examination on day 30 showed chimerism with at least 90% donor cells and complete hematological response. Chronic symptoms of graft-versus-host disease appeared only on the skin and were successfully treated with cyclosporine alone. Three years later, however, the patient experienced repeated cold-like symptoms and was hospitalized with liver dysfunction. A high fever developed and was followed by significant edema of the right side of the face. The EBV DNA copy number in whole peripheral blood was 2×10(4)/mL. Liver biopsy showed invasion of EBV-infected CD8-positive T cells. Southern blotting analysis of the whole peripheral blood showed that the T-cell receptor Cβ1 rearrangement was positive. On the basis of these results, EBV-positive T-cell LPD was diagnosed and treated with prednisolone, cyclosporine, and etoposide, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient died of cardiac function failure, pneumonia, and pulmonary hemorrhage, all of unidentified cause. Most cases of EBV-related LPD after hematopoietic stem cell transplantation consist of EBV-positive B-cell LPD, and, to our knowledge, de novo EBV-positive T-cell LPD subsequent to transplantation has not been previously reported.

A comparison of pectoralis versus lumbar skeletal muscle indices for defining sarcopenia in diffuse large B-cell lymphoma - two are better than one.

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Go, Se-Il; Park, Mi Jung; Song, Haa-Na; Kim, Hoon-Gu; Kang, Myoung Hee; Kang, Jung Hun; Kim, Hye Ree; Lee, Gyeong-Won

2017-07-18

Sarcopenia is known to be associated with poor clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL). There is no consensus concerning the optimal method to define sarcopenia in DLBCL. We retrospectively reviewed 193 DLBCL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Sarcopenia was classified by the region where the pretreatment skeletal muscle index (SMI) was measured. Both the sarcopenia-L3 and sarcopenia-pectoralis muscle (PM) groups had increased incidences of severe treatment-related toxicities and treatment discontinuation compared with the non-sarcopenia-L3 and non-sarcopenia-PM groups, respectively. The sarcopenia-L3 and non-sarcopenia-L3 groups had 5-year overall survival (OS) rates of 40.5% and 67.8% (p sarcopenia-PM and non-sarcopenia-PM groups had 5-year OS rates of 35.9% and 69.0% (p sarcopenia-L3 alone and sarcopenia-PM alone groups were compared, there were no differences in baseline characteristics, treatment toxicity, or survival. In multivariate analysis, when compared with the non-sarcopenia-both group, OS was significantly worse in the sarcopenia-both group (HR, 2.480; 95% CI, 1.284 - 4.792; p = 0.007), but not in patients with either sarcopenia-L3 alone or sarcopenia-PM alone (p = 0.151). L3- and PM-SMIs are equally useful to define sarcopenia, which is related to intolerance to R-CHOP therapy and to worse survival in patients with DLBCL. More prognostic information can be obtained when these two SMIs are combined to define sarcopenia.

Medicinal therapy of malignant lymphomas

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Aul, C.; Schroeder, M.; Giagounidis, A.

2002-01-01

Chemotherapy represents the most important therapeutic option in malignant lymphomas. Low to intermediate risk Hodgkin's disease is treated by a combination of chemotherapy and radiation. The new chemotherapy protocol BEACOPP has improved the outcome of advanced stages in comparison with the internationally accepted standard protocol COPP/ABVD. Dependent on the initial staging, cure rates between 50 and 95% can be achieved. Indolent non-Hodgkin's lymphomas usually present in advanced stages of disease. Chemotherapy in these cases has palliative character and aims at improving patients'quality of life and at avoiding complications due to the disease. In aggressive and very aggressive non-Hodgkin's lymphoma chemotherapy is curative and must be initiated immediately irrespective of the staging results. The efficacy of the standard protocol CHOP (cyclophosphamide,doxorubicin, vincristine and prednisone), that was established in the 1970s, has recently been improved by shortening of the therapy interval (CHOP-14 vs.CHOP-21),addition of etoposide (CHOEP) and combination with the monoclonal antibody rituximab (R-CHOP). The value of high dose chemotherapy with stem cell transplantation has been shown unequivocally only for aggressive non-Hodgkin lymphoma and relapsed Hodgkin's disease responsive to chemotherapy. The therapeutic strategy of malignant lymphomas is likely to be improved within the next years due to the introduction of novel cytostatic agents, the broadening application of monoclonal antibodies,upcoming new transplantation procedures and the development of substances with molecular targets.To rapidly increase our current knowledge on the topic it is mandatory to include patients into the large national and international multicenter studies. (orig.) [de

Prediction of Central Nervous System Relapse of Diffuse Large B-Cell Lymphoma Using Pretherapeutic [18F]2-Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography/Computed Tomography.

Science.gov (United States)

Song, Yoo Sung; Lee, Won Woo; Lee, Jong Seok; Kim, Sang Eun

2015-11-01

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare complication, but has a poor prognosis with unknown pathophysiology. Recent trials of CNS prophylaxis have shown to be ineffective, despite patient's selection using several known clinical risk factors. In this study, the authors evaluated the value of pretreatment [F]2-Fluoro-2-deoxyglucose positron emission tomography in predicting CNS relapse in DLBCL patients.The authors analyzed 180 pathologically confirmed DLBCL patients, retrospectively. Patients underwent [F]2-Fluoro-2-deoxyglucose positron emission tomography/computed tomography before first line rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone therapy. Clinical characteristics were evaluated and total lesion glycolysis (TLG) with a threshold margin of 50% was calculated.Among age, sex, Ann Arbor stage, International Prognostic Index, revised International Prognostic Index, high serum lactate dehydrogenase level, presence of B symptoms, bulky disease (≥10 cm), extranodal lesion involvement, bone marrow involvement, high metabolic tumor volume ( >450 mL), and high TLG50 (>2000), the high TLG50 was the only significant prognostic factor for predicting CNS relapse in a multivariate analysis (P = 0.04). Kaplan-Meir survival analysis between high TLG50 (>2000) and low TLG50 (≤2000) groups revealed significantly different mean progression free survival (PFS) of 1317.2 ± 134.3 days and 1968.6 ± 18.3 days, respectively (P positron emission tomography/computed tomography is the most significant predictor of CNS relapse in un-treated DLBCL patients.

Randomized Clinical Trial to Assess the Efficacy of Radiotherapy in Primary Mediastinal Large B-Lymphoma

International Nuclear Information System (INIS)

Avilés, Agustin; Neri, Natividad; Fernández, Raúl; Huerta-Guzmán, Judith; Nambo, María J.

