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Sample records for vincristine actinomycin-d cyclophosphamide

  1. ACTINOMYCIN D ANALOGUES

    DEFF Research Database (Denmark)

    1997-01-01

    The present invention relates to new compounds being structurally and functionally similar to Actinomycin D and to combinatorial libraries of such compounds. The Actinomycin D analogues according to the present invention comprise two linear or cyclic peptide moieties constituted by $g...

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

    Science.gov (United States)

    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.

  3. Inpatient versus outpatient vincristine, dactinomycin, and cyclophosphamide for pediatric cancers: Quality and cost implications.

    Science.gov (United States)

    Beaty, Rachel S; Bernhardt, M Brooke; Berger, Amanda H; Hesselgrave, Joy E; Russell, Heidi V; Okcu, M Fatih

    2015-11-01

    Approximately 18% of the United States' gross domestic product is attributed to healthcare expenditures. Several studies have illustrated that shifting healthcare from the inpatient to the outpatient setting is more cost effective, in addition to improving patient satisfaction. Vincristine, dactinomycin, and cyclophosphamide (VAC) are used together to treat children with solid tumors. Our traditional treatment approach included a two day inpatient admission. The purpose of this project was to establish a process for the administration of VAC in the outpatient setting to improve satisfaction, and reduce costs. We aimed to benchmark practice standards with other institutions, revised our treatment approach to permit outpatient administration, and implemented the new protocol in a stepwise manner. We collected caregiver satisfaction metrics through the use of surveys. Costs of encounters were obtained from administrative data. Total costs and costs by service type were compared using descriptive and mean comparisons. Seven patients received a total of 31 cycles of VAC in the outpatient setting. The time to achieve an appropriate pre-chemotherapy specific gravity was reduced by a median of 120 min. In addition, time spent in the hospital setting was reduced by a mean of 27.2 hr. Adverse effects were minimal and all caregivers reported greater satisfaction with the outpatient regimen. Outpatient administration of VAC was $3,300 less on average compared to the inpatient administration. Outpatient VAC provides a safe alternative for administration that reduces healthcare costs, reduces healthcare utilization, and improves patient satisfaction. © 2015 Wiley Periodicals, Inc.

  4. 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

  5. Frequency and severity of neutropenia in diffuse large B-cell non Hodgkin's lymphoma after first cycle of chemotherapy comprising cyclophosphamide, doxorubicin, vincristine with prednisolone.

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    Nadeem, Mohammad; Idrees, Muhammad; Khattak, Javeed; Hussain, Iftikhar; Amin, Zulfiqar; Arif, Salman; Zeeshan, Mansoor; Hussain, Mussavir

    2011-01-01

    Chemotherapy used for malignant diseases may produce severe neutropenia in first cycle which may compel for dose modification and early termination of therapy. This descriptive cross sectional study was planned to see the frequency and severity of neutropenia after first cycle of chemotherapy comprising cyclophosphamide, doxorubicin, vincristine with prednisolon in patients of diffuse large B-cell non Hodgkin's lymphoma presenting at Oncology Department Combined Military Hospital Rawalpindi from August 2009 to July 2010. Thirty patients of diffuse large B-cell non Hodgkin's lymphoma diagnosed on lymph node biopsy presenting for the first time at Oncology Department Combined Military Hospital Rawalpindi were included. They were admitted in the ward and evaluated with history, physical examination and staging investigations. Patients were then planned for first cycle of chemotherapy comprising cyclophosphamide, doxorubicin, and vincristine with prednisolon. After the first cycle of chemotherapy they were monitored for expected neutropenia in the ward. The neutrophil counts were repeated on days 7 and 10 following chemotherapy. Neutropenia was graded as defined in the operational definition and all the data was entered on a specially designed data card. As much as 3.3% of patients suffered from grade IV neutropenia (absolute neutrophil count of chemotherapy comprising cyclophosphamide, doxorubicin, vincristine with prednisolon in diffuse large B-cell non Hodgkin's lymphoma. Further studies are required to find the risk factors to predict this complication in our population.

  6. Obinutuzumab or Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Previously Untreated Diffuse Large B-Cell Lymphoma.

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    Vitolo, Umberto; Trněný, Marek; Belada, David; Burke, John M; Carella, Angelo Michele; Chua, Neil; Abrisqueta, Pau; Demeter, Judit; Flinn, Ian; Hong, Xiaonan; Kim, Won Seog; Pinto, Antonio; Shi, Yuan-Kai; Tatsumi, Yoichi; Oestergaard, Mikkel Z; Wenger, Michael; Fingerle-Rowson, Günter; Catalani, Olivier; Nielsen, Tina; Martelli, Maurizio; Sehn, Laurie H

    2017-11-01

    Purpose Rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is the standard of care in previously untreated diffuse large B-cell lymphoma (DLBCL). Obinutuzumab (G) is a glycoengineered, type II, anti-CD20 monoclonal antibody. GOYA was a randomized phase III study that compared G-CHOP with R-CHOP in patients with previously untreated advanced-stage DLBCL. Methods Patients (N = 1,418) were randomly assigned to receive eight 21-day cycles of G (n = 706) or R (n = 712), plus six or eight cycles of CHOP. Primary end point was investigator-assessed progression-free survival (PFS). Results After median observation of 29 months, the number of investigator-assessed PFS events was similar between G (201; 28.5%) and R (215; 30.2%), stratified hazard ratio was 0.92 (95% CI, 0.76 to 1.11; P = .39), and 3-year PFS rates were 70% and 67%, respectively. Secondary end points of independently reviewed PFS, other time-to-event end points, and tumor response rates were similar between arms. In exploratory subgroup analyses, patients with germinal-center B cell-like subtype had a better PFS than did patients with activated B cell-like subtype, irrespective of treatment. Frequencies of grade 3 to 5 adverse events (AEs; 73.7% v 64.7%, respectively) and serious AEs (42.6% v 37.6%, respectively) were higher with G-CHOP compared with R-CHOP. Fatal AE frequencies were 5.8% for G-CHOP and 4.3% for R-CHOP. The most common AEs were neutropenia (G-CHOP, 48.3%; R-CHOP, 40.7%), infusion-related reactions (G-CHOP, 36.1%; R-CHOP, 23.5%), nausea (G-CHOP, 29.4%; R-CHOP, 28.3%), and constipation (G-CHOP, 23.4%; R-CHOP, 24.5%). Conclusion G-CHOP did not improve PFS compared with R-CHOP in patients with previously untreated DLBCL. AEs reported with G were consistent with the known safety profile. Biomarker analyses may help define a future role for G in DLBCL.

  7. A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non-Hodgkin's lymphoma.

    Science.gov (United States)

    Cohen, Jonathon B; Switchenko, Jeffrey M; Koff, Jean L; Sinha, Rajni; Kaufman, Jonathan L; Khoury, H Jean; Bumpers, Nassoma; Colbert, Amanda; Hutchison-Rzepka, Amanda; Nastoupil, Loretta J; Heffner, Leonard T; Langston, Amelia A; Lechowicz, Mary Jo; Lonial, Sagar; Flowers, Christopher R

    2015-11-01

    Bortezomib-containing combinations are active in non-Hodgkin lymphoma (NHL) although peripheral neuropathy can limit their dose intensity. Based on our phase I findings, we conducted a phase II trial of bortezomib in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with a modified dose of vincristine. Patients with untreated indolent NHL received bortezomib (1·6 mg/m(2) ) on days 1 and 8 of a 21-day cycle for up to 8 cycles and R-CHOP with a 1·5 mg cap of vincristine. Patients achieving a complete response (CR) received maintenance rituximab, and remaining patients received maintenance rituximab and bortezomib. The primary endpoint was CR rate; secondary survival analyses were evaluated using the Kaplan-Meier method. Among 29 eligible patients, NHL morphologies included follicular (n = 20), marginal zone (n = 5) and small lymphocytic lymphoma (n = 4). Nineteen patients had CR (66%) and 10 had partial response (34%), yielding a 100% overall response rate. With a median follow-up of 48·7 months, the 4-year progression-free and overall survivals were 83% and 93%. Twenty-two patients experienced peripheral neuropathy of any grade, and two had grade 3 neuropathy. The combination of bortezomib with R-CHOP is effective for indolent NHL, and we plan to evaluate therapies incorporating novel proteasome inhibitors in future studies in NHL. © 2015 John Wiley & Sons Ltd.

  8. A Phase II Study of Bortezomib Added to Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients with Previously Untreated Indolent non-Hodgkin’s Lymphoma

    Science.gov (United States)

    Cohen, Jonathon B.; Switchenko, Jeffrey M.; Koff, Jean L.; Sinha, Rajni; Kaufman, Jonathan L.; Khoury, H. Jean; Bumpers, Nassoma; Colbert, Amanda; Hutchison-Rzepka, Amanda; Nastoupil, Loretta J.; Heffner, Leonard T.; Langston, Amelia; Lechowicz, Mary Jo; Lonial, Sagar; Flowers, Christopher R.

    2015-01-01

    Summary Bortezomib-containing combinations are active in non-Hodgkin lymphoma (NHL) although peripheral neuropathy can limit its dose intensity. Based on our phase I findings, we conducted a phase II trial of bortezomib in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with a modified dose of vincristine. Patients with untreated indolent NHL received bortezomib (1.6 mg/m2) on days 1 and 8 of a 21-day cycle for up to 8 cycles and R-CHOP with a 1.5 mg cap of vincristine. Patients achieving a complete response (CR) received maintenance rituximab, and remaining patients received maintenance rituximab and bortezomib. The primary endpoint was CR rate; secondary survival analyses were evaluated using the Kaplan-Meier method. Among 29 eligible patients, NHL morphologies included follicular (n=20), marginal zone (n=5) and small lymphocytic lymphoma (n=4). Nineteen patients had CR (66%) and 10 had partial response (34%), yielding a 100% overall response rate. With a median follow-up of 48.7 months, the 4-year progression-free and overall survivals were 83% and 93%. Twenty-two patients experienced peripheral neuropathy of any grade, and 2 had grade 3 neuropathy. The combination of bortezomib with R-CHOP is effective for indolent NHL, and we plan to evaluate therapies incorporating novel proteasome inhibitors in future studies in NHL. PMID:26248505

  9. Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Chemotherapy in Mantle Cell Lymphoma Patients Is Associated with Higher Rates of Hematopoietic Progenitor Cell Mobilization Failure despite Plerixafor Rescue.

    Science.gov (United States)

    Salhotra, Amandeep; Shan, Yuan; Tsai, Ni-Chun; Sanchez, James F; Aldoss, Ibrahim; Ali, Haris; Paris, Tanya; Spielberger, Ricardo; Cao, Thai M; Nademanee, Auayporn; Forman, Stephen J; Chen, Robert

    2017-08-01

    Induction regimens for mantle cell lymphoma (MCL) can be categorized into highly intensive regimens containing cytarabine and less intense regimens, such as rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) or rituximab with bendamustine (R-bendamustine). Prior publications have shown rituximab and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD) can be associated with stem cell mobilization failures. However, those studies did not include the use of plerixafor as rescue for stem cell mobilization failure. We examined our database of 181 consecutive MCL patients who received upfront therapy from 2005 to 2015 with either R-hyperCVAD or less intense chemotherapy (R-bendamustine and R-CHOP only) regimens to assess impact of frontline chemotherapy on collection of hematopoietic cell progenitors before autologous stem cell transplantation (ASCT). In the preplerixafor era (before August 16, 2009), a significant difference in peripheral blood stem cell (PBSC) collection failure between the R-hyperCVAD (12%) and other chemotherapy (11%) groups was not established. However, in the postplerixafor era, use of R-hyperCVAD chemotherapy was associated with significantly higher rates of hematopoietic progenitor cell collection failures (17%) compared with that observed in the other chemotherapy group (4%; P = .04). The rates of mobilization failure declined to 4% in the postplerixafor era from 11% in the preplerixafor era for patients receiving less intensive chemotherapy. Conversely, the rate of mobilization failure increased in the R-hyperCVAD group from 12% in the preplerixafor era to 17% in the postplerixafor era. Plerixafor does not overcome the negative impact of R-hyperCVAD on PBSC mobilization, and caution is warranted in using R-hyperCVAD in patients with newly diagnosed MCL who are candidates for ASCT. Copyright © 2017 The American Society for Blood and Marrow Transplantation

  10. Cyclophosphamide

    Science.gov (United States)

    ... cancer (cancer that begins in the female reproductive organs where eggs are formed), and breast cancer. Cyclophosphamide ... Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat ...

  11. Studies of lymphocyte growth and differentiation. [Actinomycin-D, amatin, phytohemagglutinin

    Energy Technology Data Exchange (ETDEWEB)

    1975-01-01

    Progress is reported on the following research projects: post-transcriptional regulation of ribosome synthesis; use of exponential acrylamide gel electrophoresis for resolving different precursor particles; regulation of nuclear RNA synthesis; effects of PHA, amatin, and actinomycin-D on RNA synthesis in chromatin of lymphocytes; and kinetic analysis of PHA-stimulated peripheral lymphocytes from patients with leukemia and lymphoma. (HLW)

  12. The Elevation of Cardio-Ankle Vascular Index in a Patient With Malignant Lymphoma Treated With a Combination Therapy of Rituximab and Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone

    Science.gov (United States)

    Shimizu, Naomi; Ban, Noriko; Watanabe, Yasuhiro; Rikitake, Asami; Watanabe, Rena; Tanaka, Sho; Sato, Yuta; Imamura, Haruki; Kawana, Hidetoshi; Yamaguchi, Takashi; Saiki, Atsuhito; Tatsuno, Ichiro; Shirai, Kohji

    2017-01-01

    An increased risk of arteriosclerosis has been noted in cancer survivors. Currently, there are only a few reports available that consider the risk of arteriosclerosis in patients treated with chemotherapy. Patients with an advanced stage B-cell malignant lymphoma are typically treated with a combination therapy of rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Complications such as diabetes mellitus (DM), hyperlipidemia (HL), and osteoporosis due to prednisolone and cardiotoxicity due to anthracyclines are well known. However, there are no studies that have investigated the link between R-CHOP therapy and arteriosclerosis. We discussed a patient with follicular lymphoma who was evaluated using cardio-ankle vascular index (CAVI) as an arterial stiffness parameter during R-CHOP therapy in this report. She achived complete remission after the eighth course therapy without complications such as hypertension (HT), HL, DM, and infection. This patient showed elevated CAVI with new plaque formation in the carotid arteries after the end of chemotherapy. These data indicate that R-CHOP therapy may progress the arteriosclerosis. PMID:28725323

  13. Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14).

    Science.gov (United States)

    Fridrik, Michael A; Jaeger, Ulrich; Petzer, Andreas; Willenbacher, Wolfgang; Keil, Felix; Lang, Alois; Andel, Johannes; Burgstaller, Sonja; Krieger, Otto; Oberaigner, Willi; Sihorsch, Kurt; Greil, Richard

    2016-05-01

    Chemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is the standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin may induce early and late cardiotoxicity. Non-pegylated liposomal (NPL) doxorubicin may reduce cardiotoxicity. Patients with untreated CD20+ DLBCL were randomised to conventional R-CHOP chemoimmunotherapy or rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone (R-COMP) with doxorubicin substituted by NPL-doxorubicin. Left ventricular ejection fraction (LVEF) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were measured before each treatment cycle and after the end of treatment. The mean LVEF of 178 and 158 measurements in the R-COMP and R-CHOP arms was 63.31% and 62.25%, respectively (P = 0.167). During treatment the LVEF measurements were below 50% in 10/218 (4.6%) in the R-COMP arm and 31/196 (15.8%) in the R-CHOP arm (Ptreatment (P = 0.013). There were more serious adverse events in the R-CHOP arm (26 versus 40, P = 0.029). Infections were more common (15 versus 28) in the R-CHOP arm. In patients with normal cardiac function, six cycles of R-CHOP resulted in a low rate of early cardiotoxicity. NPL-doxorubicin did not reduce cardiotoxicity, although cardiac safety signals were elevated in R-CHOP compared to R-COMP. Cephalon provided the Arbeitsgemeinschaft Medikamentöse Tumortherapie with NPL-doxorubicin and an unrestricted grant, but was not involved in the study protocol, data acquisition, data analysis or the writing of the paper. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.

    Science.gov (United States)

    Thieblemont, Catherine; Tilly, Hervé; Gomes da Silva, Maria; Casasnovas, Rene-Olivier; Fruchart, Christophe; Morschhauser, Franck; Haioun, Corinne; Lazarovici, Julien; Grosicka, Anida; Perrot, Aurore; Trotman, Judith; Sebban, Catherine; Caballero, Dolores; Greil, Richard; van Eygen, Koen; Cohen, Amos M; Gonzalez, Hugo; Bouabdallah, Reda; Oberic, Lucie; Corront, Bernadette; Choufi, Bachra; Lopez-Guillermo, Armando; Catalano, John; Van Hoof, Achiel; Briere, Josette; Cabeçadas, Jose; Salles, Gilles; Gaulard, Philippe; Bosly, Andre; Coiffier, Bertrand

    2017-08-01

    Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Lenalidomide, an immunomodulatory agent, has shown activity in DLBCL. This randomized phase III trial compared lenalidomide as maintenance therapy with placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction. Methods Patients with previously untreated DLBCL or other aggressive B-cell lymphoma were 60 to 80 years old, had CR or PR after six or eight cycles of R-CHOP, and were randomly assigned to lenalidomide maintenance 25 mg/d or placebo for 21 days of every 28-day cycle for 24 months. The primary end point was progression-free survival (PFS). Results A total of 650 patients were randomly assigned. At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median PFS was not reached for lenalidomide maintenance versus 58.9 months for placebo (hazard ratio, 0.708; 95% CI, 0.537 to 0.933; P = .01). The result was consistent among analyzed subgroups (eg, male v female, age-adjusted International Prognostic Index 0 or 1 v 2 or 3, age younger than 70 v ≥ 70 years), response (PR v CR) after R-CHOP, and positron emission tomography status at assignment (negative v positive). With longer median follow-up of 52 months (October 2016), overall survival was similar between arms (hazard ratio, 1.218; 95% CI, 0.861 to 1.721; P = .26). Most common grade 3 or 4 adverse events associated with lenalidomide versus placebo maintenance were neutropenia (56% v 22%) and cutaneous reactions (5% v 1%), respectively. Conclusion Lenalidomide maintenance for 24 months after obtaining a CR or PR to R-CHOP significantly prolonged PFS in elderly patients with DLBCL.

