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Sample records for cyclophosphamide mitoxantrone vincristine

  1. [Combination chemotherapy with vincristine, melphalan, CCNA, cyclophosphamide, prednisone in myeloma].

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    Le Loët, X; Monconduit, M; Menard, J F; Deshayes, P; Grobois, B; Tanguy, A; Prevost, E; Piguet, H

    1984-05-01

    The authors report the results of a prospective, multi-centre trial involving 87 patients with previously untreated myeloma who were treated by combination chemotherapy consisting of melphalan, cyclophosphamide, CCNU, prednisone and vincristine. 83.1% of patients had a high tumour mass (stage III on Durie and Salmon's classification). The response to treatment could be evaluated in 76 patients and 70% were found to respond. The median actuarial survival of the whole population is 30 months. The survival is significantly longer (p less than 0.001) in responders (median 40 months) than in non-responders (median: 17 months); the survival is significantly shorter (p less than 0.01) in subjects with renal failure (median: 10 months) than in subjects without renal failure (median: 36 months). This treatment is sufficiently well tolerated to be administered on an outpatient basis. One case of acute monoblastic leukaemia was observed. These results are similar to those reported in the literature.

  2. Treatment of advanced seminoma with cyclophosphamide, vincristine and carboplatin on an outpatient basis

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    Sleijfer, S; Willemse, PHB; deVries, EGE; vanderGraaf, WTA; Mulder, NH; Schraffordt Koops, H.

    This study describes the efficacy and toxicity of a combination regimen consisting of cyclophosphamide, vincristine (oncovin) and carboplatin (COC) for advanced seminoma on an outpatient basis. Twenty-seven patients (mean age 43 years, range 28-63 years) were classified as stage IIC (n = 5), stage

  3. Chemotherapy with cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP) in childhood acute lymphoblastic leukemia (ALL).

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    Sallan, S E; Camitta, B M; Chan, D M; Traggis, D; Jaffe, N

    1977-01-01

    Three groups of children with acute lymphoblastic leukemia (ALL) were treated with intermittent cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP). Group A (no prior relapse) and Group B (prior single-agent relapse) received COAP after 12 months on another chemotherapy regimen. Children in Group C (prior relapse on multiagent regimens) received COAP following A-COAP (asparaginase plus COAP) reinduction. Median disease-free survival after beginning COAP was not reached for Group A, but was only 7 months for Groups B and C. As of November 1976, there were 8 of 15 Group A patients, 1 of 12 Group B patients, and 1 of 28 Group C patients who had remained disease-free from 38 to 60 (median 54.5) months and were off chemotherapy. COAP has activity in childhood ALL. However, effectiveness is markedly diminished in patients with prior bone marrow relapse.

  4. Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer.

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    Khan, Tanweera S; Sundin, Anders; Juhlin, Claes; Wilander, Erik; Oberg, Kjell; Eriksson, Barbro

    2004-01-01

    The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial.

  5. High-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone for remission induction in refractory adult acute leukemia.

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    Guthrie, T H

    1987-04-01

    Fifteen consecutive patients with refractory adult acute leukemia (RAAL) were treated with a combination of high-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone (Hi-COAP). The initial nine patients received cyclophosphamide 350 mg/m2 as a 24-hour intravenous (IV) infusion over 5 days; cytarabine, 100 mg/m2 IV bolus every 12 hours for ten doses; vincristine, 2.0 mg IV bolus on day 1; and prednisone, 100 mg orally for 7 days. The last six patients had the cyclophosphamide infusion lengthened to 7 days, and the cytarabine increased to 14 doses. All patients were evaluable for toxicity and response. Seven patients (47%) obtained a complete remission and six patients (40%) a partial remission. Median duration of all remissions has been 7.0 months with a range of 1 to 32 months. Toxicity has been limited to primarily myelosuppression with no hemorrhagic cystitis, central nervous system (CNS), hepatic, or pulmonary toxicity noted. Gastrointestinal toxicity was mild, with no effect on nutritional status noted. Median duration of complete responders was 8.5 months. Thus, Hi-COAP demonstrates promising efficacy with minimal toxicity in RAAL and warrants further exploration in multiinstitutional trials.

  6. Chemotherapy of acute leukemia: a comparison of vincristine, cytarabine, and prednisone alone and in combination with cyclophosphamide or daunorubicin.

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    Coltman, C A; Bodey, G P; Hewlett, J S; Haut, A; Bickers, J; Balcerzak, S P; Costanzi, J J; Freireich, E J; McCredie, K B; Groppe, C; Smith, T L; Gehan, E A

    1978-09-01

    Adults (274) with acute leukemia (AML) were randomly assigned to one of three treatment regimens: vincristine, prednisone, cytarabine--(1) 100 mg/sq m/day with cyclophosphamide (COAP); (2) 100 mg/sq m/day with daunorubicin (DOAP); and 200 mg/sq m/day (OAP). Cytarabine was infused continuously for five days. Patients entering complete remission randomly received maintenance treatment with COAP or OAP. For 197 previously untreated AML patients given COAP, DOAP, or OAP, remission rates were 37%, 35%, and 43%, respectively; median lengths, 40, 45, and 90 weeks; median survival, 7, 11, and 8 weeks. No statistically significant difference was found among treatments. Therefore, adding cyclophosphamide or daunorubicin, or using the COAP regimen with continuously infused cytarabine, produced no significant improvement over previously reported regimens. There was no significant difference in remission lengths in previously untreated AML patients maintained on OAP (median 81 weeks) or COAP (median 65 weeks).

  7. Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma.

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    Stiff, P J; McKenzie, R S; Alberts, D S; Sosman, J A; Dolan, J R; Rad, N; McCloskey, T

    1994-01-01

    To develop an active high-dose chemotherapy regimen for the treatment of ovarian carcinoma. Due to the rapid development a drug resistance, conventional chemotherapy cures only 20% of patients with advanced disease. However, in vitro data demonstrate a steep dose-response curve to a variety of agents, most notably mitoxantrone. A phase I study of escalated bolus mitoxantrone (10 to 25 mg/m2 x 3) and cyclophosphamide (30 to 50 mg/kg x 3) with a 5-day infusion of carboplatin (1,500 mg/m2) and an autologous bone marrow transplant (ABMT) was performed. Mitoxantrone pharmacokinetics were performed to document levels required to kill platinum-resistant ovarian carcinoma in vitro. We treated 25 patients; the maximum-tolerated total doses (MTD) were 75 mg/m2 for mitoxantrone, 120 mg/kg for cyclophosphamide, and 1,500 mg/m2 for carboplatin. The dose-limiting toxicity was gastrointestinal, with severe diarrhea, ileus, and resulting sepsis. Transient partial deafness was seen in four patients, and acute renal failure (ARF) occurred in one patient at the first dose level, but was eliminated in subsequent patients with aggressive hydration. There were four early deaths due to ARF (n = 1), Legionella pneumonia (n = 1), and sepsis (n = 2). Peak mitoxantrone levels at the MTD were 623 to 2,810 ng/mL, and the area under the curve (AUC) values of the concentration versus time measurements were 560 to 1,700 ng/mL/h. Of 20 assessable patients, 65% responded, with a 45% complete remission (CR) rate. All six of the assessable patients with ovarian cancer responded: CR in five (83%) and partial remission (PR) in one (17%); the CRs have lasted 7 to 30+ months. Responses were also seen in testicular and breast carcinoma. This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.

  8. Treatment of diffuse histiocytic and diffuse mixed non-Hodgkin lymphomas with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

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    Cohen, Y; Epelbaum, R; Ben-Shahar, M; Ron, Y; Haim, N

    1988-01-01

    During 1977 to 1985 90 patients with large-cell non-Hodgkin lymphoma (diffuse histiocytic or diffuse mixed according to Rapport classification) were treated by the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with a mean follow-up of 41 months. Thirty-four patients were treated with radiation therapy as well. The mean number of CHOP cycles to achieve complete response was 4.0 and the mean total number of cycles was 6.6. For 78 patients it was possible to calculate relative dose intensity (RDI) for each drug and the average RDI. Sixty-four patients (71%) achieved CR. The actuarial 5-year survival rate of all patients was 52%. The median RDI for cyclophosphamide was 0.72, for doxorubicin 0.70, for vincristine 0.69 and the median average RDI was 0.69. The following favorable prognostic factors were found to be of statistical significance: female sex and stages I-III as compared to stage IV. The 5-year survival rate for stage I & II patients treated by CHOP plus radiotherapy was 70% as compared to 55% for those treated by CHOP only; this difference was not statistically significant.

  9. An analysis of a multiple-drug program in the treatment of patients with advanced breast cancer utilizing 5-fluorouracil, cyclophosphamide, and prednisone with or without vincristine.

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    Ahmann, D L; Bisel, H F; Hahn, R G; Eagan, R T; Edmonson, J H; Steinfeld, J L; Tormey, D C; Taylor, W F

    1975-12-01

    Ninety patients with advanced breast cancer received a polychemotherapeutic program composed of 5-fluorouracil, cyclophosphamide, and prednisone with or without vincristine as a control group in a series of four consecutive Phase II clinical trials of new drug programs. Objective regression rates were 59% without vincristine and 46% with vincristine. Projected mean length of regressions exceeds 1 year. Site of dominant disease, disease-free interval, or performance scale score (if score was 0, 1, or 2, ECOG scale) failed to influence response rates; decreasing response rates were noted as the length of time increased after menopause. No advantage existed in patients experiencing severe myelosuppression (nadir leukocyte count of less than 1,500/mm), and appreciable response rates occurred without significant myelosuppression. The addition of vincristine to the regimen failed to increase the response rates, and only increased toxicity. The program as outlined is reasonably tolerable and effective for this group of patients with advanced breast cancer.

  10. [A case of sarcomatoid malignant peritoneal mesothelioma responding to combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine(CYVADIC)].

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    Kusama, Toshiyuki; Kodaka, Taiichi; Tsunemine, Hiroko; Akasaka, Hiroshi; Koizumi, Naoki; Fujimoto, Koji; Sakano, Shigeru; Ito, Rieko; Kondo, Takeshi; Kitazawa, Sohei; Yamamura, Hisako; Takahashi, Katsuhito

    2009-03-01

    A 66-year-old woman was seen at our hospital because of abdominal fullness. A computed tomography(CT)revealed massive tumors in abdominal cavity. The patient underwent surgery consisting of tumorectomy, segmental gastrectomy, partial resection of small intestin, transverse colectomy, left oophorectomy and gastrostomy. By using immunohistochemical staining, the patient was diagnosed as sarcomatoid malignant peritoneal mesothelioma. Rapidly abdominal fullness occurred as of 22 days after the operation, and an abdominal CT revealed the massive recurrent tumors. We started a combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine (CYVADIC). The recurrent tumors showed remarkable reduction after the two courses of CYVADIC chemotherapy. Although we next started carboplatin and paclitaxel combination chemotherapy, she died due to rapidly progression of the disease with disseminated intravascular coagulation after 132 days of the operation. Malignant mesothelioma, especially sarcomatoid mesothelioma, is known to have a poor prognosis. However, our case suggests that we could improve the prognosis of sarcomatoid malignant mesothelioma by aggressive chemotherapy.

  11. Treatment of malignant phaeochromocytoma with a combination of cyclophosphamide, vincristine and dacarbazine: own experience and overview of the contemporary literature.

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    Deutschbein, Timo; Fassnacht, Martin; Weismann, Dirk; Reincke, Martin; Mann, Klaus; Petersenn, Stephan

    2015-01-01

    Malignant phaeochromocytomas are rare and highly aggressive tumours. This retrospective study evaluated the outcome of combined chemotherapy with cyclophosphamide, vincristine and dacarbazine (also known as CVD regimen). Patients with histologically and radiologically confirmed malignant phaeochromocytoma who were treated with the CVD regimen for progressive disease were retrospectively identified from chart review. Treatment cycles were usually repeated at 21-day intervals, with cyclophosphamide (750 mg/m(2) ), vincristine (1·4 mg/m(2) ) and dacarbazine (600 mg/m(2) ) on day 1, and dacarbazine only (600 mg/m(2) ) on day 2. The main outcome measures were best response during treatment and progression-free survival. Eight patients (4 males; median age 55·5 (range 31-77) years) with progressive disease underwent a median of 6 (range 3-11) cycles. Best treatment responses were as follows: partial response, n = 2 (25%); stable disease, n = 3 (38%); and progressive disease, n = 3 (38%). The median progression-free survival was 5·4 (range 2·5-26·8) months. After the initial administration of 6 cycles, two patients received a second course of chemotherapy with another 6 cycles after new progressive disease had been detected. Subsequently, these patients were progression-free for another 6·0 and 6·4 months. Mild gastrointestinal symptoms and fatigue were the most common adverse events. Although objective tumour response rates were lower than previously reported in small series, the CVD regimen allowed disease stabilization for a substantial period of time and may therefore be considered as a treatment option in advanced stages. To improve disease outcome, however, new therapeutic approaches and larger multicentre studies are needed. © 2014 John Wiley & Sons Ltd.

  12. Selection of resistant acute myeloid leukemia SKM-1 and MOLM-13 cells by vincristine-, mitoxantrone- and lenalidomide-induced upregulation of P-glycoprotein activity and downregulation of CD33 cell surface exposure.

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    Imrichova, D; Messingerova, L; Seres, M; Kavcova, H; Pavlikova, L; Coculova, M; Breier, A; Sulova, Z

    2015-09-18

    Bone marrow cells and peripheral blood mononuclear cells obtained from both acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients contain upregulated levels of cell surface antigen CD33 compared with healthy controls. This difference enables the use of humanized anti-CD33 antibody conjugated to cytotoxic agents for CD33 targeted immunotherapy. However, the expression of the membrane-bound drug transporter P-glycoprotein (P-gp) has been shown to be critical for resistance against the cytotoxicity of a humanized anti-CD33 antibody conjugated to maytansine-derivative DM4. The aim of the present study was to examine whether the expression of P-gp in AML cell lines is associated with changes in CD33 expression. For this purpose, we established drug resistant variants of SKM-1 and MOLM-13 AML cell lines via the selection of parental cells for resistance to vincristine, mitoxantrone and lenalidomide. All three substances induced a multidrug resistance (MDR) phenotype in SKM-1 cells associated with strong upregulation of P-gp and downregulation of CD33. However, in MOLM-13 cells, the upregulation of P-gp and downregulation of CD33 were present only in cells selected for resistance to vincristine and mitoxantrone but not lenalidomide. Inverse expression of P-gp and CD33 were observed in all resistant variants of SKM-1 and MOLM-13 cells. The MDR phenotype of resistant variants of SKM-1 and MOLM-13 cells was associated with alterations in apoptotic regulatory proteins and downregulation of the multidrug resistance associated protein 1 and breast cancer resistance protein.

  13. A Case of Long-term Survival of Advanced Paratesticular Rhabdomyosarcoma Treated With a Multimodal Therapy Including a Combination of Cyclophosphamide, Vincristine, Doxorubicin and Dacarbazine

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    Makoto Isono

    2016-07-01

    Full Text Available There is no established treatment for advanced rhabdomyosarcoma (RMS with metastases at the time of diagnosis. A 17-year-old male was referred to our hospital because of a right scrotal mass. Computed tomography showed multiple lung metastases with pleural effusion and retroperitoneal lymph node metastasis, and bone scintigraphy revealed multiple bone metastases. Right high orchiectomy was performed and the tumor was diagnosed as paratesticular embryonal RMS. He was treated with a multimodal therapy including 17 cycles of combination chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dacarbazine (CYVADIC and achieved a long-term survival of 4 years.

  14. Cyclophosphamide

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    ... lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute myeloid leukemia (AML, ANLL), and acute lymphoblastic leukemia (ALL). It ... a reliable method of birth control to prevent pregnancy. Cyclophosphamide may harm the fetus.if you are ...

  15. Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage II and IV low-grade malignant non-Hodgkin's lymphoma

    NARCIS (Netherlands)

    A. Hagenbeek; H. Eghbali; S. Monfardini; U. Viloto; P.J. Hoskin; C. de Wolf-Peeters; K. MacLennan; E. Staab-Renner; J. Kalmus; A. Schott; I. Teodorovic; A. Negrouk; M. van Glabbeke; R. Marcus

    2006-01-01

    Purpose To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study. Patients and Methods Between 1993 and 1997

  16. Pulmonary intravascular large B-cell lymphoma successfully treated with rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone immunochemotherapy: Report of a patient surviving for over 1 year.

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    Nishii-Ito, Shizuka; Izumi, Hiroki; Touge, Hirokazu; Takeda, Kenichi; Hosoda, Yuzuru; Yamasaki, Akira; Kuwamoto, Satoshi; Shimizu, Eiji; Motokura, Toru

    2016-12-01

    A 73-year-old man with a history of lethargy, fever and dyspnea was admitted to Tottori University Hospital. A computed tomography (CT) scan revealed splenomegaly and diffusely spreading ground-glass opacities (GGOs) in both lungs. A video-assisted thoracoscopic surgery (VATS)-guided lung biopsy revealed intravascular proliferation of large atypical lymphoid cells in the arteries, veins and alveolar walls. The patient was diagnosed with intravascular large B-cell lymphoma (IVLBCL); he received 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) immunochemotherapy and has remained in complete remission for >1 year. Although IVLBCL is a rare disease, it should be considered in the differential diagnosis of pulmonary diffuse lesions that present with GGOs on CT scans.

  17. Cost-effectiveness analysis of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (VR-CAP) in patients with previously untreated mantle cell lymphoma.

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    van Keep, Marjolijn; Gairy, Kerry; Seshagiri, Divyagiri; Thilakarathne, Pushpike; Lee, Dawn

    2016-08-04

    Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin's lymphoma. Bortezomib is the first product to be approved for the treatment of patients with previously untreated MCL, for whom haematopoietic stem cell transplantation is unsuitable, and is used in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (VR-CAP). The National Institute of Health and Care Excellence recently recommended the use of VR-CAP in the UK following a technology appraisal. We present the cost effectiveness analysis performed as part of that assessment: VR-CAP versus the current standard of care regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in a UK setting. A lifetime economic model was developed with health states based upon line of treatment and progression status. Baseline patient characteristics, dosing, safety and efficacy were based on the LYM-3002 trial. As overall survival data were immature, survival was modelled by progression status, and post-progression survival was assumed equal across arms. Utilities were derived from LYM-3002 and literature, and standard UK cost sources were used. Treatment with VR-CAP compared to R-CHOP gave an incremental quality-adjusted life year (QALY) gain of 0.81 at an additional cost of £16,212, resulting in a base case incremental cost-effectiveness ratio of £20,043. Deterministic and probabilistic sensitivity analyses showed that treatment with VR-CAP was cost effective at conventional willingness-to-pay thresholds (£20,000-£30,000 per QALY). VR-CAP is a cost-effective option for previously untreated patients with MCL in the UK.

  18. [Primary diffuse large B-cell lymphoma of the uterine cervix successfully treated with rituximabplus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy-a case report].

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    Hashimoto, Akari; Fujimi, Akihito; Kanisawa, Yuji; Matsuno, Teppei; Okuda, Toshinori; Minami, Shinya; Doi, Tadashi; Ishikawa, Kazuma; Uemura, Naoki; Jyomen, Yuko; Tomaru, Utano

    2013-12-01

    Primary malignant lymphoma of the uterine cervix is a rare disease, and the therapeutic strategy has not been clearly established. A 45-year old woman presented with vaginal bleeding and hypermenorrhea in January 2012. Physical examination revealed a mass in the pelvic cavity approximately the size of a neonate's head. Pelvic magnetic resonance imaging(MRI) showed a solid mass 11 cm in size in the uterine cervix with homogeneous low intensity on T1-weighted images, iso-high intensity on T2-weighted images, and heterogeneous iso-high intensity on gadolinium-diethylenetriaminepentaacetate(Gd- DTPA)-enhanced images. Multiple lymphadenopathy were also detected in the pelvis. The Papanicolaou smear indicated class 5 cervical cytology, and a subsequent histological examination by a punch biopsy of the cervix showed diffuse infiltration of medium- to large-sized mononuclear cells that stained positive for CD20 and CD79a and negative for CD3, CD5, and EBER. Bone marrow biopsy revealed no abnormality. Positron emission tomography-computed tomography(PET-CT)showed strong fluorodeoxyglucose(FDG)accumulation in the uterine cervix mass, and in the pelvic and right inguinal lymphadenopathy. The patient was diagnosed with diffuse large B-cell lymphoma of the uterine cervix, Ann Arbor stage II AE. She was successfully treated with 8 courses of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone(R-CHOP) chemotherapy, and maintains a complete remission.

  19. Carboplatin and etoposide (CarE) combined with radiotherapy and vincristine, doxorubicin and cyclophosphamide (VAC) in limited small cell lung cancer

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    Viren, M. (Kuopio Univ. Hospital (Finland). Dept. of Radiotherapy and Oncology); Liippo, K.; Salomaa, E.R. (Turku Univ. Central Hospital (Finland). Dept. of Diseases of the Chest); Ojala, A. (Tampere Univ. Hospital (Finland). Dept. of Radiotherapy); Helle, L. (Kotka Central Hospital (Finland). Dept. of Radiotherapy); Jakobson, M. (Central Hospital of Middle Finland, Jyvaeskylae (Finland). Dept. of Radiotherapy); Jaervinen, M. (Central Hospital of Kanta-Haeme, Haemeenlinna (Finland). Dept. of Diseases of the Chest); Paloheimo, S. (Satalinna Hospital (Finland). Dept. of Disease of the Chest); Salmi, R. (Vaasa Central Hospital (Finland). Dept. of Radiotherapy and Oncology); Nikkanen, V. (Turku Univ. Central Hospital (Finland). Dept. of Radiotherapy and Oncology)

    1992-01-01

    Sixty-eight patients with limited small cell lung cancer were treated between April 1988 and October 1990 with combination carboplatin 450 mg/m[sup 2] i.v. on day 1 and etoposide 100 mg/m[sup 2] i.v. on days 1-3 (CarE) for two courses, followed by thoracic radiotherapy (TRT) 50 Gy, and then vincristine 1 mg/m[sup 2], doxorubicin 50 mg/m[sup 2] and cyclophosphamide 750 mg/m[sup 2] on day one (VAC) for four courses. Prophylactic cranial irradiation (30 Gy) was given to patients with CR after completion of chemotherapy. Sixty patients (89%) achieved an objective response (40% complete responses). The median time to progression was 8.5 months and median survival time 12.1 months. Predicted one- and two-year survival was 50% and 12% respectively. Myelosuppression was the main toxicity, with WHO grade 3 and 4 leukipenia occurring in 32% of VAC courses. There were 5 (7%) treatment-related deaths, all of them during VAC. We conclude that the present combination is active in terms of response rate, but it did not demonstrate any superiority in survival. The frequency of haematological toxicity was substantial during VAC courses. (orig.).

  20. Interval compressed vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide in patients with advanced Ewing’s and other Small Round Cell Sarcomas

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    Whelan Jeremy

    2012-09-01

    Full Text Available Abstract Background To evaluate tolerability and maintenance of dose intensity of 2 weekly treatment with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide (VDC/IE in patients with advanced small round cell sarcomas including Ewing family tumours (EFT, desmoplastic small round cell tumours (DSRCT and undifferentiated high grade round cell sarcomas (UHGRCS. Methods Retrospective review of 16 patients treated at a single centre with VDC/IE. Dose received, treatment delay, toxicity and clinical outcome were recorded for each cycle up to a maximum of 14 cycles. Results A total 193 cycles of VDC/IE were administered to 10 patients with EFT, 4 with DSRCT and 2 with UHGRCS. Median age was 22 years with 75% over 18 years. Metastases were present in 14 patients. The mean duration of each cycle was 16.7 days. Febrile neutropenia occurred in 14 % of cycles, and grade 3/4 haematologic toxicity including anaemia and thrombocytopenia in 16 % and 11 % of cycles respectively. Seven patients had a dose reduction. Five patients discontinued VDC/IE early due to toxicity. Conclusions This schedule of VDC/IE is feasible in patients with EFT and DSRCT including adults and those with metastases. Its comparison with other standard regimens for these diseases is justified.

  1. Expression of CD40 is a positive prognostic factor of diffuse large B-cell lymphoma treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone

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    Song G

    2016-06-01

    Full Text Available Guoqi Song,1 Huiyun Ni,1 Linqing Zou,2 Shukui Wang,3 Fuliang Tian,4 Hong Liu,1 William C Cho5 1Department of Hematology, Affiliated Hospital of Nantong University, Nantong, 2Department of Human Anatomy, Nantong University, Nantong, 3Central Laboratory of Nanjing First Hospital, Nanjing Medical University, Nanjing, 4Maternal and Child Health Hospital of Lianyungang, Lianyungang, Jiangsu, People’s Republic of China; 5Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong Objectives: The objective of this study was to investigate the expression level of CD40 and its role in the prognosis of patients with diffuse large B-cell lymphoma (DLBCL who were treated with rituximab-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.Design and methods: The immunohistochemical expressions of CD40 in 186 well-characterized DLBCL patients were evaluated by tissue microarrays, thereby revealing the relationship of the molecule CD40 with known tumor, patient-related variables, and survival rates.Results: The results showed that CD40 expressions were not statistically different between the germinal center B-cell-like (GCB type and the non-GCB type. We also analyzed the relationships of CD40 expression with overall survival (OS and progression-free survival (PFS in DLBCL patients who were uniformly treated with R-CHOP. A low expression of CD40 compared to high expression is related to poor OS and PFS. Conclusion: Our findings indicate that the CD40 level at onset acts as an independent prognostic predictor of DLBCL patients treated with R-CHOP. Keywords: CD40, diffuse large B-cell lymphoma, R-CHOP, prognostic factor

  2. Randomized trial comparing cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with rotational CMF, epirubicin and vincristine as primary chemotherapy in operable breast carcinoma.

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    Cocconi, Giorgio; Di Blasio, Beatrice; Boni, Corrado; Bisagni, Giancarlo; Ceci, Guido; Rondini, Ermanno; Bella, Mariangela; Leonardi, Francesco; Savoldi, Luisa; Camisa, Roberta; Bruzzi, Paolo

    2002-07-15

    According to the overview of Early Breast Cancer Trialists' Collaborative Group, anthracycline containing regimens are superior to cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant chemotherapy for breast carcinoma, but no comparative information is available in terms of primary chemotherapy. In the current randomized controlled trial, the authors compared CMF with a chemotherapy regimen including CMF, epirubicin, and vincristine (CMFEV). Two hundred eleven patients with Stages I and II palpable breast carcinoma and tumor diameter > 2.5 cm or < or = 2.5 cm with cytologically proven axillary lymph node involvement were randomized to receive CMF (arm A) or CMFEV regimen (arm B) for four cycles before surgery. After surgery, patients in both arms received adjuvant CMF for three cycles; the postmenopausal patients also received tamoxifen for two years. There were no significant differences in the complete response (CR) and in the CR plus partial response (PR) rates between the two arms. In the subset analysis, among premenopausal patients, significantly higher rates of CR (26% vs 4%, P = 0.004) and of CR + PR rates (80% vs 54%, P = 0.007) were observed in the CMFEV, as compared to the CMF arm. Multivariate analysis confirmed the presence of a significant interaction between menopausal status and type of treatment on the probability of achieving CR (P = 0.02) or CR + PR (P = 0.01). There were no major differences in the side effects of the two treatments, with the exception of more frequent alopecia in the experimental arm. The results of the current study are in line with those of previous published randomized clinical trials comparing regimens without and with anthracycline as adjuvant treatment, indicating an agreement between the short term response to primary chemotherapy and the long term results observed in the adjuvant setting. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10678

  3. Risk–Benefit Analysis of Pediatric-Inspired Versus Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Protocols for Acute Lymphoblastic Leukemia in Adolescents and Young Adults

    Science.gov (United States)

    Guzauskas, Gregory F.; Villa, Kathleen F.; Vanhove, Geertrui F.; Fisher, Vicki L.

    2017-01-01

    Purpose: To estimate the risk–benefit trade-off of a pediatric-inspired regimen versus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) for first-line treatment of adolescents/young adult (AYA; ages 16–39 years) patients with Philadelphia-negative acute lymphoblastic leukemia. Methods: Patient outcomes were simulated using a 6-state Markov model, including complete response (CR), no CR, first relapse, second CR, second relapse, and death. A Weibull distribution was fit to the progression-free survival curve of hyper-CVAD–treated AYA patients from a single-center study, and comparable patient data from a retrospective study of pediatric regimen–treated AYA patients were utilized to estimate a relative progression difference (hazard ratio = 0.51) and model survival differences. Health-state utilities were estimated based on treatment stage, with an assumption that the pediatric protocol had 0.10 disutility compared with hyper-CVAD before the maintenance phase of treatment. Total life-years and quality-adjusted life-years (QALYs) were compared between treatment protocols at 1, 5, and 10 years, with additional probabilistic sensitivity analyses. Results: Treatment with the pediatric-inspired protocol was associated with a 0.04 increase in life-years, but a 0.01 decrease in QALYs at 1 year. By years 5 and 10, the pediatric-inspired protocol resulted in 0.18 and 0.24 increase in life-years and 0.25 and 0.32 increase in QALYs, respectively, relative to hyper-CVAD. The lower quality of life associated with the induction and intensification phases of pediatric treatment was offset by more favorable progression-free survival and overall survival relative to hyper-CVAD. Conclusions: Our exploratory analysis suggests that, compared with hyper-CVAD, pediatric-inspired protocols may increase life-years throughout treatment stages and QALYs in the long term. PMID:27779442

  4. Persistent improved results after adding vincristine and bleomycin to a cyclophosphamide/hydroxorubicin/Vm-26/prednisone combination (CHVmP) in stage III-IV intermediate- and high-grade non-Hodgkin's lymphoma. The EORTC Lymphoma Cooperative Group.

    Science.gov (United States)

    Meerwaldt, J H; Carde, P; Somers, R; Thomas, J; Kluin-Nelemans, J C; Bron, D; Noordijk, E M; Cosset, J M; Bijnens, L; Teodorovic, I; Hagenbeek, A

    1997-01-01

    CHOP has been and still is regarded by many as the 'standard' treatment of advanced non-Hodgkin's lymphoma. In 1980 the EORTC Lymphoma Cooperative Group started a study to evaluate the addition of vincristine and bleomycin to its standard four-drug combination chemotherapy, CHVmP (cyclophosphamide, hydroxorubicin, Vm-26, prednisone). Eligible patients were stage III or IV, intermediate- to high-grade non-Hodgkin's lymphoma (Working Formulation E-I). One-hundred-eighty-nine patients were entered, of whom 140 were eligible and evaluable. A previous report showed an improved response rate and failure-free survival (FFS) and overall survival for the combination CHVmP-VB. At ten years, the outcome still favors the addition of vincristine and bleomycin. The FFS was 34% vs. 23% and the overall survival 34% vs 22%. This difference was mainly due to a difference in CR rate (74% vs. 49%), Relapse-free survival for patients reaching a CR was the same in both arms. When the patients were grouped according to the International Prognostic Factor Index, no statistically significant difference could be observed in favor of one treatment within either group. This trial clearly demonstrates the benefit gained by the addition of vincristine and bleomycin to 'standard' chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma.

  5. Vincristine, doxorubicin and mitomycin (VAM) in patients with advanced breast cancer previously treated with cyclophosphamide, methotrexate and fluorouracil (CMF). A clinical trial of the Piedmont Oncology Association (POA).

    Science.gov (United States)

    Shipp, S K; Muss, H B; Westrick, M A; Cooper, M R; Jackson, D V; Richards, F C; White, D R; Stuart, J J; Christian, R M; Ramseur, W

    1983-01-01

    Thirty-six evaluable patients with advanced breast cancer who had failed prior CMF therapy [15 (42%) as adjuvant treatment and 21 (58%) for advanced disease] were treated with a combination of vincristine, doxorubicin, and mitomycin (VAM). There was one CR and 10 PR, giving a response rate of 31% (P, 95% confidence interval, 15%-47%). Response was not significantly related to age, performance status, disease-free interval, dominant site of disease, number of sites of disease, or estrogen receptor status. The median duration of response was 5 months for patients attaining CR or PR and 4.6 months for patients with stable disease. The median survival for patients with CR or PR of 7.9 months was not better than for those with stable disease (8.0 months), but both groups had significantly longer survival than those with initial progression. Patients who received VAM after failing adjuvant CMF had a 53% response rate (8 of 15), as against a 14% response rate (3 of 21) in those failing CMF for advanced disease (P less than 0.05). In spite of this difference, the survival distributions for these two groups were not significantly different. Myelosuppression was moderate and no cardiac toxicity was seen. The addition of mitomycin to vincristine and doxorubicin in previously treated patients does not appear to improve the results obtained with vincristine and doxorubicin alone.

  6. 来自澳大利亚的经验:成人急性淋巴细胞白血病用Hyper-CVAD治疗的结果%Outcome of Treatment of Adult Acute Lymphoblastic Leukemia with Hyperfractionated Cyclophosphamide,Doxorubicin, Vincristine, Dexamethasone/Methotrexate, Cytarabine: Results from An Australian Population

    Institute of Scientific and Technical Information of China (English)

    李军民; 陆泽生

    2011-01-01

    1 文献来源Morris K,Weston H,Mollee P,et al.Outcome of treatment of adult acute lymphoblastic leukemia with hypeffractionated Cyclophosphamide,Doxorubicin,Vincristine,Dexamethasone/Methotrexate,Cytarabine:Results from an Australian population [J].Leuk Lymphoma,2011,52( 1 ):85-91.2 证据水平2b.%Department of Hematology, Ruijin Hospital, Shanghai Jiaotong Unverisity School of Medicine, Shanghai Institute of Hematology, Shanghai 200025, China

  7. Clinicopathologic significance of tumor microenvironment CD11c, and FOXP3 expression in diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, anthracycline, vincristine, and prednisone (R-CHOP) combination chemotherapy.

    Science.gov (United States)

    Lee, Seul; Kim, Dong Hyun; Oh, Sung Yong; Kim, So Yeon; Koh, Myeong Seok; Lee, Ji Hyun; Lee, Suee; Kim, Sung-Hyun; Kwak, Jong-Young; Pak, Min Gyoung; Ju, Mi Ha; Kim, Hyo-Jin; Jeong, Jin Sook

    2017-03-01

    CD11c is a dendritic cell marker in humans, which potentially induces a cytotoxic effect on lymphoma cells. Forkhead boxP3 (FOXP3) is a regulator of T lymphocyte in the microenvironment of the lymphoma. The principal objective of this study was to determine whether the tumors' microenvironment expressions of CD11c and FOXP3 are predictive of clinical outcomes in diffuse large B-cell lymphoma (DLBCL) patients receiving treatment with rituximab, cyclophosphamide, anthracycline, vincristine, and prednisone (R-CHOP) combination chemotherapy. The study population consisted of 100 patients with DLBCL. The CD11c and FOXP3 expression in primary tumors' microenvironment were evaluated using an immunohistochemistry (IHC). CD11c and FOXP3 expression positivity in microenvironment were 25% and 35%, respectively. Each one counted for 1 point. In CD11c and FOXP3 stain, positive was counted as 0 and negative was 1. The points were separated into low risk (0 to 1) and high risk (2) groups. Only the extranodal DLBCL patient group analysis conveyed significant differences of progression-free survival (p = 0.019) and overall survival (p = 0.039) between the two groups. We can achieve possible clinical significance of lymphoma tumor microenvironments through CD11c and FOXP3 IHC stains in extranodal DLBCL patients receiving R-CHOP therapy.

  8. Bioavailability of cyclosphosphamide and vincristine after intraperitoneal administration in cats

    NARCIS (Netherlands)

    Voorhorst, M.J.; van Maarseveen, E.M.; van Lankveld, A.J.; Teske, E.

    2014-01-01

    Cyclophosphamide and vincristine are widely used intravenous chemotherapeutic agents in both human and veterinary oncology. Although intravenous administration of these chemotherapeutics is the gold standard in most treatment protocols, this route of administration has several disadvantages (e.g. lo

  9. 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.

  10. Vincristine Lipid Complex Injection

    Science.gov (United States)

    Vincristine lipid complex is used to treat a certain type of acute lymphoblastic leukemia (ALL; a type of cancer ... least two different treatments with other medications. Vincristine lipid complex is in a class of medications called ...

  11. Long term outcome of localized aggressive non-Hodgkin lymphoma treated with a short weekly chemotherapy regimen (doxorubicin, cyclophosphamide, bleomycin, vincristine, and prednisone) and involved field radiotherapy: result of a Gruppo Italiano Multiregionale per lo Studio dei Linfomi e Leucenie (GIMURELL) study.

    Science.gov (United States)

    Cabras, Maria Giuseppina; Mamusa, Angela Maria; Vitolo, Umberto; Freilone R, Roberto; Dessalvi, Paolo; Orsucci, Lorella; Tonso, Anna; Levis, Alessandro; Liberati, Marina; Lay, Giancarlo; Angelucci, Emanuele

    2009-09-01

    Recently, management of limited stage diffuse large cell lymphoma (DLCL) is trending toward a low intensity chemotherapy approach. Since 1993 we have used a brief weekly (6 weeks) chemotherapy scheme (Doxorubicin, Cyclophosphamide, Bleomycin, Vincristine, and Prednisone = ACOP-B) followed by involved field radiotherapy in 207 consecutive patients with well defined localized DLCL without age limit (median 57 years, range 18-85). Treatment was completed as designed in 183 of 207 patients (88%). One hundred and ninety-nine patients (96%) achieved complete remission. At a median follow-up of 66 months 170 patients are alive (82%), 168 of them free of disease. Twenty-nine patients experienced relapse after achieving a complete remission. Kaplan-Meier, risk of relapse was 24% after 13 years. Thirty (14.5%) patients have died, 14 (6.8%) due to lymphoma progression, one due to regimen toxicity and 15 (7.2%) from other causes while remaining in complete remission. The probability of overall survival and event free survival at 13 years was 78% (95% CI 70-87%) and 63% (95% CI 50-75), respectively. Crude rate of secondary malignancy was 5.26 /1000 person-years. The ACOP-B regimen plus involved field radiotherapy is well tolerated both short and long term and is an effective chemotherapy scheme for very well defined limited stage aggressive non-Hodgkin lymphomas in all age categories.

  12. Successful Treatment of Multifocal Histiocytic Sarcoma Occurring after Renal Transplantation with Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone (CLAG-M Followed by Allogeneic Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Julia Tomlin

    2015-01-01

    Full Text Available Histiocytic sarcoma (HS is a rare, aggressive malignancy. Lesions previously called HS were typically non-Hodgkin lymphomas, not HS. As such, chemotherapy directed at lymphoid neoplasms was frequently successful, but it is unclear if these regimens are ideal for HS. We present a 33-year-old African gentleman who underwent sequential renal transplants for glomerulonephritis. He subsequently developed HS of the upper airway and multiple cutaneous sites. The patient received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP followed by salvage ifosfamide, carboplatin, and etoposide (ICE but had continuous progression of cutaneous involvement. Cladribine, high-dose cytarabine, G-CSF, and mitoxantrone (CLAG-M yielded a partial response with near resolution of disease. Ultimately, the patient achieved a complete remission after myeloablative allogeneic hematopoietic stem cell transplant. HS occurring after solid organ transplant raises the possibility of HS as a potential posttransplant malignancy. The use of CLAG-M has not been reported in HS. In this case, histiocyte-directed chemotherapy with CLAG-M was superior to lymphoma-directed regimens.

  13. Cyclophosphamide Injection

    Science.gov (United States)

    ... lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute myeloid leukemia (AML, ANLL), and acute lymphoblastic leukemia (ALL). It ... a reliable method of birth control to prevent pregnancy. Cyclophosphamide may harm the fetus.if you are ...

  14. Mitoxantrone-Induced Suicidal Erythrocyte Death

    Directory of Open Access Journals (Sweden)

    Markus Arnold

    2014-11-01

    Full Text Available Background/Aims: Mitoxantrone, a cytotoxic drug used for the treatment of malignancy and multiple sclerosis, is at least in part effective by triggering apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a type of suicidal cell death. Hallmarks of eryptosis are cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signalling involved in eryptosis include Ca2+-entry, ceramide formation and oxidative stress. Methods: Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, formation of reactive oxidant species (ROS from 2′,7′-dichlorodihydrofluorescein-diacetate fluorescence, and ceramide abundance from binding of fluorescent antibodies in flow cytometry. Results: A 48 hours exposure to mitoxantrone was followed by significant decrease of forward scatter (≥ 5 μg/ml mitoxantrone and increase of annexin-V-binding (≥ 10 μg/ml mitoxantrone, effects paralleled by significant increases of ROS formation (25 μg/ml mitoxantrone and ceramide abundance (25 μg/ml mitoxantrone. The effect of mitoxantrone was not significantly modified by nominal absence of extracellular Ca2+ but significantly blunted by the antioxidant N-acetylcysteine (1 mM. Conclusions: Mitoxantrone triggers cell membrane scrambling, an effect not requiring entry of extracellular Ca2+ but at least partially due to formation of ROS and ceramide.

  15. Vincristine induced cranial polyneuropathy.

    Science.gov (United States)

    Bay, Ali; Yilmaz, Cahide; Yilmaz, Nebi; Oner, Ahmet Faik

    2006-06-01

    We describe a 5-year-old girl showed recovery of vincristine induced cranial polyneuropathy with pyridoxine and pyridostigmine treatment. A 5-year-old girl was diagnosed preB cell Acute Lymphoblastic Leukemia (ALL). She received chemotherapy according to the previously described modified St. Jude total therapy studies XIII. Five days after the fourth dose of vincristine, she presented with bilateral ptosis. Neurological examination revealed bilateral ptosis, and complete external opthalmoplegia with normal pupillary and corneal reflexes. She received 3.8 mg cumulative dose of vincristin before development of ptosis. A neuroprotective and neuroregenerative treatment attempt with pyridoxine and pyridostigmine was initiated. The bilateral ptosis markedly improved after 7 days of pyridoxine and pyridostigmine treatment and completely resolved after two weeks. The both agents were given for 3 weeks and were well tolerated without any side effects. During the follow up period we did not observe residue or recurrence of the ptosis.

  16. Cyclophosphamide and Doxorubicin Induced Melanonychia: A Case Report.

    Science.gov (United States)

    Prajapati, Vivek Bhanubhai; Madhyastha, Sharath; Acharya, Raviraj; Gopalaswamy, Vinaya; Doddamani, Akhila

    2017-01-01

    Chemotherapeutic agents may rarely cause discoloration and hyperpigmentation of the nails. We present a patient who developed blackish discoloration of nails also referred as melanonychia during six cycles of R-CHOP chemotherapy regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) for the treatment of Non Hodgkin Lymphoma (NHL) follicular type. The patient developed blackish brown discoloration in all the nails. As suggested by previous literature evidence the melanonychia could be associated with cyclophosphamide and doxorubicin. According to the Naranjo causality assessment scale, we established that there was a 'probable' association of nail discoloration with the drug.

  17. Vincristine-Induced Cranial Neuropathy

    Directory of Open Access Journals (Sweden)

    Ahmad TALEBIAN*

    2014-01-01

    Full Text Available How to Cite This Article: Talebian A, Goudarzi RM, Mohammadzadeh M , Mirzadeh AS. Vincristine-Induced Cranial Neuropathy. Iran J Child Neurol. 2014 Winter; 8(1:66-68. AbstractVincristine (VCR is a vinca alkaloid that is used for treatment of many malignancies.The vinca alkaloids are neurotoxic, usually causing a peripheral neuropathy, but cranial neuropathies are rare as side effects. Described here is the case of a 2.5-year-old boy, a known case of Wilms’ tumor, treated by vincristine (0/067 mg/kg/day and dactinomycin (0/045 mg/kg/day after surgery. Three weeks after treatment, he presented with bilateral ptosis.Neurological examination revealed bilateral ptosis with normal pupillary reflex and eye movement. He received 3.015 mg cumulative dose of vincristine before development of ptosis.Treatment with pyridoxine (150 mg/m2 p.o. BID and pyridostigmine (3 mg/kg p.o. BID started as neuroprotective agents, and after 7 days the problem disappeared.The treatment continued for 6 weeks and there were no signs of ptosis or a recurrence in follow up 2 months later. References:Toopchizade V, Hosseini M, et al. Electrophysiological signs of neuropathy caused by vincristine. Medical Journal of Tabriz University of Medical Sciences. 2010 Autumn;31(3; 19-25.Gursel E.S. Vincristine-Induced Unilateral Ptosis in a Child. Pediatr Neurol 2009; 41:461-463.Ngamphaiboon N, Sweeney R, Wetzler M, Wang ES. Pyridoxine treatment of vincristine-induced cranial polyneuropathy in an adult patient with acute lymphocytic leukemia: Case report and review of the literature. Leuk Res. 2010 Aug;34(8:e194-6.Lash SC, Williams CP, Marsh CS, Crithchley C, Hodgkins PR, Mackie EJ. Acute Sixth-Nerve Palsy After Vincristine Therapy. Journal of AAPOS 2004 Feb;8(1: 67-8.Bay A, Yilmaz C, Yilmaz N, Oner AF. Vincristine induced cranial polyneuropathy. Indian J Pediatr. 2006 Jun;73(6:531-3.Tuxen M K, Hansen SW. Complication of treatment, Neurotoxicity secondary to antineoplastic

  18. Mitoxantrone-Surfactant Interactions: A Physicochemical Overview

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    Mirela Enache

    2016-10-01

    Full Text Available Mitoxantrone is a synthetic anticancer drug used clinically in the treatment of different types of cancer. It was developed as a doxorubicin analogue in a program to find drugs with improved antitumor activity and decreased cardiotoxicity compared with the anthracyclines. As the cell membrane is the first barrier encountered by anticancer drugs before reaching the DNA sites inside the cells and as surfactant micelles are known as simple model systems for biological membranes, the drugs-surfactant interaction has been the subject of great research interest. Further, quantitative understanding of the interactions of drugs with biomimicking structures like surfactant micelles may provide helpful information for the control of physicochemical properties and bioactivities of encapsulated drugs in order to design better delivery systems with possible biomedical applications. The present review describes the physicochemical aspects of the interactions between the anticancer drug mitoxantrone and different surfactants. Mitoxantrone-micelle binding constants, partitions coefficient of the drug between aqueous and micellar phases and the corresponding Gibbs free energy for the above processes, and the probable location of drug molecules in the micelles are discussed.

  19. Failure of vincristine induce twinning

    Science.gov (United States)

    Binder, M.

    1984-01-01

    Mammalian ova do not contain axes of symmetry from which are derived embryonic axes of symmetry. Mammalian axis determination is an early embryologic event occurring at about the time that monozygous twinning in mice. (Kaufma MH & O'Shea KS, 1978, Nature 276:707) and an attempt was made to reproduce their work in several strains of mice. Over 3200 embryos were examined without any twins being found. To rule out the possibility that vincristine caused twinning plus some lethal malformation (with subsequent resorption of the embryo) the embryos were examined 36-60 hours after vincristine treatment.

  20. Vincristine-Induced Cranial Neuropathy

    Directory of Open Access Journals (Sweden)

    Ahmad TALEBIAN*

    2013-12-01

    Full Text Available How to Cite This Article: Talebian A, Goudarzi RM, Mohammadzadeh M , Mirzadeh AS. Vincristine-Induced Cranial Neuropathy. Iran J Child Neurol. 2014 Winter; 8(1:66-68. Abstract Vincristine (VCR is a vinca alkaloid that is used for treatment of many malignancies. The vinca alkaloids are neurotoxic, usually causing a peripheral neuropathy, but cranial neuropathies are rare as side effects. Described here is the case of a 2.5-year-old boy, a known case of Wilms’ tumor, treated by vincristine (0/067 mg/kg/day and dactinomycin (0/045 mg/kg/day after surgery. Three weeks after treatment, he presented with bilateral ptosis. Neurological examination revealed bilateral ptosis with normal pupillary reflex and eye movement. He received 3.015 mg cumulative dose of vincristine before development of ptosis. Treatment with pyridoxine (150 mg/m2 p.o. BID and pyridostigmine (3 mg/kg p.o. BID started as neuroprotective agents, and after 7 days the problem disappeared. The treatment continued for 6 weeks and there were no signs of ptosis or a recurrence in follow up 2 months later.

  1. Vincristine-induced cranial neuropathy.

    Science.gov (United States)

    Talebian, Ahmad; Goudarzi, Razieh Moazam; Mohammadzadeh, Mahdi; Mirzadeh, Azadeh Sadat

    2014-01-01

    Vincristine (VCR) is a vinca alkaloid that is used for treatment of many malignancies. The vinca alkaloids are neurotoxic, usually causing a peripheral neuropathy, but cranial neuropathies are rare as side effects. Described here is the case of a 2.5-year-old boy, a known case of Wilms' tumor, treated by vincristine (0.067 mg/kg/day) and dactinomycin (0.045 mg/kg/day) after surgery. Three weeks after treatment, he presented with bilateral ptosis. Neurological examination revealed bilateral ptosis with normal pupillary reflex and eye movement. He received 3.015 mg cumulative dose of vincristine before development of ptosis. Treatment with pyridoxine (150 mg/m2 p.o. BID) and pyridostigmine (3 mg/kg p.o. BID) was started as neuroprotective agents, and after 7 days the problem disappeared. The treatment continued for 6 weeks and there were no signs of ptosis or a recurrence in follow up 2 months later.

  2. Vincristine liposomal--INEX: lipid-encapsulated vincristine, onco TCS, transmembrane carrier system--vincristine, vincacine, vincristine sulfate liposomes for injection, VSLI.

    Science.gov (United States)

    2004-01-01

    INEX Pharmaceuticals is developing a liposomal formulation of vincristine [Onco TCS, vincacine, VSLI, Vincristine sulfate liposomes for injection] for the treatment of relapsed aggressive non-Hodgkin's lymphoma (NHL) and other cancers. It is being developed using INEX's proprietary drug-delivery technology platform called the transmembrane carrier systems (TCS), which enables the targeted intracellular delivery of various therapeutic agents. Liposomal vincristine is expected to have certain advantages over the existing standard preparation of vincristine because the use of TCS technology enables the vincristine to circulate in the blood for longer, accumulate in the tumour, and be released over an extended period of time at the tumour site. The application of TCS technology to any agent, including vincristine, has the potential to increase the efficacy and decrease the side effects of the agent. INEX decided in 1998 to focus on gaining approval for liposomal vincristine in the treatment of relapsed aggressive NHL because no standard therapy was approved for this indication. In 1999, liposomal vincristine was granted accelerated development status by the US FDA, which enables the FDA to approve it based on the surrogate endpoint of a single clinical trial. In addition, the FDA granted liposomal vincristine fast track status in August 2000. In April 2001, INEX and Elan Corporation formed a joint venture for the development and commercialisation of liposomal vincristine, with both companies contributing assets to the venture including worldwide rights to the product and intellectual property rights. The joint venture was called IE Oncology. However, in June 2002, Elan announced that it was going to focus its business strategy on three specific areas, which would not include cancer therapies. INEX announced it had regained 100% ownership of liposomal vincristine in April 2003, by reacquiring the 19.9% equity interest held by Elan and in addition retaining a fully paid

  3. Pyridoxine and pyridostigmine treatment in vincristine-induced neuropathy.

    Science.gov (United States)

    Ozyurek, Hamit; Turker, Hande; Akbalik, Mehtap; Bayrak, Ayse Oytun; Ince, Hulya; Duru, Feride

    2007-09-01

    Vincristine is a commonly used antineoplastic drug and frequently causes neurotoxicity. Here the authors report a 4-year-old boy with acute lymphoblastic leukemia in whom vincristine-induced peripheral and cranial neuropathy developed during remission induction therapy. The patient seemed to benefit from pyridoxine and pyridostigmine therapy greatly and this therapy is recommended in patients with severe vincristine-induced neuropathy.

  4. Thermodynamical study of interaction of histone H1 chromosomal protein and mitoxantrone anticancer drug

    Energy Technology Data Exchange (ETDEWEB)

    Jafargholizadeh, Naser [Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran (Iran, Islamic Republic of); Zargar, Seyed Jalal, E-mail: Zargar@khayam.ut.ac.ir [Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran (Iran, Islamic Republic of); Safarian, Shahrokh; Habibi-Rezaei, Mehran [Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran (Iran, Islamic Republic of)

    2012-06-10

    Highlights: Black-Right-Pointing-Pointer For the first time, our results show mitoxantrone anticancer drug binds to histone H1, via hydrophobic, hydrogen, van der Waals and electrostatic interactions. Black-Right-Pointing-Pointer Binding of mitoxantrone molecules to histone H1 is positive cooperative. Black-Right-Pointing-Pointer Histone H1 may be considered as a new target for mitoxantrone at the chromatin level. - Using ultraviolet spectroscopy technique, we have investigated the interaction of anticancer drug, mitoxantrone with calf thymus histone H1 chromosomal protein in 100 mM phosphate buffer, pH 7.0, at temperatures 300 and 310 K. UV spectroscopy results show interactions between mitoxantrone and histone H1 with a positive cooperative binding process which was confirmed by Scatchard plot. According to the obtained results, it is concluded that histone H1 can be considered as a target for mitoxantrone binding at the chromatin level.

  5. Theoretical study of functionalized single-walled carbon nanotube (5, 5 with Mitoxantrone drug

    Directory of Open Access Journals (Sweden)

    F. Shojaie

    2016-04-01

    Full Text Available Objective(s: First principles calculations were performed to study four multiple sclerosis drugs namely, Ampyra, Fingolimod, Mitoxantrone and Eliprodil in gas and liquid phases using Density Functional Theory (DFT. Computational chemistry simulations were carried out to compare calculated quantum chemical parameters for Ampyra, Fingolimod, Mitoxantrone and Eliprodil. Materials and Methods: All calculations were performed using DMol3 code which is based on DFT.  The Double Numerical basis set with Polarization functions (DNP was used.Results: Mitoxantrone has highest HOMO energy, global softness, solvation energy and molecular mass and lowest LUMO energy, energy gap, global hardness and total energy in comparison to Ampyra, Fingolimod and Eliprodil in gas and solvent phases. Calculations were carried out to study the interaction of covalently binding Mitoxantrone to functionalized carbon nanotube. The Mitoxantrone local reactivity was studied through the Fukui indices in order to predict both the reactive centers and the possible sites of nucleophilic and electrophilic attacks. The Mitoxantrone binding energy  is calculated to be 6.507 eV in gas phase and -9.943 eV in solvent phase that is a decrease in BE as the drug phase changes from gas to liquid.Conclusion: The simulation results show Mitoxantrone is quite a reactive drug. The quantum chemical parameters of pristine nanotube and f-SWNT-Mitoxantrone showed that reactivity of f-SWNT-Mitoxantrone increased in comparison to pristine nanotube in both phases.

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

    Institute of Scientific and Technical Information of China (English)

    Lingjuan Tang; Zhenrong Sun; Jianyu Guo; Zugeng Wang

    2006-01-01

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

  7. Mitoxantrone induces natural killer cell maturation in patients with secondary progressive multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Coralie Chanvillard

    Full Text Available Mitoxantrone is one of the few drugs approved for the treatment of progressive multiple sclerosis (MS. However, the prolonged use of this potent immunosuppressive agent is limited by the appearance of severe side effects. Apart from its general cytotoxic effect, the mode of action of mitoxantrone on the immune system is poorly understood. Thus, to develop safe therapeutic approaches for patients with progressive MS, it is essential to elucidate how mitoxantrone exerts it benefits. Accordingly, we initiated a prospective single-arm open-label study with 19 secondary progressive MS patients. We investigated long-term effects of mitoxantrone on patient peripheral immune subsets using flow cytometry. While we corroborate that mitoxantrone persistently suppresses B cells in vivo, we show for the first time that treatment led to an enrichment of neutrophils and immunomodulatory CD8(low T cells. Moreover, sustained mitoxantrone applications promoted not only persistent NK cell enrichment but also NK cell maturation. Importantly, this mitoxantrone-induced NK cell maturation was seen only in patients that showed a clinical response to treatment. Our data emphasize the complex immunomodulatory role of mitoxantrone, which may account for its benefit in MS. In particular, these results highlight the contribution of NK cells to mitoxantrone efficacy in progressive MS.

  8. Cyclophosphamide in diffuse lung damage.

    Science.gov (United States)

    Musiatowicz, B; Sulkowska, M; Sulik, M; Famulski, W; Dziecioł, J; Sobaniec-Lotowska, M; Baltaziak, M; Arciuch, L; Rółkowski, R; Jabłońska, E

    1997-01-01

    Some cyclophosphamide toxic effects on lung tissue are presented. Cyclophosphamide metabolism, pathogenesis of lung damage and morphological lung tissue changes caused by that agent were characterized. Attention was focused on BAL evaluation as a useful method in the monitoring of lung tissue damage degree.

  9. Cyclophosphamide-induced symptomatic hyponatraemia

    NARCIS (Netherlands)

    Bruining, D M; van Roon, E N; de Graaf, H; Hoogendoorn, M

    2011-01-01

    Cyclophosphamide is an alkylating agent used in antineoplastic and immunosuppressive therapies. Symptomatic hyponatraemia is a rare but life-threatening complication in patients treated with cyclophosphamide. We report the case of a 64-year-old woman with breast cancer who developed severe symptomat

  10. Infused vincristine and adriamycin with high dose methylprednisolone (VAMP) in advanced previously treated multiple myeloma patients.

    Science.gov (United States)

    Forgeson, G. V.; Selby, P.; Lakhani, S.; Zulian, G.; Viner, C.; Maitland, J.; McElwain, T. J.

    1988-01-01

    Forty-five patients with relapsed or refractory multiple myeloma received continuous infusions of vincristine (0.4 mg total dose daily for 4 days) and adriamycin (9 mg m-2 daily for 4 days) with a high dose of methylprednisolone (1 g m-2 i.v. or p.o. daily by 1 h infusion), the VAMP regimen. Sixteen (36%) responded, with a median duration of remission of 11 months and median survival of 20 months. Major toxicities encountered were infective and cardiovascular. Two smaller groups of myeloma patients were treated with high dose methylprednisolone (HDMP) alone, or VAMP plus weekly low dose cyclophosphamide (Cyclo-VAMP). HDMP produced short responses in 25% of patients with less toxicity than VAMP. Cyclo-VAMP was used in a highly selected group of patients who had previously responded to high dose melphalan. It was well tolerated and produced responses in 61% of this group. PMID:3207601

  11. Vincristine induced cortical blindness: An alarming but reversible side effect

    Directory of Open Access Journals (Sweden)

    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.

  12. Spinal MRI of vincristine neuropathy mimicking Guillain-Barre syndrome

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  13. Continuous infusion of low-dose doxorubicin, epirubicin and mitoxantrone in cancer chemotherapy: a review.

    Science.gov (United States)

    Greidanus, J; Willemse, P H; Uges, D R; Oremus, E T; De Langen, Z J; De Vries, E G

    1988-12-09

    With the recent development of reliable portable pumps and safe venous access systems, continuous infusion of chemotherapeutic agents on an out-patient basis has become feasible. Advantages of continuous infusion are the long-term exposure of tumour cells to the drug and the fact that most toxic effects are reduced for doxorubicin, epirubicin and mitoxantrone due to elimination of the high peak plasma levels. Preliminary data for doxorubicin suggest that its antitumour activity is maintained. Pharmacokinetic studies with epirubicin and mitoxantrone showed a linear relationship between drug dose infused and the steady-state plasma level for these drugs. The area under the curve for leukocytes drug level was higher during continuous infusion than after an equitoxic bolus injection of epirubicin and mitoxantrone. Well-randomized clinical trials will be necessary to investigate the role of continuous infusion of antracyclines and mitoxantrone in cancer chemotherapy in the future.

  14. Interaction of mitoxantrone, as an anticancer drug, with chromatin proteins, core histones and H1, in solution.

    Science.gov (United States)

    Hajihassan, Zahra; Rabbani-Chadegani, Azra

    2011-01-01

    In the present study, for the first time we have investigated the interaction of anticancer drug mitoxantrone with histone H1 and core histone proteins in solution using fluorescence, UV/Vis, CD spectroscopy and thermal denaturation techniques. The results showed that mitoxantrone reduced the absorbencies of H1 and core histone proteins at 210 nm (hypochromicity) and fluorescence emission intensity was decreased in a dose dependent. Binding of mitoxantrone changed secondary structures of the proteins as circular dichroism analysis confirmed it. Also, mitoxantrone increased the melting temperature of core histones at the final step of denaturation. The results suggest higher affinity of mitoxantrone to histone H1 compared to core histones providing histone proteins as a new target for mitoxantrone action at the chromatin level. Copyright © 2010 Elsevier B.V. All rights reserved.

  15. Pro: Cyclophosphamide in lupus nephritis

    NARCIS (Netherlands)

    Kallenberg, Cees G. M.

    2016-01-01

    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 d

  16. Pro: Cyclophosphamide in lupus nephritis

    NARCIS (Netherlands)

    Kallenberg, Cees G. M.

    2016-01-01

    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 d

  17. Acute myeloid leukaemia induced by mitoxantrone: case report Leucemia mielóide aguda induzida por mitoxantrone: relato de caso

    Directory of Open Access Journals (Sweden)

    Walter Oleschko Arruda

    2005-06-01

    Full Text Available Mitoxantrone (MX is an immunosupressant drug used in secondarily progressive multiple sclerosis (SPMS and in relapsing-remitting multiple sclerosis (RRMS. It has a leukemogenesis potential induced by cytogenetic abnormalities, though with a low incidence. Promyelocitic leukaemia (type M3 and other forms of acute myeloblastic leukaemias (M4 and M5 have been described in a few MS patients who received MX during their treatment. We describe a white female patient, 47 year-old, with SPMS (EDSS = 4 with 14 years of disease. She received MX during her disease and developed acute promyelocytic leukaemia (M3, with severe thrombocytopenia 30 months later. She ultimately died due to intracerebral hemorrhage. Other cases of treatment related to AML are reviewed and discussed.Mitoxantrone (MX é uma agente imunossupressor utilizado nas formas progressivas secundárias de esclerose múltipla (EM ou formas surto-remissão sem resposta com outras formas de tratamento (p.ex. beta-interferon, acetato de glatirâmer. Com o uso desta medicação, ocorre uma incidência maior, embora pequena, de desenvolvimento de leucemia mielóide aguda induzida por quimioterápicos. Descrevemos o caso de uma paciente com forma progressiva secundária de EM, submetida a uma dose única de MX de 15mg e que 30 meses após desenvolveu quadro fulminante de leucemia promieloblástica aguda (M3, com trombocitopenia grave. A paciente faleceu por hemorragia intracerebral maciça. É feita revisão de outros casos relatados na literatura e os possíveis mecanismos de desenvolvimento desta complicação grave secundária ao uso do MX.

  18. Chlorambucil-Induced Radiation Recall Dermatitis.

    Science.gov (United States)

    Clark, Eileen; Boffa, Michael; Magri, Claude; Muscat, Victor

    2015-01-01

    A 65-year-old woman was diagnosed with low-grade non-Hodgkin lymphoma (Figure 1). She was treated with six cycles of cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), and prednisolone (CHOP) and three cycles of fludarabine and mitoxantrone. Ten months later she received radiotherapy to the left groin (total dose of 50 Gy in 25 fractions over 5 weeks) without complications.

  19. Intralesional vincristine combined with cryotherapy for recalcitrant verrucas.

    Science.gov (United States)

    Lee, Jong-Rok; Youn, Jeong-Hwan; Roh, Joo-Young

    2011-01-01

    Verrucas are often recalcitrant to conventional cryotherapy. Since 1970, intralesional bleomycin has been used off-label by dermatologists. But in some cases, the results of intralesional bleomycin were disappointing. Vincristine is a well-known vinca alkaloid antiblastic drug that has been used for treating hematological neoplasm and nephroblastomas. It was reported good efficacy of intralesional vincristine for treating nodular lesion in classic Kaposi sarcoma. Its use in epithelial neoplasm and Kaposi sarcoma may support its efficacy in recalcitrant verrucas. The three patients selected for the study presented severe verrucas on foot, and they had already undergone cryotherapy several times and there was no improvement. They got intralesional vincristine injection on their verrucas. The target lesion was infiltrated with 0.03 mL of vincristine sulphate at a concentration of 1 µg/mL. The injected amount of vincristine was proportional to the diameter of the nodule. After two treatments had been completed, there was a great decrease of lesion size compared with the other lesions. The three patients complained of pain lasting for several days. This pain was generally well tolerated. Intralesional vincristine injection on verruca is an effective and rapid novel method, and when combined with cryotherapy, shows excellent therapeutic response.

  20. Calorimetric and spectroscopic studies on the interaction of anticancer drug mitoxantrone with human serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Keswani, Neelam [Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076 (India); Kishore, Nand, E-mail: nandk@chem.iitb.ac.in [Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076 (India)

    2011-09-15

    Highlights: > Human serum albumin exhibits two binding sites for mitoxantrone. > Discrepancies in calorimetric and spectroscopic results clarify binding sites. > Effect of ionic strength on binding permitted detailed analysis of interactions. > Electrostatic interactions predominate in binding. > One binding site on protein does not have tryptophan in immediate vicinity. - Abstract: Binding of the anticancer drug mitoxantrone with the protein human serum albumin (HSA) has been studied by using isothermal titration calorimetry (ITC), in combination with fluorescence, UV-visible, and circular dichroism spectroscopy. The thermodynamic parameters of binding have been evaluated from ITC and spectroscopic results and compared. The ITC results demonstrate that the binding of mitoxantrone with HSA occurs according to two sets of binding sites on the protein as opposed to the fluorescence and UV-visible spectroscopic results. Blockage of one binding site on HSA for mitoxantrone in the presence of NaCl indicates strong involvement of electrostatic interactions in the binding of the drug with the protein. An insignificant temperature dependence of the association constant observed in fluorescence measurements suggests a very low enthalpy of binding which is in close agreement with the results obtained from ITC measurements. Fluorescence life time measurements suggest formation of a static complex between mitoxantrone and HSA. The discrepancies in the ITC and fluorescence results suggest that one of the binding sites on the protein for mitoxantrone does not contain tryptophan residue in its immediate vicinity. The calorimetric and spectroscopic results have provided quantitative information on the binding of mitoxantrone with HSA and suggest that the binding is dominated by electrostatic interactions.

  1. Mitoxantrone and Analogues Bind and Stabilize i-Motif Forming DNA Sequences

    Science.gov (United States)

    Wright, Elisé P.; Day, Henry A.; Ibrahim, Ali M.; Kumar, Jeethendra; Boswell, Leo J. E.; Huguin, Camille; Stevenson, Clare E. M.; Pors, Klaus; Waller, Zoë A. E.

    2016-12-01

    There are hundreds of ligands which can interact with G-quadruplex DNA, yet very few which target i-motif. To appreciate an understanding between the dynamics between these structures and how they can be affected by intervention with small molecule ligands, more i-motif binding compounds are required. Herein we describe how the drug mitoxantrone can bind, induce folding of and stabilise i-motif forming DNA sequences, even at physiological pH. Additionally, mitoxantrone was found to bind i-motif forming sequences preferentially over double helical DNA. We also describe the stabilisation properties of analogues of mitoxantrone. This offers a new family of ligands with potential for use in experiments into the structure and function of i-motif forming DNA sequences.

  2. Combination therapy with mitoxantrone and plasma exchange in aggressive relapsing remitting multiple sclerosis: A preliminary clinical study

    Directory of Open Access Journals (Sweden)

    Nasim Tabrizi

    2012-01-01

    Full Text Available Background: The efficacy of mitoxantrone induction therapy in rapidly worsening multiple sclerosis (MS is well established. Plasma exchange is also applied as an adjuvant in exacerbations of relapsing MS. The aim of this study was to compare the efficacy of combination therapy with mitoxantrone and plasma exchange versus mitoxantrone alone in patients with aggressive MS. Materials and Methods: Forty patients with aggressive relapsing remitting MS were randomly put into two groups. The first group underwent monthly plasma exchange for three successive months, followed by 12 mg/m 2 mitoxantrone at the end of each course and two more doses of 6 mg/m 2 mitoxantrone in 3-month intervals. The second group received the same doses of mitoxantrone only without plasma exchange. At the end of 8 months treatment course, clinical reassessment and neuroimaging was performed and treatment was continued with interferon-β. Results: At the end of induction therapy, Expanded Disability Status Scale score was significantly improved in both groups (P < 0.001. Number of demyelinating and gadolinium-enhancing plaques in brain magnetic resonance imaging (MRI was prominently reduced in group 2 (P ≤ 0.05, but the changes were not statistically significant in group 1, except for juxtacortical plaques. Conclusion: Administration of mitoxantrone as an induction therapy in patients of aggressive relapsing remitting MS results in significant improvement of their clinical state and MRI activity. However, combination of plasma exchange with mitoxantrone gives no more benefits than mitoxantrone alone and sometimes worsens the situation possibly by reduction of mitoxantrone efficacy as a result of plasma exchange.

  3. Response of Human Prostate Cancer Cells to Mitoxantrone Treatment in Simulated Microgravity Environment

    Science.gov (United States)

    Zhang, Ye; Edwards, Christopher; Wu, Honglu

    2011-01-01

    This study explores the changes in growth of human prostate cancer cells (LNCaP) and their response to the treatment of antineoplastic agent, mitoxantrone, under the simulated microgravity condition. In comparison to static 1g, microgravity and simulated microgravity have been shown to alter global gene expression patterns and protein levels in various cultured cell models or animals. However, very little is known about the effect of altered gravity on the responses of cells to drugs, especially chemotherapy drugs. To test the hypothesis that zero gravity would result in altered regulation of cells in response to antineoplastic agents, we cultured LNCaP cells for 96 hr either in a High Aspect Ratio Vessel (HARV) bioreactor at the rotating condition to model microgravity in space or in the static condition as a control. 24 hr after the culture started, mitoxantrone was introduced to the cells at a final concentration of 1 M. The mitoxantrone treatment lasted 72 hr and then the cells were collected for various measurements. Compared to static 1g controls, the cells cultured in the simulated microgravity environment did not show significant differences in cell viability, growth rate, or cell cycle distribution. However, in response to mitoxantrone (1uM), a significant proportion of bioreactor cultured cells (30%) was arrested at G2 phase and a significant number of these cells were apoptotic in comparison to their static controls. The expressions of 84 oxidative stress related genes were analyzed using Qiagen PCR array to identify the possible mechanism underlying the altered responses of bioreactor culture cells to mitoxantrone. Nine out of 84 genes showed higher expression at four hour post mitoxantrone treatment in cells cultured at rotating condition compared to those at static. Taken together, the results reported here indicate that simulated microgravity may alter the responses of LNCaP cells to mitoxantrone treatment. The alteration of oxidative stress pathways

  4. Mitoxantrone-loaded albumin microspheres for localized intratumoral chemotherapy of breast cancer

    Science.gov (United States)

    Almond, Brett Anthony

    The safety and efficacy of conventional chemotherapy is limited by its toxicity. The direct intratumoral injection of free or microsphere-loaded antineoplastic drugs is a promising modality for the treatment of solid tumors. Intratumoral chemotherapy delivers high localized doses of cytotoxic drugs to the tumor tissues than does systemic (intravenous) chemotherapy and it decreases systemic drug concentrations and toxicities. The use of drug-loaded microspheres also provides a prolonged release of drug into the surrounding tumor tissues, increasing exposure of the neoplasm to therapeutic levels of the cytotoxic drug. Mitoxantrone and 5-fluorouracil-loaded albumin microspheres were synthesized. The microspheres were synthesized using a suspension crosslinking technique and a glutardehyde crosslinking agent. The particle-size distribution of the microspheres was controlled by adjusting the emulsion energy and the concentration of cellulose acetate butyrate, the emulsion stabilization agent. Both microsphere size and crosslink density (glutaraldehyde concentration) were found to affect the in vitro release of loaded drugs in in vitro infinite sink conditions. The in vivo efficacy and toxicity of intratumoral chemotherapy with free and microsphere-loaded mitoxantrone were evaluated in a 16/C murine mammary adenocarcinoma model. Intratumoral chemotherapy with free mitoxantrone significantly improved survival and decreased toxicity compared to intravenously delivered drug. The efficacy of two size distributions of mitoxantrone-loaded albumin microspheres, corresponding to mean diameters of 5 to 10 mum and 20 to 40 mum, were evaluated delivered both alone and in combination with free mitoxantrone. Intratumoral injection of mitoxantrone-loaded microspheres was found to allow the safe delivery of increased doses compared to free drug. The maximum tolerated doses were approximately 40 mg/kg compared to 12 mg/kg, respectively. Intratumoral chemotherapy using free and

  5. Infusional mitoxantrone plus bolus melphalan as a stem cell transplant conditioning regimen for multiple myeloma.

    Science.gov (United States)

    Beaven, Anne W; Moore, Dominic T; Sharf, Andrew; Serody, Jonathan S; Shea, Thomas C; Gabriel, Don A

    2011-03-01

    This study combined infusional mitoxantrone with bolus melphalan as a transplant preparative regimen for multiple myeloma. Mitoxantrone was infused over 6 hr on days 6 and 5. Melphalan was given as a 15 min bolus on day 1 followed by autologous transplant on day 0. Thirty-five patients were enrolled; 57% of enrollees had received ≥ 2 prior treatments. The median overall survival was 5 years and 8 months, with 37% of the subjects alive >7 years posttransplantation. Myelosuppression and mucositis were the most frequent adverse events. This regimen is well tolerated and the survival compares well to other transplant trials.