2012-01-01

Purpose: We developed a controlled clinical trial to assess the efficacy and toxicity of adjuvant-involved field radiotherapy (IFRT) in patients with primary mediastinal B-cell lymphoma that achieved complete response after the patients were treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP-14). Methods and Materials: Between January 2001 and June 2004, 124 consecutive patients who were in complete remission after dose dense chemotherapy and rituximab administration (R-CHOP14) were randomly assigned to received IFRT (30 Gy). Sixty-three patients received IFR, and 61 patients did not (control group). Results: The study aimed to include 182 patients in each arm but was closed prematurely because in a security analysis (June 2004), progression and early relapse were more frequent in patients that did not received IFRT. Patients were followed until March 2009, at which point actuarial curves at 10 years showed that progression free-survival was 72% in patients who received IFR and 20% in the control group (p < 0.001), overall survival was 72% and 31%, respectively (p < 0.001). Acute toxicity was mild and well tolerated. Discussion: Adjuvant radiotherapy to sites of bulky disease was the only difference to have an improvement in outcome in our patients; the use of rituximab during induction did not improve complete response rates and did affect overall survival; patients who received rituximab but not IFRT had a worse prognosis. Conclusions: The use of IFRT in patients with primary mediastinal B-cell lymphoma who achieved complete response remain as the best treatment available, even in patients that received rituximab during induction.

Randomized Clinical Trial to Assess the Efficacy of Radiotherapy in Primary Mediastinal Large B-Lymphoma

Energy Technology Data Exchange (ETDEWEB)

Aviles, Agustin, E-mail: agustin.aviles@imss.gob.mx [Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico, D. F. (Mexico); Neri, Natividad [Department of Hematology, Oncology Hospital, National Medical Center, IMSS, Mexico, D. F. (Mexico); Fernandez, Raul [Department of Radiation Therapy, Oncology Hospital, National Medical Center, IMSS, Mexico, D. F. (Mexico); Huerta-Guzman, Judith; Nambo, Maria J. [Department of Hematology, Oncology Hospital, National Medical Center, IMSS, Mexico, D. F. (Mexico)

2012-07-15

Purpose: We developed a controlled clinical trial to assess the efficacy and toxicity of adjuvant-involved field radiotherapy (IFRT) in patients with primary mediastinal B-cell lymphoma that achieved complete response after the patients were treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP-14). Methods and Materials: Between January 2001 and June 2004, 124 consecutive patients who were in complete remission after dose dense chemotherapy and rituximab administration (R-CHOP14) were randomly assigned to received IFRT (30 Gy). Sixty-three patients received IFR, and 61 patients did not (control group). Results: The study aimed to include 182 patients in each arm but was closed prematurely because in a security analysis (June 2004), progression and early relapse were more frequent in patients that did not received IFRT. Patients were followed until March 2009, at which point actuarial curves at 10 years showed that progression free-survival was 72% in patients who received IFR and 20% in the control group (p < 0.001), overall survival was 72% and 31%, respectively (p < 0.001). Acute toxicity was mild and well tolerated. Discussion: Adjuvant radiotherapy to sites of bulky disease was the only difference to have an improvement in outcome in our patients; the use of rituximab during induction did not improve complete response rates and did affect overall survival; patients who received rituximab but not IFRT had a worse prognosis. Conclusions: The use of IFRT in patients with primary mediastinal B-cell lymphoma who achieved complete response remain as the best treatment available, even in patients that received rituximab during induction.

CHOD/BVAM Chemotherapy and Whole-Brain Radiotherapy for Newly Diagnosed Primary Central Nervous System Lymphoma

International Nuclear Information System (INIS)

Laack, Nadia N.; O'Neill, Brian Patrick; Ballman, Karla V.; O'Fallon, Judith Rich; Carrero, Xiomara W.; Kurtin, Paul J.; Scheithauer, Bernd W.; Brown, Paul D.; Habermann, Thomas M.; Colgan, Joseph P.; Gilbert, Mark R.; Hawkins, Roland B.; Morton, Roscoe F.; Windschitl, Harry E.; Fitch, Tom R.; Pajon, Eduardo R.

2011-01-01

Purpose: To assess the efficacy and toxicity of chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and dexamethasone (CHOD) plus bis-chloronitrosourea (BCNU), cytosine arabinoside, and methotrexate (BVAM) followed by whole-brain irradiation (WBRT) for patients with primary central nervous system lymphoma (PCNSL). Methods and Materials: Patients 70 years old and younger with newly diagnosed, biopsy-proven PCNSL received one cycle of CHOD followed by two cycles of BVAM. Patients then received WBRT, 30.6 Gy, if a complete response was evoked, or 50.4 Gy if the response was less than complete; both doses were given in 1.8-Gy daily fractions. The primary efficacy endpoint was 1-year survival. Results: Thirty-six patients (19 men, 17 women) enrolled between 1995 and 2000. Median age was 60.5 years (range, 34 to 69 years). Thirty (83%) patients had baseline Eastern Cooperative Oncology Group performance scores of 0 to 1. All 36 patients were eligible for survival and response evaluations. Median time to progression was 12.3 months, and median survival was 18.5 months. The percentages of patients alive at 1, 2, and 3 years were 64%, 36%, and 33%, respectively. The best response was complete response in 10 patients and immediate progression in 7 patients. Ten (28%) patients had at least one grade 3 or higher neurologic toxicity. Conclusions: This regimen did improve the survival of PCNSL patients but also caused substantial toxicity. The improvement in survival is less than that reported with high-dose methotrexate-based therapies.

Cost-benefit analysis of prophylactic granulocyte colony-stimulating factor during CHOP antineoplastic therapy for non-Hodgkin's lymphoma.

Science.gov (United States)

Dranitsaris, G; Altmayer, C; Quirt, I

1997-06-01

Several randomised comparative trials have shown that granulocyte colony-stimulating factor (G-CSF) reduces the duration of neutropenia, hospitalisation and intravenous antibacterial use in patients with cancer who are receiving high-dosage antineoplastic therapy. However, one area that has received less attention is the role of G-CSF in standard-dosage antineoplastic regimens. One such treatment that is considered to have a low potential for inducing fever and neutropenia is the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) for non-Hodgkin's lymphoma. We conducted a cost-benefit analysis from a societal perspective in order to estimate the net cost or benefit of prophylactic G-CSF in this patient population. This included direct costs for hospitalisation with antibacterial support, as well as indirect societal costs, such as time off work and antineoplastic therapy delays secondary to neutropenia. The findings were then tested by a comprehensive sensitivity analysis. The administration of G-CSF at a dosage of 5 micrograms/kg/day for 11 doses following CHOP resulted in an overall net cost of $Can1257. In the sensitivity analysis, lowering the G-CSF dosage to 2 micrograms/kg/day generated a net benefit of $Can6564, indicating a situation that was cost saving to society. The results of the current study suggest that the use of G-CSF in patients receiving CHOP antineoplastic therapy produces a situation that is close to achieving cost neutrality. However, low-dosage (2 micrograms/kg/day) G-CSF is an economically attractive treatment strategy because it may result in overall savings to society.