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

    Directory of Open Access Journals (Sweden)

    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

  16. Outcome of pregnancy subsequent to chemotherapy with actinomycin-D in low risk gestational trophoblastic neoplasia

    Directory of Open Access Journals (Sweden)

    Soheila Aminimoghaddam

    2017-07-01

    Methods: A retrospective cohort study was conducted on patients with GTN who were referred to Firoozgar and Mirza Koochak Khan teaching hospitals during 10 years, starting from 2004. The inclusion criterion was patients with low-risk persistent GTN after molar pregnancy, EP, and abortion, that treated with single agent chemotherapy actinomycin-D. After following the patients for 12 months, patients with serum βHCG lower than 5 mIU/ml, who intended to have child were allowed to become pregnant. The following items were observed in the study: age, body mass index (BMI, parity, chemotherapy duration, and pregnancy outcomes such as spontaneous abortion or preterm labor, pre-eclampsia, stillbirth, fetal malformation, and repeated molar pregnancy. Results: 74 patients were monitored, 83.78% of them had uncomplicated pregnancy and labor, 4.05% had the abortion, 4.05% had second molar pregnancy, 2.7% had pre-eclampsia, 5.40% had preterm labor. Moreover, stillbirth and malformation did not occur in this study even after chemotherapy treatment. There was not any significant correlation between age, BMI, parity, and chemotherapy duration with pregnancy outcomes. Conclusion: The outcomes of pregnancy after chemotherapy with actinomycin-D is similar to the general population who did not have chemotherapy. The abortion rate and repeated molar pregnancy were similar between population and sample too. Thus, the study shows that the cured patients with low-risk GTN have as much chance of having a normal pregnancy as normal women. In other words, treatment with actinomycin-D does not have any adverse effect in future pregnancies.

  17. A Phase II Study of Cyclophosphamide, Etoposide, Vincristine and Prednisone (CEOP) Alternating with Pralatrexate (P) as Front Line Therapy for Patients with Peripheral T-Cell Lymphoma (PTCL): Final Results from the T- Cell Consortium Trial

    Science.gov (United States)

    Advani, Ranjana H.; Ansell, Stephen M.; Lechowicz, Mary Jo; Beaven, Anne W.; Loberiza, Fausto; Carson, Kenneth R.; Evens, Andrew M.; Foss, Francine; Horwitz, Steven; Pro, Barbara; Brown, Lauren Pinter; Smith, Sonali M.; Shustov, Andrei R.; Savage, Kerry J.; Vose, Julie

    2017-01-01

    Summary Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II–IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3–4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survial, were 39% (95% confidence interval 21–57) and 60% (95% confidence interval 39–76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21.5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need. PMID:26627450

  18. Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models

    Directory of Open Access Journals (Sweden)

    Ruth B. Siboni

    2015-12-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is an inherited disease characterized by the inability to relax contracted muscles. Affected individuals carry large CTG expansions that are toxic when transcribed. One possible treatment approach is to reduce or eliminate transcription of CTG repeats. Actinomycin D (ActD is a potent transcription inhibitor and FDA-approved chemotherapeutic that binds GC-rich DNA with high affinity. Here, we report that ActD decreased CUG transcript levels in a dose-dependent manner in DM1 cell and mouse models at significantly lower concentrations (nanomolar compared to its use as a general transcription inhibitor or chemotherapeutic. ActD also significantly reversed DM1-associated splicing defects in a DM1 mouse model, and did so within the currently approved human treatment range. RNA-seq analyses showed that low concentrations of ActD did not globally inhibit transcription in a DM1 mouse model. These results indicate that transcription inhibition of CTG expansions is a promising treatment approach for DM1.

  19. A resonance light scattering quenching system for studying DNA sequence recognition of actinomycin D.

    Science.gov (United States)

    Chen, Zhanguang; Zhang, Guomin; Chen, Xi; Chen, Junhui; Qian, Sihua; Li, Qiang

    2012-02-07

    The DNA sequence recognition study of DNA-targeted anticancer drugs is a theoretical basis for improving the selectivity of anticancer drugs. With the high synergy effect of cocoamidopropyl hydroxy sulfobetaine (HSB), a resonance light scattering (RLS) quenching system for DNA sequence recognition studies of actinomycin D (ACTD) was developed in this contribution. By the strategy, DNA sequence selectivity as well as the recognition mechanisms of ACTD was systematically investigated. The results suggested that ACTD had the selectivity to single-stranded DNA (ssDNA) with an equilibrium constant (K(RLS)) of 12.4 mmol mg(-1). Also it had a preference for Guanine and Cytosine bases with a K(RLS) of 6.69 L mmol(-1). The selectivity mechanism between ACTD and DNA was also well discussed with the help of UV-Vis absorption spectroscopy. Compared with other methods, the RLS quenching system has the advantages of reliability and speediness, and it avoids complex modification processes and is a better bionic system for the above research. Results obtained from this work would supply a theoretical basis for improving anticancer activity and designing similar anticancer drugs.

  20. Induction of the bystander effect in Chinese hamster V79 cells by actinomycin D.

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    Jin, Cuihong; Wu, Shengwen; Lu, Xiaobo; Liu, Qiufang; Qi, Ming; Lu, Shuai; Xi, Qi; Cai, Yuan

    2011-05-10

    Bystander effect (BE) can be induced by ionizing radiation and chemicals, including alkylating agents. Ionizing radiation mostly induces the bystander effect by causing double-strand DNA breakage in the exposed cells. However, the chemical-induced bystander effect is poorly studied. Here we chose actinomycin D (ACTD), a genotoxic chemotherapeutic drug, to investigate whether it could cause bystander effect in Chinese hamster V79 cells. Results are that (1) ACTD induced apoptosis in V79 cells and an optimal apoptosis model in V79 cells was established with ACTD (4 mg/L, 1h); (2) using apoptosis rate, chromosome aberration, and ultrastructure changes as endpoints of bystander effect, ACTD could induce bystander effect in V79 cells; (3) as in the exposed cells, ACTD mainly induced apoptosis in bystander V79 cells cultured in different period conditioned medium; (4) the strongest bystander effect was induced by 4 h conditioned medium collected from cells treated with ACTD. It suggests that ACTD could cause BE through the medium soluble factors excreted from exposed cells during apoptosis and ACTD-induced BE was a novel quantitative and kinetic response. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  1. Human leukocyte antigen-DR expression on flow cytometry and tumor-associated macrophages in diffuse large B-cell lymphoma treated by rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone therapy: retrospective cohort study.

    Science.gov (United States)

    Yamamoto, Wataru; Nakamura, Naoya; Tomita, Naoto; Takeuchi, Kengo; Ishii, Yoshimi; Takahashi, Hiroyuki; Watanabe, Reina; Takasaki, Hirotaka; Motomura, Shigeki; Kobayashi, Shoichi; Yokose, Tomoyuki; Ishigatsubo, Yoshiaki; Sakai, Rika

    2014-12-01

    Loss of human leukocyte antigen (HLA)-DR expression may be related to a poor prognosis of diffuse large B-cell lymphoma (DLBCL), and tumor-associated macrophages (TAMs) may influence tumor progression. We retrospectively reviewed 36 patients with newly diagnosed DLBCL who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy at Kanagawa Cancer Center in Japan from 2004 to 2010. HLA-DR expression by lymphoma cells was evaluated using flow cytometry, and TAMs in lymphoma tissue were detected by immunohistochemistry for CD68 as a marker of macrophages and CD163 as a marker of M2 TAMs. Three-year overall survival was, respectively, 100% versus 69.6% in the HLA-DR "bright" and "not bright" groups (p = 0.012). Patients from the HLA-DR "not bright" group with strong CD163 expression had a much worse prognosis than other patients. The HLA-DR status shown by flow cytometry can be used to predict the prognosis of patients with DLBCL receiving R-CHOP therapy and prognostic accuracy can be increased by also assessing TAMs.

  2. Identification of copper(II) binding sites in actinomycin D, a cytostatic drug--correlation of coordination with DNA damage.

    Science.gov (United States)

    Szczepanik, Wojciech; Kaczmarek, Piotr; Jezowska-Bojczuk, Małgorzata

    2004-12-01

    Actinomycin D (AD) is a potent anticancer drug widely applied in therapy, which however exhibits very high toxicity in humans. As the character of donors present in the AD molecule seems to be very favorable for Cu(II) ions, we undertook the coordination study on the Cu(II)-AD system. Potentiometric experiments proved a formation of very stable complexes and with the use of spectroscopic methods the identification of the binding sites was made. The values of potential energy minima, provided by theoretical modeling, confirmed the feasibility of formation of the complexes in water solution. We also demonstrated a significant effect of Cu(II) ions on AD interactions with DNA. The strand-nicking activity was observed. This process could be correlated with the speciation of complex forms. We also found out that in the presence of H2O2, low levels of Cu(II)-AD complexes induce the formation of considerable amounts of linearised plasmid. In consequence, the hypothesis is proposed that the physiologically available cupric ions may participate in the drug-induced toxic effects.

  3. Effect of N-hydroxyurea, mitomycin C and actinomycin D on tumour formation on the leaves of Kalanchoe daigremontiana

    Directory of Open Access Journals (Sweden)

    Józef Koawalczyk

    2014-01-01

    Full Text Available The leaves of Kalanchoe daigremontiana wounded and infected with Agrobacterium tumefaciens were treated with single doses of inhibitors (hydroxyurea - 190, mitomycin - 0.5, actinomycin - 2 µ,g per leaf. After delaying the time' of dosage of inhibitors during five days after inoculation, changes in susceptibility of the system to antitumorous activity of analysed compounds were observed. In several hours after inoculation (period of the bacteria metabolic activity in wounds all the inhibitors prevent strongly the tumour formation. At the time between 14 and 72 hours after inoculation, including the phase of tumour induction, the system becomes sensitive to the DNA synthesis inhibitors, particularly hydroxyurea. The intensified action of actinomycin appears again only about 60 hours after inoculation and lasts till the end of experiment (the initiation of the transformed plant cell proliferation. According to the literature the antitumorous effect of inhibitors could be connected with their action on the bacteria metabolism inside the host tissue. The activities of hydroxyurea and mitomycin in the second period correspond with the intensive DNA synthesis in plant cells, which is induced by wounding. The effect of actinomycin D in 60 hours after inoculation could depend upon the inhibition of the proliferation of the transformed host cells.

  4. Second cancer incidence in primary mediastinal B-cell lymphoma treated with methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin regimen with or without rituximab and mediastinal radiotherapy: Results from a monoinstitutional cohort analysis of long-term survivors.

    Science.gov (United States)

    De Sanctis, Vitaliana; Alfò, Marco; Di Rocco, Alice; Ansuinelli, Michela; Russo, Eleonora; Osti, Mattia F; Valeriani, Maurizio; Minniti, Giuseppe; Grapulin, Lavinia; Musio, Daniela; Bracci, Stefano; Spagnoli, Alessandra; Moleti, Maria Luisa; Tombolini, Vincenzo; Martelli, Maurizio

    2017-12-01

    Our aim is to assess the incidence of second cancer in long-time surviving primary mediastinal B-cell lymphoma (PMBCL) patients treated with combined radiochemoimmunotherapy (standard methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin with rituximab and mediastinal radiation therapy at a dose of 30 to 36 Gy). For this purpose, 92 points were evaluated. After a median overall survival of 137 months (range 76-212), we recorded second cancer in 3 of 80 long-surviving patients (3.75%) with cumulative incidence of 3.47% at 15 years and 11% at 17 years, with a 17-year second cancer-free survival of 82%. We observed 2 papillary thyroid cancers with a standardized incidence ratio (SIR) of 7.97 and an absolute excess risk (AER) of 17. 84 and 1 acute myeloid leukemia (AML) with an SIR of 66.53 and an AER of 10.05. No breast cancer occurred. Although we should take into account the limits of the proposed statistical analysis, combined modality treatment was related to a significant SIR and AER for thyroid cancer and acute myeloid leukemia. Copyright © 2017 John Wiley & Sons, Ltd.

  5. N-hydroxyurea, mitomycin C and actinomycin D activity in the process of tumour formation on the primary leaves of the 'Pinto' bean

    Directory of Open Access Journals (Sweden)

    Aldona Rennert

    2014-01-01

    Full Text Available Mitomycin C (MC, N-hydroxyurea (HU and actinomycin D (AD inhibit tumour formation on the primary leaves of Pinto beans. Agrobacterium tumefaciens was inoculated into bean leaves with application of the above named inhibitors at various times. It was found that MC action is strongest during inoculation and immediately after it, the maximal effect of HU take place within 12 h after inoculation, whereas the antitumour action of AD starts as late as 12 h after leaf inoculation. In view of the different degree of susceptibility of bacteria and plant cells to the inhibitors applied, the above described results allowed to distinguish three critical periods in the process of tumour formation in the tested host-pathogen system.

  6. Cyclophosphamide (Cytoxan)

    Science.gov (United States)

    ... the introduction of cyclophosphamide in the treatment of Wegener’s granulomatosis in the 1970s, Wegener’s was almost invariably a ... in the oral daily form. Among patients with Wegener’s granulomatosis treated with oral daily cyclophosphamide at the National ...

  7. Comparing and evaluating the efficacy of methotrexate and actinomycin D as first-line single chemotherapy agents in low risk gestational trophoblastic disease.

    Science.gov (United States)

    Lee, Young Jae; Park, Jeong Yeol; Kim, Dae Yeon; Suh, Dae Shik; Kim, Jong Hyeok; Kim, Yong Man; Kim, Young Tak; Nam, Joo Hyun

    2017-03-01

    The aim of this study was to compare responses to single-agent chemotherapies and evaluate the predictive factors of resistance in low risk (LR) gestational trophoblastic disease (GTD). The chemotherapy agents included methotrexate (MTX) and actinomycin D (ACT-D). We conducted a retrospective study of 126 patients with GTD who were treated between 2000 and 2013. A total of 71 patients with LR GTD were treated with MTX (8-day regimen or weekly regimen, n=53) or ACT-D (bi-weekly pulsed regimen or 5-day regimen, n=18). The successful treatment group and the failed treatment group were compared and analyzed to identify prognostic factors. The complete response rates were 83.3% for ACT-D and 62.2% for MTX, with no statistically significant difference. There was no severe adverse effect reported for either group. Longer interval durations from the index pregnancy (>2 months, p=0.040) and larger tumor size (>3 cm, p=0.020) were more common in non-responders than in responders; these results were statistically significant. Based on our results, ACT-D may be a better option than MTX as a first-line single chemotherapy agent for LR GTD. The bi-weekly pulsed ACT-D regimen had minimal, or at least the same, toxicities compared with MTX. However, due to the lack of strong supporting evidence, it cannot be conclusively stated that this is the best single agent for first-line chemotherapy in LR GTD patients. Further larger controlled trials will be necessary to establish the best guidelines for GTD treatment.

  8. Crosstalk Influence between P38MAPK and Autophagy on Mitochondria-Mediated Apoptosis Induced by Anti-Fas Antibody/Actinomycin D in Human Hepatoma Bel-7402 Cells

    Directory of Open Access Journals (Sweden)

    Yu Wang

    2017-10-01

    Full Text Available Our previous study indicated that anti-Fas antibody/actinomycin D (AF/AD induced apoptosis of human hepatocellular carcinoma Bel-7402 cells; however, crosstalk influence between P38MAPK and autophagy on mitochondria-mediated apoptosis induced by AF/AD in Bel-7402 cells remains unclear. Therefore, effect of AF/AD on apoptosis, autophagy, phosphorylated-P38MAPK (p-P38MAPK, and membrane potential (ΔΨm with or without the P38MAPK inhibitor SB203580 or the autophagy inhibitor 3-methyladenine (3-MA in Bel-7402 cells was investigated in the present study. The results showed that AF/AD resulted in induction of apoptosis concomitant with autophagy, upregulation of p-P38MAPK and autophagy-associated gene proteins (Atg5-Atg12 protein complex, Atg7, Atg10, Beclin-1, LC3 I, and LC3 II, and downregulation of ΔΨm in Bel-7402 cells. In contrast, SB203580 attenuated the effects of AF/AD in Bel-7402 cells. Furthermore, the findings also demonstrated that 3-MA inhibited the impact of AF/AD on autophagy, Atg5-Atg12 protein complex, Atg7, Atg10, Beclin-1, LC3 I, LC3 II, and ΔΨm, and promoted the influence of AF/AD on apoptosis and p-P38MAPK in Bel-7402 cells. Taken together, we conclude that crosstalk between P38MAPK and autophagy regulates mitochondria-mediated apoptosis induced by AF/AD in Bel-7402 cells.

  9. 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.

  10. vincristine

    African Journals Online (AJOL)

    PRECIOUS

    2009-12-01

    Dec 1, 2009 ... 5Centro Universitário da Zona Oeste- UEZO, Avenida Manuel Caldeira de Alvarenga, 1203. Campo Grande, RJ 23070-. 200, Brazil. 6Instituto Nacional do Câncer, Coordenadoria de Pesquisa, Praça Cruz Vermelha, Rio de Janeiro, RJ, Brazil. 7Universidade Estácio de Sá, Instituto das Ciências da Saúde, ...

  11. 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

  12. Glutamic acid modification of vincristine toxicity.

    Science.gov (United States)

    Jackson, D V; Rosenbaum, D L; Carlisle, L J; Long, T R; Wells, H B; Spurr, C L

    1984-09-01

    The principal limiting feature of the antitumor agent, vincristine, in the clinic has been neurotoxicity; there are no known agents which can routinely prevent or decrease this side effect. Glutamic acid in laboratory and clinical investigations in the early 1960s was found to antagonize vinblastine, another clinically useful vinca alkaloid. Glutamic acid 250 mg/kg/d i.p. was given to normal mice treated with repetitive doses of vincristine 1.5 mg/kg every other day. When glutamic acid was given both before and during vincristine administration, it produced a 49-79% increase in survival compared to control mice receiving vincristine only (p less than 0.01). Other schedules of glutamic acid administration were ineffective. Also, there appeared to be a delay in development of neurotoxic manifestations (toe-walking gait) but the results were not as consistent as the improvement in survival. Glutamic acid given to tumor-bearing mice (P-388 and P-1534 murine leukemia) did not inhibit the antitumor effect of vincristine-induced host toxicity in a schedule-dependent fashion without inhibition of the antitumor effect of vincristine.

  13. Cyclophosphamide-Induced Cardiomyopathy

    Science.gov (United States)

    Dhesi, Sumandeep; Chu, Michael P.; Blevins, Gregg; Paterson, Ian; Larratt, Loree; Oudit, Gavin Y.

    2013-01-01

    Cyclophosphamide is increasingly used to treat various types of cancers and autoimmune conditions. Higher doses of this drug may produce significant cardiac toxicity, including fatal hemorrhagic myocarditis. In this review, we present a case of cyclophosphamide-induced cardiomyopathy requiring mechanical circulatory support. We also describe the pathophysiology, clinical manifestations, and risk factors for this important clinical entity and propose early detection and management strategies. PMID:26425570

  14. Cyclophosphamide-Induced Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Sumandeep Dhesi MD

    2013-01-01

    Full Text Available Cyclophosphamide is increasingly used to treat various types of cancers and autoimmune conditions. Higher doses of this drug may produce significant cardiac toxicity, including fatal hemorrhagic myocarditis. In this review, we present a case of cyclophosphamide-induced cardiomyopathy requiring mechanical circulatory support. We also describe the pathophysiology, clinical manifestations, and risk factors for this important clinical entity and propose early detection and management strategies.