  6. Effect of noscapine and vincristine combination on demyelination and cell proliferation in vitro.

    Science.gov (United States)

    Hiser, Laree; Herrington, Betty; Lobert, Sharon

    2008-08-01

    Peripheral neuropathy is a common, dose-limiting side effect of vincristine, a frontline therapy for acute lymphoblastic leukemia. Combination chemotherapy that reduces the neurotoxicity without compromising the efficacy of vincristine would improve patient outcomes. We performed in vitro studies using a combination of microtubule-binding antimitotics, noscapine and vincristine. In cell cultures containing neurons, astrocytes, and oligodendrocytes, vincristine caused demyelination as shown by transmission electron microscopy. A combination of vincristine and noscapine protected against demyelination. Human acute lymphoblastic and acute myelogenous leukemia cell lines CCRF-CEM and HL-60, respectively, were used to determine the antiproliferative effect of this novel drug combination. Vincristine and noscapine decreased cell proliferation with IC(50) concentrations of 1 nM and 20 microM, respectively. Analysis of dose-effect relationships using isobolograms and combination indices demonstrated that noscapine acts synergistically with vincristine. Thus, noscapine is a promising candidate for use with vincristine to decrease neurotoxicity and enhance antineoplastic effectiveness.

  7. Response of Human Prostate Cancer Cells to Mitoxantrone Treatment in Simulated Microgravity Environment

    Science.gov (United States)

    Zhang, Ye; Wu, Honglu

    2012-07-01

    RESPONSE OF HUMAN PROSTATE CANCER CELLS TO MITOXANTRONE TREATMENT IN SIMULATED MICROGRAVITY ENVIRONMENT Ye Zhang1,2, Christopher Edwards3, and Honglu Wu1 1 NASA-Johnson Space Center, Houston, TX 2 Wyle Integrated Science and Engineering Group, Houston, TX 3 Oregon State University, Corvallis, OR This study explores the changes in growth of human prostate cancer cells (LNCaP) and their response to the treatment of an antineoplastic agent, mitoxantrone, under the simulated microgravity condition. In comparison to static 1g, microgravity and simulated microgravity have been shown to alter global gene expression patterns and protein levels in various cultured cell models or animals. However, very little is known about the effect of altered gravity on the responses of cells to the treatment of drugs, especially chemotherapy drugs. To test the hypothesis that zero gravity would result in altered regulations of cells in response to antineoplastic agents, we cultured LNCaP cells in either a High Aspect Ratio Vessel (HARV) bioreactor at the rotating condition to model microgravity in space or in the static condition as control, and treated the cells with mitoxantrone. Cell growth, as well as expressions of oxidative stress related genes, were analyzed after the drug treatment. Compared to static 1g controls, the cells cultured in the simulated microgravity environment did not present significant differences in cell viability, growth rate, or cell cycle distribution. However, after mitoxantrone treatment, a significant proportion of bioreactor cultured cells became apoptotic or was arrested in G2. Several oxidative stress related genes also showed a higher expression level post mitoxantrone treatment. Our results indicate that simulated microgravity may alter the response of LNCaP cells to mitoxantrone treatment. Understanding the mechanisms by which cells respond to drugs differently in an altered gravity environment will be useful for the improvement of cancer treatment on

  8. Vincristine sulfate liposomal injection for acute lymphoblastic leukemia [Corrigendum

    Directory of Open Access Journals (Sweden)

    Soosay Raj TA

    2013-12-01

    Full Text Available Soosay Raj TA, Smith AM, Moore AS. Int J Nanomedicine. 2013;8:4361–4369.On page 4366, Table 1, Notes,Notes: Reproduced with permission of Wiley and Sons. Moore A, Pinkerton R. Vincristine: can its therapeutic index be enhanced? Pediatr Blood Cancer. 2009;53(7:1180–1187.22Should readNotes: Copyright © 2009, Wiley-Liss Inc. This material is reproduced with permission of John Wiley and Sons, Inc. Moore A, Pinkerton R. Vincristine: can its therapeutic index be enhanced? Pediatr Blood Cancer. 2009;53(7:1180–1187.22Read the original article

  9. Cyclophosphamide-induced temporomandibular synostosis.

    Science.gov (United States)

    Bacon, W

    1983-06-01

    The study of malformations helps toward a better understanding of normal development, which is of significance to the orthodontist. Experiments in teratology have induced an extensive variety of facial abnormalities, but temporomandibular joint (TMJ) synostosis has never been previously reported. Ten pregnant female rabbits were treated with a daily injection of 50 mg. cyclophosphamide (DNA synthesis inhibitor), from day 11 to day 14, which is the period that precedes formation of the face. The control sample comprised five female rabbits. The fetuses were obtained by cesarean section on day 28 and stained with alizarin. Six of the ten treated female animals produced offspring that had TMJ synostosis. The skull with TMJ synostosis showed a retrognathic mandibular pattern in relation to the maxilla, and the bony trabeculae in the mandibular angle showed a downward orientation instead of the horizontal orientation seen in animals without synostosis. The length of the heads was significantly smaller in the treatment group than in the control group; within the treatment group, the heads with synostosis were significantly smaller than those without synostosis. It could be hypothesized that the cyclophosphamide might have affected intrinsic factors in the temporomandibular mesenchyma; an impairment in the development and function of the mandibular musculature, which is a vital factor in joint development and maintenance, might also have contributed to the genesis of the malformation. The association of immobilization and mandibular hypodevelopment seems to be in agreement with today's theories on maxillofacial growth.

  10. Weekly low-dose mitoxantrone plus doxorubicin as second-line chemotherapy for advanced breast cancer

    NARCIS (Netherlands)

    M. Bontenbal (Marijke); A.S.Th. Planting (André); C.J. Rodenburg (C.); A. Dees; J. Verweij (Jaap); C.C.M. Bartels (Carina); J. Alexieva-Figusch (Jana); W.L.J. van Putten (Wim); J.G.M. Klijn (Jan)

    1992-01-01

    textabstractWeekly low dose mitoxantrone (3 mg/m2) plus doxorubicin (8 mg/m2) was administered as second-line chemotherapy to 33 patients with advanced breast cancer. Four out of 28 evaluable patients (14%) obtained a partial response with a median duration of 34 weeks (range 18-67+ weeks), while 8

  11. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells

    DEFF Research Database (Denmark)

    Miyake, K; Mickley, L; Litman, Thomas

    1999-01-01

    Reports of multiple distinct mitoxantrone-resistant sublines without overexpression of P-glycoprotein or the multidrug-resistance associated protein have raised the possibility of the existence of another major transporter conferring drug resistance. In the present study, a cDNA library from mito...

  12. Use of peptide antibodies to probe for the mitoxantrone resistance-associated protein MXR/BCRP/ABCP/ABCG2

    DEFF Research Database (Denmark)

    Litman, Thomas; Jensen, Ulla; Hansen, Alastair

    2002-01-01

    Recent studies have characterized the ABC half-transporter associated with mitoxantrone resistance in human cancer cell lines. Encoded by the ABCG2 gene, overexpression confers resistance to camptothecins, as well as to mitoxantrone. We developed four polyclonal antibodies against peptides...... corresponding to four different epitopes on the mitoxantrone resistance-associated protein, ABCG2. Three epitopes localized on the cytoplasmic region of ABCG2 gave rise to high-affinity antibodies, which were demonstrated to be specific for ABCG2. Western blot analysis of cells with high levels of ABCG2 showed...

  13. Vincristine sulfate liposomal injection for acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Soosay Raj TA

    2013-11-01

    Full Text Available Trisha A Soosay Raj,1 Amanda M Smith,2 Andrew S Moore,1,21Royal Children's Hospital, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland, Australia; 2Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, QLD, AustraliaAbstract: Vincristine (VCR is one of the most extensively used cytotoxic compounds in hemato-oncology. VCR is particularly important for the treatment of acute lymphoblastic leukemia (ALL, a disease that accounts for approximately one-third of all childhood cancer diagnoses. VCR's full therapeutic potential has been limited by dose-limiting neurotoxicity, classically resulting in autonomic and peripheral sensory–motor neuropathy. In the last decade, however, the discovery that liposomal encapsulation of chemotherapeutics can modulate the pharmacokinetic characteristics of a compound has stimulated much interest in liposomal VCR (vincristine sulfate liposomal injection [VSLI] formulations for the treatment of ALL and other hematological malignancies. Promising data from recent clinical trials investigating VSLI in adults with ALL resulted in US Food and Drug Administration approval for use in patients with Philadelphia chromosome (t[9;22]/BCR–ABL1 (Ph-negative (Ph- disease. Additional clinical trials of VSLI in adults and children with both Ph-positive (Ph+ and Ph- ALL are ongoing. Here we review the preclinical and clinical experience to date with VSLI for ALL.Keywords: vincristine sulfate liposomal injection, liposomes, sphingosomal vincristine, acute lymphoblastic leukemia, chemotherapy

  14. Compound list: cyclophosphamide [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available cyclophosphamide CPA 00024 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/cycloph...osphamide.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/cycloph...osphamide.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.

  15. Oxidative metabolism of the anti-cancer agent mitoxantrone by horseradish, lacto-and lignin peroxidase.

    Science.gov (United States)

    Brück, Thomas B; Brück, Dieter W

    2011-02-01

    Mitoxantrone (MH(2)X), an anthraquinone-type anti-cancer agent used clinically in the treatment of human malignancies, is oxidatively activated by the peroxidase/H(2)O(2) enzyme system. In contrast to the enzymatic mechanisms of drug oxidation, the chemical transformations of MH(2)X are not well described. In this study, MH(2)X metabolites, produced by the horseradish, lacto- or lignin peroxidase (respectively HRP, LPO and LIP)/H(2)O(2) system, were investigated by steady-state spectrokinetic and HPLC-MS methods. At an equimolar mitoxantrone/H(2)O(2) ratio, the efficacy of the enzyme-catalyzed oxidation of mitoxantrone decreased in the following order: LPO > HRP > LIP, which accorded with the decreasing size of the substrate access channel in the enzyme panel examined. In all cases, the central drug oxidation product was the redox-active cyclic metabolite, hexahydronaphtho-[2,3-f]-quinoxaline-7,12-dione (MH(2)), previously identified in the urine of mitoxantrone-treated patients. As the reaction progressed, data gathered in this study suggests that further oxidation of the MH(2) side-chains occurred, yielding the mono- and dicarboxylic acid derivatives respectively. Based on the available data a further MH(2) derivative is proposed, in which the amino-alkyl side-chain(s) are cyclised. With increasing H(2)O(2) concentrations, these novel MH(2) derivatives were oxidised to additional metabolites, whose spectral properties and MS data indicated a stepwise destruction of the MH(2) chromophore due to an oxidative cleavage of the 9,10-anthracenedione moiety. The novel metabolites extend the known sequence of peroxidase-induced mitoxantrone metabolism, and may contribute to the cytotoxic effects of the drug in vivo. Based on the structural features of the proposed MH(2) oxidation products we elaborate on various biochemical mechanisms, which extend the understanding of mitoxantrone's pharmaceutical action and its clinical effectiveness with a particular focus on

  16. Mitoxantrone in secondarily progressive multiple sclerosis: a series of 18 patients Mitoxantrone na esclerose múltipla secundária progressiva relato de 18 casos

    Directory of Open Access Journals (Sweden)

    María Belén Montú

    2005-06-01

    Full Text Available Mitoxantrone hydrochloride (Novantrone® is an anthracenedione that has been used as one of the latest in a long line of general immunosuppresive agents studied in multiple sclerosis (MS. We reviewed the clinical, laboratory, neuroimaging and echocardiography data of 18 patients from February 2001 to March 2004 out of a total number of 100 patients with definite MS. Fourteen patients were women (77.7% and four were men. The mean age of the patients was 41.6±10 years old (confidence intervals 95%: 36.4-46.7 years old. The mean duration of disease was 10.5±6.3 years. Fourteen patients had the secondarily progressive form of MS, and four had the relapsing-remitting form. Mitoxantrone is an useful and clinically effective drug in MS and its major limitation is the potencial cardiotoxicity due to cumulative dose (140 mg.Hidrocloridrato de mitoxantrone (Novantrone® é um antracenedione utilizado como o agente mais recente de uma longa linha de imunossupressivos gerais estudados em esclerose múltipla (EM. Realizamos revisão de dados clínicos, laboratoriais, de neuroimagem e ecocardiografia de 18 pacientes, no período de fevereiro de 2001 a março de 2004, a partir de um total de 100 pacientes com EM definida. Quatorze pacientes eram do sexo feminino (77,7% e quatro eram do sexo masculino. A idade média dos pacientes foi 41,6±10 anos (intervalo de confiança 95%: 36,4-46,7 anos. A duração média da doença foi 10,5±6,3 anos. Quatorze pacientes apresentavam a forma secundária progressiva de EM e quatro a forma surto-remissão. O mitoxantrone é uma droga útil e clinicamente eficaz , sendo a principal limitação sua potencial cardiotoxicidade devido à dose cumulativa (140 mg.

  17. Vincristine sulfate liposomal injection for acute lymphoblastic leukemia

    OpenAIRE

    Soosay Raj TA; Smith AM; Moore AS

    2013-01-01

    Trisha A Soosay Raj,1 Amanda M Smith,2 Andrew S Moore,1,21Royal Children's Hospital, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland, Australia; 2Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, QLD, AustraliaAbstract: Vincristine (VCR) is one of the most extensively used cytotoxic compounds in hemato-oncology. VCR is particularly important for the treatment of acute lymphoblastic leukemia (ALL), a...

  18. Sensitizing cancer cells to TRAIL-induced death by micellar delivery of mitoxantrone.

    Science.gov (United States)

    Grandhi, Taraka Sai Pavan; Potta, Thrimoorthy; Taylor, David J; Tian, Yanqing; Johnson, Roger H; Meldrum, Deirdre R; Rege, Kaushal

    2014-01-01

    TNFα-related apoptosis-inducing ligand (TRAIL) induces death selectively in cancer cells. However, subpopulations of cancer cells are either resistant to or can develop resistance to TRAIL-induced death. As a result, strategies that overcome this resistance are currently under investigation. We have recently identified several US FDA-approved drugs with TRAIL-sensitization activity against prostate, breast and pancreatic cancer cells. Mitoxantrone, a previously unknown TRAIL sensitizer identified in the screen, was successfully encapsulated in methoxy-, amine- and carboxyl-terminated PEG-DSPE micelles in order to facilitate delivery of the drug to cancer cells. All three micelle types were extensively characterized for their physicochemical properties and evaluated for their ability to sensitize cancer cells to TRAIL-induced death. Our results indicate that micelle-encapsulated mitoxantrone can be advantageously employed in synergistic treatments with TRAIL, leading to a biocompatible delivery system and amplified cell killing activity for combination chemotherapeutic cancer treatments.

  19. [Novobiocin inhibits angiogenesis and shows synergistic effect with vincristine].

    Science.gov (United States)

    Yang, Jun; Jiang, Min; Zhen, Yong-su

    2003-10-01

    To study the anti-angiogenic activity of novobiocin and its mechanism of action. The anti-angiogenic activity of novobiocin was determined using chick embryo chorioallantoic membrane(CAM) assay. MTT assay, zymography and related assays were used to observe the effects of drugs on bovine aorta endothelial cells and human pulmonary carcinoma PG cells. Novobiocin at the doses of 100 and 200 micrograms/egg inhibited angiogenesis by 31.6% and 68.7% in CAM, respectively. The combination of novobiocin and vincristine enhanced the anti-angiogenic effect. Novobiocin inhibited the proliferation of bovine aortic endothelial cells in a concentration-dependent manner. In addition, novobiocin suppressed MMP-2 secretion, migration, and tube formation of endothelial cells. As determined by MTT assay, novobiocin in combination with vincristine displayed synergistic effect on the proliferation of PG cells, This study demonstrates that novobiocin is active in suppressing angiogenesis and the anti-angiogenic activity may be enhanced by combination with vincristine. The anti-angiogenic activity of novobiocin may be related, at least in part, to its inhibition of cell proliferation, cell migration, tube formation and secretion of matrix metalloproteinases.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  1. A functional assay for detection of the mitoxantrone resistance protein, MXR (ABCG2)

    DEFF Research Database (Denmark)

    Robey, R W; Honjo, Y; van de Laar, A

    2001-01-01

    The fluorescent compounds rhodamine 123, LysoTracker Green DMD-26, mitoxantrone, and BODIPY-prazosin were used with the antagonist fumitremorgin C (FTC) in order to develop functional assays for the half-transporter, MXR/BCRP/ABCP1. A measure of FTC-inhibitable efflux was generated for each...... as determined by Northern blotting, r(2)=0.89 and r(2)=0.70 respectively. In contrast, rhodamine and LysoTracker were not able to reliably detect MXR. Cytotoxicity assays performed on two of the four unselected cell lines confirmed increased sensitivity to mitoxantrone in the presence of FTC. FTC was found...... to be a specific inhibitor of MXR, with half-maximal inhibition of MXR-associated ATPase activity at 1 microM FTC. Short term selections of the SF295, KM12, NCI-H460 and A549 cell lines in mitoxantrone resulted in a small but measurable increase in MXR by both Northern blot and functional assay. These studies show...

  2. Electrochemical Behavior of Mitoxantrone and Its Determination at a Pt/C Implanted Modified Microelectrode

    Institute of Scientific and Technical Information of China (English)

    QIAN Yong-gui; SUN Zi-jie; HU Jing-bo; LU Yi-qiang; LI Qi-long

    2004-01-01

    In a 0.02 mol/L Na2HPO4-KH2PO4(PBS) buffer solution(pH=6.82), the electrochemical behavior of mitoxantrone was studied by linear-sweep voltammetry and cyclic voltammetry at a Pt/C ion implantation modified microelectrode. A sensitive reduction peak was observed. The peak potential was -0.72 V(vs.SCE), the peak current was proportional to the concentration of mitoxantrone within the ranges of 7.0×10-8-9.0×10-7 mol/L and 1.0×10-6-2.4×10-5 mol/L, with a detection limit of 4.0×10-8 mol/L. The linear correlation coefficients were 0.9994 and 0.9992, respectively. This method has been applied to the direct determination of mitoxantrone in simulated urine. The recoveries were in the range from 96.2% to 105.9%. The reduction process was a quasi-reversible one with adsorptive characteristics at the Pt/C microelectrode. The electrode reaction rate constant ks and the electron transfer coefficient α of the system were determined to be 4.5 and 0.65 s-1, respectively. The experiments showed that Pt element had surely been implanted into the surface of the carbon fiber, and the atomic Pt improved the electrocatalytic activity. The Pt/C microelectrode had a good stability and reproducibility.

  3. Targeted Tumor Therapy with "Magnetic Drug Targeting": Therapeutic Efficacy of Ferrofluid Bound Mitoxantrone

    Science.gov (United States)

    Alexiou, Ch.; Schmid, R.; Jurgons, R.; Bergemann, Ch.; Arnold, W.; Parak, F.G.

    The difference between success or failure of chemotherapy depends not only on the drug itself but also on how it is delivered to its target. Biocompatible ferrofluids (FF) are paramagnetic nanoparticles, that may be used as a delivery system for anticancer agents in locoregional tumor therapy, called "magnetic drug targeting". Bound to medical drugs, such magnetic nanoparticles can be enriched in a desired body compartment (tumor) using an external magnetic field, which is focused on the area of the tumor. Through this form of target directed drug application, one attempts to concentrate a pharmacological agent at its site of action in order to minimize unwanted side effects in the organism and to increase its locoregional effectiveness. Tumor bearing rabbits (VX2 squamous cell carcinoma) in the area of the hind limb, were treated by a single intra-arterial injection (A. femoralis) of mitoxantrone bound ferrofluids (FF-MTX), while focusing an external magnetic field (1.7 Tesla) onto the tumor for 60 minutes. Complete tumor remissions could be achieved in these animals in a dose related manner (20% and 50% of the systemic dose of mitoxantrone), without any negative side effects, like e.g. leucocytopenia, alopecia or gastrointestinal disorders. The strong and specific therapeutic efficacy in tumor treatment with mitoxantrone bound ferrofluids may indicate that this system could be used as a delivery system for anticancer agents, like radionuclids, cancer-specific antibodies, anti-angiogenetic factors, genes etc.

  4. Effect of Salvia officinalis Hydroalcoholic Extract on Vincristine-induced Neuropathy in Mice

    Institute of Scientific and Technical Information of China (English)

    Ali Namvaran Abbas Abad; Mir Hadi Khayate Nouri; Farzaneh Tavakkoli

    2011-01-01

    AIM:Vincristine is one of the most commonly used chemotherapeutic drugs to treat a variety of malignant diseases,including leukemia and lymphoma.Studies have shown that vincristine cause painful effects,whereas Salvia ofcinalis(SO)showed analgesic and anti-inflammatory effects.The aim of this study is to investigate the effects of the SO hydro-alcoholic extract on vincristine-induced peripheral neuropathy in mice in comparison with morphine.METHODS:Experiments were performed on 60 NMRI male mice weighing 25-30g divided into six groups.The individual groups received normal saline,SO hydro-alcoholic extract,vincristine,SO hydro-alcoholic extract and vincristine(12 days before formalin test),morphine,and vincristine and morphine,respectively.The injected hind paw biting and licking was measured in a 5-minute interval for one hour.RESULTS:The results showed that formalin induce significant(P<0.05)pain responses(the fast phase:0-5 min and the second phase:15-40 min after injection).Administration of SO extract before formalin testshowed significant(P<0.05)decrease of pain response in the second phase.Administration of vincristine caused significant(P<0.05)increase in the second phase of pain response.Injections of SO extract and vincristine showed that SO significantly(P<0.05)decrease the second phase of vincristine-induced pain.Morphine decreased vincristine-induced pain in the first and second phase of formalin test significantly(P<0.05).In comparison,morphine showed analgesig effects in the first phase and SO extract showed significant(P<0.05)anti-inflammatory effects in the second phase of formalin test.CONCLUSION:Both SO and vincristine showed analgesic and painful neuropathic effects,suggesting that SO extract could be useful in the treatment of vincristine-induced peripheral neuropathic pain.

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

    Directory of Open Access Journals (Sweden)

    Ana Laura Guzmán-Ortiz

    2017-05-01

    Conclusions: 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.

  6. Cyclophosphamide-induced reversible posterior leukoencephalopathy syndrome.

    Science.gov (United States)

    Abenza-Abildua, Maria Jose; Fuentes, Blanca; Diaz, Domingo; Royo, Aranzazu; Olea, Teresa; Aguilar-Amat, Maria Jose; Diez-Tejedor, Exuperio

    2009-01-01

    Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical radiological syndrome, characterised by acute headache, altered consciousness, seizures and hypertension. The most frequent causes are hypertensive encephalopathy, eclampsia and some immunosuppressive therapies. The pathogenesis remains unclear, but it appears to be related to altered cerebral circulation, producing oedema that can be seen on MRI, and it resolves in 2 or 3 weeks. In the present report, a possible first reported case of cyclophosphamide-induced RPLS in a 27-year-old man with high blood pressure (HBP) and glomerulonephritis caused by Goodpasture syndrome, treated with cyclophosphamide during the last month and prednisone for glomerulonephritis resulting from Goodpasture syndrome without other immunosuppressive drugs, is described.Symptoms appeared during a hypertensive crisis, but when cyclophosphamide was replaced by rituximab and hypertension was controlled, the patient did not have neurological symptoms. Almost all reported cases induced by immunosuppressive therapy or other causes were associated with hypertension as well.

  7. 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

  8. 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

    2000-01-01

    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 n

  9. Vincristine pharmacokinetics is related to clinical outcome in children with standard risk acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Loennerholm, Gudmar; Frost, Britt-Marie; Abrahamsson, Jonas; Behrendtz, Mikael; Castor, Anders; Forestier, Erik; Heyman, Mats; Uges, Donald R. A.; de Graaf, Siebold S. N.

    2008-01-01

    Vincristine is a key drug in the treatment of childhood and adult acute lymphoblastic leukemia (ALL), and many other childhood malignancies. Despite decades of wide clinical use, no data on the correlation between vincristine pharmacokinetics and long-term clinical outcome have been published. We he

  10. Mitoxantrone and acquired Long-QT Syndrome. Case presentation. Mitoxantrone y síndrome QT prolongado adquirido. Presentación de un caso.

    Directory of Open Access Journals (Sweden)

    Lázaro Enrique De la Cruz Aviléz

    2009-05-01

    Full Text Available The acquired Long-QT Syndrome can be caused by more than 100 non anti-arrhythmic drugs. These drugs block potassium channels; particularly the IKr which extends the ventricular repolarization beyond 450 ms. This syndrome is associated with ventricular helical tachycardia that could potentially cause immediate death. We report a patient with diagnosis of leukaemia who was treated with mitoxantrone and presented syncope. The electrocardiogram showed an interval QTc of 576 ms. After an exclusion diagnosis we concluded that there could be an association with the use of this drug caused by its toxic effects for the cardiac system. Mitoxantrone interferes in ionic transportation through cellular membrane, delays the exit of potassium from the cells and acts in the functioning of ATP asa Na/K altering the ventricular repolarization; however, it is not on the list of drugs that enlarge the QT interval. Our objective with this work is to raise the interest on new reports on this subject, and to establish a more direct causal relation through the evidence derived from new experiences. El síndrome QT largo adquirido puede ser producido entre otros aspectos por más de 100 fármacos no antiarrítmicos. Estos tienen la capacidad de bloquear los canales de potasio; fundamentalmente los IKr, prolongan la repolarización ventricular más allá de los 450 ms. Este síndrome se asocia a taquicardias ventriculares helicoidales con potencial para producir una muerte súbita. Se reporta un paciente con diagnóstico de leucemia tratado con mitoxantrone, que presentó un síncope. Además, en el electrocardiograma se constató el hallazgo de un intervalo QTc de 576 ms. Después de realizar un diagnóstico de exclusión, se concluyó que podía haber una asociación con el uso del fármaco, por sus efectos tóxicos para el sistema cardiaco. El mitoxantrone, entre otras cosas, interfiere en el trasporte de iones a través de la membrana celular, retarda la salida de

  11. A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone.

    Science.gov (United States)

    Greidanus, J; de Vries, E G; Mulder, N H; Sleijfer, D T; Uges, D R; Oosterhuis, B; Willemse, P H

    1989-06-01

    A phase I study of mitoxantrone given as a continuous infusion for 21 days using a venous access port and a portable pump was performed. The first dose step was 0.3 mg/m2/d for 21 days. Courses were repeated every 6 weeks. Dose increment per step was 0.1 mg/m2/d in the first three dose steps and 0.2 mg/m2/d in the latter dose steps. Twenty-five patients entered the study and received a total of 50 courses, with a median of two courses (range, one to five). Up to 0.5 mg/m2/d, no toxicity (according to the World Health Organization [WHO] criteria) occurred. At 0.7 mg/m2/d, one patient experienced grade 2 leukocytopenia and at the 0.9 mg/m2/d dose step, one patient experienced grade 2 leukocytopenia, grade 1 thrombocytopenia, and grade 1 hair loss. At 1.1 mg/m2/d, two of six patients had grade 3 leukocytopenia, and in one patient treatment was discontinued after two days because of myocardial infarction. In both patients receiving 1.3 mg/m2/d, treatment was discontinued after 2 weeks because of grade 3 leukocytopenia. Three patients at the 1.1 mg/m2/d, dose step and two patients at the 1.3 mg/m2/d dose step experienced some nausea in the last week of the infusion period. One patient developed subclavian vein thrombosis. No infectious complications occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Plasma steady-state was reached after 35 hours. During steady-state there was a linear relationship between the mitoxantrone dose administered and the level of mitoxantrone in plasma (r = .93, P less than .005). The mitoxantrone level in leukocytes increased significantly during the infusion period at the 0.9 mg/m2, the 1.1 mg/m2, and the 1.3 mg/m2 dose steps. The area under the curve (AUC) in leukocytes was higher with continuous infusion of 1.1 mg/m2/d for 21 days compared with bolus injection of 12 mg/m2. Mitoxantrone could be detected in plasma for at least five days after the end of the 21

  12. Impact of Mitoxantrone on MRI Findings in Patients with Secondary Progressive Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Maryam Afraze

    2010-05-01

    Full Text Available Objective: Determining the effect of Mitoxantrone on MRI findings in patients with secondary progressive multiple sclerosis (SPMS "nPatients and Methods: In clinical trial, 25 SPMS patients were enrolled in this study. Brain and spinal cord MRI were performed before and after treatment with Mitoxantrone. The number, shape, and distribution of the plaques and the size of the largest and smallest plaques were assessed in T1 W, T2 W and FLAIR sequences and compared before and after treatment. "nResults: The mean age of the patients was 38.9 years (24-57. There were 15 women and 10 men. The mean plaque count reduction after treatment was 3±2.6, 3.3±2.5 and 3.1±2.3 in T1W, T2W and FLAIR sequences, respectively (all p<0.0001. The mean of the greatest plaque size reduction was 4.3±3.7 mm in T1W, 4.6±4.1 mm in T2W and 4.6±3.9 mm in the FLAIR sequence (all p<0.0001. The mean of the smallest plaque size reduction was 0.29±0.44, 0.29±0.52 and 0.24±0.53 mm in T1W, T2W and FLAIR sequences, respectively (all p<0.0001. There was no significant difference regarding the location and shape of the plaques before and after treatment (both p's>0.3. Also, there was not any significant difference between before and after treatment images regarding edema and ventricular dilation (p>0.9."nConclusion: Mitoxantrone can decrease the number and size of plaques in SPMS patients.

  13. Vincristine sulfate liposomal injection for acute lymphoblastic leukemia.

    Science.gov (United States)

    Raj, Trisha A Soosay; Smith, Amanda M; Moore, Andrew S

    2013-01-01

    Vincristine (VCR) is one of the most extensively used cytotoxic compounds in hemato-oncology. VCR is particularly important for the treatment of acute lymphoblastic leukemia (ALL), a disease that accounts for approximately one-third of all childhood cancer diagnoses. VCR's full therapeutic potential has been limited by dose-limiting neurotoxicity, classically resulting in autonomic and peripheral sensory-motor neuropathy. In the last decade, however, the discovery that liposomal encapsulation of chemotherapeutics can modulate the pharmacokinetic characteristics of a compound has stimulated much interest in liposomal VCR (vincristine sulfate liposomal injection [VSLI]) formulations for the treatment of ALL and other hematological malignancies. Promising data from recent clinical trials investigating VSLI in adults with ALL resulted in US Food and Drug Administration approval for use in patients with Philadelphia chromosome (t[9;22]/BCR-ABL1) (Ph)-negative (Ph-) disease. Additional clinical trials of VSLI in adults and children with both Ph-positive (Ph+) and Ph- ALL are ongoing. Here we review the preclinical and clinical experience to date with VSLI for ALL.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Detection of Asymptomatic Cardiac Metastasis and Successful Salvage Chemotherapy Comprising a Prednisone, Etoposide, Procarbazine, and Cyclophosphamide Regimen in an Elderly Japanese Patient Suffering from a Delayed Recurrence of Diffuse Large B-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Keita Tagami

    2012-01-01

    Full Text Available We report a case of facial diffuse large B-cell lymphoma (DLBCL associated with recurrent metastasis in the heart and other sites in a 76-year-old Japanese woman. Initially, she developed DLBCL in her left upper eyelid that spread into the left orbit (Ann Arbor classification stage I. The lesion went into clinical regression after 4 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy followed by radiotherapy. More than 3 years later, the lymphoma recurred in her facial skin, together with metastases in the mediastinal lymph nodes and the heart; the tumor in the heart was successfully detected by PET/CT and cardiac MRI. To treat the recurrent lesions, we performed a salvage chemotherapy regimen comprising prednisone, etoposide, procarbazine, and cyclophosphamide, which successfully induced tumor regression.

  16. NMR structure of dual site binding of mitoxantrone dimer to opposite grooves of parallel stranded G-quadruplex [d-(TTGGGGT)]4.

    Science.gov (United States)

    Pradeep, Tarikere Palakshan; Barthwal, Ritu

    2016-01-01

    The formation of complex between anti-cancer drug mitoxantrone (MTX) and tetra-molecular parallel G-quadruplex DNA [d-(TTGGGGT)]4 has been studied by solution state one and two dimensional NMR spectroscopy. Mitoxantrone forms a head-to-tail dimer and binds at two opposite grooves of the G-quadruplex. The Job's method of continuous variation and thermal melting studies independently ascertain binding stoichiometry of 4:1 in mitoxantrone:DNA complex. The existence of only four guanine NH peaks corresponding to the four G-quartets during the course of titration shows that C4 symmetry of G-quadruplex is intact upon binding of mitoxantrone. The specific inter molecular short distance contacts between protons of two mitoxantrone molecules of dimer, that is, ring A protons with ring C and side chain methylene protons, confirms the formation of mitoxantrone head-to-tail dimer. The observed 38 Nuclear Overhauser Enhancement (NOE) cross peaks between MTX and G-quadruplex DNA indicate formation of a well-defined complex. The three dimensional structure of 4:1 mitoxantrone:[d-(TTGGGGT)]4 complex computed by using experimental distance restraints followed by restrained Molecular Dynamics (rMD) simulations envisages the critical knowledge of specific molecular interactions within ligand-G-quadruplex complex. The findings are of direct interest in development of anti-cancer therapeutic drug based on G-quadruplex stabilization, resulting in telomerase inhibition.

  17. Mitoxantrone as a contributing factor in medication-related osteonecrosis of the jaws.

    Science.gov (United States)

    Bagan, J V; Bagan, L; Poveda, R; Scully, C

    2016-03-01

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is usually initiated by dental surgery, but is occasionally exacerbated by other antiresorptive (denosumab) and anti-angiogenic therapies, and in such cases is currently termed medication-related osteonecrosis of the jaws (MRONJ). The case of a 58-year-old female with breast cancer who developed multiple and ultimately fatal metastases despite 3 years of treatment with chemotherapeutic drugs and intravenous bisphosphonates, is presented herein. Her malignant disease worsened and she was started on mitoxantrone. She developed a severe adverse reaction to this drug soon after starting treatment. As well as diarrhoea and vomiting, she had a very aggressive gingival inflammation with multiple ulcerations in both jaws and wide areas of necrotic bone, affecting the attached gingiva, and seemingly unrelated to dental plaque. These ulcerations and the exposed necrotic bone persisted for more that 6 months, until her death. This report describes a case in which severe gingival ulcerations that occurred after mitoxantrone treatment for metastatic breast cancer were a local factor that initiated MRONJ.

  18. Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues.

    Science.gov (United States)

    Patel, Krupa J; Trédan, Olivier; Tannock, Ian F

    2013-07-01

    Pharmacokinetic analyses estimate the mean concentration of drug within a given tissue as a function of time, but do not give information about the spatial distribution of drugs within that tissue. Here, we compare the time-dependent spatial distribution of three anticancer drugs within tumors, heart, kidney, liver and brain. Mice bearing various xenografts were treated with doxorubicin, mitoxantrone or topotecan. At various times after injection, tumors and samples of heart, kidney, liver and brain were excised. Within solid tumors, the distribution of doxorubicin, mitoxantrone and topotecan was limited to perivascular regions at 10 min after administration and the distance from blood vessels at which drug intensity fell to half was ~25-75 μm. Although drug distribution improved after 3 and 24 h, there remained a significant decrease in drug fluorescence with increasing distance from tumor blood vessels. Drug distribution was relatively uniform in the heart, kidney and liver with substantially greater perivascular drug uptake than in tumors. There was significantly higher total drug fluorescence in the liver than in tumors after 10 min, 3 and 24 h. Little to no drug fluorescence was observed in the brain. There are marked differences in the spatial distributions of three anticancer drugs within tumor tissue and normal tissues over time, with greater exposure to most normal tissues and limited drug distribution to many cells in tumors. Studies of the spatial distribution of drugs are required to complement pharmacokinetic data in order to better understand and predict drug effects and toxicities.

  19. Mitoxantrone Therapy for Acute Posterior Multifocal Placoid Pigment Epitheliopathy with Cerebral Vasculitis

    Directory of Open Access Journals (Sweden)

    Hélène Massé

    2009-01-01

    Full Text Available Purpose. To report favorable outcome of a case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE associated with cerebral vasculitis after treatment with immunosuppressive therapy by mitoxantrone. Design. Single case report. Method. A 22-year-old man presented with acute isolated bilateral loss of vision revealing APMPPE. Corticosteroid therapy was initiated and visual acuity gradually improved. Seventeen days later, visual function deteriorated again, associated with flu-like syndrome and severe headaches. A relapse of APMPPE was diagnosed, complicated with lymphocytic meningitis and cerebral ischemia. Intravenous therapy with mitoxantrone was performed in combination with methylprednisolone. Results. Headaches disappeared in a few days whereas visual acuity gradually improved and stabilized at 20/40 in the right eye and 20/32 in the left eye. No adverse event was observed. Clinical improvement was confirmed by magnetic resonance imaging. Conclusion. Cerebral vasculitis is the most severe complication of the extraocular manifestations of APMPEE. This diagnosis should be evoked when severe headaches or behavior disorder are associated with APMPEE.

  20. Posaconazole-Vincristine Coadministration Triggers Seizure in a Young Female Adult: A Case Report

    Directory of Open Access Journals (Sweden)

    Dalia A. Hamdy

    2012-01-01

    Full Text Available Coadministration of azoles and vincristine has been shown to increase vincristine neurotoxic effects due to the inhibition of cytochrome P450 (CYP isoform 3A4, for which vincristine is a substrate. Despite the absence of any casual relationship between seizure and coadministration of azoles, few case reports of vincristine-induced seizure have been documented after coadministration of fluconazole or posaconazole in children. In this paper we are reporting the first young female adult who experienced generalized seizure after coadministration of posaconazole and vincristine. The 19-year-old female was diagnosed with acute lymphoblastic leukemia. She started induction phase of Berlin Frankfurt Muenster protocol along with posaconazole 200 mg three times daily as prophylactic antifungal therapy. Five days after the third vincristine dose, she developed generalized seizure accompanied by high blood pressure and SIADH. Her neurological exam/CT scan did not show any abnormality. In conclusion, this study reports a novel finding in the sense that all previous case reports pertaining to posaconazole-vincristine-induced seizure in literature involved children. Physicians should be made aware of this rare possible outcome to closely monitor their patients and take appropriate measures to prevent such possible adverse effect.

  1. Pulse cyclophosphamide therapy for inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Zsolt Barta; László Tóth; Margit Zeher

    2006-01-01

    AIM: To assess the efficacy of intravenous cyclophosphamide pulse therapy for refractory inflammatory bowel disease (IBD).METHODS: We included in our cohort eight patients with (moderate/severe) steroid refractory IBD (4 with ulcerative colitis and 4 with Crohn's disease). They all received 6 cycles of intravenous cyclophosphamide (800mg) per month.RESULTS: Patients entered into remission after the second/third cyclophosphamide pulse. Disease activity decreased. There were no side effects and toxicity. All the patients went into long lasting remission. All Crohn's disease patients and 3 of 4 ulcerative colitis patients achieved complete remission. One patient with ulcerative colitis showed an impressive clinical response but did not enter into remission. For the maintenance, patients with Crohn's disease were treated with methotrexate (15 mg/wk) and patients with ulcerative colitis were treated with azathioprine (2.5 mg/kg body weight/d).CONCLUSION: Remission was maintained in all patients for 6 mo on the average. The drug was well tolerated. These findings suggest that aggressive immunosuppressive therapy may be useful in some refractory patients and further controlled study should be considered in order to fully evaluate this type of treatment as a potential therapy for IBD.

  2. A combination therapy with fludarabine, mitoxantrone and rituximab induces complete immunophenotypical remission in B-cell prolymphocytic leukaemia

    OpenAIRE

    Tempescul, Adrian; Feuerbach, Johanna; Ianotto, Jean-Christophe; Dalbies, Florence; Marion, Veronique; Bris, Marie-Josée; De Braekeleer, Marc; Berthou, Christian

    2008-01-01

    A combination therapy with fludarabine, mitoxantrone and rituximab induces complete immunophenotypical remission in B-cell prolymphocytic leukaemia phone: +33-298-223504 (Tempescul, Adrian) (Tempescul, Adrian) Department of Clinical Hematology, Institute of Cancerology and Hematology - CHU Morvan, Avenue Foch - 29609 - Brest - FRANCE (Tempescul, Adrian) Department of Clinical Hematology, Institute of Cancerology and Hematology - CHU Morvan, Avenue Foch - 2...

  3. Phase I/II Trial of Epothilone Analog BMS-247550, Mitoxantrone, and Prednisone in HRPC Patients Previously Treated with Chemotherapy

    Science.gov (United States)

    2006-07-01

    colitis; dry mouth; flatulence; gastritis; GI perforation; paralytic ileus Hemorrhage/Bleeding – CNS hemorrhage; epistaxis; hematemesis; hemoptysis...excreted via the biliary system, with about 10% excreted in the urine. Mitoxantrone has been found to be tolerable when administered on a three week

  4. Vincristine-Induced Neuropathy Presenting as Ptosis and Ophthalmoplegia in a 2-Year-Old Boy.

    Science.gov (United States)

    Palkar, Amit H; Nair, Akshay Gopinathan; Desai, Roshani J; Potdar, Nayana A; Shinde, Chhaya A

    2015-07-07

    Vincristine is used in the treatment of leukemias, solid tumors, and lymphomas. A case of a 2-year-old boy undergoing treatment for leukemia who developed sudden onset bilateral ptosis and ophthalmoplegia along with generalized neuropathy due to vincristine's neurotoxic effects is presented. He was successfully treated with pyridoxine and pyridostigmine. The possible mechanisms of action and the treatment for vincristine-induced neuropathy are discussed. Prompt treatment and close follow-up is needed, especially in children because prolonged ptosis and motility restriction may have a profound effect on a child's visual function.

  5. Vincristine for refractory autoimmune thrombocytopenic purpura in pregnancy. A case report.

    Science.gov (United States)

    Gross, Z; Rodriguez, J J; Stalnaker, B L

    1995-10-01

    Autoimmune thrombocytopenic purpura is a common disease during pregnancy. Newborns of affected mothers commonly develop thrombocytopenia. Standard therapy consists of corticosteroids, hyperimmune gamma globulin and splenectomy. Severe autoimmune thrombocytopenic purpura was diagnosed in a 22-year-old woman, gravida 2, para 1, at 28 weeks' gestation. A sufficient response was obtained after vincristine was added to the treatment with corticosteroids, hyperimmune gamma globulin and danazole. A male infant weighing 2,545 g was delivered by cesarean section at 33.5 weeks' gestation. There were no maternal or fetal complications except for severe newborn thrombocytopenia, which resolved with medical therapy. Vincristine has been used in all trimesters of pregnancy, with favorable outcomes in most cases. This is the first reported case of successful vincristine treatment for autoimmune thrombocytopenic purpura in pregnancy. Vincristine, when carefully used, offers an option for unusually refractory cases of autoimmune thrombocytopenic purpura before delivery.

  6. The combinational effect of vincristine and berberine on growth inhibition and apoptosis induction in hepatoma cells.

    Science.gov (United States)

    Wang, Ling; Wei, Dandan; Han, Xiaojuan; Zhang, Wei; Fan, Chengzhong; Zhang, Jie; Mo, Chunfen; Yang, Ming; Li, Junhong; Wang, Zhe; Zhou, Qin; Xiao, Hengyi

    2014-04-01

    The use of vincristine, a known antitumor agent, in hepatoma therapy is limited particularly because of its toxic effect. Meanwhile, berberine has drawn increasing attention to its antineoplastic effect in recent years. In view of the advantages of combinational drug treatment reported in anti-cancer chemotherapy, we evaluated the effects of co-treatment of vincristine and berberine on hepatic carcinoma cell lines in this study. We find that combinational usage of these two drugs can significantly induce cell growth inhibition and apoptosis even under a concentration of vincristine barely showing cytotoxicity in the same cells when used alone. The underlying mechanism about this combinational effect was addressed in this study by monitoring the signals related to mitochondrial function, apoptotic pathway and endoplasmic reticulum stress. Our results suggest a new value of berberine as a potential adjuvant agent in cancer chemotherapy and provide a hopeful approach for developing hepatoma therapy by utilizing the combinational effect of vincristine and berberine.

  7. Association of CYP3A5 Expression and Vincristine Neurotoxicity in Pediatric Malignancies in Turkish Population.

    Science.gov (United States)

    Kayilioğlu, Hülya; Kocak, Ulker; Kan Karaer, Derya; Percin, Emriye F; Sal, Ertan; Tekkesin, Funda; Isik, Melek; Oner, Nergiz; Belen, Fatma B; Yilmaz Keskin, Ebru; Okur, Arzu; Albayrak, Meryem; Kaya, Zuhre; Pinarli, Faruk G; Yenicesu, Idil; Karadeniz, Ceyda; Oguz, Aynur; Gursel, Turkiz

    2017-08-01

    Vincristine is a widely used chemotherapeutic agent in the treatment of childhood malignancies. Neuropathy is the most common adverse effect. CYP3A4 and CYP3A5 enzymes of cytochrome p450 enzyme system are responsible in vincristine metabolism. Genetic polymorphism may alter the vincristine metabolism and the neurotoxicity rate. In this study, distribution of CYP3A5 alleles among Turkish children with malignancies, relation between CYP3A5 genotype and neurotoxicity rates, as well as severity and duration of neuropathy and total vincristine doses were investigated. Patient group consisted of 115 patients (age, 1 to 17 y) with acute lymphoblastic leukemia and solid tumors, who were treated with vincristine consisting chemotherapy protocols. Control group consisted of 50 children without any neurological symptom or disorders. All patient files were reviewed for presence and severeness of neurotoxicity symptoms. Blood samples were obtained and CYP3A5 genotypes were analyzed. Neurotoxicity occurred in 20.8% of patients. Although it was found to occur more frequently after 4 doses of vincristine, and rates were higher in the low-dose vincristine group suggesting other contributing factors. Although neurotoxicity rate in the CYP3A5*1/*3 genotype was 17.6%, it was 21.6% in the CYP3A5*3/*3 genotype and the difference was not statistically significant (P<0.05). This study suggested that vincristine-related neurotoxicity is dose-independent and genotype is not the only causative factor in the occurrence of neurotoxicity in these patients.

  8. Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

    NARCIS (Netherlands)

    Ryan, C.J.; Rosenthal, M.; Ng, S.; Alumkal, J.; Picus, J.; Gravis, G.; Fizazi, K.; Forget, F.; Machiels, J.P.; Srinivas, S.; Zhu, M.; Tang, R.; Oliner, K.S.; Jiang, Y.; Loh, E.; Dubey, S.; Gerritsen, W.R.

    2013-01-01

    PURPOSE: To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).

  9. Vincristine chemotherapy trials and pharmacokinetics in tasmanian devils with tasmanian devil facial tumor disease.

    Directory of Open Access Journals (Sweden)

    David N Phalen

    Full Text Available Tasmanian Devil Facial Tumor Disease (DFTD is a transmissible cancer threatening to cause the extinction of Tasmanian Devils in the wild. The aim of this study was to determine the susceptibility of the DFTD to vincristine. Escalating dosage rates of vincristine (0.05 to 0.136 mg/kg were given to Tasmanian devils in the early stages of DFTD (n = 8. None of these dosage rates impacted the outcome of the disease. A dosage rate of 0.105 mg/kg, a rate significantly higher than that given in humans or domestic animals, was found to the highest dosage rate that could be administered safely. Signs of toxicity included anorexia, vomiting, diarrhea and neutropenia. Pharmacokinetic studies showed that, as with other species, there was a rapid drop in blood concentration following a rapid intravenous infusion with a high volume of distribution (1.96 L/kg and a relatively long elimination half life (11 h. Plasma clearance (1.8 ml/min/kg was slower in the Tasmanian devil than in humans, suggesting that pharmacodynamics and not pharmacokinetics explain the Tasmanian devil's ability to tolerate high dosage rates of vincristine. While providing base-line data for the use of vincristine in Tasmanian devils and possibly other marsupials with vincristine susceptible cancers, these findings strongly suggest that vincristine will not be effective in the treatment of DFTD.

  10. A novel chemiluminescence assay of mitoxantrone based on diperiodatocuprate(III) oxidation

    Science.gov (United States)

    Yao, Hanchun; Zhang, Min; Zeng, Wenyuan; Zeng, Xiaoying; Zhang, Zhenzhong

    2014-01-01

    A novel and strong chemiluminescence (CL) of luminol with diperiodatocuprate (K5[Cu(HIO6)2]) was observed in alkaline medium. After the addition of mitoxantrone (MTX) into this system, the CL intensity could be greatly inhibited by MTX. Based on the phenomenon, a sensitive CL method was established for analysis of MTX combining with flow injection technology. Under optimum experimental conditions, the CL intensity was linearly related to the logarithm concentration of MTX from 5.0 × 10-9-1.0 × 10-7 g/ml with the detection limit of 1.1 × 10-9 g/ml (S/N = 3). The relative standard deviation was 1.2% for 5.0 × 10-8 g/ml of MTX. The proposed method was successfully applied for determination of MTX in pharmaceutical preparations and biological fluids. The possible CL reaction mechanism was also discussed briefly.

  11. Investigation on a Potential Targeting Drug Delivery System Consisting of Folate, Mitoxantrone and Human Serum Albumin

    Institute of Scientific and Technical Information of China (English)

    ZHOU Qiu-Jua; BI Ya-Jing; XIANG Jun-Feng; TANG Ya-Lin; YANG Qian-Fan; XU Guang-Zhi

    2008-01-01

    A potential targeting drug delivery system consisting of folate (FA), the targeting molecule, human serum al- bumin (HSA), the carrier, and mitoxantrone (MTO), the medicine, has been designed. Data obtained by UV absorp-tion, fluorescence, and NMR techniques indicated the formation of ternary complexes and possible application to building a targeting drug delivery system by using FA, MTO and HSA. Furthermore, cytotoxicity assay indicated that the toxicity of the FA-HSA-MTO against PC-3 cell line was 79.95%, which was much higher than that of free MTO tested in totally the same conditions. About 30% increase of the toxicity should be owed to the targeting ef-fect of FA. Thus, the feasibility and validity of a novel targeting drug delivery system, FA-HSA-MTO, was con-firmed.

  12. HLA Haplotype Mismatch Transplants and Posttransplant Cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Andrea Bacigalupo

    2016-01-01

    Full Text Available The use of high dose posttransplant cyclophosphamide (PT-CY introduced by the Baltimore group approximately 10 years ago has been rapidly adopted worldwide and is becoming a standard for patients undergoing unmanipulated haploidentical (HAPLO transplants. PT-CY has been used following nonmyeloablative as well as myeloablative conditioning regimens, for bone marrow or peripheral blood grafts, for patients with malignant and nonmalignant disorders. Retrospective comparisons of HAPLO grafts with conventional sibling and unrelated donor grafts have been published and suggest comparable outcome. The current questions to be answered include the use of PT-CY for sibling and unrelated donors transplant, possibly in the context of prospective randomized trial.

  13. Vincristine-induced bystander effect in human lymphocytes.

    Science.gov (United States)

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

    2016-07-01

    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 6μM, 22±2.12 at 12μM or 28.25±5.13 at 15μM vs. a control value of 4.75±1.59. MN levels for VCR, expressed as micronucleated mononucleates were: 2.75±0.88 at 0.0μM, 27.25±2.30 at 0.4μM, 46.25±1.94 at 0.8μM, 98.25±7.25 at 1.6μM. 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 bystander effect induced by VCR. In fact, we observed an increased level of ROS, IL-32 and TGF-β in the CM from VCR treated cultures, not present in MMC treated cultures. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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

  15. Increasing the dosage of vincristine: a clinical and pharmacokinetic study of continuous-infusion vincristine in children with central nervous system tumors.

    NARCIS (Netherlands)

    Kellie, S.J.; Koopmans, P.P.; Earl, J.; Nath, C.; Roebuck, D.; Uges, D.R.A.; Graaf, S.S.N. de

    2004-01-01

    BACKGROUND: Vincristine (VCR) is widely used to treat patients with malignant disease; among the patients treated with VCR are children with brain tumors. In vitro studies have demonstrated that the cytotoxic activity of VCR is related to both extracellular concentration and duration of exposure. Th

  16. Efficacy and safety of Mitoxantrone, as an initial therapy, in multiple sclerosis: Experience in an Indian tertiary care setting

    Directory of Open Access Journals (Sweden)

    Singhal B

    2009-01-01

    Full Text Available Background and Purpose : Mitoxantrone is an approved disease modifying agent for treatment of multiple sclerosis (MS. The aim of the study was to assess its efficacy and safety in Indian MS patients. Materials and Methods : A total of 23 patients with clinically definite MS (Poser criteria were enrolled in an open label study. Of which, 21 satisfied the McDonald′s criteria for MS and two satisfied the diagnostic criteria of neuromyelitis optica (NMO. The numbers of relapses and expanded disability status scale (EDSS score were used as primary and secondary outcome measures. The patients were monitored for the adverse effects. Results : In 17 (15 MS and two NMO patients who completed one year of therapy, there was significant difference in the mean annual relapse rates [before 0.879±0.58; on mitoxantrone 0.091±0.17, (P=0.003]. Of the 17 patients, ten (MS 9 and NMO 1 completed therapy for two years. Annual relapse rates [before (1.024±0.59, on therapy (0.155±0.21, (P=0.0054] and EDSS score [before start of therapy 5.3, at the end of therapy 2.4, (P=0.001] showed significant benefit in the ten patients who completed two years therapy. This benefit persisted during the mean follow-up period of two and a half years after completion of therapy. The adverse events noted in the entire cohort were leucopenia in four patients and asymptomatic reversible decrease in cardiac ejection fraction in one patient. Leucopenia was severe in two patients requiring discontinuation of the therapy and mitoxantrone was also discontinued in the patient with cardiotoxicity. Conclusions : Mitoxantrone, as an initial therapy, decreases clinical exacerbations and disability progression, and has a reasonable safety profile in Indian patients with MS and NMO.

  17. Imaging enhancement of malignancy by cyclophosphamide: surprising chemotherapy opposite effects

    Science.gov (United States)

    Yamauchi, Kensuke; Yang, Meng; Hayashi, Katsuhiro; Jiang, Ping; Xu, Mingxu; Yamamoto, Norio; Tsuchiya, Hiroyuki; Tomita, Katsuro; Moossa, A. R.; Bouvet, Michael; Hoffman, Robert M.

    2008-02-01

    Although side effects of cancer chemotherapy are well known, "opposite effects" of chemotherapy which enhance the malignancy of the treated cancer are not well understood. We have observed a number of steps of malignancy that are enhanced by chemotherapy pre-treatment of mice before transplantation of human tumor cells. The induction of intravascular proliferation, extravasation, and colony formation by cancer cells, critical steps of metastasis was enhanced by pretreatment of host mice with the commonly-used chemotherapy drug cyclophosphamide. Cyclophosphamide appears to interfere with a host process that inhibits intravascular proliferation, extravasation, and extravascular colony formation by at least some tumor cells. Cyclophosphamide does not directly affect the cancer cells since cyclophosphamide has been cleared by the time the cancer cells were injected. Without cyclophosphamide pretreatment, human colon cancer cells died quickly after injection in the portal vein of nude mice. Extensive clasmocytosis (destruction of the cytoplasm) of the cancer cells occurred within 6 hours. The number of apoptotic cells rapidly increased within the portal vein within 12 hours of injection. However, when the host mice were pretreated with cyclophosphamide, the cancer cells survived and formed colonies in the liver after portal vein injection. These results suggest that a cyclophosphamide-sensitive host cellular system attacked the cancer cells. This review describes an important unexpected "opposite effects" of chemotherapy that enhances critical steps in malignancy rather than inhibiting them, suggesting that certain current approaches to cancer chemotherapy should be modified.

  18. Cyclophosphamide administration routine in autoimmune rheumatic diseases: a review.

    Science.gov (United States)

    Teles, Kaian Amorim; Medeiros-Souza, Patrícia; Lima, Francisco Aires Correa; Araújo, Bruno Gedeon de; Lima, Rodrigo Aires Correa

    2016-09-17

    Cyclophosphamide (CPM) 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 (pre-ChT), administration of cyclophosphamide, and post-chemotherapy (post-ChT), 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.

  19. 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.

  20. Antinociceptive effect of matrine on vincristine-induced neuropathic pain model in mice.

    Science.gov (United States)

    Linglu, Dun; Yuxiang, Li; Yaqiong, Xu; Ru, Zhou; Lin, Ma; Shaoju, Jin; Juan, Du; Tao, Sun; Jianqiang, Yu

    2014-06-01

    Chemotherapy drugs treatment causes neuropathic pain, hyperalgesia and allodynia are common components of neuropathic pain, so effectively therapeutic strategy is required. In this study, we evaluated the antinociceptive effects of matrine on vincristine-induced neuropathic pain in mice. Vincristine (100 μg/kg i.p.) was administered once per day for 7 days (day 0-6) in mice. Matrine (15, 30, 60 mg/kg, i.p.) was repeated administration in early phase (day 0-6) or late phase (day 7-13). Hyperalgesia and allodynia were evaluated by withdrawal response using von Frey filaments, plantar and cold-plate on 7, 14 and 21 day. Injection of vincristine produced mechanical hyperalgesia and cold allodynia. Matrine was found to produce a protective role in both von Frey filaments and cold-plate test. The analysis of the effect supports the hypothesis that matrine is useful in therapy of vincristine-induced neuropathic pain. In conclusion, this study demonstrates that administration of matrine is associated with antinociceptive effect on mechanical and cold stimuli in a mice model of vincristine-induced neuropathy pain.

  1. Mogoltacin enhances vincristine cytotoxicity in human transitional cell carcinoma (TCC) cell line.

    Science.gov (United States)

    Behnam Rassouli, F; Matin, M M; Iranshahi, M; Bahrami, A R; Neshati, V; Mollazadeh, S; Neshati, Z

    2009-03-01

    Bladder cancer is the second common cancer of the genitourinary system throughout the world and intravesical chemotherapy is usually used to reduce tumour recurrence and progression. Human transitional cell carcinoma (TCC) is an epithelial-like adherent cell line originally established from primary bladder carcinoma. Here we report the effect of mogoltacin, a sesquiterpene coumarin from Ferula badrakema on TCC cells. Mogoltacin was isolated from the fruits of F. badrakema, using silica gel column chromatography and preparative thin layer chromatography. Mogoltacin did not have any significant cytotoxicity effect on neoplastic TCC cells at 16, 32, 64, 128, 200 and 600 microg ml(-1) concentrations. In order to analyse its combination effect, TCC cells were cultured in the presence of various combining concentrations of mogoltacin and vincristine. Cells were then observed for morphological changes (by light microscopy) and cytotoxicity using MTT assay. The effect of mogoltacin on vincristine toxicity was studied after 24, 48 and 72 h of drug administration. The results of MTT assay showed that mogoltacin can significantly enhance the cytotoxicity of vincristine and confirmed the morphological observations. Results revealed that combination of 40 microg ml(-1) vincristine with 16 microg ml(-1) mogoltacin increased the cytotoxicity of vincristine after 48 h by 32.8%.

  2. Effect of Cyclophosphamide on Neural Tube Development in Chick Embryos

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    SHABANA SULTANA

    2014-06-01

    Full Text Available Cyclophosphamide is a nitrogen mustard alkylating agent. CP has potent immunosuppressive properties and issued clinically in a number of autoimmune disorders like Wegener’s granulomatosis, rheumatoid arthritis, nephritic syndrome, systemic lupus erythematous and has also been used to prevent organ rejection after transplantation. In the present study fertilized eggs were administered with cyclophosphamide and the development of neural tube was studied after 21 days. The histological and gross features of neural tube were identified. Cyclophosphamide cytotoxicity results in depression of proliferation of cell activity associated with malformations and embryonic death. Injection of the drug causes depression of mitotic activity by day 2 which produces malformations.

  3. Unusual nail pigmentation following cyclophosphamide-containing chemotherapy regimen

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    Kumar Santosh

    2010-01-01

    Full Text Available Cyclophosphamide therapy may rarely cause pigmentation of the nails which is of different patterns. We report a patient who developed pigmentation of nails after six cycles of cyclophosphamide, methotrexate, and 5-flourouracil chemotherapy, each repeated after 28 days for breast cancer. The patient developed nail pigmentation that started proximally and spread distally and involved all the nails of both hands and feet except the second and third toenails of right foot. Using Naranjo ADR Probability Scale, the case revealed a "probable" association with cyclophosphamide.

  4. Reversal of in vitro cellular MRP1 and MRP2 mediated vincristine resistance by the flavonoid myricetin

    NARCIS (Netherlands)

    Zanden, van J.J.; Mul, de A.; Wortelboer, H.M.; Usta, M.; Bladeren, van P.J.; Rietjens, I.M.C.M.; Cnubben, N.H.P.

    2005-01-01

    In the present study, the effects of myricetin on either MRP1 or MRP2 mediated vincristine resistance in transfected MDCKII cells were examined. The results obtained show that myricetin can inhibit both MRP1 and MRP2 mediated vincristine efflux in a concentration dependent manner. The IC50 values fo

  5. Effectiveness of Pyridoxine and Pyridostigmine in the Treatment of Vincristine-Induced Bilateral Ptosis and External Ophthalmoplegia: A Case Report

    Directory of Open Access Journals (Sweden)

    Osman Okan Olcaysu

    2014-08-01

    Full Text Available In this manuscript, we present the case of a patient with acute lymphoblastic leukemia who developed vincristine-induced bilateral ptosis and external ophthalmoplegia and who was treated successfully with pyridoxine and pyridostigmine. Pyridostigmine and pyridoxine are promising treatment option in cases of vincristine-induced neuropathy. (Turk J Ophthalmol 2014; 44: 330-1

  6. Effectiveness of Pyridoxine and Pyridostigmine in the Treatment of Vincristine-Induced Bilateral Ptosis and External Ophthalmoplegia: A Case Report

    OpenAIRE

    2014-01-01

    In this manuscript, we present the case of a patient with acute lymphoblastic leukemia who developed vincristine-induced bilateral ptosis and external ophthalmoplegia and who was treated successfully with pyridoxine and pyridostigmine. Pyridostigmine and pyridoxine are promising treatment option in cases of vincristine-induced neuropathy. (Turk J Ophthalmol 2014; 44: 330-1)

  7. Multifunctional hyaluronic acid modified graphene oxide loaded with mitoxantrone for overcoming drug resistance in cancer

    Science.gov (United States)

    Hou, Lin; Feng, Qianhua; Wang, Yating; Yang, Xiaomin; Ren, Junxiao; Shi, Yuyang; Shan, Xiaoning; Yuan, Yujie; Wang, Yongchao; Zhang, Zhenzhong

    2016-01-01

    Multifunctional nanosheets (HA-GO/Pluronic) with targeted chemo-photothermal properties were successfully developed for controlled delivery of mitoxantrone (MIT) to overcome multidrug resistance (MDR). In vitro release profiles displayed that both an acidic environment and a NIR laser could trigger and accelerate the release of a drug, which ensured nanosheets were stable in blood circulation and released MIT within tumor cells under laser irradiation. HA-GO/Pluronic nanosheets were taken up into MCF-7/ADR cells via receptor-mediated endocytosis, which further facilitated escapement of P-gp efflux. Compared with MIT solution, MIT/HA-GO/Pluronic showed greater cytotoxicity and increase in cellular MIT accumulation in MCF-7/ADR cells. Cell apoptosis and cell cycle arrest studies also revealed that MIT/HA-GO/Pluronic was more potent than MIT/GO/Pluronic and MIT solution. The anticancer efficacy in vivo was evaluated in MCF-7 and MCF-7/ADR-bearing mice, and inhibition of tumors by MIT/HA-GO/Pluronic with NIR laser irradiation was the most effective among all MIT formulations. In summary, the MIT/HA-GO/Pluronic system had striking functions such as P-gp reversible inhibitor and anticancer efficacy, and could present a promising platform for drug-resistant cancer treatment.

  8. Chromium(VI) but not chromium(III) species decrease mitoxantrone affinity to DNA.

    Science.gov (United States)

    Nowicka, Anna M; Stojek, Zbigniew; Hepel, Maria

    2013-01-31

    Binding of mitoxantrone (MXT) to double-stranded DNA has been investigated as a model drug-DNA binding system to evaluate the effects of various forms of chromium on the binding properties. We have found that Cr(III), which binds strongly to DNA, does not affect the MXT affinity to DNA. In contrast, Cr(VI), in the form of chromate ions CrO(4)(2-), decreases the MXT affinity to DNA despite electrostatic repulsions with phosphate-deoxyribose chains of DNA. The MXT-DNA binding constant was found to decrease from (1.96 ± 0.005) × 10(5) to (0.77 ± 0.018) × 10(5) M(-1) for Cr(VI) concentration changing from 0 to 30 μM. The influence of Cr(VI) on MXT-DNA binding has been attributed to the oxidation of guanine residue, thus interrupting the intercalation of MXT into the DNA double helix at the preferential CpG intercalation site. This supposition is corroborated by the observed increase in the MXT binding site size from 2 bp (base pairs) to 4-6 bp in the presence of Cr(VI). The measurements of the MXT-DNA binding constant and the MXT binding site size on a DNA molecule have been carried out using spectroscopic, voltammetric, and nanogravimetric techniques, providing useful information on the mechanism of the interactions.

  9. Mitoxantrone in the treatment of multiple sclerosis: a single-center experience

    Directory of Open Access Journals (Sweden)

    Özlem Taşkapılıoğlu

    2012-06-01

    Full Text Available OBJECTIVE: To investigate the secondary progressive multiple sclerosis (SPMS patients treated with mitoxantrone (MIT and discuss the effectiveness and side effects of MIT. METHODS: We retrospectively investigated 48 SPMS patients who completed or were still receiving MIT treatment. Expanded Disability Status Scale (EDSS scores of the patients were determined who had detailed examination before the treatment. Complete blood count, urine examination, chest x-ray, kidney and liver function tests, transthoracic echocardiography were performed at initiation and during follow-up and 10 mg/m2 MIT was administered every three months. The data were assessed in order to determine the effectiveness and side effects. RESULTS: A total of 48 patients, 34 women and 14 men, had an age of 42 (26-55 years at the initiation of MIT treatment. The duration of the treatment was 12 (3-30 months. The median EDSS scores were 6 (4-8 before the treatment and 6 (4-9 after the treatment. EDSS scores improved in 6 patients, deteriorated in 12 patients and 30 patients remained with stable EDSS scores during the treatment. Seventeen patients had no side effects however 31 patients developed side effects. CONCLUSION: On the basis of this study, which is a clinical assessment of the effectiveness and side effects of MIT, we conclude that MIT can limit disability in SPMS patients and it is useful in treating SPMS patients due to favorable risk-benefit ratio.

  10. Improved anti-melanoma effect of a transdermal mitoxantrone ethosome gel.

    Science.gov (United States)

    Yu, Xiang; Du, Lina; Li, Yu; Fu, Guiying; Jin, Yiguang

    2015-07-01

    Melanomas are malignant tumors characterized by early metastasis, rapid development, poor prognosis and high mortality. A highly effective and convenient method is necessary for long-term treatment of melanomas. Mitoxantrone (MTO) was topically applied for melanoma therapy using an MTO ethosome gel. Firstly, an ethosome was prepared from MTO, phospholipids, ethanol and water followed by addition of hydroxypropyl methylcellulose to obtain an ethosome gel. The ethosome was characterized. The cytotoxicity on B16 melanoma cells was evaluated on an electrical cell-substrate impedance sensing system with a novel modified chip. In vivo anti-melanoma effect of the ethosome gel was explored. Immunohistochemical and flow cytometric investigations were done. The MTO ethosomes had the size of 78nm and the zeta potential of -55mV. The ethosomes were flexible vesicles and showed much higher in vitro permeability across the rat skin than MTO aqueous solutions. The ethosomes had significant cytotoxicity and higher in vivo anti-melanoma effect than MTO solutions. The calreticulin membrane translocation of B16 cells was improved by the MTO ethosomes and the cell uptake of MTO was confirmed. The MTO ethosome gel is a promising transdermal delivery system for melanoma therapy with the advantages of non-invasion and no significant side effects.

  11. Vincristine-induced peripheral neuropathy in a neonate with congenital acute lymphoblastic leukemia.

    Science.gov (United States)

    Baker, Steven K; Lipson, David M

    2010-04-01

    We report the case of a 46-day-old boy with a fulminant vincristine-induced peripheral neuropathy after treatment for congenital acute lymphoblastic leukemia. Flaccid paralysis developed at the end of the first phase of induction, requiring intubation and ventilation for 51 days. Treatment was initiated with levocarnitine, N-acetylcysteine, and pyridoxine and progressive reversal of the neuropathy occurred over the next 4 months. Potential differences in pathogenesis and presentation of vincristine neurotoxicity and Guillian-Barre syndrome in the neonate are discussed.

  12. Clinical Presentation of Inadvertent Intrathecal Vincristine Masquerading Guillain-Barre Syndrome.

    Science.gov (United States)

    Saha, Agni Sekhar; Islam, Md Fekarul; Bhattacharya, Sukanta; Giri, Prabhas Prasun

    2016-06-01

    Vincristine, a potent chemotherapeutic agent, is highly neurotoxic. If given intrathecally by accident it is almost always fatal. We are reporting a 6 year old girl with acute lymphoblastic leukaemia in complete remission, who was given inadvertent intrathecal Vincristine instead of Methotrexate. She developed gradually progressive quadriplegia and respiratory paralysis requiring prolonged mechanical ventilation, initially mimicking Guillain-Barre Syndrome, both clinically and electro-physiologically. She also developed progressive encephalopathy. The clinical deterioration subsequently plateaued without any significant improvement and after more than 5 months, she finally expired.

  13. SPERM MATURATIONAL DEFECT AFTER CYCLOPHOSPHAMIDE TREATMENT

    Directory of Open Access Journals (Sweden)

    Z. N. Kashmiri

    2014-06-01

    Full Text Available During normal spermatogenesis, most of the round spermatid’s cytoplasm was phagocytosed as ‘residual bodies’ by the Sertoli cell at spermiogenesis, and only a small cytoplasmic residue i.e. ‘cytoplasmic droplet’ remains applied to the elongated spermatid after release from the germinal epithelium. A characteristic morphological change on spermatozoa during epididymal transit was the caudal migration of the cytoplasmic droplet away from the neck via the principal piece, however, while studying the Cyclophosphamide (CPA induced sperm morphological changes from the cauda epididymis in male Wistar rat, Rattus norvegicus using phase contrast microscope it was noticed that the sub-chronic and acute doses of CPA caused retention of cytoplasmic droplet on the mid-piece. Thus from the foregoing it was concluded that beside CPA being an inhibitor of spermatogenesis, it also interferes with the maturation of spermatozoa by the retention of cytoplasmic droplet perhaps due to alteration in epididymal secretory and absorptive functions thus leading to infertility.

  14. Enantioselective induction of cyclophosphamide metabolism by phenytoin.

    Science.gov (United States)

    Williams, M L; Wainer, I W; Embree, L; Barnett, M; Granvil, C L; Ducharme, M P

    1999-01-01

    The objective of this study was to investigate the effect of phenytoin (PHE) on cyclophosphamide (CP) disposition. CP was administered to 6 adult patients in a preparative regimen for bone marrow transplantation consisting of busulfan and CP. Three of the patients received PHE and the other 3 "control" patients received diazepam (DZP) as anti-epileptic prophylactic treatment. Plasma samples were collected at intervals up to 24 h after CP administration. The plasma concentrations of (R)- and (S)-CP and their respective N-dechloroethylated metabolites, (R)- and (S)-DCE-CP were simultaneously fitted using an enantiospecific 2-compartment pharmacokinetic (PK) model with Bayesian control estimation. DZP had no significant effect on the metabolism of CP and any of its PK parameters. PHE, however, increased significantly the formation of (S)-DCE-CP while having no effect on the formation of (R)-DCE-CP. These results suggest that different enzymes are responsible for the formation of (S)-DCE-CP from (S)-CP and (R)-DCE-CP from (R)-CP. Additionally, assuming that PHE does not affect the passive renal elimination of (R)- and (S)-CP, this analysis suggests that the clearance of both (R)- and (S)-CP to 4-hydroxy-CP (the activation pathway) is increased by PHE.