Dorsal Column Degeneration after Bortezomib Therapy in a Patient with Multiple Myeloma

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Tatsuro Joh

2009-10-01

Full Text Available We present here a case of dorsal column degeneration in a female patient with multiple myeloma following exposure to bortezomib. Two days after intravenous administration of a first course of bortezomib 1 mg/m2, the patient developed rapidly-progressive numbness, pain and muscle weakness in the bilateral upper and lower limbs. Following gancyclovir treatment of subsequent cytomegalovirus viremia, the patient went on to receive a course of EPOCH (etoposide 50 mg/m2/day on days 1–4, vincristine 0.4 mg/m2/day on days 1–4, doxorubicin 10 mg/m2/day on days 1–4, cyclophosphamide 750 mg/m2/day on day 6, and prednisolone 60 mg/m2/day on days 1–6. Shortly thereafter, the patient developed bilateral Aspergillus pneumonia. Despite treatment with appropriate antifungal agents, the patient died from respiratory failure due to bilateral diffuse alveolar damage of the lungs and without recovery of severe sensory and motor neuropathy prior to her death. Post mortem examination revealed spongy degeneration of the dorsal column from the medulla oblongata to the cervical spinal cord. Bortezomib-associated peripheral neuropathy in patients with multiple myeloma has been commonly reported but appears to resolve in a majority of these patients after dose reduction or discontinuation. We believe this to be the first report of spinal cord abnormalities in a patient with multiple myeloma treated with bortezomib. Further investigation is required to ascertain the exact mechanism of this central neurotoxic effect and to identify appropriate neuroprotective strategies.

Retrospective evaluation of doxorubicin-piroxicam combination for the treatment of transitional cell carcinoma in dogs.

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Robat, C; Burton, J; Thamm, D; Vail, D

2013-02-01

To determine whether doxorubicin-piroxicam combination is safe and has activity against transitional cell carcinoma in dogs. Data was collected retrospectively from 34 dogs from two institutions over a 6-year period. Signalment, clinical presentation, treatment specifics, adverse events, response, progression-free survival and overall survival time were evaluated. Dogs received doxorubicin every 3 weeks and daily piroxicam; 17 dogs (50%) had surgery. Clinical presentations were those typically reported for transitional cell carcinoma. Mean number of doses administered was 3·5. Of the 23 dogs with measurable disease, 14 (60·5%) had stable disease, 7 (30·5%) had progressive disease and 2 (9%) a partial response. Adverse events were generally manageable, and gastrointestinal in origin; one dog died of treatment-related complications. Overall median progression-free survival and overall survival were 103 and 168 days, respectively. Cytoreductive surgery did not result in prolongation of progression-free survival, but significantly prolonged overall survival. All dogs but one died as a result of disease progression. Doxorubicin-piroxicam combination therapy is well-tolerated in dogs with transitional cell carcinoma although progression-free survival, overall survival and biological response rates appear modest. Combination with surgery appears to offer a survival advantage; however, this may reflect tumour location and volume. Prospective studies are necessary to compare activity of combination doxorubicin-piroxicam to currently applied therapies. © 2013 British Small Animal Veterinary Association.

Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients

NARCIS (Netherlands)

Mulder, Renée L.; Paulides, Marios; Langer, Thorsten; Kremer, Leontien C. M.; van Dalen, Elvira C.

2012-01-01

Background Alkylating agents, such as cyclophosphamide and ifosfamide, play a major role in the improved survival of children and young adults with bone and soft tissue sarcoma. However, there is still controversy as to their comparative anti-tumour efficacy and possible adverse effects. This is an

Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients

NARCIS (Netherlands)

Mulder, Renée L.; Paulides, Marios; Langer, Thorsten; Kremer, Leontien C. M.; van Dalen, Elvira C.

2015-01-01

Alkylating agents, such as cyclophosphamide and ifosfamide, play a major role in the improved survival of children and young adults with bone and soft tissue sarcoma. However, there is still controversy as to their comparative anti-tumour efficacy and possible adverse effects. This is the second

Comparison of the Lonidamine Potentiated Effect of Nitrogen Mustard Alkylating Agents on the Systemic Treatment of DB-1 Human Melanoma Xenografts in Mice.

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Nath, Kavindra; Nelson, David S; Putt, Mary E; Leeper, Dennis B; Garman, Bradley; Nathanson, Katherine L; Glickson, Jerry D

2016-01-01

Previous NMR studies demonstrated that lonidamine (LND) selectively diminishes the intracellular pH (pHi) of DB-1 melanoma and mouse xenografts of a variety of other prevalent human cancers while decreasing their bioenergetic status (tumor βNTP/Pi ratio) and enhancing the activities of melphalan and doxorubicin in these cancer models. Since melphalan and doxorubicin are highly toxic agents, we have examined three other nitrogen (N)-mustards, chlorambucil, cyclophosphamide and bendamustine, to determine if they exhibit similar potentiation by LND. As single agents LND, melphalan and these N-mustards exhibited the following activities in DB-1 melanoma xenografts; LND: 100% tumor surviving fraction (SF); chlorambucil: 100% SF; cyclophosphamide: 100% SF; bendamustine: 79% SF; melphalan: 41% SF. When combined with LND administered 40 min prior to administration of the N-mustard (to maximize intracellular acidification) the following responses were obtained; chlorambucil: 62% SF; cyclophosphamide: 42% SF; bendamustine: 36% SF; melphalan: 10% SF. The effect of LND on the activities of these N-mustards is generally attributed to acid stabilization of the aziridinium active intermediate, acid inhibition of glutathione-S-transferase, which acts as a scavenger of aziridinium, and acid inhibition of DNA repair by O6-alkyltransferase. Depletion of ATP by LND may also decrease multidrug resistance and increase tumor response. At similar maximum tolerated doses, our data indicate that melphalan is the most effective N-mustard in combination with LND when treating DB-1 melanoma in mice, but the choice of N-mustard for coadministration with LND will also depend on the relative toxicities of these agents, and remains to be determined.

Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.

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Daruka Mahadevan

Full Text Available Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL, while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932 mouse model showed tumor growth inhibition (TGI of ∼ 10-20% (p = 0.001 for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001. M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.

Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.

Science.gov (United States)

Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S; Manziello, Ann; Mount, David W; Persky, Daniel O; Fisher, Richard I; Miller, Thomas P; Qi, Wenqing

2014-01-01

Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼ 10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.

Hypothalamic Energy Metabolism Is Impaired By Doxorubicin Independently Of Inflammation In Non-tumour-bearing Rats.

OpenAIRE

Antunes, Barbara M M; Lira, Fabio Santos; Pimentel, Gustavo Duarte; Rosa Neto, José Cesar; Esteves, Andrea Maculano; Oyama, Lila Missae; de Souza, Cláudio Teodoro; Gonçalves, Cinara Ludvig; Streck, Emilio Luiz; Rodrigues, Bruno; dos Santos, Ronaldo Vagner; de Mello, Marco Túlio

2016-01-01

We sought to explore the effects of doxorubicin on inflammatory profiles and energy metabolism in the hypothalamus of rats. To investigate these effects, we formed two groups: a control (C) group and a Doxorubicin (DOXO) group. Sixteen rats were randomly assigned to either the control (C) or DOXO groups. The hypothalamus was collected. The levels of interleukin (IL)-1β, IL-6, IL-10, TNF-α and energy metabolism (malate dehydrogenase, complex I and III activities) were analysed in the hypothala...