  15. Severe Refractory Immune Thrombocytopenia Successfully Treated with High-Dose Pulse Cyclophosphamide and Eltrombopag

    Directory of Open Access Journals (Sweden)

    Faiz Anwer

    2015-01-01

    Full Text Available Severe refractory ITP is clinically challenging and a variety of single or combination chemotherapies have been tried with limited outcome. We report a case of ITP that was unresponsive to multiple agents including high-dose steroid, IVIG, Rho(D immune globulin, rituximab, cyclosporine, azathioprine, vincristine, mycophenolate mofetil, romiplostim, and eltrombopag; however, it achieved complete remission with combination treatment of cyclophosphamide and eltrombopag.

  16. Pegylated niosomal nanoparticles loaded with vincristine ...

    African Journals Online (AJOL)

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

  17. 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.

  18. Intravascular large B-cell lymphoma : remission after rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy

    NARCIS (Netherlands)

    Horváth, Barbara; Demeter, Judit; Eros, Nóra; Hársing, Judit; Csomor, Judit; Matolcsy, András; Bottlik, Gyula; Gyori, Gabriella; Marschalkó, Márta; Kárpáti, Sarolta

    2009-01-01

    Intravascular lymphoma is an uncommon, very aggressive extranodal non-Hodgkin lymphoma that most frequently involves the skin and central nervous system. Most cases are of B-cell origin; T-cell phenotype is extremely rare. Malignant cells proliferate within the lumens of capillaries, arterioles,

  19. 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.)

  20. Superiority of cisplatin or carboplatin in combination with teniposide and vincristine in the induction chemotherapy of small-cell lung cancer. A randomized trial with 5 years follow up

    DEFF Research Database (Denmark)

    Lassen, U; Kristjansen, P E; Osterlind, K

    1996-01-01

    . PATIENTS AND METHODS: From November 1985 to September 1991, 484 consecutive, previously untreated patients with SCLC, performance status 0-4, entered a three armed randomized trial with three cycles of cisplatin (arm I) or carboplatin (arm II) in combination with teniposide and vincristine alternating...... with three treatment blocks of cyclophosphamide, etoposide, lomustine and vincristine (block A), doxorubicin and vincristine (block B) and cisplatin, hexamethylmelamine and vindesine (block C) versus alternating treatment with block A, B and C (arm III). RESULTS: No difference in efficacy or toxicity...... was found between cisplatin and carboplatin at the present dosages. Induction chemotherapy with teniposide plus cisplatin or carboplatin did not result in higher complete response rates (objective response rates 63%, 72% and 65%, respectively) or in significantly greater toxicity, but overall survival...

  1. Treatment outcomes of AIDS-associated Kaposi's sarcoma under a routine antiretroviral therapy program in Lilongwe, Malawi: bleomycin/vincristine compared to vincristine monotherapy.

    Directory of Open Access Journals (Sweden)

    Albert A Mwafongo

    Full Text Available Despite Kaposi's sarcoma (KS being the most prevalent AIDS-associated cancer in resource limited settings, optimal treatment options remain unknown. We assessed whether bleomycin/vincristine compared to vincristine monotherapy was associated with improved treatment outcomes for AIDS-associated KS among patients initiating combination antiretroviral therapy (cART in Malawi.All patients initiating cART and chemotherapy for AIDS-related KS were identified from an electronic data system from the HIV Lighthouse Clinic from 2002 to 2011. Treatment responses were compared between patients receiving vincristine monotherapy and vincristine/bleomycin. Binomial regression models were implemented to assess probability of tumor improvement for patients receiving vincristine/bleomycin compared to vincristine monotherapy after a complete cycle of chemotherapy (9-10 months. A chi-squared test was used to compare changes in CD4 count after six months of chemotherapy.Of 449 patients with AIDS-associated KS on chemotherapy, 94% received vincristine monotherapy and 6% received bleomycin/vincristine. Distribution of treatment outcomes was different: 29% of patients on vincristine experienced tumor improvement compared to 53% of patients on bleomycin/vincristine. Patients receiving bleomycin/vincristine were 2.25 (95% CI: 1.47, 3.44 times as likely to experience tumor improvement as to those on vincristine monotherapy. This value changed little after adjustment for age and baseline CD4 count: 2.46 (95% CI: 1.57, 3.86. Change in CD4 count was similar for patients receiving vincristine monotherapy and bleomycin/vincristine (p = 0.6.Bleomycin/vincristine for the treatment of AIDS-associated KS was associated with better tumor response compared to vincristine monotherapy without impairing CD4 count recovery. Replication in larger datasets and randomized controlled trials is necessary.

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

    Science.gov (United States)

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

    2014-11-01

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

  3. An automated HPLC method to determine intracellular vincristine concentrations in mononuclear cells of children with acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Groninger, E; Koopmans, P; Kamps, W; Uges, D

    A method to determine intracellular vincristine concentrations in vivo in leukemic cells of patients is useful to investigate mechanisms of vincristine resistance. We developed a high-performance liquid chromatographic (HPLC) method to measure vincristine concentrations in human mononuclear cells

  4. Pro: Cyclophosphamide in lupus nephritis

    NARCIS (Netherlands)

    Kallenberg, Cees G. M.

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

  5. Compound list: cyclophosphamide [Open TG-GATEs

    Lifescience Database Archive (English)

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

  6. Mechanism of interaction of vincristine sulphate and rifampicin with ...

    Indian Academy of Sciences (India)

    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 ...

  7. Optimal management of low-risk gestational trophoblastic neoplasia.

    Science.gov (United States)

    Goldstein, Donald P; Berkowitz, Ross S; Horowitz, Neil S

    2015-01-01

    Low-risk gestational trophoblastic neoplasia is a highly curable form of gestational trophoblastic neoplasia that arises largely from molar pregnancy and, on rare occasions, from other types of gestations. Risk is defined as the risk of developing drug resistance as determined by the WHO Prognostic Scoring System. All patients with non-metastatic disease and patients with risk scores disease. The sequential use of methotrexate and actinomycin D is associated with a complete remission rate of 80%. The most commonly utilized regimen for the treatment of patients resistant to single-agent chemotherapy is a multiagent regimen consisting of etoposide, methotrexate, actinomycin D, vincristine and cyclophosphamide. The measurement of human chorionic gonadotropin provides an accurate and reliable tumor marker for diagnosis, monitoring the effects of chemotherapy and follow-up to determine recurrence. Pregnancy is allowed after 12 months of normal serum tumor marker. Pregnancy outcomes are similar to those of normal population.

  8. Clinical Pharmacokinetics and Effects of Vincristine Sulfate in Dogs with Transmissible Venereal Tumor (TVT)

    OpenAIRE

    HANTRAKUL, Supannika; Klangkaew, Narumol; KUNAKORNSAWAT, Sunee; TANSATIT, Tawewan; POAPOLATHEP, Ammart; KUMAGAI Susumu; POAPOLATHEP, Saranya

    2014-01-01

    This study was conducted to evaluate the pharmacokinetic characteristics of vincristine and their correlation with its clinical effects in dogs with transmissible venereal tumor (TVT). Dogs with TVT were intravenously administered vincristine sulfate at a dose of 0.7 mg/m2 of body surface area. Blood samples were collected starting from 5 min to 48 hr after drug administration. The plasma concentration of vincristine was determined using liquid chromatography-tandem mass spectrometry (LC-MS/M...

  9. Single-Centre Experience of Systemic Treatment with Vincristine, Ifosfamide, and Doxorubicin Alternating with Etoposide, Ifosfamide, and Cisplatin in Adult Patients with Ewing Sarcoma

    Directory of Open Access Journals (Sweden)

    Annelies Requilé

    2017-01-01

    Full Text Available The treatment of Ewing sarcoma (ES in adult patients requires a multidisciplinary approach. Systemic therapy remains an important component of clinical management of this disease. ES is extremely rare in adult patients. Due to the rarity of the disease, no standard of care in terms of chemotherapy for the adult population exists, and the level of evidence for individual agents or some multidrug combinations is limited. Most regimens that are used in both adults and children include anthracyclines, etoposide, vincristine, cyclophosphamide, and ifosfamide. In this report, we describe our experience with the alternating use of triple combination therapies based on vincristine, ifosfamide, and doxorubicin (VIA and an etoposide, ifosfamide, and cisplatin combination (VIP. We retrospectively evaluated the response rates, outcome, and tolerance of adult patients (n = 64 treated with VIA/VIP between 1990 and 2014. The patients included were treated with perioperative chemotherapy (53.1% neoadjuvant therapy and 17.2% adjuvant therapy or had synchronous metastases at diagnosis (29.7%. Five-year overall survival rate was 52.2% for all patients, 72.2% for patients with localized disease, and 5.3% in patients with synchronous metastases. Overall response rate (ORR was 37% after 2 cycles of VIA and 2 cycles of VIP. There were no patients with progressive disease (PD.

  10. 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

  11. Lipid peroxidation in rats treated with vincristine sulphate and nandrolone decanoate

    Directory of Open Access Journals (Sweden)

    D.B Martins

    2011-02-01

    Full Text Available Brain and serum lipid peroxidation was studied in rats treated with vincristine sulphate and different doses of nandrolone decanoate. Thirty rats were distributed into six groups (n=5. The treatments were applied once a week for two weeks. Sample collection was performed in the third week. Treatments during the first week were: G1 (control - physiologic solution, G2 - vincristine sulphate (4mg/m², G3 - physiologic solution, G4 - physiologic solution, G5- vincristine sulphate (4mg/m², and G6 - vincristine sulphate (4mg/m². In the second week, they were: G1 (control - physiologic solution, G2- physiologic solution, G3 - nandrolone decanoate (1.8mg/kg-1, G4 - nandrolone decanoate (10mg/kg-1, G5 - nandrolone decanoate (1.8mg/kg-1, and G6 - nandrolone decanoate (10mg/kg-1. Lipid peroxidation increased with the isolated use of vincristine and nandrolone decanoate, and with vincristine associated to the highest dose of the ester as well. These results suggest that vincristine sulphate and nandrolone decanoate increase free radical production. Therapeutic dose of nandrolone decanoate when associated with vincristine sulphate proved to be beneficial, as it was able to protect the organism from damaging processes involved in free radical production

  12. Severe neurological disorders and refractory aspergillosis in an adolescent treated by vincristine and voriconazole.

    Science.gov (United States)

    Bennis, Y; Bodeau, S; Lutun, A; Gourmel, A; Solas, C; Quaranta, S; Guillaume, N; Chouaki, T; Lemaire-Hurtel, A-S; Masmoudi, K

    2017-08-10

    Voriconazole and vincristine are major therapeutics in paediatric haematology. However, the risk-benefit ratio of the treatment of invasive aspergillosis with voriconazole in patients receiving vincristine-based chemotherapy remains unclear. We report severe peripheral and central neurological disorders in a 14-year-old girl with T-cell acute lymphoblastic leukaemia and pulmonary aspergillosis. The case describes a strong exacerbation by voriconazole of the vincristine-induced neuropathic pains. It shows the high variability of the trough serum concentration of voriconazole leading to antifungal treatment failure and suggests that its own central neurotoxicity could also be potentiated by vincristine. Given the risk of either insufficient antifungal efficacy or excessive neurological disorders, this case warns on a probable unfavourable risk-benefit profile of voriconazole during vincristine-based chemotherapy in adolescents. © 2017 John Wiley & Sons Ltd.

  13. 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.

  14. Infantile fibrosarcoma treated with postoperative vincristine and dactinomycin.

    Science.gov (United States)

    Yoshihara, Hiroki; Yoshimoto, Yuri; Hosoya, Yosuke; Hasegawa, Daisuke; Kawano, Takafumi; Sakoda, Akiko; Okita, Hajime; Manabe, Atsushi

    2017-03-01

    Infantile fibrosarcoma is a non-rhabdomyosarcoma soft-tissue sarcoma that occurs in infancy and which has a relatively good prognosis. A vincristine and dactinomycin (VA) regimen has been shown to be effective, although the duration of chemotherapy has not been well defined. We describe the case of a 4-month-old boy with a mass at the left dorsum of the foot who was diagnosed with infantile fibrosarcoma after resection of the tumor, the margin of which was macroscopically positive. VA treatment was carried out with careful monitoring of response and adverse effects. Pancytopenia was seen during the second cycle, and therapy was reduced thereafter. The treatment was continued for 38 weeks (12 cycles). There was no functional impairment, and no evidence of recurrence at 18 months after therapy. © 2017 Japan Pediatric Society.

  15. Clinical Outcomes for Systemic Corticosteroids Versus Vincristine in Treating Kaposiform Hemangioendothelioma and Tufted Angioma.

    Science.gov (United States)

    Liu, Xiaohan; Li, Jiaying; Qu, Xinhua; Yan, Weili; Zhang, Ling; Zhang, Shanyong; Yang, Chi; Zheng, Jiawei

    2016-05-01

    A meta-analysis was performed to evaluate the efficacy and safety of systemic corticosteroids versus those of vincristine in the treatment of kaposiform hemangioendothelioma (KHE) and tufted angioma (TA).A literature search of PubMed, Embase, and Web of Science was performed for clinical studies on systemic corticosteroid versus vincristine therapies in treating KHE/TA. Pooled relative risks (RRs) and response rate with 95% confidence intervals (CIs) were used to measure outcomes. Heterogeneity, subgroup analysis, sensitivity analysis, and publication bias analysis were performed for result evaluation.Thirteen studies, comprising 344 participants, were used in the analysis. Vincristine therapy was found to be relatively more effective than systemic corticosteroids (RRs = 0.45, 95%CI: 0.35-0.58). The result of pooled adverse reactions response rate for systemic corticosteroids was 0.31 (95%CI, 0.18-0.43), significantly higher than that for vincristine, which was 0.12 (95%CI, 0.06-0.19). In subgroup analyses, factors including mean age and race of patients, and period of follow-up were examined as possible sources of heterogeneity.This is the first meta-analysis estimating the clinical outcomes of systemic corticosteroids in comparison with those of vincristine in the treatment of KHE/TA. The results showed that vincristine was considerably more effective with lower complication rates than systemic corticosteroids; thus, vincristine could be suggested as the first-line therapy for KHE/TA.

  16. PARALYTIC ILEUS AS A SIDE EFFECT OF VINCRISTINE AND ITRACONAZOLE TREATMENT

    Directory of Open Access Journals (Sweden)

    Samo Zver

    2003-09-01

    Full Text Available Background. Vincristin is an important and frequently used chemoterapeutic drug in the treatment of malignant lymphoproliferative disease. Among its side effects are well known bone marrow supression and polyneuropathia. But common physicians are not familiar with vincristine bowel peristaltics inhibitory effect.Patient and methods. This study presents 64-years old patient with acute lymphoblastic leukemia (ALL who was treated with chemotherapy which included vincristine. Two weeks after the treatment started paralytic ileus developed which was later sucessfully treated with laxatives and prokynetic drugs. Secondary causes for ileus development were excluded. Literature data was reviewed and a higher incidence of paralytic ileus in vincristine treated patients was found, especially when they are given concomitant itraconazole. Our patient received concommitant itraconazole as a part of antifungal prophylaxis against invasive aspergillosis which is a perceived routine on hematological departments.Conclusions. Vincristine treated patients should be carefully observed regarding bowel peristaltics and obstipation. If obstipation or even paralytic ileus developes, we must stop vincristine therapy. All patients receiving vincristine must receive fluconazol instead of itraconazol as a part of antifungal prophylaxis.

  17. Vincristine toxicity with co-administration of fluconazole during induction therapy for pediatric acute lymphoblastic leukemia.

    Science.gov (United States)

    Smitherman, Andrew B; Faircloth, Cassidy B; Deal, Allison; Troy, Michael; Gold, Stuart H

    2017-10-01

    Antifungal prophylaxis is recommended for patients with acute lymphoblastic leukemia (ALL) during high-risk periods such as induction; however, increased vincristine toxicities have been reported with the co-administration of triazole antifungals. We sought to determine whether vincristine-associated toxicities are higher among children with ALL concurrently given fluconazole prophylaxis compared to no prophylaxis. Using a retrospective cohort design, we reviewed records of pediatric patients treated for newly diagnosed ALL from 2003 to 2013. Patients were classified by fluconazole exposure during induction. The development of vincristine-associated toxicity and vincristine dose adjustment were the primary outcomes evaluated. The adjusted risk difference (RD) for vincristine-related toxicity associated with triazole exposure was determined. We identified 197 patients meeting inclusion criteria for evaluation, 160 (81%) of whom received fluconazole prophylaxis. Among patients receiving fluconazole, 36/160 (22%) developed vincristine toxicity compared to 7/37 (19%) among those not receiving prophylaxis (RD: 3%, 95% confidence interval [CI] -11 to 18%). Adjusting for patient age and race, no statistically significant increased risk for vincristine-associated toxicity with fluconazole exposure was observed (RD 5%, 95% CI -8 to 17%). An increased risk for vincristine-associated toxicity was independently associated with age 10 years or older (RD 19%, 95% CI 4-34%). Co-administration of fluconazole during induction therapy for pediatric ALL does not significantly increase the risk for vincristine-associated toxicities; however, patients 10 years or older are at an increased risk for toxicity independent of fluconazole exposure. Prophylaxis with fluconazole during induction therapy for pediatric ALL, if warranted, appears to be a safe clinical practice. © 2017 Wiley Periodicals, Inc.

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

    OpenAIRE

    Chinnamadasamy Kalidass; Veerabahu Ramasamy Mohan; Arjunan Daniel

    2009-01-01

    Callus cultures of Catharanthus roseus L. were established to verify whether they produce vincristine as the intact plant. Different growth regulator combinations were applied to Murashige and Skoog (MS) medium to influence the level of production of vincristine. The effects of various combinations (0.5 µM to 3.0 µM) of auxin and cytokinin on the growth and accumulation of vincristine were investigated. MS medium supplemented with 2,4-Dichlorophenoxy acetic acid (2,4-D) 1.0 µM and 6-furfur...

  19. 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.

  20. 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.

  1. Cyclophosphamide induced Haemorrhagic Cystitis; a review of ...

    African Journals Online (AJOL)

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

  2. Carbamazepine induces bioactivation of cyclophosphamide and thiotepa

    NARCIS (Netherlands)

    Ekhart, Corine; Rodenhuis, Sjoerd; Beijnen, Jos H.; Huitema, Alwin D. R.

    2009-01-01

    PURPOSE: We report a patient with metastatic breast cancer who received three cycles of high-dose chemotherapy with cyclophosphamide [1,000 mg/(m(2) day)], thiotepa (80 mg/(m(2) day) and carboplatin (dose calculated based on modified Calvert formula with 3.25 mg min/ml as daily target AUC) over 4

  3. 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.

  4. Modified CVAD and modified CBAD compared to high-dose cyclophosphamide for peripheral blood stem cell mobilization in patients with multiple myeloma.