  15. Pistachio supplementation attenuates motor and cognition impairments induced by cisplatin or vincristine in rats

    Directory of Open Access Journals (Sweden)

    Leila Golchin

    2015-01-01

    Conclusion: We conclude that pistachio in the diet following anticancer drugs such as cisplatin and vincristine might have a protective effect against anticancer drug-induced disruptions in motor and cognitive function. However, further studies are needed to elucidate the exact mechanisms of this protective effect of pistachio.

  16. Malnourished Malawian patients presenting with large Wilms tumours have a decreased vincristine clearance rate

    NARCIS (Netherlands)

    T. Israels; C.W.N. Damen; M. Cole; N. van Geloven; A.V. Boddy; H.N. Caron; J.H. Beijnen; E.M. Molyneux; G.J. Veal

    2010-01-01

    Introduction: In developing countries, patients with a Wilms' tumour often present late with a high degree of malnutrition and large tumours. We investigated whether this affects vincristine pharmacokinetics. Methods: Patients newly diagnosed with Wilms' tumour in Malawi and the UK were included. We

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

    NARCIS (Netherlands)

    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 blood-bra

  18. Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing: a surrogate marker of brain penetration.

    NARCIS (Netherlands)

    Kellie, S.J.; Barbaric, D.; Koopmans † , P.P.; Earl, J.; Carr, D.J.; Graaf, S.S.N. de

    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 blood-bra

  19. [Effect of vincristine on molar development and jaw growth in rats].

    Science.gov (United States)

    Sedlecki, S; Jakovljević, A; Pap, K

    1989-01-01

    A cystostatic of group Vinca-alcaloides, Vincristine, is often used in chemotherapy. As a microtubular poison it reacts with microtubular molecules of cell cytoplasma and in response to dose administrated decelerates or stops cell division. Since the information about the effect of this drug on molar teeth has not been found in available literature the aim of this study was to investigate the effect of vincristine on tooth development and jaw growth in rats. The experiment was carried out on Wistar rats of both sexes. Vincristine (Oncovin, "Lilly") was injected to animals in the dose of 0.1 mg/kg b.w. seven or eight days following birth. Treated and control animals were sacrificed on the 24th postnatal day. Radiographs of the mandibule were used to study tooth development. The morphometric examination concerned the following parameters: in maxillar frontal and posterior arc width and height; vertical and sagital dimension as well as length of incisive crown in the mandibule. The results of the analysis suggested that the teeth of treated rats were retarded in development compared to the control animals. Morphometric investigations showed that in treated rats both jaws were decelerated in growth in comparison to the control group but with no statistical significance. It should be emphasized that a 16-day-period was too short that full efficet of Vincristine should be established in rats and lead to a result which could suggest a certain molar development and jaw growth.

  20. The impact of mitoxantrone on neurological disability in active multiple sclerosis patients

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    Mesaroš Šarlota

    2004-01-01

    Full Text Available Several in vivo and in vitro studies showed that mitoxantrone (MTX, a novel anthracendione antineoplastic agent, had an immunomodulatory effect that suppressed humoral immunity, reduced T-cell numbers, lessened helper activity, enhanced suppressor function and had some positive effect on acute and chronic experimental allergic encephalomyelitis in rats. Up to now, several trials of therapy with MTX have been performed in patients with multiple sclerosis (MS. MTX has been recently shown to reduce disease activity, as expressed by reducing relapse rate and decreasing new, active MRI lesions, in a selected group of patients with active relapsing-remitting (RR MS. Furthermore, more recently, it has been demonstrated that MTX reduce neurological disability in secondary progressive MS. We designed the open-label clinical trial involving 35 MS patients with active disease in order to evaluate the long-term clinical effects of 6-months MTX treatment during a follow-up period of 20-46 months (mean, 30 months. The study comprised 35 patients, who met the Poser criteria for clinically definite MS. All patients were clinically treated at the Institute of Neurology, Clinical Centre of Serbia, Belgrade, during the period from March 1996 to August 2000. The neurological disability state was evaluated at the entry, every month until completion of the therapy and every six months until August 2000, by means of Kurtzke Expanded Disability Status Scale (EDSS score. All patients had active MS. The criteria for disease activity were: 1 at least 2 relapses within the previous 2 years, or 2 progression of at least 1.0 point on EDSS scale during the same period. The included patients did not receive immunosuppressive therapy six months prior to the entry. The patients were assigned to receive MTX 20 mg intravenously (iv per month and methylprednisolone 1g iv per month, over six months. The clinical characteristics and demographic data of patients included in the study

  1. Pulmonary intravascular large B-cell lymphoma successfully treated with rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone immunochemotherapy: Report of a patient surviving for over 1 year

    OpenAIRE

    NISHII-ITO, SHIZUKA; Izumi, Hiroki; Touge, Hirokazu; TAKEDA, KENICHI; Hosoda, Yuzuru; Yamasaki, Akira; Kuwamoto, Satoshi; Shimizu, Eiji; Motokura, Toru

    2016-01-01

    A 73-year-old man with a history of lethargy, fever and dyspnea was admitted to Tottori University Hospital. A computed tomography (CT) scan revealed splenomegaly and diffusely spreading ground-glass opacities (GGOs) in both lungs. A video-assisted thoracoscopic surgery (VATS)-guided lung biopsy revealed intravascular proliferation of large atypical lymphoid cells in the arteries, veins and alveolar walls. The patient was diagnosed with intravascular large B-cell lymphoma (IVLBCL); he receive...

  2. [Combination chemotherapy with POMB/ACE (cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide) in advanced non-seminomatous testicular tumor].

    Science.gov (United States)

    Masuda, F; Kawahara, M; Asano, K; Shirakawa, H

    1995-10-01

    Four cases with non-seminomatous testicular tumor in stage III completed chemotherapy with POMB/ACE. Of these 4 cases, metastasis to retroperitoneal lymph nodes was found in all of them. In addition, metastasis to the lung was noted in 3, and to the left supraclavicular lymph nodes in one. After orchiectomy, 5 courses of POMB/ACE therapy were given to each of the 4 cases. Tumor marker returned to normal value in all of the cases after 3-4 courses of treatment, with disappearance of metastasis to the lung and supraclavicular lymph nodes. However, the response rate in metastasis to retroperitoneal lymph nodes was CR in one case, and PR in 3. Therefore, retroperitoneal lymph nodes were excised in all 3 cases. Histologically, 2 of the 3 were found to have necrotic tissues. The remaining one patient had teratoma. An additional 1-3 courses of POMB/ACE therapy were given to these 3 cases. These 4 cases are alive without recurrence 6 years and 4 months, 5 years and 8 months, 4 years and 9 months, and 2 years 9 months, respectively, after orchiectomy. Thus POMB/ACE therapy is considered to be a useful method in the treatment of advanced testicular tumor.

  3. Human Chorionic Gonadotropin (hCG) Regression Curve for Predicting Response to EMA/CO (Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide and Vincristine) Regimen in Gestational Trophoblastic Neoplasia.

    Science.gov (United States)

    Rattanaburi, Athithan; Boonyapipat, Sathana; Supasinth, Yuthasak

    2015-01-01

    An hCG regression curve has been used to predict the natural history and response to chemotherapy in gestational trophoblastic disease. We constructed hCG regression curves in high-risk gestational trophoblastic neoplasia (GTN) treated with EMA/CO and identified an optimal hCG level to detect EMA/CO resistance in GTN. Eighty-one women with GTN treated with EMA/CO were classified as primary high-risk GTN (n=65) and single agent-resistance GTN (n=16). The hCG levels prior to each course of chemotherapy were plotted in the 10th, 50th, and 90th percentiles to construct the hCG regression curves. Diagnostic performance was evaluated for an optimal cut-off value. The median hCG levels were 264,482 mIU/mL mIU/mL and 495.5 mIU/mL mIU/mL for primary high-risk GTN and single agent-resistance GTN, respectively. The 50th percentile of the hCG level in primary high-risk GTN and single agent-resistance turned to normal before the 4th and the 2nd course of chemotherapy, respectively. The 90th percentile of the hCG level in primary high-risk GTN and single agent-resistance turned to normal before the 9th and the 2nd course of chemotherapy, respectively. The hCG level of ≥118.6 mIU/mL mIU/mL at the 5thcourse of EMA/CO predicted the EMA/CO resistance in primary high-risk GTN patients with a sensitivity of 85.7% and a specificity of 100%. EMA/CO resistance in primary high-risk GTN can be predicted by using an hCG regression curve in combination with the cut-off value of 118.6 mIU/mL at the 5thcourse of chemotherapy.

  4. Relapse in childhood acute lymphoblastic leukemia after elective cessation of initial treatment: failure of subsequent treatment with cyclophosphamide, cytosine arabinoside, vincristine and prednisone (COAP).

    Science.gov (United States)

    Sallan, S E; Hitchcock-Bryan, S

    1981-01-01

    Although the majority of children with acute lymphoblastic leukemia (ALL) can electively stop treatment after 2 1/2-5 years of continuous disease-free remission, 20-25% of those patients relapse after discontinuation of therapy. We treated 15 patients whose disease recurred after stopping treatment. Fourteen of them attained complete remission, but the median duration of disease-free survival was only 11 months. In this population, the site of initial relapse, bone marrow or testicle, did not influence subsequent outcome. Patients who relapsed within six months of stopping initial therapy had shorter second remissions than those who relapsed after six months. We conclude that the combination chemotherapy utilized in this study was inadequate for the control of relapsed ALL. Future programs will have to use different drug combinations or bone marrow transplantation.

  5. Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone.

    Directory of Open Access Journals (Sweden)

    Kemal Alpay

    Full Text Available Although c-Abl has increasingly emerged as a key player in the DNA damage response, its role in this context is far from clear. We studied the effect of inhibition of c-Abl kinase activity by imatinib with chemotherapy drugs and found a striking difference in cell survival after combined mitoxantrone (MX and imatinib treatment compared to a panel of other chemotherapy drugs. The combinatory treatment induced apoptosis in HeLa cells and other cancer cell lines but not in primary fibroblasts. The difference in MX and doxorubicin was related to significant augmentation of DNA damage. Transcriptionally active p53 accumulated in cells in which human papillomavirus E6 normally degrades p53. The combination treatment resulted in caspase activation and apoptosis, but this effect did not depend on either p53 or p73 activity. Despite increased p53 activity, the cells arrested in G2 phase became defective in this checkpoint, allowing cell cycle progression. The effect after MX treatment depended partially on c-Abl: Short interfering RNA knockdown of c-Abl rendered HeLa cells less sensitive to MX. The effect of imatinib was decreased by c-Abl siRNA suggesting a role for catalytically inactive c-Abl in the death cascade. These findings indicate that MX has a unique cytotoxic effect when the kinase activity of c-Abl is inhibited. The treatment results in increased DNA damage and c-Abl-dependent apoptosis, which may offer new possibilities for potentiation of cancer chemotherapy.

  6. Preparation and functional characterization of tumor-targeted folic acid-chitosan conjugated nanoparticles loaded with mitoxantrone

    Institute of Scientific and Technical Information of China (English)

    王炜; 童春义; 刘星言; 李涛; 刘斌; 熊炜

    2015-01-01

    Folic acid conjugated chitosan was prepared by cross-linking reaction with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), and then used as a template to prepare folic acid-chitosan (FA-CS) conjugated nanoparticles and load mitoxantrone nanoparticles (FA-CSNP/MTX). Drug dissolution testing, CCK-8 method, and confocal microscopy were used to detect their controlled-release capability in different situations and the specific uptake by HONE1 cells. The experimental results show that the nanoparticles have uniform size distribution of 48−58 nm. The highest encapsulation rate of the particles on mitoxantrone hydrochloride (MTX) is (77.5±1.9)%, and the drug loading efficiency is (18.4±0.4)%. The sustained release effect, cell growth inhibition activity and targeting effect of the FA-CS/MTX nanoparticles are good in artificial gastric fluid and intestinal fluid. It is demonstrated that the FA-CSNP system is a potentially useful system for the targeted delivery of anticancer drug MTX.

  7. Daunorubicin Versus Mitoxantrone Versus Idarubicin As Induction and Consolidation Chemotherapy for Adults With Acute Myeloid Leukemia: The EORTC and GIMEMA Groups Study AML-10

    Science.gov (United States)

    Mandelli, Franco; Vignetti, Marco; Suciu, Stefan; Stasi, Roberto; Petti, Maria-Concetta; Meloni, Giovanna; Muus, Petra; Marmont, Filippo; Marie, Jean-Pierre; Labar, Boris; Thomas, Xavier; Di Raimondo, Francesco; Willemze, Roel; Liso, Vincenzo; Ferrara, Felicetto; Baila, Liliana; Fazi, Paola; Zittoun, Robert; Amadori, Sergio; de Witte, Theo

    2009-01-01

    Purpose To compare the antitumor efficacy of three different anthracyclines in combination with cytarabine and etoposide in adult patients with newly diagnosed acute myeloid leukemia (AML). Patients and Methods We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive induction-consolidation chemotherapy containing either daunorubicin, idarubicin, or mitoxantrone. After achieving complete remission (CR), patients were assigned to undergo either allogeneic or autologous stem-cell transplantation (SCT), depending on the availability of a sibling donor. Results The overall CR rate (69%) was similar in the three groups. Autologous SCT was performed in 37% of cases in the daunorubicin arm versus only 29% and 31% in mitoxantrone and idarubicin, respectively (P < .001). However, the disease-free survival (DFS) and survival from CR were significantly shorter in the daunorubicin arm: the 5-year DFS was 29% versus 37% and 37% in mitoxantrone and idarubicin, respectively. The proportion of patients who underwent allogeneic SCT (22%) was equivalent in the three treatment groups, and the outcome was similar as well: the 5-year overall survival rates were 34%, 34%, and 31%, respectively. Conclusion In adult patients with AML who do not receive an allogeneic SCT, the use of mitoxantrone or idarubicin instead of daunorubicin enhances the long-term efficacy of chemotherapy. PMID:19826132

  8. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial

    DEFF Research Database (Denmark)

    de Bono, Johann Sebastian; Oudard, Stephane; Ozguroglu, Mustafa;

    2010-01-01

    Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer...

  9. Phase I Study of Valspodar (PSC-833) with Mitoxantrone and Etoposide in Refractory and Relapsed Pediatric Acute Leukemia: A Report from the Children’s Oncology Group

    Science.gov (United States)

    O’Brien, Maureen M.; Lacayo, Norman J.; Lum, Bert L.; Kshirsagar, Smita; Buck, Steven; Ravindranath, Yaddanapudi; Bernstein, Mark; Weinstein, Howard; Chang, Myron N.; Arceci, Robert J.; Sikic, Branimir I.; Dahl, Gary V.

    2009-01-01

    Background Valspodar, a non-immunosuppressive analog of cylosporine, is a potent P-glycoprotein (MDR1) inhibitor. As MDR1-mediated efflux of chemotherapeutic agents from leukemic blasts may contribute to drug resistance, a phase 1 study of valspodar combined with mitoxantrone and etoposide in pediatric patients with relapsed or refractory leukemias was performed. Procedure Patients received a valspodar loading dose (2 mg/kg) followed by a five-day continuous valspodar infusion (8, 10, 12.5 or 15 mg/kg/day) combined with lower than standard doses of mitoxantrone and etoposide. The valspodar dose was escalated using a standard 3 + 3 phase I design. Results 21 patients were evaluable for toxicity and 20 for response. The maximum tolerated dose (MTD) of valspodar was 12.5 mg/kg/day, combined with 50% dose-reduced mitoxantrone and etoposide. The clearance of mitoxantrone and etoposide was decreased by 64% and 60%, respectively, when combined with valspodar. Dose-limiting toxicities included stomatitis, ataxia, and bone marrow aplasia. Three of 11 patients with acute lymphoblastic leukemia (ALL) had complete responses while no patient with acute myeloid leukemia (AML) had an objective response. In vitro studies demonstrated P-glycoprotein expression on the blasts of five of 14 patients, although only one had inhibition of rhodamine efflux by valspodar. Conclusions While this regimen was tolerable, responses in this heavily pretreated population were limited to a subset of patients with ALL. PMID:20209646

  10. Cyclophosphamide in the treatment of toxic epidermal necrolysis.

    Science.gov (United States)

    Frangogiannis, N G; Boridy, I; Mazhar, M; Mathews, R; Gangopadhyay, S; Cate, T

    1996-10-01

    A patient with non-small cell lung carcinoma and recent radiotherapy for brain metastases developed toxic epidermal necrolysis (TEN) shortly after therapy with phenytoin was initiated for a seizure. Exfoliation progressed to involve 90% of her body surface despite treatment with high-dose corticosteroids for 5 days, but sloughing and systemic toxicity ceased within 2 days of initiating therapy with intravenous cyclophosphamide (300 mg/day). Reepithelialization rapidly followed. This experience and the reports of others suggest that intravenous cyclophosphamide is helpful in the treatment of TEN.

  11. A randomized trial of cyclophosphamide, doxorubicin, and prednisone versus cyclophosphamide, 5-fluorouracil, and prednisone in patients with metastatic breast cancer.

    Science.gov (United States)

    Ahmann, D L; Schaid, D J; Ingle, J N; Bisel, H F; Schutt, A J; Buckner, J C; Long, H J; Rubin, J

    1991-06-01

    Ninety-four patients were entered in a clinical trial assessing the clinical activity of cyclophosphamide, doxorubicin, and prednisone (CAP) versus a combination of cyclophosphamide. 5-Fluorouracil, and prednisone (CFP) in patients with advanced breast cancer. Objective response rates were comparable, 49% for CFP and 46% for CAP. There was no statistical difference between the duration of response of the two regimens or in time to progression. Most importantly, survival differences were not apparent. Both regimens were clinically tolerable and toxicities, for the most part, were comparable. Thus, no therapeutic advantage existed for either of these polychemotherapy regimens in patients with advanced breast cancer.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Intralesional vincristine use for treatment of squamous cell carcinoma in a puma (Puma concolor).

    Science.gov (United States)

    Sandoval, Blanca Juarez; Amat, Azlan Che'; Sabri, Jasni; Ramli, Mat Naim

    2013-12-01

    A 14-yr-old male puma (Puma concolor) was presented to the veterinary staff of the National Zoo in Malaysia for an auricular mass. Squamous cell carcinoma was diagnosed by histologic examination of a biopsy. Systemic administration of chemotherapy using vincristine (0.5 mg/m2 i.v. q. 7 days for six treatments) and prednisolone (2 mg/kg i.m. q. 72 hr x 7 days) caused side effects of vomiting, weight loss, and alopecia and did not improve the size or appearance of the tumor. Intralesional vincristine injections (0.2 mg q. 7 days for two treatments) and prednisolone (2 mg/kg i.m. q. 72 hr x 15 days) were administered, resulting in complete tumor regression after 14 days of treatment.

  14. Syndrome of recurrent increased secretion of antidiuretic hormone following multiple doses of vincristine.

    Science.gov (United States)

    Stuart, M J; Cuaso, C; Miller, M; Oski, F A

    1975-03-01

    The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been recognized to occur following treatment with vincristine. None of the reports have provided information regarding its potential for recurrence on further challenge with vincristine (VCR), an agent generally required for repeated use in patients with malignancies. Symptomatic hyponatremia and SIADH that occurred 8 days following administration of VCR in a child with acute lymphatic leukemia was documented with specific radioimmunoassay of urinary ADH levels. The further occurrence of recurrent elevations in ADH excretion 8-10 days following repeated treatment with VCR was also observed. However, SIADH was prevented by prophylactic rigorous fluid restriction. The occurrence of SIADH following VCR therefore does not preclude the further safe usage of this drug.

  15. Assessment of the therapeutic benefit of dexamethasone cyclophosphamide pulse versus only oral cyclophosphamide in phase II of the dexamethasone cyclophosphamide pulse therapy: A preliminary prospective randomized controlled study

    Directory of Open Access Journals (Sweden)

    Nisha V Parmar

    2013-01-01

    Full Text Available Background: Dexamethasone cyclophosphamide pulse (DCP therapy is an established mode of treatment for pemphigus in India. Aims: To assess the therapeutic benefit of additional DCPs (phase II, consolidation phase versus immediate oral cyclophosphamide, usually used in phase III (maintenance phase, after initial DCP therapy (phase I and to assess which laboratory test (DIF or ELISA will reflect the clinical relapse best. Methods: Nineteen newly recruited patients of pemphigus vulgaris (PV received monthly DCPs in phase I and were then randomized into two groups. Group A (10 patients received monthly DCPs for nine months and Group B (nine patients received only oral cyclophosphamide for nine months. Direct immunofluorescence (DIF and enzyme-linked immunosorbent assay (ELISA were tested before starting DCP regimen, and at 0,3,6,9 months after randomization. Results: Clinical relapse by the end of follow-up period occurred in only one patient in each group. In these cases, DIF became (again positive before the relapse. No statistically significant difference between the two groups was found at three, six and nine months by ELISA indices and DIF grading. Conclusion: Although the DCP regimen is the standard therapy for pemphigus in India, we found no difference in the clinical outcome between patients receiving nine DCPs in phase II and patients shifted directly from phase I to III. Periodic testing using DIF and Dsg ELISA were found to be useful to monitor disease activity and predict a relapse. Further large scale studies are required to assess if patients can be shifted directly from phase I to III and maintained only on oral cyclophosphamide.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Differential display of vincristine-resistance-related genes in gastric cancer SGC7901 cells

    Institute of Scientific and Technical Information of China (English)

    Xin Wang; Bo-Rong Pan; Jian-Ping Jin; Dai-Ming Fan; Mei Lan; Yong-Quan Shi; Ju Lu; Yue-Xia Zhong; Han-Ping Wu; Hui-Hong Zai; Jie Ding; Kai-Cun Wu

    2002-01-01

    AIM: To isolate and clone the vincristine-resistine-relatedgenes in gastric cancer SGC7901 cell line and to clarify themultidrug-resistant molecular mechanism of gastric cancercells.METHODS: The modified differential-display polymerasechain reaction (DD-PCR) was used to examine thedifferences in the mRNA composition of Vincristine-resistantgastric cancer SGC 7901 cells (SGC7901/VCR), induced byvincristine sulfate versus SGC7901cells. The differentiallyexpressed cDNA fragments were confirmed byreverseNorthern analysis, sequencing, BLAST analysis andNorthern bolt analysis.RESULTS: DD-PCR identified that 54 cDNA fragments werepreferentially expressed in SGC 7901/VCR cells. When thesecDNA fragments were analyzed by reverseNorthern blot, 20were reproducibly expressed at a high level in SGC7901/VCR. Sequencing and BLAST analysis revealed that sevenof the genes were known genes: ADP-ribosylation factor 4,cytochrorne oxidase subunit Ⅱ, Ss-A/Ro ribonucleoprteinautoantigen 60kd subunit, ribosomal protein S13, galaectin-8 gene, oligophrenin 1 mRNA, and ribosomal protein L23mRNA; and thirteen of the genes were unknown genes. Thelength and abundance of the four unknown genes mRNAwere further confirmed by Northern blot analysis.CONCLUSION: The twenty differential known and unknowngenes may be related to the vincristine-resistant mechanismin human gastric cancer SGC7901 cell line.

  18. Cardanol: toxicogenetic assessment and its effects when combined with cyclophosphamide

    Directory of Open Access Journals (Sweden)

    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.

  19. Clinical efficacy of cyclophosphamide in treatment of primary sclerosing cholangitis

    Institute of Scientific and Technical Information of China (English)

    程鹏

    2014-01-01

    Objective To investigate the clinical efficacy of cy-clophosphamide in the treatment of primary sclerosing cholangitis(PSC).Methods Twenty-four patients with PSC who received treatment in the department of gastroenterology in our hospital from January 2004 to December2012 were selected as subjects and divided into observation group(n=13)and control

  20. Effects of chlordiazepoxide, diazepam and oxazepam on the antitumor activity, the lethality and the blood level of active metabolites of cyclophosphamide and cyclophosphamide oxidase activity in mice.

    Science.gov (United States)

    Sasaki, K; Furusawa, S; Takayanagi, G

    1983-10-01

    Effects of chlordiazepoxide, diazepam and oxazepam on the antitumor activity and acute toxicity of cyclophosphamide and the level of its active metabolites in the plasma were investigated in mice. Cyclophosphamide was administered 24 h after the final injection of chlordiazepoxide, diazepam or oxazepam (100 mg/kg/d for 3 d, i.p.). Pretreatment with these drugs increased the acute toxicity of cyclophosphamide (300 or 450 mg/kg, i.p.), whereas drugs had no effect on the antitumor activity of cyclophosphamide (100 mg/kg, i.p.) against Ehrlich solid carcinoma. A high level of active metabolites of cyclophosphamide in the plasma after the administration of cyclophosphamide (300 or 450 mg/kg, i.p.) was observed in chlordiazepoxide-, diazepam- or oxazepam-treated mice. On the other hand, chlordiazepoxide, diazepam or oxazepam enhanced significantly the activity of cyclophosphamide oxidase in hepatic microsomes. It is concluded that potentiation of the acute toxicity at a high dose of cyclophosphamide by chlordiazepoxide, diazepam and oxazepam is due to an induction of microsomal drug-metabolizing enzyme which are responsible for the in vivo activation of cyclophosphamide.

  1. Cyclophosphamide-Induced Severe Acute Hyponatremic Encephalopathy in Patients with Breast Cancer: Report of Two Cases

    Directory of Open Access Journals (Sweden)

    Michelle Baker

    2014-07-01

    Full Text Available Background: Cyclophosphamide is an alkylating agent widely used in antineoplastic and immunosuppressive therapies. Symptomatic hyponatremia can be a rare but life-threatening complication in patients treated with cyclophosphamide. Case Presentations: We report 2 patients who presented with severe acute hyponatremic encephalopathy after receiving their first cycles of a low-dose cyclophosphamide-containing regimen for breast cancer. In case 1, a 58-year-old female received the combination of docetaxel and cyclophosphamide, and in case 2, a 56-year-old female received the combination of doxorubicin and cyclophosphamide. Both patients recovered after correction of their serum sodium concentration without neurological deficits. Future cycles of chemotherapy were well tolerated without recurrence of hyponatremia after cyclophosphamide was discontinued from the respective regimens. Conclusion: Clinicians must always keep in mind that acute hyponatremic encephalopathy can be induced by low-dose cyclophosphamide.

  2. Intravenous immunoglobulin and mitoxantrone stop the progression of secondary progressive multiple sclerosis in a patient with interferon intolerance.

    Science.gov (United States)

    Rodríguez Orozco, Alain R

    2004-01-01

    A 36 year-old female patient with secondary progressive multiple sclerosis accompanied by neuropsychiatric depression and history of intolerance to beta-interferon was treated with mitoxantrone (MX) and intravenous immunoglobulin (IVIG) for 2 years. Both clinical response and magnetic resonance imaging were performed at the end. With a combination of MX and IVIG long-term treatment, her disabilities improved as measured by the Expanded Disability Status Scale (EDSS). The combination therapy was well-tolerated. It represents an alternative to treat patients who do not respond well to cytostatics alone, or in those in whom intolerance to interferons may also occur. Immunomodulation with intravenous immunoglobulin stopped the progression of the disease and avoided subsequent exacerbations during 24 months. The role of high doses of immunoglobulins in the treatment of patients with secondary progressive MS deserves clinical trials to evaluate the stopping of progression of the disease in comparison to remissions induced by cytostatics, interferons and steroids.

  3. Design of multifunctional magnetic iron oxide nanoparticles/mitoxantrone-loaded liposomes for both magnetic resonance imaging and targeted cancer therapy

    Directory of Open Access Journals (Sweden)

    He Y

    2014-08-01

    Full Text Available Yingna He,1 Linhua Zhang,2 Dunwan Zhu,2 Cunxian Song2 1Laboratory of Chinese Medicine Pharmacology, College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China; 2Key Laboratory of Biomedical Material of Tianjin, Institute of Biomedical Engineering, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, People’s Republic of China Abstract: Tumor-targeting multifunctional liposomes simultaneously loaded with magnetic iron oxide nanoparticles (MIONs as a magnetic resonance imaging (MRI contrast agent and anticancer drug, mitoxantrone (Mit, were developed for targeted cancer therapy and ultrasensitive MRI. The gonadorelin-functionalized MION/Mit-loaded liposome (Mit-GML showed significantly increased uptake in luteinizing hormone–releasing hormone (LHRH receptor overexpressing MCF-7 (Michigan Cancer Foundation-7 breast cancer cells over a gonadorelin-free MION/Mit-loaded liposome (Mit-ML control, as well as in an LHRH receptor low-expressing Sloan-Kettering HER2 3+ Ovarian Cancer (SK-OV-3 cell control, thereby leading to high cytotoxicity against the MCF-7 human breast tumor cell line. The Mit-GML formulation was more effective and less toxic than equimolar doses of free Mit or Mit-ML in the treatment of LHRH receptors overexpressing MCF-7 breast cancer xenografts in mice. Furthermore, the Mit-GML demonstrated much higher T2 enhancement than did Mit-ML controls in vivo. Collectively, the study indicates that the integrated diagnostic and therapeutic design of Mit-GML nanomedicine potentially allows for the image-guided, target-specific treatment of cancer. Keywords: multifunctional liposome, magnetic resonance imaging, theranostic nanomedicine, mitoxantrone, gonadorelin

  4. Dexamethasone-cyclophosphamide pulse therapy in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Dhabhai Ravindra

    2005-01-01

    Full Text Available BACKGROUND AND AIMS: Therapy systemic lupus erythematosus (SLE has been generally discouraging. Methyl-prednisolone pulse therapy has been used for various connective tissue disorders. We used intravenous dexamethasone cyclophosphamide pulse therapy to treat SLE. METHODS: Fourteen patients (10 females and 4 males between the age of 15-48 years with definite or classical clinical criteria laid by American Rheumatism Association criteria were treated by Dexamethasone-Cyclophosphamide pulse (DCP therapy at our center. RESULTS: It was possible to induce a complete clinical remission with DCP therapy in most of the patients thereby offering them life free from disease and drugs. The side effects commonly observed with conventional daily dose regimen of corticosteroids were not present or were mild. CONCLUSIONS: Almost all patients had good response after 3-4 pulses to allow them a normal life style. Fever, malar rash and oral ulceration responded early but photosensitivity, discoid rash, alopecia and joint pains took some more time.

  5. 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.

  6. Evaluation of the antineoplastic activity of mitoxantrone-L-carnitine combination therapy on an experimental solid form of ehrlich tumour in mice.

    Science.gov (United States)

    Niang, M; Melka, M; Stoklasová, A; Cerman, J; Tomsík, P

    2006-12-01

    We have commenced a series of experiments to evaluate the effect of carnitine derivatives on the antineoplastic activity of mitoxantrone (MX) on various animal cancers. This report describes the therapeutic effect of MX in combination with l-carnitine (LCAR) on the growth of a solid form of Ehrlich tumour inoculated into mice. LCAR was administered subcutaneously at doses of either 200 or 100mgkg(-1) on day 6 and 13 after tumour inoculation, 1h prior to the treatment with MX. Mitoxantrone was administered intravenously at doses of 3 or 6mgkg(-1). We found that LCAR had no potentiating effect on the efficacy of MX, in terms of either slowing tumour growth or increasing the survival of mice. Nevertheless, therapeutic effects can be assumed at higher doses of both drugs based on values calculated from an index of relative hazards.

  7. Processed Aloe vera Gel Ameliorates Cyclophosphamide-Induced Immunotoxicity

    OpenAIRE

    Sun-A Im; Ki-Hyang Kim; Hee-Suk Kim; Ki-Hwa Lee; Eunju Shin; Seon-Gil Do; Tae Hyung Jo; Young In Park; Chong-Kil Lee

    2014-01-01

    The effects of processed Aloe vera gel (PAG) on cyclophosphamide (CP)-induced immunotoxicity were examined in mice. Intraperitoneal injection of CP significantly reduced the total number of lymphocytes and erythrocytes in the blood. Oral administration of PAG quickly restored CP-induced lymphopenia and erythropenia in a dose-dependent manner. The reversal of CP-induced hematotoxicity by PAG was mediated by the functional preservation of Peyer’s patch cells. Peyer’s patch cells isolated from C...

  8. Glutamic acid not beneficial for the prevention of vincristine neurotoxicity in children with cancer.

    Science.gov (United States)

    Bradfield, Scott M; Sandler, Eric; Geller, Thomas; Tamura, Roy N; Krischer, Jeffrey P

    2015-06-01

    Vincristine causes known side effects of peripheral sensory, motor, autonomic and cranial neuropathies. No preventive interventions are known. We performed a randomized, placebo-controlled, double-blind trial of oral glutamic acid as a preventive agent in pediatric patients with cancer who would be receiving vincristine therapy for at least 9 consecutive weeks (Stratum 1 = Wilms tumor and rhabdomyosarcoma) or 4 consecutive weeks in conjunction with steroids (Stratum 2 = Acute lymphoblastic leukemia and non-Hodgkin lymphoma). At designated time points, a scored neurologic exam using the Modified Balis Pediatric Scale of Peripheral Neuropathies was performed to document neurologic toxicity. Between 2007 and 2012, 250 patients were enrolled (Stratum 1 = 50, Stratum 2 = 200). The glutamic acid treated group did not have a significantly lower percentage of neurotoxicity compared to placebo treated group either overall or within stratum or age subgroups. The only subgroup which was suggestive of treatment effect was for age. Patients 13 years or older showed a larger benefit in favor of glutamic acid (P = 0.055) compared to patients less than 13 years (P = 1.00). Constipation was the most frequently reported (14%) Grade II or higher neurotoxicity. Vincristine-associated neurotoxicity in pediatric oncology remains a frequent complication of chemotherapy for multiple diagnoses with an approximate 30% of patients affected. Glutamic acid is not effective for prevention in pre-adolescents. There is a suggestion of benefit in patients 13 years or older, but the study was not designed to provide adequate power to test the treatment effect within this age group alone. © 2014 Wiley Periodicals, Inc.

  9. Atomic Force Microscopy Studies on DNA Structural Changes Induced by Vincristine Sulfate and Aspirin

    Science.gov (United States)

    Zhu, Yi; Zeng, Hu; Xie, Jianming; Ba, Long; Gao, Xiang; Lu, Zuhong

    2004-04-01

    We report that atomic force microscopy (AFM) studies on structural variations of a linear plasmid DNA interact with various concentrations of vincristine sulfate and aspirin. The different binding images show that vincrinstine sulfate binding DNA chains caused some loops and cleavages of the DNA fragments, whereas aspirin interaction caused the width changes and conformational transition of the DNA fragments. Two different DNA structural alternations could be explained by the different mechanisms of the interactions with these two components. Our work indicates that the AFM is a powerful tool in studying the interaction between DNA and small molecules.

  10. Atomic force microscopy studies on circular DNA structural changes by vincristine and aspirin.

    Science.gov (United States)

    Xiao, Zhongdang; Cao, Lili; Zhu, Dan; Lu, Zuhong

    2011-01-01

    In this chapter, we have presented materials and methods to study the interaction between DNA and small molecule drugs by AFM. The detailed AFM imaging of the circular DNA after incubation with -various concentrations of vincristine and aspirin have been demonstrated. The immobilization of DNA fragments on mica surface as well as the force between tip and sample plays an important role for successful imaging of DNA-drug complexes. How to quantitatively describe the conformations and structures of circular DNA molecules and their changes is also introduced. Our work indicates that the AFM is a powerful tool in studying the interaction between DNA and small molecules.

  11. Evaluation of VP-16 and the combination of adriamycin and vincristine in advanced breast cancer.

    Science.gov (United States)

    Eagan, R T; Ahmann, D L; Bisel, H F

    1976-01-01

    39 previously treated patients with metastatic breast cancer were treated in a partially randomized study evaluating VP-16 and the combination of Vincristine (VCR) and Adriamycin (ADR). Of the 19 patients treated with VP-16 initially, two had partial remissions. No responses were noted in eleven patients who corssed-over after failing VCR plus ADR. Of the 20 patients treated with VCR plus ADR initially, four patients had partial responses. An additional 2/15 patients responded on crossover after failing initially on VP-16. No significant differences in time to last follow-up or death could be detected between the two treatment programs.

  12. Vincristine, adriamycin, and mitomycin (VAM) therapy for previously treated breast cancer. A preliminary report.

    Science.gov (United States)

    Oster, M W; Park, Y

    1983-01-15

    Fifteen patients with metastatic breast cancer previously treated with chemotherapy were treated with a regimen consisting of vincristine, Adriamycin, and mitomycin. Eleven patients (73%) responded with three complete and eight partial responses. The median duration of response was eight months. While all four nonresponders died within five months, the median duration of survival of responders was 18 months. Toxicity was significant but tolerable. Thus, this preliminary report suggests that this regimen is active in advanced previously treated breast cancer, providing meaningful remissions with acceptable toxicity.

  13. 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.

  14. Use of pyridoxine and pyridostigmine in children with vincristine-induced neuropathy.

    Science.gov (United States)

    Akbayram, Sinan; Akgun, Cihangir; Doğan, Murat; Sayin, Refah; Caksen, Huseyin; Oner, Ahmet Faik

    2010-06-01

    Four children with vincristine (VCR)-induced neuropathy are being reported. All cases were followed with the diagnosis of acute lymphoblastic leukemia. Two were boys aged between 2 and 13 year. Electromyographic examination consisted of sensoriomotor polyneuropathy with axonal involvement in three patients. In another patient, it consisted of motor axonal polyneuropathy. In all patients, pyridoxine and pyridostigmine were successfully used in the treatment of VCR-induced neuropathy. They recovered completely with this drug combination. Recovering period of symptoms was between 1-2 week.

  15. Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors.

    Science.gov (United States)

    Wang, Yunfei; Cao, Shu-e; Tian, Jianmin; Liu, Guozhe; Zhang, Xiaoran; Li, Pingfa

    2013-11-29

    Common chemotherapeutic agents such as vincristine often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is refractory to common analgesics and represents a challenging clinical issue. Angelicae dahuricae radix is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the active component(s) that attribute to the analgesic action have not been identified. This work described the anti-hyperalgesic effect of one coumarin component, auraptenol, in a mouse model of chemotherapeutic agent vincristine-induced neuropathic pain. We reported that auraptenol dose-dependently reverted the mechanical hyperalgesia in mice within the dose range of 0.05-0.8 mg/kg. In addition, the anti-hyperalgesic effect of auraptenol was significantly blocked by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). Within the dose range studied, auraptenol did not significantly alter the general locomotor activity in mice. Taken together, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust analgesic efficacy in mice. These data support further studies to assess the potential of auraptenol as a novel analgesic for the management of neuropathic pain.

  16. Vincristine-induced central neurotoxicity in a collie homozygous for the ABCB1Δ mutation.

    Science.gov (United States)

    Krugman, L; Bryan, J N; Mealey, K L; Chen, A

    2012-03-01

    A six-year-old, neutered, female collie was presented to an oncology specialty service after developing tetraparesis and self-mutilation that progressively worsened while receiving chemotherapy for lymphoma. Neurologic examination revealed ataxia, paresis and diminished conscious proprioception in all limbs with entire spinal reflexes. Magnetic resonance imaging of the brain and spinal cord was normal. Electromyography of the limbs ruled out a vincristine-induced peripheral neuropathy. Cerebrospinal fluid analysis and cerebrospinal fluid and serum testing for Neospora and Toxoplasma were normal. Results of MDR1 genotyping revealed that the dog was homozygous for the ABCB1-1Δ (MDR1) mutation. This clinical presentation strongly resembled the effects seen from inadvertent intrathecal administration of vincristine in humans. Dogs that are homozygous for the ABCB1-1Δ (MDR1) mutation should not receive standard dosages of chemotherapy drugs known to be eliminated by P-glycoprotein, the gene product of ABCB1. Testing for this mutation is strongly recommended before chemotherapy initiation for at-risk breeds.

  17. Treatment Efficiency of Free and Nanoparticle-Loaded Mitoxantrone for Magnetic Drug Targeting in Multicellular Tumor Spheroids

    Directory of Open Access Journals (Sweden)

    Annkathrin Hornung

    2015-09-01

    Full Text Available Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT employing superparamagnetic iron oxide nanoparticles (SPION loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in the healthy tissue. For translation of nanomedicine from bench to bedside, nanoparticle-mediated effects have to be studied carefully. In this study, we compare the effect of SPION, unloaded or loaded with the cytotoxic drug mitoxantrone (MTO with the effect of free MTO, on the viability and proliferation of HT-29 cells within three-dimensional multicellular tumor spheroids. Fluorescence microscopy and flow cytometry showed that both free MTO, as well as SPION-loaded MTO (SPIONMTO are able to penetrate into tumor spheroids and thereby kill tumor cells, whereas unloaded SPION did not affect cellular viability. Since SPIONMTO has herewith proven its effectivity also in complex multicellular tumor structures with its surrounding microenvironment, we conclude that it is a promising candidate for further use in magnetic drug targeting in vivo.

  18. Prevention of the exposure by cyclophosphamide oral tablet

    OpenAIRE

    Hanada, Takae; Takami, Yoichiro; Moriyama, Kei; Oro, Masafumi; Ogawa, Takehiro; Moriyasu, Hiroko; Inoue, Yuka; Kanemitsu, Asako; Kawamoto, Eiko; Nagase, Ayaka; Hamahara, Anna; Yamamoto, Atsuko; Shimada, Kenichi; TAKAHASHI, Masashi; Egawa, Takashi

    2015-01-01

    Background Unintended exposure to antitumor agents from an oral medicine may place healthcare workers and patients taking medicine at risk. In this study, the exposure to blister pack by CP (cyclophosphamide) and appropriate preventive procedures were examined. Findings CP detected inside the blister pack of the tested seven lots by LC-MS/MS ranged from 8.2 to 199.6 ng. Raman imaging clearly showed that CP ingredient was completely covered by the tablet coating layer and had not leached out o...

  19. Influence of functional polymorphisms of the MDR1 gene on vincristine pharmacokinetics in childhood acute lymphoblastic leukemia.

    NARCIS (Netherlands)

    Plasschaert, S.L.A.; Groninger, E.; Boezen, M.; Kema, I.P.; Vries, E.G.F. de; Uges, D.R.A.; Veerman, A.J.P.; Kamps, W.A.; Vellenga, E.; Graaf, S.S.N. de; Bont, E.S. de

    2004-01-01

    OBJECTIVE: Our objective was to investigate the effect of single nucleotide polymorphisms (SNPs) in the P-glycoprotein MDR1 gene on vincristine pharmacokinetics and side effects in childhood acute lymphoblastic leukemia. METHODS: From 52 of 70 children who participated in a previous study on vincris

  20. Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma

    NARCIS (Netherlands)

    Segeren, CM; Sonneveld, P; van der Holt, B; Baars, JW; Biesma, DH; Cornellissen, JJ; Croockewit, AJ; Dekker, AW; Fibbe, WE; Lowenberg, B; Kooy, MV; van Oers, MHJ; Richel, DJ; Vellenga, E; Verhoef, GEG; Wijermans, PW; Wittebol, S; Lokhorst, HM

    1999-01-01

    We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4mg and doxorubicin 9 mg/m(2) as a rapid intravenous infusion for 4d together with intermittent high-dose dexamethasone 40 mg (VAD) for remission induction

  1. 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 compu...

  2. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis : long-term follow-up

    NARCIS (Netherlands)

    Harper, Lorraine; Morgan, Matthew D.; Walsh, Michael; Hoglund, Peter; Westman, Kerstin; Flossmann, Oliver; Tesar, Vladimir; Vanhille, Phillipe; de Groot, Kirsten; Luqmani, Raashid; Felipe Flores-Suarez, Luis; Watts, Richard; Pusey, Charles; Bruchfeld, Annette; Rasmussen, Niels; Blockmans, Daniel; Savage, Caroline O.; Jayne, David

    2012-01-01

    Introduction The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were

  3. Randomised comparison of cisplatin with cyclophosphamide/cisplatin and with cyclophosphamide/doxorubicin/cisplatin in advanced ovarian cancer. Gruppo Interegionale Cooperativo Oncologico Ginecologia.

    Science.gov (United States)

    1987-08-15

    565 patients with stage III-IV epithelial ovarian cancer were randomly assigned to receive cisplatin (P), cyclophosphamide and cisplatin (CP), or cyclophosphamide, doxorubicin, and cisplatin (CAP). Data on 531 patients were analysed. Treatment with CAP resulted in a significantly higher overall (complete and partial) response rate (66 vs 56 vs 49% for CAP, CP, and P, respectively), but the rate of complete surgical response for the three treatment arms was similar (26, 21, and 20%). Size of residual tumour after first surgery and Karnofsky index were the best predictors of complete remission. Survival and disease-free survival were not significantly different in the three arms, although progression-free survival was significantly longer after CAP. However, tumour size, cell type, and Karnofsky index, but not therapy, were independent predictors for survival. Haematological toxicity was highest with CAP. The addition of cyclophosphamide or doxorubicin and cyclophosphamide to cisplatin does not substantially increase the number of potentially curable, advanced ovarian cancer patients.

  4. Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients

    DEFF Research Database (Denmark)

    Faurschou, Mikkel; Sørensen, Inge Juul; Mellemkjaer, Lene

    2008-01-01

    To describe the incidence of malignancies in a cohort of Danish patients with Wegener's granulomatosis (WG) and to investigate the cancer risk associated with cyclophosphamide (CYC) -therapy in WG.......To describe the incidence of malignancies in a cohort of Danish patients with Wegener's granulomatosis (WG) and to investigate the cancer risk associated with cyclophosphamide (CYC) -therapy in WG....

  5. Effect of cyclophosphamide on the microanatomy of liver of albino rats

    Directory of Open Access Journals (Sweden)

    Javed Ahmad Khan

    2014-08-01

    Conclusion: Cyclophosphamide induces histological changes like fatty infiltration and central vein congestion in the liver. These changes are with low doses given for longer durations and manifest earlier when larger doses are used. Thus it is advised that patients receiving cyclophosphamide should be periodically evaluated for liver dysfunction. [Int J Res Med Sci 2014; 2(4.000: 1466-1469

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Spinal Changes of a Newly Isolated Neuropeptide Endomorphin-2 Concomitant with Vincristine-Induced Allodynia

    Science.gov (United States)

    Huang, Ben-Qing; Liu, Ji-Dong; Liu, Hui; Zhang, Nan; Li, Li; Chen, Jian-Hua

    2014-01-01

    Chemotherapy-induced neuropathic pain (CNP) is the major dose-limiting factor in cancer chemotherapy. However, the neural mechanisms underlying CNP remain unclear. There is increasing evidence implicating the involvement of spinal endomorphin-2 (EM2) in neuropathic pain. In this study, we used a vincristine-evoked rat CNP model displaying mechanical allodynia and central sensitization, and observed a significant decrease in the expression of spinal EM2 in CNP. Also, while intrathecal administration of exogenous EM2 attenuated allodynia and central sensitization, the mu-opioid receptor antagonist β-funaltrexamine facilitated these events. We found that the reduction in spinal EM2 was mediated by increased activity of dipeptidylpeptidase IV, possibly as a consequence of chemotherapy-induced oxidative stress. Taken together, our findings suggest that a decrease in spinal EM2 expression causes the loss of endogenous analgesia and leads to enhanced pain sensation in CNP. PMID:24586889

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

    DEFF Research Database (Denmark)

    Ejlertsen, B.; Mouridsen, Henning Torbøl; Jensen, M.B.;

    2010-01-01

    .70 in the CMF arm (P = .01). The hazard ratio for death was 0.70 in both the C arm (P = .02) and the CMF arm (P = .02) at 10 years, and the overall survival (OS) benefit was maintained during 25 years of follow-up. No significant differences were observed in IDF5 or OS between the C arm and the CMF arm...... 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...... (the CMF arm). RESULTS: The 10-year invasive disease-free survival (IDFS) rate was 38.6% in the control arm compared with 55.5% in the C arm, 48.8% in the CMF arm, and 35.2% in the levamisole arm. Compared with the control arm, the hazard ratio for an IDFS event was 0.62 in the C arm (P = .001) and 0...

  9. 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

    .70 in the CMF arm (P = .01). The hazard ratio for death was 0.70 in both the C arm (P = .02) and the CMF arm (P = .02) at 10 years, and the overall survival (OS) benefit was maintained during 25 years of follow-up. No significant differences were observed in IDFS or OS between the C arm and the CMF arm...... 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...... (the CMF arm). RESULTS: The 10-year invasive disease-free survival (IDFS) rate was 38.6% in the control arm compared with 55.5% in the C arm, 48.8% in the CMF arm, and 35.2% in the levamisole arm. Compared with the control arm, the hazard ratio for an IDFS event was 0.62 in the C arm (P = .001) and 0...

  10. Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia.

    Science.gov (United States)

    Visani, G; Milligan, D; Leoni, F; Chang, J; Kelsey, S; Marcus, R; Powles, R; Schey, S; Covelli, A; Isidori, A; Litchman, M; Piccaluga, P P; Mayer, H; Malagola, M; Pfister, C

    2001-05-01

    PSC 833 (Valspodar) can reverse multidrug resistance (MDR) in patients with hematologic malignancies, but alters the pharmacokinetics of concomitant anticancer agents. A phase I, dose-finding study was initiated to define a safe and effective regimen of mitoxantrone, etoposide, and cytarabine (MEC) when administered with PSC 833 to patients with early relapsed or refractory acute myeloid leukemia (AML). Poor-prognosis AML patients refractory to first-line induction therapy or relapsing within 9 months of attaining complete remission (CR) were treated with cytarabine (1.0 g/m2/day), etoposide (30 mg/m2/day), and mitoxantrone at a dose of either 3.0 mg/m2/day (cohort 1) or 4.5 mg/m2/day (cohorts 2 and 3) for 6 days plus continuous-infusion PSC 833 (10 mg/kg/24 h with a 2.0 mg/kg loading dose) for 6 or 7 days each 21-day cycle. Patients achieving CR were given a 4-day MEC plus PSC 833 consolidation cycle. Twenty-three patients were enrolled (eight with primary refractory AML and 15 in relapse). Dose-limiting toxicity occurred in one of six patients in cohort 2 (grade 4 mucositis) and one of seven patients in cohort 3 (grade 4 hyperbilirubinemia). The maximum tolerated dose of mitoxantrone was defined as 4.5 mg/m2/day. Clinically significant grade 4 hyperbilirubinemia, possibly related to PSC 833, occurred in four patients. Hematologic toxicities were as expected in this patient population, but were not dose limiting. Mild to moderate cerebellar ataxia and paresthesia occurred in six (26%) and five (22%) patients, respectively, but were not dose limiting. Overall, six of 23 (26%) patients achieved CR, including five patients with demonstrated P-glycoprotein expression and/or function. The median overall survival was 4 months. All six patients with a CR were alive and four (17%) patients were disease free at 12 months. Blood levels of PSC 833 were well above the target level of 1000 ng/ml, a concentration that is known to reverse MDR in vitro. PSC 833 reduced the

  11. Alemtuzumab as rescue therapy in a cohort of 16 aggressive multiple sclerosis patients previously treated by Mitoxantrone: an observational study.

    Science.gov (United States)

    Le Page, Emmanuelle; Deburghgraeve, Véronique; Lester, Marie-Antoinette; Cardiet, Isabelle; Leray, Emmanuelle; Edan, Gilles

    2015-01-01

    Our study aimed to describe safety and neurological impact of alemtuzumab as last-line rescue therapy in aggressive multiple sclerosis (MS) patients, previously treated by Mitoxantrone (MITOX). Between June 2004 and October 2013, 13 patients received alemtuzumab at 20 mg/day and 3 at 12 mg/day for 5 days. EDSS, relapses, secondary progression were prospectively assessed 12 and 6 months before treatment, at baseline and every 3 months. Mean follow-up was 6.2 years [1-10]. Mean age at alemtuzumab start was 40 years [26-49] for 8 Secondary Progressive (SP) and 30 years [26-35] for 8 Relapsing-Remitting (RR) patients. MS duration was 13.7 (± 3) and 8.3 (± 4) years, respectively. During the 12 months before alemtuzumab, annual relapse rate was 0.75 and 3.14, respectively and the 16 patients accumulated 2-30 new gadolinium enhancing lesions. 4 patients (suboptimal responders) received alemtuzumab during MITOX and 12 patients 1-7.8 years after MITOX. Out of 8 SPMS, 2 were disease free up to last visit (4.7 and 8 years), 5 improved or stabilized but only transiently and 1 worsened. Out of 8 RRMS, 1 remained stable up to last visit (8.7 years) despite 1 relapse and active MRI at 18 months and 7 improved (1-4 point EDSS): 4 remained disease free up to last visit (12, 24, 38 months and 7 years), 2 were successfully retreated at 25 and 33 months and 1 worsened progressively 24 months after alemtuzumab. 2 patients developed Grave's disease and 1 hypothyroidism. Alemtuzumab controls aggressive RRMS despite previous use of MITOX.

  12. Effects of cyclophosphamide on the kaolin consumption (pica behavior) in five strains of adult male rats.

    Science.gov (United States)

    Tohei, Atsushi; Kojima, Shu-ichi; Ikeda, Masashi; Hokao, Ryoji; Shinoda, Motoo

    2011-07-01

    It is known that pica, the consumption of non-nutritive substances such as kaolin, can be induced by administration of toxins or emetic agents in rats. In the present study, we examined the effects of intraperitoneal (i.p.) administration of cyclophosphamide on pica behavior and on the concentration of 5-hydroxyindoleacetic acids (5HIAA) in cerebrospinal fluid (CSF) in the following five strains of adult male rats: Sprague Dawley (SD), Wistar, Fischer 344 (F344), Wistar-Imamichi (WI) and Long Evans (LE). Cyclophosphamide (25 mg or 50 mg/kg) was injected (i.p.) into the rats and kaolin and food intake were measured at 24 hr after injection. The animals were anesthetized with urethane (1 g/kg) at 3 hr after injection of cyclophosphamide, and CSF was collected from the cisterna magna. WI and LE rats clearly showed pica behavior as compared with the other strains. In LE rats, the concentration of 5HIAA in CSF also increased in a dose-dependent manner of cyclophosphamide. The pretreatment with ondansetron (5-HT(3) antagonist) restored both changes (kaolin consumption and 5HIAA levels) induced by cyclophosphamide. These results suggest that the LE rat is sensitive to cyclophosphamide, that pica induced by cyclophosphamide mimics many aspects of emesis including the serotonergic response in the central nervous system and that use of the pica model would be a practical method for evaluating the effects of antiemetic drugs in addition to the mechanism of emesis.

  13. Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies.

    Science.gov (United States)

    Dowlati, Afshin; Lazarus, Hillard M; Hartman, Paul; Jacobberger, James W; Whitacre, Cecilia; Gerson, Stanton L; Ksenich, Pamela; Cooper, Brenda W; Frisa, Phyllis S; Gottlieb, Megan; Murgo, Anthony J; Remick, Scot C

    2003-12-01

    Bryostatin 1 activates protein kinase C (PKC) with short-term exposure and results in depletion of PKC with prolonged exposure. Preclinical in vitro and in vivo studies demonstrate synergistic activity and increased tumor apoptosis in B-cell malignancies when a prolonged infusion of bryostatin 1 is followed by vincristine. We embarked on a Phase I trial of bryostatin 1 as a 24-h continuous infusion followed by bolus vincristine in patients with refractory B-cell malignancies other than acute leukemias. Twenty-four evaluable patients were enrolled. The dose-limiting toxicity was myalgia. The MTD and recommended Phase II dose of bryostatin 1 was 50 microg/m2/24 h followed by vincristine 1.4 mg/m2 (maximum total dose of 2 mg) repeated every 2 weeks. Significant antitumor activity was observed in this relapsed population, including patients who had failed high-dose chemotherapy. This included 5 durable complete and partial responses and 5 patients with stable disease lasting > or =6 months (range, 6-48+ months). Median time to response was 8 months. Correlative studies demonstrated a progressive increase in serum interleukin-6 with bryostatin 1 infusion followed by an additional increase after vincristine. Flow cytometry for detection of apoptosis in B and T cells showed an initial decrease in apoptotic frequency in CD5+ cells within 6 h of bryostatin 1 infusion compatible with its known increase in PKC activity in the majority of patients followed by a return to baseline or overall increase in apoptotic frequency after completion of infusion. All (5 of 5) patients who had an overall increase in apoptotic frequency in CD5+ cells achieved either a clinical response or prolonged stable disease. Four of these 5 patients did not have the initial decrement in apoptosis at 6 h. Given the lack of myelosuppression and early evidence of clinical efficacy, additional exploration of this regimen in non-Hodgkin's lymphoma and multiple myeloma is warranted.

  14. Phase II study of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine chemotherapy with radiotherapy for treating malignant glioma in children.

    OpenAIRE

    Levin, V A; Lamborn, K.; Wara, W.; R. Davis; Edwards, M.; Rabbitt, J.; Malec, M.; Prados, M D

    2000-01-01

    We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and ...

  15. 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

  16. Crocetin induces cytotoxicity and enhances vincristine-induced cancer cell death via p53-dependent and -independent mechanisms

    Institute of Scientific and Technical Information of China (English)

    Ying-jia ZHONG; Yong QIN; Lin-chuan; LIAO Xia WANG; Fang SHI; Xue-lian ZHENG; Qiong WANG; Lan YANG; Hong SUN; Fan HE; Lin ZHANG; Yong LIN

    2011-01-01

    To investigate the anticancer effect of crocetin,a major ingredient in saffron,and its underlying mechanisms.Methods:Cervical cancer cell line HeLa,non-small cell lung cancer cell line A549 and ovarian cancer cell line SKOV3 were treated with crocetin alone or in combination with vincristine.Cell proliferation was examined using MTT assay.Cell cycle distribution and sub-G1 fraction were analyzed using flow cytometric analysis after propidium iodide staining.Apoptosis was detected using the Annexin V-FITC Apoptosis Detection Kit with flow cytometry.Cell death was measured based on the release of lactate dehydrogenase (LDH).The expression levels of p53 and p21wAF1/Cip1 as well as caspase activation were examined using Western blot analysis.Results:Treatment of the 3 types of cancer cells with crocetin (60-240 μmol/L) for 48 h significantly inhibited their proliferation in a concentration-dependent manner.Crocetin (240 μmol/L) significantly induced cell cycle arrest through p53-dependent and -independent mechanisms accompanied with p21WAF1/Cip1 induction.Crocetin (120-240 μmoVL) caused cytotoxicity in the 3 types of cancer cells by enhancing apoptosis in a time-dependent manner.In the 3 types of cancer cells,crocetin (60 μmol/L) significantly enhanced the cytotoxicity induced by vincristine (1 μmol/L).Furthermore,this synergistic effect was also detected in the vincristine-resistant breast cancer cell line MCF-7/VCR.Conclusion:Ccrocetin is a potential anticancer agent,which may be used as a chemotherapeutic drug or as a chemosensitizer for vin-cristine.

  17. The effect of increased lipoproteins levels on the disposition of vincristine in rat.

    Science.gov (United States)

    Khalil, Hadeel A; Belal, Tarek S; El-Yazbi, Ahmed F; Hamdy, Dalia A

    2016-09-09

    Vincristine (VCR), an antineoplastic agent, is a key component in the treatment of acute lymphoblastic leukemia, lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor diseases. Recently, high incidence of hyperlipidemia was reported to be associated with allogenic hematopoietic stem cell transplantation and VCR/L-asparaginase therapy. The aim of this study is to test the effects of incremental increase in lipoproteins levels on vincristine disposition in rat. To study VCR pharmacokinetics and protein binding, rats (n = 25) were assigned to three groups, normal lipidemic (NL), intermediate (IHL) and extreme hyperlipidemic (HL). Hyperlipidemia was induced by ip injection of (1 g/Kg) poloxamer 407 in rats. Serial blood samples were collected using the pre-inserted jugular vein cannula for 72 h post VCR (0.15 mg/Kg) i.v. dose. VCR unbound fractions in NL, IHL and HL plasma were determined using ultrafiltration kits. VCR demonstrated a rapid distribution phase (6-8 h) followed by a slower elimination phase with a mean elimination t½ of ~ 14 h. VCR exhibited moderate binding to plasma proteins ~ 83 %. It showed a relatively small Vc (~0.17 L/Kg) and a larger Vβ (1.53 L/Kg) indicating good tissue distribution. As the lipoproteins levels were increased, no significant changes were noted in VCR unbound fraction, plasma concentration, or volume of distribution indicating low affinity to lipoprotein binding. Induced HL also did not affect VCR elimination where similar VCR AUC0-∞, Cl and elimination phase t½ were reported along the different lipemic groups. Incremental increase in lipoprotein levels resulted in no significant effect on VCR disposition as such ALL malignant lymphoma and allogenic hematopoietic stem cell transplantation patients need not to worry about HL-VCR interaction. Whether, HL can potentiate another drug-drug or drug-disease interaction involving VCR warrants further studying and monitoring to ensure therapeutic safety and

  18. Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors

    Institute of Scientific and Technical Information of China (English)

    Zhao YAN; Zhong-ling ZHU; Zheng-zi QIAN; Ge HU; Hua-qing WANG; Wan-hui LIU; Guang CHENG

    2012-01-01

    Aim:To evaluate the single- and multiple-dose pharmacokinetics of vincristine sulfate liposomes (VSLI) in patients with advanced solid tumors.Methods:In single-dose pharmacokinetic study,16 patients were administered VSLI (1.5,2.0,or 2.3 mg.m-2) through intravenous infusion.Another 6 patients receiving vincristine sulfate (VCR,2.0 mg) were taken as the control.In multiple-dose pharmacokinetic study,12 patients were administered VSLI (1.5 or 1.8 mg.m-2) through intravenous infusion weekly for 4 consecutive weeks.The plasma concentration of VSLI was determined using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.Results:After intravenous infusion of the single dose of VSLI,the plasma concentrations were characterized by bi-exponential decline curves.No statistically significant differences were observed between the main pharmacokinetic parameters in the 3 dose groups.Compared with the patients receiving VCR,the patients treated with VSLI displayed an increase in the area under the plasma concentration vs time curve (AUC),and a decrease in plasma clearance rates.On the 4th cycle in the multiple-dose study,the plasma concentration of VCR in all subjects prior to the weekly administration was below the lower limit of quantification (LLOQ).The calculated pharmacokinetic parameters from the subjects in the multiple-and single-dose (1.5 mgm-2) groups had no significant differences.Although the administration of liposomal VCR may significantly elevate the plasma concentration of VCR,VSLI-associated adverse events were similar to those associated with conventional VCR.Conclusion:VSLI exhibits a lower clearance and a higher AUC compared with conventional VCR.No accumulation was observed in patients exposed to VSLI for 4 consecutive weeks.VSLI was generally tolerated in the subjects.The phase Ⅱ dose of VSLI may be recommended as 4 doses of 1.5 mg·m-2 for treatment of patients with advanced solid tumors.

  19. Vincristine, Ifosfamide, and Doxorubicin for Initial Treatment of Ewing Sarcoma in Adults.

    Science.gov (United States)

    Wagner, Michael J; Gopalakrishnan, Vancheswaran; Ravi, Vinod; Livingston, J Andrew; Conley, Anthony P; Araujo, Dejka; Somaiah, Neeta; Zarzour, Maria A; Ratan, Ravin; Wang, Wei-Lien; Patel, Shreyaskumar R; Lazar, Alexander; Ludwig, Joseph A; Benjamin, Robert S

    2017-07-14

    There are no clinical trials specifically addressing chemotherapy for adults with Ewing sarcoma (ES). Five-year event-free survival (EFS) of adults on pediatric studies of ES (44%-47%) is worse than that of children treated with the same therapy (69%). The object of this study was to review the results of therapy with vincristine, ifosfamide, and doxorubicin (VID) in the multidisciplinary treatment of adults with ES at our institution. Charts for adults treated for ES from 1995 to 2011 were retrospectively reviewed. Clinician-reported radiographic tumor response, type of local therapy, pathologic response, and survival data were collected. Seventy-one patients were identified who received VID as initial therapy. The median age was 25 (range: 16-64). Forty-two patients (59%) presented with a localized disease and 29 patients (41%) presented with a distant metastasis. Of all patients treated with VID, 83.6% showed a radiological response. Patients who presented with a localized disease had a 5-year overall survival (OS) of 68% (median not reached), compared with 10.3% (median: 1.9 years) in those who presented with distant metastases. Five-year EFS was 67%. The nine patients with a pelvic primary tumor had inferior 5-year OS (42%) to the 33 with primary tumors at other sites (75%). The 5-year OS of those who had greater than or equal to 95% necrosis after neoadjuvant VID (n = 20; 5-year OS: 84%) was superior to those who had less than 95% necrosis (n = 13; 5-year OS: 53%). In adults with primary ES, VID combined with an adjuvant strategy based on post-treatment percent necrosis has favorable outcomes compared with historical adult controls. Ewing sarcoma (ES) is a rare tumor in adults, and there are no dedicated clinical trials in the adult population. Most therapy is modeled after the published pediatric studies, although the small numbers of adult patients included on those studies did significantly worse than the children. We modeled our treatment on other

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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.

  2. Busulfan,cyclophosphamide and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma

    Institute of Scientific and Technical Information of China (English)

    张春阳

    2013-01-01

    Objective To evaluate the efficacy and safety of dose-reduced intravenous busulfan,cyclophosphamide and etoposide(BCV)as conditioning for autologous stem cell transplantation(ASCT)in multiple myeloma(MM)

  3. Enantioselectivity in the Metabolism of Cyclophosphamide in Patients With Multiple or Systemic Sclerosis.

    Science.gov (United States)

    de Castro, Francine Attié; Simões, Belinda Pinto; Coelho, Eduardo Barbosa; Lanchote, Vera Lucia

    2017-01-13

    The aim of this study was to evaluate the enantioselective pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide and carboxyethylphosphoramide mustard in patients with systemic or multiple sclerosis. Patients with systemic sclerosis (n = 10) or multiple sclerosis (n = 10), genotyped for the allelic variants of CYP2C9*2 and CYP2C9*3 and of the CYP2B6 G516T polymorphism, were treated with 50 mg cyclophosphamide/kg daily for 4 days. Serial blood samples were collected up to 24 hours after administration of the last cyclophosphamide dose. Cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide enantiomers were analyzed in plasma samples using liquid chromatography-tandem mass spectrometry coupled to chiral column Chiralcel OD-R or Chiralpak AD-RH. Cytokines IL-2, IL-4, IL-6, IL-8, IL-10, IL- 12p70, IL-17, TNF-α, and INT-δ in the plasma samples collected before cyclophosphamide infusion were analyzed by Milliplex MAP human cytokine/chemokine. Pharmacokinetic parameters showed higher plasma concentrations of (S)-(-)-cyclophosphamide (AUC 215.0 vs 186.2 μg·h/mL for multiple sclerosis patients and 219.1 vs 179.2 μg·h/mL for systemic sclerosis patients) and (R)-4-hydroxycyclophosphamide (AUC 5.6 vs 3.7 μg·h/mL for multiple sclerosis patients and 6.3 vs 5.6 μg·h/mL for systemic sclerosis patients) when compared to their enantiomers in both groups of patients, whereas the pharmacokinetics of the carboxyethylphosphoramide metabolite was not enantioselective. Cytokines' plasma concentrations were similar between multiple and systemic sclerosis groups. The pharmacokinetics of cyclophosphamide is enantioselective in patients with systemic sclerosis and multiple sclerosis, with higher plasma concentrations of the (S)-(-)-cyclophosphamide enantiomer due to the preferential formation of the (R)-4-hydroxycyclophosphamide metabolite.

  4. Mechanism of interaction of vincristine sulphate and rifampicin with bovine serum albumin: A spectroscopic study

    Indian Academy of Sciences (India)

    Bhalchandra P Kamat; Jaldappa Seetharamappa

    2005-11-01

    The mechanism of interaction of vincristine sulphate (VS) and rifampicin (RF) with bovine serum albumin (BSA) has been studied by quenching of BSA fluorescence by RF/VS. The Stern-Volmer plot indicates the presence of a static component in the quenching mechanism. Results also show that both the tryptophan residues of BSA are accessible to VS and RF. The high magnitude of rate constant of quenching indicates that the process of energy transfer occurs by intermolecular interaction and VS/RFbinding site is in close proximity to the tryptophan residues of BSA. Binding studies in the presence of a hydrophobic probe, 8-anilino-1-naphthalene-sulphonic acid sodium salt (ANS) indicate that the VS and RF compete with ANS for hydrophobic sites on the surface of BSA. Small decreases in critical micellar concentrations (CMC) of anionic surfactants in presence of VS/ RF show that the ionic character of VS/RF also contributes to binding. The temperature dependence of the association constant is used to estimate the values of the thermodynamic parameters involved in the interaction of VS/RF with BSA and the results indicate that hydrophobic forces play a significant role in the binding. Circular dichroism studies reveal that the change in helicity of BSA are due to binding of VS/RF to BSA.

  5. Antinociceptive effects of fucoidan in rat models of vincristine-induced neuropathic pain.

    Science.gov (United States)

    Hu, Chuanyin; Zhao, Yun-Tao; Zhang, Guoping; Xu, Ming-Feng

    2017-02-01

    Chemotherapeutic drugs commonly induce peripheral neuropathic pain, which limit their clinic use. In the present study, the effect of fucoidan on the development of vincristine‑induced neuropathic pain was evaluated and the underlying mechanism was examined. A neuropathy model was established in Sprague‑Dawley rats by intraperitoneal injection of vincristine sulfate 50 µg/kg once a day for 10 consecutive days. Fucoidan (50, 100 or 200 mg/kg.) and pregabalin (10 mg/kg) were injected for 14 consecutive days. Behavioral assessments were then performed and the expression of GABAB receptor was determined. The results showed that a single treatment with fucoidan did not prevent the induction of vincristine‑induced mechanical or cold allodynia. However, repeated fucoidan administration attenuated vincristine‑induced mechanical and cold allodynia in a dose‑dependent manner. Additionally, the analgesic effects of fucoidan contributed to an upregulation in the expression of GABAB receptor in the spinal cord. Furthermore, all the effects of fucoidan against vincristine‑induced neuropathy were reversed by saclofen, a selective GABAB receptor antagonist. These results suggested that the antinociceptive effects of fucoidan may be through activation of GABAB receptor, and fucoidan may be a promising drug for the treatment of chemotherapeutic drug-induced neuropathic pain.

  6. Lymph cancer chemotherapy: delivery of doxorubicin–gemcitabine prodrug and vincristine by nanostructured lipid carriers

    Science.gov (United States)

    Ni, Shuqin; Qiu, Lei; Zhang, Guodong; Zhou, Haiyan; Han, Yong

    2017-01-01

    Purpose Radiation and chemotherapy are the most common course of treatment for B-cell lymphoma. Doxorubicin (DOX), gemcitabine (GEM), and vincristine (VCR) are the commonly used antilymphoma chemotherapeutic drugs. The aim of this study is to construct a novel drug delivery system for the combination delivery of the three drugs on lymphoma. Materials and methods DOX–GEM prodrug was synthesized. Novel nanostructured lipid carriers (NLCs) containing DOX–GEM prodrug and VCR were prepared and used to treat B-cell lymphoma through in vivo treatment to a lymph cancer animal model. The systemic toxicity of the nanomedicine was also evaluated during the treatment. Results DOX–GEM prodrug and VCR-loaded NLCs (DOX–GEM VCR NLCs) exhibited the highest antitumor effect in B-cell lymphoma cells and lymphoma animal xenografts when compared with the single drug-loaded NLCs and the drug solutions. Conclusion It could be concluded that the highest antitumor effect can be achieved by the system due to the stable drug-loading capacity, attractive anticancer therapeutic effects, and reduced toxicities in human Burkitt’s lymphoma cell line and mice-bearing cancer model. The resulting DOX–GEM VCR NLCs could be an efficient antilymph cancer agent and could be developed further for the treatment of other tumors.

  7. CHEMOTHERAPY FOR ADVANCED NASOPHARYNGEAL CARCINOMA WITH METHOTREXATE, VINCRISTINE, CISPLATIN AND ADRIAMYCIN

    Institute of Scientific and Technical Information of China (English)

    苏勇; 张锦明; 夏云飞; 朱荣; 钱朝南; 莫浩元

    2002-01-01

    Objective: To evaluate the efficacy and toxicity of M-VCA (methortrexate 30 mg/m2, vincristine 2 mg, cisplatin 70 mg/m2, adriamycin 30 mg/m2) combination chemotherapy for advanced nasopharyngeal carcinoma. Methods: Thirty-five patients with advanced nasopharyngeal carcinoma, including 11 patients with untreated local advanced nasopharyngeal carcinoma and 24 patients with local-regional recurrent or metastatic nasopharyngeal carcinoma, received the chemotherapy of M-VCA. The cycle was repeated on day 22 for two cycles. All patients completed the chemotherapy courses. Results: The overall response rate was 75%, with untreated local advanced nasopharyngeal carcinomas 11/11(100%), local-regional recurrent nasopharyngeal carcinomas 12/18(67%), lung metastases 8/9(89%), bone metastases 5/9(56%), and liver metastases 1/2(50%). The main side effects included mild to moderate degree alopecia, nausea/vomiting, and neutropenia. Conclusion: M-VCA is well tolerated and has good efficacy for advanced nasopharyngeal carcinoma and is worth investigating further.