Polymeric composite membranes for temperature and pH-responsive delivery of doxorubicin hydrochloride

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Sahar Mohamaddoust Aliabadi

2015-07-01

Full Text Available Objective(s: Nowadays hydrogels are one of the upcoming classes of polymer-based controlled-release drug delivery systems. Temperature and pH-responsive delivery systems have drawn much attention because some diseases reveal themselves by a change in temperature and/or pH. The objective of this work is to prepare and characterize composite membrane using responsive nanoparticles into a polymer matrix. Materials and Methods: These nanoparticles were made of the copolymer poly (N-isopropylacrylamide-co-methaçrylic acid by an aqueous dispersion polymerization process and are responsible for dual sensitivity to temperature and pH. Morphology study with SEM, swelling behavior with Dynamic Light Scattering Technique, in vitro drug release behavior with side-by-side Diffusion Cells were also investigated in this paper. Doxorubicin hydrochloride was used as a model solute. Results:The study on the release of doxorubicin hydrochloride showed that the release rate was higher at pH 5 than pH 7.4, increased with the increase of temperature. Nevertheless, ionic strength only poses a minor direct effect at higher pH. Conclusion:Such system may be potentially used as a tumor-targeting doxorubicin hydrochloride delivery in the body.

RITA enhances chemosensivity of pre-B ALL cells to doxorubicin by inducing p53-dependent apoptosis.

Science.gov (United States)

Kazemi, Ahmad; Safa, Majid; Shahbazi, Atefeh

2011-07-01

The use of low-molecular-weight, non-peptidic molecules that disrupt the interaction between the p53 tumor suppressor and its negative regulator MDM2 has provided a promising alternative for the treatment of different types of cancer. Here, we used small-molecule reactivation of p53 and induction of tumor cell apoptosis (RITA) to sensitize leukemic NALM-6 cells to doxorubicin by upregulating p53 protein. RITA alone effectively inhibited NALM-6 cells viability in dose-dependent manner as measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay and induced apoptosis as evaluated by flow cytometry, whereas RITA in combination with doxorubicin enhanced NALM-6 cells to doxorubicin-sensitivity and promoted doxorubicin induced apoptosis. Levels of p53 protein and its proapoptotic target genes, quantified by western blot and real-time PCR respectively, showed that expression of p53 was significantly increased after RITA treatment. Using p53 inhibitors PFT-alpha and PFT-mu it was shown that p53-mediated apoptosis induced by RITA can be regulated by both p53-transcription-dependent and -independent pathways. Moreover, RITA-induced apoptosis was accompanied by the activation of caspase-3 and PARP cleavage. Therefore, exploiting synergistic effects between RITA and chemotherapeutics might be an effective clinical strategy for leukemia chemotherapy.

Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma

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Terence C. Tang

2010-03-01

Full Text Available Hepatocellular carcinoma (HCC is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG, which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX, UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.

Continuous low-dose oral chemotherapy in recurrent and persistent carcinoma of cervix following chemoradiation: A comparative study between prolonged oral cyclophosphamide and oral etoposide

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Upasana Baruah

2014-01-01

Full Text Available Aim: To compare the efficacy and toxicities of low-dose oral cyclophosphamide and oral etoposide in patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy. Materials and Methods: 30 patients with recurrent and persistent cervical cancer with gross pelvic disease were enrolled in this trial. The patients were randomly divided into two groups of 15 patients each with one group receiving low dose oral cyclophosphamide (100 mg/day and the other group receiving low-dose oral etoposide (50 mg/day. Results were statistically analysed by IBM SPSS Statistics 19. Results: Oral etoposide was not well tolerated with grade 2 neutropenia occurring in 33.3% and grade 3 neutropenia in 6.6% and thrombocytopenia occurring in 13.3%. Oral cyclophosphamide group on the other hand was better tolerated with none of the patients having thrombocytopenia and 6.6% patients having grade 2 neutropenia. There were two complete response (15.38% and one partial response at the end of study (7.6% in the cyclophosphamide group whereas there was no complete response and two partial response (16.6% in the oral etoposide group. Conclusion: Long-term, low-dose oral etoposide was found to be less tolerated without any significant effect with patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy in contrast to oral cyclophosphamide which was found to be effective and well-tolerated by the patients.

A facile doxorubicin-dichloroacetate conjugate nanomedicine with high drug loading for safe drug delivery.

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Yang, Conglian; Wu, Tingting; Qin, Yuting; Qi, Yan; Sun, Yu; Kong, Miao; Jiang, Xue; Qin, Xianya; Shen, Yaqi; Zhang, Zhiping

2018-01-01

Doxorubicin (DOX) is an effective chemotherapeutic agent but severe side effects limit its clinical application. Nanoformulations can reduce the toxicity while still have various limitations, such as complexity, low drug loading capability and excipient related concerns. An amphiphilic conjugate, doxorubicin-dichloroacetate, was synthesized and the corresponding nanoparticles were prepared. The in vitro cytotoxicity and intracellular uptake, in vivo imaging, antitumor effects and systemic toxicities of nanoparticles were carried out to evaluate the therapeutic efficiency of tumor. Doxorubicin-dichloroacetate conjugate can self-assemble into nanoparticles with small amount of DSPE-PEG 2000 , leading to high drug loading (71.8%, w/w) and diminished excipient associated concerns. The nanoparticles exhibited invisible systemic toxicity and high maximum tolerated dose of 75 mg DOX equiv./kg, which was 15-fold higher than that of free DOX. It also showed good tumor targeting capability and enhanced antitumor efficacy in murine melanoma model. This work provides a promising strategy to simplify the drug preparation process, increase drug loading content, reduce systemic toxicity as well as enhance antitumor efficiency.

Comparative cytotoxicity of gold-doxorubicin and InP-doxorubicin conjugates.

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Zhang, Xuan; Chibli, Hicham; Kong, Dekun; Nadeau, Jay

2012-07-11

Direct comparisons of different types of nanoparticles for drug delivery have seldom been performed. In this study we compare the physical properties and cellular activity of doxorubicin (Dox) conjugates to gold nanoparticles (Au) and InP quantum dots of comparable diameter. Although the Au particles alone are non-toxic and InP is moderately toxic, Au-Dox is more effective than InP-Dox against the Dox-resistant B16 melanoma cell line. Light exposure does not augment the efficacy of InP-Dox, suggesting that conjugates are breaking down. Electron and confocal microscopy and atomic absorption spectroscopy reveal that over 60% of the Au-Dox conjugates reach the cell nucleus. In contrast, InP-Dox enters cell nuclei to a very limited extent, although liberated Dox from the conjugates does eventually reach the nucleus. These observations are attributed to faster Dox release from Au conjugates under endosomal conditions, greater aggregation of InP-Dox with cytoplasmic proteins, and adherence of InP to membranes. These findings have important implications for design of active drug-nanoparticle conjugates.