    Science.gov (United States)

    Gettys, Suzanne C; Gulbis, Alison; Wilhelm, Kaci; Sasaki, Koji; Dinh, Yvonne; Rondon, Gabriela; Qazilbash, Muzaffar H

    2017-04-01

    The optimal regimen for peripheral blood stem cell (PBSC) mobilization in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (auto-HCT) has not been established. Experience at The University of Texas MD Anderson Cancer Center suggests in addition to single-agent cyclophosphamide (Cy), modified cyclophosphamide, vincristine, doxorubicin, and dexamethasone (mCVAD), and modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone (mCBAD) may be successful chemomobilization regimens. This retrospective review included 167 patients (66 with Cy, 74 with mCVAD, and 27 with mCBAD) with multiple myeloma undergoing mobilization for auto-HCT between January 1, 2006 and September 30, 2013. The primary objective was to evaluate and compare the successful mobilization of CD34+ cells among high-dose Cy, mCVAD or mCBAD. Successful mobilization (≥2×10 6 CD34+ cells/kg) was achieved in all patients, while 65 (98%), 72 (97%), and 27 (100%) patients achieved an optimal mobilization (≥4×10 6 CD34+ cells/kg) in the Cy, mCVAD, and mCBAD groups, respectively. There was no significant difference in the number of apheresis sessions (P=.63), incidence of febrile neutropenia (P=.57), or hospital admission rates (P=.55). Either Cy, mCVAD, or mCBAD can yield successful PBSC mobilization in patients with multiple myeloma undergoing auto-HCT. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. [Phase III study of chemotherapy in low-malignancy non-Hodgkin's lymphomas: comparison of vincristine-vindesine combination chemotherapy].

    Science.gov (United States)

    Heim, M E; Fritze, D; Ho, A D; Mebes, W; Abel, U

    1987-12-01

    In a phase-III study in non-Hodgkin's lymphoma of low malignancy we compared a combination therapy with vincristine (COP) with a vindesine combination (CEP). Remission rates, duration of remission and survival was favorable for the CEP combination without reaching the level of significance. The peripheral neurotoxicity of grade 2 and 3 according to WHO criteria was observed more frequently with vincristine. The vincristine-induced neurotoxicity in 6 patients was not impaired when a change was made to vindesine treatment.

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

    Science.gov (United States)

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

    2014-12-01

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

  7. Sustained delivery of vincristine inside an orthotopic mouse sarcoma model decreases tumor growth.

    Science.gov (United States)

    Harris, Jamie C; Coburn, Jeannine M; Kajdacsy-Balla, Andre; Kaplan, David L; Chiu, Bill

    2016-12-01

    Sarcoma accounts for 20% of solid tumors in children. Surgery has significant morbidity. We hypothesized that delivering chemotherapy directly into tumors through sustained release silk systems could slow tumor growth. Human Ewing sarcoma cells A673 were cultured with vincristine and doxorubicin to determine half maximal inhibitory concentration (IC50). Cells were injected into mouse hind leg to create orthotopic tumors. Tumor volumes were measured using ultrasound. When volume reached >250mm(3,) interventions included: implantation of drug-free silk foam (Control-F), doxorubicin 400μg foam (Dox400-F), vincristine 50μg foam (Vin50-F), drug-free silk gel (Control-G), vincristine 50μg gel (Vin50-G), or single dose intravenous vincristine 50μg (Vin50-IV). End-point was volume>1000mm(3). Kaplan Meier and ANOVA were used. IC50 for vincristine and doxorubicin was 0.5ng/mL and 200ng/mL, respectively. There was no difference between Dox400-F [6±1days to end point (DTEP)] and Control-F (5±1.3 DTEP). Vin50-F (12.4±3.5 DTEP) had slower growth compared to Control-F (pinside the sarcoma tumor with silk gel decreased tumor growth. Applying this intratumoral treatment strategy may potentially decrease the extent of surgical excision. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Effective Treatment of Transmissible Venereal Tumors in Dogs with Vincristine and IL2.

    Science.gov (United States)

    DEN Otter, Willem; Hack, Margot; Jacobs, John J L; Tan, Jurgen F V; Rozendaal, Lawrence; VAN Moorselaar, R Jeroen A

    2015-06-01

    To improve treatment of inoperable transmissible venereal tumors (TVTs) in dogs. Recently, we showed that TVT is sensitive to intratumoral treatment with interleukin-2 (IL2). In addition it is known that TVT is sensitive to intravenous treatment with vincristine. In the present study we tried to establish the therapeutic effect of intratumoral treatment with vincristine and IL2. We treated 12 dogs with TVT with 1-4 intratumoral treatments with vincristine and IL-2. Per treatment we used vincristine (0.5-0.7 mg/m(2)) and IL2 (2×10(6) units). The injections were given at weekly intervals. Early therapeutic effects were: three complete regressions, four partial regressions, three stable disease, and two progressive disease. Late therapeutic effects were established 45-60 months after the first presentation; there were five complete regressions, no partial regressions, nor stable or progressive diseases. Interestingly, all five dogs with late therapeutic effects were in good health. No tumor recurrence was noted. Intratumoral treatment of TVT with vincristine and IL2 appears to have impressive therapeutic effects. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. 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%.

  10. Semen quality during vincristine treatment in dogs with transmissible venereal tumor.

    Science.gov (United States)

    Saratsis, P; Ypsilantis, P; Tselkas, K

    2000-03-15

    The aim of this study was to evaluate the direct effects of vincristine on semen quality in dogs with transmissible venereal tumor (TVT). We examined the semen of 17 dogs suffering from TVT during vincristine treatment. Each animal received 0.6 mg, i.v. vincristine sulphate per square meter of body surface, per week for 4 wk until complete regression of the tumor. The following semen parameters were evaluated: semen volume (second fraction), sperm concentration, total spermatozoa per ejaculate, percentage of progressively motile spermatozoa, percentage of dead spermatozoa, percentage of swollen spermatozoa (hypo-osmotic swelling test) and percentage of morphologically abnormal spermatozoa (primary and secondary defects). Semen was collected and evaluated prior to the beginning of treatment, 3 d after each vincristine injection and 15 d after the last injection. Semen characteristics transiently deteriorated during treatment, but returned to normal 15 d later. These changes were attributed to a direct effect of vincristine on the extragonadal spermatozoal reserves contained in the epididymis and ductus deferens. A GnRH stimulation test was also performed after each semen collection in order to assess the function of the hypothalamic-pituitary-Leydig cell axis. No effect was noted on the above axis.

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

    Directory of Open Access Journals (Sweden)

    Chinnamadasamy Kalidass

    2009-11-01

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

  12. Result of cyclophosphamide effect on meristematic cells of anaerobic respiration

    Directory of Open Access Journals (Sweden)

    Maria Podbielkowska

    2014-01-01

    Full Text Available Hypertrophy of rough ER under the influence of cyclophosphamide (oncostatic substance in meristematic cells of normal and modified glycolysis pathways has been demonstrated. The organization of ergastoplasmic structures has been considered as a process of adaptation to the changed energy conditions caused by cyclophosphamide since analogous changes in protoplastic structures have been found in meristematic cells of oxygen respiration.

  13. [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.

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

    Science.gov (United States)

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

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

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

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    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. Erythrocyte dysplasia in peripheral blood smears from 5 thrombocytopenic dogs treated with vincristine sulfate.

    Science.gov (United States)

    Collicutt, Nancy B; Garner, Bridget

    2013-12-01

    Secondary dyserythropoiesis has been associated with vincristine administration in dogs. Evaluation of bone marrow aspirates for the presence of morphologic abnormalities in the erythroid lineage aids in the diagnosis. However, morphologic features of circulating erythroid precursors in these cases have not been described previously. The purpose of this report was to describe the cytologic features of dyserythropoiesis in peripheral blood and also bone marrow smears in a case series of dogs with immune-mediated thrombocytopenia (IMT) treated with vincristine sulfate. Nineteen dogs receiving vincristine for treatment of IMT were identified by retrospectively searching a computerized medical record system. There were 5 dogs that had dysplastic erythroid precursors in peripheral blood smears within 7 days of vincristine treatment. Two of those 5 dogs also had evidence for erythrodysplasia in modified Wright's-stained bone marrow smears obtained postvincristine administration. Morphologic changes included bizarre or inappropriate mitotic figures, abnormal nuclear configurations (fragmentation, elongation, indentation, and binucleation), atypical nuclear remnants (Howell-Jolly bodies), or nuclear and cytoplasmic asynchrony within the erythroid precursors. A brief review of the literature with discussion of the etiologies for dyserythropoiesis is provided. The dyserythropoiesis was clinically insignificant in all 5 cases and resolved. However, pathologists and clinicians should be aware of these potential findings to prevent misdiagnosis of other conditions. © 2013 American Society for Veterinary Clinical Pathology and European Society for Veterinary Clinical Pathology.

  17. A Clinico-pathological study on the effect of vincristine on transmissible venereal tumour in dogs.

    Science.gov (United States)

    Nak, D; Nak, Y; Cangul, I T; Tuna, B

    2005-09-01

    Transmissible venereal tumour (TVT) is a coitally transmitted neoplasm of dogs and is common among sexually active dogs, where sexual behaviour is not under control. Several treatment options are available for the treatment of the tumour, with chemotherapy being the most commonly employed. In this study, we investigated the clinical and cytological changes after weekly vincristine sulphate administration in 38 cases of naturally occurring TVT. Tumours totally regressed in 31 dogs after two to seven doses (mean 3.54 +/- 1.01) of vincristine. One dog died after the fifth dose of vincristine, and in six dogs, an additional treatment with doxorubicin was needed. Masses were still present in four dogs and the histopathological examination revealed small nodules of granulation tissue in two dogs, while viable tumour cells were identified in the remaining two cases. No recurrences were observed in a follow-up period of 7-49 months (mean 13.64 +/- 9.66); in one dog, granulation tissue was detected in the surgery site after 2 months. Treatment success could easily be followed by the cytological changes. In conclusion, vincristine was found to be effective chemotherapeutic agent.

  18. Resulting alterations at the level of testes and semen in dogs submitted to vincristine sulphate administra tion

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    Carlos Roberto Daleck

    1995-03-01

    Full Text Available Sperm analysis and testicular histological studies were performed before and after vincristine sulphate treatment, in fourteen male dogs. In group I (n = 8, unilateral orchiectomy was carried out before and after mitostatic treatment, and testicular and epididymal biopsies were examined histologically. All histological examinations showed a slight to moderate degeneration of testicular tissue. In group II (n = 6 semen was collected and was submitted to laboratorial analysis. After vincristine treatment, middle piece and tail abnormalities were found. However, as physical and morphological abnormalities showed to be reversible, vincristine sulphate therapy may be used in such species.

  19. 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. Copyright © 2016. Published by Elsevier Editora Ltda.

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

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    Kaian Amorim Teles

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

  1. Vincristine modulates the expression of Ki67 and apoptosis in naturally occurring canine transmissible venereal tumor (TVT).

    Science.gov (United States)

    Özalp, G R; Zik, B; Bastan, A; Peker, S; Özdemir-Salci, E S; Bastan, I; Darbaz, I; Salar, S; Karakas, K

    2012-07-01

    We investigated eight adult dogs that were brought to veterinary clinics with a history of transmissible venereal tumors (TVT). Our goal was to demonstrate the occurrence of apoptosis and the cessation of cell proliferation at every phase of scheduled chemotherapy for naturally occurring TVT. Tissue samples were collected immediately after weekly treatments with vincristine sulfate and processed for histological purposes. Sections 5 μm thick were stained by the TUNEL reaction for apoptosis and immunostained for Ki67 as a proliferation marker. We observed that after vincristine applications, tumor cell proliferation ceased and apoptosis increased. Ki67 HSCORE values were significantly lowered after the first and second treatments with the chemotherapeutic agent compared to controls, whereas TUNEL HSCORE values were significantly higher after two applications of vincristine compared to controls. Our results suggest that scheduled vincristine sulfate applications stabilize the induction of tumor regression by inducing apoptosis and preventing cell proliferation.

  2. Exogenous induction of HO-1 alleviates vincristine-induced neuropathic pain by reducing spinal glial activation in mice.

    Science.gov (United States)

    Shen, Yan; Zhang, Zhi-Jun; Zhu, Ming-Di; Jiang, Bao-Chun; Yang, Tian; Gao, Yong-Jing

    2015-07-01

    Chemotherapy drugs such as vincristine can produce painful peripheral neuropathy for which is still lack of effective treatment. Recent studies have demonstrated that neuroinflammation plays an important role in the pathogenesis of neuropathic pain. Heme oxygenase 1 (HO-1) was shown to mediate the resolution of inflammation. In this study, we investigated the contribution of HO-1 in the modulation of vincristine-induced pain and the mechanisms implicated. Injection of vincristine induced persistent mechanical allodynia and thermal hyperalgesia in mice. The expression of HO-1 mRNA and protein was increased in 2 weeks in the spinal cord. Immunostaining showed that HO-1 was mainly expressed in neurons of spinal cord dorsal horn in naïve animals, but induced in astrocytes and microglia after vincristine injection. Intraperitoneal injection of HO-1 inducer increased HO-1 expression in the spinal cord and attenuated vincristine-induced pain. Persistent induction of HO-1 by intraspinal injection of HO-1-expressing lentivirus alleviated vincristine-induced pain for more than 2 weeks. Furthermore, vincristine induced activation of glial cells (astrocytes and microglia), phosphorylation of MAPKs (JNK, ERK, and p38), and production of TNF-α and monocyte chemoattractant protein-1 in the spinal cord, which were all reduced by intrathecal injection of HO-1 inducer. Taken together, our data provide the first evidence that induction of HO-1 attenuates vincristine-induced neuropathic pain via inhibition of glia-mediated neuroinflammation in the spinal cord. This suggests that exogenously induced HO-1 may have potential as therapy in chemotherapy-induced neuropathic pain. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide.

    Science.gov (United States)

    Fouad, Amr A; Qutub, Hatem O; Al-Melhim, Walid N

    2016-07-01

    This study investigated the possible hepatoprotection of punicalagin in rats received cyclophosphamide (20mg/kg/day, i.p., for 7 days). Punicalagin given at two doses, 15 and 30mg/kg/day, p.o., for 7 days, starting the same day of cyclophosphamide administration. Punicalagin significantly and dose-dependently reduced the elevations of serum alanine aminotransferase, and liver nuclear factor-κB p65, tumor necrosis factor-α, interleukin-1β, malondialdehyde, nitric oxide, Bax/Bcl-2 ratio, inducible nitric oxide synthase, caspases 3 and 9 activities, and prevented the decrease of hepatic total antioxidant capacity. Punicalagin also attenuated the histopathological liver tissue damage, and decreased cyclooxygenase-2 expression in liver of rats received cyclophosphamide in a dose-dependent manner. It was concluded that punicalagin protected rat liver against cyclophosphamide toxicity by inhibiting oxidative/nitrosative stress, inflammation, and apoptosis. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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    Shiva Joohari

    2015-06-01

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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  6. Effect of duration of exposure to verapamil on vincristine activity against multidrug-resistant human leukemic cell lines.

    Science.gov (United States)

    Cass, C E; Janowska-Wieczorek, A; Lynch, M A; Sheinin, H; Hindenburg, A A; Beck, W T

    1989-11-01

    Verapamil sensitizes multidrug-resistant cell lines to various heterocyclic anticancer drugs by inhibition of energy-dependent release of drug, presumably by interaction with membrane glycoproteins involved in drug efflux. This work assessed verapamil sensitization of human multidrug-resistant lymphocytic and myeloid leukemic cell lines (CEM/VLB100, HL-60/AR) to vincristine during exposures of short duration (4 h). When cells were transferred to drug-free medium immediately after simultaneous 4-h exposures to vincristine and verapamil, the antiproliferative activity of vincristine was not altered in CEM/VLB100 cells and was only moderately increased in HL-60/AR cells. In contrast, when cells were transferred to verapamil-containing medium, vincristine activity was greatly increased against both CEM/VLB100 and HL-60/AR cells. Verapamil enhanced accumulation and inhibited release of [3H]vincristine by CEM/VLB100 and HL-60/AR cells, indicating that the sensitization was due to an increase in cell-associated vincristine after transfer of cells to vincristine-free medium. Slot blot analysis of cellular RNA with the pMDR1 probe revealed high levels of expression of the mdr1 gene in CEM/VLB100 cells but no detectable expression in HL-60/AR cells. Consistent with this finding, polypeptides (Mr 170,000 to 180,000) that were recognized by a monoclonal antibody (C219) against P-glycoprotein were greatly overexpressed in CEM/VLB100 cells, but were expressed at low levels, if at all, in HL-60/AR cells. These results demonstrate the importance of duration of exposure to verapamil in reversing multidrug resistance, not only in cells that overexpress P-glycoprotein but also in cells, such as HL-60/AR, that express little, if any, P-glycoprotein.

  7. Vinblastine and Vincristine Production on Madagascar Periwinkle (Catharanthus roseus (L. G. Don Callus Culture Treated with Polethylene Glycol

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    Nisa Nur Iskandar

    2016-03-01

    Full Text Available Vinblastine and vincristine are secondary metabolites from Madagascar periwinkles that have a very high economic value as chemotherapy drugs. These compounds are naturally produced in a very low quantity in planta. One promising alternative method for vinblastine and vincristine production is to use a treatment that can trigger plant stress response in vitro. This study has been done to evaluate the effect of drought stress using polyethylene glycol (PEG on vinblastine and vincristine production in the C. roseus callus culture, which were grown on medium Zenk supplemented with plant growth regulators (PGR 1 μM NAA + 10 μM Kinetin to induce laticifer and idioblast differentiation. 13-week-old callus cultures were then treated with 0%, 6%, 9%, and 12% (w/v PEG4000 each for 0, 24, 48, and 72 hours. Biochemical analysis was performed using HPLC to determine the levels of vinblastine and vincristine, while the presence of differentiated cells (idioblasts and laticifers was determined using a histochemical method. Protein profiles of the culture were determined by SDS-Page. The results showed that drought treatment with PEG4000, until the concentration was 12% (w/v, did not significantly affect the production of vinblastine and vincristine, but might affect terpenoid production. Histochemical analysis confirmed the presence of idioblasts, non-elongated laticifers, and laticifers that were producing and accumulating terpenoids highest in the 12% PEG treatment. PEG treatments also did not change the protein profile of callus.

  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 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.

  10. 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.

  11. Effects of cyclophosphamide and a metabolite, acrolein, on Naegleria fowleri in vitro and in vivo.

    OpenAIRE

    Zhang, L; Marciano-Cabral, F; Bradley, S G

    1988-01-01

    Mice challenged intranasally with Naegleria fowleri died of primary amoebic meningoencephalitis. Mice given 30 mg of cyclophosphamide per kg of body weight daily for 10 days starting 2 days before challenge were protected. Neither cyclophosphamide nor serum from cyclophosphamide-treated mice inhibited N. fowleri in vitro. A metabolic product of cyclophosphamide, acrolein, inhibited growth and enflagellation of N. fowleri. Acrolein at 40 microM was amoebicidal. Acrolein injured starved cells a...

  12. Management and survival of patients with FIGO high-risk gestational trophoblastic neoplasia: the U.K. experience, 1995-2010.