  8. Advanced adult esthesioneuroblastoma successfully treated with cisplatin and etoposide alternated with doxorubicin, ifosfamide and vincristine.

    Science.gov (United States)

    Turano, Salvatore; Mastroianni, Candida; Manfredi, Caterina; Biamonte, Rosalbino; Ceniti, Silvia; Liguori, Virginia; De Simone, Rosanna; Conforti, Serafino; Filice, Aldo; Rovito, Antonio; Viscomi, Caterina; Patitucci, Giuseppe; Palazzo, Salvatore

    2010-05-01

    The esthesioneuroblastoma is a rare neuroendocrine tumor that derives from the olfactory cells. In the last 20 years, around 1,000 cases have been described, with an overall survival rate of 60-70% at 5 years. The most common symptoms are nasal bleeding, nasal clogging and, in locally advanced cases, signs/symptoms of intracranic hypertension such as papilla edema, cefalea, and vomiting. The standard treatments are surgery and radiotherapy. Chemotherapy can be used in an adjuvant/neoadjuvant setting and in the metastatic phase, even if its role is still not established with certainty. Here, the case is reported of a young man (38 years old) with a locally advanced esthesioneuroblastoma. Two months before coming to our clinic, he had been treated elsewhere with debulking surgery through bilateral frontal craniotomy. After surgery, MRI showed residual disease in the nasal cavities and in the medial wall of the orbits responsible for blindness and bilateral exophthalmos within a month: a very short time. Octreoscan and whole body CT scan confirmed a locally advanced disease, in the absence of metastases. Chemotherapy was begun with cisplatin and etoposide alternated with doxorubicin, ifosfamide and vincristine with granulocyte colony-stimulating factor (G-CSF) support after every cycle. Soon after the first cycle, an important reduction of pain and decrease of the exophthalmos and vertigos was observed. No improvement in blindness was seen. The patient is still stable after 24 months of follow up.

  9. Hepatoprotective activity of white horehound (Marrubium vulgare) extract against cyclophosphamide toxicity in male rats.

    Science.gov (United States)

    Ettaya, Amani; Dhibi, Sabah; Samout, Noura; Elfeki, Abdelfettah; Hfaiedh, Najla

    2016-04-01

    The hepatoprotective activity of Marrubium vulgare against cyclophosphamide toxicity in Wistar rats was evaluated. Adult male rats were divided into 4 groups of 6 each: a control group, a group injected with cyclophosphamide (150 mg·kg(-1)) for 3 days, a group orally given a M. vulgare aqueous extract ((500 mg of dry leaves)·kg(-1)·day(-1)) for 30 days then treated with cyclophosphamide, and a group receiving only M. vulgare for 30 days. After 33 days of treatment, activities of alanine amino transferase (ALAT), aspartate amino transferase (ASAT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) were determined in serum. Moreover, lipid peroxidation level and superoxide dismutase (SOD) activities, catalase (CAT) and glutathione peroxidase (GPx) were measured in liver. Alterations of these hepatic biomarkers and increased lipid peroxidation confirmed cyclophosphamide-induced liver toxicity. Cyclophosphamide also decreased the enzymatic defense system against oxidative stress. However, when this drug was administered in rats given M. vulgare extract, all the biological parameters underwent much less alteration. Administration of M. vulgare extract was found to be beneficial by attenuating cyclophosphamide-induced liver damage. The protective effect of the plant is mainly attributed to its antioxidant properties and the existence of phenolic acids and flavonoids, as highlighted by HPLC-based analysis.

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

    Directory of Open Access Journals (Sweden)

    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

  11. 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.

  12. Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models

    Directory of Open Access Journals (Sweden)

    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.

  13. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia

    Science.gov (United States)

    Diouf, Barthelemy; Crews, Kristine R.; Lew, Glen; Pei, Deqing; Cheng, Cheng; Bao, Ju; Zheng, Jie J.; Yang, Wenjian; Fan, Yiping; Wheeler, Heather E.; Wing, Claudia; Delaney, Shannon M.; Komatsu, Masaaki; Paugh, Steven W.; McCorkle, Joseph Robert; Lu, Xiaomin; Winick, Naomi J.; Carroll, William L.; Loh, Mignon L.; Hunger, Stephen P.; Devidas, Meenakshi; Pui, Ching-Hon; Dolan, M. Eileen; Relling, Mary V.; Evans, William E.

    2015-01-01

    Importance With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is compelling need to mitigate treatment toxicities that can compromise quality of life. Peripheral neuropathy is the major dose-limiting toxicity of the microtubule inhibitor vincristine, an anticancer agent given to every child with ALL. Objective Identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL. Design, Setting and Participants All patients had been enrolled in one of two prospective clinical trials for childhood ALL that included treatment with 36–39 doses of vincristine. Genome-wide single nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in all patients from whom DNA was available (n=321 patients); 222 patients (median age at 6.0 years, range 0.1–18.8 years) enrolled between 1994–1998 on the St. Jude Children’s Research Hospital protocol Total XIIIB (St. Jude cohort) with toxicity followed through January 2001, and 99 patients (median age 11.4 years, range 3.0–23.8 years) enrolled between 2007–2010 on the Children’s Oncology Group protocol AALL0433 (COG cohort) with toxicity followed through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity. Exposures Treatment with vincristine at a dosage of 1.5 or 2.0 mg/m2 as a component of protocol directed chemotherapy for childhood ALL. Main Outcomes and Measures Vincristine-induced peripheral neuropathy was assessed at each clinic visit using the National Cancer Institute Common Terminology Criteria for Adverse Events and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life-threatening (grade 4). Results Grade 2–4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (n=64 of 222) in

  14. Yangjing Capsule Ameliorates Spermatogenesis in Male Mice Exposed to Cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Hongle Zhao

    2015-01-01

    Full Text Available Yangjing capsule (YC, a traditional Chinese compound herbal preparation, has been proven as an effective drug to improve spermatogenesis in clinical practice. However, its pharmacological mechanisms were not fully clarified. This study was designed to investigate the protective effects of YC on spermatogenesis in the mouse model of spermatogenesis dysfunction induced by cyclophosphamide (CP. The administration of YC significantly increased the epididymal index, sperm count, and sperm motility of model mice. Histopathological changes demonstrated that CP caused obvious structural damage to testis, which were reversed by the administration of YC. Results from TUNEL assay showed that treatment with YC dramatically decreased the apoptosis of spermatogenic cell induced by CP. Moreover, YC treatment could inhibit the mRNA and protein expression of Bax to Bcl-2 and also raised expression of AR at both mRNA and protein levels. These data suggest that YC might ameliorate spermatogenesis in male mice exposed to CP through inhibiting the apoptosis of spermatogenic cell and enhancing the actions of testosterone in spermatogenesis.

  15. Inhibition of cyclophosphamide-induced teratogenesis by beta-ionone.

    Science.gov (United States)

    Gomes-Carneiro, M R; De-Oliveira, A C A X; De-Carvalho, R R; Araujo, I B; Souza, C A M; Kuriyama, S N; Paumgartten, F J R

    2003-03-03

    Beta-ionone (BI) is a degraded (C 13) sesquiterpene found in plant essential oils. It has been used in the synthesis of perfume chemicals and vitamin A. Recently, it was reported that BI is a rather potent in vitro inhibitor of CYP2B1-catalysed reactions in rat liver microsomes. The present study was performed to investigate whether inhibition of CYP2B1 reactions by BI could lead to an attenuation of cyclophosphamide (CP)-induced embryotoxicity in the rat. In a preliminary experiment, a dose-dependent prolongation of pentobarbital sleeping time in male and female Wistar rats suggested that BI inhibits CYP2B1 in vivo as well. In a second experiment, rats were treated by gavage with BI (0, 250, 500, 750 or 1000 mg/kg body wt) 45 min prior to a subcutaneous injection of either CP (7.5 mg/kg body wt) or its vehicle (saline) on day 11 of pregnancy. BI alone, at the highest dose tested, caused a high proportion of resorptions. Lower doses of BI, however, clearly attenuated CP-induced embryolethality and teratogenicity. These results seem to support the view that, as far as rats are concerned, CYP2B1 plays an important role in the conversion of CP into its embryolethal and teratogenic metabolites.

  16. Fertility preservation in patients receiving cyclophosphamide therapy for renal disease.

    Science.gov (United States)

    Gajjar, Radha; Miller, Steven D; Meyers, Kevin E; Ginsberg, Jill P

    2015-07-01

    Cyclophosphamide continues to have an important role in the treatment of renal disease, including nephrotic syndrome and lupus nephritis, despite known complications of gonadotoxicity and potential infertility in both male and female patients. It is important that the physician recommending this therapy mitigates the effect of the drug on fertility by adhering to recommendations on dosing limits and offering fertility-preserving strategies. In addition to well-established methods, such as sperm banking and embryo cryopreservation, advances in reproductive technology have yielded strategies such as oocyte cryopreservation, resulting in more fertility-preserving options for the pediatric patient. Despite these advances, there continues to be a significant barrier to referral and access to sperm banks and fertility specialists. These issues are further complicated by ethical issues associated with the treatment of pediatric patients. In this review we explore the development of recommended dosing limits and include a discussion of the available fertility-preserving methods, strategies for increasing access to fertility specialists, and the ethical considerations facing the pediatric healthcare provider.

  17. [Effect of cyclophosphamide in experimental histoplasmosis in the rat].

    Science.gov (United States)

    Gago, J G; Godio, C M; Ochoa, L B; Negroni, R; Nejamkis, M R

    1998-01-01

    Histoplasmosis is a fungal disease caused by the dimorphous fungus Histoplasma capsulatum (Hc). Cyclophosphamide (Cy) was used as an immunomodulator capable of modifying the course of the disease, as well as of regulating the mechanisms involved in T-lymphocyte mediated immune response. Rats were subjected to intracardiac inoculation of Hc followed by a fractionated treatment with a 100 mg/kg body weight dose of Cy on days +4, +5, +6, +7 and +11 pi. Until day 26 pi, treatment with Cy caused 85% mortality whereas no mortality was observed among animals only inoculated with Hc. On day 14 pi, the group of Hc animals showed a delayed hypersensitivity test (DH) of 26.60 + 13.96 as determined by the swelling of the leg. Conversely, DH was significantly depressed in rats inoculated with Hc and treated with Cy: 3.88 +/- 1.00 (p < 0.01). Colony forming units count in this group was 2020 CFU/g of spleen, and 24 CFU/g of spleen (p < 0.01) in controls. A macroscopic study of the organs revealed that the animals in the Hc+Cy group had spleenomegaly and lungs with granuloma and hemorrhagic spots. The controls only presented small lung abscesses. These findings lead to the conclusion that Cy causes a deterioration of cell mediated immune response which results in the manifestation of an acute, fatal experimental mycosis.

  18. Processed Aloe vera Gel Ameliorates Cyclophosphamide-Induced Immunotoxicity

    Directory of Open Access Journals (Sweden)

    Sun-A Im

    2014-10-01

    Full Text Available The effects of processed Aloe vera gel (PAG on cyclophosphamide (CP-induced immunotoxicity were examined in mice. Intraperitoneal injection of CP significantly reduced the total number of lymphocytes and erythrocytes in the blood. Oral administration of PAG quickly restored CP-induced lymphopenia and erythropenia in a dose-dependent manner. The reversal of CP-induced hematotoxicity by PAG was mediated by the functional preservation of Peyer’s patch cells. Peyer’s patch cells isolated from CP-treated mice, which were administered PAG, produced higher levels of T helper 1 cytokines and colony-stimulating factors (CSF in response to concanavalin A stimulation as compared with those isolated from CP-treated control mice. PAG-derived polysaccharides directly activated Peyer’s patch cells isolated from normal mice to produce cytokines including interleukin (IL-6, IL-12, interferon-γ, granulocyte-CSF, and granulocyte-macrophage-CSF. The cytokines produced by polysaccharide-stimulated Peyer’s patch cells had potent proliferation-inducing activity on mouse bone marrow cells. In addition, oral administration of PAG restored IgA secretion in the intestine after CP treatment. These results indicated that PAG could be an effective immunomodulator and that it could prevent CP-induced immunotoxic side effects.

  19. Processed Aloe vera gel ameliorates cyclophosphamide-induced immunotoxicity.

    Science.gov (United States)

    Im, Sun-A; Kim, Ki-Hyang; Kim, Hee-Suk; Lee, Ki-Hwa; Shin, Eunju; Do, Seon-Gil; Jo, Tae Hyung; Park, Young In; Lee, Chong-Kil

    2014-10-24

    The effects of processed Aloe vera gel (PAG) on cyclophosphamide (CP)-induced immunotoxicity were examined in mice. Intraperitoneal injection of CP significantly reduced the total number of lymphocytes and erythrocytes in the blood. Oral administration of PAG quickly restored CP-induced lymphopenia and erythropenia in a dose-dependent manner. The reversal of CP-induced hematotoxicity by PAG was mediated by the functional preservation of Peyer's patch cells. Peyer's patch cells isolated from CP-treated mice, which were administered PAG, produced higher levels of T helper 1 cytokines and colony-stimulating factors (CSF) in response to concanavalin A stimulation as compared with those isolated from CP-treated control mice. PAG-derived polysaccharides directly activated Peyer's patch cells isolated from normal mice to produce cytokines including interleukin (IL)-6, IL-12, interferon-γ, granulocyte-CSF, and granulocyte-macrophage-CSF. The cytokines produced by polysaccharide-stimulated Peyer's patch cells had potent proliferation-inducing activity on mouse bone marrow cells. In addition, oral administration of PAG restored IgA secretion in the intestine after CP treatment. These results indicated that PAG could be an effective immunomodulator and that it could prevent CP-induced immunotoxic side effects.

  20. Estudio electrofisiologico en la neuropatia por Vincristina Vincristine neuropathy: an electrophysiological study

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    Olga P. Sanz

    1975-12-01

    Full Text Available Diez pacientes afectados por diversas patologías que requerían tratamiento crónico con Vincristina, fueron sometidos a estudios electrofisiológicos en los que se valoró: el número de unidades motoras (UM funcionantes en los músculos de la eminencia tenar, los valores de los incrementos medios de UM, velocidad de conducción motora y su latencia residual en el nervio mediano, la velocidad de conducción sensitiva del mismo nervio y el estado de la transmisión neuromuscular. Los valores obtenidos fueron comparados con grupos controles. Los resultados mostraron disminución del número de UM; las UM remanentes presentaron amplitud reducida junto a otras cuyo tamaño no superaba el del grupo control, hecho que sugiere la incapacidad de lograr una reinervación adecuada. Las velocidades de conducción motora y sensitiva mostraron valores diminuídos, con mayor compromiso en los segmentos distales. Junto a estos datos se halló respuesta miasteniforme al estímulo repetitivo. Todos estos resultados permiten postular la existencia de un compromiso de la unidad motora, abarcando todos sus segmentos, en pacientes intoxicados con Vincristina.Ten patients treated with vincristine were submitted for electrophysiological examination. It was investigated the number of motor units within the thenar muscle following a technique described previously (Sica et al. — 1974; motor and sensitive conduction velocities as well as motor distal latencies in the median nerve were studied following conventional techniques. The behaviour of the evoked muscle potential with repetitive supramaximal stimulation over the median nerve was also investigated. The findings were compared with control groups. The estimated number of motor units was disminished in eight of ten patients and the average number was significantly different from the control group (control 318 ± 71 UM; patients 174 ± 84 UM; P < 0.001. The potential amplitudes in most of the surviving units were

  1. Vocal cord palsy after vincristine treatment in a child and the inefficacy of glutamic acid in the prevention of relapse: a case report

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    Farruggia Piero

    2012-05-01

    Full Text Available Abstract Introduction Vincristine is an antineoplastic drug with a well known efficacy for the treatment of acute lymphoblastic leukemia and many solid tumors. No more than 20 pediatric patients with vincristine-induced vocal cord palsy have been reported, and to the best of our knowledge this is the first case where glutamic acid was administered with the aim of preventing a relapse of laryngeal dysfunction. Case presentation The larynx paralysis presented with hoarseness and stridor in a Caucasian 18-month-old girl and spontaneously resolved in about a month. In order to administer a subsequent full dose of vincristine, our patient received oral glutamic acid whose efficacy against vincristine neurological side effects has been previously reported. Conclusions Since in our patient the amino acid proved to be ineffective in the prevention of laryngeal paralysis relapse, we suggest that a dose reduction of vincristine should be preferred by oncologists as an initial approach after a case of drug-induced vocal cord palsy.

  2. High Performance Liquid Chromatographic Assay for the Simultaneous Determination of Posaconazole and Vincristine in Rat Plasma

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    Hadeel A. Khalil

    2015-01-01

    Full Text Available Purpose. Developing a validated HPLC-DAD method for simultaneous determination of posaconazole (PSZ and vincristine (VCR in rat plasma. Methods. PSZ, VCR, and itraconazole (ITZ were extracted from 200 μL plasma using diethyl ether in the presence of 0.1 M sodium hydroxide solution. The organic layer was evaporated in vacuo and dried residue was reconstituted and injected through HC-C18 (4.6 × 250 mm, 5 μm column. In the mobile phase, acetonitrile and 0.015 M potassium dihydrogen orthophosphate (30 : 70 to 80 : 20, linear gradient over 7 minutes pumped at 1.5 mL/min. VCR and PSZ were measured at 220 and 262 nm, respectively. Two Sprague Dawley rats were orally dosed PSZ followed by iv dosing of VCR and serial blood sampling was performed. Results. VCR, PSZ, and ITZ were successfully separated within 11 min. Calibration curves were linear over the range of 50–5000 ng/mL for both drugs. The CV% and % error of the mean were ≤18% and limit of quantitation was 50 ng/mL for both drugs. Rat plasma concentrations of PSZ and VCR were simultaneously measured up to 72 h and their calculated pharmacokinetics parameters were comparable to the literature. Conclusion. The assay was validated as per ICH guidelines and is appropriate for pharmacokinetics drug-drug interaction studies.

  3. Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma.

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    Schütt, P; Ebeling, P; Buttkereit, U; Brandhorst, D; Opalka, B; Hoiczyk, M; Flasshove, M; Hense, J; Bojko, P; Metz, K; Moritz, T; Seeber, S; Nowrousian, M R

    2005-01-01

    The present study aimed to evaluate the side-effects and efficacy of thalidomide in combination with an anthracycline-containing chemotherapy regimen in previously untreated myeloma patients. Thalidomide (400 mg/d) was combined with bolus injections of vincristine and epirubicin and oral dexamethasone (VED). Chemotherapy cycles were repeated every 3 wk until no further reduction in myeloma protein was observed, whereas the treatment with thalidomide was continued until disease progression. Thirty-one patients were enrolled, 12 patients were exclusively treated with thalidomide in combination with VED and 19 patients additionally received high-dose melphalan, for consolidation. Adverse events and response to therapy were assessed prior to treatment with high-dose chemotherapy. Response to thalidomide combined with VED was complete remission in six patients (19%), partial remission in 19 patients (61%), stable disease in five patients (16%), and progressive disease in one patient (3.2%). Grade 3 and 4 adverse events consisted of leukocytopenia in 10 patients (32%), and thrombocytopenia and anemia in one patient each (3.2%). Neutropenic infections grade 3 and 4 occurred in seven (23%) and three patients (9.7%), respectively, including two patients (6.5%) who died from septic shock. Deep vein thrombosis occurred in eight patients (26%), constipation in 20 patients (65%), and polyneuropathy in 20 patients (65%). The probability of event-free survival and overall survival in the whole group of patients at 36 months were 26 and 62%, respectively. In conclusion, the combination of thalidomide with VED appears to be highly effective in previously untreated patients with multiple myeloma, but it is associated with a high rate of thrombotic events, polyneuropathy, and neutropenic infections.

  4. Synergistic Interaction Between Dexmedetomidine and Ulinastatin Against Vincristine-Induced Neuropathic Pain in Rats.

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    Nie, Bilin; Zhang, Subo; Huang, Zhuxi; Huang, Jingxiu; Chen, Xiaodi; Zheng, Yaochao; Bai, Xiaohui; Zeng, Weian; Ouyang, Handong

    2017-07-08

    Antimicrotubulin chemotherapeutic agents such as vincristine (VCR), often induce peripheral neuropathic pain. It is usually permanent and seriously harmful to cancer patients' quality of life and can result in the hampering of clinical treatments. Currently, there is no definitive therapy, and many of the drugs approved for the treatment of other neuropathic pain have shown little or no analgesic effect. It is therefore vital to find new and novel therapeutic strategies for patients suffering from chemotherapeutic agent-induced neuropathic pain to improve patients' quality of life. This study shows that intrathecal injections of dexmedetomidine (DEX), or intraperitoneally administered ulinastatin (UTI) significantly reduces Sprague Dawley rats' mechanical allodynia induced by VCR via upregulation of interleukin-10 expression and activating the α2-adrenergic receptor in dorsal root ganglion (DRG). Moreover, when combined there is a synergistic interaction between DEX and UTI, which acts against VCR-induced neuropathic pain. This synergistic interaction between DEX and UTI may be partly attributed to a common analgesic pathway in which the upregulation of interleukin -10 plays an important role via activating α2-adrenergic receptor in rat dorsal root ganglion. The combined use of DEX and UTI does not affect the rat's blood pressure, heart rate, sedation, motor score, spatial learning, or memory function. All of these show that the combined use of DEX and UTI is an effective method in relieving VCR-induced neuropathic pain in rats. This article documents the synergistic interaction between 2 widely used drugs, DEX and UTI, against VCR-induced neuropathic pain. The results provide a potential target and novel drug administrated method for the clinical treatment of chemotherapy-induced peripheral neuropathic pain. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

  5. Hyaluronic acid-coated cationic nanostructured lipid carriers for oral vincristine sulfate delivery.

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    Gao, Xuan; Zhang, Jun; Xu, Qiang; Huang, Zun; Wang, Yiyue; Shen, Qi

    2017-04-01

    The goal of this research is to structure a hyaluronic acid modified nanostructured lipid carrier (HA-NLCs) for vincristine sulfate (VCR) delivery, and detect its efficiency to improve the oral bioavailability. Emulsion solvent evaporation method was used to prepare the HA-NLCs nanoparticles. The particle size, zeta potential and entrapment efficiency of VCR-NLCs and HA-NLCs were 187 ± 3.52 nm, -8.61 ± 1.29 mV, 33.12 ± 1.16% and 192 ± 4.41 nm, -32.82 ± 2.64 mV, 34.41 ± 2.21%, respectively. HA-NLCs could significantly improve the cellular uptake efficiency and cytotoxicity in MCF-7 cells than other VCR formulations. The expressions of apoptosis related protein Caspase-3, Caspase-9, Bax and Bcl-2 were estimated by western blot assay in MCF-7 cells, and HA-NLCs exhibited the strongest effect in promoting cell apoptosis. The pharmacokinetics of HA-NLCs was evaluated in Sprague-Dawley male rats and the relative oral bioavailability of HA-NLCs and VCR-NLCs was improved about 1.8-fold and two-fold compared with VCR solution, respectively. Therefore, these results indicated that HA-NLCs could significantly improve the oral bioavailability and was a promising vehicle for the oral delivery of VCR.

  6. Development of PLGA nanoparticles simultaneously loaded with vincristine and verapamil for treatment of hepatocellular carcinoma.

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    Song, Xiang Rong; Zheng, Yu; He, Gu; Yang, Li; Luo, You Fu; He, Zhi Yao; Li, Shuang Zhi; Li, Jun Ming; Yu, Shui; Luo, Xun; Hou, Shi Xiang; Wei, Yu Quan

    2010-12-01

    Hepatocellular carcinoma (HCC) is one of the malignant tumors with poor chemo-sensitivity to vincristine sulfate (VCR) due to multi-drug resistance (MDR). Combinations of encapsulated VCR and verapamil hydrochloride (VRP, a chemo-sensitizer) might be a potential strategy to improve HCC therapeutic efficacy of VCR. PLGA nanoparticles (PLGANPs) simultaneously loaded with VCR and VRP (CVn) were prepared. The entrapment efficiencies of VCR and VRP were 70.92 ± 3.78% and 85.78 ± 3.23%, respectively (n = 3). The HCC therapeutic activity of CVn was assessed using MTT assay. In BEL7402 and BEL7402/5-FU human hepatocarcinoma cell lines, CVn had the same antitumor effect as one free drug/another agent-loaded PLGANPs (C + Vn or Cn + V) combination and coadministration of two single-agent-loaded PLGANPs (Cn + Vn), which was slightly higher than that of the free VCR/VRP combination (C - V). CVn might cause lower normal tissue drug toxicity by the enhanced permeation and retention effect in vivo. Additionally, CVn might cause fewer drug-drug interaction and be the most potential formulation to simultaneously deliver VCR and VRP to the target cell in vivo than the other three nanoparticle formulations (C + Vn, Cn + V, and Cn + Vn). Therefore, we speculate that CVn might be the most effective preparation in the treatment of drug-resistant human HCC in vivo. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association

  7. Cyclophosphamide alters the gene expression profile in patients treated with high doses prior to stem cell transplantation.

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    Ibrahim El-Serafi

    Full Text Available 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.

  8. Population pharmacokinetics of cyclophosphamide and metabolites in children with neuroblastoma: a report from the Children's Oncology Group.

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    McCune, Jeannine S; Salinger, David H; Vicini, Paolo; Oglesby, Celeste; Blough, David K; Park, Julie R

    2009-01-01

    Cyclophosphamide-based regimens are front-line treatment for numerous pediatric malignancies; however, current dosing methods result in considerable interpatient variability in tumor response and toxicity. In this pediatric population, the authors' objectives were (1) to quantify and explain the pharmacokinetic variability of cyclophosphamide and 2 of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM), and (2) to apply a population pharmacokinetic model to describe the disposition of cyclophosphamide and these metabolites. A total of 196 blood samples were obtained from 22 children with neuroblastoma receiving intravenous cyclophosphamide (400 mg/m2/d) and topotecan. Blood samples were quantitated for concentrations of cyclophosphamide, HCY, and CEPM using liquid chromatography-mass spectrometry and analyzed using nonlinear mixed-effects modeling with the NONMEM software system. After model building was complete, the area under the concentration-time curve (AUC) was computed using NONMEM. Cyclophosphamide elimination was described by noninducible and inducible routes, with the latter producing HCY. Glomerular filtration rate was a covariate for the fractional elimination of HCY and its conversion to CEPM. Considerable interpatient variability was observed in the AUC of cyclophosphamide, HCY, and CEPM. These results represent a critical first step in developing pharmacokinetic-linked pharmacodynamic studies in children receiving cyclophosphamide to determine the clinical relevance of the pharmacokinetic variability in cyclophosphamide and its metabolites.

  9. Population Pharmacokinetics of Cyclophosphamide and Metabolites in Children with Neuroblastoma: a Report from the Children’s Oncology Group

    Science.gov (United States)

    McCune, Jeannine S.; Salinger, David H.; Vicini, Paolo; Oglesby, Celeste; Blough, David K.; Park, Julie R.

    2009-01-01

    Cyclophosphamide-based regimens are front-line treatment for numerous pediatric malignancies, however current dosing methods result in considerable interpatient variability in tumor response and toxicity. In this pediatric population, our objectives were to 1. quantify and explain the pharmacokinetic variability of cyclophosphamide, and two of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM); 2. apply a population pharmacokinetic model to describe the disposition of cyclophosphamide and these metabolites. A total of 196 blood samples were obtained from 22 children with neuroblastoma receiving intravenous (IV) cyclophosphamide (400 mg/m2/day) and topotecan. Blood samples were quantitated for concentrations of cyclophosphamide, HCY and CEPM using liquid chromatography-mass spectrometry and analyzed using nonlinear mixed effects modeling with NONMEM software system. After model building was complete, the area under the concentration-time curve (AUC) was computed using NONMEM. Cyclophosphamide elimination was described by noninducible and inducible routes with the latter producing HCY. Glomerular filtration rate (GFR) was a covariate for the fractional elimination of HCY and its conversion to CEPM. Considerable interpatient variability was observed in the AUC of cyclophosphamide, HCY and CEPM. These results represent a critical first step in developing pharmacokinetic-linked pharmacodynamic studies in children receiving cyclophosphamide to determine the clinical relevance of the pharmacokinetic variability in cyclophosphamide and its metabolites. PMID:18927240

  10. Copper ion-mediated liposomal encapsulation of mitoxantrone: the role of anions in drug loading, retention and release.

    Science.gov (United States)

    Li, Chunlei; Cui, Jingxia; Li, Yingui; Wang, Caixia; Li, Yanhui; Zhang, Lan; Zhang, Li; Guo, Wenmin; Wang, Jinxu; Zhang, Hongwu; Hao, Yanli; Wang, Yongli

    2008-08-01

    Besides pH gradient, other transmembrane gradients such as metal ion gradient could be also employed to load drugs into liposomes. In pH gradient method, anions have an important role since they could form specific aggregates with drugs, and then affect drug release kinetics from vesicles. To explore the role of anions in metal ion gradient method, copper ion-mediated mitoxantrone (MIT) loading was investigated systematically. When empty liposomes exhibiting a transmembrane copper ion gradient (300 mM) were mixed with MIT in a molar ratio of 0.2:1, after 5 min incubation at 60 degrees C, >95% MIT could be loaded into vesicles and the encapsulation was stable, regardless of the kinds of anions and initial intraliposomal pH values. The encapsulation ratio decreased with increased MIT/lipid molar ratio. But even when the molar ratio increased to 0.4, >90% encapsulation could still be achieved. In the presence of nigericin and ammonium, the drug loading profiles were affected to different degree with respect to both drug loading rate and encapsulation ratio. Relative to CuSO(4)-containing systems, CuCl(2) mediated MIT loading was unstable. Both nigericin and ammonium could alter the absorption spectra of liposomal MITs loaded with CuSO(4) gradient. In vitro release studies were performed in glucose/histidine buffer and in 50% human plasma using a dialysis method. In both of release media, CuCl(2)-containing vesicles displayed rapid release kinetics in comparison with CuSO(4) systems; and during the experiment period, MIT was lost from the vesicles continuously. When the formulations were injected into BDF1 mice at a dose of 4 mg/kg, all the liposomal formulations exhibited enhanced blood circulation time, with half-life values of 6.8-7.2h, significantly compared to the rapid clearance of free-MIT. In L1210 ascitic model, CuCl(2) formulation was more therapeutically active than CuSO(4) formulation. At a dose of 6 mg/kg, the treatment with CuCl(2) formulation resulted in

  11. Overexpression of Mcl-1 Confers Multidrug Resistance, Whereas Topoisomerase IIβ Downregulation Introduces Mitoxantrone-Specific Drug Resistance in Acute Myeloid Leukemia

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    Hermanson, David L.; Das, Sonia G.; Li, Yunfang

    2013-01-01

    Drug resistance is a serious challenge in cancer treatment and can be acquired through multiple mechanisms. These molecular changes may introduce varied extents of resistance to different therapies and need to be characterized for optimal therapy choice. A recently discovered small molecule, ethyl-2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) (CXL017), reveals selective cytotoxicity toward drug-resistant leukemia. A drug-resistant acute myeloid leukemia cell line, HL60/MX2, also failed to acquire resistance to CXL017 upon chronic exposure and regained sensitivity toward standard therapies. In this study, we investigated the mechanisms responsible for HL60/MX2 cells’ drug resistance and the molecular basis for its resensitization. Results show that the HL60/MX2 cell line has an elevated level of Mcl-1 protein relative to the parental cell line, HL60, and its resensitized cell line, HL60/MX2/CXL017, whereas it has a reduced level of topoisomerase IIβ. Mcl-1 overexpression in HL60/MX2 cells is mainly regulated through phospho-extracellular signal-regulated protein kinases 1 and 2–mediated Mcl-1 stabilization, whereas the reduction of topoisomerase IIβ in HL60/MX2 cells is controlled through genetic downregulation. Upregulating Mcl-1 introduces multidrug resistance to standard therapies, whereas its downregulation results in significant cell death. Downregulating topoisomerase IIβ confers resistance specifically to mitoxantrone, not to other topoisomerase II inhibitors. Overall, these data suggest that Mcl-1 overexpression is a critical determinant for cross-resistance to standard therapies, whereas topoisomerase IIβ downregulation is specific to mitoxantrone resistance. PMID:23696245

  12. 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

  13. Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation.

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    Hughes, Francis M; Vivar, Nivardo P; Kennis, James G; Pratt-Thomas, Jeffery D; Lowe, Danielle W; Shaner, Brooke E; Nietert, Paul J; Spruill, Laura S; Purves, J Todd

    2014-02-01

    Bladder inflammation (cystitis) underlies numerous bladder pathologies and is elicited by a plethora of agents such as urinary tract infections, bladder outlet obstruction, chemotherapies, and catheters. Pattern recognition receptors [Toll-like receptors (TLRs) and Nod-like receptors (NLRs)] that recognize pathogen- and/or damage-associated molecular patterns (PAMPs and/or DAMPs, respectively) are key components of the innate immune system that coordinates the production (TLRs) and maturation (NLRs) of proinflammatory IL-1β. Despite multiple studies of TLRs in the bladder, none have investigated NLRs beyond one small survey. We now demonstrate that NLRP3 and NLRC4, and their binding partners apoptosis-associated speck-like protein containing a COOH-terminal caspase recruitment domain (ASC) and NLR family apoptosis inhibitory protein (NAIP), are expressed in the bladder and localized predominantly to the urothelia. Activated NLRs form inflammasomes that activate caspase-1. Placement of a NLRP3- or NLRC4-activating PAMP or NLRP3-activating DAMPs into the lumen of the bladder stimulated caspase-1 activity. To investigate inflammasomes in vivo, we induced cystitis with cyclophosphamide (CP, 150 mg/kg ip) in the presence or absence of the inflammasome inhibitor glyburide. Glyburide completely blocked CP-induced activation of caspase-1 and the production of IL-1β at 4 h. At 24 h, glyburide reduced two markers of inflammation by 30-50% and reversed much of the inflammatory morphology. Furthermore, glyburide reversed changes in bladder physiology (cystometry) induced by CP. In conclusion, NLRs/inflammasomes are present in the bladder urothelia and respond to DAMPs and PAMPs, whereas NLRP3 inhibition blocks bladder dysfunction in the CP model. The coordinated response of NLRs and TLRs in the urothelia represents a first-line innate defense that may provide an important target for pharmacological intervention.

  14. Bronchoalveolar lavage and response to cyclophosphamide in scleroderma alveolitis.

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    Colaci, M; Sebastiani, M; Giuggioli, D; Manfredi, A; Spagnolo, P; Luppi, F; Richeldi, L; Ferri, Clodoveo

    2010-03-01

    Systemic sclerosis (SSc) is characterized by abnormal fibrosis of the skin and internal organs, particularly the lungs. Recent reports have revealed a lack of correlation between bronchoalveolar lavage (BAL) variations and response to cyclophosphamide (CYC) in patients with scleroderma-related alveolitis. Our study aimed to evaluate whether the normalization of BAL cellularity correlates with long-term response to CYC. We retrospectively studied 26 consecutive SSc patients with alveolitis diagnosed by BAL and treated with CYC therapy (cumulative dosage 26.5 +/- 11.7 g; 21.1 +/- 8.9 months of treatment). We evaluated high-resolution computed tomography (HRCT), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) variations before and after CYC. Radiological and functional parameters were re-evaluated in 23 patients after 1-year follow-up. BAL cellularity normalized after CYC therapy in 12/26 (46.2%) patients (group 1), while it remained abnormal in 14/26 (53.8%) (group 2). FVC and DLCO of group 1 slightly increased after CYC (p = 0.014 and p = 0.07, respectively) and remained stable at follow-up, whereas in group 2 they did not change after CYC and at follow-up (p = not significant). Moreover, at the end of CYC, FVC and/or DLCO showed a clinical improvement/stabilization in all patients of group 1 versus 8/14 of group 2, while at the re-evaluation 1 year after completing CYC, 2/11 patients of group 1 worsened versus 5/12 of group 2. HRCT progression was observed in 1/11 of group 1 and 8/12 of group 2 (p = 0.009). BAL fluid normalization after CYC therapy correlated with long-term response to treatment, contrary to what is observed in individuals with persistent alveolitis.

  15. Con: Cyclophosphamide for the treatment of lupus nephritis.

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    Mok, Chi Chiu

    2016-07-01

    Kidney involvement is a major determinant for morbidity and mortality in patients with systemic lupus erythematosus. The treatment target of lupus renal disease is to induce and maintain remission and to minimize disease or treatment-related comorbidities. Cyclophosphamide (CYC), in conjunction with glucocorticoids, has conventionally been used for the initial treatment of lupus nephritis. However, the major concerns of CYC are its toxicities, such as infertility, urotoxicity and oncogenicity, which are particularly relevant in women of childbearing age. As a result, maintenance therapy of lupus nephritis with an extended course of CYC pulses has largely been replaced by other immunosuppressive agents such as mycophenolate mofetil (MMF) and azathioprine. Recent randomized controlled trials have demonstrated non-inferiority of MMF to pulse CYC as induction therapy of lupus nephritis. Although MMF as induction-maintenance therapy has been increasingly used in lupus nephritis, its efficacy in the long-term preservation of renal function remains to be elucidated. MMF is not necessarily less toxic than CYC. Meta-analyses of clinical trials show similar incidence of infective complications and gastrointestinal adverse events in both MMF- and CYC-based regimens. However, considering the reduction in gonadal toxicity and the risk of oncogenicity, MMF may be used as first-line therapy of lupus nephritis. Tacrolimus (TAC) has recently been shown to be equivalent to either MMF or CYC for inducing remission of lupus nephritis and may be considered as another non-CYC alternative. Combined low-dose MMF and TAC appears to be more effective than CYC pulses in Chinese patients with lupus nephritis and has the potential to replace the more toxic CYC regimens in high-risk patients. Currently, CYC still plays an important role in the management of lupus nephritis patients with impaired or rapidly deteriorating renal function, crescentic glomerulonephritis or as salvage therapy for

  16. Therapeutically optimized rates of drug release can be achieved by varying the drug-to-lipid ratio in liposomal vincristine formulations.

    Science.gov (United States)

    Johnston, Michael J W; Semple, Sean C; Klimuk, Sandra K; Edwards, Katarina; Eisenhardt, Merete L; Leng, Esther C; Karlsson, Göran; Yanko, Daniel; Cullis, Pieter R

    2006-01-01

    The anti-tumor efficacy of liposomal formulations of cell cycle dependent anticancer drugs is critically dependent on the rates at which the drugs are released from the liposomes. Previous work on liposomal formulations of vincristine have shown increasing efficacy for formulations with progressively slower release rates. Recent work has also shown that liposomal formulations of vincristine with higher drug-to-lipid (D/L) ratios exhibit reduced release rates. In this work, the effects of very high D/L ratios on vincristine release rates are investigated, and the antitumor efficacy of these formulations characterized in human xenograft tumor models. It is shown that the half-times (T(1/2)) for vincristine release from egg sphingomyelin/cholesterol liposomes in vivo can be adjusted from T(1/2) = 6.1 h for a formulation with a D/L of 0.025 (wt/wt) to T(1/2) = 117 h (extrapolated) for a formulation with a D/L ratio of 0.6 (wt/wt). The increase in drug retention at the higher D/L ratios appears to be related to the presence of drug precipitates in the liposomes. Variations in the D/L ratio did not affect the circulation lifetimes of the liposomal vincristine formulations. The relationship between drug release rates and anti-tumor efficacy was evaluated using a MX-1 human mammary tumor model. It was found that the antitumor activity of the liposomal vincristine formulations increased as D/L ratio increased from 0.025 to 0.1 (wt/wt) (T(1/2) = 6.1-15.6 h respectively) but decreased at higher D/L ratios (D/L = 0.6, wt/wt) (T(1/2) = 117 h). Free vincristine exhibited the lowest activity of all formulations examined. These results demonstrate that varying the D/L ratio provides a powerful method for regulating drug release and allows the generation of liposomal formulations of vincristine with therapeutically optimized drug release rates.

  17. An open add-on study on cyclophosphamide in patients with refractory myasthenic crisis

    Institute of Scientific and Technical Information of China (English)

    蒋建明; 涂来慧; 吴涛; 张仁琴; 丁素菊; 蔡建英

    2003-01-01

    Objective: To assess the efficacy and side effects of cyclophosphamide on refractory myasthenic crisis.Methods: Five patients of myasthenic crisis refractory to usual comprehensive treatment, entered an open additional study with cyclophosphamide 200 mg VD q.d or 400 mg VD q.o.d with 6-10 g of total dosage.The patients were followed up for 1-8 years.Results: All the 5 patients were effectively treated with obvious remission in 3 and improvement in 2.Two patients have returned to partial work.The side effects were tolerable.Conclusion: The present clinical trial showed that cyclophosphamide was effective, particularly in a long term as an additional therapy for treating MG patients with refractory crisis of myasthenia gravis.

  18. 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.

  19. NMR and mass spectrometric characterization of vinblastine, vincristine and some new related impurities - part I.

    Science.gov (United States)

    Dubrovay, Zsófia; Háda, Viktor; Béni, Zoltán; Szántay, Csaba

    2013-10-01

    In the course of exploring the possibilities of developing a new, improved process at Gedeon Richter for the production of the "bisindole" alkaloids vinblastine (VLB) and vincristine (VCR), some novel VLB/VCR-related trace impurities were detected by analytical HPLC. Following isolation by preparative HPLC, a combination of 1D and 2D ultra high-field NMR and high-resolution (HR) (LC-)MS/MS studies allowed the structural identification and complete spectral characterization of several hitherto unpublished VLB/VCR-analogue impurities. Since the impurities could not be isolated in entirely pure forms and were available only in minute, mass-limited quantities, accessing the spectral information needed for their ab initio structure determination was met with various practical difficulties. Successful structure determination therefore relied heavily on the availability and use of detailed and definitive spectral data for both VLB and VCR. In particular, the utilization of detailed (1)H, (13)C, and (15)N NMR assignments as well as (1)H-(1)H, (1)H-(13)C and (1)H-(15)N spin-spin connectivities pertaining to different solvents for VLB/VCR base and sulphate salt was required. Although NMR studies on VLB base and other bisindoles were reported earlier in the literature, an NMR characterization of VLB and VCR under the above-mentioned circumstances and using ultra-high field instrumentation is either scarcely available or entirely lacking, therefore the necessary data had to be obtained in-house. Likewise, a modern tandem HR-ESI-MS/MS(n) fragmentation study of VLB and VCR has not been published yet. In the present paper we therefore give a thorough NMR and MS characterization of VLB and VCR specifically with a view to filling this void and to provide sufficiently extensive and solid reference data for the structural investigation of the aforementioned VLB/VCR impurities. Besides being scientifically relevant in its own right, the disclosed data should be useful for anyone

  20. Total Synthesis of Vinblastine, Vincristine, Related Natural Products, and Key Structural Analogues

    Science.gov (United States)

    Ishikawa, Hayato; Colby, David A.; Seto, Shigeki; Va, Porino; Tam, Annie; Kakei, Hiroyuki; Rayl, Thomas J.; Hwang, Inkyu; Boger, Dale L.

    2009-01-01

    Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)–NaBH4/air solution leads to oxidation of the C15′–C20′ double bond and reduction of the intermediate iminium ion directly providing vinblastine (40–43%) and leurosidine (20–23%), its naturally occurring C20′ alcohol isomer. The yield of coupled products, which exclusively possess the natural C16′ stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20′ alcohols is >60%. Preliminary studies of Fe(III)–NaBH4/air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identified alternatives to O2 trap at the oxidized carbon, provides a unique entry into C20′ functionalized vinblastines, and affords initial insights into the observed C20′ diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Δ19′,20′-anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key

  1. Long-term outcome after cyclophosphamide treatment in children with steroid-dependent and frequently relapsing minimal change nephrotic syndrome.

    NARCIS (Netherlands)

    Kyrieleis, H.A.; Levtchenko, E.N.; Wetzels, J.F.M.

    2007-01-01

    BACKGROUND: Seventy percent of children with minimal change nephrotic syndrome (MCNS) have a steroid-dependent or frequent relapsing course of the disease, and most are treated with cyclophosphamide. We describe the clinical course of children with biopsy-proven MCNS treated with cyclophosphamide fo

  2. A comparative effectiveness research of azathioprine and cyclophosphamide on the clinical and serological response in pemphigus vulgaris

    Directory of Open Access Journals (Sweden)

    Kabir Sardana

    2016-01-01

    Full Text Available Context: A prospective study was carried out to examine the efficacy of cyclophosphamide and azathioprine in pemphigus vulgaris. Aims: To compare the clinical and serological effect of azathioprine and cyclophosphamide in pemphigus patients. Materials and Methods: Prospective, institutional based study was conducted twenty-one patients of pemphigus vulgaris were initiated on either azathioprine (n = 9 or cyclophosphamide (n = 7 in addition to prednisolone and were evaluated clinically (mucosal and cutaneous severity and serologically enzyme-linked immunosorbent assay (ELISA at 0, 3 and 6 months. Results: Azathioprine had a slower onset of action with a statistically significant improvement seen by 6 months (P = 0.016. Cyclophosphamide had a faster onset of action (3 months though there was no statistical difference in the efficacy between the two at the end of 6 months. The (RonT was 33.3-44.4% for azathioprine and 28.8-42.9% for cyclophosphamide at 6 months. Though ELISA had a high sensitivity and specificity for diagnosis, as a tool for assessing therapeutic response a significant decrease was seen only till 3 months. This was restricted to Dsg1 for the azathioprine group and both Dsg3 and Dsg1 levels for the cyclophosphamide group. There were two deaths, both in the cyclophosphamide group. Conclusions: Azathiorpine and cyclophosphamide are equally effective for mucosal and cutaneous disease in pemphigus after 6 months of therapy. Dsg ELISA is useful for diagnosis of pemphigus but is not a useful tool for monitoring response to therapy.

  3. Chronic cyclophosphamide exposure alters the profile of rat sperm nuclear matrix proteins.

    Science.gov (United States)

    Codrington, Alexis M; Hales, Barbara F; Robaire, Bernard

    2007-08-01

    Chronic exposure of male rats to the alkylating agent cyclophosphamide, a well-known male-mediated developmental toxicant, alters gene expression in male germ cells as well as in early preimplantation embryos sired by cyclophosphamide-exposed males. Sperm DNA is organized by the nuclear matrix into loop-domains in a sequence-specific manner. In somatic cells, loop-domain organization is involved in gene regulation. Various structural and functional components of the nuclear matrix are targets for chemotherapeutic agents. Consequently, we hypothesized that cyclophosphamide treatment would alter the expression of sperm nuclear matrix proteins. Adult male rats were treated for 4 wk with saline or cyclophosphamide (6.0 mg kg(-1) day(-1)), and the nuclear matrix was extracted from cauda epididymal sperm. Proteins were analyzed by two-dimensional gel electrophoresis. Identified proteins within the nuclear matrix proteome were mainly involved in cell structure, transcription, translation, DNA binding, protein processing, signal transduction, metabolism, cell defense, or detoxification. Interestingly, cyclophosphamide selectively induced numerous changes in cell defense and detoxification proteins, most notably, in all known forms of the antioxidant enzyme glutathione peroxidase 4, in addition to an uncharacterized 54-kDa form; an overall increase in glutathione peroxidase 4 immunoreactivity was observed in the nuclear matrix extracts from cyclophosphamide-exposed spermatozoa. An increase in glutathione peroxidase 4 expression suggests a role for this enzyme in maintaining nuclear matrix stability and function. These results led us to propose that a change in composition of the nuclear matrix in response to drug exposure was a factor in altered sperm function and embryo development.

  4. Treatment of Acute Antibody-Mediated Renal Allograft Rejection With Cyclophosphamide.

    Science.gov (United States)

    Waiser, Johannes; Duerr, Michael; Budde, Klemens; Rudolph, Birgit; Wu, Kaiyin; Bachmann, Friederike; Halleck, Fabian; Schönemann, Constanze; Lachmann, Nils

    2017-10-01

    Antibody-mediated rejection (AMR) is a major risk for renal allograft survival. Throughout decades, cyclophosphamide treatment has been proven to be effective in patients with antibody-associated autoimmune diseases. We investigated whether cyclophosphamide combined with plasmapheresis and intravenous immunoglobulins is an option for patients with AMR. Between March 2013 and November 2015, we initiated treatment of 13 consecutive patients with biopsy-proven acute AMR with intravenous cyclophosphamide pulses (15 mg/kg adapted to age and renal function) at 3-week intervals, PPH (6×), and high-dose intravenous immunoglobulin (1.5 g/kg). Treatment was completed after 6 cyclophosphamide pulses or in case of return to baseline serum creatinine together with reduction of donor-specific HLA antibodies (DSA) below 500 mean fluorescence intensity. Eleven of 13 patients completed treatment. Median follow-up was 18 (12-44) months. At the end of follow-up, graft survival was 77% (10/13). The 3 graft losses were caused at least in part by nonadherence and premature termination of treatment. Serum creatinine increased from 1.7±0.4 mg/dL at 3 months before diagnosis to 3.7±2.4 mg/dL at diagnosis (P = 0.01), and decreased to 2.1 ± 0.7 mg/dL at 3 months after diagnosis (P = 0.01). In 7 (64%) of 11 patients, who completed treatment, DSA decreased, in 4 (36%) of 11 DSA were below 500 mean fluorescence intensity after treatment. Dose reductions had to be performed in 3 of 13 patients for leukopenia. We observed 14 hospitalizations in 9 of 13 patients. To our knowledge, this is the first systematic report on cyclophosphamide-based treatment of acute AMR based on modern diagnostics. Treatment was effective and relatively safe. Future studies will show, whether cyclophosphamide proves to be a valuable alternative for the treatment of AMR.

  5. Pemetrexed and cyclophosphamide combination therapy for the treatment of non-small cell lung cancer.

    Science.gov (United States)

    Li, Dong; He, Song

    2015-01-01

    Lung cancer is the leading cause of cancer-related mortality. This study was undertaken to investigate the efficacy and safety of adding regulatory T cell inhibitor cyclophosphamide to pemetrexed therapy for the second-line treatment of NSCLC with wild-type epidermal growth factor receptor (EGFR). A total of 70 patients were screened between March 2011 and December 2013, out of which 62 patients were enrolled in the study. Patients were randomized to receive 500 mg/m(2) pemetrexed in combination with 20 mg/kg cyclophosphamide in a 21 day cycle (n=30) or 500 mg/m(2) pemetrexed (n=32), and followed up for 30 months. Disease progression was observed in 23 patients in the pemetrexed plus cyclophosphamide arm and 27 patients in the pemetrexed monotherapy arm. Median progression-free survival was 3.6 months (95% confidence interval [CI], 1.3 to 5.9 months) in the pemetrexed plus cyclophosphamide arm and 2.2 months (95% CI, 1.3 to 3.1 months) in the pemetrexed monotherapy arm. The 6-month PFS rates were 22% (95% CI, 10 to 34) and 14.5% (95% CI, 6 to 23) in the pemetrexed plus cyclophosphamide arm and pemetrexed monotherapy arm, respectively. Median overall survival was 9.8 months for the pemetrexed combination therapy arm and 8.8 months for the pemetrexed arm, and the 1-year survival rates were 46% and 33%, respectively. The present study showed that pemetrexed in combination with low-dose cyclophosphamide may be a better treatment approach than pemetrexed monotherapy when considering second-line treatment for wild-type EGFR NSCLC.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone is beneficial but toxic in very elderly patients with diffuse large B-cell lymphoma : a population-based cohort study on treatment, toxicity and outcome

    NARCIS (Netherlands)

    Boslooper, Karin; Kibbelaar, Robby; Storm, Huib; Veeger, Nic J. G. M.; Hovenga, Sjoerd; Woolthuis, Gerhard; van Rees, Bas; de Graaf, Elly; van Roon, Eric; Kluin-Nelemans, Hanneke C.; Joosten, Peter; Hoogendoorn, Mels

    2014-01-01

    To assess treatment strategies, toxicity and outcome in very elderly patients (aged >= 75 years) diagnosed with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, an observational population-based cohort study was performed. From 103 patients with a median age of 81 years, data of clinical

  8. Human chorionic gonadotropin (hCG) regression normograms for patients with high-risk gestational trophoblastic neoplasia treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) chemotherapy

    NARCIS (Netherlands)

    Lybol, C.; Westerdijk, K.; Sweep, F.C.; Ottevanger, P.B.; Massuger, L.F.A.G.; Thomas, C.M.G.

    2012-01-01

    Background We present normograms for human chorionic gonadotropin (hCG) regression in patients with high-risk gestational trophoblastic neoplasia (GTN) successfully treated with multiagent chemotherapy in order to predict treatment resistance. Patients and methods We collected data for 46 patients w

  9. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the treatment of stage IE/IIE extranodal natural killer/T cell lymphoma, nasal type: 13-year follow-up in 135 patients.

    Science.gov (United States)

    Wang, Liang; Xia, Zhong-jun; Huang, Hui-qiang; Lu, Yue; Zhang, Yu-jing

    2012-11-01

    We conducted a retrospective study of 135 patients of stage IE/IIE extranodal natural killer/T cell lymphoma, nasal type (ENKTL) treated with CHOP as induction chemotherapy to find some valuable prognostic factors and analyze the usefulness of International Prognostic Index (IPI) and Korean Prognostic Index (KPI) in predicting prognosis. Most of the patients were in the low-risk group (IPI score 0-1). Complete remission (CR) after induction chemotherapy was achieved in 31.8 % of the patients, which increased to 69.6 % after radiotherapy. The 2-, 5-, and 10-year overall survival (OS) rates were 60, 48, and 43 %, respectively. Patients with better performance status (ECOG 0-1), normal serum LDH level, without local invasiveness, low KPI scores, and IPI score of 0 had significantly better overall survival (P KPI score systems should be improved further to classify patients into different groups, and should be validated in larger prospective trials. Due to the multi-drug resistance mechanism of ENKTL, CHOP is no longer the state of art and novel drugs should be incorporated into future treatments.

  10. Hepatitis C-Induced Hepatitis Flare in a Patient with Non-Hodgkin B-Cell Lymphoma Treated by Rituximab Including Chemotherapy (Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin - Vincristine, Prednisolone Regimen

    Directory of Open Access Journals (Sweden)

    Asim Ulcay

    2014-06-01

    Full Text Available Hepatitis virus infections can lead to more critical outcomes such as severe hepatic dysfunction, failure and fulminancy in immunosuppressive patients compared to immunocompetent individuals. It is globally accepted that reactivation of both Hepatitis B virus [HBV ] and Hepatitis C virus [HCV] occurs after chemotherapy and antibody treatments of malignant diseases or solid organ/ bone marrow transplant in recipient patients. Especially among B-cell Non Hodgkin Lymphoma [NHL] patients, according to various studies, the seroprevelance of HCV is higher than that of the general population. On the other hand the role of HCV in the pathogenesis and etiology of NHL has been suggested. Today, cytotoxic drugs, corticosteroids, rituximab and hepatotoxic regimens are administered to NHL patients. Specifically, it has been emphasized that the utilization of rituximab [Anti CD20 antibody ] regiments for B-cell NHL patients may result with flares in HCV patients conspicuously. Here, we report the case of an acute flare up due to HCV infection in a patient who underwent a 4 month course of rituximab containing chemotherapy against a B cell NHL [CD20+ ] disease and a dramatic recovery from HCV infection at the end. [Dis Mol Med 2014; 2(3.000: 51-54

  11. Cyclophosphamide-induced changes of serum angiotensin converting enzyme activity and pulmonary microvessels ultrastructure.

    Science.gov (United States)

    Musiatowicz, B; Terlikowski, S; Sulik, M; Famulski, W; Giedrojć, J; Jakubowski, A; Sobaniec-Lotowska, M; Pasztaleniec, L; Baltaziak, M; Jabłońska, E

    1997-01-01

    The effect of cyclophosphamide (CP) on the ultrastructure of the lung tissue and the activity of angiotensin converting enzyme (ACE) in serum was evaluated in rats. The animals were given cyclophosphamide (CP) in a single intraperitoneal dose of 150 mg/kg b.w. ACE activity was evaluated in the blood serum collected from the left ventricle of the heart using the spectrophometric method. In all time subgroups, the CP-receiving animals showed a decrease in ACE activity. Ultrastructural examinations of CP-treated animals revealed increased adhesion of neutrophiles and monocytes to the damage endothelium of the alveolar septa vessels and focally accumulation of the platelets.

  12. Kaposi's sarcoma in an elderly man with Wegener's granulomatosis treated with cyclophosphamide and corticosteroids.

    Science.gov (United States)

    Erban, S B; Sokas, R K

    1988-05-01

    The association of Kaposi's sarcoma with malignant lymphoreticular diseases and immunosuppressive therapy is well documented. This report describes an elderly man who presented with fulminant Wegener's granulomatosis that responded to treatment with cyclophosphamide and corticosteroids. Rapidly progressing cutaneous Kaposi's sarcoma developed ten weeks after the start of immunosuppressive therapy yet regressed on discontinuation of the corticosteroid therapy, despite continuation of cyclophosphamide therapy. To our knowledge, this is the first reported case of Kaposi's sarcoma occurring in association with Wegener's granulomatosis. The literature on Kaposi's sarcoma in immunosuppressed patients is reviewed.

  13. The influence of the protector thiol L-cystein on the toxic and therapeutic responses of stabilized "activated" cyclophosphamide (4-(S-ethanol)-sulfido-cyclophosphamide).

    Science.gov (United States)

    Voelcker, G; Laber, P; Rockinger, H; Wientzek, C; Hohorst, H J

    1984-01-01

    The influence of L-cystein on the toxic and therapeutic responses of 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stabilized "activated" cyclophosphamide, was investigated. Stabilized "activated" cyclophosphamides hydrolyze under physiological conditions to 4-hydroxycyclophosphamide (4-OH-CP). The antitumor activity of P1 was investigated on a heterotransplanted human bladder sarcoma in nude mice and in perfusion experiments carried out on the isolated tumor bearing limb in rats. Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is decreased by the protector thiol L-cystein. Simultaneous application of double molar amounts of L-cystein reduces toxicity in nude mice to approximately one-third. Therapeutic activity is not affected by this ratio of L-cystein so that the protector thiol increases the therapeutic efficacy of P1. Higher amounts of L-cystein reduce both the acute toxicity in nude mice and the therapeutic efficacy against the human xenograft. The perfusion experiments demonstrate that a P1 concentration necessary to cure rats with tumor bearing limb is only tolerated in combination with L-cystein.

  14. A trial to assess the efficacy of glutamic acid in prevention of vincristine-induced neurotoxicity in pediatric malignancies: a pilot study.

    Science.gov (United States)

    Mokhtar, Galila M; Shaaban, Sanaa Y; Elbarbary, Nancy Samir; Fayed, Waleed A

    2010-11-01

    Vincristine is considered as a backbone of therapy in the induction and consolidation phases of pediatric malignancies. Neurotoxicity is a principal side effect of its use. This study is a randomized single-blinded placebo-controlled clinical trial to evaluate the role of glutamic acid in ameliorating neurotoxicity in pediatric patients with hematologic and solid tumors receiving vincristine during induction course. Fifty-four patients in the glutamic acid group received glutamic acid 1.5 grams daily orally in 3 divided doses during the 4-week induction with vincristine in a dose of 1.5 mg/m² IV weekly. Placebo group (40 patients) received oral placebo 3 times daily in the same way as the glutamic acid group. The onset of neurotoxicity was significantly earlier in placebo group than in glutamic acid group regarding tendon Achilles reflex, Patellar reflex, parasthesia, and increased frequency of constipation. This was statistically significant mostly in third and fourth visits, no severe cases of strength and mental alteration side effects in both groups. Glutamic acid was well tolerated with no gastrointestinal side effects in patients. This study suggests that the coadministration of oral glutamic acid with repetitive intravenous bolus injections of vincristine resulted in a reduction of its neurotoxicity.

  15. Leukemia from dermal exposure to cyclophosphamide among nurses in the Netherlands: Quantitative assessment of the risk

    NARCIS (Netherlands)

    Fransman, W.; Kager, H.; Meijster, T.; Heederik, D.; Kromhout, H.; Portengen, L.; Blaauboer, B.J.

    2014-01-01

    Several studies showed that oncology nurses are exposed to antineoplastic drugs via the skin during daily activities. Several antineoplastic drugs (including cyclophosphamide) have been classified as carcinogenic to humans. This study aims to assess the leukemia risk of occupational exposure to

  16. Leukemia from dermal exposure to cyclophosphamide among nurses in the Netherlands : Quantitative assessment of the risk

    NARCIS (Netherlands)

    Fransman, Wouter; Kager, Hans; Meijster, Tim; Heederik, Dick; Kromhout, Hans; Portengen, Lützen; Blaauboer, Bas J.

    2014-01-01

    Several studies showed that oncology nurses are exposed to antineoplastic drugs via the skin during daily activities. Several antineoplastic drugs (including cyclophosphamide) have been classified as carcinogenic to humans. This study aims to assess the leukemia risk of occupational exposure to

  17. Wirksamkeit und Verträglichkeit von Cyclophosphamid bei Multipler Sklerose: Eine retrospektive Analyse

    OpenAIRE

    2008-01-01

    Cyclophosphamid (Endoxan) ist ein zytostatisches Medikament, welches wegen seiner immunsuppressiven Wirkung eine breite Anwendung in der Therapie systemischer Autoimmunerkrankungen findet. Es wird als Medikation bei schwerer chronisch-progressiver Multipler Sklerose empfohlen, um die weitere Progredienz einzuschränken oder zu verhindern. Bisherige klinische Studien über den Wert dieses therapeutischen Einsatzes liefern aber kontroverse Ergebnisse. Aus diesem Grund erschien es sinnvoll...

  18. Cyclophosphamide for Rapid-Onset Obesity, Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome

    OpenAIRE

    Paz-Priel, Ido; Cooke, David W.; Chen, Allen R

    2010-01-01

    Patients with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor syndrome have poor long-term outcomes. We report a patient who was treated successfully with high-dose cyclophosphamide immunoablation. This experience offers a novel therapeutic approach and an indirect insight into the underlying pathogenesis of this syndrome.

  19. Combination chemotherapy with cyclophosphamide, thalidomide and dexamethasone for patients with refractory, newly diagnosed or relapsed myeloma.

    Science.gov (United States)

    Sidra, Gamal; Williams, Cathy D; Russell, Nigel H; Zaman, Sonya; Myers, Bethan; Byrne, Jennifer L

    2006-06-01

    We evaluated the combination of thalidomide, pulsed dexamethasone and weekly cyclophosphamide (CTD) for the treatment of patients with newly diagnosed, relapsed or VAD-refractory multiple myeloma. We found that this combination was highly effective in inducing responses in all treatment groups with an overall response rate of 83.8%. CTD was well tolerated and did not impair stem cell mobilization.

  20. 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 inhibit...

  1. 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

  2. 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 the c...

  3. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial

    NARCIS (Netherlands)

    Grootscholten, C.; Ligtenberg, G.; Hagen, E. C.; van den Wall Bake, A. W. L.; de Glas-Vos, J. W.; Bijl, M.; Assmann, K. J.; Bruijn, J. A.; van Houwelingen, H. C.; Derksen, R. H. W. M.; Berden, J. H. M.; Weening, J.J.

    2006-01-01

    Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), w

  4. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial.

    NARCIS (Netherlands)

    Grootscholten, C.; Ligtenberg, G.; Hagen, E.C.; Wall Bake, A.W. van den; Glas-Vos, J.W. de; Bijl, M.; Assmann, K.J.M.; Bruijn, J.A.; Weening, J.J.; Houwelingen, H.C. van; Derksen, R.H.W.M.; Berden, J.H.M.

    2006-01-01

    Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), w

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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

  7. Antioxidative effect of ginseng stem-leaf saponins on oxidative stress induced by cyclophosphamide in chickens.

    Science.gov (United States)

    Yu, J; Chen, Y; Zhai, L; Zhang, L; Xu, Y; Wang, S; Hu, S

    2015-05-01

    Previous investigation demonstrated that oral administration of ginseng stem-leaf saponins in chickens could enhance the immune response. The present study was designed to evaluate the effects of ginseng stem-leaf saponins on oxidative stress induced by cyclophosphamide in chickens. One hundred and twenty chickens were randomly divided into 5 groups. Groups 1 to 4 received intramuscular injection of cyclophosphamide to induce oxidative stress while group 5 was injected with saline solution and served as control. Following administration of cyclophosphamide, groups 1 to 3 were orally administered ginseng stem-leaf saponins at 2.5, 5, and 10 mg/kg BW in drinking water for 7 d, respectively. After that, the spleen, thymus, bursa, and serum were collected to measure the indices of the organs and oxidative parameters. The results showed that ginseng stem-leaf saponins significantly inhibited cyclophosphamide-induced oxidative stress by increasing the organ indices, total antioxidant capacity, and the levels of glutathione, ascorbic acid, and α-tocopherol, while elevating the activity of total superoxide dismutase, catalase, and glutathione peroxidase, as well as decreasing the protein carbonyl content and malondialdehyde. Therefore, ginseng stem-leaf saponins could be a promising agent against oxidative stress in the poultry industry.

  8. 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.

  9. Cyclophosphamide: effect in the biodistribution of the radiopharmaceutical in female mice

    Energy Technology Data Exchange (ETDEWEB)

    Alves, I.P. [Comissao Nacional de Energia Nuclear (CNEN), Rio de Janeiro, RJ (Brazil); Paula, E.F. de; Correa, T.G.; Freitas, L.C. de; Fonseca, L. [Instituto Nacional do Cancer, Rio de Janeiro, RJ (Brazil); Bernardo Filho, M. [Universidade do Estado, Rio de Janeiro, RJ (Brazil). Inst. de Biologia

    1995-12-31

    The effect of cyclophosphamide in the biological distribution of pertechnetate ({sup 99m} TcO{sub 4}), entered intravenously in mice (female) Balb/c in two doses with an interval of 48 hours. Then, a dose of {sup 99m} Tc, as Na{sup 99m} Tc O{sub 4} (250 kBq), milked from a {sup 99} Mo/{sup 99m} Tc generator was administered. These animals were sacrificed, the organs isolated and the activities determined in a well counter. The percentage of radioactivity was calculated dividing the activity in each organ by the sum of the activities in the isolated organs. The analysis of the results has shown that cyclophosphamide did not modify the radioactivity in heart, kidney and stomach. In the spleen the percentage of radioactivity per gram of tissue increased (6.83 to 9.14). Cyclophosphamide increased radioactivity in brain, thyroid, uterus, ovary, liver and lung. These results can be explained by the metabolic process and/or therapeutic effect of cyclophosphamide. (author). 13 refs, 4 tabs.

  10. Polaprezinc attenuates cyclophosphamide-induced cystitis and related bladder pain in mice

    Directory of Open Access Journals (Sweden)

    Masahiro Murakami-Nakayama

    2015-02-01

    Full Text Available Cav3.2 T-type Ca2+ channels targeted by H2S, a gasotransmitter, participate in cyclophosphamide-induced cystitis and bladder pain. Given that zinc selectively inhibits Cav3.2 among T-channel isoforms and also exhibits antioxidant activity, we examined whether polaprezinc (zinc-l-carnosine, a medicine for peptic ulcer treatment and zinc supplementation, reveals preventive or therapeutic effects on bladder inflammation and/or pain in the mouse with cyclophosphamide-induced cystitis, a model for interstitial cystitis. Systemic administration of cyclophosphamide caused cystitis-related symptoms including increased bladder weight and vascular permeability, and histological signs of bladder edema, accompanied by bladder pain-like nociceptive behavior/referred hyperalgesia. All these symptoms were significantly attenuated by oral preadministration of polaprezinc at 400 mg/kg. The same dose of polaprezinc also prevented the increased malondialdehyde level, an indicator of lipid peroxidation, and protein upregulation of cystathionine-γ-lyase, an H2S-generating enzyme, but not occludin, a tight junction-related membrane protein, in the bladder tissue of cyclophosphamide-treated mice. Oral posttreatment with polaprezinc at 30–100 mg/kg reversed the nociceptive behavior/referred hyperalgesia in a dose-dependent manner without affecting the increased bladder weight. Together, our data show that zinc supplementation with polaprezinc prevents the cyclophosphamide-induced cystitis probably through the antioxidant activity, and, like T-channel blockers, reverses the established cystitis-related bladder pain in mice, suggesting novel therapeutic usefulness of polaprezinc.

  11. Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts.

    Science.gov (United States)

    Al-Katib, A M; Smith, M R; Kamanda, W S; Pettit, G R; Hamdan, M; Mohamed, A N; Chelladurai, B; Mohammad, R M

    1998-05-01

    The down-regulation of multidrug resistance (mdr1) gene expression as detected by competitive reverse transcription-PCR and the antitumor activity of bryostatin 1 (Bryo1) are investigated in a newly established cell line from a patient with relapsed diffuse large cell lymphoma (DLCL). The cell line (WSU-DLCL2) grows in liquid culture and forms s.c. tumors in mice with severe combined immune deficiency. WSU-DLCL2 is a mature B-cell line (IgG lambda) that is negative for EBV nuclear antigen, expresses the multidrug resistance phenotype, and has t(14;18)(q32;q21) plus other chromosomal aberrations. Exposure of the WSU-DLCL2 cells to Bryo1 in culture reversed the multidrug resistance phenotype within 24 h. A functional assay revealed a 4-fold increase in [3H]vincristine accumulation in Bryo1-treated cells compared with control. Vincristine (VCR), doxorubicin, Bryo1, and 1-beta-D-arabinofuranosylcytosine showed no clinically significant activity when given alone to WSU-DLCL2-bearing severe combined immune deficiency mice. However, when given 24 h before each cytotoxic agent, Bryo1 substantially increased the antitumor activity of VCR but not 1-beta-D-arabinofuranosylcytosine. There was a statistically significant (P animals compared with untreated controls. In vivo, a competitive reverse transcription-PCR assay revealed decreased mdr1 RNA expression 24 h after Bryo1 treatment. These findings taken together indicate that Bryo1-induced down-regulation of mdr1 might be one mechanism by which Bryo1 potentiates VCR activity. The sequential use of both agents resulted in clinically significant antitumor activity in this lymphoma model.

  12. Retrospective comparison between a regular and a split-dose protocol of 5-fluorouracil, cisplatin, and mitoxantrone for the treatment of far advanced hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Pan Kuang-Tse

    2011-03-01

    Full Text Available Abstract Background In patients with advanced hepatocellular carcinoma (HCC, combination chemotherapy using 5- fluorouracil, cisplatin, and mitoxantrone (FMP could achieve a response rate > 20%, but the beneficial effect was compromised by formidable adverse events. Chemotherapy given in a split-dose manner was associated with reduced toxicities. In this retrospective study, we compared the efficacies and side effects between a regular and a split-dose FMP protocol approved in our medical center. Methods From 2005 to 2008, the clinical data of 84 patients with far advanced HCC, who had either main portal vein thrombosis and/or extrahepatic metastasis, were reviewed. Of them, 65 were treated by either regular (n = 27 or split-dose (n = 38 FMP and had completed at least one therapeutic course. The remaining 19 patients were untreated. Clinical parameters, therapeutic responses, survivals and adverse events were compared. Results The median overall survival was 6.0, 5.2, and 1.5 months, respectively, in patients receiving regular FMP, split-dose FMP, and no treatment (regular versus split-dose group, P = 0.447; regular or split-dose versus untreated group; P Conclusions Comparable overall survival was observed between patients receiving regular and split-dose FMP therapies. Patients receiving split-dose therapy had a significantly lower risk of grade 3/4 neutropenia. Positive anti-hepatitis C virus antibody, smaller tumor size, and absence of previous anti-cancer therapy were independent predictors for successful disease control.

  13. Visual recovery in a man with the rare combination of mtDNA 11778 LHON mutation and a MS-like disease after mitoxantrone therapy.

    Science.gov (United States)

    Buhmann, C; Gbadamosi, J; Heesen, C

    2002-10-01

    We describe a young man with prognostic unfavourable homoplasmatic mitochondrial DNA(mt DNA) 11778 Leber's hereditary optic neuropathy (LHON) point mutation and confirmed multiple sclerosis (MS). This combination of LHON and MS-like disease is rare in both sexes, and in men has been described in only a few case reports. In a 4-year follow-up during immunosuppressive therapy with mitoxantrone, we found a remarkable time delayed visual recovery 12 months after acute onset of rapid sequential bilateral subtotal visual loss followed by episodes of isolated acute demyelinative optic neuropathy. Visual recovery to such extent after this latency is uncommon in both mtDNA 11778 LHON mutation and optic neuritis (ON) in MS. Relapses in visual deterioration must be considered as extremely rare in LHON. This case might support the hypothesis of an immunological pathogenetic factor in combined LHON and MS, and possibly in LHON alone. We suggest a search for the LHON mutation in MS patients with predominant visual impairment, independent of patients' gender.