Spectroscopic and molecular modeling study on the interaction of ctDNA with 3′-deoxy-3′-azido doxorubicin

International Nuclear Information System (INIS)

Geng, Shaoguang; Cui, Yanrui; Liu, Qingfeng; Cui, Fengling; Zhang, Guisheng; Chi, Yanwei; Peng, Hao

2013-01-01

The method of synthesizing 3′-deoxy-3′-azido doxorubicin (ADOX) directly from doxorubicin has been developed. This study presents the interaction between ADOX and calf thymus deoxyribonucleic acid (ctDNA) by using spectroscopic methods and molecular modeling techniques. Iodide quenching, fluorescence polarization, viscosity and molecular modeling studies of ADOX–ctDNA interactions indicated that ADOX was an intercalator of ctDNA and preferentially bound to C–G rich regions of ctDNA. Simultaneously, spectroscopic results indicated that the quenching mechanism of ADOX–ctDNA was a static quenching. According to thermodynamic parameters, electrostatic force played roles in the interaction of ADOX with ctDNA. -- Highlights: ●An approach to 3′-deoxy-3′-azido doxorubicin (ADOX) from doxorubicin was developed. ●The quenching mechanism of ADOX with ctDNA was a static quenching type. ●The binding mode between ADOX and ctDNA was intercalative binding. ●The results of molecular docking corroborated results of spectra investigations

TVP1022 and propargylamine protect neonatal rat ventricular myocytes against doxorubicin-induced and serum starvation-induced cardiotoxicity.

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Kleiner, Yana; Bar-Am, Orit; Amit, Tamar; Berdichevski, Alexandra; Liani, Esti; Maor, Gila; Reiter, Irina; Youdim, Moussa B H; Binah, Ofer

2008-09-01

We recently reported that propargylamine derivatives such as rasagiline (Azilect) and its S-isomer TVP1022 are neuroprotective. The aim of this study was to test the hypothesis that the neuroprotective agents TVP1022 and propargylamine (the active moiety of propargylamine derivatives) are also cardioprotective. We specifically investigated the protective efficacy of TVP1022 and propargylamine in neonatal rat ventricular myocytes (NRVM) against apoptosis induced by the anthracycline chemotherapeutic agent doxorubicin and by serum starvation. We demonstrated that pretreatment of NRVM cultures with TVP1022 or propargylamine attenuated doxorubicin-induced and serum starvation-induced apoptosis, inhibited the increase in cleaved caspase 3 levels, and reversed the decline in Bcl-2/Bax ratio. These cytoprotective effects were shown to reside in the propargylamine moiety. Finally, we showed that TVP1022 neither caused proliferation of the human cancer cell lines HeLa and MDA-231 nor interfered with the anti-cancer efficacy of doxorubicin. These results suggest that TVP1022 should be considered as a novel cardioprotective agent against ischemic insults and against anthracycline cardiotoxicity and can be coadministered with doxorubicin in the treatment of human malignancies.

Complete remission of coronary vasculitis in Churg-Strauss Syndrome by prednisone and cyclophosphamide.

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Riksen, Niels P; Gehlmann, Helmut; Brouwer, Annemarie E; van Deuren, Marcel

2013-03-01

The heart is involved in up to 50% of all patients with Churg-Strauss syndrome, but vasculitis of the coronary arteries has only been rarely documented. We present a young patient with severe coronary aneurysms and stenotic lesions due to a Churg-Strauss vasculitis. Prompt therapy with prednisone and cyclophosphamide resulted in the complete resolution of all lesions.

Tumor targeted delivery of doxorubicin in malignant peripheral nerve sheath tumors.

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A B Madhankumar

Full Text Available Peripheral nerve sheath tumors are benign tumors that have the potential to transform into malignant peripheral nerve sheath tumors (MPNSTs. Interleukin-13 receptor alpha 2 (IL13Rα2 is a cancer associated receptor expressed in glioblastoma and other invasive cancers. We analyzed IL13Rα2 expression in several MPNST cell lines including the STS26T cell line, as well as in several peripheral nerve sheath tumors to utilize the IL13Rα2 receptor as a target for therapy. In our studies, we demonstrated the selective expression of IL13Rα2 in several peripheral nerve sheath tumors by immunohistochemistry (IHC and immunoblots. We established a sciatic nerve MPNST mouse model in NIH III nude mice using a luciferase transfected STS26T MPNST cell line. Similarly, analysis of the mouse sciatic nerves after tumor induction revealed significant expression of IL13Rα2 by IHC when compared to a normal sciatic nerve. IL13 conjugated liposomal doxorubicin was formulated and shown to bind and internalized in the MPNST cell culture model demonstrating cytotoxic effect. Our subsequent in vivo investigation in the STS26T MPNST sciatic nerve tumor model indicated that IL13 conjugated liposomal doxorubicin (IL13LIPDXR was more effective in inhibiting tumor progression compared to unconjugated liposomal doxorubicin (LIPDXR. This further supports that IL13 receptor targeted nanoliposomes is a potential approach for treating MPNSTs.

Preventive and curative effects of cyclophosphamide in an animal model of Guillain Barrè syndrome

DEFF Research Database (Denmark)

Mangano, Katia; Dati, Gabriele; Quattrocchi, Cinzia

2008-01-01

The immunosuppressive agent cyclophosphamide (CY) was tested in rat experimental allergic neuritis (EAN), a preclinical model of Guillain Barrè syndrome (GBS). CY prophylaxis (day 0 and 14 post-immunization [p.i.]) effectively prevents clinical and histological signs of EAN and also reduces...

Monitoring the behaviour of 4-ketocyclophosphamide versus cyclophosphamide during capillary gas chromatography by mass spectrometry

NARCIS (Netherlands)

Bruijn, de E.A.; Oosterom, van A.T.; Leclercq, P.A.; Haan, de J.W.; Ven, van de L.J.M.; Tjaden, U.R.