    Science.gov (United States)

    Agarwal, Roshan; Alifrangis, Costi; Everard, Janet; Savage, Philip M; Short, Dee; Tidy, John; Fisher, Rosemary A; Sebire, Neil J; Harvey, Richard; Hancock, Barry W; Coleman, Robert E; Seckl, Michael J

    2014-01-01

    To present survival rates of high-risk gestational trophoblastic neoplasia (GTN) (FIGO score > 7) patients treated between 1995 and 2010 in the U.K. Death due to GTN is largely confined to patients with high-risk disease. In the U.K. a national system ensures that all patients are treated at only 2 specialist centers: Charing Cross Hospital (CXH) in London and Weston Park Hospital (WPH) in Sheffield. A total of 196 high-risk patients were identified using the CXH and WPH GTN databases, based on the risk score at the time of presentation. In all, 140 CXH and 56 WPH high-risk patients were treated with EMA/CO (etoposide, methotrexate, actinomycin D alternating with cyclophosphamide and vincristine) and MEA (methotrexate, etoposide, actinomycin D), respectively. The FIGO score at presentation ranged from 6-23. Eight patients (7from WPH and 1 from CXH) who were treated prior to 2002 as high-risk based on their pre-2002 scoring scored a 6 using FIGO 2002. Two (1%) patients died within 4 weeks of starting treatment (early death), 12 (6%) relapsed, and 9 patients subsequently died due to drug resistance. The overall survival was 94%, with a median follow-up of 4.69 years. In the context of a national trophoblastic disease service, patients with high-risk GTN have an excellent prognosis with EMA/CO or MEA.

  13. 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

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    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.

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

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    Beatriz Ursinos Catelan Schneider

    2016-06-01

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

  15. Protective Effects of Caffeic Acid Phenethyl Ester on Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats.

    Science.gov (United States)

    Uysal, Ersin; Yılmaz, H Ramazan; Ugan, Yunus; Altuntas, Atila; Dogru, Atalay; Kutlucan, Ali; Tunc, Sevket Ercan

    2015-12-01

    We investigated the protective effect of caffeic acid phenethyl ester (CAPE) on cyclophosphamide-induced hemorrhagic cystitis in rats in comparison with 2-mercaptoethane sulfonate (MESNA). Forty male rats were randomized into four groups: group 1 (control), group 2 (cyclophosphamide), group 3 (cyclophosphamide + MESNA), group 4 (cyclophosphamide + CAPE). Cyclophosphamide injection increased malondialdehyde levels indicating oxidative stress, whereas CAPE and MESNA ameliorated malondialdehyde levels in the bladder (p hemorrhagic cystitis, we suggest that it would be more beneficial to use MESNA with CAPE to prevent histological damage. © 2015 Wiley Periodicals, Inc.

  16. Prevention of further cyclophosphamide induced hemorrhagic cystitis by hyperbaric oxygen and mesna in guinea pigs.

    Science.gov (United States)

    Korkmaz, A; Oter, S; Deveci, S; Goksoy, C; Bilgic, H

    2001-09-01

    Hyperbaric oxygen therapy and mesna have been successfully used for hemorrhagic cystitis. We defined the protective effects of hyperbaric oxygen and mesna in further cyclophosphamide induced hemorrhagic cystitis in guinea pigs. A total of 48 male guinea pigs were divided into 6 groups. All groups received 2 doses of 68.1 mg./kg. cyclophosphamide intraperitoneally at the same time intervals but group 1 served as controls. Group 2 received cyclophosphamide only, group 3 received hyperbaric oxygen treatment (2.8 ATA for 90 minutes twice daily) before and the day after further cyclophosphamide, group 4 received 21.5 mg./kg. mesna intraperitoneally only with further cyclophosphamide, group 5 received hyperbaric oxygen and mesna with further cyclophosphamide, and group 6 received hyperbaric oxygen before initial cyclophosphamide, between the 2 doses and after the further dose of cyclophosphamide, and mesna on the days of cyclophosphamide. Although mesna alone provided protection against cyclophosphamide induced cystitis in animal bladders, there was also significant damage compared with controls. When the uroprotective efficacy of mesna was supported with hyperbaric oxygen, bladder protection was promoted since mean histological scores and hematuria levels in this group did not differ from those in controls. According to this animal study using hyperbaric oxygen as adjuvant therapy in humans may be a better tool than mesna alone for the prophylaxis and treatment of cyclophosphamide induced hemorrhagic cystitis.

  17. 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

    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

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

    NARCIS (Netherlands)

    Segeren, C. M.; Sonneveld, P.; van der Holt, B.; Baars, J. W.; Biesma, D. H.; Cornellissen, J. J.; Croockewit, A. J.; Dekker, A. W.; Fibbe, W. E.; Löwenberg, B.; van Marwijk Kooy, M.; van Oers, M. H.; Richel, D. J.; Schouten, H. C.; Vellenga, E.; Verhoef, G. E.; Wijermans, P. W.; Wittebol, S.; Lokhorst, H. M.

    1999-01-01

    We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4 mg and doxorubicin 9 mg/m2 as a rapid intravenous infusion for 4 d together with intermittent high-dose dexamethasone 40 mg (VAD) for remission induction

  19. Vincristine induced apoptosis in acute lymphoblastic leukaemia cells : A mitochondrial controlled pathway regulated by reactive oxygen species?

    NARCIS (Netherlands)

    Groninger, E; Meeuwsen-De Boer, GJ; Kamps, WA; De Bont, ESJM

    2002-01-01

    Vincristine (VCR), a microtubule interfering anticancer agent, plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL). The route of VCR induced apoptosis in ALL cells is not well defined. In this study we demonstrated caspase-9 and -3 activation in vivo in bone marrow

  20. Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: A mitochondrial controlled pathway regulated by reactive oxygen species?

    NARCIS (Netherlands)

    Groninger, E.; Boer, A.W. de; Graaf, S.S.N. de; Kamps, W.A.; Bont, E.S. de

    2002-01-01

    Vincristine (VCR), a microtubule interfering anti-cancer agent, plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL). The route of VCR induced apoptosis in ALL cells is not well defined. In this study we demonstrated caspase-9 and -3 activation in vivo in bone marrow

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

    Science.gov (United States)

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

    2013-11-01

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

  2. Yeast extract elicitation increases vinblastine and vincristine yield in protoplast derived tissues and plantlets in Catharanthus roseus

    Directory of Open Access Journals (Sweden)

    Mehpara Maqsood

    Full Text Available Abstract Catharanthus roseus (L. G. Don, Apocynaceae, is an immensely important medicinal plant, produces a variety of anticancerous compounds. The yield of two most investigated alkaloids vinblastine and vincristine is unfortunately very low. A vast array of technologies including elicitation have recently been used to enrich Catharanthus alkaloid in culture. Yeast extract is a biotic elicitor, the polysaccharide and the peptide moiety have been recognized as a signalling element in enriching secondary metabolites. In this study, the yeast extract elicitation on vinblastine and vincristine was studied in various protoplast derived tissues and plantlets. Four different yeast extract treatments (T1 = 0.5 g/l, T2 = 1.0 g/l, T3 = 1.5 g/l and T4 = 2.0 g/l were prepared and used. The alkaloid was quantified and a comparative account of yield were presented by the use of High performance thin layer chromatography. The yeast extract amendment in medium improved vinblastine and vincristine yield in cultivating tissues, maximum being in germinating embryos and in in vitro raised leaf. The highest yield was in T3 (1.5 mg/l in which 22.74% vinblastine and 48.49% vincristine enrichment was noted in germinating embryos; the enhancement was however, treatment-specific. Antioxidant enzymes such as superoxide dismutase, catalase, ascorbate peroxidase and glutathione reductase activities were investigated as addition of yeast extract caused cellular stress and had enriched level of alkaloids.

  3. An Endophytic Fungus, Talaromyces radicus, Isolated from Catharanthus roseus, Produces Vincristine and Vinblastine, Which Induce Apoptotic Cell Death.

    Science.gov (United States)

    Palem, Padmini P C; Kuriakose, Gini C; Jayabaskaran, Chelliah

    2015-01-01

    Endophytic fungi isolated from Catharanthus roseus were screened for the production of vincristine and vinblastine. Twenty-two endophytic fungi isolated from various tissues of C. roseus were characterized taxonomically by sequence analysis of the internal transcribed spacer (ITS) region of rDNA and grouped into 10 genera: Alternaria, Aspergillus, Chaetomium, Colletotrichum, Dothideomycetes, Eutypella, Eutypa, Flavodon, Fusarium and Talaromyces. The antiproliferative activity of these fungi was assayed in HeLa cells using the MTT assay. The fungal isolates Eutypella sp--CrP14, obtained from stem tissues, and Talaromyces radicus--CrP20, obtained from leaf tissues, showed the strongest antiproliferative activity, with IC50 values of 13.5 μg/ml and 20 μg/ml, respectively. All 22 endophytic fungi were screened for the presence of the gene encoding tryptophan decarboxylase (TDC), the key enzyme in the terpenoid indole alkaloid biosynthetic pathway, though this gene could only be amplified from T. radicus--CrP20 (NCBI GenBank accession number KC920846). The production of vincristine and vinblastine by T. radicus--CrP20 was confirmed and optimized in nine different liquid media. Good yields of vincristine (670 μg/l) in modified M2 medium and of vinblastine (70 μg/l) in potato dextrose broth medium were obtained. The cytotoxic activity of partially purified fungal vincristine was evaluated in different human cancer cell lines, with HeLa cells showing maximum susceptibility. The apoptosis-inducing activity of vincristine derived from this fungus was established through cell cycle analysis, loss of mitochondrial membrane potential and DNA fragmentation patterns.

  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. Oral cyclophosphamide and etoposide in treatment of malignant pleural mesothelioma.

    Science.gov (United States)

    Gunduz, Seyda; Mutlu, Hasan; Goksu, Sema Sezgin; Arslan, Deniz; Tatli, Ali Murat; Uysal, Mukremin; Coskun, Hasan Senol; Bozcuk, Hakan; Ozdogan, Mustafa; Savas, Burhan

    2014-01-01

    Malignant mesothelioma (MM) is almost always fatal and few treatment options are available. The aim of this study was to evaluate the efficacy of oral cyclophosphamide and etoposide for patients who underwent standard treatment for advanced MM. This study included 22 malignant pleural mesothelioma patients who were treated with oral cyclophosphamide and etoposide (EE). The average follow-up period of the patients was 39.1 months. Under the treatment of oral EE, median progression- free survival was 7.7 months [95%CI HR (4.3-11.1)] and median overall survival was 28.1 months [95%CI HR (5.8-50.3)]. The treatment response rates were as follows: 4 patients (27.3%) had a partial response (PR), 12 (54.5%) had stable disease (SD), and progressive disease (PD) was observed in 6 (35.9%). Oral EE can be administered effectively to patients with inoperable malignant mesothelioma who had previously received standard treatments.

  7. Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses

    OpenAIRE

    Fulci, Giulia; Breymann, Laura; Gianni, Davide; Kurozomi, Kazuhiko; Rhee, Sarah S.; Yu, Jianhua; Kaur, Balveen; Louis, David N.; Weissleder, Ralph; Caligiuri, Michael A.; Chiocca, E. Antonio

    2006-01-01

    Clinical trials are testing oncolytic viruses (OVs) as therapies for cancer. We have shown that animals that have brain tumors and are treated with a herpes simplex virus (HSV)-derived OV live significantly longer when cyclophosphamide (CPA) is preadministered. Here, we explore the mechanisms behind this finding. In a syngeneic rat glioma model, intratumoral HSV administration is associated with rapid increase of natural killer cells, microglia/macrophages (CD68+ and CD163+), and IFN-γ. Pretr...

  8. Protective Effect of Hesperidin against Cyclophosphamide Hepatotoxicity in Rats

    OpenAIRE

    Amr A. Fouad; Waleed H. Albuali; Iyad Jresat

    2014-01-01

    The protective effect of hesperidin was investigated in rats exposed to liver injury induced by a single intraperitoneal injection of cyclophosphamide (CYP) at a dose of 150 mg kg-1. Hesperidin treatment (100 mg kg-1/day, orally) was applied for seven days, starting five days before CYP administration. Hesperidin significantly decreased the CYP-induced elevations of serum alanine aminotransferase, and hepatic malondialdehyde and myeloperoxidase activity, significantly pre...

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

    Directory of Open Access Journals (Sweden)

    CHENG Peng

    2013-12-01

    Full Text Available ObjectiveTo investigate the clinical efficacy of cyclophosphamide in the treatment of primary sclerosing cholangitis (PSC. MethodsTwenty-four patients with PSC who received treatment in the department of gastroenterology in our hospital from January 2004 to December 2012 were selected as subjects and divided into observation group (n=13 and control group (n=11. The control group was treated with ursodesoxycholic acid, while the observation group with ursodesoxycholic acid plus cyclophosphamide. After four weeks of treatment, clinical outcome, changes in serum bilirubin levels, and adverse reactions were compared between the two groups. Categorical data were analyzed by Fisher exact probability test, and continuous data by independent-samples t test and paired-samples t test. ResultsCompared with the control group, the observation group had a significantly higher response rate (84.62% vs 45.45%, P=0.0489, significantly more improvements in serum total and direct bilirubin levels (t=12.45, P<0.001; t=5.60, P<0.001, and a nonsignificantly higher incidence of adverse reactions (23.08% vs 18.18%, P=0.741. ConclusionCyclophosphamide has significant clinical efficacy and tolerable incidence of adverse events in the treatment of PSC, so it is worthy of application in clinical treatment.

  10. Ovarian protection in cyclophosphamide-treated mice by fennel

    Directory of Open Access Journals (Sweden)

    Azam Hassanpour

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

  11. 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

  12. 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

    2017-10-01

    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

  13. Numerical Chromosomal Abnormalities in Rat Epididymal Spermatozoa Following Chronic Cyclophosphamide Exposure1

    National Research Council Canada - National Science Library

    Tara S. Barton; Andrew J. Wyrobek; Francesca S. Hill; Bernard Robaire; Barbara F. Hales

    2003-01-01

    .... The goal of the present study was to determine the effect of chronic cyclophosphamide treatment during spermatogenesis on the frequency of numerical chromosomal anomalies in epididymal spermatozoa...

  14. Resulting alterations at the level of testes and semen in dogs submitted to vincristine sulphate administra tion

    OpenAIRE

    Carlos Roberto Daleck; Paulo Henrique Franceschini; João Guilherme Padilha Filho; Antonio Carlos Alessi; Joaquim Mansano Garcia; Maria Izabel Mello Martins; João Moreira da Costa Neto

    1995-01-01

    Sperm analysis and testicular histological studies were performed before and after vincristine sulphate treatment, in fourteen male dogs. In group I (n = 8), unilateral orchiectomy was carried out before and after mitostatic treatment, and testicular and epididymal biopsies were examined histologically. All histological examinations showed a slight to moderate degeneration of testicular tissue. In group II (n = 6) semen was collected and was submitted to laboratorial analysis. After vincristi...

  15. Long-term outcome of vincristine-aspirin-ticlopidine (VAT) therapy for vascular tumors associated with Kasabach-Merritt phenomenon.

    Science.gov (United States)

    Fernandez-Pineda, Israel; Lopez-Gutierrez, Juan Carlos; Chocarro, Gloria; Bernabeu-Wittel, Jose; Ramirez-Villar, Gema Lucia

    2013-09-01

    . This study aimed to clarify the combinatorial treatment effect of agents as aspirin and ticlopidine associated with vincristine in the management of Kasabach-Merritt phenomenon (KMP), a severe thrombocytopenic coagulopathy that occurs in the presence of an enlarging vascular tumor such as kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). . A retrospective review was conducted of medical records of all children with diagnosis of KHE or TA associated with KMP treated with vincristine-aspirin-ticlopidine (VAT) therapy at two different institutions in the same country from 1994 to 2011. Clinical features, response to VAT therapy and outcomes were recorded. . Eleven patients (mean age 11 months, range 0-36), including seven females (64%) and four males (36%), were identified. Seven patients underwent incisional biopsy and two different histologies were found, KHE in four patients and TA in three patients. Tumors were located in the head and neck (n = 5), chest wall (n = 2), arm (n = 2) and retroperitoneum (n = 2). Mean platelet level was 10,200/mm(3) (range 4,000-21,000). A plaque-like lesion with ecchymosis was the most common cutaneous manifestation (63%). All patients underwent VAT therapy. Mean duration of treatment was 3.9 months for vincristine, 13.9 months for aspirin, and 13.4 months for ticlopidine. All patients are alive with a mean follow-up of 4.5 years (range, 2-17). . Antiaggregant therapy is helpful in combination with vincristine in the treatment of KMP associated with KHE and TA. Prognosis is excellent if severe thrombocytopenia is controlled despite failure in reduction of tumor size. Copyright © 2013 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    Tandon, Pramod Kumar; Khatoon, Sayyada

    2014-01-01

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

  17. Isolation, purification and characterization of vinblastine and vincristine from endophytic fungus Fusarium oxysporum isolated from Catharanthus roseus.

    Directory of Open Access Journals (Sweden)

    Ashutosh Kumar

    Full Text Available Endophytic fungi reside in a symbiotic fashion inside their host plants, mimic their chemistry and interestingly, produce the same natural products as their hosts and are thus being screened for the production of valuable compounds like taxol, camptothecin, podophyllotoxin, etc. Vinblastine and vincristine are excellent anti-cancer drugs but their current production using plants is non-abundant and expensive. In order to make these drugs readily available to the patients at affordable prices, we isolated the endophytic fungi from Catharanthus roseus plant and found a fungus AA-CRL-6 which produces vinblastine and vincristine in appreciable amounts. These drugs were purified by TLC and HPLC and characterized using UV-Vis spectroscopy, ESI-MS, MS/MS and (1H NMR. One liter of culture filtrate yielded 76 µg and 67 µg of vinblastine and vincristine respectively. This endophytic fungal strain was identified as Fusarium oxysporum based upon its cultural and morphological characteristics and internal transcribed spacer (ITS sequence analysis.

  18. Mechlorethamine, vincristine, melphalan and prednisone (MOMP) for the treatment of relapsed lymphoma in dogs.

    Science.gov (United States)

    Back, A R; Schleis, S E; Smrkovski, O A; Lee, J; Smith, A N; Phillips, J C

    2015-12-01

    Eighty-eight dogs with relapsed lymphoma were treated with the MOMP (mechlorethamine, vincristine, melphalan and prednisone) protocol on a 28-day treatment cycle. The overall response rate (ORR) to the MOMP protocol was 51.1% for a median of 56 days (range 7-858 days). Twelve percent of dogs experienced a complete response for a median of 81 days (range 42-274 days) and 38.6% experienced a partial response for a median of 49 days (range 7-858 days). Dogs with T-cell lymphoma had an ORR of 55% for a median of 60 days (range 49-858 days) while those with B-cell lymphoma had an ORR of 57% for a median of 81 days (range 7-274 days) (P = 0.783). The overall survival time for all dogs was 183 days (range 17-974 days). Fifty-four percent of dogs experienced toxicity with the majority classified as grade I. The MOMP protocol seems well-tolerated and is an option for dogs with relapsed lymphoma. © 2013 John Wiley & Sons Ltd.