  14. Nanostructured lipid-carrageenan hybrid carriers (NLCCs) for controlled delivery of mitoxantrone hydrochloride to enhance anticancer activity bypassing the BCRP-mediated efflux.

    Science.gov (United States)

    Ling, Guixia; Zhang, Tianhong; Zhang, Peng; Sun, Jin; He, Zhonggui

    2016-08-01

    Novel nanostructured lipid-carrageenan hybrid carriers (NLCCs) were exploited for controlled delivery of water soluble chemotherapeutic agent mitoxantrone hydrochloride (MTO) with high loading capacity, sustained release property, and potential for improving oral bioavailability and antitumor efficacy. By introducing the negative polymer of carrageenan, MTO was highly incorporated into NLCCs with encapsulation efficiency of 95.8% by electrostatic interaction. In vivo pharmacokinetics of MTO solution (MTO-Sol) and MTO-NLCCs in rats demonstrated that the apparent bioavailability of MTO-NLCCs was increased to approximate 3.5-fold compared to that of MTO-Sol. The cytotoxicity investigations by MTT method indicated that NLCCs could significantly enhanced the antitumor efficacy against resistant MCF-7/MX cells. The relative cellular association of MTO-NLCCs was 9.2-fold higher than that of MTO-Sol in breast cancer resistance protein (BCRP) over-expressing MCF-7/MX cells, implying that BCRP-mediated drug efflux was diminished by the introduction of NLCCs. The endocytosis inhibition study implied that the NLCCs entered the MCF-7/MX cells by clathrin-mediated endocytosis process, which can bypass the efflux of MTO mediated by BCRP. The new developed NLCCs provide an effective strategy for oral delivery of water-soluble MTO with improved encapsulation efficiency, oral bioavailability, and cytotoxicity against resistant breast cancer cells.

  15. Folic acid-conjugated TiO2-doped mesoporous carbonaceous nanocomposites loaded with Mitoxantrone HCl for chemo-photodynamic therapy.

    Science.gov (United States)

    Li, Zhi; Ou-Yang, Ya; Liu, Yang; Wang, Yi-Qiu; Zhu, Xia-Li; Zhang, Zhen-Zhong

    2015-06-01

    Recently, porous carbons have showed great potential in many areas. In this study, TiO2-doped mesoporous carbonaceous (TiO2@C) nanoparticles were obtained by a simple one-pot hydrothermal treatment, folic acid (FA) was conjugated to TiO2@C through an amide bond, then Mitoxantrone HCl (MTX) was adsorbed onto TiO2@C-FA and a drug delivery system, TiO2@C-FA/MTX was obtained. TiO2@C-FA/MTX showed a much faster MTX release at pH 4.5 than at pH 6.0 and pH 7.4. Furthermore, compared with free MTX, this drug delivery system showed a dose-dependent cytotoxicity by varying the irradiance, and afforded higher antitumor efficacy in cultured PC3 cells in vitro. The ability of TiO2@C-FA/MTX to combine chemotherapy with photodynamic activity enhanced the cancer cell killing effect in vitro, demonstrating that TiO2@C-FA/MTX has a great potential for cancer therapy in the future.

  16. Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma

    Science.gov (United States)

    Veal, Gareth J.; Cole, Michael; Chinnaswamy, Girish; Sludden, Julieann; Jamieson, David; Errington, Julie; Malik, Ghada; Hill, Christopher R.; Chamberlain, Thomas; Boddy, Alan V.

    2016-01-01

    Introduction Variation in cyclophosphamide pharmacokinetics and metabolism has been highlighted as a factor that may impact on clinical outcome in various tumour types. The current study in children with B-cell non-Hodgkin's lymphoma (NHL) was designed to corroborate previous findings in a large prospective study incorporating genotype for common polymorphisms known to influence cyclophosphamide pharmacology. Methods A total of 644 plasma samples collected over a 5 year period, from 49 B-cell NHL patients ≤18 years receiving cyclophosphamide (250 mg/m2), were used to characterise a population pharmacokinetic model. Polymorphisms in genes including CYP2B6 and CYP2C19 were analysed. Results A two-compartment model provided the best fit of the population analysis. The mean cyclophosphamide clearance value following dose 1 was significantly lower than following dose 5 (1.83 ± 1.07 versus 3.68 ± 1.43 L/h/m2, respectively; mean ± standard deviation from empirical Bayes estimates; P < 0.001). The presence of at least one CYP2B6*6 variant allele was associated with a lower cyclophosphamide clearance following both dose 1 (1.54 ± 0.11 L/h/m2 versus 2.20 ± 0.31 L/h/m2, P = 0.033) and dose 5 (3.12 ± 0.17 L/h/m2 versus 4.35 ± 0.37 L/h/m2, P = 0.0028), as compared to homozygous wild-type patients. No pharmacokinetic parameters investigated were shown to have a significant influence on progression free survival. Conclusion The results do not support previous findings of a link between cyclophosphamide pharmacokinetics or metabolism and disease recurrence in childhood B-cell NHL. While CYP2B6 genotype was shown to influence pharmacokinetics, there was no clear impact on clinical outcome. PMID:26773420

  17. Evaluation of Protective Effects of Crocin Onembyo Developing Process in in Vitro Fertilization (IVFin Cyclophosphamide Treated Mice

    Directory of Open Access Journals (Sweden)

    F Khan Mohammadi

    2014-05-01

    Conclusion: The co-administration of crocin with CP chemotherapy caused a significant improvement in fertilizing potential and promoted the embryo development. Key words: Cyclophosphamide, Crocin, Mice, Oocyte, In vitro fertilizing

  18. Curative effect observation of patients with primary systemic amyloidosis treated by the combination of bortezomib with dexmethasone and cyclophosphamide

    Institute of Scientific and Technical Information of China (English)

    路瑾

    2013-01-01

    Objective To analyze the efficacy and side effects of the combination regimen containing bortezomib,cyclophosphamide and dexamethasone(BCD)in the treatment of primary systemic amyloidosis(PSA).Methods

  19. Sustained complete remission of steroid- and cyclophosphamide-resistant minimal-change disease with a single course of rituximab therapy

    National Research Council Canada - National Science Library

    Janardan, Jyotsna; Ooi, Khai; Menahem, Solomon

    2014-01-01

    We report a case of steroid- and cyclophosphamide-resistant nephrotic syndrome secondary to minimal-change disease occurring in an otherwise healthy 19-year-old female, responding rapidly to two doses...

  20. A Comparative Effectiveness Research of Azathioprine and Cyclophosphamide on the Clinical and Serological Response in Pemphigus Vulgaris

    Science.gov (United States)

    Sardana, Kabir; Agarwal, Pooja; Bansal, Shivani; Uppal, Beena; Garg, Vijay K

    2016-01-01

    Context: A prospective study was carried out to examine the efficacy of cyclophosphamide and azathioprine in pemphigus vulgaris. Aims: To compare the clinical and serological effect of azathioprine and cyclophosphamide in pemphigus patients. Materials and Methods: Prospective, institutional based study was conducted twenty-one patients of pemphigus vulgaris were initiated on either azathioprine (n = 9) or cyclophosphamide (n = 7) in addition to prednisolone and were evaluated clinically (mucosal and cutaneous severity) and serologically enzyme-linked immunosorbent assay (ELISA) at 0, 3 and 6 months. Results: Azathioprine had a slower onset of action with a statistically significant improvement seen by 6 months (P = 0.016). Cyclophosphamide had a faster onset of action (3 months) though there was no statistical difference in the efficacy between the two at the end of 6 months. The (RonT) was 33.3–44.4% for azathioprine and 28.8–42.9% for cyclophosphamide at 6 months. Though ELISA had a high sensitivity and specificity for diagnosis, as a tool for assessing therapeutic response a significant decrease was seen only till 3 months. This was restricted to Dsg1 for the azathioprine group and both Dsg3 and Dsg1 levels for the cyclophosphamide group. There were two deaths, both in the cyclophosphamide group. Conclusions: Azathiorpine and cyclophosphamide are equally effective for mucosal and cutaneous disease in pemphigus after 6 months of therapy. Dsg ELISA is useful for diagnosis of pemphigus but is not a useful tool for monitoring response to therapy. PMID:27512188

  1. Cyclophosphamide Perturbs Cytosine Methylation in Jurkat-T Cells through LSD1-mediated Stabilization of DNMT1 Protein

    OpenAIRE

    ZHANG Jing; Yuan, Bifeng; Zhang, Fan; Xiong, Lei; Wu, Jiang; Pradhan, Sriharsa; Wang, Yinsheng

    2011-01-01

    Aberrant cytosine methylation is known to be associated with cancer development. Here we assessed how common cancer chemotherapeutic agents perturb cytosine methylation in Jurkat-T acute lymphoblastic leukemia cells. We tested six anti-tumor agents and found that cyclophosphamide induced the most pronounced increase in global DNA cytosine methylation after a 24-hr treatment. Long-term treatment with cyclophosphamide led to a time-dependent increase in cytosine methylation level with up to 4 d...

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Immunomodulatory effect of Moringa oleifera Lam. extract on cyclophosphamide induced toxicity in mice.

    Science.gov (United States)

    Gupta, Anamika; Gautam, Manish K; Singh, Rahul K; Kumar, M Vijay; Rao, Ch V; Goel, R K; Anupurba, Shampa

    2010-11-01

    Immunomodulatory effect of ethanolic extract (50%) of M. oleifera leaves (MOE) has been studied in normal and immunosuppressed mice models. Different doses of MOE i.e. 125, 250 and 500 mg/kg body weight of mice were administered orally for 15 days. Cyclophosphamide at a dose of 30 mg/kg body weight was administered orally for the next 3 days. On day 16 and 19, hematological parameters like white blood cell (WBC) count, red blood cell (RBC) count, haemoglobin level (Hb), percent neutrophils and organ weight were recorded. Effect of MOE on phagocytic activity of mice macrophages was determined by carbon clearance test. MOE showed significant dose dependent increase in WBC, percent neutrophils, weight of thymus and spleen along with phagocytic index in normal and immunosuppressed mice. The results indicate that MOE significantly reduced cyclophosphamide induced immunosuppression by stimulating both cellular and humoral immunity.

  4. Cyclophosphamide, doxorubicin, and cisplatin combined in the treatment of advanced sarcomas.

    Science.gov (United States)

    Edmonson, J H; Hahn, R G; Schutt, A J; Bisel, H F; Ingle, J N

    1983-01-01

    Twenty-five patients with evaluable histologically confirmed inoperable metastatic sarcomas were treated once every four weeks with cyclophosphamide, doxorubicin, and cisplatin in doses of 400, 40, and 60 mg/m2, respectively. Cyclophosphamide and doxorubicin were given by rapid intravenous injection followed immediately by cisplatin by slow intravenous infusion (2-6 hr) in 1 liter of 0.45% saline with mannitol added. Leukopenia, alopecia, and vomiting were common side effects and three patients refused further treatment because of vomiting following their initial courses. No drug-related deaths occurred and we removed no one from the study because of toxicity problems. Among the 9 patients who experienced objective tumor regression were 2 of 2 with hemangiosarcoma, 3 of 5 with malignant fibrous histiocytoma, 3 of 5 with osteosarcoma, and 1 of 1 with pleomorphic liposarcoma of bone. Although not therapeutically gratifying, these results appear to be better than any previously observed at our institution.

  5. Carboplatin (JM 8), adriamycin and cyclophosphamide (JAC) in advanced ovarian carcinoma: a pilot study.

    Science.gov (United States)

    Conte, P F; Bruzzone, M; Chiara, S; Rosso, R; Giaccone, G; Carnino, F; Guercio, E; Ragni, N; Foglia, G; Bentivoglio, G

    1988-04-30

    Eleven untreated patients with advanced ovarian cancer were studied for tolerance and response to combination treatment with fixed doses of adriamycin (45 mg/m2) and cyclophosphamide (600 mg/m2) + escalating doses of carboplatin. At the first dose level of carboplatin (200 mg/m2), toxicity was acceptable. With carboplatin at 300 mg/m2, severe hematologic toxicity was observed. The dose-limiting toxicity was leukopenia. Although carboplatin was administered without any hydration, no patient experienced renal toxicity. Eight objective responses were observed in 9 clinically evaluable patients. At second look surgery, 3 complete responses and 4 partial responses were documented. Polychemotherapy with JAC (carboplatin, 200 mg/m2, adriamycin, 45 mg/m2, and cyclophosphamide, 600 mg/m2) is administrable with acceptable toxicity.

  6. Development of Reversible Posterior Leukoencephalopathy Syndrome after Cyclophosphamide Treatment in a Patient with Lupus Nephritis

    Directory of Open Access Journals (Sweden)

    Serkan YILDIZ

    2011-01-01

    Full Text Available Renal involvement in systemic lupus erythematosus is a frequent and serious complication that significantly increases morbidity and mortality. Despite all studies and usage of new drugs, treatment of lupus nephritis continues to be a problem. Diffuse proliferative lupus nephritis has a poor prognosis and aggressive treatment must be undertaken. Cyclophosphamide is commonly used in treatment despite its side effects. Reversible posterior leucoencephalopathy syndrome is a clinico-radiological syndrome manifested by blood pressure elevation, headache, visual disturbances, confusion, seizures and sometimes focal neurological signs that can develop due to usage of cytotoxic drugs. We present a case of lupus nephritis in which reversible posterior leucoencephalopathy syndrome developed after intravenous cyclophosphamide administration and recovered spontaneously by symptomatic treatment in this article.

  7. Chemotherapy of disseminated seminoma with combination of cis-diamminedichloroplatinum (II) and cyclophosphamide.

    Science.gov (United States)

    Vugrin, D; Whitemore, W J; Batata, M

    1981-01-01

    Nine patients with metastatic seminoma who had received no prior chemotherapy were induced with a combination containing cis-platinum 120 mg/m2 I.V. and cyclophosphamide 600 mg/m2 I.V. for three to six treatments at 4-6 weeks intervals, and then received maintenance with cyclophosphamide 600 mg/m2 I.V. every 3-4 weeks to complete 2 years of chemotherapy. Eight patients entered complete remission: five with chemotherapy alone and three with chemotherapy and radiation or resection of residual disease. Seven patients remain in CR with a minimum follow up of 17 months. Chemotherapy is effective in treatment of metastatic seminoma.

  8. Green tea extract increases cyclophosphamide-induced teratogenesis by modulating the expression of cytochrome P-450 mRNA.

    Science.gov (United States)

    Park, Dongsun; Jeon, Jeong Hee; Shin, Sunhee; Joo, Seong Soo; Kang, Dae-Hyuck; Moon, Seol-Hee; Jang, Min-Jung; Cho, Yeoung Mi; Kim, Jae Wook; Ji, Hyeong-Jin; Ahn, Byeongwoo; Oh, Ki-Wan; Kim, Yun-Bae

    2009-01-01

    The effects of green tea extract (GTE) on the fetal development and external, visceral and skeletal abnormalities induced by cyclophosphamide were investigated in rats. Pregnant rats were daily administered GTE (100mg/kg) by gavage for 7 d, from the 6th to 12th day of gestation, and intraperitoneally administered with cyclophosphamide (11mg/kg) 1h after the final treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarian section. Cyclophosphamide was found to reduce fetal and placental weights without increasing resorption or death. In addition, it induced malformations in live fetuses; 94.6%, 41.5% and 100% of the external (skull and limb defects), visceral (cleft palate and ureteric dilatation) and skeletal (acrania, vertebral/costal malformations and delayed ossification) abnormalities. When pre-treated with GTE, cyclophosphamide-induced body weight loss and abnormalities of fetuses were remarkably aggravated. Moreover, repeated treatment with GTE greatly increased mRNA expression and activity of hepatic cytochrome P-450 (CYP) 2B, which metabolizes cyclophosphamide into teratogenic acrolein and cytotoxic phosphoramide mustard, while reducing CYP3A expression (a detoxifying enzyme). The results suggest that repeated intake of GTE may aggravate cyclophosphamide-induced body weight loss and malformations of fetuses by modulating CYP2B and CYP3A.

  9. Survival and tumorigenesis in O6-methylguanine DNA methyltransferase-deficient mice following cyclophosphamide exposure

    OpenAIRE

    Nagasubramanian, Ramamoorthy; Hansen, Ryan J.; Delaney, Shannon M.; Cherian, Mathew M.; Samson, Leona D.; Kogan, Scott C.; Dolan, M Eileen

    2008-01-01

    O6-methylguanine DNA methyltransferase (MGMT) deficiency is associated with an increased susceptibility to alkylating agent toxicity. To understand the contribution of MGMT in protecting against cyclophosphamide (CP)-induced toxicity, mutagenesis and tumorigenesis, we compared the biological effects of this agent in transgenic Mgmt knockout and wild-type mice. In addition, neurofibromin (Nf1)+/− background was used to increase the likelihood of CP-induced tumorigenesis. Cohorts of Mgmt-profic...

  10. Safety and efficacy of combined cyclophosphamide and rituximab treatment in recalcitrant childhood lupus.

    Science.gov (United States)

    Ale'ed, Ashwaq; Alsonbul, Abdullah; Al-Mayouf, Sulaiman M

    2014-04-01

    To report the safety and efficacy of combined cyclophosphamide and rituximab treatment in Saudi children with systemic lupus erythematosus (SLE). Medical records of all children with SLE treated with cyclophosphamide and rituximab between June 2007 and June 2012 at King Faisal Specialist Hospital and Research Center, Riyadh, were reviewed for demographic characteristics, age at diagnosis, concomitant treatments, indication of using rituximab and adverse events during the treatment period. Clinical and serologic response parameters included SLE Disease Activity Index (SLEDAI), complement, anti-ds DNA antibody and ANA levels, and mean daily corticosteroid dose assessed 3 months before combined cyclophosphamide and rituximab infusion course and at 6-month interval afterward. Sixteen patients (13 girls) with refractory SLE treated with cyclophosphamide and rituximab were included. The mean age at onset of SLE was 7.8 + 3.3 years, while the mean age at diagnosis was 8.1 + 3.4 years; the mean disease duration was 4.7 + 3.2 years. All patients were treated with corticosteroid and immunosuppressive drugs. Nephritis (8 patients) was the most frequent indication; other indications included refractory arthritis, thrombocytopenia, severe mucocutaneous lesions and central nervous system involvement. All patients received 2 doses, but 4 required 4-8 extra doses. All patients showed improvement in response parameters. There was significant reduction in SLEDAI (P < 0.0002) and corticosteroid dose (P < 0.005). A total of 4 adverse events were notified; 2 developed infusion-related reactions. One patient had severe soft tissue fungal infection, and other patient had pancreatitis. Our data showed beneficial therapeutic and steroid-sparing effects of rituximab as adjunctive treatment for children with refractory SLE including both renal and extrarenal manifestations. Although rituximab was well tolerated by the majority of patients, it may associated with various adverse events.

  11. Effective chemoimmunotherapy with anti-TGFβ antibody and cyclophosphamide in a mouse model of breast cancer.

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    Xin Chen

    Full Text Available TGFβ is reportedly responsible for accumulation of CD4(+Foxp3(+ regulatory T cells (Tregs in tumor. Thus, we treated mouse 4T1 mammary carcinoma with 1D11, a neutralizing anti-TGFβ (1,2,3 antibody. The treatment delayed tumor growth, but unexpectedly increased the proportion of Tregs in tumor. In vitro, 1D11 enhanced while TGFβ potently inhibited the proliferation of Tregs. To enhance the anti-tumor effects, 1D11 was administered with cyclophosphamide which was reported to eliminate intratumoral Tregs. This combination resulted in long term tumor-free survival of up to 80% of mice, and the tumor-free mice were more resistant to re-challenge with tumor. To examine the phenotype of tumor infiltrating immune cells, 4T1-tumor bearing mice were treated with 1D11 and a lower dose of cyclophosphamide. This treatment markedly inhibited tumor growth, and was accompanied by massive infiltration of IFNγ-producing T cells. Furthermore, this combination markedly decreased the number of splenic CD11b(+Gr1(+ cells, and increased their expression levels of MHC II and CD80. In a spontaneous 4T1 lung metastasis model with resection of primary tumor, this combination therapy markedly increased the survival of mice, indicating it was effective in reducing lethal metastasis burden. Taken together, our data show that anti-TGFβ antibody and cyclophosphamide represents an effective chemoimmunotherapeutic combination.

  12. Protective effect of Satureja montana extract on cyclophosphamide-induced testicular injury in rats.

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    Abd El Tawab, Azza M; Shahin, Nancy N; AbdelMohsen, Mona M

    2014-12-05

    The present study investigated the protective effect of Satureja montana extract against cyclophosphamide-induced testicular injury in rats. Total phenolic and flavonoid contents of the extract were 1.03% and 0.34%w/w of dry herb expressed as chlorogenic acid and quercetin, respectively. HPLC analysis identified caffeic, syringic and rosmarinic acids as the chief phenolic acids, and rutin as the major flavonoid in the extract. Oral daily administration of S.montana extract (50mg/kg/day) for 7days before and 7days after an intraperitoneal injection of cyclophosphamide (200mg/kg) restored the reduced relative testicular weight, serum testosterone level and testicular alkaline phosphatase activity, raised the lowered testicular sorbitol dehydrogenase and acid phosphatase activities, and decreased the elevated testicular hemoglobin absorbance. It also attenuated lipid peroxidation, restored the lowered glutathione content, glucose-6-phosphate dehydrogenase, glutathione peroxidase and glutathione reductase activities, and improved total antioxidant capacity. Moreover, S.montana extract mitigated testicular DNA fragmentation, decreased the elevated Fas and Bax gene expression, up-regulated the decreased Bcl-2 and peroxisome proliferator-activated receptor-gamma (PPAR-γ) gene expression and normalized Akt1 protein level. Histopathological investigation confirmed the protective effects of the extract. Conclusively, S.montana extract protects the rat testis against cyclophosphamide-induced damage via anti-oxidative and anti-apoptotic mechanisms that seem to be mediated, at least in part, by PPAR-γ and Akt1 up-regulation.

  13. 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.

  14. Mitigating Role of Quercetin Against Cyclophosphamide-Induced Lung Injury in Rats

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    Nora A. Asry

    2014-05-01

    Full Text Available Quercetin (Qur, a polyphenolic flavonoid compound present in large amounts in vegetables and fruits, plays important roles in human health through its antioxidant activity. This study was conducted to investigate the possible modulatory effect of Qur against cyclophosphamide (CP-induced lung oxidative damage and to highlight the underlying mechanisms of such effect. Male Sprague-Dawely rats were divided into four groups. Group I was control. Group II received Qur (100 mg/kg/d. p.o. for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.. Group IV received Qur for 7 consecutive days, before and after CP injection.A single i.p. injection of CP markedly increased the level of serum biomarkers; total protein, LDH. Cyclophosphamide significantly increased the lung content of lipid peroxides and decreased levels of reduced glutathione. Treatment of rats with Qur for 7 days prior to and 7 days after cyclophosphamide significantly ameliorated the alterations in lung and serum biomarkers associated with inflammatory reactions. Moreover, Qur attenuated the secretion of pro-inflammatory cytokine, TNF-α in rat serum. In addition, Qur slightly ameliorated CP-induced histopathological changes in lung tissue. Our results suggest that Qur produces a protective effect against CP-induced lung injury and suggest a role of oxidative stress and inflammation in the pathogenesis.

  15. Hyperbaric oxygen-A new horizon in treating cyclophosphamide-induced hemorrhagic cystitis

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    S Ajith Kumar

    2011-01-01

    Full Text Available Hemorrhagic cystitis consists of acute or insidious diffuse bleeding from the bladder mucosa. It can be caused by radiation, drugs, autoimmune diseases, viral and bacterial infections, etc. Hemorrhagic cystitis is a well-recognized complication of cyclophosphamide therapy and it can be potentially fatal. We discuss two cases of cyclophosphamide-induced hemorrhagic cystitis where outcome of conventional management was not satisfactory and a novel therapy using hyperbaric oxygen was used. Hyperbaric oxygen therapy (HBOT reduces inflammation, stimulates neoangiogenesis, maintains tissue oxygenation and heals tissue hypoxia and radio necrosis. Patients received 100% oxygen in a hyperbaric chamber at 2.5 atmosphere absolute (ATA for 90 minutes, 5 days a week. One patient was given 36 sessions and the other was given 19 sessions of HBOT. HBOT resulted in complete cessation of bleeding; no side effect was noted during the course of therapy. There was no relapse after 12 months of cessation of treatment. In future, this form of therapy can offer a safe alternative in the treatment of cyclophosphamide-induced hemorrhagic cystitis.

  16. Long-term follow-up of rituximab plus first-line mitoxantrone, chlorambucil, prednisolone and interferon-alpha as maintenance therapy in follicular lymphoma.

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    Herold, Michael; Scholz, Christian W; Rothmann, Frank; Hirt, Carsten; Lakner, Volker; Naumann, Ralph

    2015-09-01

    The randomised, controlled OSHO#39 study showed promising results using first-line mitoxantrone, chlorambucil and prednisolone (MCP) chemotherapy plus rituximab in patients with advanced symptomatic follicular lymphoma (FL) in need of therapy. The aim of this long-term follow-up was to investigate whether clinical benefits are maintained after up to 9 years of observation. Following the 4-year follow-up of OSHO#39, 77 FL patients who received rituximab plus MCP (R-MCP) and 52 patients who received MCP (129 patients alive and not previously censored in total) were followed for 5 additional years in this prospective, non-interventional, observational study. For the efficacy analysis, data were jointly analysed with OSHO#39 data (FL intention-to-treat population: 105 patients R-MCP, 96 MCP). Patients not included in the 5-year follow-up were censored. For surviving patients, median follow-up was 102 months (R-MCP) and 87 months (MCP). Although median overall survival (OS) was not yet reached, OS was longer for patients with R-MCP compared with MCP (p = 0.0057), with 8-year-survival rates of 76.1 versus 55.9%. Further time-to-event data were substantially longer for the R-MCP group than for MCP alone: median progression-free survival (PFS) was 93.4 versus 34.9 months, and median event-free survival (EFS) 89.6 versus 26.5 months. Unplanned subanalyses of patients with and without interferon maintenance showed improved PFS and EFS without an impact on OS. The addition of rituximab to first-line MCP chemotherapy improves clinical outcomes in advanced FL patients and translates into long-term OS benefits. R-MCP remains a promising standard option for this patient group.

  17. Bioreductive activation of mitoxantrone by NADPH cytochrome P450 reductase does not change its apoptotic stimuli properties in regard to sensitive and multidrug resistant leukaemia HL60 cells.

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    Kostrzewa-Nowak, Dorota; Tarasiuk, Jolanta

    2013-12-05

    The objective of this study was to examine the effect of bioreductive activation of antitumour drug, mitoxantrone (MX), by liver NADPH cytochrome P450 reductase (CPR) on inducing apoptosis of human promyelocytic sensitive leukaemia HL60 cell line and its multidrug resistance (MDR) sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX). It was found that non-activated as well as CPR-activated form of MX used at IC90 were able to influence cell cycle of sensitive HL60 as well as resistant cells and induce apoptosis. Interestingly, it was evidenced that HL60/VINC cells were more susceptible to undergo caspase-3/caspase-8-dependent apoptosis induced by both studied forms of MX compared to HL60 and HL60/DOX cells. However, the examined agent did not change the expression of Fas receptors on the surface of HL60 sensitive as well as resistant cells regardless of its form used in the study. Obtained results suggest that CPR-dependent reductive activation of MX does not change its apoptotic stimuli properties in regard to sensitive HL60 and multidrug resistant (HL60/VINC and HL60/DOX) leukaemia cells. Nevertheless, taking into account that side toxic effects observed in course of patient treatment with antitumour drugs are dose-dependent, it seems that the reported increase in antiproliferative activity and ability to induce apoptosis of MX after its reductive activation by exogenous CPR against the MDR cells overexpressing both P-glycoprotein and MRP1 at much more lower concentrations of this drug could be of clinical importance for the treatment of tumours resistant to classical chemotherapy. © 2013 Elsevier B.V. All rights reserved.

  18. Plasma membrane targeting by short chain sphingolipids inserted in liposomes improves anti-tumor activity of mitoxantrone in an orthotopic breast carcinoma xenograft model.

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    Cordeiro Pedrosa, Lília R; van Tellingen, Olaf; Soullié, Thomas; Seynhaeve, Ann L; Eggermont, Alexander M M; Ten Hagen, Timo L M; Verheij, Marcel; Koning, Gerben A

    2015-08-01

    Mitoxantrone (MTO) is clinically used for treatment of various types of cancers providing an alternative for similarly active, but more toxic chemotherapeutic drugs such as anthracyclines. To further decrease its toxicity MTO was encapsulated into liposomes. Although liposomal drugs can accumulate in target tumor tissue, they still face the plasma membrane barrier for effective intracellular delivery. Aiming to improve MTO tumor cell availability, we used short chain lipids to target and modulate the tumor cell membrane, promoting MTO plasma membrane traversal. MTO was encapsulated in liposomes containing the short chain sphingolipid (SCS), C8-Glucosylceramide (C8-GluCer) or C8-Galactosylceramide (C8-GalCer) in their bilayer. These new SCS-liposomes containing MTO (SCS-MTOL) were tested in vivo for tolerability, pharmacokinetics, biodistribution, tumor drug delivery by intravital microscopy and efficacy, and compared to standard MTO liposomes (MTOL) and free MTO. Liposomal encapsulation decreased MTO toxicity and allowed administration of higher drug doses. SCS-MTOL displayed increased clearance and lower skin accumulation compared to standard MTOL. Intratumoral liposomal drug delivery was heterogeneous and rather limited in hypoxic tumor areas, yet SCS-MTOL improved intracellular drug uptake in comparison with MTOL. The increased MTO availability correlated well with the improved antitumor activity of SCS-MTOL in a MDAMB-231 breast carcinoma model. Multiple dosing of liposomal MTO strongly delayed tumor growth compared to free MTO and prolonged mouse survival, whereas among the liposomal MTO treatments, C8-GluCer-MTOL was most effective. Targeting plasma membranes with SCS improved MTO tumor availability and thereby therapeutic activity and represents a promising approach to improve MTO-based chemotherapy.

  19. PI3K/Akt inhibition and down-regulation of BCRP re-sensitize MCF7 breast cancer cell line to mitoxantrone chemotherapy

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    Tahereh Komeili-Movahhed

    2015-05-01

    Full Text Available Objective(s:Multidrug resistance (MDR of cancer cells is a major obstacle to successful chemotherapy. Overexpression of breast cancer resistance protein (BCRP is one of the major causes of MDR. In addition, it has been shown that PI3K/Akt signaling pathway involves in drug resistance. Therefore, we evaluated the effects of novel approaches including siRNA directed against BCRP and targeted therapy against PI3K/Akt signaling pathway using LY294002 (LY to re-sensitize breast cancer MCF7 cell line to mitoxantrone (MTX chemotherapy. Materials and Methods: Anticancer effects of MTX, siRNA, and LY alone and in combination were evaluated in MCF7 cells using MTT cytotoxicity assay and flow cytometry analysis of cell cycle distribution and apoptosis induction. Results: MTT and apoptosis assays showed that both MTX and LY inhibited cell proliferation and induced apoptosis in MCF7 cells. Results indicated that inhibition of BCRP by siRNA or PI3K/Akt signaling pathway by LY significantly increased sensitivity of MCF7 cells to antiproliferation and apoptosis induction of MTX. Furthermore, MTX showed G2/M arrest, whereas LY induced G0/G1 arrest in cell cycle distribution of MCF7 cells. Combination of siRNA or LY with MTX chemotherapy significantly increased accumulation of MCF7 cells in the G2/M phase of cell cycle. Conclusion: Combination of MTX chemotherapy with BCRP siRNA and PI3K/Akt inhibition can overcome MDR in breast cancer cells. This study furthermore suggests that novel therapeutic approaches are needed to enhance anticancer effects of available drugs in breast cancer

  20. PI3K/Akt inhibition and down-regulation of BCRP re-sensitize MCF7 breast cancer cell line to mitoxantrone chemotherapy

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    Komeili-Movahhed, Tahereh; Fouladdel, Shamileh; Barzegar, Elmira; Atashpour, Shekoufeh; Hossein Ghahremani, Mohammad; Nasser Ostad, Seyed; Madjd, Zahra; Azizi, Ebrahim

    2015-01-01

    Objective(s): Multidrug resistance (MDR) of cancer cells is a major obstacle to successful chemotherapy. Overexpression of breast cancer resistance protein (BCRP) is one of the major causes of MDR. In addition, it has been shown that PI3K/Akt signaling pathway involves in drug resistance. Therefore, we evaluated the effects of novel approaches including siRNA directed against BCRP and targeted therapy against PI3K/Akt signaling pathway using LY294002 (LY) to re-sensitize breast cancer MCF7 cell line to mitoxantrone (MTX) chemotherapy. Materials and Methods: Anticancer effects of MTX, siRNA, and LY alone and in combination were evaluated in MCF7 cells using MTT cytotoxicity assay and flow cytometry analysis of cell cycle distribution and apoptosis induction. Results: MTT and apoptosis assays showed that both MTX and LY inhibited cell proliferation and induced apoptosis in MCF7 cells. Results indicated that inhibition of BCRP by siRNA or PI3K/Akt signaling pathway by LY significantly increased sensitivity of MCF7 cells to antiproliferation and apoptosis induction of MTX. Furthermore, MTX showed G2/M arrest, whereas LY induced G0/G1 arrest in cell cycle distribution of MCF7 cells. Combination of siRNA or LY with MTX chemotherapy significantly increased accumulation of MCF7 cells in the G2/M phase of cell cycle. Conclusion: Combination of MTX chemotherapy with BCRP siRNA and PI3K/Akt inhibition can overcome MDR in breast cancer cells. This study furthermore suggests that novel therapeutic approaches are needed to enhance anticancer effects of available drugs in breast cancer. PMID:26124933

  1. Successful management of refractory pleural effusion due to systemic immunoglobulin light chain amyloidosis by vincristine adriamycin dexamethasone chemotherapy: a case report

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    Mima Akira

    2010-10-01

    Full Text Available Abstract Introduction Refractory pleural effusion in systemic immunoglobulin light chain amyloidosis without cardiac decompensation is rarely reported and has a poor prognosis in general (a median survival of 1.6 months. Moreover, the optimum treatment for this condition is still undecided. This is the first report on the successful use of vincristine, adriamycin and dexamethasone chemotherapy for refractory pleural effusion due to systemic immunoglobulin light chain amyloidosis without cardiac decompensation. Case presentation We report the case of a 68-year old Japanese male with systemic immunoglobulin light chain amyloidosis presenting with bilateral pleural effusion (more severe on the right side in the absence of cardiac decompensation that was refractory to diuretic therapy. The patient was admitted for fatigue, exertional dyspnea, and bilateral lower extremity edema. He had been receiving intermittent melphalan and prednisone chemotherapy for seven years. One month before admission, his dyspnea had got worse, and his chest radiograph showed bilateral pleural effusion; the pleural effusion was ascertained to be a transudate. The conventionally used therapeutic measures, including diuretics and thoracocentesis, failed to control pleural effusion. Administration of vincristine, adriamycin, and dexamethasone chemotherapy led to successful resolution of the effusion. Conclusion Treatment with vincristine, adriamycin, and dexamethasone chemotherapy was effective for the refractory pleural effusion in systemic immunoglobulin light chain amyloidosis without cardiac decompensation and appears to be associated with improvement in our patient's prognosis.

  2. Correlation of the clinical neurotoxicity of the vinca alkaloids vincristine, vinblastine, and vindesine with their effects on cultured rat midbrain cells.

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    King, K L; Boder, G B

    1979-01-01

    Clinical experience with three vinca alkaloids currently in use as antineoplastic agents has shown a difference in the degree of peripheral neurotoxicity manifested by these compounds: vincristine greater than vindesine greater than vinblastine. This phenomenon may reflect differences in pharmacokinetics and/or the differential response of the nerve tissue itself. Differences in pharmacokinetics can be avoided by studying the direct effects of the vinca alkaloids on primary cultures of neuronal and glial cells. Vincristine at a dose as low as 0.004 microgram/ml affects the cells with processes in cultures of dissociated newborn rat midbrain. In 3-day-old cultures, after 24 h of drug treatment there is a loss of processes and swelling of the cell body. We have used this observation as the basis for a quantitative assay of the toxicity of a series of vinca compounds, and have found that for a dose range of 0.1--0.004 microgram/ml the relative toxicity of vincristine, vinblastine, and vindesine in this system correlates with their relative clinical neurotoxicity. Validation of the predictive elements of this system awaits clinical experience with novel vinca compounds.

  3. Study of action of cyclophosphamide and extract of mycelium of Pleurotus ostreatus in vivo on mice, bearing melanoma B16-F0-GFP

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    Meerovich, Irina G.; Yang, Meng; Jiang, Ping; Hoffman, Robert M.; Gerasimenya, Valery P.; Orlov, Alexander E.; Savitsky, Alexander P.; Popov, Vladimir O.

    2005-04-01

    In this work we studied in vivo the combined action of cyclophosphamide and the extract of mycelium of Pleurotus ostreatus on mice bearing melanoma B16-F0, expressing green fluorescent protein (GFP). This model allows to recognize small-size tumors and metastases, unrecognizable by other methods. It was found that combined administration of cyclophosphamide (300 mg/kg) and the extract of mycelium of Pleurotus ostreatus (100 mg/kg), administered for 10 days after cyclophosphamide injection, as well administration of cyclophosphamide alone, cause inhibition of tumor growth about 97%. It was shown that administration of the extract of mycelium of Pleurotus ostreatus alone leads to inhibition of tumor growth of 61%. It was found that in case of combined administration of cyclophosphamide and the extract of mycelium of Pleurotus ostreatus, leucopenia was less expressed than in case of administration of cyclophosphamide alone.

  4. Nonspecifically enhanced therapeutic effects of vincristine on multidrug-resistant cancers when coencapsulated with quinine in liposomes.

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    Xu, Yuzhen; Qiu, Liyan

    2015-01-01

    The use of vincristine (VCR) to treat cancer has been limited by its dose-dependent toxicity and development of drug resistance after repeated administrations. In this study, we investigated the mechanism by which quinine hydrochloride (QN) acts as a sensitizer for VCR. Our experiments used three kinds of multidrug-resistant cancer cells and demonstrated that QN worked by inducing intracellular depletion of adenosine triphosphate, increasing adenosine triphosphatase activity, and decreasing P-glycoprotein expression. Based on these results, we designed and prepared a VCR and QN codelivery liposome (VQL) and investigated the effect of coencapsulated QN on the in vitro cytotoxicity of VCR in cells and three-dimensional multicellular tumor spheroids. The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice. The results of this in vivo study indicated that VQL could reverse VCR resistance. In addition, it reduced tumor volume 5.4-fold when compared with other test groups. The data suggest that VQL could be a promising nanoscaled therapeutic agent to overcome multidrug resistance, and may have important clinical implications for the treatment of cancer.

  5. Vincristine-sulphate-loaded liposome-templated calcium phosphate nanoshell as potential tumor-targeting delivery system.

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    Thakkar, Hetal Paresh; Baser, Amit Kumar; Parmar, Mayur Prakashbhai; Patel, Ketul Harshadbhai; Ramachandra Murthy, Rayasa

    2012-06-01

    Vincristine-sulfate-loaded liposomes were prepared with an aim to improve stability, reduce drug leakage during systemic circulation, and increase intracellular uptake. Liposomes were prepared by the thin-film hydration method, followed by coating with calcium phosphate, using the sequential addition approach. Prepared formulations were characterized for size, zeta potential, drug-entrapment efficiency, morphology by transmission electron microscopy (TEM), in vitro drug-release profile, and in vitro cell cytotoxicity study. Effect of formulation variables, such as drug:lipid ratio as well as nature and volume of hydration media, were found to affect drug entrapment, and the concentration of calcium chloride in coating was found to affect size and coating efficiency. Size, zeta potential, and TEM images confirmed that the liposomes were effectively coated with calcium phosphate. The calcium phosphate nanoshell exhibited pH-dependent drug release, showing significantly lower release at pH 7.4, compared to the release at pH 4.5, which is the pH of the tumor interstitium. The in vitro cytotoxicity study done on the lung cancer cell line indicated that coated liposomes are more cytotoxic than plain liposomes and drug solution, indicating their potential for intracellular drug delivery. The cell-uptake study done on the lung cancer cell line indicated that calcium-phosphate-coated liposomes show higher cell uptake than uncoated liposomes.

  6. [Vincristine, adriamycin, mitomycin-C and UFT (VAM-UFT) therapy in progressive or recurrent breast cancer].

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    Yasutake, K; Imamura, Y; Yoshimura, Y; Oya, M; Matsushita, K; Hozumi, T; Katou, J; Okutani, T; Irie, K

    1989-07-01

    Since June 1984, 23 cases of progressive or recurrent breast cancers were treated with combination chemotherapy of VAM-UFT consisting of vincristine, adriamycin, mitomycin C and UFT. Clinical effects of VAM-UFT therapy were 3 CR, 12 PR, and the response rate was 65.2%. Its effective interval was 3 months. But the patients treated with over 4 cycles of VAM-UFT therapy showed an 85% response rate, with a 5-month effective interval. In each patient's background, a shorter disease free interval tended to be more highly effective, but other factors were not significant. Scirrhous carcinoma of pathology evidenced slightly high response rate. Compared with the survival time of patients treated with under 3 cycles and over 4 cycles of this therapy, the latter was significantly longer. Toxicity involved leukocytopenia (74%), thrombocytopenia (22%), anemia (30%), alopecia (91%), nausea and vomiting (87%) and stomatitis (35%), but cases in which the treatment was stopped were not observed. Therefore VAM-UFT therapy had a highly therapeutic effect, reflected in an 85% response rate, for progressive or recurrent breast cancers.

  7. A study upon the influence of cyclophosphamide treatment on the red blood cells of the chicken embryo (Short Notes

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    Delia Anca HAS-LAZAU

    2006-05-01

    Full Text Available The aim of this study is to show the effect of cyclophosphamide on the eveloping red blood cells of the 3-4 days old chicken embryo, when the hematopoiesis is at its peack, located at the vitelline sack level.I have chosen to work with the chicken embryo red blood cells because they have an intense mitotic activity as well as a tumoural cell-like behaviour.It is vital to know the particularities of the cell cycle of the healthy and tumoural cells, keeping in mind that most of the cytostatics act upon the cell which are developing their cell cycle (Menkes B., Prelipceanu O., Checiu I., Căpălnăşan I. 1979.The cyclophosphamide is not stage-dependent, as it acts in all the stages of the cell cycle, its mutagen effect being accompanied also by a cell cycle stopping (Paşca C., Crăciun C., Ardelean A. 2000.Cyclophosphamide supply determines retrenchment of the cell division, transforming the normal cells into multinucleated cells, with normal ploydia. The cyclophosphamide is a cytostatic using for cancer therapy (Schiavoni G., Mattei F., Di Pucchio T., Santini S. M., Bracci L., Berardelli F., Proietti F. 2000.Reshearches have done lots of studies along the years both on mice and rats, concerning the effects of cyclophosphamide on: thymus and burse fabricio ( Giurgea R., Toma V., 1977, stromal cells of bone marrow (Anton E. 1997, pulmonary thrombocytopoiesis (Sulkowki S., Sulkowska M., Musiatowikz B. 1997.

  8. Rapamycin Prevents cyclophosphamide-induced Over-activation of Primordial Follicle pool through PI3K/Akt/mTOR Signaling Pathway in vivo.

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    Zhou, Linyan; Xie, Yanqiu; Li, Song; Liang, Yihua; Qiu, Qi; Lin, Haiyan; Zhang, Qingxue

    2017-08-16

    Primordial follicular depletion has thought to be a common adverse effect of chemotherapy especially for female of reproductive age. The study aimed to evaluate the protective effect of rapamycin on the primordial follicles and its potential mechanism for patients receiving chemotherapy. 8-week old BALB/c female mice were randomly assigned into four groups (control; rapamycin; cyclophosphamide; and rapamycin combined with cyclophosphamide). Hematoxylin staining, immunohistochemical, TUNEL, western blotting and ELISA were employed to assess inter-group differences using Student's t-test and Mann-Whitney test. Cyclophosphamide depleted the follicular reserve and induced the phosphorylation of the key proteins of PI3K/Akt/mTOR pathway in mice in a dose-dependent manner. Co-treatment with rapamycin significantly reduced primordial follicle loss at all cyclophosphamide dose groups and prevent the follicle growth wave caused by cyclophosphamide treatment (P primordial follicles in all groups and fewer apoptosis in large growing follicles were observed in ovaries from rapamycin + cyclophosphamide group compared to that received cyclophosphamide alone. Serum anti-Müllerian hormone (AMH) was significantly reduced in cyclophosphamide alone group, in contrast to the normal level in rapamycin + cyclophosphamide group. Compared to p-Akt/Akt and p-mtor/mtor, p-rps6/rps6 was significantly decreased in rapamycin + cyclophosphamide group (P primordial follicle activation induced by cyclophosphamide through PI3K/Akt/mTOR signaling pathway and thus plays a role in preserving the follicle pool. These results suggest that rapamycin may be an effective protection for ovarian function during chemotherapy, which means a new nonsurgical application for protection of ovarian reserve and prevention of POF.

  9. Synthesis, properties, and in vivo evaluation of sustained release albumin-mitoxantrone microsphere formulations for nonsystemic treatment of breast cancer and other high mortality cancers

    Science.gov (United States)

    Hadba, Ahmad Robert

    Methods for preparing mitoxantrone (MXN)-loaded albumin microspheres for the treatment of breast cancer were developed. The effect of processing conditions on the particle size of unloaded and MXN-loaded microspheres was evaluated using multivariate analyses. The data suggested that the particle size of unloaded microspheres increased as protein concentration increased or the steric stabilizer concentration decreased. In addition, synergy between these two variables was observed. In situ-loading of MXN achieved loading efficiencies in excess of 80%. Comparable efficiencies were achieved with postsynthesis loading when the microsphere were prepared from albumin-poly(glutamic acid) blends. In vitro release of MXN in phosphate buffered saline under infinite sink conditions showed that the total amount of drug released increased as the glutaraldehyde concentration decreased. This trend was reversed when the microspheres were incubated in plasma. Nanoparticles were also prepared using ethanol desolvation. These particles were dispersible in saline and easily modified with amino acids. In addition, particle size could be varied by use of different non-ionic surfactants in the preparation. The effect of intratumoral (IT) versus intravenous (IV) drug administration on tumor response and systemic toxicity was investigated in vivo using the 16/C murine mammary adenocarcinoma tumor model. The data suggested that IT-treated animals had significantly smaller tumors and lower weight loss when compared to IV-treated animals. Furthermore, the addition of surgery to the chemotherapy further improved the survival of the animals. Pilot studies using MXN-albumin microspheres suggested that microspheres could be safely administered IT in doses up to 48 mg/kg. However, there was no evidence that this higher dose resulted in improved long term survival when compared to the 32 mg/kg dose. The maximum tolerated dose of MAN given IT was approximately 12 mg/kg. The animal studies suggested

  10. Dynamics of early histopathological changes in GVHD after busulphan/cyclophosphamide conditioning regimen.

    Science.gov (United States)

    Al-Hashmi, Sulaiman; Hassan, Zuzana; Sadeghi, Behnam; Rozell, Björn; Hassan, Moustapha

    2011-08-15

    Hematopoietic stem cell transplantation (HSCT) is a curative treatment for otherwise incurable diseases. Conditioning regimen is an important part of HSCT and consists of chemotherapy with or without irradiation. Conditioning exerts myelosuppressive, immunosuppressive and antitumor effects, but also contributes to HSCT-related complications including graft-versus-host disease (GVHD). Since almost 50% of the transplanted patients are conditioned with cytostatics without irradiation, we developed and characterized a GVHD mouse model following conditioning with busulphan and cyclophosphamide. Recipient Balb/c female mice were treated with busulphan (20 mg/kg/day for 4 days) and cyclophosphamide (100 mg/kg/day for two days). After one day of rest, recipient mice were transplanted with 2×10(7) bone marrow and 3×10(7) spleen cells from male C57BL/6 (allogeneic group) or female Balb/c (syngeneic/control group) mice. The allogeneic, but not syngeneic transplanted mice developed GVHD. Histopathology of the major internal organs (liver, pancreas, spleen, lungs, heart and kidney) was examined before conditioning start, after conditioning's end and 5, 7 and 21 days after transplantation using hematoxylin-eosin staining. Decreased spleen cellularity and diminished glycogen content in the liver were observed after conditioning regimen. Histopathological changes such as vasculitis, inflammation and apoptotic cell forms in liver, spleen, pancreas, lungs and heart were observed in allogeneic transplanted mice, however, only hypocellular spleen and extramedullar hematopoiesis were detected in syngeneic transplanted animals. No morphological changes were observed in kidney in either HSCT setting. This is the first study describing early histopathological changes after conditioning regimen with busulphan/cyclophosphamide and dynamics of GVHD development in several major internal organs.

  11. Efficacy of H, antihistamine, corticosteroids and cyclophosphamide in the treatment of chronic dermographic urticaria

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    Kumar Rajesh

    2002-01-01

    Full Text Available H, antihistamines relieve urticaria by blocking the action of histamine on the target tissue, while demonstration of autoantibodies in the sera of a proportion of the patients having chronic idiopathic urticaria, use of immunosuppressive drugs for the treatment of these patients has acquired the greater rationality. We evaluated the role of corticosteroids and cyclophosphamide in the treatment of chronic dermographic urticaria. Twenty-five patients, 13 males and 12 females, between 18-53 years in age, having chronic dermographic urticaria were taken up for this study. The patients were divided into three groups. Group I patients (n=9 were treated with cetirizine hydrochloride 10 mg per day orally, group II patients (n=7 were treated with betamethasone 2 mg along with cyclophosphamide 50 mg along with cetirizine 10 mg per day for a total period of 4 weeks. The patients were evaluated every week to record the therapeutic response and side effects, and then followed up without treatment for a period of 6 months to look for recurrence of the urticaria, if any. Six patients in group I and all the patients in group II and group III had complete remission while the remaining patients in group I had partial relief. The side effects included drowsiness in 4 patients. All the patients in group II had weight gain, 4 patients had acne and 2 patients developed cushingoid features. Majority of the patients relapsed within 3 days after stopping the treatment. Supplementation of the treatment with oral corticosteroids or cyclophosphamide was more effective in controlling the symptoms as compared to cetirizine alone. But a four weeks supplementation was not adequate for preventing the relapses when the drugs were withdrawn.

  12. Urodynamic investigation of cyclophosphamide-induced overactive bladder in conscious rats

    Institute of Scientific and Technical Information of China (English)

    PAN Feng; LIU Di; HAN Xiao-min; LI Wen-cheng; PANG Zi-li; LI Bing; ZHANG Xiao-ping; XIAO Ya-jun; ZENG Fu-qing

    2012-01-01

    Background Overactive bladder (OAB) can be caused by many factors such as inflammation,bladder outlet obstruction,neurogenic factors.We performed an intraperitoneal (ip) injection of cyclophosphamide to induce cystitis in rats,which causes their detrusors to overact,to provide a valuable disease model for discussing OAB pathogenesis and to study effective curing methods.Methods Female Sprague-Dawley rats were induced to form cystitis by cyclophosphamide (200 mg/kg,ip).The day after the injection,two catheters were inserted into each rat's bladder to study its urodynamics.The BL-410 model bio-function experimental system was used to monitor bladder pressure while the rats were conscious.Unstable detrusor contractions appear in the urine storage period as a standard to determine OAB,and the positive rate was calculated.Urodynamic parameters such as bladder basal pressure (BP),maximum voiding pressure (MVP),intercontraction interval (ICI),spontaneous activity (SA),maximum cystometric capacity (MCC),and bladder compliance (BC) were recorded in each group,and a light microscope was used to observe the pathological changes in the rat bladder tissue.Results The detrusor instability rate of the model group was 83.33%.The MVP,MCC and BC of rats in the model group were lower than the control group (P <0.01),and the BP,ICI and SA of the model group rats were higher than the control group (P <0.01).The difference between the control group and the model group is statistically significant.The model group rats' bladder walls swelled and bled,the submucosa thickened and leukocyte infiltration became serious.Conclusions Acute cystitis and OAB symptoms can be induced by ip injections of cyclophosphamide in rats.This can provide a valuable animal model to study OAB in human beings.

  13. Paternal cyclophosphamide exposure induces the formation of functional micronuclei during the first zygotic division.

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    Lisanne Grenier

    Full Text Available Paternal exposures to cancer chemotherapeutics or environmental chemicals may have adverse effects on progeny outcome that are manifested in the preimplantation embryo. The objectives of this study were to determine the impact of paternal exposure to cyclophosphamide, an anticancer alkylating agent, on the formation, chromatin origin and function of micronuclei in cleavage stage rat embryos. Male Sprague-Dawley rats were gavaged with saline or cyclophosphamide (6 mg/kg/day for 4 weeks and mated to naturally cycling females to collect pronuclear zygotes and 2 to 8 cell embryos. Micronuclear chromatin structure was characterized using confocal microscopy to detect immunoreactivities for H3K9me3, a marker for maternal chromatin, and lamin B, a nuclear membrane marker. DNA synthesis was monitored using EdU (5-ethynyl-2'-deoxyuridine incorporation. Fertilization by cyclophosphamide-exposed spermatozoa led to a dramatic elevation in micronuclei in cleavage stage embryos (control embryos: 1% to 5%; embryos sired by treated males: 70%. The formation of micronuclei occurred during the first zygotic division and was associated with a subsequent developmental delay. The absence of H3K9me3 indicated that these micronuclei were of paternal origin. The micronuclei had incomplete peri-nuclear and peri-nucleolar lamin B1 membrane formation but incorporated EdU into DNA to the same extent as the main nucleus. The formation of micronuclei in response to the presence of a damaged paternal genome may play a role in increasing the rate of embryo loss that is associated with the use of assisted reproductive technologies, parenthood among cancer survivors, and paternal aging.

  14. Alternative Donor Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Refractory Severe Aplastic Anemia

    Science.gov (United States)

    DeZern, Amy E.; Zahurak, Marianna; Symons, Heather; Cooke, Kenneth; Jones, Richard J.; Brodsky, Robert A.

    2017-01-01

    Severe aplastic anemia (SAA) is a life-threatening hematopoietic stem cell disorder that is treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IST). The management of patients with refractory SAA after IST is a major challenge. Alternative donor BMT is the best chance for cure in refractory SAA, but morbidity and mortality from graft failure and complications of graft-versus-host disease (GVHD) have limited enthusiasm for this approach. Here, we employed post-transplantation high-dose cyclophosphamide in an effort to safely expand the donor pool in 16 consecutive patients with refractory SAA who did not have a matched sibling donor. Between July 2011 and August 2016, 16 patients underwent allogeneic (allo) BMT for refractory SAA from 13 haploidentical donors and 3 unrelated donors. The nonmyeloablative conditioning regimen consisted of antithymocyte globulin, fludarabine, low-dose cyclophosphamide, and total body irradiation. Post-transplantation cyclophosphamide 50 mg/kg/day i.v. on days +3 and +4 was administered for GVHD prophylaxis. Additionally, patients received mycophenolate mofetil on days +5 through 35 and tacrolimus from day +5 through 1 year. The median age of the patients at the time of transplantation was 30 (range, 11 to 69) years. The median time to neutrophil recovery over 1000 × 103/mm3 for 3 consecutive days was 19 (range, 16 to 27) days, to red cell engraftment was 25 (range, 2 to 58) days, and to last platelet transfusion to keep platelets counts over 50 × 103/mm3 was 27.5 (range, 22 to 108) days. Graft failure, primary or secondary, was not seen in any of the patients. All 16 patients are alive, transfusion independent, and without evidence of clonality. The median follow-up is 21 (range, 3 to 64) months. Two patients had grade 1 or 2 skin-only acute GVHD. These same 2 also had mild chronic GVHD of the skin/mouth requiring systemic steroids. One of these GVHD patients was able to come off all IST by 15 months and the

  15. Cyclophosphamide and epirubicin-induced diabetes mellitus in breast cancer: A rare occurrence.

    Science.gov (United States)

    Sharma, Pramod Kumar; Misra, Arup Kumar; Singh, Vikram; Gupta, Ajay; Saroha, Shrishti; Singh, Surjit

    2016-01-01

    Breast cancer is the leading cause of death in women. Epirubicin and cyclophosphamide (EC) is one of the chemotherapeutic regimens used for the treatment of breast cancer. We describe a case treated with EC regimen and who presented to us with symptoms suggestive of diabetes mellitus postchemotherapy. Absence of family history of diabetes and normal blood sugar level, prechemotherapy points toward drug-induced hyperglycemia. These chemotherapeutic agents capable of altering immune response and might act synergistically to cause immunological damage to the islets of pancreas which might precipitate diabetes mellitus. Causality analysis on Naranjo's scale indicates a possible association with regimen.

  16. Cyclophosphamide and epirubicin-induced diabetes mellitus in breast cancer: A rare occurrence

    Directory of Open Access Journals (Sweden)

    Pramod Kumar Sharma

    2016-01-01

    Full Text Available Breast cancer is the leading cause of death in women. Epirubicin and cyclophosphamide (EC is one of the chemotherapeutic regimens used for the treatment of breast cancer. We describe a case treated with EC regimen and who presented to us with symptoms suggestive of diabetes mellitus postchemotherapy. Absence of family history of diabetes and normal blood sugar level, prechemotherapy points toward drug-induced hyperglycemia. These chemotherapeutic agents capable of altering immune response and might act synergistically to cause immunological damage to the islets of pancreas which might precipitate diabetes mellitus. Causality analysis on Naranjo′s scale indicates a possible association with regimen.

  17. Can propolis and caffeic acid phenethyl ester be promising agents against cyclophosphamide toxicity?

    Science.gov (United States)

    Akyol, Sumeyya; Gulec, Mehmet Akif; Erdemli, Haci Kemal; Akyol, Omer

    2016-01-01

    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 (CP) has been used to treat a broad of malignancies including Hodgkin’s and non-Hodgkin’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 CP-induced injuries. PMID:27069732

  18. Modulation of parasitemia and antibody responce to Trypanosoma cruzy by cyclophosphamide in Calomys callosus (Rodentia, Cricetidae)

    OpenAIRE

    1992-01-01

    Calomys callosus a wild rodent, previously described as harboring Trypanosoma cruzi, has a low susceptibility to infection by this protozoan. Experiments were designed to evaluate the contribution of the immune response to the resistance to T. cruzi infection exhibited by C. calossus. Animals were submitted to injections of high (200 mg/kg body weight) and low (20 mg/kg body weight) doses of cyclophosphamide on days -1 or -1 and +5, and inoculated with 4 x 10³ T. cruzi on day O. Parasitemia, ...

  19. Successful treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in systemic lupus erythematosus (SLE) with oral cyclophosphamide.

    Science.gov (United States)

    Jasmin, R; Sockalingam, S; Shahrizaila, N; Cheah, T-E; Zain, A A; Goh, K-J

    2012-09-01

    Peripheral neuropathy is a known manifestation of systemic lupus erythematosus. However, the association of primary autoimmune inflammatory neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) with SLE is uncommon. We report a 26-year-old man who simultaneously presented with severe CIDP and photosensitive rash, but was unresponsive to intravenous immunoglobulin infusion and continued to progress. He was found to have underlying SLE and improved with combined corticosteroid and immunosuppressive therapy with oral cyclophosphamide. CIDP with underlying SLE may be more resistant to conventional therapy with IVIG, requiring the addition of other immunosuppressive agents.

  20. Effect ofBuchanania lanzan Spreng. bark extract on cyclophosphamide induced genotoxicity and oxidative stress in mice

    Institute of Scientific and Technical Information of China (English)

    Ritesh Jain; Sanmati Kumar Jain

    2012-01-01

    Objective:To elucidate the effect of ethanolic extract ofBuchanania lanzan Spreng. (B. lanan) bark against cyclophosphamide induced genotoxicity and oxidative stress in mice.Methods:The prevalence of micronuclei in bone marrow, the extent of lipid peroxidation, reduced glutathione and the status of the antioxidant enzymes, superoxide dismutase and catalase in liver of mice were used as intermediate biomarkers for chemoprotection. Lipid peroxidation and associated compromised antioxidant defenses in cyclophosphamide treated mice were observed in the liver.Results: Pre-treatment withB. lanzan250, 500 and1 000mg/ kg,p.o., daily for7 days significantly reduced the chromosomal damage and lipid peroxidation with concomitant changes in antioxidants and detoxification systems.Conclusions: These results point out the presence of chemopreventive phytoconstituents in the crude extract offering protection against cyclophosphamide induced genotoxicity and oxidative stress in mice.

  1. Reversal of multidrug resistance in vincristine-resistant human gastric cancer cell line SGC7901/VCR by LY980503

    Institute of Scientific and Technical Information of China (English)

    Da-Long Wu; Ying Xu; Li-Xin Yin; Huan-Zhang Lu

    2007-01-01

    AIM: To investigate the reversal effect of LY980503,a benflumetol derivative, on multidrug resistance in vincristine (VCR) -resistant human gastric carcinoma cell line SGC7901/VCR.METHODS: Cells of a human gastric cancer cell line,SGC7901, and its VCR-resistant variant, SGC7901/VCR,were cultivated with LY980503 and/or doxorubicin (DOX).The cytotoxicity of drugs in vitro was assayed by MTT method. Based on the flow cytometric technology, the uptake of DOX was detected in these cells by measuring DOX -associated mean fluorescence intensity (MFI).RESULTS: SGC7901/VCR cells were 23.5 times more resistant to DOX in comparison with SGC7901 cells.LY980503 at the concentrations of 2.0 μmol/L -10 μmol/L had no obvious cytotoxicity to SGC7901 and SGC7901/VCR cells. After simultaneous treatment with LY980503 at the concentrations of 2.0, 4.0 and 10 μmol/L, the ICs0 of DOX to SGC7901/VCR cells decreased from 1.6± 0.12 μmol/L to 0.55 ± 0.024, 0.25 ± 0.032 and 0.11± 0.015 μmol/L, respectively, thus, increasing the DOX sensitivity by 2.9-fold (P < 0. 05), 6.4-fold (P < 0. 01)and 14.5-fold (P < 0. 01), respectively. In the uptake study of DOX, simultaneous incubation of SGC7901/VCR cells with LY980503 significantly increased the DOX -associated MFI in SGC7901/VCR cells. No such results were found in parental SGC7901 cells.CONCLUSION: LY980503 at non-cytotoxic concentrations can effectively circumvent resistance of SGC7901/VCR cells to DOX by increasing intracellular DOX accumulation.

  2. Manganese Superoxide Dismutase Polymorphism and Breast Cancer Recurrence: A Danish Population-Based Case-Control Study of Breast Cencer Patients Treated with Cyclophosphamide Epirubicin and 5-Fluororacil

    DEFF Research Database (Denmark)

    Ording, Anne Gulbech; Cronin Fenton, Deirdre; Christensen, Mariann

    2012-01-01

    Manganese Superoxide Dismutase Polymorphism and Breast Cancer Recurrence: A Danish Population-Based Case-Control Study of Breast Cencer Patients Treated with Cyclophosphamide Epirubicin and 5-Fluororacil......Manganese Superoxide Dismutase Polymorphism and Breast Cancer Recurrence: A Danish Population-Based Case-Control Study of Breast Cencer Patients Treated with Cyclophosphamide Epirubicin and 5-Fluororacil...

  3. Manganese Superoxide Dismtase Polymorphism and Breast Cancer Recurrence: A Danish Population-Based Case-Control Study of Breast Cancer Patients Treated with Cyclophosphamide Epirubicin and 5-fluorouracil

    DEFF Research Database (Denmark)

    Ording, Anne Gulbech; Cronin Fenton, Deirdre; Christensen, Mariann

    2013-01-01

    Manganese Superoxide Dismtase Polymorphism and Breast Cancer Recurrence: A Danish Population-Based Case-Control Study of Breast Cancer Patients Treated with Cyclophosphamide Epirubicin and 5-fluorouracil......Manganese Superoxide Dismtase Polymorphism and Breast Cancer Recurrence: A Danish Population-Based Case-Control Study of Breast Cancer Patients Treated with Cyclophosphamide Epirubicin and 5-fluorouracil...

  4. Combination therapy with rituximab and cyclophosphamide in the treatment of anti-neutrophil cytoplasmic antibodies (ANCA positive pulmonary hemorrhage: case report

    Directory of Open Access Journals (Sweden)

    Lehman Thomas JA

    2011-10-01

    Full Text Available Abstract Anti-neutrophil cytoplasmic antibody (ANCA-associated vasculitis (AAV with pulmonary hemorrhage is rare in childhood. Standard treatment includes corticosteroids and cyclophosphamide (CYC, which is associated with a high level of toxicity. We report a white female with ANCA positive pulmonary hemorrhage who was treated with cyclophosphamide (CYC and rituximab (RTX combination therapy.

  5. Human CD4+CD25+ regulatory T cells are sensitive to low dose cyclophosphamide: implications for the immune response.

    Directory of Open Access Journals (Sweden)

    Daniel Heylmann

    Full Text Available Regulatory T cells (Treg play a pivotal role in the immune system since they inhibit the T cell response. It is well known that cyclophosphamide applied at low dose is able to stimulate the immune response while high dose cyclophosphamide exerts inhibitory activity. Data obtained in mice indicate that cyclophosphamide provokes a reduction in the number of Treg and impairs their suppressive activity, resulting in immune stimulation. Here, we addressed the question of the sensitivity of human Treg to cyclophosphamide, comparing Treg with cytotoxic T cells (CTL and T helper cells (Th. We show that Treg are more sensitive than CTL and Th to mafosfamide, which is an active derivative of cyclophosphamide, which does not need metabolic activation. The high sensitivity of Treg was due to the induction of apoptosis. Treg compared to CTL and Th were not more sensitive to the alkylating drugs temozolomide and nimustine and also not to mitomycin C, indicating a specific Treg response to mafosfamide. The high sensitivity of Treg to mafosfamide resulted not only in enhanced cell death, but also in impaired Treg function as demonstrated by a decline in the suppressor activity of Treg in a co-culture model with Th and Helios positive Treg. Treatment of Treg with mafosfamide gave rise to a high level of DNA crosslinks, which were not repaired to the same extent as observed in Th and CTL. Also, Treg showed a low level of γH2AX foci up to 6 h and a high level 24 h after treatment, indicating alterations in the DNA damage response. Overall, this is the first demonstration that human Treg are, in comparison with Th and CTL, hypersensitive to cyclophosphamide, which is presumably due to a DNA repair defect.

  6. Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant

    Science.gov (United States)

    Ruggeri, Annalisa; Sun, Yuqian; Labopin, Myriam; Bacigalupo, Andrea; Lorentino, Francesca; Arcese, William; Santarone, Stella; Gülbas, Zafer; Blaise, Didier; Messina, Giuseppe; Ghavamzadeh, Ardeshi; Malard, Florent; Bruno, Benedetto; Diez-Martin, Jose Luis; Koc, Yener; Ciceri, Fabio; Mohty, Mohamad; Nagler, Arnon

    2017-01-01

    Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3–4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09–2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04–2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03–2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98–2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post

  7. 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...

  8. Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant.

    Science.gov (United States)

    Barr, Paul M; Lazarus, Hillard M; Cooper, Brenda W; Schluchter, Mark D; Panneerselvam, Ashok; Jacobberger, James W; Hsu, Jack W; Janakiraman, Nalini; Simic, Aleksandra; Dowlati, Afshin; Remick, Scot C

    2009-08-01

    Bryostatin 1, isolated from a marine bryozoan, enhances the efficacy of cytotoxic agents through modulation of the protein kinase C pathway and is active in combination with vincristine for diffuse large B-cell lymphoma. Further, the apoptotic frequency of peripheral blood T lymphocytes as determined by flow cytometry may predict which patients will respond to this combination. We tested the efficacy and safety of bryostatin 1 50 microg/m(2) given over 24 hr and vincristine 1.4 mg/m(2) on days 1 and 15 every 28 days in aggressive B-cell non-Hodgkin lymphoma (NHL) relapsing after autologous stem cell transplantation. End points included tumor response, toxicity, and survival. Responses were correlated with an increase in apoptotic frequency of CD5+ cells by flow cytometry using annexin V staining. Fourteen patients were enrolled with 13 being evaluable for a response. The overall response rate was 31% with two patients achieving a complete response. The most common toxicities were Grade 3 lymphopenia (seven patients), Grade 3 to 4 neutropenia (two patients), and Grade 3 hypophosphatemia (two patients). Median progression-free and overall survivals for all patients were 5.7 and 21.4 months, respectively. One patient demonstrated an increase in T-cell apoptotic frequency, also achieving a complete response. Bryostatin 1 and vincristine have efficacy in select patients with aggressive NHL. Future investigations of agents targeting the protein kinase C pathway may benefit from early response assessment using flow cytometry to evaluate T-cell apoptosis.

  9. Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.

    Directory of Open Access Journals (Sweden)

    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.

  10. Protective Effect of Quercetin Against Oxidative Stress-induced Toxicity Associated With Doxorubicin and Cyclophosphamide in Rat Kidney and Liver Tissue.

    Science.gov (United States)

    Kocahan, Sayad; Dogan, Zumrut; Erdemli, Erman; Taskin, Eylem

    2017-03-01

    Doxorubicin and cyclophosphamide are widely used anticancer drugs with substantial toxicity in noncancerous tissue resulting from oxidative damage. Quercetin is a potent antioxidant compound. We hypothesized that quercetin administration would ameliorate the toxic effects of doxorubicin and cyclophosphamide prior to pregnancy. Cyclophosphamide, 27 mg/kg, and doxorubicin, 1.8 mg/kg, were administered to rats as intraperitoneal doses once every 3 weeks for a total of 10 weeks with or without concurrent treatment with quercetin, 10 mg/kg/d. Oxidative stress parameters were evaluated in maternal kidney and liver tissues after gestation. Doxorubicin was associated with elevated kidney tissue malondialdehyde relative to the controls and quercetin only treatment (P doxorubicin were associated with elevated malondialdehyde levels in the liver tissue (P Doxorubicin treatment was associated with decreased liver glutathione peroxidase (P doxorubicin and cyclophosphamide treatment (P doxorubicin and cyclophosphamide results in therapeutic restoration of homeostatic expression of the antioxidant parameters, reducing oxidative damage to the liver and kidney.

  11. Immunostimulative effects of Cyperus rotundus, Alpinia calcarata, Solanum surattense, Clerodendrum infortunatum and Croton laccifer extracts combination on cyclophosphamide-induced immunosupression in rats

    Directory of Open Access Journals (Sweden)

    Ediriweera P. S. Chandana

    2015-06-01

    Results: Hematological analyses revealed that total WBC and leukocyte adhesion were not significantly different in control and extract-treated groups. Expression of IL-4 and IL-10 was significantly different in treated and control groups while expression of IL-12 was not significantly different. Cyclophosphamide-induced immunosuppression of the control group caused moderate to severe skin lesions while the rats in the extract-treated group did not sustain any skin lesions. All the rats in the cyclophosphamide-treated control group died after three months while 83.33% of the cyclophosphamide + plant extract received group survived, indicating the ability of the plant combination to alleviate the immunosuppression induced by cyclophosphamide. Conclusions: Treating with ethanolic extract combination of above plant species might exert their immunomodulatory effect via cytokine expression and can attenuate the immunosuppression induced by cyclophosphamide. [J Exp Integr Med 2015; 5(2.000: 110-113

  12. Gallic acid protects against cyclophosphamide-induced toxicity in testis and epididymis of rats.

    Science.gov (United States)

    Oyagbemi, A A; Omobowale, T O; Saba, A B; Adedara, I A; Olowu, E R; Akinrinde, A S; Dada, R O

    2016-05-01

    The protective role of gallic acid (GA) on reproductive toxicity induced by cyclophosphamide (CPA), an antineoplastic drug, was investigated in male Wistar rats. Sixty rats were grouped into 10 rats per group. Group 1 (control) received distilled water. Rats in groups 2 and 3 received GA alone at 60 and 120 mg kg(-1) for 14 consecutive days, respectively. Group 4 received a single intraperitoneal dose of CPA at 200 mg kg(-1) on day 1. Groups 5 and 6 received a single dose of CPA (200 mg kg(-1) ) intraperitoneally on day 1 followed by treatment with GA at 60 and 120 mg kg(-1) for 14 consecutive days, respectively. In testes and epididymis of the treated rats, CPA administration resulted in significant elevation (P < 0.05) in malondialdehyde (MDA), nitrite and hydrogen peroxide levels. There was a significant decrease in the activities of superoxide dismutase and glutathione-S-transferase. Furthermore, there were significant reductions in plasma luteinising hormone (LH), follicle stimulation hormone (FSH) and testosterone levels, which were accompanied by significant decrease in sperm motility and viability in CPA-treated rats. Histological examination revealed marked testicular and epididymal atrophy in CPA alone treated rats and these aberrations were reversed by GA. In conclusion, GA has capacity to protect against reproductive toxicity induced by cyclophosphamide.