1987-01-01

Capillary Gas Chromatography (CGC) is capable of determining underivatized cyclophosphamide (CPA) using SCOT OV 275 columns. Then CPA is subjected to in situ degradation resulting in formation of a cyclization product which can be determined selectively in biological fluids. In routine bioanalysis

Doxorubicin-conjugated bacteriophages carrying anti-MHC class I chain-related A for targeted cancer therapy in vitro

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Phumyen A

2014-11-01

Full Text Available Achara Phumyen,1–3 Siriporn Jantasorn,1 Amonrat Jumnainsong,1 Chanvit Leelayuwat1–4 1The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL, Faculty of Associated Medical Sciences, 2The Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, 3Research Cluster: Specific Health Problem of Grater Maekong Subregion (SHeP-GMS, 4Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand Background: Cancer therapy by systemic administration of anticancer drugs, besides the effectiveness shown on cancer cells, demonstrated the side effects and cytotoxicity on normal cells. The targeted drug-carrying nanoparticles may decrease the required drug concentration at the site and the distribution of drugs to normal tissues. Overexpression of major histocompatibility complex class I chain–related A (MICA in cancer is useful as a targeted molecule for the delivery of doxorubicin to MICA-expressing cell lines. Methods: The application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide (EDC chemistry was employed to conjugate the major coat protein of bacteriophages carrying anti-MICA and doxorubicin in a mildly acid condition. Doxorubicin (Dox on phages was determined by double fluorescence of phage particles stained by M13-fluorescein isothiocyanate (FITC and drug autofluorescence by flow cytometry. The ability of anti-MICA on phages to bind MICA after doxorubicin conjugation was evaluated by indirect enzyme-linked immunosorbent assay. One cervical cancer and four cholangiocarcinoma cell lines expressing MICA were used as models to evaluate targeting activity by cell cytotoxicity test. Results: Flow cytometry and indirect enzyme-linked immunosorbent assay demonstrated that most of the phages (82% could be conjugated with doxorubicin, and the Dox-carrying phage-displaying anti-MICA (Dox-phage remained the binding activity against MICA

Tetrathiomolybdate sensitizes ovarian cancer cells to anticancer drugs doxorubicin, fenretinide, 5-fluorouracil and mitomycin C

International Nuclear Information System (INIS)

Kim, Kyu Kwang; Lange, Thilo S; Singh, Rakesh K; Brard, Laurent; Moore, Richard G

2012-01-01

Our recent study showed that tetrathiomolybdate (TM), a drug to treat copper overload disorders, can sensitize drug-resistant endometrial cancer cells to reactive oxygen species (ROS)-generating anticancer drug doxorubicin. To expand these findings in the present study we explore TM efficacy in combination with a spectrum of ROS-generating anticancer drugs including mitomycin C, fenretinide, 5-fluorouracil and doxorubicin in ovarian cancer cells as a model system. The effects of TM alone or in combination with doxorubicin, mitomycin C, fenretinide, or 5-fluorouracil were evaluated using a sulforhodamine B assay. Flow cytometry was used to detect the induction of apoptosis and ROS generation. Immunoblot analysis was carried out to investigate changes in signaling pathways. TM potentiated doxorubicin-induced cytotoxicity and modulated key regulators of apoptosis (PARP, caspases, JNK and p38 MAPK) in SKOV-3 and A2780 ovarian cancer cell lines. These effects were linked to the increased production of ROS, as shown in SKOV-3 cells. ROS scavenging by ascorbic acid blocked the sensitization of cells by TM. TM also sensitized SKOV-3 to mitomycin C, fenretinide, and 5-fluorouracil. The increased cytotoxicity of these drugs in combination with TM was correlated with the activity of ROS, loss of a pro-survival factor (e.g. XIAP) and the appearance of a pro-apoptotic marker (e.g. PARP cleavage). Our data show that TM increases the efficacy of various anticancer drugs in ovarian cancer cells in a ROS-dependent manner

Zoledronic acid enhances antitumor efficacy of liposomal doxorubicin.

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Hattori, Yoshiyuki; Shibuya, Kazuhiko; Kojima, Kaori; Miatmoko, Andang; Kawano, Kumi; Ozaki, Kei-Ichi; Yonemochi, Etsuo

2015-07-01

Previously, we found that the injection of zoledronic acid (ZOL) into mice bearing tumor induced changes of the vascular structure in the tumor. In this study, we examined whether ZOL treatment could decrease interstitial fluid pressure (IFP) via change of tumor vasculature, and enhance the antitumor efficacy of liposomal doxorubicin (Doxil®). When ZOL solution was injected at 40 µg/mouse per day for three consecutive days into mice bearing murine Lewis lung carcinoma LLC tumor, depletion of macrophages in tumor tissue and decreased density of tumor vasculature were observed. Furthermore, ZOL treatments induced inflammatory cytokines such as interleukin (IL)-10 and -12, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α in serum of LLC tumor-bearing mice, but not in normal mice, indicating that ZOL treatments might induce an inflammatory response in tumor tissue. Furthermore, ZOL treatments increased antitumor activity by Doxil in mice bearing a subcutaneous LLC tumor, although they did not significantly increase the tumor accumulation of doxorubicin (DXR). These results suggest that ZOL treatments might increase the therapeutic efficacy of Doxil via improvement of DXR distribution in a tumor by changing the tumor vasculature. ZOL treatment can be an alternative approach to increase the antitumor effect of liposomal drugs.

78 FR 47321 - Determination That CYTOXAN (Cyclophosphamide) for Injection Was Not Withdrawn From Sale for...

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2013-08-05

... marketing for reasons other than safety or effectiveness. ANDAs that refer to CYTOXAN (cyclophosphamide) for... Effectiveness AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug... sale for reasons of safety or effectiveness. This determination will allow FDA to approve abbreviated...

Percentage tumor necrosis following chemotherapy in neuroblastoma correlates with MYCN status but not survival.

Science.gov (United States)

Bomken, Simon; Davies, Beverley; Chong, Leeai; Cole, Michael; Wood, Katrina M; McDermott, Michael; Tweddle, Deborah A

2011-03-01

The percentage of chemotherapy-induced necrosis in primary tumors corresponds with outcome in several childhood malignancies, including high-risk metastatic diseases. In this retrospective pilot study, the authors assessed the importance of postchemotherapy necrosis in high-risk neuroblastoma with a histological and case notes review of surgically resected specimens. The authors reviewed all available histology of 31 high-risk neuroblastoma cases treated with COJEC (dose intensive etoposide and vincristine with either cyclophosphamide, cisplatin or carboplatin) or OPEC/OJEC (etoposide, vincristine and cyclophosphamide with alternating cisplatin [OPEC] or carboplatin [OJEC]) induction chemotherapy in 2 Children's Cancer & Leukaemia Group (CCLG) pediatric oncology centers. The percentage of postchemotherapy necrosis was assessed and compared with MYCN amplification status and overall survival. The median percentage of postchemotherapy tumor necrosis was 60%. MYCN status was available for 28 cases, of which 12 were amplified (43%). Survival in cases with ≥ 60% necrosis or ≥ 90% necrosis was not better than those with less necrosis, nor was percentage necrosis associated with survival using Cox regression. However, MYCN-amplified tumors showed a higher percentage of necrosis than non-MYCN-amplified tumors, 71.3% versus 37.2% (P = .006). This effect was not related to prechemotherapy necrosis and did not confer improved overall survival. Postchemotherapy tumor necrosis is higher in patients with MYCN amplification. In this study, postchemotherapy necrosis did not correlate with overall survival and should not lead to modification of postoperative treatment. However, these findings need to be confirmed in a larger prospective study of children with high-risk neuroblastoma.