  19. Comparison of apoptosis in canine transmissible veneral tumor (TVT pre and post chemotraoy with vincristine sulphate

    Directory of Open Access Journals (Sweden)

    Y Doustar

    2010-11-01

    Full Text Available The canine transmissible veneral tumor (CTVT is a prevalent tumor in canidae. It is transmitted by coitus, forming multiple neoplastic masses on the external genitalia of both sexes within the family canidae. CTVT have an aberrant karyotype and the origin of the neoplastic cells is undetermined but immunophenotyping suggests that the tumor has a histocytic origin. In this study 10 dogs with canine transmissible veneral tumor were selected and received vincristine sulphate (0.025 mg/kg/b.w chemotrapy to induce apoptosis in neoplastic cells. Biopsy specimens were collected from tumors during the growth phase, before and again after chemotherapy from the same dogs. The specimens were fixed in 10% formalin and then prepared routinely for H&E and TUNEL assays. Histopathological study of tissue section of CTVT before chemotherapy revealed sheets of uniform neoplastic cells, round to oval in shape with defined cytoplasmic border. There were a few TUNEL positive cells and mitotic figures. In tumor specimens after chemotherapy increased TUNEL positive cells and depilation of neoplastic cells in stroma of tumor were observed. Mean deference of histopathological changes and TUNEL positive cells before and after chemotherapy were significant (p

  20. Efficacy of adjuvant therapy with procarbazine, MCNU, and vincristine for oligodendroglial tumors

    Energy Technology Data Exchange (ETDEWEB)

    Wakabayashi, Toshihiko; Kajita, Yasukazu; Mizuno, Masaaki; Yoshida, Jun [Nagoya Univ. (Japan). School of Medicine; Nagasaka, Tetsurou

    2001-03-01

    An adjuvant chemotherapy regimen consisting of procarbazine, MCNU, and vincristine (PMV) was evaluated for the treatment of malignant oligodendroglial tumors. Ten patients with histologically proven oligodendroglial tumors were treated with PMV therapy and the effectiveness was assessed using magnetic resonance imaging. Four patients with primary tumors underwent PMV after radiation therapy, and six patients with recurrent tumors were treated using PMV only. Tumor response was defined as radiological evidence of mass size change after completion of three courses of PMV. Complete or partial responses (more than 50% reduction in tumor mass) were noted in six patients, and tumor growth stabilized in four patients. In particular, inhibition of tumor growth using PMV was achieved in three patients with recurrent oligodendroglial tumors, despite the initial response after chemoradiation therapy (interferon-{beta}, MCNU, radiation) or nitrosourea chemotherapy (ACNU, MCNU). This PMV regimen (a modified PCV regimen using drugs available in Japan) is effective for treating malignant oligodendroglial tumors despite recurrence after other initial treatment procedures. (author)

  1. 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.

  2. Extremely high exposures in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin

    NARCIS (Netherlands)

    de Jonge, Milly E.; Mathôt, Ron A. A.; van Dam, Selma M.; Beijnen, Jos H.; Rodenhuis, Sjoerd

    2002-01-01

    An obese 53-year-old woman (height 167 cm, weight 130 kg) with metastatic breast cancer received high-dose chemotherapy comprising cyclophosphamide, thiotepa and carboplatin (CTC). The cyclophosphamide (1 g/m(2) per day) and thiotepa (80 mg/m(2) per day) doses were based on body surface area (BSA)

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

    DEFF Research Database (Denmark)

    Faurschou, M.; Sorensen, I.J.; Mellemkjaer, L.

    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....

  4. Azithromycin Synergistically Enhances Anti-Proliferative Activity of Vincristine in Cervical and Gastric Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Xuezhang; Zhang, Yuyan; Li, Yong; Hao, Xiujing; Liu, Xiaoming, E-mail: erc1080@gmail.com; Wang, Yujiong, E-mail: erc1080@gmail.com [Key Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Yinchuan 750021, Ningxia (China); College of Life Science, Ningxia University, Yinchuan 750021, Ningxia (China)

    2012-12-04

    In this study, the anti-proliferative and anticancer activity of azithromycin (AZM) was examined. In the presence of AZM, cell growth was inhibited more effectively in Hela and SGC-7901 cancer cells, relative to transformed BHK-21 cells. The respective 50% inhibition of cell growth (IC{sub 50}) values for Hela, SGC-7901 and BHK-21 were 15.66, 26.05 and 91.00 µg/mL at 72 h post incubation, indicative of a selective cytotoxicity against cancer cells. Cell apoptosis analysis using Hoechst nuclear staining and annexin V-FITC binding assay further demonstrated that AZM was capable of inducing apoptosis in both cancer cells and transformed cells. The apoptosis induced by AZM was partly through a caspase-dependent mechanism with an up-regulation of apoptotic protein cleavage PARP and caspase-3 products, as well as a down-regulation of anti-apoptotic proteins, Mcl-1, bcl-2 and bcl-X1. More importantly, a combination of AZM and a low dose of the common anti-cancer chemotherapeutic agent vincristine (VCR), produced a selectively synergistic effect on apoptosis of Hela and SGC-7901 cells, but not BHK-21 cells. In the presence of 12.50 μg/mL of VCR, the respective IC{sub 50} values of Hela, SGC-7901 and BHK-21 cells to AZM were reduced to 9.47 µg/mL, 8.43 µg/mL and 40.15 µg/mL at 72 h after the incubation, suggesting that the cytotoxicity of AZM had a selective anti-cancer effect on cancer over transformed cells in vitro. These results imply that AZM may be a potential anticancer agent for use in chemotherapy regimens, and it may minimize side effects via reduction of dosage and enhancing the effectiveness common chemotherapeutic drugs.

  5. Effects of lithium on peripheral neuropathy induced by vincristine in rats.

    Science.gov (United States)

    Alimoradi, Houman; Pourmohammadi, Nasir; Mehr, Shahram Ejtemaei; Hassanzadeh, Gholamreza; Hadian, Mohammad Reza; Sharifzadeh, Mohammad; Bakhtiarian, Azam; Dehpour, Ahmad Reza

    2012-01-01

    Vincristine (VCR) as a frequently used antimitotic agent which is commonly prescribed for wide spectrum of neoplasm, causes mixed sensorimotor neuropathy. Several evidences show lithium could be a neuroprotective agent, therefore to assess whether a pretreatment and at subtherapeutic dose it could prevent the peripheral neuropathy produced by VCR, rats were treated with VCR 0.1mg/kg i.p. for 3 alternative doses and / or lithium chloride (20mg/kg or 40 mg/kg i.p. daily from the first day to the day of sacrifice). Erythrocyte lithium concentration (ELC) and plasma lithium concentration (PLC) were measured at the seventh day of study and the day of scarification. After seventh day of lithium administration, PLC and ELC reached to a steady state at subtheraputic dose and they did not significantly change at normal housing situation. Hot plate, open field test and nerve conduction velocity were used to evaluate the sensory and motor neuropathy. Only VCR treated rats showed behavioral, electrophysiological and histological evidences of a mixed sensorimotor neuropathy by significant increase in hot plate latencies and a marked decrease in total distance moved and conduction velocities in both sensory and motor nerves. Lithium at the dose of 20mg/kg and specially 40mg/kg robustly reduced the rate of mortality, general toxicity and was able to ameliorate mixed sensorimotor neuropathy induced by VCR. These results suggest that lithium at dose of 20mg/kg and 40 mg/kg, potentially by its effects on cell survival pathways such as inhibition of glycogen synthase kinase-3 (GSK3β), can prevent both motor and sensory components of VCR neuropathy.

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

    Science.gov (United States)

    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. Phase III Randomized Study of Postradiotherapy Chemotherapy with α-Difluoromethylornithine-Procarbazine, N-(2-Chloroethyl)-N′-cyclohexyl-N-nitrosurea, Vincristine (DFMO-PCV) Versus PCV for Glioblastoma Multiforme

    National Research Council Canada - National Science Library

    Victor A. Levin; Joon H. Uhm; Kurt A. Jaeckle; Ali Choucair; Patrick J. Flynn; W. K. Alfred Yung; Michael D. Prados; Janet M. Bruner; Susan M. Chang; Athanassios P. Kyritsis; Mary Jo Gleason; Kenneth R. Hess

    2000-01-01

    ... ′-cyclohexyl- N -nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven...

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

    Directory of Open Access Journals (Sweden)

    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.

  9. 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.

  10. Evidence-based practice recommendations for hydration in children and adolescents with cancer receiving intravenous cyclophosphamide

    Science.gov (United States)

    Robinson, Deborah; Schulz, Ginny; Langley, Rachel; Donze, Kevin; Winchester, Kari

    2016-01-01

    Hemorrhagic cystitis is a known complication of cyclophosphamide, an anti-neoplastic agent used to treat a variety of oncologic diseases in children. Hydration can prevent hemorrhagic cystitis; however, use varies in clinical practice. A team was assembled to develop evidence-based practice recommendations to address the following question: in a population of children with cancer, what is the appropriate pre and post hydration for the administration of different dose levels of intravenous cyclophosphamide to prevent bladder toxicity? The purpose was to identify the appropriate rate, duration and route of hydration to prevent bladder toxicity with low, intermediate and high dose cyclophosphamide. After a systematic search of the literature, 15 pieces of evidence were evaluated and used. There is a moderate level of quality evidence related to hydration for high dose cyclophosphamide and very low quality evidence related to intermediate or low dose cyclophosphamide. Three general recommendations were made for hydration associated with cyclophosphamide. There is a need for further research related to the prevention of bladder toxicity in children with cancer receiving cyclophosphamide. PMID:24799445

  11. Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses.

    Science.gov (United States)

    Fulci, Giulia; Breymann, Laura; Gianni, Davide; Kurozomi, Kazuhiko; Rhee, Sarah S; Yu, Jianhua; Kaur, Balveen; Louis, David N; Weissleder, Ralph; Caligiuri, Michael A; Chiocca, E Antonio

    2006-08-22

    Clinical trials are testing oncolytic viruses (OVs) as therapies for cancer. We have shown that animals that have brain tumors and are treated with a herpes simplex virus (HSV)-derived OV live significantly longer when cyclophosphamide (CPA) is preadministered. Here, we explore the mechanisms behind this finding. In a syngeneic rat glioma model, intratumoral HSV administration is associated with rapid increase of natural killer cells, microglia/macrophages (CD68+ and CD163+), and IFN-gamma. Pretreatment with CPA enhances HSV replication and oncolysis and reduces an HSV-mediated increase in CD68+ and CD163+ cells and intratumoral IFN-gamma. Molecular imaging shows CPA pretreatment to inhibit HSV-induced infiltration of tumor-associated phagocytic cells. Our results reveal molecular and cellular mechanisms that inhibit intratumoral spread of HSV and suggest a therapeutic path for improving the efficacy of virotherapy as a treatment for cancer.

  12. Fatal hemorrhagic cystitis induced by pelvic irradiation and cyclophosphamide therapy. Case reports and review

    Energy Technology Data Exchange (ETDEWEB)

    Price, W.E.; Keldahl, L.R.

    1990-05-01

    The potent cytotoxic drug cyclophosphamide has been used extensively for neoplastic and non-neoplastic diseases. Patients taking this drug may have received or may be receiving pelvic irradiation concurrently. This report describes two patients who developed fatal hemorrhagic cystitis induced by pelvic irradiation and cyclophosphamide therapy. Etiology, incidence, pathologic descriptions, and diagnostic and therapeutic aspects of this entity are described. The incidence and risk of serious, life-threatening bladder hemorrhage from cyclophosphamide therapy is increased by prior or concurrent pelvic irradiation. Alternative cytotoxic, non-urotoxic chemotherapy should be used in these high-risk patients.

  13. EXPRESS: Methylcobalamin ameliorates neuropathic pain induced by vincristine in rats: Effect on loss of peripheral nerve fibers and imbalance of cytokines in the spinal dorsal horn.

    Science.gov (United States)

    Xu, Jing; Wang, Wei; Zhong, Xiong-Xiong; Feng, Yiwei; Wei, Xuhong; Liu, Xian-Guo

    2016-01-01

    Vincristine, a widely used chemotherapeutic agent, often induces painful peripheral neuropathy and there are currently no effective drugs to prevent or treat this side effect. Previous studies have shown that methylcobalamin has potential analgesic effect in diabetic and chronic compression of dorsal root ganglion model; however, whether methylcobalamin has effect on vincristine-induced painful peripheral neuropathy is still unknown. We found that vincristine-induced mechanical allodynia and thermal hyperalgesia, accompanied by a significant loss of intraepidermal nerve fibers in the plantar hind paw skin and an increase in the incidence of atypical mitochondria in the sciatic nerve. Moreover, in the spinal dorsal horn, the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the protein expression of p-p65 as well as tumor necrosis factor a was increased, whereas the protein expression of IL-10 was decreased following vincristine treatment. Furthermore, intraperitoneal injection of methylcobalamin could dose dependently attenuate vincristine-induced mechanical allodynia and thermal hyperalgesia, which was associated with intraepidermal nerve fibers rescue, and atypical mitochondria prevalence decrease in the sciatic nerve. Moreover, methylcobalamin inhibited the activation of NADPH oxidase and the downstream NF-kB pathway. Production of tumor necrosis factor a was also decreased and production of IL-10 was increased in the spinal dorsal horn following methylcobalamin treatment. Intrathecal injection of Phorbol-12-Myristate-13-Acetate, a NADPH oxidase activator, could completely block the analgesic effect of methylcobalamin. Methylcobalamin attenuated vincrinstine-induced neuropathic pain, which was accompanied by inhibition of intraepidermal nerve fibers loss and mitochondria impairment. Inhibiting the activation of NADPH oxidase and the downstream NF-kB pathway, resulting in the rebalancing of proinflammatory and anti-inflammatory cytokines

  14. Fungal vincristine from Eutypella spp - CrP14 isolated from Catharanthus roseus induces apoptosis in human squamous carcinoma cell line -A431.

    Science.gov (United States)

    Kuriakose, Gini C; Palem, Padmini P C; Jayabaskaran, Chelliah

    2016-08-22

    Catharanthus roseus, a medicinal plant, is known to produce secondary metabolites, vincristine and vinblastine, which are terpenoid indole alkaloids. Previously we have reported that Eutypella spp - CrP14 isolated from stem cutting of this plant had shown significant antiproliferative activity when tested in vitro against HeLa cell line. The present study was conducted to identify the anticancer compound responsible for the anti-proliferative activity of the fungal extract and to evaluate its in vitro anticancer and apoptotic effects. The anti-proliferative activity of the fungal anticancer compound, vincristine was analyzed by MTT assay against different cancer cell lines. We examined its efficacy of apoptotic induction on A431 cells. The parameters examined included cell cycle distribution, loss of mitochondrial membrane potential (MMP), DNA fragmentation and reactive oxygen species (ROS) generation. The presence of vincristine in fungal culture filtrate was confirmed through chromatographic and spectroscopic analyses, and the amount was estimated to be 53 ± 5.0 μg/l. The partially purified fungal vincristine had strong cytotoxic activity towards human squamous carcinoma cells - A431 in the MTT assay. Furthermore, we showed that the fungal vincristine was capable of inducing apoptosis in A431 cells through generation of reactive oxygen species and activation of the intrinsic pathway leading to loss of MMP. We have demonstrated for the first time that the vincristine from Eutypella spp - CrP14 is an efficient inducer of apoptosis in A431 cells, meriting its further evaluation in vivo.

  15. 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.

  16. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis : 2-year results of a randomised trial

    NARCIS (Netherlands)

    Jones, Rachel B.; Furuta, Shunsuke; Tervaert, Jan Willem Cohen; Hauser, Thomas; Luqmani, Raashid; Morgan, Matthew D.; Peh, Chen Au; Savage, Caroline O.; Segelmark, Marten; Tesar, Vladimir; van Paassen, Pieter; Walsh, Michael; Westman, Kerstin; Jayne, David R. W.; Stegeman, C. A.

    Objectives The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12months; however, immunosuppression maintenance requirements and longer-term outcomes after

  17. Cyclophosphamide-induced intractable hemorrhagic cystitis treated with hyperbaric oxygenation and intravesical sodium hyaluronate

    Directory of Open Access Journals (Sweden)

    Chuo-Jung Tsai

    2014-12-01

    Full Text Available Cyclophosphamide is a well-known cause of hemorrhagic cystitis. However, the best treatment for hemorrhagic cystitis is still unknown. Herein, we present a patient with cyclophosphamide-induced hemorrhagic cystitis. The patient had a history of myasthenia gravis and had received cyclophosphamide therapy for 14 years. He was admitted due to gross hematuria, which was initially treated by cystoscopic fulguration, followed by continuous bladder irrigation. Due to refractory hemorrhaging, fulguration was repeated and percutaneous suprapubic cystostomy was performed. The bladder hemorrhage eventually subsided after hyperbaric oxygen therapy and intravesical sodium hyaluronate instillation. The combination of hyperbaric oxygen therapy and intravesical sodium hyaluronate instillation may be useful in severe hemorrhagic cystitis caused by cyclophosphamide.

  18. Low-dose cyclophosphamide associated with hemorrhagic cystitis in a breast cancer patient.

    Science.gov (United States)

    Marshall, Ariela; McGrath, Cindy; Torigian, Drew; Papanicolaou, Nicholas; Lal, Priti; Kaplan Tweed, Carol

    2012-01-01

    Hemorrhagic cystitis is a known complication of high-dose cyclophosphamide treatment, generally occurring at doses greater than 100 g. There are few reports of hemorrhagic cystitis occurring with low-dose cyclophosphamide therapy, and this complication has not been described in breast cancer patients. We present a case of a patient with stage IIB breast cancer who developed clinical, radiographic, and pathologic evidence of hemorrhagic cystitis after a single 600 mg/m(2) dose of cyclophosphamide. Three subsequent cycles of cyclophosphamide with the addition of IV hydration and MESNA were given without complication, and the patient's urologic symptoms resolved. Repeat cystoscopy demonstrated pathologic resolution of the cystitis. We review the literature regarding proposed mechanisms of hemorrhagic cystitis, and discuss the applicability of these hypotheses in our patient. © 2011 Wiley Periodicals, Inc.

  19. Treatment associated Mantle Cell Lymphoma with Cyclophosphamide therapy for Granulomatosis with Polyangiitis.

    Science.gov (United States)

    Sheehy, Robert; Tran, Khoa

    2015-03-01

    We present a case of a 68-year-old woman who developed mantle cell lymphoma in the setting of long-term cyclophosphamide therapy and relapsing granulomatosis with polyangiitis (Wegener's granulomatosis, GPA). Adverse outcomes associated with cyclophosphamide therapy are well documented; however, the development of non-Hodgkin's lymphoma appears rare. Cumulative dose of cyclophosphamide (>36 g) is a significant risk factor in the development of serious long-term adverse outcomes and is particularly relevant to this case in which maintenance cyclophosphamide therapy was continued, following induction, for 2 years total, on account of patient preference. This case study will highlight the patient's initial diagnosis, treatment response, relapse and subsequent complications of therapy.

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

    Science.gov (United States)

    Weber, Catherine; Kasberg, Heather; Copelan, Edward

    2012-01-01

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

  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. Cyclophosphamide-Induced Cardiomyopathy: A Case Report, Review, and Recommendations for Management.