  13. Crataegus Monogyna Aqueous Extract Ameliorates Cyclophosphamide-Induced Toxicity in Rat Testis: Stereological Evidences

    Directory of Open Access Journals (Sweden)

    Hassan Malekinejad

    2012-01-01

    Full Text Available Cyclophosphamide (CP is extensively used as an antineoplastic agent for the treatment of various cancers, as well as an immunosuppressive agent. However, despite its wide spectrum of clinical uses, CP is known to cause several adverse effects including reproductive toxicity. Crataegus monogyna is one of the oldest pharmaceutical plants that have been shown to be cytoprotective by scavenging free radicals. The present study was conducted to assess whether Crataegus monogyna fruits aqueous extract with anti-oxidant properties, could serve as a protective agent against reproductive toxicity during CP treatment in a rat model. Male Wistar rats were categorized into four groups. Two groups of rats were administered CP at a dose of 5 mg in 5 ml saline/kg/day for 28 days by oral gavages. One of these groups received Crataegus monogyna aqueous extract at a dose of 20 mg/kg/day orally four hours after cyclophosphamide administration. A vehicle treated control group and a Crataegus monogyna control group were also included. The CP-treated group showed significant decreases in the body, testes and epididymides weights as well as many histological alterations. Stereological parameters and spermatogenic activities (Sertoli cell, repopulation and miotic indices were also significantly decreased by CP treatment. Notably, Crataegus coadministration caused a partial recovery in above-mentined parameters. These findings indicate that Crataegus monogyna may be partially protective against CP-induced testicular toxicity.

  14. A Case of Polyarteritis Nodosa Associated with Vertebral Artery Vasculitis Treated Successfully with Tocilizumab and Cyclophosphamide

    Science.gov (United States)

    Watanabe, Kae; Rajderkar, Dhanashree A.; Modica, Renee F.

    2016-01-01

    Pediatric polyarteritis nodosa is rare systemic necrotizing arteritis involving small- and medium-sized muscular arteries characterized by aneurysmal dilatations involving the vessel wall. Aneurysms associated with polyarteritis nodosa are common in visceral arteries; however intracranial aneurysms have also been reported and can be associated with central nervous system symptoms, significant morbidity, and mortality. To our knowledge extracranial involvement of the vertebral arteries has not been reported but has the potential to be deleterious due to fact that they supply the central nervous system vasculature. We present a case of a 3-year-old Haitian boy with polyarteritis nodosa that presented with extracranial vessel involvement of his vertebral arteries. After thorough diagnostic imaging, including a bone scan, ultrasound, Magnetic Resonance Imaging/Angiography, and Computed Tomography Angiography, he was noted to have vertebral artery vasculitis, periostitis, subacute epididymoorchitis, arthritis, and myositis. He met diagnostic criteria for polyarteritis nodosa and was treated with cyclophosphamide, methylprednisolone, and tocilizumab, which resulted in improvement of his inflammatory markers, radiographic findings, and physical symptoms after treatment. To the authors' knowledge, this is the first report of vertebral artery vasculitis in polyarteritis nodosa as well as successful treatment of the condition using the combination cyclophosphamide and tocilizumab for this condition. PMID:27018080

  15. A Case of Polyarteritis Nodosa Associated with Vertebral Artery Vasculitis Treated Successfully with Tocilizumab and Cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Kae Watanabe

    2016-01-01

    Full Text Available Pediatric polyarteritis nodosa is rare systemic necrotizing arteritis involving small- and medium-sized muscular arteries characterized by aneurysmal dilatations involving the vessel wall. Aneurysms associated with polyarteritis nodosa are common in visceral arteries; however intracranial aneurysms have also been reported and can be associated with central nervous system symptoms, significant morbidity, and mortality. To our knowledge extracranial involvement of the vertebral arteries has not been reported but has the potential to be deleterious due to fact that they supply the central nervous system vasculature. We present a case of a 3-year-old Haitian boy with polyarteritis nodosa that presented with extracranial vessel involvement of his vertebral arteries. After thorough diagnostic imaging, including a bone scan, ultrasound, Magnetic Resonance Imaging/Angiography, and Computed Tomography Angiography, he was noted to have vertebral artery vasculitis, periostitis, subacute epididymoorchitis, arthritis, and myositis. He met diagnostic criteria for polyarteritis nodosa and was treated with cyclophosphamide, methylprednisolone, and tocilizumab, which resulted in improvement of his inflammatory markers, radiographic findings, and physical symptoms after treatment. To the authors’ knowledge, this is the first report of vertebral artery vasculitis in polyarteritis nodosa as well as successful treatment of the condition using the combination cyclophosphamide and tocilizumab for this condition.

  16. 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.

  17. Antimutagenic effects of piperine on cyclophosphamide-induced chromosome aberrations in rat bone marrow cells.

    Science.gov (United States)

    Wongpa, Sareeya; Himakoun, Lakana; Soontornchai, Sarisak; Temcharoen, Punya

    2007-01-01

    Piperine is a major pungent substance and active component of black pepper (Piper nigrum Linn.) and long pepper (Piper longum Linn.). Both plants are used worldwide as household spices and condiments. They are also used as important ingredients in folklore medicine in many Asian countries. Therefore, it is of interest to study antimutagenic effects of piperine. In this study, its influence on chromosomes was investigated in rat bone marrow cells. Male Wistar rats were orally administered piperine at the doses of 100, 400 and 800 mg/kg body weight for 24 hours then challenged with cyclophosphamide at a dose of 50 mg/kg body weight by intraperitoneal injection. Twenty-four hours thereafter, all animals were sacrificed and bone marrow samples were collected for chromosomal analysis. The results demonstrated that piperine at a dose of 100 mg/kg body weight gave a statistically significant reduction in cyclophosphamide-induced chromosomal aberrations. In conclusion, piperine may have antimutagenic potential. The underlying molecular mechanisms now require attention.

  18. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia

    Science.gov (United States)

    Badoux, Xavier C.; Keating, Michael J.; Wang, Xuemei; O'Brien, Susan M.; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Lerner, Susan; Kantarjian, Hagop

    2011-01-01

    Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes. PMID:21670470

  19. Insulin-induced enhancement of MCF-7 breast cancer cell response to 5-fluorouracil and cyclophosphamide.

    Science.gov (United States)

    Agrawal, Siddarth; Łuc, Mateusz; Ziółkowski, Piotr; Agrawal, Anil Kumar; Pielka, Ewa; Walaszek, Kinga; Zduniak, Krzysztof; Woźniak, Marta

    2017-06-01

    The study was designed to evaluate the potential use of insulin for cancer-specific treatment. Insulin-induced sensitivity of MCF-7 breast cancer cells to chemotherapeutic agents 5-fluorouracil and cyclophosphamide was evaluated. To investigate and establish the possible mechanisms of this phenomenon, we assessed cell proliferation, induction of apoptosis, activation of apoptotic and autophagic pathways, expression of glucose transporters 1 and 3, formation of reactive oxygen species, and wound-healing assay. Additionally, we reviewed the literature regarding theuse of insulin in cancer-specific treatment. We found that insulin increases the cytotoxic effect of 5-fluorouracil and cyclophosphamide in vitro up to two-fold. The effect was linked to enhancement of apoptosis, activation of apoptotic and autophagic pathways, and overexpression of glucose transporters 1 and 3 as well as inhibition of cell proliferation and motility. We propose a model for insulin-induced sensitization process. Insulin acts as a sensitizer of cancer cells to cytotoxic therapy through various mechanisms opening a possibility for metronomic insulin-based treatments.

  20. Toxic effects of different doses of cyclophosphamide on the reproductive parameters of male mice

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    Tatiane Yumi Nakamura Kanno

    2009-06-01

    Full Text Available The cyclophosphamide is used in cancer treatment. The aim of this study was evaluating the effect of different doses of this drug on male mice reproductive parameters. The cyclophosphamide was administered in the doses 100, 150, 200 e 250 mg.kg-1, intraperitoneal route, for six weeks. As a result, it was observed a decrease in body mass and a decrease in testicles and kidney's weight, in all animals treated with cyclophosphamide. Only the groups that received the doses 100, 150 mg.kg-1 of cyclophosphamide were able to fertilize their females. There was higher incidence of post- implantation losses, reabsorptions and decrease in fetal viability in the group that received the dose of 150 mg.kg-1. It was observed a reduction in epididymis and liver's weight of the animals treated with the doses 150, 200 e 250 mg.kg-1. Abnormal spermatozoa were found in the doses 200 e 250 mg.kg-1. Based on the methodology used and results obtained, it was concluded that the cyclophosphamide was toxic, considering the decrease in animal's body mass and testicle's weight; promoted hepatotoxicity and nephrotoxic effect; influenced in the animals spermatogenesis taking them to infertility and/or subfertility; decreased fetal viability, despite it didn't cause significant malformations in the offspring.A ciclofosfamida é utilizada no tratamento de câncer. Este estudo visa avaliar os efeitos das diferentes doses do fármaco nos parâmetros reprodutivos de camundongos machos. A ciclofosfamida foi administrada nas doses de 100, 150, 200 e 250 mg kg-1, via intraperitoneal por seis semanas. Como resultado observou-se diminuição de massa corporal, redução no peso de testículos e rins em todos os animais tratados com a ciclofosfamida. Apenas os grupos que receberam as doses de 100 e 150 mg kg-1 do quimioterápico foram capazes de fertilizar as fêmeas. Houve maior incidência de perdas pós-implantação, reabsorção e diminuição da viabilidade fetal no grupo que

  1. Adjuvant treatment of breast cancer patients with 1-3 positive lymph nodes: vinorelbine plus epirubicin; vinorelbine plus epirubicin sequential followed up by paclitaxel; epirubicin plus cyclophosphamide; epirubicin plus cyclophosphamide sequential followed up by paclitaxel. A phase II study.

    Science.gov (United States)

    Elling, D; Eggemann, H; Kümmel, S; Breitbach, P; Kohls, A; Morack, G; Schlosser, H; Krocker, J

    2003-06-01

    The efficacy of anthracyclin-containing adjuvant chemotherapy of node-positive breast cancer can be further improved by adding sequential paclitaxel (T). There is also clinical evidence that replacing cyclophosphamide (C) with vinorelbin (V) might further reduce toxicity. In order to assess the safety of these options, we initiated a clinical cohort study of epirubicin/cyclophoshamide and epirubicin/vinorelbine with or without sequential paclitaxel. Patients with node-positive (1-3) breast cancer were assigned to open-label epirubicin/vinorelbine (EV), epirubicin/vino-relbine and sequential paclitaxel (EV/T), epirubicin/cyclophosphamide (EC) or epirubicin/cyclophosphamide plus sequential paclitaxel (EC/T) therapy. Fifty four outpatients received a total of 304 chemotherapy cycles. There were significant differences in grade III/IV anemia only between the EV/T and EC/T groups, in favor of the EC/T group (P=0.002). The safety of paclitaxel is not impaired when given sequentially after administration of the two anthracyclin-containing regimens. The exchange of cyclophosphamide against vinorelbine leads to deteriorating safety of the EC/T regimen.

  2. PERSONALIZED DOSING OF CYCLOPHOSPHAMIDE IN THE TOTAL BODY IRRADIATION - CYCLOPHOSPHAMIDE CONDITIONING REGIMEN: A PHASE II TRIAL IN PATIENTS WITH HEMATOLOGIC MALIGNANCY

    Science.gov (United States)

    McCune, Jeannine S.; Batchelder, Ami; Guthrie, Katherine A.; Witherspoon, Robert; Appelbaum, Frederick R.; Phillips, Brian; Vicini, Paolo; Salinger, David H.; McDonald, George B.

    2009-01-01

    This study investigates the efficacy and safety of personalized cyclophosphamide (CY) dosing in 50 patients receiving CY with total body irradiation (TBI). Participants received CY 45 mg/kg with subsequent therapeutic drug monitoring with Bayesian parameter estimation to personalize the second CY dose to a target area under the curve for carboxyethylphosphoramide mustard (a reporter for CY-derived toxins) and for hydroxycyclophosphamide (to ensure engraftment). The mean second CY dose was 66 mg/kg; the total dose ranged from 45–145 mg/kg. After completion of this phase II study, we compared participants’ clinical outcomes to those of concurrent controls (N=100) who received TBI with standard CY doses of 120 mg/kg. Patients receiving personalized CY dosing had significantly lower post-conditioning peak total serum bilirubin (p=0.03); a 38% reduction in the hazard of acute kidney injury (p=0.03); and similar non-relapse and overall survival (p=0.70 and 0.63, respectively) despite lower doses of CY in most patients. PMID:19295506

  3. Mycophenolate mofetil in idiopathic membranous nephropathy: a clinical trial with comparison to a historic control group treated with cyclophosphamide.

    NARCIS (Netherlands)

    Branten, A.J.W.; Buf-Vereijken, P.W.G. du; Vervloet, M.; Wetzels, J.F.M.

    2007-01-01

    BACKGROUND: Cyclophosphamide can decrease proteinuria and improve renal function in patients with idiopathic membranous nephropathy, but has a high risk of side effects. We studied whether mycophenolate mofetil (MMF) could be a reasonable alternative with fewer side effects. STUDY DESIGN: Clinical t

  4. Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients : a prospective phase II study

    NARCIS (Netherlands)

    Hovenga, S; Daenen, SMGJ; de Wolf, JTM; van Imhoff, GW; Kluin-Nelemans, HC; Sluiter, WJ; Vellenga, E

    2005-01-01

    refractory multiple myeloma ( MM) with a response rate of 30-40% at doses of 200-800 mg but with considerable side effects. We questioned whether lower doses of thalidomide in combination with a daily dose of cyclophosphamide might be an effective regimen with fewer side effects. We included 38 pati

  5. Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer : A single-arm phase II study

    NARCIS (Netherlands)

    Vermeij, Renee; Leffers, Ninke; Hoogeboom, Baukje-Nynke; Hamming, Ineke L. E.; Wolf, Rinze; Reyners, Anna K. L.; Molmans, Barbara H. W.; Hollema, Harry; Bart, Joost; Drijfhout, Jan W.; Oostendorp, Jaap; van der Zee, Ate G. J.; Melief, Cornelis J.; van der Burg, Sjoerd H.; Daemen, Toos; Nijman, Hans W.

    2012-01-01

    The purpose of the current phase II single-arm clinical trial was to evaluate whether pretreatment with low-dose cyclophosphamide improves immunogenicity of a p53-synthetic long peptide (SLP) vaccine in patients with recurrent ovarian cancer. Patients with ovarian cancer with elevated serum levels

  6. Study on the Antiradiation role of Melatonin: An investigation on Induced Oxidative Stress Mice by Radiomimetic Drug Cyclophosphamide

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    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.

  7. Proapoptotic and Antiproliferative Effects of Thymus caramanicus on Human Breast Cancer Cell Line (MCF-7 and Its Interaction with Anticancer Drug Vincristine

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    Saeed Esmaeili-Mahani

    2014-01-01

    Full Text Available Thymus caramanicus Jalas is one of the species of thymus that grows in the wild in different regions of Iran. Traditionally, leaves of this plant are used in the treatment of diabetes, arthritis, and cancerous situation. Therefore, the present study was designed to investigate the selective cytotoxic and antiproliferative properties of Thymus caramanicus extract (TCE. MCF-7 human breast cancer cells were used in this study. Cytotoxicity of the extract was determined using MTT and neutral red assays. Biochemical markers of apoptosis (caspase 3, Bax, and Bcl-2 and cell proliferation (cyclin D1 were evaluated by immunoblotting. Vincristine was used as anticancer control drug in extract combination therapy. The data showed that incubation of cells with TCE (200 and 250 μg/mL significantly increased cell damage, activated caspase 3 and Bax/Bcl2 ratio. In addition, cyclin D1 was significantly decreased in TCE-treated cells. Furthermore, concomitant treatment of cells with extract and anticancer drug produced a significant cytotoxic effect as compared to extract or drugs alone. In conclusion, thymus extract has a potential proapoptotic/antiproliferative property against human breast cancer cells and its combination with chemotherapeutic agent vincristine may induce cell death effectively and be a potent modality to treat this type of cancer.

  8. Efficacy of reduced dose of pegfilgrastim in Japanese breast cancer patients receiving dose-dense doxorubicin and cyclophosphamide therapy.

    Science.gov (United States)

    Mizuno, Yoshio; Fuchikami, Hiromi; Takeda, Naoko; Iwai, Masaru; Sato, Kazuhiko

    2017-01-01

    This retrospective study aimed to evaluate the efficacy of a 3.6-mg dose of pegfilgrastim for primary prophylaxis in Japanese breast cancer patients receiving dose-dense chemotherapy. Patients treated with adjuvant or neoadjuvant chemotherapy for early-stage breast cancer at the Tokyo-West Tokushukai Hospital were included in this analysis. Because 6 mg pegfilgrastim has not yet been approved for use in Japan, we compared the outcomes of a dose-dense doxorubicin and cyclophosphamide regimen plus 3.6 mg pegfilgrastim support with a conventional dose epirubicin and cyclophosphamide regimen. The incidence of febrile neutropenia, relative dose intensity, dose delay, dose reduction, regimen change and hospitalization because of neutropenia were assessed. From November 2013 to March 2016, 97 patients with stage I-III invasive breast cancer were analyzed (dose-dense doxorubicin and cyclophosphamide plus 3.6-mg pegfilgrastim group, n  =  41; epirubicin and cyclophosphamide group, n  =  56; median ages, 49.0 and 48.5 years, respectively). Febrile neutropenia occurred during the first chemotherapy cycle in 7 of 56 patients (12.5%) in the epirubicin and cyclophosphamide group and 0 of 41 patients in the dose-dense doxorubicin and cyclophosphamide group (P  =  0.02). The average relative dose intensities were 97.9% and 96.8%, respectively (P  =  0.28), with corresponding dose delay rates of 4.9% (2/41) and 16.1% (9/56), respectively (P  =  0.11) and dose reduction rates of 0% (0/41) and 7.1% (4/56), respectively (P  =  0.16). Our results indicate the efficacy of a 3.6-mg pegfilgrastim dose for the primary prevention of febrile neutropenia in dose-dense doxorubicin- and cyclophosphamide-treated Japanese breast cancer patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Neoadjuvant chemotherapy of breast cancer with pirarubicin versus epirubicin in combination with cyclophosphamide and docetaxel.

    Science.gov (United States)

    Gu, Xi; Jia, Shi; Wei, Wei; Zhang, Wen-Hai

    2015-07-01

    Breast cancers (BC) are treated with surgery, radiotherapy, and chemotherapy. Neoadjuvant chemotherapy (NACT) is an emerging treatment option in many cancers and is given before primary therapy to shrink tumor size. The efficacy of NACT in varied settings of BC, such as inoperable tumors, borderline resectable tumors, and breast-conserving surgery, has been debated extensively in literature, and the results remain unclear and depended on a wide variety of factors such as cancer type, disease extent, and the specific combination of chemotherapy drugs. This study was performed to examine the efficacy, toxicity, and tolerability of pirarubicin (THP) and epirubicin (EPI) in combination with docetaxel and cyclophosphamide in a NACT setting for BC. A total of 48 patients with stage II or III breast cancers were randomly divided into two groups: THP group and EPI group. The patients in THP group received 2-4 cycles of neoadjuvant chemotherapy with DTC regimen (docetaxel, THP, cyclophosphamide), while patients in the EPI group received 2-4 cycles of DEC regimen (docetaxel, EPI, cyclophosphamide) before surgery. The incidence of adverse reactions and the efficacy of the treatment regimen were compared between the two groups. Prognostic evaluation indexes were estimated by Kaplan-Meier survival analysis, including the 5-year disease-free survival (DFS) and overall survival (OS). The overall response rate in THP group was 83.3 %, and the EPI group showed a response rate of 79.2 %, with no statistically significant difference in response rate between the two groups. The incidence of cardiac toxicity, myelosuppression, nausea, and vomiting in the THP group was significantly lower than the EPI group (all P < 0.05). The incidence of hepatic toxicity, alopecia, and diarrhea in the THP group was also lower than the EPI group, but these differences were not statistically significant. The 5-year DFS and OS in THP versus EPI groups were 80 versus 76 % (DFS) and 86 versus 81 % (OS

  10. NF-κB DNA-binding activity in embryos responding to a teratogen, cyclophosphamide

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    Brill Alexander

    2002-02-01

    Full Text Available Abstract Background The Rel/NF-κB transcription factors have been shown to regulate apoptosis in different cell types, acting as inducers or blockers in a stimuli- and cell type-dependent fashion. One of the Rel/NF-κB subunits, RelA, has been shown to be crucial for normal embryonic development, in which it functions in the embryonic liver as a protector against TNFα-induced physiological apoptosis. This study assesses whether NF-κB may be involved in the embryo's response to teratogens. Fot this, we evaluated how NF-KappaB DNA binding activity in embryonic organs demonstraiting differential sensitivity to a reference teratogen, cyclophosphamide, correlates with dysmorphic events induced by the teratogen at the cellular level (excessive apoptosis and at the organ level (structural anomalies. Results The embryonic brain and liver were used as target organs. We observed that the Cyclophosphamide-induced excessive apoptosis in the brain, followed by the formation of severe craniofacial structural anomalies, was accompanied by suppression of NF-κB DNA-binding activity as well as by a significant and lasting increase in the activity of caspases 3 and 8. However, in the liver, in which cyclophosphamide induced transient apoptosis was not followed by dysmorphogenesis, no suppression of NF-κB DNA-binding activity was registered and the level of active caspases 3 and 8 was significantly lower than in the brain. It has also been observed that both the brain and liver became much more sensitive to the CP-induced teratogenic insult if the embryos were exposed to a combined treatment with the teratogen and sodium salicylate that suppressed NF-κB DNA-binding activity in these organs. Conclusion The results of this study demonstrate that suppression of NF-κB DNA-binding activity in embryos responding to the teratogenic insult may be associated with their decreased resistance to this insult. They also suggest that teratogens may suppress NF-κB DNA

  11. VEGFR2 heterogeneity and response to anti-angiogenic low dose metronomic cyclophosphamide treatment

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    Skowronski Karolina

    2010-12-01

    Full Text Available Abstract Background Targeting tumor vasculature is a strategy with great promise in the treatment of many cancers. However, anti-angiogenic reagents that target VEGF/VEGFR2 signaling have met with variable results clinically. Among the possible reasons for this may be heterogeneous expression of the target protein. Methods Double immunofluorescent staining was performed on formalin-fixed paraffin embedded sections of treated and control SW480 (colorectal and WM239 (melanoma xenografts, and tissue microarrays of human colorectal carcinoma and melanoma. Xenografts were developed using RAG1-/- mice by injection with WM239 or SW480 cells and mice were treated with 20 mg/kg/day of cyclophosphamide in their drinking water for up to 18 days. Treated and control tissues were characterized by double immunofluorescence using the mural cell marker α-SMA and CD31, while the ratio of desmin/CD31 was also determined by western blot. Hypoxia in treated and control tissues were quantified using both western blotting for HIF-1α and immunohistochemistry of CA-IX. Results VEGFR2 is heterogeneously expressed in tumor vasculature in both malignant melanoma and colorectal carcinoma. We observed a significant decrease in microvascular density (MVD in response to low dose metronomic cyclophosphamide chemotherapy in both malignant melanoma (with higher proportion VEGFR2 positive blood vessels; 93% and colorectal carcinoma (with lower proportion VEGFR2 positive blood vessels; 60% xenografts. This reduction in MVD occurred in the absence of a significant anti-tumor effect. We also observed less hypoxia in treated melanoma xenografts, despite successful anti-angiogenic blockade, but no change in hypoxia of colorectal xenografts, suggesting that decreases in tumor hypoxia reflect a complex relationship with vascular density. Based on α-SMA staining and the ratio of desmin to CD31 expression as markers of tumor blood vessel functionality, we found evidence for increased

  12. Metronomic cyclophosphamide eradicates large implanted GL261 gliomas by activating antitumor Cd8(+) T-cell responses and immune memory.

    Science.gov (United States)

    Wu, Junjie; Waxman, David J

    2015-04-01

    Cancer chemotherapy using cytotoxic drugs can induce immunogenic tumor cell death; however, dosing regimens and schedules that enable single-agent chemotherapy to induce adaptive immune-dependent ablation of large, established tumors with activation of long-term immune memory have not been identified. Here, we investigate this issue in a syngeneic, implanted GL261 glioma model in immune-competent mice given cyclophosphamide on a 6-day repeating metronomic schedule. Two cycles of metronomic cyclophosphamide treatment induced sustained upregulation of tumor-associated CD8(+) cytotoxic T lymphocyte (CTL) cells, natural killer (NK) cells, macrophages, and other immune cells. Expression of CTL- and NK-cell-shared effectors peaked on Day 6, and then declined by Day 9 after the second cyclophosphamide injection and correlated inversely with the expression of the regulatory T cell (Treg) marker Foxp3. Sustained tumor regression leading to tumor ablation was achieved after several cyclophosphamide treatment cycles. Tumor ablation required CD8(+) T cells, as shown by immunodepletion studies, and was associated with immunity to re-challenge with GL261 glioma cells, but not B16-F10 melanoma or Lewis lung carcinoma cells. Rejection of GL261 tumor re-challenge was associated with elevated CTLs in blood and increased CTL infiltration in tumors, consistent with the induction of long-term, specific CD8(+) T-cell anti-GL261 tumor memory. Co-depletion of CD8(+) T cells and NK cells did not inhibit tumor regression beyond CD8(+) T-cell depletion alone, suggesting that the metronomic cyclophosphamide-activated NK cells function via CD8a(+) T cells. Taken together, these findings provide proof-of-concept that single-agent chemotherapy delivered on an optimized metronomic schedule can eradicate large, established tumors and induce long-term immune memory.

  13. Phase 1 and Extension Study of Clofarabine plus Cyclophosphamide in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

    Science.gov (United States)

    Faderl, S; Balakrishnan, K; Thomas, DA; Ravandi, F; Borthakur, G; Burger, J; Ferrajoli, A; Cortes, J; O’Brien, S; Kadia, T; Feliu, J; Plunkett, W; Gandhi, V; Kantarjian, HM

    2014-01-01

    Background Clofarabine is a nucleoside analog with activity in children with ALL. Based on the hypothesis that clofarabine inhibits DNA repair following exposure to DNA damaging agents, we designed a phase 1 and extension study to evaluate the combination of clofarabine with cyclophosphamide in adult patients with relapsed/refractory ALL. Methods The continual reassessment method (CRM) was used to define the maximum tolerated dose (MTD). Results Fifty patients with a median age of 30 years (range 21–72 years) were enrolled of whom 30 patients were part of the phase 1 group. Clofarabine 40 mg/m2 iv daily x 3 days and cyclophosphamide 200 mg/m2 iv q 12 hours x 3 days were established as the MTD. Dose limiting toxicities were diarrhea, transaminase elevations, and skin rashes. The response rate of the whole study group was 14% including 10% of patients who achieved complete remission (CR) or CR without platelet recovery. Three responses occurred in patients with primary refractory disease. Early mortality (< 30 days) was 6%. The median response duration was 69 days (range 5–315 days). Median overall survival was about 3 months. Compared to day 1 (cyclophosphamide alone), H2AX phosphorylation was increased on day 2 when clofarabine and cyclophosphamide were administered as a couplet (n = 8). Conclusions The combination of clofarabine plus cyclophosphamide at the doses used in this study and in a group of heavily pretreated patients with ALL is only moderately effective. Other doses, alternative schedules, or a more favorable patient population may achieve better results. (Word count: 248) PMID:24440659

  14. The Effect of Hydro-alcoholic Extract of Hyperricum PerforatumL. on Some Blood Parameters in Male Rats Treated with Cyclophosphamide

    Directory of Open Access Journals (Sweden)

    L yaghobi

    2016-05-01

    Full Text Available Background & aim: Cyclophosphamide is an anti cancer drug which causes alkylation of DNA in cells. The side effects of cyclophosphamide are bone marrow damages and anemia. Hypericum perforatum is a medicinal plant which widely used in traditional medicine. In this study the hemotopoetic effect of Hypericum perforatum leaf extract (HPE on bone marrow function and blood parameters in male rat were treated with cyclophosphamide was investigated. Methods: Forty two male Wistar rats with an average body weight of 220±25 gr were randomly divided into 6 groups (n=7: control group taking normal saline,0.5ml/day, i,p ,witness group taking cyclophosphamide (15mg/kg/day, i.p., positive control group taking HPE (200mg/kg, i.p/day,  treated groups 1, 2 and 3 recieved cyclophosphamide ,(15mg/kg/day, i.p. + 100mg/Kg, 200mg/Kg and 400mg/kg  HPE /day for 10 days, i,p. At the end of study blood samples were collected from heart directly. RBC, WBC, Hct, Hb and PL were meseaured. Data are presented as mean ± standard deviation and were analyzed using ANOVA and Tukey tests. Results: The results indicated that cyclophosphamide caused damage on bone marrow, which in this case significantly reduced the number of blood cells and platelets in the group treated with cyclophosphamide (P<0.001. Blood parameters in the groups treated with HPE increased significantly compared with the group which received cyclophosphamide alone (P<0.001. Conclusion: The Hypericum perforatum hydoethanolic extract contains antioxidant and flavonoids compounds which could protect the bone marrow tissues against cyclophosphamide.       

  15. AMELIORATIVE EFFECT OF PUNICA GRANATUM ETHANOLIC EXTRACT IN CYCLOPHOSPHAMIDE INDUCED TESTICULAR TOXICITY IN MALE WISTAR RATS

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    Divya Bhargavan

    2015-07-01

    Full Text Available Aim: To explore the potential role of Punica granatum ethanolic extract (PGEE in Cyclophosphamide (CP induced testicular toxicity. Methods: Healthy male Wistar rats were allotted to 4 groups (N=6, each Group I: Control, Group II: CP 15mg/kg twice a week, Group III: PGEE 100mg/kg, Group IV: CP and PGEE for 28 days. At the end of the treatment period, organ weight, body weight, epididymal sperm count, motility, morphology, SOD, catalase, GSH, ACP & testosterone level in the testis were evaluated. Results: The CP treated rats showed toxicity evidenced by decreased organ and body weight, decreased sperm quality and testosterone level also increase in MDA and decrease in antioxidants SOD, GSH indicating oxidative stress. In contrast PGEE co-treatment with CP resulted in significant restoration of the above mentioned parameters. Conclusion: These results indicate that PGEE attenuates CP induced testicular toxicity through its ROS scavenging activity.

  16. Antihepatotoxic efficacy of Mangifera indica L. polysaccharides against cyclophosphamide in rats.

    Science.gov (United States)

    Fahmy, Sohair R; Amien, Ahmed I; Abd-Elgleel, Fathi M; Elaskalany, Sara M

    2016-01-25

    The present study aims to evaluate the possible protective role of polysaccharides extracted from the Egyptian mango Mangifera indica L. (MPS) and/or silymarine against cyclophosphamide (CP) toxicity in male albino rats. The MPS and/or silymarin significantly decreased the activities of serum ASAT and ALAT. However, MPS (1000 mg/kg) normalized their activities towards the normal levels recording 28.75 and 78.75 U/ml respectively. The recorded data also showed the antioxidant effect of MPS by decreasing the level of malondialdehyde (MDA) and increasing the level of reduced glutathione (GSH) as well as normalized the activities of the antioxidant enzyme GST and SOD. Histopathological examinations also confirmed the protective efficacy of MPS against liver toxicity of CP. In conclusion, the recorded results of the present study support the protective role of MPS and/or silymarin against CP-induced hepatic damage.

  17. Changes in the adhesive phenotype of regional lymphocytes in rats with adjuvant arthritis: alteration by cyclophosphamide.

    Science.gov (United States)

    Altankov, G; Marinova-Mutafchieva, L; Nikolaeva, N; Penkova, R

    1991-05-01

    A quantitative spectrophotometrical method was used to study the adhesive phenotype of lymphocytes from regional lymph nodes of rats with early stage adjuvant-induced arthritis (AA), pretreated or not with cyclophosphamide (CY). The results showed that adhesion of lymphocytes from AA-sensitized lymph nodes to gelatin and collagens (type I, II, III and IV) was enhanced, especially to collagen type II. However, adhesion to fibronectin and to fibrinogen did not differ from adhesion in nontreated rats. Application of CY was found to aggravate AA development and influence the lymphocytes' adhesiveness. Adhesion was inhibited in all cases except to fibrinogen, where it was augmented, compared to the adhesion in both AA and control groups. Relationships between the lymphocyte adhesive phenotype and the expression of histological changes suggest that lymphocyte-matrix interactions could play an important role in the pathogenesis of AA development and the mechanism of CY action.

  18. Virgin coconut oil supplementation ameliorates cyclophosphamide-induced systemic toxicity in mice.

    Science.gov (United States)

    Nair, S S; Manalil, J J; Ramavarma, S K; Suseela, I M; Thekkepatt, A; Raghavamenon, A C

    2016-02-01

    Virgin coconut oil (VCO) is an unrefined kernal oil, prepared from Cocos nucifera L., having substantial nutritional and medicinal value. Experimental studies have suggested its antioxidant, anti-inflammatory, immunostimulatory and hypolipidemic effects. The present study assesses its effect on formalin-induced chronic inflammation and cyclophosphamide (CTX)-induced systemic toxicity in murine models. Oral administration of VCO effectively reduced formalin-induced paw oedema in mice with more or less similar efficacy as that of diclofenac. The CTX-induced hike in blood urea, creatinine, thiobarbituric acid reactive substances (TBARS) and liver marker enzymes in mice was marginally decreased by VCO (8 g/kg body weight) ingestion orally. The liver and kidney catalase, superoxide dismutase and glutathione peroxidase activities, together with cellular glutathione and TBARS levels, were found to be improved in these animals. Overall the study reveals the protective efficacy of VCO against secondary toxicity induced by CTX possibly through its antioxidant and anti-inflammatory properties.

  19. Treatment of Goodpasture syndrome with cyclophosphamide, prednisone and plasma exchange transfusions.

    Science.gov (United States)

    Rossen, R D; Duffy, J; McCredie, K B; Reisberg, M A; Sharp, J T; Hersh, E M; Eknoyan, G; Suki, W N

    1976-01-01

    Repeated plasm exchanges were performed in a 44-year-old man with Goodpasture syndrome, also treated with cyclophosphamide and prednisone. Improvement was observed within 3 weeks of starting the protocol, and by the 76th week, endogenous creatinine clearance had increased from 30 to 56 ml/min/1.73 M2 and serum albumin from 2.7 to 3.7 g/dl. Prior treatment with immunosuppressive drugs had not significantly influenced circulating antibody levels. But sustained suppression of antibody was achieved after the plasma exchanges were begun, suggesting that physical removal of circulating antibody combined with antiproliferative drug treatment may be a useful way to control undesirable humoral immune responses. PMID:949874

  20. Tumor xenotransplantation in Wistar rats after treatment with cyclophosphamide and total lymphoid irradiation. [X-ray

    Energy Technology Data Exchange (ETDEWEB)

    Hoogenhout, J. (St. Radbond Academic Hospital, Nijmegen, Netherlands); Kazem, I.; Jerusalem, C.R.; Bakkeren, J.A.J.; de Jong, J.; Kal, H.B.; van Munster, P.J.J.

    1982-10-01

    Three-month-old male Wistar rats were treated with cyclophosphamide and total lymphoid irradiation, and C22LR mouse osteosarcoma was transplanted into the rats. The effects of immunosuppression were monitored by lymphocyte counts, serum IgG determinations, phytohemagglutinin (PHA) and concanavalin A (Con A) responses, measurement of the proportion of B cells, and histopathological studies of the lymphoid organs. At eight days after treatment, the lymphocyte counts, IgG levels, and PHA and Con A values were decreased. Mitotic activity started in the depleted B and T cell areas of the peripheral lymphatic organs two weeks after treatment. There was a 94% graft take of the osteosarcoma. It was determined that the optimum time for tumor xenograft transplantation is 4 days after treatment. The duration of growth was 11 days, and this was followed by regression up to day 21.

  1. Tumor xenotransplantation in Wistar rats after treatment with cyclophosphamide and total lymphoid irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Hoogenhout, J.; Kazem, I.; Jerusalem, C.R.; Bakkeren, J.A.; de Jong, J.; Kal, H.B.; van Munster, P.J.

    1982-10-01

    Three-month-old male Wistar rats were treated with cyclophosphamide and total lymphoid irradiation, and C22LR mouse osteosarcoma was transplanted into the rats. The effects of immunosuppression were monitored by lymphocyte counts, serum IgG determinations, phytohemagglutinin (PHA) and concanavalin A (Con A) responses, measurement of the proportion of B cells, and histopathological studies of the lymphoid organs. At eight days after treatment, the lymphocyte counts, IgG levels, and PHA and Con A values were decreased. Mitotic activity started in the depleted B and T cell areas of the peripheral lymphatic organs two weeks after treatment. There was a 94% graft take of the osteosarcoma. It was determined that the optimum time for tumor xenograft transplantation is 4 days after treatment. The duration of growth was 11 days, and this was followed by regression up to day 21.

  2. Cardiomyopathy in patients after posttransplant cyclophosphamide-based hematopoietic cell transplantation.

    Science.gov (United States)

    Lin, Chien-Jung; Vader, Justin M; Slade, Michael; DiPersio, John F; Westervelt, Peter; Romee, Rizwan

    2017-05-15

    The use of posttransplant cyclophosphamide (PT-Cy) has contributed significantly to the success of haploidentical hematopoietic cell transplantation (HCT). Furthermore, several studies have shown promising results in the human leukocyte antigen-matched setting. However, the use of high-dose cyclophosphamide has been associated with the development of cardiomyopathy. There is a paucity of data concerning posttransplant cardiac complications in patients undergoing PT-Cy-based HCT. A retrospective analysis of 176 patients undergoing HCT with PT-Cy was performed. The overall survival, left ventricular ejection fractions, brain natriuretic peptide levels, and cardiac comorbidities were reviewed. The associations between comorbidities and the onset of heart failure were assessed with a Cox proportional hazards model. Pretransplant cardiomyopathy was found in 16 patients (9.1%) but had no effect on their posttransplant overall survival. Thirty-five patients (21.9%) developed posttransplant cardiomyopathy, which correlated with increased mortality, but this was not statistically different from the frequency-matched non-PT-Cy cohort. The majority of these cardiomyopathies occurred in the setting of an infectious milieu. An age greater than 60 years and an HCT comorbidity index score equal to or greater than 4 were the only risk factors that correlated with posttransplant cardiomyopathy. The presence of pretransplant cardiomyopathy does not negatively affect overall survival for patients who undergo HCT with PT-Cy. Furthermore, cardiomyopathy in PT-Cy patients is not caused by PT-Cy but is mostly concurrent with infectious complications and is associated with reduced overall survival. Traditional cardiovascular risk factors do not fully predict the occurrence of posttransplant cardiomyopathy. Future research is required to unravel predictive factors for cardiomyopathy after PT-Cy-based HCT. Cancer 2017;123:1800-1809. © 2017 American Cancer Society. © 2017 American Cancer

  3. Chemotherapeutic (cyclophosphamide) effects on rat breast tumor hemodynamics monitored by multi-channel NIRS

    Science.gov (United States)

    Kim, Jae G.; Zhao, Dawen; Mason, Ralph P.; Liu, Hanli

    2005-04-01

    We previously suggested that the two time constants quantified from the increase of tumor oxyhemoglobin concentration, ▵ [HbO2], during hyperoxic gas intervention are associated with two blood flow/perfusion rates in well perfused and poorly perfused regions of tumors. In this study, our hypothesis is that when cancer therapy is applied to a tumor, changes in blood perfusion will occur and be detected by the NIRS. For experiments, systemic chemotherapy, cyclophosphamide (CTX), was applied to two groups of rats bearing syngeneic 13762NF mammary adenocarcinomas: one group received a single high dose i. p. (200 mg/kg CTX) and the other group continuous low doses (20 mg/kg CTX i. p. for 10 days). Time courses of changes in tumor ▵ [HbO2] were measured at four different locations on the breast tumors non-invasively with an inhaled gas sequence of air-oxygen-air before and after CTX administration. Both rat body weight and tumor volume decreased after administration of high dose CTX, but continuous low doses showed decrease of tumor volume only. Baselines (without any therapy) intra- and inter-tumor heterogeneity of vascular oxygenation during oxygen inhalation were similar to our previous observations. After CTX treatment, significant changes in vascular hemodynamic response to oxygen inhalation were observed from both groups. By fitting the increase of ▵ [HbO2] during oxygen inhalation, we have obtained changes of vascular structure ratio and also of perfusion rate ratio before and after chemotherapy. The preliminary results suggest that cyclophosphamide has greatest effect on the well perfused tumor vasculature. Overall, our study supports our earlier hypothesis, proving that the effects of chemotherapy in tumor may be monitored non-invasively by using NIRS to detect changes of hemodynamics induced with respiratory challenges.

  4. Immunomodulating Effect of Cyclophosphamide on the Mice Infected with Candida albicans

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    aziz japoni

    2014-03-01

    Full Text Available Background & Objectives: Cyclophosphamide is an alkylating agent that stops the replication of DNA, which is used to treat various types of cancer and some autoimmune disorders. This study was aimed at then evaluating the immunomodulating effect of cyclophosphamide (Cy on the immune system of vaccinated and non-vaccinated mice.Materials & Methods: The  study was performed on three groups of mice consisting of vaccinated, non-vaccinated and control groups. Vaccination was carried out by three separated courses of C. albicans injection intraperitoneally.  Then,  the  vaccinated group  received Cy  on  day  zero  and  were  challenged  with  lethal  doses of  C. albicans  on  days  zero, one, 3, 6 and 12 post-Cy injection. Non-vaccinated group received Cy on day zero and similar to vaccinated ones were challenged with lethal doses of the organism. The control groups received  just  Cy  on  day  zero  and  were  sacrificed  on days  post-Cy injection. Then, the hemogram and the spleen and the renal tissues were studied microscopically and macroscopically.Results: In the vaccinated group, an increase in survival time, the number of polymorphonuclear and the significant hyperplasia in the white pulp on days 6 and 12 post-Cy injection were noticed. In non-vaccinated ones, these factors had significant decrease on days 1 and 3. Conclusion: It is concluded that the hyperplasia in the white pulp of spleen and an increasing in peripheral polymorphonuclear due to the selective effects of Cy could effectively protect the animal against C. albicans infection.

  5. Chemoprotective effect of Crataegus monogyna aqueous extract against cyclophosphamide-induced reproductive toxicity

    Directory of Open Access Journals (Sweden)

    Ali Shalizar Jalali

    2011-11-01

    Full Text Available AbstractCyclophosphamide (CP is extensively used as an antineoplastic agent for treatment of various cancers, as well as an immunosuppressive agent. However, despite its wide spectrum of clinical uses, CP is known to cause several adverse effects including reproductive toxicity in humans and experimental animals. Crataegus monogyna is one of the oldest medicinal plant has been shown to be cytoprotective by scavenging free radicals. The present study was conducted to assess whether Crataegus monogyna fruits aqueous extract with anti-oxidant properties could serve as a protective agent against reproductive toxicity during CP treatment in a rat model. Male Wistar rats were categorized into four groups. Two groups of rats were administered CP at a dose of 5 mg in 5 mL saline kg-1 per day for 28 days by oral gavages. One of the groups received Crataegus monogyna aqueous extract at a dose of 20 mg kg-1 per day orally four hours after cyclophosphamide administration. A vehicle-treated control group and a Crataegus monogyna control group were also included. The CP-treated group showed significant decreases in the body and organ weights and spermatogenic activities as well as many histological alterations. CP treatment also caused a significant decrease in sperm count and motility with an increase in dead and abnormal sperms. Moreover, significant decrease in serum levels of testosterone and increased serum concentrations of FSH, LH, LDH, CPK and SGOT were observed in CP-treated rats. Notably, Crataegus coadministration caused a partial recovery in above-mentioned parameters. These findings indicated that Crataegus might be partially protective against CP-induced reproductive toxicity.

  6. Role of the KATP channel in the protective effect of nicorandil on cyclophosphamide-induced lung and testicular toxicity in rats

    OpenAIRE

    Ahmed, Lamiaa A.; El-Maraghy, Shohda A.; Rizk, Sherine M.

    2015-01-01

    This study is the first to investigate the role of the KATP channel in the possible protection mediated by nicorandil against cyclophosphamide-induced lung and testicular toxicity in rats. Animals received cyclophosphamide (150 mg/kg/day, i.p.) for 2 consecutive days and then were untreated for the following 5 days. Nicorandil (3 mg/kg/day, p.o.) was administered starting from the day of cyclophosphamide injection with or without glibenclamide (5 mg/kg/day, p.o.). Nicorandil administration si...

  7. The efficacy and safety of preoperative chemotherapy with triweekly abraxane and cyclophosphamide followed by 5-Fluorouracil, epirubicin, and cyclophosphamide therapy for resectable breast cancer: a multicenter clinical trial.

    Science.gov (United States)

    Shigematsu, Hideo; Kadoya, Takayuki; Masumoto, Norio; Sasada, Tatsunari; Emi, Akiko; Ohara, Masahiro; Kajitani, Keiko; Okada, Morihito

    2015-04-01

    It has been reported that tri-weekly Abraxane therapy has better outcomes in recurrent breast cancer than tri-weekly Cremophor-based taxol therapy, and that cyclophosphamide combined with taxane shows an enhanced antitumor effect. We conducted a phase II clinical trial of preoperative chemotherapy with a combination of TRI-ABC. From September 2011 to September 2013, 4 cycles of preoperative chemotherapy with TRI-ABC followed by 4 cycles of FEC were administered in patients with resectable breast cancer. In patients with HER2-positive breast cancer, tri-weekly Trastuzumab was administered with TRI-ABC. The primary end point was the pathological complete response (pCR) rate in the breasts and lymph nodes. The treatment outcomes and safety were evaluated in 54 patients who received at least 1 dose of chemotherapy. All patients underwent radical surgery, and the overall pCR rate of 37% (20 of 54) was achieved. The pCR rates according to each subtype were 8% (2 of 24) in hormone receptor (HR)-positive HER2-negative breast cancer, 56% (5 of 9) in HR-positive HER2-positive breast cancer, 63% (5 of 8) in HR-negative HER2-positive breast cancer, and 62% (8 of 13) in triple-negative breast cancer. Multivariate analysis revealed that HR negativity and HER2 positivity were predictive factors of pCR. Clinical response was observed in 49 patients (91%). The safety profile was acceptable. Preoperative chemotherapy with TRI-ABC followed by FEC showed high efficacy and excellent safety. Further clinical studies should be conducted to compare the efficacy of TRI-ABC followed by FEC with conventional taxane-anthracycline regimens. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Clinical Effects of Mitoxantrone Plus Prednisone in Hormone Refractory Prostate Cancer%米托蒽醌联合泼尼松治疗激素抵抗性前列腺癌的临床效果

    Institute of Scientific and Technical Information of China (English)

    栾宝红; 李晓梅; 邬红霞

    2014-01-01

    Objective To explore the clinical effects of mitoxantrone plus prednisone in hormone refractory prostate cancer.Methods 90 cases of patients with hormone refractory prostate cancer were randomly divided into the experiment group and the control group .The experiment group were treated by mitoxantrone plus prednisone ,and the control group were treated by docetaxel plus prednisone .The clinical effects ,bone pain relief effect ,side effects and adverse reactions of the 2 groups were com-pared.Results There was no significant difference in the total effective rate between the experiment group (86.67%) and the control group(84.44%)(P>0.05);The PSA control time of the experiment group (25.33 ±7.57) week were lower than that of the control group(37.88 ±10.26) week (P0.05);The incidence of bone marrow suppression of the experi-ment group was 40.00%,the adverse reactions of the experiment group was 6.67%,the incidence of bone marrow suppression of the control group was 53.33%,the adverse reactions of the experiment group was 17.78%,there was no significant difference ( P>0.05).Conclusion Mitoxantrone plus prednisone for hormone refractory prostate cancer has remarkable clinical effects ,the clinical effects is similar as the docetaxel plus prednisone .Mitoxantrone plus prednisone has better effects in bone pain relief ,side effect and adverse reactions .It can improve the clinical effects by alternating the two treatments when one treatment is unsatisfac -tory.Docetaxel plus prednisone can be the save package for mitoxantrone plus prednisone .%目的:探讨米托蒽醌联合泼尼松治疗激素抵抗性前列腺癌的临床效果。方法按照随机数字表法将90例激素抵抗性前列腺癌患者均分为实验组和对照组。实验组采用米托蒽醌联合泼尼松治疗,对照组采用多西他赛联合泼尼松治疗,比较2组患者临床疗效、骨痛缓解效果及毒副作用和不良反应发生情况。结果实验组总有效率为86.67

  9. Investigation of the Proliferation, Apoptosis/Necrosis, and Cell Cycle Phases in Several Human Multiple Myeloma Cell Lines. Comparison of Viscum album QuFrF Extract with Vincristine in an In Vitro Model

    Directory of Open Access Journals (Sweden)

    Eva Kovacs

    2010-01-01

    Full Text Available Multiple myeloma is a haematological disorder of malignant plasma cells. Interleukin-6 (IL-6 is a potent growth factor for the proliferation of these cells. Vincristine as a chemotherapeutic agent is used mainly in combination with other chemotherapeutic substances in the treatment of different haematological disorders. Viscum album QuFrF (VAQuFrF extract is an experimental drug that is not used in the treatment in tumour patients. It contains 2000 ng lectin and 10 µg viscotoxin in 10 mg extract. In this study, the effects of VAQuFrF extract were compared with those of vincristine in six human multiple myeloma cell lines (Molp-8, LP-1, RPMI-8226, OPM-2, Colo-677, and KMS-12-BM using an in vitro model. As parameters, the IL-6 production, proliferation, apoptosis/necrosis, and cell cycle phases of the cells were taken. To measure the IL-6 production, apoptosis/necrosis, and cell cycle phases, the substances were tested in dose ranges of 10, 50, and 100 µg/106 cells. To measure the proliferation of the cells, the substances were tested in dose ranges of 1, 5, and 10 µg/105 cells. The profile of the antitumour effects of the two substances is identical. (1 Neither VAQuFrF extract nor vincristine produced IL-6 in any cell line. (2 Both substances inhibited the proliferation of the cells (cytostatic effect, arrested the cell cycle phases, and increased the number of apoptotic/necrotic cells (cytocidal effect. At a dose of 10 µg/105 cells, VAQuFrF more effectively inhibited the proliferation than vincristine (p < 0.01 in the cell lines Molp-8, LP-1, and RPMI-8226. (3 VAQuFrF affected the tumour cells mainly via cytostatic effect. Vincristine had a clear cytocidal effect. These findings indicate that VAQuFrF extract could be a novel drug in the treatment of multiple myeloma.

  10. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10)

    DEFF Research Database (Denmark)

    Eichhorst, Barbara; Fink, Anna-Maria; Bahlo, Jasmin

    2016-01-01

    BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less to...

  11. Dual effects of indoleamine 2,3-dioxygenase inhibitors on the therapeutic effects of cyclophosphamide and cycloplatam on Ehrlich ascites tumor in mice.

    Science.gov (United States)

    Bogdanova, L A; Morozkova, T S; Amitina, S A; Mazhukin, D G; Nikolin, V P; Popova, N A; Kaledin, V I

    2014-08-01

    Ethyl pyruvate, an inhibitor of indoleamine 2,3-dioxygenase, slightly suppressed the growth of transplantable Ehrlich tumor in mice and significantly potentiated the therapeutic effect of cyclophosphamide. Another inhibitor amidoxime produced a similar effect. However, both ethyl pyruvate and amidoxime significantly reduced the effect of cycloplatam therapy. The observed changes can be stipulated by different effects of cyclophosphamide and cycloplatam on the subpopulations of lymphoid cells taking part in the formation of antitumor immunity and resistance to tumors.

  12. In vitro incubation of bone marrow and peripheral stem cells with vincristine and methylprednisolone: functional T-cell depletion for haploidentical and autologous transplants.

    Science.gov (United States)

    Fragonas, E; Perticarari, S; Presani, G; Rabusin, M; Andolina, M; Mangiarotti, M A

    2000-11-01

    A mismatched bone marrow transplantation is feasible only if the donor's marrow lymphocytes are eliminated from the graft. This can be achieved by several methods, but all have the disadvantage of inducing a long-lasting immune deficiency while the risk of graft rejection and leukemic relapse increase. We use a sort of functional T-cell depletion by treating the cells with vincristine and methylprednisolone. This method is surely the cheapest and has allowed us to perform 60 transplants with a tolerable risk of GVHD. The treatment of the donor's lymphocytes has already been demonstrated to be able to block the mixed lymphocyte culture reaction in vitro. In this experiment Th1 and Th2 activities were almost completely blocked without reduction of lymphocyte viability and apoptosis induction.

  13. Use of cultured rat embryos to evaluate the teratogenic activity of serum: cadmium and cyclophosphamide. [Serum-based culture media for growing rat embryos is used to determine the teratogenicity of cadmium and cyclophosphamide

    Energy Technology Data Exchange (ETDEWEB)

    Klein, N. W.; Vogler, M. A.; Chatot, C. L.; Pierro, L. J.

    1979-01-01

    Head fold stage rat embryos were cultured for 48 hrs in vitro on serum taken at various intervals from rats that had been injected ip with either cadmium or cyclophosphamide. Their response was compared to that of embryos cultured for the same period on control serum to which these substances were added directly. One and 4 hr sera from cadmium injected rats (2.13 mg Cd/sup + +//kg) were lethal. Eight hr serum allowed survival but embryos were exencephalic and contained reduced amounts of protein and DNA. The response to direct cadmium was characteristically different and was related to dosage and the extent to which zero-time embryos had progressed through the head fold stage. At 1.6 ..mu..M, Cd/sup + +/-susceptible embryos were hemorrhagic but not exencephalic. One hr serum from rats given cyclophosphamide (180 mg/kg) was lethal. On 4 hr serum, embryos survived but were exencephalic and contained less protein and DNA than controls. Embryos were resistant to direct cyclophosphamide up to 800 ..mu..g per ml of medium. At this concentration, embryos appeared morphologically normal but contained reduced amounts of protein.

  14. Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy

    DEFF Research Database (Denmark)

    Comabella, M; Balashov, K; Issazadeh-Navikas, Shohreh

    1998-01-01

    Multiple sclerosis is postulated to be a Th1-type cell-mediated autoimmune disease. We investigated cytokine profiles in patients with progressive multiple sclerosis by using intracytoplasmic staining. We found increased IL-12 production by monocytes and increased IFN-gamma production by T cells...... in untreated patients as compared with controls. In patients treated with methotrexate, methylprednisolone, or cyclophosphamide/methylprednisolone (CY/MP), only CY/MP treatment normalized the elevated IL-12 production. Furthermore, CY/MP-treated patients had decreased IFN-gamma and increased IL-4, IL-5......, and TGF-beta expression. Patients followed prospectively before and after starting CY/MP treatment showed a gradual decrease in IL-12 and IFN-gamma production and an increase in IL-4 and IL-5. In vitro, addition of 4-hydroperoxycyclophosphamide, a metabolite of cyclophosphamide decreased IL-12 production...

  15. Tolerability and safety of classic cyclophosphamide, methotrexate, and fluorouracil treatment in Japanese patients with early breast cancer.

    Science.gov (United States)

    Tada, Keiichiro; Ito, Yoshinori; Takahashi, Shunji; Iijima, Kohtaro; Miyagi, Yumi; Nishimura, Seiichiro; Takahashi, Kaoru; Makita, Masujiro; Iwase, Takuji; Yoshimoto, Masataka; Kasumi, Fujio

    2006-01-01

    Few reports have addressed the feasibility and safety of classic Cyclophosphamide, Methotrexate, and Fluorouracil (CMF) therapy in Japanese female breast cancer patients. Twenty-four Japanese patients who received classic CMF, identical to the originally described treatment regimen were studied in terms of treatment dose, treatment delay, and toxicity. Classic CMF was not discontinued in any of the cases. The median delay in treatment was 14 days, and the mean administered dose of cyclophosphamide was 98.2% of the planned dose. None of the patients suffered severe side-effects such as febrile neutropenia; however, in 22 patients in whom the effect of CMF on hair loss could be assessed, 7 (31.8%) had to wear hats or wigs. Classic CMF is a feasible and safe regimen in Japanese breast cancer patients. In Japan, this regimen is still available for some specific groups of early breast cancer patients.

  16. Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice

    Energy Technology Data Exchange (ETDEWEB)

    Conklin, Daniel J., E-mail: dj.conklin@louisville.edu [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292 (United States); Haberzettl, Petra; Jagatheesan, Ganapathy; Baba, Shahid [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292 (United States); Merchant, Michael L. [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Division of Nephrology, Department of Medicine, University of Louisville, Louisville, KY 40292 (United States); Prough, Russell A. [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292 (United States); Williams, Jessica D. [University of Cincinnati College of Medicine, Internal Medicine, Cincinnati, OH 45267 (United States); Prabhu, Sumanth D. [Division of Cardiovascular Disease, University of Alabama-Birmingham, Birmingham, AL 35294 (United States); Bhatnagar, Aruni [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292 (United States); Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292 (United States)

    2015-06-01

    High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100–300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK·MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein–acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1–5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10–20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity. - Graphical abstract: Cyclophosphamide (CY) treatment results in P450-mediated metabolic formation of phosphoramide mustard and acrolein (3-propenal). Acrolein is either metabolized and

  17. Protective effect of methanolic extracts of Thymus vulgaris L. against cyclophosphamide-induced DNA damage in mouse bone marrow cells using the micronucleus test

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    Abbas Salmani

    2015-12-01

    Full Text Available Cyclophosphamide is a chemo-therapeutic agent used in the treatment of various cancers and autoimmune diseases. This composition has cytotoxic and clastogenic properties. The purpose of this study was to evaluate the protective effect of methanol extracts of Thymus vulgaris L. against DNA damage induced by cyclophosphamide in mouse bone marrow cells by the micronucleus test. The extract concentrations of 375, 750, 1500 mg/kg were injected intraperitoneally (Ip into mice for 7 consecutive days. One hour after the last injection, cyclophosphamide 50 mg/kg Ip was injected. 24 hours after cyclophosphamide injection, the animals were killed and the samples of bone marrow were prepared and stained using the standard methods. For each sample, 1000 cells of polychromatic erythrocytes (PCE and the same number of normochromatic erythrocyte (NCE and the cells containing their micronucleus were counted. Cyclophosphamide increased the frequency of micronuclei polychromatic erythrocytes (MnPCE and decreased cell proliferation (PCE/PCE+NCE. All doses of extracts significantly reduced the micronucleus frequency ratio (P<0.05. The cells proliferation ratio (PCE/PCE+NCE was also increased. The best effect in reducing the micronucleus frequency was at 1500 mg/kg dosage. Thymus extract is able to reduce the clastogenic and cytotoxic effects of cyclophosphamide, due to its antioxidant properties, playing a protective role.

  18. 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.

  19. Sustained complete remission of steroid- and cyclophosphamide-resistant minimal-change disease with a single course of rituximab therapy.

    Science.gov (United States)

    Janardan, Jyotsna; Ooi, Khai; Menahem, Solomon

    2014-06-01

    We report a case of steroid- and cyclophosphamide-resistant nephrotic syndrome secondary to minimal-change disease occurring in an otherwise healthy 19-year-old female, responding rapidly to two doses of rituximab therapy. Complete disease remission has been sustained up to last follow-up (32 months) despite CD19 recovery. Literature review suggests emerging evidence that rituximab may have a role to play in recurrent and/or refractory minimal-change disease.

  20. Sustained complete remission of steroid- and cyclophosphamide-resistant minimal-change disease with a single course of rituximab therapy

    OpenAIRE

    Janardan, Jyotsna; Ooi, Khai; Menahem, Solomon

    2014-01-01

    We report a case of steroid- and cyclophosphamide-resistant nephrotic syndrome secondary to minimal-change disease occurring in an otherwise healthy 19-year-old female, responding rapidly to two doses of rituximab therapy. Complete disease remission has been sustained up to last follow-up (32 months) despite CD19 recovery. Literature review suggests emerging evidence that rituximab may have a role to play in recurrent and/or refractory minimal-change disease.

  1. Age, anti-müllerian hormone, antral follicles count to predict amenorrhea or oligomenorrhea after chemotherapy with cyclophosphamide

    OpenAIRE

    2015-01-01

    Background A cohort study was performed to identify ovarian reserve markers (ORM) that predicts amenorrhea or oligomenorrhea 6 months after cyclophosphamide CTX in women with breast cancer. Methods 52 eumenorrheic patients with breast cancer were enrolled. FSH, anti-Müllerian hormone (AMH), antral follicles count (AFC) were measured before and 6 months after CTX. A logistic regression for independent samples and determination of the ROC curve were performed. Results The age of 32 years presen...

  2. Sustained complete remission of steroid- and cyclophosphamide-resistant minimal-change disease with a single course of rituximab therapy

    OpenAIRE

    Janardan, Jyotsna; Ooi, Khai; Menahem, Solomon

    2014-01-01

    We report a case of steroid- and cyclophosphamide-resistant nephrotic syndrome secondary to minimal-change disease occurring in an otherwise healthy 19-year-old female, responding rapidly to two doses of rituximab therapy. Complete disease remission has been sustained up to last follow-up (32 months) despite CD19 recovery. Literature review suggests emerging evidence that rituximab may have a role to play in recurrent and/or refractory minimal-change disease.

  3. Mechanisms of Fatal Cardiotoxicity following High-Dose Cyclophosphamide Therapy and a Method for Its Prevention.

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    Takuro Nishikawa

    Full Text Available Observed only after administration of high doses, cardiotoxicity is the dose-limiting effect of cyclophosphamide (CY. We investigated the poorly understood cardiotoxic mechanisms of high-dose CY. A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9. Cytotoxicity was then evaluated by 3-(4,5-dimethyl-2-thiazolyl¬2,5-diphenyl¬2H-tetrazolium bromide (MTT assay, lactate dehydrogenase release, production of reactive oxygen species (ROS, and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC, antioxidant isorhamnetin (ISO, and CYP inhibitor β-ionone (BIO. Quantifying CY and CY metabolites by means of liquid chromatography coupled with electrospray tandem mass spectrometry, we assayed culture supernatants of CYS9 with and without candidate cardioprotectant agents. Assay results for MTT showed that treatment with CY (125-500 μM did not induce cytotoxicity. CYS9, however, exhibited myocardial cytotoxicity when CY concentration was 250 μM or more. After 250 μM of CY was metabolized in S9 mix for 2 h, the concentration of CY was 73.6 ± 8.0 μM, 4-hydroxy-cyclophosphamide (HCY 17.6 ± 4.3, o-carboxyethyl-phosphoramide (CEPM 26.6 ± 5.3 μM, and acrolein 26.7 ± 2.5 μM. Inhibition of CYS9-induced cytotoxicity occurred with NAC, ISO, and BIO. When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein

  4. Altered detrusor gap junction communications induce storage symptoms in bladder inflammation: a mouse cyclophosphamide-induced model of cystitis.

    Science.gov (United States)

    Okinami, Takeshi; Imamura, Masaaki; Nishikawa, Nobuyuki; Negoro, Hiromitsu; Sugino, Yoshio; Yoshimura, Koji; Kanematsu, Akihiro; Hashitani, Hikaru; Ogawa, Osamu

    2014-01-01

    Lower urinary tract symptoms (LUTS) include storage, voiding and post-micturition symptoms, featuring many urological diseases. Storage symptoms are the most frequent among these and associated with overactive bladder and non-bacterial bladder inflammation such as interstitial cystitis/bladder pain syndrome (IC/BPS). Gap junction, a key regulator of hyperactive conditions in the bladder, has been reported to be involved in pathological bladder inflammation. Here we report involvement of gap junction in the etiology of storage symptoms in bladder inflammation. In this study, cyclophosphamide-induced cystitis was adapted as a model of bladder inflammation. Cyclophosphamide-treated mice showed typical storage symptoms including increased urinary frequency and reduced bladder capacity, with concurrent up-regulation of connexin 43 (GJA1), one of the major gap junction proteins in the bladder. In isometric tension study, bladder smooth muscle strips taken from the treated mice showed more pronounced spontaneous contraction than controls, which was attenuated by carbenoxolone, a gap junction inhibitor. In voiding behavior studies, the storage symptoms in the treated mice characterized by frequent voiding were alleviated by 18α-glycyrrhetinic acid, another gap junction inhibitor. These results demonstrate that cyclophosphamide-induced mouse model of cystitis shows clinical storage symptoms related with bladder inflammation and that gap junction in the bladder may be a key molecule of these storage symptoms. Therefore, gap junction in the bladder might be an alternative therapeutic target for storage symptoms in bladder inflammation.

  5. Altered detrusor gap junction communications induce storage symptoms in bladder inflammation: a mouse cyclophosphamide-induced model of cystitis.

    Directory of Open Access Journals (Sweden)

    Takeshi Okinami

    Full Text Available Lower urinary tract symptoms (LUTS include storage, voiding and post-micturition symptoms, featuring many urological diseases. Storage symptoms are the most frequent among these and associated with overactive bladder and non-bacterial bladder inflammation such as interstitial cystitis/bladder pain syndrome (IC/BPS. Gap junction, a key regulator of hyperactive conditions in the bladder, has been reported to be involved in pathological bladder inflammation. Here we report involvement of gap junction in the etiology of storage symptoms in bladder inflammation. In this study, cyclophosphamide-induced cystitis was adapted as a model of bladder inflammation. Cyclophosphamide-treated mice showed typical storage symptoms including increased urinary frequency and reduced bladder capacity, with concurrent up-regulation of connexin 43 (GJA1, one of the major gap junction proteins in the bladder. In isometric tension study, bladder smooth muscle strips taken from the treated mice showed more pronounced spontaneous contraction than controls, which was attenuated by carbenoxolone, a gap junction inhibitor. In voiding behavior studies, the storage symptoms in the treated mice characterized by frequent voiding were alleviated by 18α-glycyrrhetinic acid, another gap junction inhibitor. These results demonstrate that cyclophosphamide-induced mouse model of cystitis shows clinical storage symptoms related with bladder inflammation and that gap junction in the bladder may be a key molecule of these storage symptoms. Therefore, gap junction in the bladder might be an alternative therapeutic target for storage symptoms in bladder inflammation.

  6. The effects of cyclophosphamide on neurotransmission in the urinary bladder of Suncus murinus, the house musk shrew.

    Science.gov (United States)

    Mok, M H; Knight, G E; Andrews, P L; Hoyle, C H; Burnstock, G

    2000-05-12

    This study has shown that cyclophosphamide treatment of the insectivore Suncus murinus, causes a down regulation in both muscarinic and P2X receptors, together with a reduced responsiveness to exogenous histamine (0.3 mM) in the urinary bladder. Electrical field stimulation (70 V, 0.3 ms, 0.5-16 Hz, 10 s every 5 min) of bladders from both control and cyclophosphamide-treated animals showed identical responses. Since post-junctional alterations have been revealed by the reduced responsiveness to exogenous carbachol (0.1 microM-3 mM) and beta,gamma-methylene ATP (0.3-300 microM), it would appear that in the bladders of cyclophosphamide-treated animals there is also a pre-junctional effect, increased transmitter release compensating for the down regulation of the receptors. As the pattern of neurotransmission of the bladder of suncus more closely resembles that of human detrusor than other commonly studied laboratory animals, this insectivore appears to be a useful animal model for the study of bladder neurotransmission in pathophysiological conditions.

  7. Alternating chemotherapy of CHOP-Bleo and POEM-Bleo for diffuse large-cell lymphoma: a single-institutional study with a long-term follow-up.

    Science.gov (United States)

    Ohnoshi, T; Hayashi, K; Ueno, K; Tada, A; Mizuta, J; Tagawa, S; Matsutomo, S; Saito, S; Kawashima, K; Yoshino, T

    1993-08-01

    Diffuse large-cell lymphoma (DLCL) is a neoplasm that is curable with chemotherapy in an appreciable percentage of patients. However, not all patients are cured and the best drug combination and optimal dose intensity have not yet been established. In an attempt to improve complete response rate and survival with minimal toxicity, we devised an alternating combination chemotherapy consisting of CHOP-Bleo (cyclophosphamide, doxorubicin, vincristine, prednisolone, and bleomycin) and POEM-Bleo (prednisolone, vincristine, etoposide, mitoxantrone, and bleomycin). Between March 1986 and October 1990, 30 newly-diagnosed patients with advanced DLCL were treated with the regimen. Of these 30 patients, 14 (47%) were 61 years of age or more, 15 (50%) had stage IV disease, 14 (47%) presented with constitutional symptoms, and 7 (23%) had T-cell lymphoma. After the completion of therapy, 23 (77%) achieved a complete response and 6 (20%) had a partial response. The actuarial relapse-free survival at 5 years is 52% and the overall survival projected to 5 years is 47%. Toxicity was generally mild and well tolerated. Although this alternating regimen had substantial activity as front-line chemotherapy for advanced DLCL, we conclude that the observed response rate and survival do not essentially differ from those achieved with conventional regimens and further clinical trials are thus not warranted.

  8. Bronchial hyperreactivity occurs in steroid-treated guinea pigs depleted of leukocytes by cyclophosphamide

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    Murlas, C.; Roum, J.H.

    1985-05-01

    The effects of cyclophosphamide and cortisone acetate treatment on O/sub 3/-induced changes in airway mucosal morphology and bronchial reactivity were assessed in guinea pigs. Animals in groups of four were studied at 2 or 6 h after O/sub 3/ (3.0 ppm, 2 h) and in one control group. Reactivity was determined by measuring specific airway resistance during intravenous acetylcholine infusion in intact, unanesthetized, spontaneously breathing animals. After testing, tracheal tissue was obtained from all animals for light microscopic examination. Another group of 10 drug-treated and 10 normal animals were tested at 2 h, 6 h, 1 day, and 4 days after O/sub 3/. Drug treatment resulted in substantial decreases in both circulating and airway mucosal granulocytes. Two hours after O/sub 3/, a marked decrease in airway mucosal goblet cells as well as ciliated cell damage occurred in both normal and treated animals. However, only in normal animals did neutrophilic infiltration develop thereafter. Nonetheless, hyperreactivity postozone occurred and progressed similarly in both groups. Our results indicate that acute O/sub 3/-induced bronchial hyperreactivity at 2 h is associated with signs of airway mucosal injury but appears independent of granulocyte changes. Airway neutrophilic infiltration and eosinophil depletion seem to be consequences of mucosal injury from O/sub 3/ and not causes of the bronchial hyperreactivity that results.

  9. Levamisole vs. cyclophosphamide for frequently-relapsing steroid-dependent nephrotic syndrome.

    Science.gov (United States)

    Alsaran, K; Grisaru, S; Stephens, D; Arbus, G

    2001-10-01

    A retrospective analysis comparing the first-time use of levamisole (L) or cyclophosphamide (C) as second-line therapy for children with frequently relapsing, steroid-dependent (FR/SD) nephrotic syndrome, was conducted at our center. The relapse rate and the total cumulative dose of prednisone during the year prior to L/C therapy was compared to that during the year following the institution of therapy with L or C in 51 patients, between July 1992 and June 1997. An analysis of covariance was used to adjust the outcome for differences between the 2 groups of treatment in the year prior to second-line drug initiation. In the L group the mean relapse rate was lowered by 0.28 relapses/patient/month and the mean cumulative dose of prednisone was reduced by 336 mg/m2/month versus 0.32 relapses/patient/month and 387 mg/m2/month in the C group (p = 0.395. p = 0.577). No significant difference in the effectiveness of L vs. C for therapy of FR/SD nephrotic syndrome could be identified in our patients. We conclude that L may be considered an alternative for C as a first second-line agent for these patients.

  10. Enhanced selection of high affinity DNA-reactive B cells following cyclophosphamide treatment in mice.

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    Daisuke Kawabata

    Full Text Available A major goal for the treatment of patients with systemic lupus erythematosus with cytotoxic therapies is the induction of long-term remission. There is, however, a paucity of information concerning the effects of these therapies on the reconstituting B cell repertoire. Since there is recent evidence suggesting that B cell lymphopenia might attenuate negative selection of autoreactive B cells, we elected to investigate the effects of cyclophosphamide on the selection of the re-emerging B cell repertoire in wild type mice and transgenic mice that express the H chain of an anti-DNA antibody. The reconstituting B cell repertoire in wild type mice contained an increased frequency of DNA-reactive B cells; in heavy chain transgenic mice, the reconstituting repertoire was characterized by an increased frequency of mature, high affinity DNA-reactive B cells and the mice expressed increased levels of serum anti-DNA antibodies. This coincided with a significant increase in serum levels of BAFF. Treatment of transgene-expressing mice with a BAFF blocking agent or with DNase to reduce exposure to autoantigen limited the expansion of high affinity DNA-reactive B cells during B cell reconstitution. These studies suggest that during B cell reconstitution, not only is negative selection of high affinity DNA-reactive B cells impaired by increased BAFF, but also that B cells escaping negative selection are positively selected by autoantigen. There are significant implications for therapy.