In vitro effect of cyclophosphamide on the binding of radiopharmaceuticals (99m Tc O4- and 99m Tc-MDP) to blood elements

International Nuclear Information System (INIS)

Ripoll-Hamer, E.; Paula, E.F. de; Bernardo Filho, M.; Freitas, L.C.; Fonseca, L.M.; Gutfilen, B.

1995-01-01

Using an in vitro model, it was evaluated the effect of cyclophosphamide on percent radioactivity of 99m Tc O - 4 and methylene diphosphonic acid ( 99m Tc-MDP) bound to isolated blood elements. Blood samples were incubated with the two radiopharmaceuticals, plasma and blood cells were separated and precipitated, and soluble and insoluble fractions were separated. To evaluate the effect of cyclophosphamide, blood was incubated with this drug 1 h prior to the addition of the radiopharmaceuticals. The fraction of 99m Tc O - 4 radioactivity was slightly higher in plasma (61.2 to 53.8%) than in blood cells (38.8 to 46.2%) up to 6 h. The amount of 99m Tc - MDP radioactivity was higher in plasma (91.1 to 87.2%) than in blood cells (8.9 to 12.8%) up to 24 h. The binding of 99m Tc O - 4 to the insoluble fraction of plasma (4.9 to 6.1%) was low. But a small blockade (9.8 to 4.8%) was observed at 24 h. From 3 h on, cyclophosphamide slightly inhibited 99m Tc O - 4 binding to blood cells (23.1 to 16.6%) and increased it at 24 h (31.2 to 14.3%). The effect of cyclophosphamide was strongest at 24 h, with decreased radioactivity binding to the insoluble fraction of plasma (47.6 to 27.0%) and blood cells (51.2 to 23.2%). The fact that cyclophosphamide can bind to plasma proteins and/or cross the cell membrane explains in part the results obtained. (author). 20 refs., 2 tabs

Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy

NARCIS (Netherlands)

de Jonge, M. E.; Mathôt, R. A. A.; Dalesio, O.; Huitema, A. D. R.; Rodenhuis, S.; Beijnen, J. H.

2002-01-01

Reversible alopecia is a commonly observed, important and distressing complication of chemotherapy. Permanent alopecia, however, is rare after standard-dose therapy, but has occasionally been observed after high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC). We evaluated

Short course of cyclophosphamide therapy may reduce recurrence in patients with tubulointerstitial nephritis and uveitis syndrome

International Nuclear Information System (INIS)

Taheri, Shahram; Taheri Diana

2009-01-01

We report a 43-year-old woman with tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) presented with a 5-day complaint of chills and fever, anorexia, nausea, and vomiting. She had elevated BUN and creatinine and urinalysis revealed decreased concentration, proteinuria, hematuria, and pyuria. A kidney biopsy showed non-caseating granulomatous tubulointerstitial nephritis. She suffered from anterior uveitis one month before, which was managed with local ophthalmic steroids. She received two months of oral high dose prednisolone, which was tapered over the next two months, and two months of 2 mg/kg cyclophosphamide. Her renal function recovered during the first two months. Her kidney and ocular symptoms did not recur during one year of follow-up. We suggest short course of cyclophosphamide and prednisolone for treatment of TINU syndrome to decrease the recurrence of kidney and ocular involvement. (author)

Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells.

Science.gov (United States)

Kemp, Kevin; Morse, Ruth; Sanders, Kelly; Hows, Jill; Donaldson, Craig

2011-07-01

The adverse effects of melphalan and cyclophosphamide on hematopoietic stem cells are well-known; however, the effects on the mesenchymal stem cells (MSCs) residing in the bone marrow are less well characterised. Examining the effects of chemotherapeutic agents on patient MSCs in vivo is difficult due to variability in patients and differences in the drug combinations used, both of which could have implications on MSC function. As drugs are not commonly used as single agents during high-dose chemotherapy (HDC) regimens, there is a lack of data comparing the short- or long-term effects these drugs have on patients post treatment. To help address these problems, the effects of the alkylating chemotherapeutic agents cyclophosphamide and melphalan on human bone marrow MSCs were evaluated in vitro. Within this study, the exposure of MSCs to the chemotherapeutic agents cyclophosphamide or melphalan had strong negative effects on MSC expansion and CD44 expression. In addition, changes were seen in the ability of MSCs to support hematopoietic cell migration and repopulation. These observations therefore highlight potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies. Furthermore, this study suggests that if the damage caused by chemotherapeutic agents to marrow MSCs is substantial, it would be logical to use cultured allogeneic MSCs therapeutically to assist or repair the marrow microenvironment after HDC.

APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation.

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VanKlompenberg, Monica K; Leyden, Emily; Arnason, Anne H; Zhang, Jian-Ting; Stefanski, Casey D; Prosperi, Jenifer R

2017-11-28

Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of Adenomatous Polyposis Coli (APC) in the Mouse Mammary Tumor Virus - Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance. Our data demonstrate that MMTV-PyMT; Apc Min/+ cells have increased signal transducer and activator of transcription 3 (STAT3) activation. STAT3 can be constitutively activated in breast cancer, maintains the tumor initiating cell (TIC) population, and upregulates multidrug resistance protein 1 (MDR1). The activation of STAT3 in the MMTV-PyMT; Apc Min/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT; Apc Min/+ cells may be responsible for the increased STAT3 activation. Inhibiting STAT3 with a small molecule inhibitor A69 in combination with doxorubicin, but not cisplatin, restores drug sensitivity. A69 also decreases doxorubicin enhanced MDR1 gene expression and the TIC population enhanced by loss of APC. In summary, these results have revealed the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance.

Involvement of miR-30c in resistance to doxorubicin by regulating YWHAZ in breast cancer cells

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Fang, Y. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Shen, H. [Department of Oncology, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Cao, Y. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Li, H. [Department of Central Laboratory, The Fourth Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Qin, R. [Department of Oncology, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Chen, Q. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Long, L. [Department of Oncology, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Zhu, X.L. [Department of Central Laboratory, The Fourth Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Xie, C.J. [Department of Central Laboratory, The First Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China); Xu, W.L. [Department of Central Laboratory, The Fourth Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu (China)

2014-01-10

MicroRNAs (miRNAs) are small RNA molecules that modulate gene expression implicated in cancer, which play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. The aim of this study was to investigate whether miR-30c mediated the resistance of breast cancer cells to the chemotherapeutic agent doxorubicin (ADR) by targeting tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ). miR-30c was downregulated in the doxorubicin-resistant human breast cancer cell lines MCF-7/ADR and MDA-MB-231/ADR compared with their parental MCF-7 and MDA-MB-231 cell lines, respectively. Furthermore, we observed that transfection of an miR-30c mimic significantly suppressed the ability of MCF-7/ADR to resist doxorubicin. Moreover, the anti-apoptotic gene YWHAZ was confirmed as a target of miR-30c by luciferase reporter assay, and further studies indicated that the mechanism for miR-30c on the sensitivity of breast cancer cells involved YWHAZ and its downstream p38 mitogen-activated protein kinase (p38MAPK) pathway. Together, our findings provided evidence that miR-30c was one of the important miRNAs in doxorubicin resistance by regulating YWHAZ in the breast cancer cell line MCF-7/ADR.