    Science.gov (United States)

    Dhesi, Sumandeep; Chu, Michael P; Blevins, Gregg; Paterson, Ian; Larratt, Loree; Oudit, Gavin Y; Kim, Daniel H

    2013-01-01

    Cyclophosphamide is increasingly used to treat various types of cancers and autoimmune conditions. Higher doses of this drug may produce significant cardiac toxicity, including fatal hemorrhagic myocarditis. In this review, we present a case of cyclophosphamide-induced cardiomyopathy requiring mechanical circulatory support. We also describe the pathophysiology, clinical manifestations, and risk factors for this important clinical entity and propose early detection and management strategies.

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

    OpenAIRE

    Weber, Catherine; Kasberg, Heather; Copelan, Edward

    2012-01-01

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

  4. Uroprotective effect of pentoxifylline in cyclophosphamide-induced hemorrhagic cystitis in rats.

    Science.gov (United States)

    Abo-Salem, Osama M

    2013-07-01

    The role of phosphodiesterase inhibitor, pentoxifylline, in the prevention of cyclophosphamide-induced hemorrhagic cystitis was evaluated in a rat model. Hemorrhagic cystitis was induced in rats by an intraperitoneal (i.p.) injection of a single dose of cyclophosphamide (150 mg/kg). Pentoxifylline (150 mg/kg/day/ip) was administered for 10 days followed by cyclophosphamide. Hemorrhagic cystitis was well characterized macroscopically, microscopically, and biochemically. Cyclophosphamide induced bladder injury including acute severe inflammation, vascular congestion, severe edema, hemorrhage, inflammatory cell infiltration in the lamina propria, and epithelial denudation; as well as it notably elevated serum inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1β), bladder content of malondialdehyde and total nitrate, accompanied with depletion of bladder antioxidant enzymes activities (glutathione peroxidase, superoxide dismutase, glutathione-S-transferase, and catalase). Prior administration of pentoxifylline improved all biochemical and histologic alterations induced by the cytotoxic drug cyclophosphamide. In conclusion, pentoxifylline has proven uroprotective efficacy in the cyclophosphamide-induced hemorrhagic cystitis model, possibly through modulating the release of inflammatory cytokines and nitric oxide and restoring the oxidant/antioxidant balance. © 2013 Wiley Periodicals, Inc.

  5. Premature ovarian failure due to cyclophosphamide: A report of four cases in dermatology practice

    Directory of Open Access Journals (Sweden)

    Saoji Vikrant

    2008-01-01

    Full Text Available Immunosuppressant drugs like cyclophosphamide are used in the treatment of a variety of skin disorders. Though it is a very useful drug, it has some serious side-effects. Prolonged amenorrhea due to premature ovarian failure leading to infertility is one of the serious side-effects of cyclophosphamide. Four cases of cyclophosphamide-induced premature ovarian failure are presented. Two patients of scleroderma, one patient of pemphigus and one patient of hypersensitivity vasculitis developed amenorrhea due to premature ovarian failure leading to infertility after receiving cyclophosphamide 50 mg OD for eight months to one year. The ages of these patients ranged from 28-38 years. All these patients had good improvement of their disease with cyclophosphamide. These patients did not experience any other side-effects and their routine blood and urine tests were normal. There were no spontaneous menses during the follow-up period of one to two years. Because of the serious risk of developing premature ovarian failure, cyclophosphamide should be avoided in those patients where the family is not complete.

  6. 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.

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

    Science.gov (United States)

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

    2014-08-01

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

  8. SENSITIVE METHOD FOR THE DETERMINATION OF VINCRISTINE IN HUMAN SERUM BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY AFTER ONLINE COLUMN-EXTRACTION

    NARCIS (Netherlands)

    BLOEMHOF, H; VANDIJK, KN; DEGRAAF, SSN; VENDRIG, DEMM; UGES, DRA

    1991-01-01

    A column-switching high-performance liquid chromatographic method was developed for the determination of vincristine in serum. Sample preparation was carried out by means of on-line column-extraction, using a C18 reversed-phase preconcentration column. This technique is simple (minimizing manual

  9. Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma

    NARCIS (Netherlands)

    Lokhorst, H. M.; Sonneveld, P.; Cornelissen, J. J.; Joosten, P.; van Marwijk Kooy, M.; Meinema, J.; Nieuwenhuis, H. K.; van Oers, M. H.; Richel, D. J.; Segeren, C. N.; Veth, G.; Verdonck, L. F.; Wijermans, P. W.

    1999-01-01

    We performed a phase II study to test the efficacy and feasibility of induction therapy with vincristine, adriamycin and dexamethasone (VAD) and intermediate-dose melphalan, 70 mg/m2 (IDM), to autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma (MM). A total of 77

  10. Design of a drug-drug interaction study of vincristine with azole antifungals in pediatric cancer patients using clinical trial simulation

    NARCIS (Netherlands)

    van Hasselt, J. G. Coen; van Eijkelenburg, Natasha K. A.; Beijnen, Jos H.; Schellens, Jan H. M.; Huitema, Alwin D. R.

    2014-01-01

    The aim of the current work was to perform a clinical trial simulation (CTS) analysis to optimize a drug-drug interaction (DDI) study of vincristine in children who also received azole antifungals, taking into account challenges of conducting clinical trials in this population, and, to provide a

  11. Design of a drug-drug interaction study of vincristine with azole antifungals in pediatric cancer patients using clinical trial simulation

    NARCIS (Netherlands)

    van Hasselt, J G Coen; van Eijkelenburg, Natasha K A; Beijnen, Jos H; Schellens, Jan H M; Huitema, Alwin D R

    2014-01-01

    BACKGROUND: The aim of the current work was to perform a clinical trial simulation (CTS) analysis to optimize a drug-drug interaction (DDI) study of vincristine in children who also received azole antifungals, taking into account challenges of conducting clinical trials in this population, and, to

  12. Severe infections in patients with autoimmune diseases treated with cyclophosphamide.

    Science.gov (United States)

    Cavallasca, Javier A; Costa, Cecilia A; Maliandi, Maria Del Rosario; Contini, Liliana E; Fernandez de Carrera, Elena; Musuruana, Jorge L

    2015-01-01

    Infectious diseases are a significant cause of morbidity and mortality in patients with connective tissue diseases. Corticosteroids and immunosuppressive drugs, such as cyclophosphamide (CYC), increases the risk of infections. The objective of this study was to estimate the incidence rates of severe infections in patients who received treatment with CYC. The records of 60 patients with systemic autoimmune diseases who received treatment with CYC were retrospectively reviewed. We evaluated the rate of severe infections that occurred during CYC therapy and the 3 subsequent months. Systemic lupus erythematosus was the most common disease, and diffuse proliferative glomerulonephritis the most frequent indication. Severe infection occurred in 9 patients (15%). Community acquired pneumonia was the most frequent infection with 3 cases (33%) followed by Herpes Zoster with 2 reports (22%). The cumulative dose of corticosteroid was the only significant risk factor for infection 32.8±16.7 vs. 20.1±15.3 P=.007. The use of lower doses of corticosteroids and an aggressive management of infectious complications, allows for an acceptable safety profile in patients treated with CYC. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

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

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    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.

  14. Processed Aloe vera Gel Ameliorates Cyclophosphamide-Induced Immunotoxicity

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    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.

  15. Chemoprotective potential of Coccinia indica against cyclophosphamide-induced toxicity.

    Science.gov (United States)

    Nitharwal, Ramesh K; Patel, Hasit; Karchuli, Manvendra Singh; Ugale, Rajesh Ramesh

    2013-01-01

    Although cyclophosphamide (CP), an alkylating agent, is used in the treatment of cancer owing to its broad-spectrum efficacy, its metabolites exhibit severe undesired toxicities in normal cells. The present study was aimed to investigate the chemoprotective potential of Coccinia indica against CP-induced oxidative stress, genotoxicity, and hepatotoxicity. Rodents were orally pre-treated with Coccinia indica extract (200, 400, and 600 mg/kg) for five consecutive days. On 5th day, these animals were injected with CP (50 mg/kg i.p) and sacrificed after 24 hrs. for the evaluation of oxidative stress, hepatotoxicity, micronucleus formation, and chromosomal aberrations. We found that the CP significantly increased malondialdehyde (MDA) and decreased catalase and glutathione (GSH) levels in brain, and it was significantly reversed by Coccinia indica extract (400 and 600 mg/kg). Further, pre-treatment with Coccinia indica extract (200, 400, 600 mg/kg) significantly and dose-dependently reduced micronuclei formation and incidence of aberrant cells. We also found that the CP-induced increase in the serum biomarker enzymes like alkaline phosphatase (ALP), alkaline aminotransferase (ALT), and aspartate aminotransferase (AST) were significantly reduced by Coccinia indica extract. Thus, the present results indicate the protective effect of Coccinia indica extract against CP-induced oxidative stress, genotoxicity, as well as hepatotoxicity.

  16. Efficacy and Safety of Tacrolimus Versus Cyclophosphamide for Primary Membranous Nephropathy: A Meta-Analysis.

    Science.gov (United States)

    Zhu, Lin-Bo; Liu, Lin-Lin; Yao, Li; Wang, Li-Ning

    2017-02-01

    The objective of this systematic review was to compare the efficacy and safety of tacrolimus with cyclophosphamide in primary membranous nephropathy (PMN) patients. We conducted a literature search in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CCRCT). Any study that compared the efficacy or safety between tacrolimus and cyclophosphamide in the adult PMN patients was included. We included four randomized controlled trials and two prospective cohort studies with 389 PMN patients. The pooled results using the Dersimonian and Laird method showed that renal remission rates at the longest follow-up periods were not significantly different between the tacrolimus and cyclophosphamide groups (overall remission, six trials, n = 389, relative risk [RR] 0.994 [95% confidence interval [CI] 0.768-1.286); complete remission, six trials, n = 389, RR 1.256 [95% CI 0.733-2.150]). Further analyses found that tacrolimus was comparable with cyclophosphamide for inducing renal remission within 1 year but inferior to cyclophosphamide after 1-year follow-up. It should be noted that only two studies reported the outcomes after 1-year follow-up, which might be considered as weak evidence. The rates of relapse and the drop-outs due to adverse effects were not significantly different (relapse, six trials, n = 389, RR 2.244 [95% CI 0.892-5.644]; drop-outs, six trials, n = 389, RR 1.330 [95% CI 0.412-4.291]). However, the cyclophosphamide group had a significantly higher risk of leukopenia than the tacrolimus group (four trials, n = 216, RR 0.203 [95% CI 0.045-0.916]), whereas the rates of tremor were significantly higher in the tacrolimus group than in the cyclophosphamide group (three trials, n = 202, RR 8.939 [95% CI 1.694-47.173]). The quality and short follow-up durations of the studies limited the reliability of our conclusions. Tacrolimus was comparable with cyclophosphamide for inducing renal remission of PMN patients within 1 year, but the

  17. Safety and efficacy of intravenous cyclophosphamide pulse therapy in therapy refractory Crohn's disease patients.

    Science.gov (United States)

    Hirschmann, S; Atreya, R; Englbrecht, M; Neurath, M F

    2017-02-01

    A major challenge in the management of persistently active Crohn's disease patient's refractory to treatment regimen following the current guidelines is the induction of remission, which is a prerequisite for subsequent maintenance therapy. The aim of this study was to evaluate both the clinical and endoscopic benefit of intravenous cyclophosphamide pulse therapy in patients with active and therapy refractory Crohn's disease. Nine patients with acute moderate to severe Crohn's disease, not responding to conventional as well as biological therapy regimen received 3 - 9 cycles of monthly treatments with intravenous cyclophosphamide (680 - 1000 mg) in an uncontrolled setting and were retrospectively analyzed. Eight of nine patients (88.9%) had a clinical response (measured by a decrease in the Harvey-Bradshaw index, HBI ≥ 3) and two of nine patients (22.2%) achieved clinical remission (HBI ≤ 4) at week 8 after two applications of intravenous cyclophosphamide therapy. These response and remission rates remained unchanged after individual completion of cyclophosphamide therapy. Median HBI decreased from 18 (7 - 25) at the beginning of therapy to 7 (3 - 18) at week 8. 5 of 9 patients (56%) showed endoscopic response (defined by a reduction of ulcers) and one patient (11%) reached endoscopic remission (defined by the absence of ulcers) after the last application of cyclophosphamide. Arthralgia, which was present in 4 of 9 (44%) patients, was unchanged in most patients after cyclophosphamide therapy, although one patient described a marked reduction in joint pain. Cyclophosphamide pulse therapy was well tolerated during the whole treatment course in all subjects. One patient with long-standing Crohn's disease was diagnosed with a high-grade intraepithelial neoplasia in the rectum and underwent surgical intervention, where the diagnosis of an early stage adenocarcinoma was made. We concluded that intravenous cyclophosphamide pulse therapy was well tolerated by most

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

    Directory of Open Access Journals (Sweden)

    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

  19. [Cyclophosphamide pulse therapy effective for childhood-onset refractory multiple sclerosis: a case report].

    Science.gov (United States)

    Ikeda, Tae; Kagitani-Shimono, Kuriko; Iwatani, Yoshiko; Kitai, Yukihiro; Tachibana, Masaya; Tominaga, Koji; Okinaga, Takeshi; Nagai, Toshisaburo; Ozono, Keiichi

    2013-01-01

    We report a case of a 15-year-old girl with relapsing-remitting multiple sclerosis (MS) who received cyclophosphamide pulse therapy. At the age of 5 years, she displayed symptoms such as headache and unconsciousness after varicella infection as the first episode of MS. She had been treated with methylprednisolone pulse therapy, intravenous immunoglobulin, interferon-beta1b, and azathioprine. However, she had relapsed 12 times by the age of 15 years. At this time, she showed weakness and severe paralysis of her left leg, and even 1 month after methylprednisolone pulse therapy, she still had gait impairment and showed gadolinium-enhanced lesion on brain magnetic resonance imaging. We then started cyclophosphamide pulse therapy (600 mg/m2) once a month for 12 months combined with interferon-beta1a. She had no serious side effects and she could walk again after 4 months on cyclophosphamide treatment. She has been free from relapse for 2 years and 8 months until the present time. Although only a few studies have indicated the efficacy of cyclophosphamide pulse therapy for childhood MS, we consider careful use of cyclophosphamide could be one of the options for refractory childhood MS.

  20. Acrocomia aculeata prevents toxicogenetic damage caused by the antitumor agent cyclophosphamide.

    Science.gov (United States)

    Magosso, M F; Carvalho, P C; Shneider, B U C; Pessatto, L R; Pesarini, J R; Silva, P V B; Correa, W A; Kassuya, C A L; Muzzi, R M; Oliveira, R J

    2016-05-06

    Acrocomia aculeata is a plant rich in antioxidant compounds. Studies suggest that this plant has anti-inflammatory, antidiabetic, and diuretic potential. We assessed the antigenotoxic, antimutagenic, immunomodulation, and apoptotic potentials of A. aculeata alone and in combination with an antitumor agent, cyclophosphamide. Swiss male mice (N = 140) were used. The animals were divided into 14 experimental groups as follows: a negative group, a positive group (100 mg/kg cyclophosphamide), groups that only received the oil extracted from the almond (AO) and from the pulp (PO) of A. aculeata at doses of 3, 15, and 30 mg/kg, and the associated treatment groups (oils combined with cyclophosphamide) involving pretreatment, simultaneous, and post-treatment protocols. Data suggest that both oils were chemopreventive at all doses, based on the tested protocols. The highest damage reduction percentages, observed for AO and PO were 88.19 and 90.03%, respectively, for the comet assay and 69.73 and 70.93%, respectively, for the micronucleus assay. Both AO and PO demonstrated immunomodulatory activity. The oils reduced the capacity of cyclophosphamide to trigger apoptosis in the liver, spleen, and kidney cells. These results suggest that A. aculeate AO and PO can be classified as a functional food and also enrich other functional foods and nutraceuticals with chemopreventive features. However, they are not appropriate sources for chemotherapeutic adjuvants, in particular for those used in combination with cyclophosphamide.

  1. Cellular mechanisms of cyclophosphamide-induced taste loss in mice.

    Directory of Open Access Journals (Sweden)

    Nabanita Mukherjee

    Full Text Available Many commonly prescribed chemotherapy drugs such as cyclophosphamide (CYP have adverse side effects including disruptions in taste which can result in loss of appetite, malnutrition, poorer recovery and reduced quality of life. Previous studies in mice found evidence that CYP has a two-phase disturbance in taste behavior: a disturbance immediately following drug administration and a second which emerges several days later. In this study, we examined the processes by which CYP disturbs the taste system by examining the effects of the drug on taste buds and cells responsible for taste cell renewal using immunohistochemical assays. Data reported here suggest CYP has direct cytotoxic effects on lingual epithelium immediately following administration, causing an early loss of taste sensory cells. Types II and III cells in fungiform taste buds appear to be more susceptible to this effect than circumvallate cells. In addition, CYP disrupts the population of rapidly dividing cells in the basal layer of taste epithelium responsible for taste cell renewal, manifesting a disturbance days later. The loss of these cells temporarily retards the system's capacity to replace Type II and Type III taste sensory cells that survived the cytotoxic effects of CYP and died at the end of their natural lifespan. The timing of an immediate, direct loss of taste cells and a delayed, indirect loss without replacement of taste sensory cells are broadly congruent with previously published behavioral data reporting two periods of elevated detection thresholds for umami and sucrose stimuli. These findings suggest that chemotherapeutic disturbances in the peripheral mechanisms of the taste system may cause dietary challenges at a time when the cancer patient has significant need for well balanced, high energy nutritional intake.

  2. Modulation of cyclophosphamide-induced early lung injury by allicin.

    Science.gov (United States)

    Ashry, Nora A; Gameil, Nariman M; Suddek, Ghada M

    2013-06-01

    Cyclophosphamide (CP) causes lung injury in rats through its ability to generate free radicals with subsequent epithelial and endothelial cell damage. This study was conducted to assess whether allicin can ameliorate CP-induced early lung injury in rats. Male Sprague Dawely rats were divided into four groups. Group I was the control group. Group II received allicin (50 mg/kg/d, p.o.) for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.). Group IV received allicin for seven consecutive days, before and after CP injection (150 mg/kg, i.p.). The parameters of study were serum biomarkers, lung tissue antioxidant profile and histopathological changes in lung tissue. A single intraperitoneal injection of CP markedly altered the levels of several biomarkers in lung homogenates. Significant increases in lung content of lipid hydroperoxides were seen that paralleled the decreased levels of total reduced glutathione. Superoxide dismutase activity (SOD) was significantly increased. CP increased the level of serum biomarkers; total protein, lactate dehydrogenase (LDH) and tumor necrosis factor-alpha (TNF-α). Pretreatment of rats daily with oral allicin seven days prior to and seven days after CP inject significantly inhibited the development of lung injury, prevented the alterations in lung and serum biomarkers associated with inflammatory reactions, with less lipid peroxidation (LP) and restoration of antioxidants. Moreover, allicin attenuated the secretion of proinflammatory cytokine, TNF-α expression in rat serum. In addition, allicin effectively blunted CP-induced histopathological changes in lung tissue. Our results suggest that allicin is efficient in blunting CP-induced pulmonary damage.