  11. Renoprotective effect of Mangifera indica polysaccharides and silymarin against cyclophosphamide toxicity in rats

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    Ahmed I. Amien

    2015-10-01

    Full Text Available The present study aims to evaluate the possible protective role of polysaccharides extracted from the Egyptian mango Mangifera indica L. (MPS and silymarin against cyclophosphamide (CP nephrotoxicity in male albino rats. Male rats were randomly divided into, control group (administered distilled water orally for 10 days and MPS (500, 1000 mg/kg, p.o. and/or silymarin (150 mg/kg, p.o. treated groups for 10 days. In the last 5 days of treatment rats were administered CP (150 mg/kg, i.p. The MPS revealed significant prophylactic effect against kidney injury induced by CP as demonstrated by enhancement of the kidney function via decreasing serum creatinine, urea and uric acid. Treatment of rats with MPS extract and/or silymarin significantly increased the level of reduced glutathione (GSH and superoxide dismutase (SOD activity while decreased the level of total malondialdehyde (MDA and glutathione-S-transferase (GST. Also, histopathological examinations confirmed the protective efficacy of MPS and/or silymarin against CP nephrotoxicity. In conclusion, the obtained results of the present study support the protective antioxidant role of MPS and/or silymarin against CP-induced kidney disorder in rats.

  12. Fludarabine, cyclophosphamide, and rituximab in salvage therapy of Waldenström's macroglobulinemia.

    Science.gov (United States)

    Tedeschi, Alessandra; Ricci, Francesca; Goldaniga, Maria Cecilia; Benevolo, Giulia; Varettoni, Marzia; Motta, Marina; Pioltelli, Pietro; Gini, Guido; Barate', Claudia; Luraschi, Annamaria; Vismara, Eleonora; Frustaci, Anna Maria; Nichelatti, Michele; Vitolo, Umberto; Baldini, Luca; Morra, Enrica

    2013-04-01

    The combination FCR (fludarabine, cyclophosphamide, and rituximab) proved to be active in Waldenström's macroglobulinemia in a mixed population of untreated and previously treated patients. Prolonged myelosuppression and concerns about purine analogue treatment led to the conclusion that this regimen should be avoided in younger patients in first-line treatment. In this retrospective study on 40 patients we observed a response rate of 80% (32) after FCR salvage treatment with 32.5% (13) of patients reaching at least a very good partial remission. None of the prognostic variables had a significant effect on response or good quality of response achievement. Median event-free survival was reached at 77 months; median progression-free survival was not reached after a median follow-up of 51 months with any difference when categorizing patients according to quality of response. The results of this study suggest that the FCR regimen might overcome poor prognostic features and should be taken into account as salvage treatment. Tardive immunosuppression and myelosuppression warrant accurate patient follow-up.

  13. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study.

    Science.gov (United States)

    Bringhen, Sara; Petrucci, Maria Teresa; Larocca, Alessandra; Conticello, Concetta; Rossi, Davide; Magarotto, Valeria; Musto, Pellegrino; Boccadifuoco, Luana; Offidani, Massimo; Omedé, Paola; Gentilini, Fabiana; Ciccone, Giovannino; Benevolo, Giulia; Genuardi, Mariella; Montefusco, Vittorio; Oliva, Stefania; Caravita, Tommaso; Tacchetti, Paola; Boccadoro, Mario; Sonneveld, Pieter; Palumbo, Antonio

    2014-07-03

    This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) ≥65 years of age or who were ineligible for autologous stem cell transplantation. Patients (N = 58) received CCyd for up to 9 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required carfilzomib dose reductions. In summary, results showed high complete response rates and a good safety profile. This trial was registered at clinicaltrials.gov as #NCT01346787.

  14. Chemoprotective effects of Ganoderma atrum polysaccharide in cyclophosphamide-induced mice.

    Science.gov (United States)

    Yu, Qiang; Nie, Shao-Ping; Wang, Jun-Qiao; Liu, Xiao-Zhen; Yin, Peng-Fei; Huang, Dan-Fei; Li, Wen-Juan; Gong, De-Ming; Xie, Ming-Yong

    2014-03-01

    In this study, the chemoprotective effects of Ganoderma atrum polysaccharide (PSG-1) in cyclophosphamide (Cy) treated mice were investigated. In Cy-treated mice, PSG-1 treatment accelerated recovery dose-dependently of peripheral red blood cells, white blood cells and platelets, enhanced splenic natural killer cell activity and cytotoxic T lymphocyte activity. In addition, PSG-1 elevated CD4(+) T lymphocyte counts as well as the CD4(+)/CD8(+) ratio dose-dependently. Furthermore, PSG-1 restored the levels of IL-2, INF-γ, IL-10, IgA, IgM and IgG, as well as hemolysin in the sera. Finally, PSG-1 can also significantly increase the total antioxidant capacity, activities of superoxidase dismutase, catalase and glutathione peroxidase, and decrease the malondialdehyde level in vivo. These findings indicate that PSG-1 plays an important role in the protection against myelosuppression and immunosuppression and oxidative stress in Cy-treated mice and could be a potential immunomodulatory agent.

  15. Blueberry Anthocyanins-Enriched Extracts Attenuate Cyclophosphamide-Induced Cardiac Injury.

    Directory of Open Access Journals (Sweden)

    Yunen Liu

    Full Text Available We sought to explore the effect of blueberry anthocyanins-enriched extracts (BAE on cyclophosphamide (CTX-induced cardiac injury. The rats were divided randomly into five groups including normal control, CTX 100 mg/kg, BAE 80mg/kg, CTX+BAE 20mg/kg and CTX+BAE 80mg/kg groups. The rats in the three BAE-treated groups were administered BAE for four weeks. Seven days after BAE administration, rats in CTX group and two BAE-treated groups were intraperitoneally injected with a single dose of 100 mg/kg CTX. Cardiac injury was assessed using physiological parameters, Echo, morphological staining, real-time PCR and western blot. In addition, cardiotoxicity indices, inflammatory cytokines expression and oxidative stress markers were also detected. Four weeks 20mg/kg and 80mg/kg dose of BAE treatment following CTX exposure attenuated mean arterial blood pressure, heart rate and activities of heart enzymes, improved cardiac dysfunction, left ventricular hypertrophy and fibrosis. Importantly, BAE also attenuated CTX-induced LV leukocyte infiltration and inflammatory cytokines expression, ameliorated oxidative stress as well as cardiomyocyte apoptosis. In conclusion, BAE attenuated the CTX-induced cardiac injury and the protective mechanisms were related closely to the anti-inflammatory, antioxidant and anti-inflammatory characteristics of BAE.

  16. Oral cyclophosphamide improves pulmonary function in scleroderma patients with fibrosing alveolitis: experience in one centre.

    Science.gov (United States)

    Beretta, Lorenzo; Caronni, Monica; Raimondi, Massimo; Ponti, Alessandra; Viscuso, Tiziana; Origgi, Laura; Scorza, Raffaella

    2007-02-01

    Lung involvement constitutes nowadays the major cause of morbidity and mortality in scleroderma patients. Pulmonary fibrosis in systemic sclerosis (SSc) is thought to be the consequence of interstitial inflammation. Early diagnosis and treatment of active alveolitis is essential to prevent the deterioration of pulmonary function, improving outcome in SSc patients. The aim of the study was to investigate the effect of 1-year treatment with oral cyclophosphamide (CYC) on the evolution of interstitial lung disease in scleroderma patients with a diagnosis of active alveolitis. An open-label one-arm monocenteric study was conducted on 33 scleroderma patients with active alveolitis--defined as the presence of areas of 'ground-glass attenuation' on high-resolution computed tomography and a recent deterioration in lung function-treated with oral CYC 2 mg kg-1 day-1 for 1 year and medium-low dose steroids (prednisone 25 mg for 3 months and then tapered to 5 mg/day). Results showed that diffusing capacity for carbon monoxide (DLco) values remained stable after 6 months of treatment and significantly increased after 12 months (2.06+/-1.38, 2.21+/-1.62 and 2.39+/-1.64 mmol/min/kPa, at baseline/6/12 months, respectively; palveolitis, with beneficial effects lasting up to 1 year after interruption. The higher efficacy in those patients with an early pulmonary disease stage and a lower radiological grade underlies the importance of an early diagnosis and intervention.

  17. Protective effects of boron on cyclophosphamide induced lipid peroxidation and genotoxicity in rats.

    Science.gov (United States)

    Ince, Sinan; Kucukkurt, Ismail; Demirel, Hasan Huseyin; Acaroz, Damla Arslan; Akbel, Erten; Cigerci, Ibrahim Hakki

    2014-08-01

    The aim of the present study was to evaluate the possible protective effect of boron (B) on cyclophosphamide (CYC) induced oxidative stress in rats. Totally, thirty Wistar albino male rats were fed standard rodent diet and divided into 5 equal groups: physiological saline was given intraperitoneally (i.p.) to the control group (vehicle treated), to the second group only 75 mg kg(-1) CYC was given i.p. on the 14th d, and boron was administered (5, 10, and 20 mg kg(-1), i.p.) to the other groups for 14 d and CYC (75 mg kg(-1), i.p.) on the 14th d. CYC caused increase of malondialdehyde and decrease of glutathione levels, decrease of superoxide dismutase activities in erythrocyte and tissues, decrease of erythrocyte, heart, lung, and brain catalase, and plasma antioxidant activities. Also, CYC treatment caused to DNA damage in mononuclear leukocytes. Moreover, B exhibited protective action against the CYC-induced histopathological changes in tissues. However, treatment of B decreased severity of CYC-induced lipid peroxidation and genotoxicity on tissues. In conclusion, B has ameliorative effects against CYC-induced lipid peroxidation and genotoxicity by enhancing antioxidant defence mechanism in rat.

  18. Treatment of refractory juvenile idiopathic arthritis via pulse therapy using methylprednisolone and cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Tania Caroline Monteiro de Castro

    Full Text Available CONTEXT: Patients with refractory juvenile idiopathic arthritis can benefit from aggressive therapy. CASE REPORT: We followed the clinical course of 4 patients (2 male, 2 female aged 9.1-17.8 years (mean of 14.5 years with polyarticular onset of juvenile rheumatoid arthritis and one 16-year-old boy with juvenile spondyloarthropathy associated with inflammatory bowel disease. All the juvenile rheumatoid arthritis patients fulfilled the diagnostic criteria established by the American College of Rheumatology. All patients had unremitting arthritis despite maximum therapy. All patients began receiving treatment using intravenous cyclophosphamide at 500-750 mg/m² and intravenous methylprednisolone at 30 mg/kg, for 3 days monthly (1 g maximum. The patients received between 3 and 11 monthly treatments, and/or 3-5 treatments every two months for 12 months, according to the severity of the disease and/or response to the therapy. All but one patient were evaluated retrospectively at the start (time 0 and 6 months (time 1, and 12 months (time 2 after the beginning of the treatment. A rapid and clinically significant suppression of systemic and articular manifestations was seen in all patients. Our results showed the favorable effect of this treatment on the clinical and some laboratory manifestations of juvenile idiopathic arthritis.

  19. Antigenotoxic effects of a polyherbal drug septilin against the genotoxicity of cyclophosphamide in mice

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    S. Shruthi

    2016-01-01

    Full Text Available Septilin (Spt is a polyherbal drug formulation from Himalaya Drug Company, consisting of extracts from different medicinal plants and minerals. In the traditional system of medicine, septilin is being used as immunomodulatory, antioxidant and anti-inflammatory agent. In the present study, the protective effects of septilin against the genotoxicity of cyclophosphamide (CP a widely used alkylating anticancer drug was evaluated by using in vivo micronucleus (MN and sperm shape abnormality assays in Swiss albino mice. CP administered intraperitoneally at a dose of 50 mg/kg b.w. was used as positive mutagen. Different doses of septilin viz., 125, 250 and 500 mg/kg b.w. was orally administered for 5 consecutive days. CP was administered intraperitoneally on 5th day. MN and sperm preparations were made after 24 h and 35 days respectively. CP induced significant MN in both bone marrow and peripheral blood cells and also a high frequency of abnormal sperms. In septilin supplemented animals, no significant induction of MN and abnormal sperms was recorded. In septilin supplemented groups, a dose dependent significant decrease in CP induced clastogenicity was observed. Thus the current in vivo study revealed the antigenotoxic effects of septilin against CP induced damage, in both somatic and germ cells of Swiss albino mice.

  20. Comparison of doxorubicin-cyclophosphamide with doxorubicin-dacarbazine for the adjuvant treatment of canine hemangiosarcoma.

    Science.gov (United States)

    Finotello, R; Stefanello, D; Zini, E; Marconato, L

    2017-03-01

    Canine hemangiosarcoma (HSA) is a neoplasm of vascular endothelial origin that has an aggressive biological behaviour, with less than 10% of dogs alive at 12-months postdiagnosis. Treatment of choice consists of surgery followed by adjuvant doxorubicin-based chemotherapy. We prospectively compared adjuvant doxorubicin and dacarbazine (ADTIC) to a traditional doxorubicin and cyclophosphamide (AC) treatment, aiming at determining safety and assessing whether this regimen prolongs survival and time to metastasis (TTM). Twenty-seven dogs were enrolled; following staging work-up, 18 were treated with AC and 9 with ADTIC. Median TTM and survival time were longer for dogs treated with ADTIC compared with those receiving AC (>550 versus 112 days, P = 0.021 and >550 versus 142 days, P = 0.011, respectively). Both protocols were well tolerated, without need for dose reduction or increased interval between treatments. A protocol consisting of combined doxorubicin and dacarbazine is safe in dogs with HSA and prolongs TTM and survival time. © 2015 John Wiley & Sons Ltd.

  1. Effect of melatonin on apoptosis, proliferation and differentiation of urothelial cells after cyclophosphamide treatment.

    Science.gov (United States)

    Zupancic, Dasa; Jezernik, Kristijan; Vidmar, Gaj

    2008-04-01

    Melatonin was recently shown to have protective effects against cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) by diminishing bladder oxidative stress. HC is accompanied by destruction of the bladder urothelium and followed by apoptosis and rapid regeneration via proliferation and differentiation of urothelial cells, reaching complete restoration of normal urothelium in three weeks. Therefore, the effect of melatonin on apoptosis, proliferation and differentiation of urothelial cells, during destruction and regeneration of the urothelium three-weeks after a single dose CP treatment, was studied. F344 male rats were injected intraperitoneally with saline (control group) or melatonin (Mel group) or a single dose of CP (100 mg/kg; CP group) or melatonin (10 mg/kg) with CP (Mel + CP group). Melatonin co-treatment with CP significantly reduced apoptosis and increased proliferation of urothelial cells at day 1 and thus prevented extensive loss of cells from the urothelium. However, proliferation indices at days 4 and 7 after melatonin and CP co-treatment suddenly dropped and therefore the development of hyperplasia was prevented. Melatonin co-treatment with CP also resulted in earlier differentiation of superficial urothelial cells. Melatonin seems to have protective effect against CP-induced urothelial damage and a favorable impact on regeneration and restoration of normal urothelium, since it reduces the number of apoptotic and proliferating urothelial cells and results in their earlier differentiation.

  2. Melatonin prevents the development of hyperplastic urothelium induced by repeated doses of cyclophosphamide.

    Science.gov (United States)

    Zupancic, Dasa; Vidmar, Gaj; Jezernik, Kristijan

    2009-06-01

    Repeated cyclophosphamide (CP) chemotherapy increases the risk of developing bladder cancer, which could be due to the extremely rapid proliferation of urothelial cells observed in hyperplastic urothelium induced by CP treatment. We investigated the effect of melatonin on the development of urothelial hyperplasia induced by repeated CP treatment. Male ICR mice were injected with CP (150 mg/kg) or melatonin (10 mg/kg) with CP once a week for 3, 4 and 5 weeks. Transmission and scanning electron microscopy, immunohistochemistry and Western blot analysis were used to study the ultrastructure, apoptosis, proliferation and differentiation of urothelial cells. Repeated doses of CP caused the development of hyperplastic urothelium with up to ten cell layers and increased proliferation and apoptotic indices regarding Ki-67 and active caspase-3 immunohistochemistry, respectively. Scanning electron microscopy observations, cytokeratin and asymmetrical unit membrane immunohistochemistry and Western blot analysis showed a lower differentiation state of superficial urothelial cells. Melatonin co-treatment prevented the development of hyperplastic urothelium, statistically significantly decreased proliferation and apoptotic indices after four and five doses of CP and caused higher differentiation state of superficial urothelial cells.

  3. Green tea infusion improves cyclophosphamide-induced damage on male mice reproductive system

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    Mariane Magalhães Zanchi

    2015-01-01

    Full Text Available Green tea presents catechins as its major components and it has a potential antioxidant activity. Cyclophosmamide (CP is an antineoplastic and immunosuppressive agent, known to reduce fertility. In the present study, we evaluated the effect of green tea infusion on cyclophosphamide-induced damage in male mice reproductive system. Mice received green tea infusion (250 mg/kg or vehicle by gavage for 14 days. Saline or CP were injected intraperitoneally at a single dose (100 mg/kg at the 14th day. Animals were euthanized 24 h after CP administration and testes and epididymis were removed for biochemical analysis and sperm evaluation. Catechins concentration in green tea infusion was evaluated by HPLC. CP increased lipid peroxidation, DNA damage and superoxide dismutase activity whereas sperm concentration, glutathione peroxidase (GPx, glutathione S-transferase (GST and 17β-hydroxysteroid (17β-HSD dehydrogenase activities were reduced in both tissues tested. Catalase activity and protein carbonyl levels were changed only in testes, after CP administration. Green tea pre-treatment reduced significantly lipid peroxidation, protein carbonylation, DNA damage and restored GPx and GST activity in testes. In epididymis, therapy significantly increased sperm concentration and restored GPx and 17β-HSD activity. Green tea improves CP-induced damage on reproductive system, probably due to their high catechins content.

  4. [Examination of the safety of docetaxel/cyclophosphamide combination therapy for advanced recurrent breast cancer].

    Science.gov (United States)

    Yoneyama, Kimiyasu; Koshida, Yoshitomo; Toriumi, Fumiki; Murayama, Takaya; Toeda, Hiroyuki; Imazu, Yoshihiro; Motegi, Katsuhiko; Akamatsu, Hidetoshi; Ohyama, Renpei

    2006-10-01

    In the treatment of recurrent breast cancer in patients previously treated with anthracycline drugs, taxane drugs are generally used. This time, we retrospectively studied the safety of docetaxel/cyclophosphamide combination therapy (hereinafter referred to as TC therapy). Ten patients (mean age: 52.8 years old) were included in the study. Metastatic/recurrent sites included 3 skin, 2 each of contralateral breast, lung and bone, and 1 each of liver, carcinomatous pleurisy and supraclavicular lymph node. Seven patients had a history of anthracycline treatment. The patients received TC at doses of 60 mg/m(2) and 500 mg/m(2), respectively, every 3 weeks. With regard to adverse events, non-hematotoxic events included alopecia in all the patients, generalized malaise in 5, and abnormal nail in 1. Hematotoxic events were grades 2 and 3 decreased neutrophil count in 5 patients. One patient had grade 4 pyrexia associated with oral candida. The patient was admitted and treated with fluid replacement and granulocyte colony-stimulating factor (G-CSF). There were no other patients in whom the treatment was prolonged or dosage was reduced due to adverse reactions. TC therapy is considered to be a beneficial treatment method in terms of safety since it can be instituted on an outpatient basis.

  5. Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide

    Institute of Scientific and Technical Information of China (English)

    Yan JIANG; Jing ZHAO; Hui-jing QI; Xiao-lin LI; Shi-rong ZHANG; Daniel W.SONG; Chi-yang YU

    2013-01-01

    Busulfan/cyclophosphamide (Bu/Cy) conditioning regimen has been widely used to treat cancer patients,while their effects on major internal organs in females are not fully understood.We treated female mice with Bu/Cy,and examined the histopathology of major internal organs on Day 30 after the treatment.The results show that Bu/Cy treatment affected the ovaries most extensively,while it had less effect on the spleen,lungs,and kidneys,and no effect on the heart,liver,stomach,and pancreas.To better understand the effect of Bu/Cy on the ovaries,we counted follicles,and determined the levels of ovarian steroids.The Bu/Cy-treated mice showed a reduction of primordial and primary follicles (P<0.01) on Day 30 and a marked loss of follicles at all developmental stages (P<0.01) on Day 60.Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%,respectively.Thus,there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice; this is a profile similar to what is found in women with premature ovarian failure (POF).The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF.

  6. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia

    Science.gov (United States)

    Parikh, Sameer A.; Keating, Michael J.; O'Brien, Susan; Wang, Xuemei; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Estrov, Zeev; Badoux, Xavier; Lerner, Susan

    2011-01-01

    Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation. PMID:21750315

  7. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL

    Science.gov (United States)

    Badoux, Xavier C.; Keating, Michael J.; Wang, Xuemei; O'Brien, Susan M.; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Lerner, Susan; Kantarjian, Hagop

    2011-01-01

    Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute–Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population. PMID:21245487

  8. Cyclophosphamide Induces an Early Wave of Acrolein-Independent Apoptosis in the Urothelium.

    Science.gov (United States)

    Hughes, Francis M; Corn, Alexa G; Nimmich, Andrew R; Pratt-Thomas, Jeffery D; Purves, J Todd

    2013-08-01

    Hemorrhagic cystitis (HC or bladder inflammation) affects a significant number of patients undergoing cyclophosphamide (CP) chemotherapy despite treatment with 2-mercaptoethane sulfonate (Mesna) to inactivate the metabolite acrolein. While the mechanism is unknown, there is clearly acrolein-independent damage to the urothelium. In this study we have explored the induction of apoptosis in the urothelium as a marker of damage and the mechanism underlying the acrolein-independent apoptosis. Apoptosis in urothelium (caspase-3/7 activity and Poly (ADP-ribosyl) polymerase (PARP) cleavage) was measured following CP administration (80 mg/kg). Sodium 2-mercaptoethane sulfonate (Mesna) was used to mask acrolein's effect. An IL-1β receptor antagonist and a cell-permeable caspase-1 inhibitor were used to assess the involvement of IL-1β and caspase-1, respectively. Two waves of apoptosis were detected following CP administration, one peaking at 2 h and a second at 48 h. The first wave was independent of acrolein. Caspase-1 was also active at 2 h and activation of caspase-3/7 was blocked by a caspase-1 inhibitor but not an IL-1β receptor antagonist suggesting the direct activation of caspase-3/7 by caspase-1 without the need for IL-1β as an intermediate. Our results indicate that CP initiates an early, acrolein-independent wave of apoptosis that results from direct cleavage of caspase-3/7 by caspase-1.

  9. Gonadal status following bone marrow transplantation with low dose busulfan-cyclophosphamide regimen

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    Mohsen Khosh niat Nikoo

    2006-02-01

    Full Text Available Background: Gonadal dysfunction is one of the short and long-term side effects following bone marrow transplantation (BMT. We assessed hypophyseal-gonadal axis after BMT by low dose busulfan-cyclophosphamide conditioning regimen (120 mg/kg. Methods: In this cohort study, we evaluated gonadal function in 48 patients (25 pubert males and 23 pubert females. Data were obtained by history, physical examination, LH, FSH, prolactin, estradiol (E2, progesterone, testosterone and semen analysis before BMT and in 6 and 12 months of post-BMT. Results: Gonadal axis in 16 male subjects (64% was normal before BMT and remained normal in 6 subjects (37% 12 months post BMT. In another 10 patients (63%, hypogonadism was started in 6 months post BMT. Spermatogenesis failure (31%, low level of testosterone (25% and spermatogenesis failure plus low level of testosterone in 12.5% were found. Gonadal axis in 20 female subjects (87% was normal before BMT, but remained normal only in 10% of subject until the end of the study. Other patients (90% had primary hypogonadism in 6 months of post BMT. Conclusion: There is a high prevalence of gonadal dysfunction following BMT in both adult sexes (especially in female patients. Therefore, regular gonadal assessment is recommended following BMT.

  10. Human Umbilical Cord Mesenchymal Stem Cells Therapy in Cyclophosphamide-Induced Premature Ovarian Failure Rat Model

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    Dan Song

    2016-01-01

    Full Text Available Premature ovarian failure (POF is one of the most common causes of infertility in women. In our present study, we established cyclophosphamide- (CTX- induced POF rat model and elucidated its effect on ovarian function. We detected the serum estrogen, follicle stimulating hormone, and anti-Müllerian hormone of mice models by ELISA and evaluated their folliculogenesis by histopathology examination. Our study revealed that CTX administration could severely disturb hormone secretion and influence folliculogenesis in rat. This study also detected ovarian cells apoptosis by deoxy-UTP-digoxigenin nick end labeling (TUNEL and demonstrated marked ovarian cells apoptosis in rat models following CTX administration. In order to explore the potential of human umbilical cord mesenchymal stem cells (UCMSCs in POF treatment, the above indexes were used to evaluate ovarian function. We found that human UCMSCs transplantation recovered disturbed hormone secretion and folliculogenesis in POF rat, in addition to reduced ovarian cell apoptosis. We also tracked transplanted UCMSCs in ovaries by fluorescence in situ hybridization (FISH. The results manifested that the transplanted human UCMSCs could reside in ovarian tissues and could survive for a comparatively long time without obvious proliferation. Our present study provides new insights into the great clinical potential of human UCMSCs in POF treatment.

  11. Immune response against large tumors eradicated by treatment with cyclophosphamide and IL-12.

    Science.gov (United States)

    Tsung, K; Meko, J B; Tsung, Y L; Peplinski, G R; Norton, J A

    1998-02-01

    Previous studies have demonstrated eradication of small (4-8 mm) established murine MCA207 sarcomas by treatment with systemic IL-12. Analysis of the mechanism has revealed a cellular and molecular immune response at the tumor typical of a Th1 cell-mediated, macrophage-effected, delayed-type hypersensitivity (DTH) response. In the current study we investigate the immune response against long term established, large MCA207 tumors induced by combined treatment with IL-12 and cyclophosphamide (Cy), an agent known to potentiate the DTH response. Our results demonstrate that s.c. large MCA207 tumors (15-20 mm) that are refractory to treatment by either IL-12 or Cy alone can be completely eradicated by the combination of Cy and IL-12. IL-12 is apparently the only cytokine capable of mediating tumor eradication, and the effect is dependent on IFN-gamma. The contribution of Cy is probably due to immunopotentiation of DTH rather than to direct cytotoxicity to the tumor. The regression of these large tumors takes >4 wk and, in many cases, is self-sustained, in that little or no additional IL-12 is needed beyond the initial week of administration. Analysis of the cellular and molecular events at the tumor site suggests that the mechanism is a Th1-mediated antitumor immune response.

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

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    Shien,Tadahiko

    2011-08-01

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

  13. Clinical efficacy of capecitabine and cyclophosphamide (XC) in patients with metastatic breast cancer.

    Science.gov (United States)

    Shien, Tadahiko; Doihara, Hiroyoshi; Nishiyama, Keiko; Masuda, Hiroko; Nogami, Tomohiro; Ikeda, Hirokuni; Taira, Naruto

    2011-08-01

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

  14. Effects of cyclophosphamide on immune system and gut microbiota in mice.

    Science.gov (United States)

    Xu, Xiaofei; Zhang, Xuewu

    2015-02-01

    Cyclophosphamide (CP) is the most commonly used drug in autoimmune disease, cancer, blood and marrow transplantation. Recent data revealed that therapy efficacy of CP is gut microbiota-dependent. So, it is very important to understand how CP affects intestinal microbiota and immune function. In this study, the effects of CP on mice immuno-activity were firstly evaluated, then, the fecal microbiota from normal and CP-treated mice was compared, and the characteristic bacterial diversity and compositions were identified, using 454 pyrosequencing technology. The results showed that CP reduced the diversity and shifted the fecal microbiota composition. Specifically, CP treatment decreased the proportion of Bacteroidetes while increased the proportion of Firmictutes in the microbial community. Most importantly, specific microbiota signatures belonging to Bacteroides acidifaciens, Streptococcaceae and Alistipes were also identified, which would provide new insight into the efficacy and side effects in clinical usage of CP. This should be helpful for further demonstration of CP's action mechanism, development of personalized therapy strategies, and prediction of potential side effects related to various treatment regimens of CP. Copyright © 2014 Elsevier GmbH. All rights reserved.

  15. Transplacental inhibitory effect of carrot juice on the clastogenicity of cyclophosphamide in mice

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    Gimmler-Luz Maria Clara

    1999-01-01

    Full Text Available Genetic damage during the prenatal period can provoke important neoplastic alterations and other diseases in postnatal life. Beta-carotene (ßC is considered to be one of the most important anticarcinogens in the diet and can protect mammalian cells against genotoxic events. As carrots are important dietary source of ßC, we decided to test the effect of fresh carrot juice (CaJ on cyclophosphamide (CP-induced genotoxicity in maternal and fetal erythropoietic tissues. The treatment with CaJ started on the 7th day of the pregnancy of BALB/c female mice. We observed, on the 16th gestational day, that this treatment did not modify the spontaneous frequency of micronucleated polychromatic erythrocytes (mPCE in the bone marrow of the females nor in the livers of their fetuses. The mPCE frequency observed 24 h after an intraperitoneal injection of CP (40 mg/kg on the 15th day was significantly lower in CaJ-pretreated pregnant female bone marrow and in the liver of their fetuses than those observed in the group treated with CP only. These results demonstrate the presence of natural anticlastogens in carrots.

  16. Pulse cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies.

    Science.gov (United States)

    Boyer, Olivia; Balzamo, Eve; Charbit, Marina; Biebuyck-Gougé, Nathalie; Salomon, Rémi; Dragon-Durey, Marie-Agnès; Frémeaux-Bacchi, Véronique; Niaudet, Patrick

    2010-05-01

    We report 3 children with atypical hemolytic uremic syndrome associated with anti-complement factor H (CFH) autoantibodies who presented with sustained remission with low antibody titers and normal kidney function after plasma exchanges (PEs) and cyclophosphamide pulses. The 3 children initially presented with acute vomiting, fatigue, gross hematuria, hypertension, hemolytic anemia, thrombocytopenia, nephrotic syndrome, and acute kidney injury. C3 levels were normal in patients 1 and 3 and low in patient 2 (0.376 mg/mL [0.376 g/L]). CFH antibody titers were increased (15,000 to > 32,000 arbitrary units [AU]). Patient 1, an 11-year-old boy, was treated with 12 PEs, leading to a decrease in CFH antibody titer (to 800 AU). A first relapse 1 month later was treated with 6 PEs and 4 rituximab infusions. A second relapse 3 months later required 5 PEs, and the patient received oral steroids (0.5 mg/d/kg body weight) and 5 cyclophosphamide pulses (1 g/1.73 m(2)), leading to sustained remission with normal kidney function (estimated glomerular filtration rate [eGFR], 120 mL/min/1.73 m(2) [2.0 mL/s/1.73 m(2)]) and a stable decrease in CFH antibody titer (to 2,000 AU) 3 years later. Patient 2, a 5-year-old boy, required dialysis therapy for 2 weeks. He received 3 plasma infusions without remission. Six PEs associated with 2 cyclophosphamide pulses (0.5 g/1.73 m(2)) and steroids (1 mg/d/kg body weight) led to rapid remission, with eGFR of 107 mL/min/1.73 m(2) [1.78 mL/s/1.73 m(2)] and a prolonged decrease in CFH antibody titer after 15 months (1,300 AU). Patient 3, a 16-month-old boy, was treated with oral steroids (1 mg/d/kg body weight), 2 PEs, and 2 cyclophosphamide pulses (0.5 g/1.73 m(2)), resulting in a stable decrease in CFH antibody titer to 276 AU. Kidney function quickly normalized (eGFR, 110 mL/min/1.73 m(2) [1.83 mL/s/1.73 m(2)]) and has remained normal after 14 months. All 3 patients show a homozygous deletion mutation of the CFHR1 and CFHR3 genes

  17. A randomised study comparing granulocyte-colony stimulating factor (G-CSF) with G-CSF plus thymostimulin in the treatment of haematological toxicity in patients with advanced breast cancer after high dose mitoxantrone therapy.

    Science.gov (United States)

    Sanchiz, F; Milla, A

    1996-01-01

    54 patients with advanced breast cancer were randomised into a prospective, non-blinded, controlled trial to receive: mitoxantrone 28 mg/m2 intravenous day 1 and granulocyte-colony stimulating factor (G-CSF) 5 micrograms/kg/day subcutaneously days 2 to 16 (n = 27) or the same regimen plus thymostimulin (TS) 50 mg/day intramuscular at days 2 to 16 (n = 27). The median time to reach a neutrophil count greater than 0.5 x 10(9)/l was lower in the G-CSF+TS treated group (9.13 versus 3.24 days; P < 0.0005). More patients experienced neutropenic fever in the G-CSF group than in the G-CSF+TS group (59.3% versus 22.2%, P = 0.0119). The incidence, duration and severity of clinically or bacteriologically documented infection were lower in patients who received TS. 16 patients (59.3%) in the G-CSF group contracted infection, and 4 patients (14.8%) receiving G-CSF+TS (P = 0.0016). These data indicate that the combination of G-CSF and TS is well-tolerated and may enhance haematological recovery following myelosuppressive chemotherapy in patients with advanced breast cancer.

  18. Effects of melatonin on DNA damage induced by cyclophosphamide in rats

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    Ferreira, S.G.; Peliciari-Garcia, R.A. [Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas I, Universidade de São Paulo, São Paulo, SP (Brazil); Takahashi-Hyodo, S.A. [Área de Ciências da Saúde, Universidade Braz Cubas, Mogi das Cruzes, SP (Brazil); Rodrigues, A.C. [Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP (Brazil); Amaral, F.G. [Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas I, Universidade de São Paulo, São Paulo, SP (Brazil); Berra, C.M. [Departamento de Microbiologia, Instituto de Ciências Biomédicas II, Universidade de São Paulo, São Paulo, SP (Brazil); Bordin, S.; Curi, R.; Cipolla-Neto, J. [Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas I, Universidade de São Paulo, São Paulo, SP (Brazil)

    2013-03-08

    The antioxidant and free radical scavenger properties of melatonin have been well described in the literature. In this study, our objective was to determine the protective effect of the pineal gland hormone against the DNA damage induced by cyclophosphamide (CP), an anti-tumor agent that is widely applied in clinical practice. DNA damage was induced in rats by a single intraperitoneal injection of CP (20 or 50 mg/kg). Animals received melatonin during the dark period for 15 days (1 mg/kg in the drinking water). Rat bone marrow cells were used for the determination of chromosomal aberrations and of formamidopyrimidine DNA glycosylase enzyme (Fpg)-sensitive sites by the comet technique and of Xpf mRNA expression by qRT-PCR. The number (mean ± SE) of chromosomal aberrations in pinealectomized (PINX) animals treated with melatonin and CP (2.50 ± 0.50/100 cells) was lower than that obtained for PINX animals injected with CP (12 ± 1.8/100 cells), thus showing a reduction of 85.8% in the number of chromosomal aberrations. This melatonin-mediated protection was also observed when oxidative lesions were analyzed by the Fpg-sensitive assay, both 24 and 48 h after CP administration. The expression of Xpf mRNA, which is involved in the DNA nucleotide excision repair machinery, was up-regulated by melatonin. The results indicate that melatonin is able to protect bone marrow cells by completely blocking CP-induced chromosome aberrations. Therefore, melatonin administration could be an alternative and effective treatment during chemotherapy.

  19. Dexamethasone cyclophosphamid pulse therapy in pemphigus-appraisal of its outcome

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    Prabhash Kulhari

    2012-01-01

    Full Text Available Introduction :- Pemphigus is the commonest autoimmune vesicobullous disorder on the the Indian subcontinent. the mainstay of treatment of the disease is systemic steroid and other immunosuppresive therapies. Dexamethasone-cyclophosphamide(DCP pulse therapy was designated by pasricha for pemphigus in 1981 with the aim of reducing toxicity of corticosteroid and also achieve better results. Method:- Thirty one patients admitted at department of dermatology ASSAM MEDICAL COLLEGE,DIBRUGARH were enrolled for study prospectively from 2008-2011.Diagnosis of pemphigus was based on clinical feature, tzanck smear and biopsy. Confirmation was carried out by direct immunofluorascence.DCP pulse was given to confirmed cases of pemphigus. we enrolled 31 patients with pemphigus for DCP pulse therapy in our hospital during this period out of which 27 patients were pemphigus vulgaris and 4 were pemphigus folIacious. male to female ratio was 1.2:1.Of 31 patients enrolled for this treatment,6 patients could not complete the treatment and 2 patient died due to cardiovascular failure(not related to treatment. Of remaining 23 patients ,15 have alredy completed the treatment and are free of disease even after withdrawl of all treatment. 5 patients are in remission but have not completed the treatment schedule whereas 3 patients are still having clinical evidence of disease although it has already become much milder .Various side effects seen in our patients were candidiasis (2,tuberculosis(1, acneiform eruption(2, osteoporosis(1, cataract(2, hair fall(2, gastritis(3, avascular necrosis(1.Our finding are very consistent with previous reports that DCP pulse therapy is very effective in pemphigus and having lesser side effects in comparison to daily steroid .

  20. Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children

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    José Eugenio Vázquez Meraz

    2016-01-01

    Full Text Available Fifty-six aphaereses were performed in 23 pediatric patients with malignant hematological and solid tumors, following three different protocols for PBPC mobilization and distributed as follows: A: seventeen mobilized with 4 g/m2 of cyclophosphamide (CFA and 10 μg/kg/day of granulocyte colony stimulating factor (G-CSF, B: nineteen with CFA + G-CSF, and C: twenty only with G-CSF when the WBC count exceeded 10 × 109/L. The average number of MNC/kg body weight (BW/aphaeresis was 0.4 × 108 (0.1–1.4, 2.25 × 108 (0.56–6.28, and 1.02 × 108 (0.34–2.5 whereas the average number of CD34+ cells/kg BW/aphaeresis was 0.18 × 106/kg (0.09–0.34, 1.04 × 106 (0.19–9.3, and 0.59 × 106 (0.17–0.87 and the count of CFU/kg BW/aphaeresis was 1.11 × 105 (0.31–2.12, 1.16 × 105 (0.64–2.97, and 1.12 × 105 (0.3–6.63 in groups A, B, and C, respectively. The collection was better in group B versus group A (p=0.007 and p=0.05, resp. and in group C versus group A (p=0.08 and p=0.05, resp.. The collection of PBPCs was more effective in the group mobilized with CFM + G-CSF when the WBC exceeded 10 × 103/μL in terms of MNC and CD34+ cells and there was no toxicity of the chemotherapy.

  1. Speman®, A Proprietary Ayurvedic Formulation, Reverses Cyclophosphamide-Induced Oligospermia In Rats.

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    Mohd. Azeemuddin Mukram

    2013-04-01

    Full Text Available Background: This investigation was aimed to evaluate the effect of Speman®, a well known ayurvedic proprietary preparation, in an experimental model of cyclophosphamide-(CP induced oligospermia in rats.Materials and Methods: Thirty male rats were randomized in to five, equally-sized groups. Rats in group 1 served as a normal control; group 2 served as an untreated positive control; groups 3, 4, 5 received  Speman® granules  at doses of 300, 600, and 900mg/kg body weight p.o. respectively, once daily for 13 days. On day four, one hour after the respective treatment, oligospermia was induced by administering a single dose of CP (100mg/kg body weight p.o.  to all the groups except group1. At the end of the study period the rats were euthanised and accessory reproductive organs were weighed and subjected to histopathological examination. The semen samples were subject to enumeration of sperms.  Weight of the reproductive organs, histopathological examination of the tissues, and sperm count were the parameters studied to understand the effect of Speman® on rats with CP-induced oligospermia.Results: Changes that occurred due to the administration of CP at a dose of 100 mg/kg body weight were dose dependently reversed with Speman® at a dose of 300, 600, and 900 mg/kg body weight. There was a statistically significant increase in sperm count and the weight of the seminal vesicle, epididymis, and prostate.Conclusion: Findings of this investigation indicate that Speman® dose dependently reversed the CP-induced derangement of various parameters pertaining to the reproductive system.  This could explain the total beneficial actions of Speman® reported in several other clinical trials.

  2. The effects of oral glutamine on cyclophosphamide-induced nephrotoxicity in rats.

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    Abraham, Premila; Isaac, Bina

    2011-07-01

    Nephrotoxicity is one of the adverse side effects of cyclophosphamide (CP) chemotherapy. In a recent study, we have demonstrated that oxidative stress and glutathione depletion play important roles in CP-induced renal damage. The aim of the study was to verify whether glutamine, the precursor for glutathione synthesis, prevents CP-induced oxidative stress and renal damage using a rat model. Adult male rats were administered a single dose of 150 mg/ kg body weight of CP intraperitoneally. The glutamine-pretreated rats were administered 1 gm/kg body weight of glutamine orally 2 h before the administration of CP. Vehicle/glutamine-treated rats served as controls. All the rats were killed 16 h after the dose of CP/vehicle. The kidneys were removed and used for light microscopic and biochemical studies. The markers of oxidative stress including malondialdehyde content, protein carbonyl content, protein thiol, reduced glutathione and myeloperoxidase activity, a marker of neutrophil infiltration, were measured in kidney homogenates. CP treatment-induced damage to kidney involved the glomeruli and the tubules. Pretreatment with glutamine reduced CP-induced glutathione depletion and increased myeloperoxidase activity. However, it did not prevent CP-induced lipid peroxidation, protein carbonylation and renal damage. The results of the present study suggest that glutamine pretreatment does not prevent CP-induced lipid peroxidation and renal damage, although it prevents CP-induced glutathione depletion and neutrophil infiltration significantly. It is suggested that mechanisms other than oxidative stress may also be involved and/or oxidative stress may be consequence and not the cause of CP induced renal damage.

  3. The protective effect of Moringa oleifera leaves against cyclophosphamide-induced urinary bladder toxicity in rats.

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    Taha, Nevine R; Amin, Hanan Ali; Sultan, Asrar A

    2015-02-01

    Cyclophosphamide (CP), an alkylating antineoplastic agent is widely used in the treatment of solid tumors and B-cell malignant disease. It is known to cause urinary bladder damage due to inducing oxidative stress. Moringa oleifera (Mof) is commonly known as drumstick tree. Moringa leaves have been reported to be a rich source of β-carotene, protein, vitamin C, calcium, and potassium. It acts as a good source of natural antioxidants; due to the presence of various types of antioxidant compounds such as ascorbic acid, flavonoids, phenolics and carotenoids. The aim of this work was to test the possible antioxidant protective effects of M. oleifera leaves against CP induced urinary bladder toxicity in rats. Female Wister albino rats were divided into 4 groups. Group I served as control, received orally normal saline, group II received a single dose CP 100mg/kg intraperitoneally, group III and VI both received orally hydroethanolic extract of Mof; 500 mg/kg and 1000 mg/kg respectively daily for a week, 1h before and 4h after CP administration. Rats were sacrificed 24h after CP injection. The bladder was removed, sectioned, and subjected to light, transition electron microscopic studies, and biochemical studies (measuring the parameter of lipid peroxidation; malondialdehyde along with the activities of the antioxidant enzyme reduced glutathione). The bladders of CP treated rats showed ulcered mucosa, edematous, hemorrhagic, and fibrotic submucosa by light microscopy. Ultrastructure observation showed; losing large areas of uroepithelium, extended intercellular gaps, junction complexes were affected as well as damage of mitochondria in the form of swelling and destruction of cristae. Biochemical analysis showed significant elevation of malondialdhyde, while reduced glutathione activity was significantly lowered. From the results obtained in this work, we can say that Moringa leaves play an important role in ameliorating and protecting the bladder from CP toxicity.

  4. Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

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    Paul B Comish

    Full Text Available Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1 mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2% and to 80% in the male offspring of L1 (control value 33%. These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼ 70% of control and induced atrophic seminiferous tubules in ∼ 30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i DNA damage is a common mechanism leading to induction of testicular cancer, ii increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.

  5. Myelosuppression After Frontline Fludarabine, Cyclophosphamide, and Rituximab in Patients With Chronic Lymphocytic Leukemia

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    Strati, Paolo; Wierda, William; Burger, Jan; Ferrajoli, Alessandra; Tam, Constantine; Lerner, Susan; Keating, Michael J.; O’Brien, Susan

    2015-01-01

    BACKGROUND The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced improved response rates and a prolonged survival in patients with chronic lymphocytic leukemia (CLL). However, its therapeutic power is counterbalanced by significant hematologic toxicity. Persistent and new-onset cytopenia after the completion of FCR raise concern about disease recurrence, the development of therapy-related myeloid malignancies (TRMM), and infections. METHODS A total of 207 patients with CLL who achieved complete response, complete response with incomplete bone marrow recovery, or nodular partial remission were analyzed after frontline FCR therapy. RESULTS Three months after the completion of therapy, 35% of patients had developed grade 2 to 4 cytopenia (according to Common Terminology Criteria for Adverse Events [version 4.0]). Factors found to be associated with cytopenia at 3 months after therapy were older age, advanced Rai stage disease, and lower baseline blood counts. Moreover, patients with cytopenia were less likely to have completed 6 courses of therapy with FCR. At 6 months and 9 months after therapy, the prevalence of grade 2 to 4 cytopenia was 24% and 12%, respectively. No differences in progression-free survival and overall survival were noted between cytopenic and noncytopenic patients or between patients with persistent and new-onset cytopenia. The prevalence of TRMM was 2.3% and did not differ significantly between cytopenic and noncytopenic patients or between those with persistent and new-onset disease. Late infections were more common in patients who were cytopenic at 9 months (38%) and were mostly bacterial (67%). CONCLUSIONS Cytopenia after the completion of therapy is a common complication of frontline FCR that improves over time, particularly for new-onset cases. The presence of persistent cytopenia (lasting up to 9 months after the completion of therapy) should not raise concern about CLL recurrence of the development of TRMM, but

  6. Preserved learning and memory following 5-fluorouracil and cyclophosphamide treatment in rats.

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    Long, Jeffrey M; Lee, Garrick D; Kelley-Bell, Bennett; Spangler, Edward L; Perez, Evelyn J; Longo, Dan L; de Cabo, Rafael; Zou, Sige; Rapp, Peter R

    2011-11-01

    Some patients experience enduring cognitive impairment after cancer treatment, a condition termed "chemofog". Animal models allow assessment of chemotherapy effects on learning and memory per se, independent of changes due to cancer itself or associated health consequences such as depression. The present study examined the long-term learning and memory effects of a chemotherapy cocktail used widely in the treatment of breast cancer, consisting of 5-fluorouracil (5FU) and cyclophosphamide (CYP). Eighty 5-month old male F344 rats received contextual and cued fear conditioning before treatment with saline, or a low or high dose drug cocktail (50mg/kg CYP and 75 mg/kg 5FU, or 75 mg/kg CYP and 120 mg/kg 5FU, i.p., respectively) every 30 days for 2 months. After a 2-month, no-drug recovery, both long-term retention and new task acquisition in the water maze and 14-unit T-maze were assessed. Neither dose of the CYP/5FU cocktail impaired retrograde fear memory despite marked toxicity documented by enduring weight loss and 50% mortality at the higher dose. Acquisition in the water maze and Stone maze was also normal relative to controls in rats treated with CYP/5FU. The results contribute to a growing literature suggesting that learning and memory mediated by the hippocampus can be relatively resistant to chemotherapy. Future investigation may need to focus on assessments of processing speed, executive function and attention, and the possible interactive contribution of cancer itself and aging to the post-treatment development of cognitive impairment. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Glutathione S Transferases Polymorphisms Are Independent Prognostic Factors in Lupus Nephritis Treated with Cyclophosphamide.

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    Alexandra Audemard-Verger

    Full Text Available To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs in lupus nephritis (LN treated with cyclophosphamide (CYC. CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST.We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR was defined as proteinuria ≤0.33g/day and serum creatinine ≤124 µmol/l. Partial remission (PR was defined as proteinuria ≤1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline.Most patients were women (84% and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile→105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile→105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR (OR = 5.01 95% CI [1.02-24.51] and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064-10.58]. No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed.This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.

  8. Distinct effects of mycophenolate mofetil and cyclophosphamide on renal fibrosis in NZBWF1/J mice.

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    Yung, Susan; Zhang, Qing; Chau, Mel K M; Chan, Tak Mao

    2015-01-01

    Progression to chronic renal failure varies between patients with lupus nephritis. We compared the effects of mycophenolate mofetil (MMF) and cyclophosphamide (CTX), on renal histology and cellular pathways of fibrosis in murine lupus nephritis. Female NZBWF1/J mice were randomized to treatment with vehicle, methylprednisolone (MP) alone, MMF + MP or CTX + MP for up to 12 weeks, and the effects on clinical parameters, renal histology, and fibrotic processes were investigated. Treatment with MMF + MP or CTX + MP both improved survival, renal function, and decreased anti-dsDNA antibody level and immune complex deposition in kidneys of mice with active nephritis. Vehicle-treated mice showed progressive increase in mesangial proliferation, inflammatory cell infiltration and renal tubular atrophy, associated with PKC-α activation, increased TGF-β1 expression and increased matrix protein deposition. MP treatment alone did not have any significant effect. MMF + MP or CTX + MP treatment for 12 weeks reduced these abnormalities. MMF + MP was more effective than CTX + MP in suppressing fibrotic mediators, histological fibrosis score and expression of TGF-β1, fibronectin and collagen I in the kidney. Results from in vitro experiments on human mesangial cells (HMC) showed that mycophenolic acid (MPA) was more effective than CTX in suppressing PKC-α activation and TGF-β1 secretion induced by human polyclonal anti-dsDNA antibodies. While both MPA and CTX decreased TGF-β1- and TNF-α-induced fibronectin synthesis, only MPA decreased IL-6 induced fibronectin synthesis. MPA and CTX show distinct effects on fibrotic and inflammatory processes in NZBWF1/J murine lupus nephritis, suggesting that MMF + MP may be more effective than CTX + MP in preserving normal renal histology in lupus nephritis.

  9. Lung damage following bone marrow transplantation. II. The contribution of cyclophosphamide

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    Varekamp, A.E.; de Vries, A.J.; Zurcher, C.; Hagenbeek, A.

    1987-10-01

    The effect of high-dose cyclophosphamide (Cy), either alone or in combination with irradiation, upon the development of interstitial pneumonitis (IP) after bone marrow transplantation (BMT) was investigated in a Brown Norway rat model. The parameters that were examined included ventilation rate, mortality, and histopathology. No damage to the lungs was observed in rats given Cy alone in supralethal dosages plus BMT, and mortality resulted from severe aplasia of hemopoietic and lymphoid tissues with multifocal hemorrhages, secondary infections, and sepsis. Two separate periods of mortality were observed within the first 180 days following whole thorax irradiation with a high dose rate (HDR; 0.8 Gy/min) or a low dose rate (LDR; 0.05 Gy/min). The addition of Cy prior to irradiation resulted in an increased mortality in the first period (before day 100) in all experimental groups. The influence of Cy on mortality at 180 days however, was different for the HDR and LDR experiments. The LD50-180 after HDR irradiation, dose range 8 to 18 Gy, was not significantly altered by the addition of Cy (100 mg/kg) 1 day prior to irradiation, whereas Cy (100 mg/kg) 1 day prior to LDR irradiation, dose range: 16 to 24 Gy, caused an enhancement of radiation damage with a decrease of the LD50-180 by 1.33 Gy. The dose modification factor (DMF) was 1.07. This enhancement was no longer significant after splitting up the dose of Cy in two dosages of 50 mg/kg given on 2 consecutive days prior to irradiation with a LDR. The extrapolation of the data in this rat model to available dose-response curves on IP after BMT and radiation pneumonitis in humans, implied that non-infectious IP is a radiation pneumonitis that is only slightly enhanced by Cy.

  10. Protective effect of quercetin on skeletal and neural tube teratogenicity induced by cyclophosphamide in rat fetuses

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    Khaksary Mahabady, Mahmood; Gholami, Mohammad Reza; Najafzadeh Varzi, Hossein; Zendedel, Abolfazl; Doostizadeh, Mona

    2016-01-01

    Cyclophosphamide (CP) is a drug commonly used to treat neoplastic disease and some autoimmune diseases. It is also a well-known and well-studied teratogen causing a variety of birth defects in fetuses of pregnant women treated with the drug. There are many reports that show the adverse effects of CP can be decreased by use of antioxidant drugs. It appears that, quercetin has antioxidant effect. The aim of this study was prevention or decrease of teratogenicity of CP in fetuses of rats by quercetin. This study was performed on 35 pregnant rats divided into six groups. Control group was received normal saline (5 mL kg-1, intraperitoneally) and 2-6 groups received a single dose of CP (15 mg kg-1), a single dose of quercetin (75 or 200 mg kg-1), CP plus quercetin (75 or 200 mg kg-1) intraperitoneally at 9th day of gestation, respectively. Fetuses were collected at 20th day of gestation and after determination of weight and crown rump length were stained by alizarin red – alcian blue method and skeletal system were examined by stereomicroscope. The results showed that the cleft palate, exencephaly, spina bifida and omphalocele incidence were 55.56%, 27.77%, 33.34% and 11.11%, in fetuses of rat that received only CP, respectively. However, it decreased to 16.00%, 16.00%, 16.00% and 8.00% by quercetin (75 mg kg-1) and so to 12.90%, 12.90%, 6.45% and 3.28% by quercetin (200 mg kg-1), respectively. On the basis of results, quercetin significantly can decrease teratogenicity induced by CP. PMID:27482358

  11. Effects of melatonin on DNA damage induced by cyclophosphamide in rats

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    S.G. Ferreira

    2013-03-01

    Full Text Available The antioxidant and free radical scavenger properties of melatonin have been well described in the literature. In this study, our objective was to determine the protective effect of the pineal gland hormone against the DNA damage induced by cyclophosphamide (CP, an anti-tumor agent that is widely applied in clinical practice. DNA damage was induced in rats by a single intraperitoneal injection of CP (20 or 50 mg/kg. Animals received melatonin during the dark period for 15 days (1 mg/kg in the drinking water. Rat bone marrow cells were used for the determination of chromosomal aberrations and of formamidopyrimidine DNA glycosylase enzyme (Fpg-sensitive sites by the comet technique and of Xpf mRNA expression by qRT-PCR. The number (mean ± SE of chromosomal aberrations in pinealectomized (PINX animals treated with melatonin and CP (2.50 ± 0.50/100 cells was lower than that obtained for PINX animals injected with CP (12 ± 1.8/100 cells, thus showing a reduction of 85.8% in the number of chromosomal aberrations. This melatonin-mediated protection was also observed when oxidative lesions were analyzed by the Fpg-sensitive assay, both 24 and 48 h after CP administration. The expression of Xpf mRNA, which is involved in the DNA nucleotide excision repair machinery, was up-regulated by melatonin. The results indicate that melatonin is able to protect bone marrow cells by completely blocking CP-induced chromosome aberrations. Therefore, melatonin administration could be an alternative and effective treatment during chemotherapy.

  12. Effects of melatonin on DNA damage induced by cyclophosphamide in rats

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    S.G. Ferreira

    2013-08-01

    Full Text Available The antioxidant and free radical scavenger properties of melatonin have been well described in the literature. In this study, our objective was to determine the protective effect of the pineal gland hormone against the DNA damage induced by cyclophosphamide (CP, an anti-tumor agent that is widely applied in clinical practice. DNA damage was induced in rats by a single intraperitoneal injection of CP (20 or 50 mg/kg. Animals received melatonin during the dark period for 15 days (1 mg/kg in the drinking water. Rat bone marrow cells were used for the determination of chromosomal aberrations and of formamidopyrimidine DNA glycosylase enzyme (Fpg-sensitive sites by the comet technique and of Xpf mRNA expression by qRT-PCR. The number (mean ± SE of chromosomal aberrations in pinealectomized (PINX animals treated with melatonin and CP (2.50 ± 0.50/100 cells was lower than that obtained for PINX animals injected with CP (12 ± 1.8/100 cells, thus showing a reduction of 85.8% in the number of chromosomal aberrations. This melatonin-mediated protection was also observed when oxidative lesions were analyzed by the Fpg-sensitive assay, both 24 and 48 h after CP administration. The expression of Xpf mRNA, which is involved in the DNA nucleotide excision repair machinery, was up-regulated by melatonin. The results indicate that melatonin is able to protect bone marrow cells by completely blocking CP-induced chromosome aberrations. Therefore, melatonin administration could be an alternative and effective treatment during chemotherapy.

  13. Efficacy of Rosmarinus officinalis leaves extract against cyclophosphamide-induced hepatotoxicity.

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    El-Naggar, Sabry A; Abdel-Farid, Ibrahim B; Germoush, Mousa O; Elgebaly, Hassan A; Alm-Eldeen, Abeer A

    2016-10-01

    Context Cyclophosphamide (CTX) is used to treat different cancer types, although it causes severe hepatotoxicity due to its oxidative stress effect. Rosmarinus officinalis, L. (Lamiaceae) has a therapeutic potential against hepatotoxicity due to its antioxidant activity. Objective The objective of this study is to investigate the phytochemical analysis of the methanol extract of Rosmarinus officianalis leaves (MEROL) and its efficacy against CTX-induced hepatotoxicity. Materials and methods The phytochemical analyses were assessed spectrophotometericaly. To assess the MEROL efficacy, 72 Swiss albino mice were divided into six groups. Group 1 was control, groups 2 and 3 included mice which were injected intraperitoneally (i.p.) with 100 or 200 mg/kg of MEROL at days 1, 4, 7, 10, 13 and 16; group 4 was injected (i.p.) with CTX (200 mg/kg) at day 17, groups 5 and 6 were injected (i.p.) with MEROL as groups 3 and 4 followed by 200 mg/kg CTX at day 17, respectively. At day 22, six mice from each group were sacrificed and the others were sacrificed at day 37. Results MEROL has a high content of total phenolics, saponins, total antioxidant capacity and DPPH radical scavenging activity. The median lethal dose (LD50) value of MEROL was 4.125 g/kg b.w. The inhibitory concentration 50 (IC50) value for DPPH radical scavenging was 55 μg/mL. Pretreatment with 100 mg/kg MEROL for 16 d ameliorated CTX-induced hepatotoxicity represented in lowering the levels of the aspartate aminotransferase (AST) and lipid profile and minimizing the histological damage. Conclusions Pretreatment with 100 mg/kg b.w. MEROL mitigated CTX-induced hepatotoxicity due to its antioxidant activity.

  14. Photocatalytic oxidation of 5-fluorouracil and cyclophosphamide via UV/TiO2 in an aqueous environment.

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    Lin, Hank Hui-Hsiang; Lin, Angela Yu-Chen

    2014-01-01

    Cytostatic drugs are a class of pharmaceuticals that are increasingly used in cancer therapies; 5-fluorouracil is one of the most commonly used cytostatic (antineoplastic) drugs in the world. This study applied photocatalytic oxidation to remove 5-fluorouracil. Degussa P25 showed a higher photocatalytic degradation efficiency for 5-fluorouracil removal than Aldrich TiO2 and ZnO. Under optimal conditions (20 mg L(-1) TiO2 at pH 5.8), 200 μg L(-1) 5-fluorouracil can be removed within 2 h (k = 0.0375 min(-1)). 5-fluorouracil was found to be decomposed by near-surface OH free radicals produced from valence holes (hvb(+)). At a relatively high concentration, 5-fluorouracil (27.6 mg L(-1)) is >99.9% removed within 4 h by 300 mg L(-1) Degussa P25, while 24 h is required to reach complete mineralization with 96.7% fluoride recovery. Cyclophosphamide is another widely used cancer drug that follows a similar decomposition pathway. Cyclophosphamide (27.6 mg L(-1)) was also >99.9% eliminated within 4 h, but dechlorination and mineralization reached only 79.9% and 55.1%, respectively, after 16 h of irradiation. Together with the results for Microtox(®), it is suggested that the oxidation products of cyclophosphamide are even more recalcitrant and toxic. For engineering practices, despite the fact that photocatalytic oxidation can rapidly remove target antineoplastic, it is also important to further evaluate the treatment efficiency of the photoproducts.

  15. Severe multiorganic flare of systemic lupus erythematosus successfully treated with rituximab and cyclophosphamide avoiding high doses of prednisone.

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    Gonzalez-Echavarri, C; Pernas, B; Ugarte, A; Ruiz-Irastorza, G

    2014-03-01

    Both acute pancreatitis and diffuse alveolar haemorrhage are rare conditions associated with systemic lupus erythematosus (SLE). In this case report, a 23-year-old female with SLE was diagnosed with lupus-associated pancreatitis and, within a few days and despite initial therapy with pulse methyl-prednisolone, subsequently suffered an acute respiratory failure due to a diffuse alveolar haemorrhage. The patient was admitted to the intensive care unit and treatment was intensified with cyclophosphamide and rituximab, which shortly induced the complete remission of SLE with resolution of both clinical conditions. She completed treatment with six pulses of cyclophosphamide followed by azathioprine, hydroxychloroquine and prednisone at initial doses of 20 mg/d with rapid tapering to 5 mg/d, without relapse of the disease during the following year. This case can illustrate that, even in severe, life-threatening SLE flares, it is possible to avoid high-dose prednisone, which has been associated with severe side effects, including infections. Acute pancreatitis and diffuse alveolar haemorrhage are rare conditions caused by SLE. DAH can be a life-threatening complication, with an early mortality of at least 50%. When facing such severe SLE activity, there is a general tendency to use high doses of prednisone as the initial therapy, maintaining such high doses for long periods of time, even after the clinical situation has subsided. We report a case of a young woman with SLE, suffering from acute pancreatitis and diffuse alveolar haemorrhage, who was successfully treated with pulse methyl-prednisolone, hydroxychloroquine, cyclophosphamide and rituximab, combined with medium doses of prednisone.

  16. Improvement of neurological symptoms and memory and emotional status in a case of seronegative Sneddon syndrome with cyclophosphamide.

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    Hannon, Peter M; Kuo, Sheng-Han; Strutt, Adriana M; York, Michele K; Kass, Joseph S

    2010-07-01

    Sneddon syndrome (SS) is characterized by livedo racemosa, recurrent ischemic strokes, and often progressive vascular dementia. Treatment options for SS center on either anticoagulation or immunosuppression to prevent strokes and to dissipate the skin findings, with these modalities based historically on the presence or absence of antiphospholipid antibodies (APA) respectively. However, few effective treatments have been reported to reverse the cognitive decline in SS. We report a case of a woman with seronegative SS (absence of APA) with cognitive decline who demonstrated objective and subjective improvements in her memory and emotional functioning after treatment with cyclophosphamide.

  17. Macrophage activation syndrome as the initial manifestation of severe juvenile onset systemic lupus erythematosus. Favorable response to cyclophosphamide.

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    Torres Jiménez, Alfonso; Solís Vallejo, Eunice; Zeferino Cruz, Maritza; Céspedes Cruz, Adriana; Sánchez Jara, Berenice

    2014-01-01

    The macrophage activation syndrome is a rare but potentially fatal complication of patients with autoimmune rheumatic diseases. This is a clinicopathological entity characterized by activation of histiocytes with prominent hemophagocytosis in the bone marrow and other reticuloendothelial systems. In patients with lupus it may mimic an exacerbation of the disease or infection. We report the case of a 7-year-old girl in whom the diagnosis of lupus erythematosus and macrophage activation syndrome was simultaneously made with response to the use of cyclophosphamide.

  18. Treatment of Vasodilator-resistant Mixed Connective Tissue Disease-associated Pulmonary Arterial Hypertension with Glucocorticoid and Cyclophosphamide.

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    Sugawara, Eri; Kato, Masaru; Hisada, Ryo; Oku, Kenji; Bohgaki, Toshiyuki; Horita, Tetsuya; Yasuda, Shinsuke; Atsumi, Tatsuya

    2017-01-01

    Pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MTCD), in contrast to other types of PAH, may respond to immunosuppressive therapy. Most PAH cases with an immunosuppressant response were in the early stages of the disease (WHO functional class III or less). The present case was a 34-year-old woman with MCTD-associated PAH (WHO functional class IV) who was resistant to a combination of three vasodilators. Afterwards, she was treated with glucocorticoid and cyclophosphamide. This case suggested the potential benefit of immunosuppressants in patients with severe MCTD-associated PAH.

  19. Vascular normalization in orthotopic glioblastoma following intravenous treatment with lipid-based nanoparticulate formulations of irinotecan (Irinophore C™, doxorubicin (Caelyx® or vincristine

    Directory of Open Access Journals (Sweden)

    Waterhouse Dawn

    2011-04-01

    Full Text Available Abstract Background Chemotherapy for glioblastoma (GBM patients is compromised in part by poor perfusion in the tumor. The present study evaluates how treatment with liposomal formulation of irinotecan (Irinophore C™, and other liposomal anticancer drugs, influence the tumor vasculature of GBM models grown either orthotopically or subcutaneously. Methods Liposomal vincristine (2 mg/kg, doxorubicin (Caelyx®; 15 mg/kg and irinotecan (Irinophore C™; 25 mg/kg were injected intravenously (i.v.; once weekly for 3 weeks in Rag2M mice bearing U251MG tumors. Tumor blood vessel function was assessed using the marker Hoechst 33342 and by magnetic resonance imaging-measured changes in vascular permeability/flow (Ktrans. Changes in CD31 staining density, basement membrane integrity, pericyte coverage, blood vessel diameter were also assessed. Results The three liposomal drugs inhibited tumor growth significantly compared to untreated control (p trans in the orthotopic tumors (p Conclusion The results are consistent with a partial restoration of the blood-brain barrier following treatment. Further, treatment with the selected liposomal drugs gave rise to blood vessels that were morphologically more mature and a vascular network that was more evenly distributed. Taken together the results suggest that treatment can lead to normalization of GBM blood vessel the structure and function. An in vitro assay designed to assess the effects of extended drug exposure on endothelial cells showed that selective cytotoxic activity against proliferating endothelial cells could explain the effects of liposomal formulations on the angiogenic tumor vasculature.

  20. Baicalein Triggers Mitochondria-Mediated Apoptosis and Enhances the Antileukemic Effect of Vincristine in Childhood Acute Lymphoblastic Leukemia CCRF-CEM Cells

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    Yun-Ju Chen

    2013-01-01

    Full Text Available Acute lymphoblastic leukemia (ALL accounts for approximately 75% of childhood leukemia, and chemotherapy remains the mainstay therapy. Baicalein is an active flavonoid used in traditional Chinese medicine and has recently been found to have anticancer, anti-inflammatory, and antiallergic properties. This study aims to investigate the molecular apoptotic mechanisms of baicalein in CCRF-CEM leukemic cells and to evaluate the combined therapeutic efficacy of baicalein with several commonly used chemotherapeutic drugs in CCRF-CEM cells. Our results demonstrate that baicalein induces mitochondria-dependent cleavage of caspases-9 and -3 and PARP with concomitant decreases in IAP family proteins, survivin, and XIAP. Furthermore, our results present for the first time that baicalein triggers a convergence of the intrinsic and extrinsic apoptotic pathways via the death receptor-caspase 8-tBid signaling cascade in CCRF-CEM cells. In addition, we also present for the first time that the combination of baicalein and vincristine results in a synergistic therapeutic efficacy. Overall, this combination strategy is recommended for future clinical trials in the treatment of pediatric leukemia owing to baicalein’s beneficial effects in alleviating the vomiting, nausea, and skin rashes caused by chemotherapy.

  1. Achillea millefolium inflorescence aqueous extract ameliorates cyclophosphamide-induced toxicity in rat testis: stereological evidences%Achillea millefolium inflorescence aqueous extract ameliorates cyclophosphamide-induced toxicity in rat testis:stereological evidences

    Institute of Scientific and Technical Information of China (English)

    Ali Shalizar Jalali; Shapour Hasanzadeh; Hassan Malekinejad

    2012-01-01

    Cyclophosphamide (CP) is extensively used for the treatment of various cancers,as well as an immunosuppressive agent.However,CP is known to cause several adverse effects including reproductive toxicity.Achillea millefolium,a widely distributed medicinal plant,is highly regarded for its medicinal activities,including antioxidant and anti-inflammatory properties.The present study was conducted to assess whether Achillea millefolium inflorescences aqueous extract with antioxidant and anti-inflammatory activities could serve as a protective agent against reproductive toxicity during CP treatment.Male Wistar rats were categorized into four groups.Two groups of rats were administered CP at a dose of 5mg·kg-1·d-1 for 28 d by oral gavages.One of these groups received Achillea aqueous extract at a dose of 1.2 g·kg-1·d-1 orally 4 h after cyclophosphamide administration.A vehicle treated control group and an Achillea control group were also included.Thc CP-trcatcd group showed significant decreases in the body,testes and epididymides weights as well as many histological alterations.Stereological parameters,spermatogenic activities and testicular antioxidant capacity along with epididymal sperm count and serum testosterone concentration were also significantly decreased by CP treatment.Notably,Achillea co-administration caused a partial recovery in above-mentioned parameters.These findings indicate that Achillea millefolium inflorescence aqueous extract may be partially protective against CP-induced testicular toxicity.

  2. Long-term results of a randomized trial comparing cisplatin with cisplatin and cyclophosphamide with cisplatin, cyclophosphamide, and adriamycin in advanced ovarian cancer. GICOG (Gruppo Interregionale Cooperativo Oncologico Ginecologia), Italy.

    Science.gov (United States)

    1992-05-01

    We report the long-term results of a randomized trial comparing cisplatin (P) with cisplatin and cyclophosphamide (CP) with cisplatin, cyclophosphamide, and adriamycin (CAP) in advanced ovarian cancer. Overall, this update confirms previously published data on 529 cases. Median survival times for the three treatments--CAP, CP, and P--are, respectively, 23, 20, and 19 months. The differences among the three arms are still nonsignificant and the estimated percentage survival at 7 years and confidence limits are, respectively, 21.7 (14.9-28.4), 17.0 (11.0-22.9), and 12.2 (6.9-17.4). According to the results of the Cox regression model on prognostic factors, higher grading, a larger residual tumor size, and performance status less than 80 (Karnovsky) all were independently associated with a poorer outcome, while a serous histotype was related to a better prognosis. The other variables (age, stage, center, type of surgery) initially included in the model did not appear to be significantly related to prognosis. The implications of these long-terms results relative to the application of combination chemotherapy with CAP or CP are discussed.

  3. The Effect of Hydro-Alcoholic Garlic Extract on Testis Weight and Spermatogenesis in Mature Male Rats under Chemotherapy with Cyclophosphamide

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    Marzie Mirfard

    2011-12-01

    Full Text Available Background & Objectives: Cyclophosphamide (with the brand name of Endoxana is an anti-cancer drug used in chemotherapy. The side effects of this drug include anoretic, nausea, decrease in genital gland function, creating amenorrhea, azoospermia and oligospermia. Garlic has been used throughout history as a medicinal drug and a beneficial spice in cooking. The beneficial effects of garlic which have been studied are its anti-oxidant, antibacterial, anti- atherosclerosis, anti-blood platelet effects as well as its role in reducing blood glucose and fat. Garlic has many compounds mostly contain a sulfuric content such as Di-alkyl Di-sulfide (Alicin, Di alyl Di sulfide (DAS, that caused antioxidant and protective properties. Materials & Methods: Cyclophosphamide and garlic extract were given to 56 rats for a period of 28 days. The rats were weighted and after anesthesia, their testis was taken out and tissue dissections were obtained, Student t-test was applied for the statistical analysis. Results: The results show that cyclophosphamide alone leads to a reduction in body and testis weight, and spermatogenesis compared to the control group. In the group that used cyclophosphamide along with garlic extract, as the dose of extract increased, the body and testis weight and spermatogenesis increased in the rats. Conclusion: It seems, the existing compounds in garlic extract can control active metabolites caused by cyclophosphamide and the destructive effect of this drug. Prescribing garlic extract along with cyclophosphamide can possibly be beneficial and effective due to the anti-oxidant characteristics of garlic and also its effect on reducing harmful metabolites.

  4. Cyclophosphamide therapy for corticoresistant drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a patient with severe kidney and eye involvement and Epstein-Barr virus reactivation.