An epidural neuroblastoma causing spinal cord compression in a 67-year-old woman

Directory of Open Access Journals (Sweden)

Ethan Taub

2010-04-01

Full Text Available We report a case of disseminated neuroblastoma (NB causing epidural spinal cord compression in a 67-year-old woman. Because NB is primarily a tumor of infancy and childhood, less is known about its clinical course and optimal treatment in adults. This patient was treated with a thoracic laminectomy and tumor resection; polychemotherapy with one cycle of vindesine, cisplatin, and etoposide; one cycle of vincristine, dacarbazine, ifosfamide, and doxorubicin; and radiotherapy to the spine. She remained able to walk but died 8.5 months later of diffuse systemic tumor progression.

Post-induction residual disease in translocation t(12;21)-positive childhood ALL

DEFF Research Database (Denmark)

Seyfarth, Jeanette; Madsen, Hans O; Nyvold, Charlotte

2003-01-01

of induction therapy (prednisolone, vincristine, doxorubicin, i.t. methotrexate) by a competitive, clone-specific, semi-nested PCR analysis. RESULTS: Among 96 children diagnosed with ALL, and quantified for post induction residual disease, 32 were t(12;21)-positive. The median residual disease was similar...... and Oncology (NOPHO) ALL-MRD 95 study, which includes children from Iceland, Norway, and Denmark diagnose d with ALL, patients were screened for the presence of t(12; 21) by reverse transcriptase-polymerase chain reaction (RT-PCR) at diagnosis, and their residual disease was quantified after 4 weeks...

Theoretical, clinical and pharmacokinetic aspects of cancer chemotherapy administered by continuous infusion

International Nuclear Information System (INIS)

Sikic, B.I.

1986-01-01

This chapter reviews some of the theoretical and empirical aspects of the administration of anti-cancer drugs by continuous intravenous infusion in conjunction with radiation therapy. The variables contributing to schedule dependence of anti-cancer drugs are discussed. A table shows the improved therapeutic index of Bleomycin by continuous infusion in mice. The use of Cytarabine, a pyrimidine anti-metabolite which kills cells during S-phase or DNA synthesis, is examined. Fluorouracil and Doxorubicin are examined and several other drugs including vincristine, vinblastine, etoposide, and cisplatin are discussed

Cancer screening tests for small animals.

Science.gov (United States)

Schleis, Stephanie E

2014-09-01

Cancer is increasingly more common. Several tests for the diagnosis and treatment of cancer in companion animals have been developed. Screening tests discussed include those for lymphoid neoplasia, hemangiosarcoma, and transitional cell carcinoma of the bladder. None of these tests should be used in isolation for diagnosis. Vincristine and doxorubicin are mainstays in the treatment of canine lymphoma. However, it is important and accepted practice to test individuals of predisposed breeds for this mutation before administering these drugs in a lymphoma protocol. Copyright © 2014 Elsevier Inc. All rights reserved.

Xanthohumol, a Prenylated Chalcone from Hops, Inhibits the Viability and Stemness of Doxorubicin-Resistant MCF-7/ADR Cells

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Ming Liu

2016-12-01

Full Text Available Xanthohumol is a unique prenylated flavonoid in hops (Humulus lupulus L. and beer. Xanthohumol has been shown to possess a variety of pharmacological activities. There is little research on its effect on doxorubicin-resistant breast cancer cells (MCF-7/ADR and the cancer stem-like cells exiting in this cell line. In the present study, we investigate the effect of xanthohumol on the viability and stemness of MCF-7/ADR cells. Xanthohumol inhibits viability, induces apoptosis, and arrests the cell cycle of MCF-7/ADR cells in a dose-dependent manner; in addition, xanthohumol sensitizes the inhibition effect of doxorubicin on MCF-7/ADR cells. Interestingly, we also find that xanthohumol can reduce the stemness of MCF-7/ADR cells evidenced by the xanthohumol-induced decrease in the colony formation, the migration, the percentage of side population cells, the sphere formation, and the down-regulation of stemness-related biomarkers. These results demonstrate that xanthohumol is a promising compound targeting the doxorubicin resistant breast cancer cells and regulating their stemness, which, therefore, will be applied as a potential candidate for the development of a doxorubicin-resistant breast cancer agent and combination therapy of breast cancer.

Potentiation of in vitro and in vivo antitumor efficacy of doxorubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells

International Nuclear Information System (INIS)

Rathos, Maggie J; Khanwalkar, Harshal; Joshi, Kavita; Manohar, Sonal M; Joshi, Kalpana S

2013-01-01

In the present study, we show that the combination of doxorubicin with the cyclin-dependent kinase inhibitor P276-00 was synergistic at suboptimal doses in the non-small cell lung carcinoma (NSCLC) cell lines and induces extensive apoptosis than either drug alone in H-460 human NSCLC cells. Synergistic effects of P276-00 and doxorubicin on growth inhibition was studied using the Propidium Iodide (PI) assay. The doses showing the best synergistic effect was determined and these doses were used for further mechanistic studies such as western blotting, cell cycle analysis and RT-PCR. The in vivo efficacy of the combination was evaluated using the H-460 xenograft model. The combination of 100 nM doxorubicin followed by 1200 nM P276-00 showed synergistic effect in the p53-positive and p53-mutated cell lines H-460 and H23 respectively as compared to the p53-null cell line H1299. Abrogation of doxorubicin-induced G2/M arrest and induction of apoptosis was observed in the combination treatment. This was associated with induction of tumor suppressor protein p53 and reduction of anti-apoptotic protein Bcl-2. Furthermore, doxorubicin alone greatly induced COX-2, a NF-κB target and Cdk-1, a target of P276-00, which was downregulated by P276-00 in the combination. Doxorubicin when combined with P276-00 in a sequence-specific manner significantly inhibited tumor growth, compared with either doxorubicin or P276-00 alone in H-460 xenograft model. These findings suggest that this combination may increase the therapeutic index over doxorubicin alone and reduce systemic toxicity of doxorubicin most likely via an inhibition of doxorubicin-induced chemoresistance involving NF-κB signaling and inhibition of Cdk-1 which is involved in cell cycle progression

Chemoembolization (TACE) of Unresectable Intrahepatic Cholangiocarcinoma with Slow-Release Doxorubicin-Eluting Beads: Preliminary Results