    Science.gov (United States)

    Laban, Emilie; Hainaut-Wierzbicka, Eva; Pourreau, François; Yacoub, Mokrane; Sztermer, Emilie; Guillet, Gérard; Touchard, Guy; Bridoux, Frank

    2010-03-01

    DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is a severe adverse drug reaction with significant mortality, characterized by erythroderma, fever, lymphadenopathy, and visceral involvement. We report a case of multivisceral DRESS syndrome with posterior multifocal placoid pigment epitheliopathy and acute tubulointerstitial nephritis responsible for dialysis-dependent acute kidney failure in the context of reactivation of Epstein-Barr virus infection. Because of resistance of the skin and kidney manifestations to prolonged corticosteroid therapy, a 6-month course of oral cyclophosphamide resulted in complete recovery of all symptoms. To our knowledge, this is the first case showing the efficacy of cyclophosphamide in severe DRESS syndrome.

  5. Single pre-treatment with hypericin, a St. John's wort secondary metabolite, attenuates cisplatin- and mitoxantrone-induced cell death in A2780, A2780cis and HL-60 cells.

    Science.gov (United States)

    Jendželovská, Zuzana; Jendželovský, Rastislav; Hiľovská, Lucia; Kovaľ, Ján; Mikeš, Jaromír; Fedoročko, Peter

    2014-10-01

    St. John's wort (SJW, Hypericum perforatum L.) is a commonly used natural antidepressant responsible for the altered toxicity of some anticancer agents. These interactions have been primarily attributed to the hyperforin-mediated induction of some pharmacokinetic mechanisms. However, as previously demonstrated by our group, hypericin induces the expression of two ABC transporters: multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP). Because cisplatin (CDDP) and mitoxantrone (MTX) are potential substrates of ABC transporters, we investigated the effect of 24h hypericin pre-treatment on the cytotoxicity of CDDP and MTX in human cancer cell lines. CDDP-sensitive and -resistant ovarian adenocarcinoma cell lines A2780/A2780cis, together with HL-60 promyelocytic leukemia cells and ABCG2-over-expressing cBCRP subclone, were used in our experiments. We present CDDP cytotoxicity attenuated by hypericin pre-treatment in both A2780 and A2780cis cells and MTX cytotoxicity in HL-60 cells. In contrast, hypericin potentiated MTX-induced death in cBCRP cells. Interestingly, hypericin did not restore cell proliferation in rescued cells. Nevertheless, hypericin did increase the expression of MRP1 transporter in A2780 and A2780cis cells indicating the impact of hypericin on certain resistance mechanisms. Additionally, our results indicate that hypericin may be the potential substrate of BCRP transporter. In conclusion, for the first time, we report the ability of hypericin to affect the onset and/or progress of CDDP- and MTX-induced cell death, despite strong cell cycle arrest. Thus, hypericin represents another SJW metabolite that might be able to affect the effectiveness of anti-cancer drugs and that could interact with ABC transporters, particularly with BCRP.

  6. Mizoribine versus mycophenolate mofetil or intravenous cyclophosphamide for induction treatment of active lupus nephritis

    Institute of Scientific and Technical Information of China (English)

    Feng Xuebing; Gu Fei; Chen Weiwei; Liu Yan; Wei Hua; Liu Lin; Yin Songlou

    2014-01-01

    Background Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus.Although there have been substantial improvements in LN treatment over the last decade,the outcome remains unoptimistic in a considerable percentage of patients.The aim of this study was to evaluate the efficacy and safety of mizoribine (MZR),a novel selective inhibitor of inosine monophosphate dehydrogenase,as induction treatment for active LN in comparison with mycophenolate mofetil (MMF) and intravenous cyclophosphamide (CYC).Methods Ninety patients with active LN were observed.Thirty patients were given MZR orally at the dose of 300 mg every other day.Thirty patients took MMF at 2 g per day in two divided doses.Thirty patients received CYC intravenously 0.5 g every 2 weeks.Therapeutic effects and adverse events (AEs) were evaluated at the end of 24-week treatment.Oneway analysis of variance (ANOVA) followed by Dunn's test was applied to compare the difference among the groups.For comparing categorical data between two groups,X2 test was employed.Results Early responses at week 12 were achieved by 73.3%,90.0%,and 96.7% in MZR,MMF,and CYC groups,respectively.There was no significant difference in the complete remission rates (22.7%,24.0%,and 25.0%,respectively) or overall response rates (68.2%,72.0%,and 75.0%,respectively) among the three groups at week 24.The most prominent drop-down of Systemic Lupus Erythematosus Disease Activity Index scores was observed in MMF or CYC group,and the decline of health assessment questionnaire scores in MZR or MMF group was more prominent than that in the CYC group at week 12.Serum complement 3 (C3) or C4 levels were elevated in all groups after the treatments.CYC was more effective in inhibiting anti-double-stranded DNA antibody,while MZR was more effective in inhibiting antinuclear antibody.The incidences of AEs in patients treated with CYC were significantly higher than those in patients treated with MZR

  7. Simvastatin suppresses cyclophosphamide-induced changes in urodynamics and bladder inflammation.

    Science.gov (United States)

    Hughes, Francis M; McKeithan, Paige; Ellett, Justin; Armeson, Kent E; Purves, J Todd

    2013-01-01

    To assess the ability of daily oral simvastatin administration to reduce the negative urodynamic changes associated with cyclophosphamide (CP)-induced cystitis and to prevent bladder inflammation. Patients undergoing CP chemotherapy frequently develop cystitis, leading to urinary dysfunction and hemorrhage. Recent studies have suggested statins possess anti-inflammatory properties and might be uroprotective. Urodynamic properties were analyzed in 4 groups of female Sprague-Dawley rats: group 1, vehicle (300 μL, 0.5% methylcellulose, orally for 7 days); group 2, simvastatin (1 mg/rat/d); group 3, vehicle plus CP (intraperitoneally 80 mg/kg, 24 h before cystometry); and group 4, simvastatin plus CP. The inflammation in the groups was assessed using Evans blue extravasation. CP stimulated significant increases in the number of nonvoiding contractions (0.83±0.26 vs 4.97±1.90; P=.03) and decreases in the peak voiding pressure (53.46±5.08 vs 33.34±4.37 cm H2O; P=.01). Simvastatin returned these parameters to the control levels of 1.62±0.73 (P=.70) and 45.98±7.78 cm H2O (P=.38). CP at this level caused a slight, but significant, increase in the voided volume (0.82±0.13 vs 1.16±0.14 mL; P=.04), which returned to control levels (0.74±0.12 mL; P=.65) with simvastatin. Other urodynamic parameters, such as the threshold pressure, were not affected by simvastatin or CP, or the combination of the 2. CP-induced inflammation in the bladder (Evans blue extravasation) was suppressed by simvastatin. Simvastatin was effective at ameliorating the negative urodynamic changes and inflammation in the bladder after CP administration and is a potential therapy for preventing side effects in patients undergoing this chemotherapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Hypertension and Afro-descendant ethnicity: a bad interaction for lupus nephritis treated with cyclophosphamide?

    Science.gov (United States)

    de Castro, W P; Morales, J V; Wagner, M B; Graudenz, M; Edelweiss, M I; Gonçalves, L F

    2007-01-01

    Hypertension and ethnicity are important prognostic factors in evolution of lupus nephritis. A cohort of 75 patients with lupus nephritis treated with cyclophosphamide was conducted to investigate the evolution of creatinine levels between Caucasians and Afro-descendants. A multiple linear model was used to evaluate the combined effects of ethnicity and hypertension over delta creatinine controlling confounders. Sample characteristics were: 85% females; mean (+/-SD) age of 33.6 +/- 12.0 years; 77% Caucasians; 40% hypertensive at renal biopsy; 91% WHO class IV; mean basal creatinine: 1.5 +/- 1.3 mg/dL; mean final creatinine: 2.1 +/- 2.5 mg/dL; 40% anaemia; proteinuria: 5.4 +/- 4.8 g/day. Comparing Caucasians and Afro-descendants, it was found: 28.1% versus 72.2% for hypertension (P = 0.002); 31.6% versus 66.7% for anaemia (P = 0.018); 5.9 +/- 5.0 versus 3.8 +/- 4.0. g/day (P = 0.02) for proteinuria. Other comparisons including basal creatinine did not reach statistical significance. Comparing outcomes between Caucasians and Afro-descendants, it was found: 10.5% versus 22.2% for doubling of creatinine (P = 0.24); 0.41 +/- 2.03 versus 1.05 +/- 2.41 for delta creatinine ( P = 0.29); 8.8% versus 22.2% for haemodialysis (P = 0.21) and 3.5% versus 5.6% for death (P = 0.99). Analysing delta creatinine with multiple linear regression showed that hypertension had a significant overall effect (b = 0.80; SE = 0.32; P = 0.015), ethnicity alone was not significant (b = 0.35; SE = 0.29; P = 0.228); however, the effect of hypertension on delta creatinine was more intense among Afro-descendants than among Caucasians (interaction term b = - 0.83; SE = 0.37; P = 0.027). Afro-descendants lupus patients experience worst prognosis of renal function probably due to the effect of hypertension and not ethnicity per se.

  9. Avocado fruit (Persea americana Mill) exhibits chemo-protective potentiality against cyclophosphamide induced genotoxicity in human lymphocyte culture.

    Science.gov (United States)

    Paul, Rajkumar; Kulkarni, Paresh; Ganesh, Narayan

    2011-01-01

    Diets rich in fruits and vegetables have been associated with reduced risks for many types of cancers. Avocado (Persea americana Mill.) is a widely consumed fruit containing many cancer preventing nutrients, vitamins and phytochemicals. Studies have shown that phytochemicals extracted from the avocado fruit selectively induce cell cycle arrest, inhibit growth, and induce apoptosis in precancerous and cancer cell lines. Our recent studies indicate that phytochemicals extracted with 50% Methanol from avocado fruits help in proliferation of human lymphocyte cells and decrease chromosomal aberrations induced by cyclophosphamide. Among three concentrations (100 mg, 150 mg and 200 mg per Kg Body Weight), the most effective conc. of extract was 200 mg/Kg Body Wt. It decreased significant level of numerical and structural aberrations (breaks, premature centromeric division etc. up to 88%, p < 0.0001)), and accrocentric associtation within D & G group (up to 78%, p = 0.0008). These studies suggest that phytochemicals from the avocado fruit can be utilized for making active chemoprotective ingredient for lowering the side effect of chemotherapy like cyclophosphamide in cancer therapy.

  10. Occurrence of cyclophosphamide and ifosfamide in aqueous environment and their removal by biological and abiotic wastewater treatment processes.

    Science.gov (United States)

    Česen, Marjeta; Kosjek, Tina; Laimou-Geraniou, Maria; Kompare, Boris; Širok, Brane; Lambropolou, Dimitra; Heath, Ester

    2015-09-15

    Cytostatic drug residues in the aqueous environment are of concern due to their possible adverse effects on non-target organisms. Here we report the occurrence and removal efficiency of cyclophosphamide (CP) and ifosfamide (IF) by biological and abiotic treatments including advanced oxidation processes (AOPs). Cyclophosphamide was detected in hospital wastewaters (14-22,000 ng L(-1)), wastewater treatment plant influents (19-27 ng L(-1)) and effluent (17 ng L(-1)), whereas IF was detected only in hospital wastewaters (48-6800 ng L(-1)). The highest removal efficiency during biological treatment (attached growth biomass in a flow through bioreactor) was 59 ± 15% and 35 ± 9.3% for CP and IF, respectively. Also reported are the removal efficiencies of both compounds from wastewater using hydrodynamic cavitation (HC), ozonation (O3) and/or UV, either individually or in combination with hydrogen peroxide (H2O2). Hydrodynamic cavitation did not remove CP and IF to any significant degree. The highest removal efficiencies: 99 ± 0.71% for CP and 94 ± 2.4% for IF, were achieved using UV/O3/H2O2 at 5 g L(-1) for 120 min. When combined with biological treatment, removal efficiencies were >99% for both compounds. This is the first report of combined biological and AOP treatment of CP and IF from wastewater with a removal efficiency >99%.

  11. Protective effect of curcumin and chlorophyllin against DNA mutation induced by cyclophosphamide or benzo[a]pyrene

    Energy Technology Data Exchange (ETDEWEB)

    Ibrahim, M.A.; Elbehairy, A.M.; Ghoneim, M.A.; Amer, H.A. [Cairo Univ., Giza (Egypt). Biochemistry Dept. and Biotechnology Center

    2007-03-15

    The current study was carried out to evaluate the potency of curcumin and chlorophyllin as natural antioxidants to reduce the oxidative stress markers induced by cyclophosphamide (CP) and benzo[a]pyrene [B(a)P] which were used as free radical inducers. For this purpose, 126 male albino rats were used. The animals were assigned into 4 main groups: negative control group; oxidant-treated group (subdivided into two subgroups: cyclophosphamide- treated group and benzo[a]pyrene-treated group); curcumin-treated group; and chlorophyllin-treated group. Liver samples were collected after two days post the oxidant inoculation and at the end of the experimental period (10 weeks). These samples were examined for determination of liver microsomal malondialdehyde (MDA), DNA fragmentation, restriction fragment length polymorphism (RFLP) and 8-hydroxy deoxyguanosine (8-OHdG) concentration. Both CP and B(a)P caused increments in DNA fragmentation percentages, liver microsomal MDA, concentration of 8-OHdG and induced point mutation. Treatment of rats with either curcumin or chlorophyllin revealed lower DNA fragmentation percentages, liver microsomal MDA concentration, concentration of 8-OHdG and prevented induction of mutations, i. e., reversed the oxidative stress induced by CP and B(a)P and proved that they were capable of protecting rats against the oxidative damage evoked by these oxidants. (orig.)

  12. Protective effect of curcumin and chlorophyllin against DNA mutation induced by cyclophosphamide or benzo[a]pyrene.

    Science.gov (United States)

    Ibrahim, Marwa A; Elbehairy, Adel M; Ghoneim, Magdy A; Amer, Hassan A

    2007-01-01

    The current study was carried out to evaluate the potency of curcumin and chlorophyllin as natural antioxidants to reduce the oxidative stress markers induced by cyclophosphamide (CP) and benzo[a]pyrene [B(a)P] which were used as free radical inducers. For this purpose, 126 male albino rats were used. The animals were assigned into 4 main groups: negative control group; oxidant-treated group (subdivided into two subgroups: cyclophosphamide-treated group and benzo[a]pyrene-treated group); curcumin-treated group; and chlorophyllin-treated group. Liver samples were collected after two days post the oxidant inoculation and at the end of the experimental period (10 weeks). These samples were examined for determination of liver microsomal malondialdehyde (MDA), DNA fragmentation, restriction fragment length polymorphism (RFLP) and 8-hydroxy deoxyguanosine (8-OHdG) concentration. Both CP and B(a)P caused increments in DNA fragmentation percentages, liver microsomal MDA, concentration of 8-OHdG and induced point mutation. Treatment of rats with either curcumin or chlorophyllin revealed lower DNA fragmentation percentages, liver microsomal MDA concentration, concentration of 8-OHdG and prevented induction of mutations, i.e., reversed the oxidative stress induced by CP and B(a)P and proved that they were capable of protecting rats against the oxidative damage evoked by these oxidants.

  13. High content analysis of an in vitro model for metabolic toxicity: results with the model toxicants 4-aminophenol and cyclophosphamide.

    Science.gov (United States)

    Cole, Stephanie D; Madren-Whalley, Janna S; Li, Albert P; Dorsey, Russell; Salem, Harry

    2014-12-01

    In vitro models that accurately and rapidly assess hepatotoxicity and the effects of hepatic metabolism on nonliver cell types are needed by the U.S. Department of Defense and the pharmaceutical industry to screen compound libraries. Here, we report the first use of high content analysis on the Integrated Discrete Multiple Organ Co-Culture (IdMOC) system, a high-throughput method for such studies. We cultured 3T3-L1 cells in the presence and absence of primary human hepatocytes, and exposed the cultures to 4-aminophenol and cyclophosphamide, model toxicants that are respectively detoxified and activated by the liver. Following staining with calcein-AM, ethidium homodimer-1, and Hoechst 33342, high content analysis of the cultures revealed four cytotoxic endpoints: fluorescence intensities of calcein-AM and ethidium homodimer-1, nuclear area, and cell density. Using these endpoints, we observed that the cytotoxicity of 4-aminophenol in 3T3-L1 cells in co-culture was less than that observed for 3T3-L1 monocultures, consistent with the known detoxification of 4-aminophenol by hepatocytes. Conversely, cyclophosphamide cytotoxicity for 3T3-L1 cells was enhanced by co-culturing with hepatocytes, consistent with the known metabolic activation of this toxicant. The use of IdMOC plates combined with high content analysis is therefore a multi-endpoint, high-throughput capability for measuring the effects of metabolism on toxicity.

  14. VINDESINE WITH CYCLOPHOSPHAMIDE-EPIRUBICIN-CISPLATIN IN THE TREATMENT LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER

    Institute of Scientific and Technical Information of China (English)

    HU Yan-ping; KE Yu-hua; FU Xiao-yu

    1999-01-01

    Objective: To evaluate the addition of vindesine to a cyclophosphamide-epirubicin-cisplatin (CAP) regimen for treating the patients with locally advanced non-small cell lung cancer (NSCLC). Methods: From May 1994to August 1998, 59 previously untreated patients with stage Ⅲa and Ⅲb non-small cell lung cancer were enrolled into this trial. Patients characteristics were the following: the median age was 52 years; the median performance status was 1; there were 19 stage Ⅲa and 40 stage Ⅲb; there were 47 adenocarcinoma, 10squamous cell carcinoma and 2 large cell carcinoma. All patients were treated with vindesine (2 mg/m2, on day 1and day 8), cyclophosphamide (0.6/m2, on day 1),epirubicin (40 mg/m2, on day 1) and cisplatin (60 mg/m2,on day 1) every 3 or 4 weeks. Results: Four achieved a complete response (6.8%), 29 achieved a partial response (49.2%), 15 had stable disease, and 10 had progressive disease. A clinical improvement was in 45 of 59 patients (76.3%). The most frequent major toxic effects were myelosuppression, nausea and vomiting.Conclusion: The vindesine with CAP regimen was active combination chemotherapy in patients with locally advanced NSCLC accompanied by the limited side effects.

  15. Phase II Trial of Radiotherapy After Hyperbaric Oxygenation With Multiagent Chemotherapy (Procarbazine, Nimustine, and Vincristine) for High-Grade Gliomas: Long-Term Results

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Kazuhiko, E-mail: kogawa@med.u-ryukyu.ac.jp [Department of Radiology, University of the Ryukyus, Okinawa (Japan); Ishiuchi, Shogo [Department of Neurosurgery, University of the Ryukyus, Okinawa (Japan); Inoue, Osamu [Department of Hyperbaric Medicine, University of the Ryukyus, Okinawa (Japan); Yoshii, Yoshihiko [Department of Neurosurgery, University of the Ryukyus, Okinawa (Japan); Department of Neurosurgery, Tsukuba Memorial Hospital, Tsukuba (Japan); Saito, Atsushi [Department of Neurosurgery, University of the Ryukyus, Okinawa (Japan); Department of Neurosurgery, Tsukuba Medical Center Hospital, Tsukuba (Japan); Watanabe, Takashi [Department of Neurosurgery, University of the Ryukyus, Okinawa (Japan); Iraha, Shiro [Department of Radiology, Okinawa South Medical Center, Okinawa (Japan); Department of Radiology, University of the Ryukyus, Okinawa (Japan); Toita, Takafumi; Kakinohana, Yasumasa; Ariga, Takuro; Kasuya, Goro; Murayama, Sadayuki [Department of Radiology, University of the Ryukyus, Okinawa (Japan)

    2012-02-01

    Purpose: To analyze the long-term results of a Phase II trial of radiotherapy given immediately after hyperbaric oxygenation (HBO) with multiagent chemotherapy in adults with high-grade gliomas. Methods and Materials: Patients with histologically confirmed high-grade gliomas were administered radiotherapy in daily 2 Gy fractions for 5 consecutive days per week up to a total dose of 60 Gy. Each fraction was administered immediately after HBO, with the time interval from completion of decompression to start of irradiation being less than 15 minutes. Chemotherapy consisting of procarbazine, nimustine, and vincristine and was administered during and after radiotherapy. Results: A total of 57 patients (39 patients with glioblastoma and 18 patients with Grade 3 gliomas) were enrolled from 2000 to 2006, and the median follow-up of 12 surviving patients was 62.0 months (range, 43.2-119.1 months). All 57 patients were able to complete a total radiotherapy dose of 60 Gy immediately after HBO with one course of concurrent chemotherapy. The median overall survival times in all 57 patients, 39 patients with glioblastoma and 18 patients with Grade 3 gliomas, were 20.2 months, 17.2 months, and 113.4 months, respectively. On multivariate analysis, histologic grade alone was a significant prognostic factor for overall survival (p < 0.001). During treatments, no patients had neutropenic fever or intracranial hemorrhage, and no serious nonhematologic or late toxicities were seen in any of the 57 patients. Conclusions: Radiotherapy delivered immediately after HBO with multiagent chemotherapy was safe, with virtually no late toxicities, and seemed to be effective in patients with high-grade gliomas.

  16. miR-133a enhances the sensitivity of Hep-2 cells and vincristine-resistant Hep-2v cells to cisplatin by downregulating ATP7B expression.

    Science.gov (United States)

    Wang, Xurui; Zhu, Wei; Zhao, Xiaodong; Wang, Ping

    2016-06-01

    The expression levels of the copper transporter P-type adenosine triphosphatase (ATP7B) are known correlate with tumor cell sensitivity to cisplatin. However, the mechanisms underlying cisplatin resistance remained poorly understood. Therefore, in the present study, we treated Hep-2 cells and in-house-developed vincristine-resistant Hep-2v cells with 50, 100, or 200 µM cisplatin and assessed cell viability after 24 or 48 h. Hep-2v cells were shown to be resistant to 50-200 µM cisplatin. Furthermore, using immunofluorescence staining and western blot analysis, we noted that ATP7B, but not copper-transporting ATPase 1 (ATP7A), expression was significantly increased in Hep-2v cells, and this increase was maintained at a higher level compared with Hep-2 cells. As ATP7B is a target of microRNA 133a (miR‑133a), the ability of miR‑133a to influence cisplatin sensitivity in Hep-2v cells was then assessed by CCK-8 assay. We noted that miR‑133a expression was lower in both Hep-2 and Hep-2v cells compared with epithelial NP69 cells. Following treatment with 50 µM cisplatin, in Hep-2v cells expressing exogenous miR‑133a we noted reduced ATP7B expression, and these cells had a significantly lower survival rate compared with the control. The present study demonstrates that miR‑133a enhances the sensitivity of multidrug-resistant Hep-2v cells to cisplatin by downregulating ATP7B expression.

  17. Chlorophyllin in the intra-uterine development of mice exposed or not to cyclophosphamide - doi: 10.4025/actascihealthsci.v35i2.12470

    Directory of Open Access Journals (Sweden)

    Vessia Silva Leite

    2013-06-01

    Full Text Available Chlorophyllin, a sodium-copper salt synthesized from chlorophyll, has already proved to have anticlastogenic, antimutagenic and anticarcinogenic activity, however few are the studies in the teratogenicity area. The present study evaluated the effects of chlorophyllin in intra-uterine development of mice exposed or not to cyclophosphamide. Pregnant females were divided into 8 groups of 15 animals each, G01 - PBS (0.1 mL 10.0-1 g orally; G02 – cyclophosphamide (20.0 mg kg-1 i.p.; G03, G04 and G05 - chlorophyllin at concentrations of (5.0, 10.0 and 15.0 mg kg-1 orally; G06, G07 and G08 (5.0, 10.0 and 15.0 mg kg-1 orally, of chlorophyllin, respectively, and (20.0 mg kg-1 i.p. of cyclophosphamide. In the 18th day the females were submitted to laparotomy and females and fetuses analyzed. The results showed that the chlorophyllin was not effective in protecting the reproductive parameters as well as teratogenicity. Finally, it was observed that the presence of chlorophyllin increased the frequency of some malformations when combined with cyclophosphamide. However, it was not teratogenic and not embryo lethal in this experimental design.

  18. Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy.

    Science.gov (United States)

    van der Most, Robbert G; Currie, Andrew J; Mahendran, Sathish; Prosser, Amy; Darabi, Anna; Robinson, Bruce W S; Nowak, Anna K; Lake, Richard A

    2009-08-01

    Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67(hi)) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67(hi) CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.

  19. Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats.

    Science.gov (United States)

    Kitamura, Yoshihisa; Kanemoto, Erika; Sugimoto, Misaki; Machida, Ayumi; Nakamura, Yuka; Naito, Nanami; Kanzaki, Hirotaka; Miyazaki, Ikuko; Asanuma, Masato; Sendo, Toshiaki

    2017-04-01

    In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in rats treated with a combination of doxorubicin and cyclophosphamide. Combined treatment with doxorubicin and cyclophosphamide produced cognitive impairment and anxiety-like behavior in rats. Nicotine treatment reversed the inhibition of novel location recognition induced by the combination treatment. This effect of nicotine was blocked by methyllycaconitine, a selective α7 nicotinic acetylcholine receptor (nAChR) antagonist, and dihydro-β-erythroidine, a selective α4β2 nAChR antagonist. In addition, nicotine normalized the amount of spontaneous alternation seen during the Y-maze task, which had been reduced by the combination treatment. This effect of nicotine was inhibited by dihydro-β-erythroidine. In comparison, nicotine did not affect the anxiety-like behavior induced by the combination treatment. Furthermore, the combination treatment reduced the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus, and this was also prevented by nicotine. Finally, the combination of doxorubicin and cyclophosphamide significantly reduced hippocampal α7 nAChR mRNA expression. These results suggest that nicotine inhibits doxorubicin and cyclophosphamide-induced cognitive impairment via α7 nAChR and α4β2 nAChR, and also enhances hippocampal neurogenesis.

  20. Quantitative and qualitative aspects of topoisomerase I and II alpha and beta in untreated and platinum/cyclophosphamide treated malignant ovarian tumors

    NARCIS (Netherlands)

    van der Zee, A G; de Jong, Steven; Keith, W N; Hollema, H; Boonstra, H; de Vries, Liesbeth

    1994-01-01

    Quantitative and qualitative aspects of topoisomerase (Topo) I and II were studied in 17 malignant ovarian tumors [eight untreated and nine after platinum/cyclophosphamide (Pt/Cy) chemotherapy]. Median Topo II catalytic activity was lower (P <0.05) in tumors after Pt/Cv chemotherapy in comparison to

  1. Long-term follow-up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis

    NARCIS (Netherlands)

    Arends, Suzanne; Grootscholten, Cecile; Derksen, Ronald H. W. M.; Berger, Stefan P.; de Sevaux, Ruud G. L.; Voskuyl, Alexandre E.; Bijl, Marc; Berden, Jo H. M.

    2012-01-01

    Objectives The objectives of this study are to analyse the long-term follow-up of a randomised controlled trial of induction treatment with azathioprine/methylprednisolone (AZA/MP) versus high-dose intravenous cyclophosphamide (ivCY) in patients with proliferative lupus nephritis (LN) and to evaluat

  2. Long-term follow-up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis.

    NARCIS (Netherlands)

    Arends, S.; Grootscholten, C.; Derksen, R.H.W.M.; Berger, S.P.; Sevaux, R.G.L. de; Voskuyl, A.E.; Bijl, M. van der; Berden, J.H.M.

    2012-01-01

    OBJECTIVES: The objectives of this study are to analyse the long-term follow-up of a randomised controlled trial of induction treatment with azathioprine/methylprednisolone (AZA/MP) versus high-dose intravenous cyclophosphamide (ivCY) in patients with proliferative lupus nephritis (LN) and to evalua

  3. [A case of possible retroperitoneal metastasis of breast cancer successfully treated with oral S-1 and cyclophosphamide therapy after TC therapy].

    Science.gov (United States)

    Yoneyama, Kimiyasu; Takeshita, Toshio; Suzuki, Hiroshi; Morise, Masaki; Suzuki, Tetsutarou; Kishi, Shinya; Tsutsui, Atsuko; Matsumoto, Akiko

    2011-03-01

    We report a case of possible retroperitoneal metastasis of breast cancer successfully treated with oral S-1 and cyclophosphamide therapy after docetaxel and cyclophosphamide (TC) therapy. A 57-year-old woman with a history of bilateral breast cancer showed an increase in tumor markers during treatment with oral anastrozole as postoperative adjuvant therapy 4 years after her second cancer surgery. After careful examination, the patient was diagnosed as having multiple bone metastases and her medication was changed to oral letrozole. After 3 months, the patient developed left back pain and was referred to our hospital. CT scanning showed an enhanced mass in the region from the left perirenal and posterior pararenal spaces to the left psoas major muscle and the anterior aspect of the left iliacus muscle, suggesting retroperitoneal metastasis. TC therapy was performed and, as a result, tumor markers decreased and the mass disappeared on CT imaging. After discontinuation of TC therapy, the tumor markers increased again, following which oral S-1 and cyclophosphamide therapy were administered, and the tumor markers decreased. At the time of this writing, the patient is still undergoing therapy, and no recurrence has been observed. We concluded that oral S-1 and cyclophosphamide therapy were useful in the present case and were associated with few adverse effects.

  4. Cyclophosphamide effect on paracoccidioidomycosis in the rat Efecto de la ciclofosfamida en ratas con paracoccidioidomicosis

    Directory of Open Access Journals (Sweden)

    J. L. Blejer

    1995-06-01

    Full Text Available Paracoccidioidomycosis is an endemic fungal disease widely distributed throughout Latin America. The potent immunosuppressor cyclophosphamide (CY has been used to modulate host immune response to Paracoccidioides brasiliensis in an experimental model. Inbred male Buffalo/Sim rats weighing 250-300 g were inoculated with 5 x 10(6 P. brasiliensis cells of the yeast phase form by intracardiac route. One group of animals was treated with 20 mg/kg body weight at days +4, +5, +6, +7, +11 and +12 post-infection (pi., while a control group was infected alone. No mortality was recorded in either group. Treated rats presented: a a decrease in granuloma size, which contained less fungal cells; b a lack of specific antibodies up to 35 days pi., and c a significant increase in the footpad swelling test (DTH against paracoccidioidin. Splenic cell transfer from CY-treated P. brasiliensis-infected donors to recipients infected alone led to a significant increase in DTH response in the latter versus untreated infected controls. Likewise, in treated infected recipients transferred with untreated infected donor spleen cells, footpad swelling proved greater than in controls. Thus, it would seem that each successive suppressor T lymphocyte subset belonging to the respective cascade may be sensitive to repeated CY doses administered up to 12 days pi.. Alternatively, such CY schedule may induce the appearance of a T cell population capable of amplifying DTH response.La paracoccidioidomicosis es una enfermedad endémica fúngica ampliamente distribuida en Latino-América. La ciclofosfamida ha sido usada como potente inmunosupresor para modular la respuesta inmune, en un modelo experimental infectado con Paracoccidioides brasiliensis. Ratas machos Buffalo/Sim endocriadas de 250-300 gr. de peso, fueron inoculadas por via intracardiaca con 5.10 6 células de P. brasiliensis en fase levaduriforme. Un grupo de animales fue tratado con 20 mg/kg de peso de ciclofosfamida en

  5. Comparing the interaction of cyclophosphamide monohydrate to human serum albumin as opposed to holo-transferrin by spectroscopic and molecular modeling methods: evidence for allocating the binding site.

    Science.gov (United States)

    Tousi, Shirin Hamed-Akbari; Saberi, Mohammad Reza; Chamani, Jamshidkhan

    2010-12-01

    The interaction between cyclophosphamide monohydrate with human serum albumin (HSA) and human serum transferrin (hTf) was studied with UV absorption, fluorescence and circular dichroism (CD) spectroscopies as well as molecular modeling. Based on the fluorescence quenching results, it was determined that HSA and hTf had two classes of apparent binding constants and binding sites at physiological conditions. The K(SV1), K(SV2), n(1) and n(2) values for HSA were found to be 8.6 x 10(8) Lmol(-1), 6.34 x 10(8) Lmol(-1), 0.7 and 0.8, respectively, and the corresponding results for hTf were 6.08 x 10(7) Lmol(-1), 4.65 x 10(7) Lmol(-1), 1.3 and 2.6, respectively. However, the binding affinity of cyclophosphamide monohydrate to HSA was more significant than to hTf. Circular dichroism results demonstrated that the binding of cyclophosphamide to HSA and hTf induced secondary changes in the structure and that the a-helix content became altered into b-sheet, turn and random coil forms. The participation of tyrosyl and tryptophan residues of proteins was also estimated in the drug-HSA and hTf complexes by synchronous fluorescence. The micro-environment of the HSA and hTf fluorophores was transferred to hydrophobic and hydrophilic conditions, respectively. The distance r between donor and acceptor was obtained by the Forster energy according to fluorescence resonance energy transfer (FRET) and found to be 1.84 nm and 1.73 nm for HSA and hTf, respectively. This confirmed the existence of static quenching for both proteins in the presence of cyclophosphamide monohydrate. Site marker competitive displacement experiments demonstrated that cyclophosphamide bound with high affinity to Site II, sub-domain IIIA of HSA, and for hTf, the C-lobe constituted the binding site. Furthermore, a study of molecular modeling showed that cyclophosphamide situated in domain II in HSA was bound through hydrogen bonding with Arg 257 and Ser 287, and that cyclophosphamide was situated in the C-lobe in h

  6. A proof-of-principle study of epigenetic therapy added to neoadjuvant doxorubicin cyclophosphamide for locally advanced breast cancer.

    Directory of Open Access Journals (Sweden)

    Claudia Arce

    Full Text Available Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy.This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655. After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day -7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate.16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1-2. Five (31% patients had clinical CR and eight (50% PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6% had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5mC content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively.Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the

  7. Modified conditioning regimen busulfan-cyclophosphamide followed by allogeneic stem cell transplantation in patients with multiple myeloma

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xiao-hui; LU Dao-pei; HUANG Xiao-jun; LIU Kai-yan; XU Lan-ping; LIU Dai-hong; CHEN Huan; CHEN Yu-hong; WANG Jing-zhi; HAN Wei

    2007-01-01

    Background Allogeneic stem cell transplantation is a potential curative approach in patients with multiple myeloma.The very high transplant related mortality associated with standard allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative treatment modality. The challenge for clinical investigators is to reduce the incidence of post-transplant complications for patients receiving autologous hematopoietic stem cell transplantion for multiple myeloma. In this study the toxicity and efficacy of modified myeloablative conditioning regimen followed by allogeneic stem cell transplantation was investigated in patients with multiple myeloma.Methods The conditioning regimen consisted of hydroxyurea, cytarabine, busulfan, cyclophosphamide, and semustine.Ten patients underwent allogeneic transplantation among them hydroxyurea (40 mg/kg) was administered twice on day -10 and cytarabine (2 g/m2) was given on day -9, busulfan was administered orally in four divided doses daily for 3 days (days -8 to -6). The dose of busulfan was 12 mg/kg in the protocol followed by cyclophosphamide intravenously over 1hour on days -5 and -4 (1.8 g/m2), and with semustine (Me-CCNU) 250 mg/m2 on day -3.Results Chimerism data were available on all patients and all patients achieved full donor chimerism without graft failure. Six patients had not acute graft-versus-host disease (GVHD, 36.4%; 95% CI:13.9%-38.6%). Two patients (18.2%) developed grade Ⅰ acute GVHD (95% CI:10.9%-35.9%) and grade Ⅱ acute GVHD occurred in one patient (9.1%;95% CI: 8.4%-32.3%). Severe grade Iva GVHD was seen in one patient, who died from acute GVHD. The incidence of chronic GVHD was 22.2% (95% CI: 11.7%-36.7%), among them one died of severe grade IV GVHD and one developed multiorgan failure on day +170; the treatment-related mortality was 22.0% (95% CI: 10.3%-34.1%). The overall 4-year survival rate was 67.8% (95% CI: 16.3%-46.7%). The estimated 4-year

  8. Optimization of preparation technology of Vincristine Sulfate Liposomes by orthogonal test%正交试验优化硫酸长春新碱脂质体的制备工艺

    Institute of Scientific and Technical Information of China (English)

    吴溪; 李文静; 杨志强; 王杏林; 张雪冰

    2015-01-01

    Objective To prepare stable Vincristine Sulfate Liposomes.Methods Single factor tests were used to investigate the effects of formulation and process factors, such as phospholipids and cholesterol radio, drug fat ratio, fat concentration, drug loading temperature, drug loading time, and pH value of water external phase on the encapsulation efficiency of Vincristine Sulfate Liposomes. Then, the optimal preparation technology of Vincristine Sulfate Liposomes with SPC-3 and DSPC as phospholipid material was optimized by orthogonal test to investigate influence of drug loading temperature, drug fat ratio, and drug loading time to the preparation technology, taking encapsulation efficiency as index.Results The best formulation and process of Vincristine Sulfate Liposomes was as following: vincristine sulfate solution and blank liposome solution was mixed by the ratio of 1:20, and then Na2HPO4 was used to regulate the pH value of liposome external phase to 7.2. SPC-3 liposomes uptook drugs at 65℃, and the drug loading time was 30 min. DSPC liposomes uptook drugs at 60℃, and the drug loading time was 10 min.Conclusion The optimized preparation technology of Vincristine Sulfate Liposomes is stable and feasible.%目的:制备性质稳定的硫酸长春新碱脂质体。方法采用单因素试验考察磷脂与胆固醇比例、药脂比、脂质浓度、载药温度、载药时间、外水相 pH 值对硫酸长春新碱脂质体包封率的影响。以包封率为指标,分别以氢化磷脂(SPC-3)和二硬脂酰磷脂酰胆碱(DSPC)为磷脂材料,通过正交试验考察载药温度、药脂比和载药时间对制备工艺的影响,优化出硫酸长春新碱脂质体的最佳制备工艺。结果硫酸长春新碱脂质体的最佳制备工艺为:将药物溶液(按照药物含量计)和空白脂质体溶液(按照脂质含量计)按照1∶20的比例混合,用Na2HPO4直接调节外水相pH值至7.2。SPC-3脂质体在65℃

  9. Comparison of the effectiveness and toxicity of neoadjuvant chemotherapy regimens, capecitabine/epirubicin/cyclophosphamide vs 5-fluorouracil/epirubicin/cyclophosphamide, followed by adjuvant, capecitabine/docetaxel vs docetaxel, in patients with operable breast cancer

    Science.gov (United States)

    Zhang, Minmin; Wei, Wei; Liu, Jianlun; Yang, Huawei; Jiang, Yi; Tang, Wei; Li, Qiuyun; Liao, Xiaoming

    2016-01-01

    The aim of this study was to compare the effectiveness and toxicity of neoadjuvant chemotherapy regimens, xeloda/epirubicin/cyclophosphamide (XEC) vs 5-fluorouracil/epirubicin/cyclophosphamide (FEC), followed by adjuvant chemotherapy regimens, capecitabine/taxotere (XT) vs taxotere (T), in axillary lymph node (LN)-positive early-stage breast cancer. In this randomized, Phase III trial, 137 patients with operable primary breast cancer (T2-0, N0-1) who were tested axillary LN positive through aspiration biopsy of axillary LNs were randomized (1:1) to four 3-weekly cycles of XEC or FEC. Patients underwent surgery within 4–6 weeks after the fourth cycle, followed by four adjuvant cycles of 3-weekly XT or T. The primary end point was tumor pathological complete response. Toxicity profiles were secondary objectives. In total, 131 patients had clinical and radiological evaluation of response and underwent surgery. Treatment with XEC led to an increased rate of pathological complete response in primary tumor (18% vs 6%, respectively, P=0.027) and objective remission rate (87% vs 73%, P=0.048) compared to FEC. Clinical complete response occurred in 20% and 7% for XEC and FEC, respectively. Compared to FEC, XEC was associated with more hand-foot syndrome (57% vs 11%, P<0.001) and 3/4 grade nausea/vomiting/diarrhea (30% vs 14%, P=0.034) but less phlebitis (3% vs 14%, P=0.035). XT and T adjuvant chemotherapy regimens were well tolerated: treatment-related 3/4 grade adverse events occurred in 28% and 17% of patients receiving XT and T, respectively. PMID:27354816

  10. A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer.

    Science.gov (United States)

    Chen, Gang; Gupta, Richa; Petrik, Silvia; Laiko, Marina; Leatherman, James M; Asquith, Justin M; Daphtary, Maithili M; Garrett-Mayer, Elizabeth; Davidson, Nancy E; Hirt, Kellie; Berg, Maureen; Uram, Jennifer N; Dauses, Tianna; Fetting, John; Duus, Elizabeth M; Atay-Rosenthal, Saadet; Ye, Xiaobu; Wolff, Antonio C; Stearns, Vered; Jaffee, Elizabeth M; Emens, Leisha A

    2014-10-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines are bioactive, but limited by disease burden and immune tolerance. Cyclophosphamide augments vaccine activity in tolerant neu mice and in patients with metastatic breast cancer. HER2-specific monoclonal antibodies (mAb) enhance vaccine activity in neu mice. We hypothesized that cyclophosphamide-modulated vaccination with HER2-specific mAb safely induces relevant HER2-specific immunity in neu mice and patients with HER2+ metastatic breast cancer. Adding both cyclophosphamide and the HER2-specific mAb 7.16.4 to vaccination maximized HER2-specific CD8+ T-cell immunity and tumor-free survival in neu transgenic mice. We, therefore, conducted a single-arm feasibility study of cyclophosphamide, an allogeneic HER2+ GM-CSF-secreting breast tumor vaccine, and weekly trastuzumab in 20 patients with HER2+ metastatic breast cancer. Primary clinical trial objectives were safety and clinical benefit, in which clinical benefit represents complete response + partial response + stable disease. Secondary study objectives were to assess HER2-specific T-cell responses by delayed type hypersensitivity (DTH) and intracellular cytokine staining. Patients received three monthly vaccinations, with a boost 6 to 8 months from trial entry. This combination immunotherapy was safe, with clinical benefit rates at 6 months and 1 year of 55% [95% confidence interval (CI), 32%-77%; P = 0.013] and 40% (95% CI, 19%-64%), respectively. Median progression-free survival and overall survival durations were 7 months (95% CI, 4-16) and 42 months (95% CI, 22-70), respectively. Increased HER2-specific DTH developed in 7 of 20 patients [of whom 4 had clinical benefit (95% CI, 18-90)], with a trend toward longer progression-free survival and overall survival in DTH responders. Polyfunctional HER2-specific CD8+ T cells progressively expanded across vaccination cycles. Further investigation of cyclophosphamide-modulated vaccination

  11. Treatment of advanced breast cancer with cyclophosphamide, 5-fluorouracil, and prednisone with and without methanol-extracted residue of BCG.

    Science.gov (United States)

    Britell, J C; Ahmann, D L; Bisel, H F; Frytak, S; Ingle, J N; Rubin, J; O'Fallon, J R

    1979-01-01

    The value of immunotherapy as an adjuvant to chemotherapy for advanced breast cancer is an unsettled question. To clarify this issue, 71 women with measurable or evaluable metastatic breast cancer were randomized to receive cyclophosphamide, 5-fluorouracil, and prednisone (CFP) with or without methanol-extracted residue of Bacillus Calmette-Guerin (MER). The total regression rates were 52% (CFP) and 39% (CFP + MER), including complete regression rates of 13% (CFP) and 65% (CFP + MER). The median duration of regressions for CFP-treated patients was 257-261 days and for CFP + MER-treated patients was 385 days. The median time to progression was 248-261 days in the CFP group and 159 days in the CFP-MER group. Projected median survival for both treatment groups is 20 months. Immunotherapy (MER) as used in this study does not appear to augment regression rates or vurvival for patients with advanced breast cancer receiving CFP.

  12. [Successful treatment of B-cell prolymphocytic leukemia (B-PLL) with FCR-Lite (fludarabine, cyclophosphamide, rituximab) protocol].

    Science.gov (United States)

    Telek, Béla; Batár, Péter; Rejto, László; Udvardy, Miklós

    2010-08-01

    B-cell prolymphocytic leukemia (B-PLL) is a rare disorder characterized by marked lymphocytosis in the peripheral blood, matured lymphocytic infiltration in the bone marrow and splenomegaly. It has a distinct immunophenotype (CD19, CD20, CD22, FMC7, intensive surface immunoglobulin positivity) which helps to differentiate from other lymphoproliferative malignancies. It has a poor prognosis and its treatment is unsettled. The authors present a case of a patient with typical B-PLL treated with FCR-Lite (fludarabine, cyclophosphamide, rituximab) protocol achieving complete hematological (and immunophenotypic) remission. The treatment was well tolerated. Neither major infective complication nor tumor lysis syndrome was observed. According to the author's experience the FCR-Lite protocol can not only be used in patients with CLL but it also can be effective in patients with B-PLL. No clinical experience has been reported yet in the literature with this protocol.

  13. Mechanism on activation of mouse liver microsomal glutathione S—transferase—I by cyclophosphamide treatment in vivo

    Institute of Scientific and Technical Information of China (English)

    ZhenY; LouYJ

    2002-01-01

    Membrane-associated microsomal glutathione S-transferase-I (mGST-I) is activated easily by alkyl agent or electrophilic metabolite.It was expected that toxic drugs and their metabolites derived from biotransformation by cytochrome P-450 maybe bind to and activate the mGST-I that can accelerate the metabolism of drugs to form inactive metabolites and simultaneously protect cell from damages.The aim of the present study was to investigate whether mGST-I is activated by cyclophosphamide(CP) treatment and to explore the possible mechanism in vivo.The results suggested that the main mechanism of mGST-I activation caused by overdose CP treatment is the unique sulfhydryl modification on its Cys-49.

  14. mRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma

    DEFF Research Database (Denmark)

    Borch, Troels Holz; Engell-Noerregaard, Lotte; Zeeberg Iversen, Trine;

    2016-01-01

    INTRODUCTION: Vaccination with dendritic cells (DCs) has generally not fulfilled its promise in cancer immunotherapy due to ineffective translation of immune responses into clinical responses. A proposed reason for this is intrinsic immune regulatory mechanisms, such as regulatory T cells (Tregs......). A metronomic regimen of cyclophosphamide (mCy) has been shown to selectively deplete Tregs. To test this in a clinical setting, we conducted a phase I trial to evaluate the feasibility and safety of vaccination with DCs transfected with mRNA in combination with mCy in patients with metastatic malignant......th vaccines. Immune monitoring consisted of IFNγ ELISpot assay, proliferation assay, and flow cytometry for enumeration of immune cell subsets. RESULTS: Toxicity was manageable. Eighteen patients were evaluable after six cycles. Of these, nine patients had progressive disease as best response...

  15. Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony-stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Strati, Paolo; Ferrajoli, Alessandra; Lerner, Susan; O'Brien, Susan; Wierda, William; Keating, Michael J; Faderl, Stefan

    2014-04-01

    Fludarabine, cyclophosphamide and rituximab (FCR), the standard of care for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), is associated with a high rate of neutropenia and infectious complications. Granulocyte macrophage colony-stimulating factor (GM-CSF) reduces myelosuppression and can potentiate rituximab activity. We conducted a clinical trial combining GM-CSF with FCR for frontline treatment of 60 patients with CLL. Eighty-six percent completed all six courses and 18% discontinued GM-CSF for toxicity: grade 3-4 neutropenia was observed in 30% of cycles, and severe infections in 16% of cases. The overall response rate was 100%. Both median event-free survival (EFS) and overall survival (OS) have not been reached. Longer EFS was associated with favorable cytogenetics. GM-CSF led to a lower frequency of infectious complications than in the historical FCR group, albeit similar EFS and OS.

  16. Recrudescence induced by cyclophosphamide of chronic Trypanosoma cruzi infection in mice is influenced by the parasite strain

    Directory of Open Access Journals (Sweden)

    Maria Elizabeth S Pereira

    1996-02-01

    Full Text Available Reactivation of chronic chagasic patients may occur upon use of immunosuppressive drugs related to kidney or heart transplantation or when they are affected by concomitant HIV infection. This recrudescence, however, does not occur in all chagasic patients exposed to immunosuppressive agents. We therefore investigated the influence of Trypanosoma cruzi strains in the recrudescence of the parasitism in mice at the chronic phase treated with cyclophosphamide, an immunosuppressor that blocks lymphocytes DNA synthesis and therefore controls B cells response. A large variation was detected in the percentages of newly established acute phases in the groups of mice inoculated with the different strains. We suggest that reactivation of chronic T. cruzi infections is influenced by the parasite intrinsic characteristics, a phenomenon that might occur in the human disease.

  17. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL

    DEFF Research Database (Denmark)

    Geisler, Christian H; van T' Veer, Mars B; Jurlander, Jesper

    2014-01-01

    heavy chain genes, deletion 17p or 11q, or trisomy 12. Fit patients were randomized to receive either 6 28-day cycles of oral FC chemotherapy (days 1 through 3: fludarabine 40 mg/m(2) per day and cyclophosphamide 250 mg/m(2) per day: n = 139) or FC plus subcutaneous alemtuzumab 30 mg day 1 (FCA, n = 133......). FCA prolonged the primary end point, progression-free survival (3-year progression-free survival 53 vs 37%, P = .01), but not the secondary end point, overall survival (OS). However, a post hoc analysis showed that FCA increased OS in patients younger than 65 years (3-year OS 85% vs 76%, P = .035...

  18. Effect of the molecular mass of tremella polysaccharides on accelerated recovery from cyclophosphamide-induced leucopenia in rats.

    Science.gov (United States)

    Jiang, Rui-Zhi; Wang, Ying; Luo, Hao-Ming; Cheng, Yan-Qiu; Chen, Ying-Hong; Gao, Yang; Gao, Qi-Pin

    2012-03-23

    The body of tremella were decocted with water, and hydrolyzed with 0.1 mol/L hydrochloric acid for different times, giving tremella polysaccharides with six molecular mass values. The structures of all the tremella polysaccharides had non-reducing terminals of β-D-pyranglucuronide, the backbone was composed of (1 → 3)-linked β-D-manno-pyranoside, and the side chain composed of (1 → 6)-linked β-D-xylopyranoside was attached to the C(2) of the backbone mannopyranoside. Immunomodulatory effect studies indicated that tremella polysaccharides increased the counts of leukocytes in the peripheral blood which were significantly lowered by cyclophosphamide, and the lower the molecular mass of the tremella polysaccharide, the better this effect was.

  19. Effect of the Molecular Mass of Tremella Polysaccharides on Accelerated Recovery from Cyclophosphamide-Induced Leucopenia in Rats

    Directory of Open Access Journals (Sweden)

    Qi-Pin Gao

    2012-03-01

    Full Text Available The body of tremella were decocted with water, and hydrolyzed with 0.1 mol/L hydrochloric acid for different times, giving tremella polysaccharides with six molecular mass values. The structures of all the tremella polysaccharides had non-reducing terminals of β-D-pyranglucuronide, the backbone was composed of (1→3-linked β-D-manno-pyranoside, and the side chain composed of (1→6-linked β-D-xylopyranoside was attached to the C2 of the backbone mannopyranoside. Immunomodulatory effect studies indicated that tremella polysaccharides increased the counts of leukocytes in the peripheral blood which were significantly lowered by cyclophosphamide, and the lower the molecular mass of the tremella polysaccharide, the better this effect was.

  20. Cyclophosphamide-induced cystitis increases bladder CXCR4 expression and CXCR4-macrophage migration inhibitory factor association.

    Directory of Open Access Journals (Sweden)

    Pedro L Vera

    Full Text Available BACKGROUND: Macrophage migration inhibitory factor (MIF is a pro-inflammatory cytokine involved in cystitis and a non-cognate ligand of the chemokine receptor CXCR4 in vitro. We studied whether CXCR4-MIF associations occur in rat bladder and the effect of experimental cystitis. METHODS AND FINDINGS: Twenty male rats received saline or cyclophosphamide (40 mg/kg; i.p.; every 3(rd day to induce persistent cystitis. After eight days, urine was collected and bladders excised under anesthesia. Bladder CXCR4 and CXCR4-MIF co-localization were examined with immunhistochemistry. ELISA determined MIF and stromal derived factor-1 (SDF-1; cognate ligand for CXCR4 levels. Bladder CXCR4 expression (real-time RTC-PCR and protein levels (Western blotting were examined. Co-immunoprecipitations studied MIF-CXCR4 associations.Urothelial basal and intermediate (but not superficial cells in saline-treated rats contained CXCR4, co-localized with MIF. Cyclophosphamide treatment caused: 1 significant redistribution of CXCR4 immunostaining to all urothelial layers (especially apical surface of superficial cells and increased bladder CXCR4 expression; 2 increased urine MIF with decreased bladder MIF; 3 increased bladder SDF-1; 4 increased CXCR4-MIF associations. CONCLUSIONS: These data demonstrate CXCR4-MIF associations occur in vivo in rat bladder and increase in experimental cystitis. Thus, CXCR4 represents an alternative pathway for MIF-mediated signal transduction during bladder inflammation. In the bladder, MIF may compete with SDF-1 (cognate ligand to activate signal transduction mediated by CXCR4.

  1. Occupational exposures among nurses caring for chemotherapy patients -Quantitative analysis of cyclophosphamide and α-fluoro-β-alanine in urine.

    Science.gov (United States)

    Sasaki, Makiko; Ishii, Noriko; Kikuchi, Yukiko; Kudoh, Yukiko; Sugiyama, Reiko; Hasebe, Makiko

    2016-10-07

    The aim of this study was to measure the antineoplastic drug content in urine and verify the situation of occupational exposure of the antineoplastic drug among nurses who care for patients undergoing chemotherapy. Ten female nurses who were caring for patients receiving chemotherapy were the subjects of this study. Urine samples were collected over 24-hour periods, and each sample was analyzed. The excretion of cyclophosphamide (CP) and α-fluoro-β-alanine (FBAL) were measured in the urine of the 10 nurses. CP and FBAL were detected separately using gas chromatography tandem mass spectrometry (GC-MSMS) methods (Exposure Control, the Netherlands). CP was detected in 24 urine samples of 9 nurses. The total amount of CP excreted ranged from 5.4 to 44.2 ng/24-hours. The mean amount of CP excreted per nurse was 16.8 ng/24-hours. No significant difference was observed between the hospital I and II. FBAL was not detected in any of the urine samples. CP was detected in the urine of the nurses prior to their work shift. Moreover, CP was detected in the urine of the nurses who were not caring for patients in the intravenous drip of CP. There was most what answered that there was hair loss in health condition. The results reveal that almost all nurses were exposed to cyclophosphamide. Even when the patient in the intravenous drip of CP was not being cared for, it became clear that exposure by CP existed. As the route of the exposure to CP, the inhalation or dermal absorption can be considered. To ensure minimum exposed to antineoplastic drugs, suitable personal protective equipment needs to be equipped also of various scenes of caring for chemotherapy patients. Moreover, it is important to keep an eye on the monitoring of the antineoplastic drug in the environment and a nurse's health condition periodically going forward.

  2. Immunosuppression in sheep induced by cyclophosphamide, bluetongue virus and their combination: Effect on clinical reaction and viremia.

    Science.gov (United States)

    Chatzinasiou, Evangelia; Chaintoutis, Serafeim C; Dovas, Chrysostomos I; Papanastassopoulou, Maria; Papadopoulos, Orestis

    2017-03-01

    The main purpose of this work was to establish an experimental model for immunosuppression in sheep, and evaluate its possible effects on bluetongue viremia. Animals were allocated in 4 groups: Cy (cyclophosphamide), BT (bluetongue), CyBT (combined Cy and BT) and Co (control), and underwent clinical evaluations, virological testing, peripheral blood immunophenotyping and determination of antiviral humoral immune responses. Intravenous administration of cyclophosphamide (37.5 mg/kg body weight) resulted in immunosuppresion induction, as significant drops were observed in blood leukocytes and lymphocyte subset counts (CD2(+), CD4(+), CD8(+), CD19(+)), lasting 3-10 days after its administration. Reduction in B-cell (CD19(+)) counts was more pronounced than in T-/NK-cell (CD2(+)) counts (92% and 59%, respectively). BTV-9 inoculation resulted in pronounced lymphocytopenia observed from day 1 post-inoculation. Their combined administration resulted in a more intense immunosuppressive effect, as indicated by the greater reduction in lymphocyte, granulocyte, CD4(+) and CD8(+) cell counts. In group CyBT, earlier initiation of fever by one day (day 6 p.i.) compared to group BT (day 7 p.i.), and delay in antibody responses by one day was observed, compared to group BT. Neutralizing antibodies in both groups (BT, CyBT) were detectable from day 10 p.i., but no significant titer differences were observed. Infectious virus titers were detected from day 4 p.i. in group BT and from day 3 in group CyBT. Statistical significances in virus titers were also observed (greatest mean titer difference: 1.4 log10 CEID50/ml RBCs at day 5 p.i., P bluetongue. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Improved survival in young children with acute granulocytic leukemia treated with combination therapy using cyclophosphamide, oncovin, cytosine arabinoside, and prednisone.

    Science.gov (United States)

    Madanat, F F; Sullivan, M P

    1979-09-01

    Seven of 17 children (41%) under 5 years of age with acute granulocytic leukemia (AGL) treated with either cytosine arabinoside-cytoxan (CA-CYT) or Mini-COAP (CA-CYT with vincristine sulfate [VCR] and prednisone) have been in continuous complete remission 4 years or more. CA and CYT were each given in the dosage of 120 mg/m2 intravenously, daily in 3 divided doses, for 4 days. Induction consisted of two courses given at intervals of 2 weeks; during maintenance the courses were repeated at intervals of 4 weeks. In the Mini-COAP regimen, standard 28-day VCR-prednisone therapy was superimposed on CA-CYT induction and 4-day VCR-prednisone pulses were superimposed on CA-CYT maintenance. Transient moderate to severe myelosuppression was frequent; other manifestations of toxicity were mild. Administration of drugs at home was feasible in many instances. Mini-COAP was proved to be an effective therapeutic regimen for young children with AGL and should be considered as initial therapy.

  4. The JAK2 inhibitors CEP-33779 and NVP-BSK805 have high P-gp inhibitory activity and sensitize drug-resistant cancer cells to vincristine.

    Science.gov (United States)

    Cheon, Ji Hyun; Kim, Kyeong Seok; Yadav, Dharmendra Kumar; Kim, Mihyun; Kim, Hyung Sik; Yoon, Sungpil

    2017-09-02

    P-glycoprotein (P-gp) is overexpressed in cancer cells in order to pump out chemotherapeutic drugs, and is one of the major mechanisms responsible for multidrug resistance (MDR). It is important to identify P-gp inhibitors with low toxicity to normal cells in order to increase the efficacy of anti-cancer drugs. Previously, a JAK2 inhibitor CEP-33779 demonstrated inhibitory actions against P-gp and an ability to sensitize drug-resistant cancer cells to treatment. In the present study, we tested another JAK2 inhibitor NVP-BSK805 for P-gp inhibitory activity. In molecular docking simulation modeling, NVP-BSK805 showed higher binding affinity docking scores against a P-gp member (ABCB1) than CEP-33779 did. Furthermore, we found that lower doses of NVP-BSK805 are required to inhibit P-gp in comparison with that of CEP-33779 or verapamil (an established P-gp inhibitor) in KBV20C cells, suggesting that NVP-BSK805 has higher specificity. NVP-BSK805, CEP-33779, and verapamil demonstrated similar abilities to sensitize KBV20C cells to vincristine (VIC) treatment. Our results suggested that the JAK2 inhibitors were able to inhibit P-gp pump-action via a direct binding mechanism, similar to verapamil. However, JAK2 inhibitor-induced sensitization was not observed in VIC-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. FACS, western-blot, and annexin V analyses were used to further investigate the mechanism of action of JAK2 inhibitors in VIC-treated KBV20C cells. Both CEP-33779 and NVP-BSK805 induced the sensitization of KBV20C cells to VIC treatment via the same mechanisms; they each caused a reduction in cell viability, increased G2 arrest, and upregulated expression of the DNA damaging protein pH2AX when used as co-treatments with VIC. These findings indicate that inhibition of JAK2 may be a promising target in the treatment of cancers that are resistant to anti-mitotic drugs. Copyright © 2017 Elsevier Inc. All rights

  5. Pneumonitis and pulmonary fibrosis in a patient receiving adjuvant docetaxel and cyclophosphamide for stage 3 breast cancer: a case report and literature review

    Directory of Open Access Journals (Sweden)

    Ochoa Roberto

    2012-11-01

    Full Text Available Abstract Introduction Pulmonary toxicities associated with chemotherapeutic agents utilized as adjuvant therapy in patients with breast cancer are distinctly uncommon. The chemotherapy regimen of docetaxel/cyclophosphamide has a more favorable therapeutic index compared to anthracycline-based regimens due to a significantly lower incidence of heart failure and leukemia. Consequently, docetaxel/cyclophosphamide is the preferred adjuvant chemotherapy of choice in older women or in women where anthracyclines may be contraindicated. Pulmonary complications in patients with breast cancer receiving taxane-based adjuvant chemotherapy in the absence of radiation are distinctly uncommon. Here, we report the case of a patient receiving adjuvant docetaxel/cyclophosphamide who developed rapid-onset, biopsy-proven interstitial pneumonitis. Case presentation A 72-year-old Hispanic woman was diagnosed as having stage 3 hormone-receptor positive, human epidermal growth factor receptor 2/neu negative, invasive breast cancer. Due to the estimated 10-year risk of recurrence of approximately 80 percent, a decision was made to treat our patient with adjuvant chemotherapy. Due to her age and increased risk of cardiac toxicity with anthracycline-based chemotherapy regimens, our patient was treated with docetaxel/cyclophosphamide chemotherapy for a total of four planned cycles. However, approximately two weeks after receiving the third cycle of chemotherapy, our patient developed rapidly progressive dyspnea, and a non-productive cough and went to the emergency room at an outside medical facility. She was found to have mild hypoxemia, and new onset of peripheral, subpleural fibrotic changes not present on pre-treatment scans. A thorascopic-guided wedge biopsy of the lung tissue revealed subacute interstitial pneumonitis. Our patient made a rapid clinical recovery after treatment with corticosteroids. Conclusions Interstitial pneumonitis is a rare complication of

  6. Comparison of the effectiveness and toxicity of neoadjuvant chemotherapy regimens, capecitabine/epirubicin/cyclophosphamide vs 5-fluorouracil/epirubicin/cyclophosphamide, followed by adjuvant, capecitabine/docetaxel vs docetaxel, in patients with operable breast cancer

    Directory of Open Access Journals (Sweden)

    Zhang MM

    2016-06-01

    Full Text Available Minmin Zhang,* Wei Wei,* Jianlun Liu, Huawei Yang, Yi Jiang, Wei Tang, Qiuyun Li, Xiaoming Liao Department of Breast Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China *These authors contributed equally to this work Abstract: The aim of this study was to compare the effectiveness and toxicity of neoadjuvant chemotherapy regimens, xeloda/epirubicin/cyclophosphamide (XEC vs 5-fluorouracil/epirubicin/cyclophosphamide (FEC, followed by adjuvant chemotherapy regimens, capecitabine/taxotere (XT vs taxotere (T, in axillary lymph node (LN-positive early-stage breast cancer. In this randomized, Phase III trial, 137 patients with operable primary breast cancer (T2-0, N0-1 who were tested axillary LN positive through aspiration biopsy of axillary LNs were randomized (1:1 to four 3-weekly cycles of XEC or FEC. Patients underwent surgery within 4–6 weeks after the fourth cycle, followed by four adjuvant cycles of 3-weekly XT or T. The primary end point was tumor pathological complete response. Toxicity profiles were secondary objectives. In total, 131 patients had clinical and radiological evaluation of response and underwent surgery. Treatment with XEC led to an increased rate of pathological complete response in primary tumor (18% vs 6%, respectively, P=0.027 and objective remission rate (87% vs 73%, P=0.048 compared to FEC. Clinical complete response occurred in 20% and 7% for XEC and FEC, respectively. Compared to FEC, XEC was associated with more hand-foot syndrome (57% vs 11%, P<0.001 and 3/4 grade nausea/vomiting/diarrhea (30% vs 14%, P=0.034 but less phlebitis (3% vs 14%, P=0.035. XT and T adjuvant chemotherapy regimens were well tolerated: treatment-related 3/4 grade adverse events occurred in 28% and 17% of patients receiving XT and T, respectively. Keywords: breast cancer, capecitabine, docetaxel, neoadjuvant chemotherapy, curative effect, toxic side effects

  7. Cyclophosphamide-refractory scleroderma-associated interstitial lung disease: remarkable clinical and radiological response to a single course of rituximab combined with high-dose corticosteroids.

    LENUS (Irish Health Repository)

    Haroon, Muhammad

    2011-10-01

    We would like to report our experience of using rituximab in cyclophosphamide refractory, rapidly progressive interstitial lung disease (ILD) in a patient with limited scleroderma. A 40-year-old man presented with 10-week history of inflammatory polyarthritis, which responded to a short course of oral corticosteroids. However, 3 weeks later, he developed new onset of exertional dyspnoea. High-resolution CT of the thorax was suggestive of early ILD. Surgical lung biopsy showed features of fibrotic non-specific interstitial pneumonia. He was diagnosed with scleroderma on the basis of: presence of anticentromere antibodies, Raynaud\\'s phenomenon, pulmonary fibrosis, digital oedema and hypomotility along with a dilated oesophagus. He was treated aggressively with pulse doses of corticosteroids and cyclophosphamide; however, his ILD continued to deteriorate. At this stage, he received rituximab (two pulses of 1 g each), which led to a gradual clinical improvement. Now, 12 months since his rituximab infusion, he walks 2 miles daily without any exertional dyspnoea.

  8. Successful Use of Cyclophosphamide as an Add-On Therapy for Multiple Myeloma Patients with Acquired Resistance to Bortezomib or Lenalidomide

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    Shigeki Ito

    2013-01-01

    Full Text Available Novel agents such as thalidomide, lenalidomide, and bortezomib have been shown to possess potent activity against multiple myeloma. However, the treatment strategy for patients who acquired resistance to these agents has not been established. In addition to switching drug classes, intensified treatment strategy, including increase in the dosage of current agents and addition of other agents, may be considered for these patients. We here describe 2 myeloma patients with acquired resistance to bortezomib or lenalidomide, in whom add-on therapy with low-dose cyclophosphamide was effective and tolerable. These cases suggest that add-on therapy with cyclophosphamide is one of the treatment options to overcome resistance to novel agents in patients with multiple myeloma. A larger prospective study is needed to clarify the efficacy and safety of this strategy for novel agent-resistant multiple myeloma.

  9. Baseline proteinuria, urinary osmotic pressure, and renal function as positive predictors of corticosteroids plus cyclophosphamide treatment efficacy in IgA nephropathy

    Institute of Scientific and Technical Information of China (English)

    Fang Jing; Li Wenge; Li Duo; Tan Zhao

    2014-01-01

    Background Very limited data are available on factors predictive of corticosteroids plus cyclophosphamide treatment efficacy on IgA nephropathy (IgAN).The aim of the study was to research the clinical factors predictive of treatment efficacy in IgAN.Methods One hundred and fifty-nine patients with IgAN (proteinuria ≥2 g/d and estimated glomerular filtration rate 30-89 ml·min-1·1.73 m-2) were treated with corticosteroids/cyclophosphamide followed by a 12-month follow-up.According to their response,these patients were divided into remission group (proteinuria <0.5 g/d) and non-remission group (proteinuria ≥0.5 g/d),and their clinical data collected.Results In the present study,72.96% of the individuals underwent a complete remission,and their response was related to baseline proteinuria,urinary osmotic pressure,and renal function (P <0.05).Patients with baseline proteinuria more than 3 g/d,urinary osmotic pressure greater than 600 mOsm/L,and eGFR 60-89 ml·min-1·1.73 m-2 responded well to the combination of corticosteroids and cyclophosphamide (86.90% vs.57.33%,P=0.000; 81.48% vs.64.10%,P=0.014; 83.17% vs.55.17%,P=0.000).Conclusion The response to the combination of corticosteroids and cyclophosphamide might be well associated with baseline proteinuria,urinary osmotic pressure,and renal function in patients with IgAN.

  10. Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

    Science.gov (United States)

    Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

    2017-03-01

    Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571.

  11. The influence of glutathion S-transferase P-1 polymorphism A313G rs1695 on the susceptibility to cyclophosphamide hematologic toxicity in Indonesian patients

    Directory of Open Access Journals (Sweden)

    Dita Hasni

    2016-07-01

    Full Text Available Background: Chemotherapy often causes side effects such as hematologic toxicity. The degree of toxicity is often associated with genetic polymorphism. This study aims to determine the influence of GSTP1 A313G polymorphism, an enzyme responsible for detoxifying cyclophosphamid, on incidence and severity of cyclophosphamid hematologic toxicity.Methods: 91 Indonesian females diagnosed with breast cancer at Haji Adam Malik Central General Hospital, Medan, receiving cyclophosphamide, doxorubicin/epirubicin and 5-FU were included in this retrospective cohort study. DNA was extracted from peripheral leukocytes and GSTP1 A313G genotyping was analyzed using polymerase chain reaction-restriction length fragment polymorphism (PCR-RFLP. Genotype deviation and allele frequencies were also determined by Hardy-Weinberg Equilibrium. The degrees of hematologic toxicity (leucopenia and neutropenia data after chemotherapy cycles 1 and 3 were collected from the patient medical records. The data were analyzed using chi-square test.Results: 60.4% of the patients had the wildtype (A/A, while 29.7% were heterozygous (A/G, and 9.9% were homozygous mutant (G/G. There was no significant deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium. The G allele (A/G & G/G contributes to more severe degree of leukopenia compared to patients with wild type allele (A/A  (p<0.05 after the 3rd chemotherapy cycles.Conclusion: There was association between GSTP1 polymorphism with the degree of hematologic toxicity in breast cancer patients receiving cyclophosphamide chemotherapy regimen.

  12. A strategy of tumor treatment in mice with doxorubicin-cyclophosphamide combination based on dendritic cell activation by human double-stranded DNA preparation

    OpenAIRE

    Alyamkina, Ekaterina A; Nikolin, Valeriy P; Popova, Nelly A.; Dolgova, Evgenia V; Proskurina, Anastasia S; Orishchenko, Konstantin E.; Efremov, Yaroslav R.; Chernykh, Elena R.; Ostanin, Alexandr A.; Sidorov, Sergey V; Ponomarenko, Dmitriy M.; Zagrebelniy, Stanislav N; Bogachev, Sergey S.; Shurdov, Mikhail A

    2010-01-01

    Background Immunization of mice with tumor homogenate after combined treatment with cyclophosphamide (CP) and double-stranded DNA (dsDNA) preparation is effective at inhibition of growth of tumor challenged after the treatment. It was assumed that this inhibition might be due to activation of the antigen-presenting cells. The purpose was to develop improved antitumor strategy using mice. We studied the combined action of cytostatics doxorubicin (Dox) plus CP with subsequent dsDNA preparation ...

  13. Protective effects of a by-product of the pecan nut industry (Carya illinoensis) on the toxicity induced by cyclophosphamide in rats Carya illinoensis protects against cyclophosphamide-induced toxicity.

    Science.gov (United States)

    Benvegnú, D; Barcelos, R C S; Boufleur, N; Reckziegel, P; Pase, C S; Müller, L G; Martins, N M B; Vareli, C; Bürger, M E

    2010-01-01

    This study investigated the antioxidant effects of pecan nut (Carya illinoensis) shell aqueous extract (AE) on toxicity induced by cyclophosphamide (CP) in the heart, kidney, liver, bladder, plasma and erythrocytes of rats. Rats were treated with water or pecan shell AE (5%) ad libitum, replacing drinking water for 37 days up to the end of the experiment. On day 30, half of each group received a single administration of vehicle or CP 200 mg/kg-ip. After 7 days, the organs were removed. Rats treated with CP showed an increase in lipid peroxidation (LP) and decrease in reduced glutathione (GSH) levels in all structures. Catalase (CAT) activity was increased in the heart and decreased in liver and kidney. Besides, CP treatment decreased plasmatic vitamin C (VIT C) levels and induced bladder macroscopical and microscopical damages. In contrast, co-treatment with pecan shell AE prevented the LP development and the GSH depletion in all structures, except in the heart and plasma, respectively. CAT activity in the heart and liver as well as the plasmatic VIT C levels remained unchanged. Finally, AE prevented CP-induced bladder injury. These findings revealed the protective role of pecan shell AE in CP-induced multiple organ toxicity.

  14. Quantitative texture-based assessment of one-year changes in fibrotic reticular patterns on HRCT in scleroderma lung disease treated with oral cyclophosphamide

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyun J.; Brown, Matthew S. [David Geffen School of Medicine, UCLA, Center for Computer Vision and Imaging Biomarker, Department of Radiological Sciences, Los Angeles, CA (United States); Elashoff, Robert [David Geffen School of Medicine, UCLA, Department of Biostatistics and Biomathematics, Los Angeles, CA (United States); Li, Gang [School of Public Health, UCLA, Department of Biostatistics, Los Angeles, CA (United States); Gjertson, David W. [School of Public Health and David Geffen School of