  3. Cellular mechanisms of cyclophosphamide-induced taste loss in mice.

    Science.gov (United States)

    Mukherjee, Nabanita; Pal Choudhuri, Shreoshi; Delay, Rona J; Delay, Eugene R

    2017-01-01

    Many commonly prescribed chemotherapy drugs such as cyclophosphamide (CYP) have adverse side effects including disruptions in taste which can result in loss of appetite, malnutrition, poorer recovery and reduced quality of life. Previous studies in mice found evidence that CYP has a two-phase disturbance in taste behavior: a disturbance immediately following drug administration and a second which emerges several days later. In this study, we examined the processes by which CYP disturbs the taste system by examining the effects of the drug on taste buds and cells responsible for taste cell renewal using immunohistochemical assays. Data reported here suggest CYP has direct cytotoxic effects on lingual epithelium immediately following administration, causing an early loss of taste sensory cells. Types II and III cells in fungiform taste buds appear to be more susceptible to this effect than circumvallate cells. In addition, CYP disrupts the population of rapidly dividing cells in the basal layer of taste epithelium responsible for taste cell renewal, manifesting a disturbance days later. The loss of these cells temporarily retards the system's capacity to replace Type II and Type III taste sensory cells that survived the cytotoxic effects of CYP and died at the end of their natural lifespan. The timing of an immediate, direct loss of taste cells and a delayed, indirect loss without replacement of taste sensory cells are broadly congruent with previously published behavioral data reporting two periods of elevated detection thresholds for umami and sucrose stimuli. These findings suggest that chemotherapeutic disturbances in the peripheral mechanisms of the taste system may cause dietary challenges at a time when the cancer patient has significant need for well balanced, high energy nutritional intake.

  4. [Transfection of eucaryotic cells using cytochrome CYP450 2B6 gene: sensitivity to cyclophosphamide].

    Science.gov (United States)

    Kolomeĭchuk, S N; Abakumova, O Iu; Maslov, M A; Kalashnikova, E A; Morozova, N G; Serebrennikova, G A; Shvets, V I; Sokolov, N N

    2002-01-01

    Sensitivity of 293 human epithelial kidney cells transfected by human cytochrome CYP450 gene to cyclophosphamide was investigated. Transfection was carried out by plasmid DNA containing CYP2B6 gene complexed with cationic liposomes. Liposomes were prepared from mixture of cationic lipids and cholesterol at different molar ratios. Experimental protocol included the following steps: transfection of epithelial kidney cells by complexes of plasmid DNA-cationic liposomes, clone selection in the medium with antibiotic Geneticin G418, selected clone harvesting and their treatment by cyclophosphamide as following cytotoxicity evaluation. It was shown that addition of 0.25 mM of cyclophosphamide resulted in death of 40-45% transfected cell population.

  5. Pharmacokinetics of cyclophosphamide and thiotepa in a conventional fractionated high-dose regimen compared with a novel simplified unfractionated regimen

    NARCIS (Netherlands)

    Ekhart, Corine; Rodenhuis, Sjoerd; Beijnen, Jos H.; Huitema, Alwin D. R.

    2009-01-01

    High-dose alkylating chemotherapy with cyclophosphamide (4000 or 6000 mg/m2) and thiotepa (320 or 480 mg/m2) has commonly been administered in a fractionated regimen over 4 days. A simplified unfractionated regimen would be preferable, especially because cyclophosphamide and thiotepa have been shown

  6. High-Risk Premenopausal Luminal A Breast Cancer Patients Derive no Benefit from Adjuvant Cyclophosphamide-based Chemotherapy

    DEFF Research Database (Denmark)

    Nielsen, Torsten O; Jensen, Maj-Brit; Burugu, Samantha

    2017-01-01

    interaction test.Experimental Design: The Danish Breast Cancer Cooperative Group 77B clinical trial randomized 1,072 premenopausal women to no systematic treatment (control), levamisole, cyclophosphamide, or cyclophosphamide-methotrexate-fluorouracil arms. All arms included radiotherapy but no endocrine...

  7. Can propolis and caffeic acid phenethyl ester (CAPE be promising agents against cyclophosphamide toxicity?

    Directory of Open Access Journals (Sweden)

    Sumeyya Akyol

    2016-03-01

    Full Text Available Propolis is a mixture having hundreds of polyphenols including caffeic acid phenethyl ester (CAPE. They have been using in several medical conditions/diseases in both in vitro and in vivo experimental setup. Cyclophosphamide has been used to treat a broad of malignancies including Hodgkin's and non-Hodgking's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, Ewing's sarcoma, breast cancer, testicular cancer, etc. It may cause several side effects after treatment. In this mini review, the protective effects of propolis and CAPE were compared each other in terms of effectiveness against cyclophosphamide-induced injuries. [J Intercult Ethnopharmacol 2016; 5(1.000: 105-107

  8. Effects of Adding Vindoline and MeJA on Production of Vincristine and Vinblastine, and Transcription of their Biosynthetic Genes in the Cultured CMCs of Catharanthus roseus.

    Science.gov (United States)

    Zhang, Wenjin; Yang, Jiazeng; Zi, Jiachen; Zhu, Jianhua; Song, Liyan; Yu, Rongmin

    2015-12-01

    Vincristine and vinblastine were found by Liquid Chromatography-Mass Spectrometry (LC-MS) in Catharanthus roseuscambial meristem cells (CMCs) jointly treated with 0.25 mM vindoline and methyl jasmonate (MeJA), suggesting that C. roseus CMCs contain a complete set of the enzymes which are in response to convert vindoline into vincristine and vinblastine. Based on the facts that the transcript levels of vindoline-biosynthetic genes (STR, SGD and D4H) were up-regulated instead of being down-regulated by adding itself to the culture, and that the transcriptional factor ORCA3 was up-regulated simultaneously, we further confirmed that the transcription of STR, SGD, D4H was manipulated by ORCA3.

  9. Prevalence of different cytomorphological types of transmissible venereal tumours and the association with prognosis in dogs treated with vincristine sulphate – Retrospective study

    Directory of Open Access Journals (Sweden)

    Cristiane Sella Paranzini

    2015-12-01

    Full Text Available Canine transmissible venereal tumours (CTVT are the most commonly diagnosed tumours in veterinary hospitals. CTVT is morphologically classified as a round cell tumour, although the exact origin of the cells is unknown. Immunohistochemical studies have suggested histiocytic and mesenchymal origin. CTVT can be classified as lymphocyte-like, plasmocyte-like, and mixed according to their cytomorphological features. The treatment of choice for CTVT is chemotherapy with vincristine sulphate applied weekly; this produces a good prognosis. However, an increase in the number of chemotherapy applications and adjuvant therapies has become common. The aim of this study was to determine the association of cytomorphological types of CTVT with resistance and partial resistance to vincristine sulphate and the possible need for a large number of chemotherapy sessions. A retrospective study of a 24-month period evaluated 46 diagnosed and treated cases of CTVT. It was concluded that there is a higher prevalence of plasmacyte-like, followed by mixed and lymphocyte-like CTVT. The cytomorphological type did not differ in relation to the response to the treatments with vincristine sulphate and the number of chemotherapy sessions necessary for CTVT regression has increased by factors not yet elucidated.

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

    Directory of Open Access Journals (Sweden)

    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

  11. 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.

  12. 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

  13. 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.

  14. 78 FR 47321 - Determination That CYTOXAN (Cyclophosphamide) for Injection Was Not Withdrawn From Sale for...

    Science.gov (United States)

    2013-08-05

    ... (cyclophosphamide) for Injection (lyophilized formulations), 100 milligrams (mg)/vial, 200 mg/vial, 500 mg/vial, 1... formulations), 100 mg/vial and 200 mg/vial, were not withdrawn from sale for reasons of safety or effectiveness... Cosmetic Act (21 U.S.C. 355(j)(7)), which requires FDA to publish a list of all approved drugs. FDA...

  15. Dose-Dense Epirubicin and Cyclophosphamide Followed by Weekly Paclitaxel in Node-Positive Breast Cancer

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    Hamid Reza Mirzaei

    2014-01-01

    Full Text Available Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement in node-positive breast cancer patients but the optimal dose schedule has still remained undetermined. Objectives. The feasibility of dose-dense epirubicin in combination with cyclophosphamide (EC followed by weekly paclitaxel as adjuvant chemotherapy in node-positive breast cancer patients was investigated. Methods. All patients were treated with epirubicin (100 mg/m2 and cyclophosphamide (600 mg/m2 every two weeks for four cycles with daily Pegfilgrastim (G-CSF that was administered 3–10 days after each cycle of epirubicin and cyclophosphamide infusion which followed by (80 mg/m2 paclitaxel for twelve consecutive weeks. Results. Sixty consecutive patients were analyzed, of whom 57 patients (95% completed the regimen and no case of toxicity-related death was observed. Grade 3/4 hematologic toxicity was uncommon and the most common grade 3/4 nonhematological adverse event was neuropathy disorders. Conclusions. Dose-dense epirubicin and cyclophosphamide followed by weekly paclitaxel with G-CSF support is a well-tolerated and feasible regimen in node-positive breast cancer patients without serious complications.

  16. 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...

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

    Science.gov (United States)

    Casanova, Natalia A; Simoniello, María Fernanda; López Nigro, Marcela Mabel; Carballo, Marta A

    2017-01-01

    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.

  18. 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.

  19. Protective effects of crocin on testes of adult cyclophosphamide treated mice

    Directory of Open Access Journals (Sweden)

    2014-04-01

    Full Text Available Background & aim: The side effect of cyclophosphamide is to reduce fertility or even sterility in men treated with these medications. This study was performed to improve these side effects. Methods: In the present experimental study, 15 male mice (20-25 g were divided into three groups. The control group was treated with 0.1cc of saline daily. The sham group received 15 mg/kg cyclophosphamide once a week and the experimental group was treated with 200 mg/kg Crocin intraperitoneally along with cyclophosphamide. Five weeks after injection total antioxidant capacity of serum was measured. The testes were studied for histological and morphometric parameters. The collected data was analyzed by ANOVA. Results: Histomorphometrical study indicated that epithelial thickness, diameter of seminiferous tubules and Leydig cells of experimental group was significantly greater than sham controls (p<0.05. Mean distribution of mast cells in the sham group compared to the experimental group showed a significant increase (p<0.05. Additionally, positive PAS reaction, alkaline phosphatase and vegetable fat in the cytoplasm of Leydig cells of sham control were observed, whereas in the other groups not seen. In addition, total antioxidant capacity of sham group decreased significantly compared to the control and experimental groups with the sham control and experimental groups ((p<0.05. Conclusion: in general Crocin could significantly prevent the side effects of cyclophosphamide therapy.

  20. Effect of Lycopene on Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats

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    Akram Jamshidzadeh

    2009-03-01

    Full Text Available Background: Cylophosphamide is used alone or in combinationwith other drugs for treatment of neoplastic diseases.Hemorrhagic cystitis is a major potential toxicity and doselimiting side effect of cyclophosphamide. The aim of thisstudy was to evaluate the effects of lycopene compared withsome antioxidants for the prevention of cyclophosphamideinduced hemorrhagic cystitis in rats.Methods: In this study, male Sparague-Dawley rats dividedinto 17 groups of six animals. Group 1 received saline (10ml/kg, i.p as normal control, group 2 received cyclophosphamide(200 mg/kg, i.p as a single dose, groups 3-10 receivedMesna (40 mg/kg, i.p, N-acetylcysteine (100 mg/kg i.p, dithiotheritol(50 mg/kg, i.p, L-carnitine (200 and 400 mg/kg,i.p, grape seed extract (500 mg/kg i.p and lycopene (0.1 and0.5 mg/kg, i.p alone. Groups 11-17 received Mesna (40 mg/kg,i.p, N-acetylcysteine (100 mg/kg, i.p, dithiotheritol (50 mg/kg,i.p, L-carnitine (400 mg/kg, i.p, grape seed extract (500mg/kg, i.p and lycopene (0.1 and 0.5 mg/kg, i.p, 5 minutesbefore, and 2 and 6 hours after administration of 200 mg/kgcyclophosphamide. Pathological and biochemical analysis wasevaluated 24 hours after cyclophosphamide administration.Results: Mesna and N-acetylcysteine resulted in some but notfull protection against cyclophosphamide toxicity compared tothe controls. Lycopene (0.1 and 0.5 mg/kg was efficient inprotecting the bladder from cyclophosphamide induced hemorrhagiccystitis. However, dithiotheritol, L- carnitine andgrape seed extract did not prevent hemorrhagic cystitis.Conclusion: Our results suggest that pre and co- treatment oflycopene (0.1 and 0.5 mg/kg with cyclophosphamide mayhave therapeutic potential to inhibit the hemorrhagic cystitisby cyclophosphamide.

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

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    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.

  2. Randomized study of whole-abdomen irradiation versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sell, A.; Bertelsen, K.; Andersen, J.E.; Stroyer, I. (Arhus Univ. Hospital (Denmark))

    1990-06-01

    From 1 September 1981 to 1 January 1987, 118 patients with FIGO Stage IB, IC, IIA, IIB, and IIC epithelial ovarian cancer were randomized to abdominal irradiation or pelvic irradiation + cyclophosphamide. There was no difference between the regimens with respect to recurrence-free survival (55%) and 4-year overall survival (63%). At routine second-look laparotomy, 16% of patients without clinical detectable tumor showed recurrence. Twenty-five percent of the patients treated with pelvic irradiation + cyclophosphamide had hemorrhagic cystitis, probably caused by radiation damage and cyclophosphamide cystitis. Eight percent had late gastrointestinal symptoms requiring surgery.

  3. Conservative Chemotherapy in Gestational Trophoblastic Disease: Experience With Etoposide, Methotrexate, and Dactinomycin Chemotherapy.

    Science.gov (United States)

    Byun, Seung Won; Park, Tae Chul; Bae, Seog Nyeon

    2016-05-01

    The goal of this study was to evaluate the efficacy, toxicity, and survival of patients in our institution treated by EMA (etoposide, methotrexate [MTX], and dactinomycin) chemotherapy for 3 groups of patients: ones that had low-risk gestational trophoblastic disease (GTD) that was resistant to MTX (group A), those with high-risk GTD (group B), and the group having low-risk GTD but the cancer being metastatic (group C). The medical records of 58 patients who received EMA chemotherapy in groups A, B, and C in the 2000 to 2012 period at St Mary's Hospital were examined. Clinical characteristics, chemotherapy responses, causes of treatment failure, and cases of drug toxicity were analyzed retrospectively. Treatment with the EMA regimen resulted in primary remission in 52 (96%) of 54 patients and resistance in 2 of the patients (3%). In the resistance group, one belonged to group B and was treated with etoposide, MTX, and actinomycin D with cyclophosphamide and vincristine (EMA-EP) and the other belonged to group A and died of refractory disease. World Health Organization (WHO) grade 4 leukocytopenia and thrombocytopenia with the EMA regimen occurred in 6% and 0.4% of the cycles, respectively; the other toxic effects were acceptable and manageable. Median cycles of EMA chemotherapy during the treatment were 7, 8, and 8 in groups A, B, and C, respectively. There was some reduction in total chemo cycle and toxicity, as compared with a previously reported study using the alternative cyclophosphamide and vincristine regimen. Among the EMA treated patients, 1 patient with a second malignancy of breast cancer was documented. In addition, 5 child births for the treated patients were recorded during the follow-up period of mostly 10 years. The EMA chemotherapy seemed to reduce treatment duration and the relapse rate without increasing the adverse effects in patients with MTX resistance and low-risk GTD, but having confirmed metastatic lesions. Although this study had some

  4. Term pregnancy with choriocarcinoma presenting as severe fetal anemia and postpartum hemorrhage.

    Science.gov (United States)

    Peng, Hsiu-Huei; Ng, Zooi-Ping; Tang, Yun-Hsin; Chua, Angelica Anne A; Huang, Kuan-Gen

    2016-06-01

    Term pregnancy with choriocarcinoma is a rare condition that can be a serious health threat to both the mother and the fetus. We present a rare case of term pregnancy with choriocarcinoma presenting as severe fetal anemia and postpartum hemorrhage. A 34-year-old woman, gravida 3 para 2, was admitted for profuse vaginal bleeding 2 weeks after cesarean delivery of a full-term anemic baby. Transvaginal sonography revealed a 4.7-cm×10.6-cm heterogenous lesion in the endometrial cavity. Dilatation and curettage was done and a pathologic report revealed choriocarcinoma. Metastatic workup showed lung metastasis. The patient achieved remission after eight cycles of chemotherapy in the form of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine. There was no evidence of recurrence in the subsequent 3 years of regular follow up. Although fetomaternal hemorrhage is a rare form of presentation of choriocarcinoma, its presence should alert the physician to investigate the cause further. This chemotherapy regimen was effective in our case and the patient needed to be followed up carefully. Copyright © 2016. Published by Elsevier B.V.

  5. Chick embryo chorioallantoic membrane (CAM): an alternative predictive model in acute toxicological studies for anti-cancer drugs

    Science.gov (United States)

    KUE, Chin Siang; TAN, Kae Yi; LAM, May Lynn; LEE, Hong Boon

    2015-01-01

    The chick embryo chorioallantoic membrane (CAM) is a preclinical model widely used for vascular and anti-vascular effects of therapeutic agents in vivo. In this study, we examine the suitability of CAM as a predictive model for acute toxicology studies of drugs by comparing it to conventional mouse and rat models for 10 FDA-approved anticancer drugs (paclitaxel, carmustine, camptothecin, cyclophosphamide, vincristine, cisplatin, aloin, mitomycin C, actinomycin-D, melphalan). Suitable formulations for intravenous administration were determined before the average of median lethal dose (LD50) and median survival dose (SD50) in the CAM were measured and calculated for these drugs. The resultant ideal LD50 values were correlated to those reported in the literature using Pearson’s correlation test for both intravenous and intraperitoneal routes of injection in rodents. Our results showed moderate correlations (r2=0.42 − 0.68, P<0.005–0.05) between the ideal LD50 values obtained using the CAM model with LD50 values from mice and rats models for both intravenous and intraperitoneal administrations, suggesting that the chick embryo may be a suitable alternative model for acute drug toxicity screening before embarking on full toxicological investigations in rodents in development of anticancer drugs. PMID:25736707

  6. Metastatic choriocarcinoma as initial presentation of small bowel perforation in absence of primary uterine lesion: a case report.

    Science.gov (United States)

    Cho, En Bee; Byun, Jung Mi; Jeong, Dae Hoon; Yoon, Hye Kyoung; Kim, Young Nam; Sung, Moon Su; Lee, Kyung Bok; Kim, Ki Tae

    2016-11-11

    Choriocarcinoma is a highly malignant tumor of gestational trophoblastic neoplasia that characteristically spreads via the bloodstream. Small bowel metastasis is very rare, and a small number of cases of choriocarcinoma metastasis to small bowel have been reported. We report a case of a 40-year-old woman presenting with acute abdominal pain and vaginal bleeding due to small bowel perforation secondary to jejunal metastasis. In our case, metastatic choriocarcinoma was present in the small bowel, lung, and liver, but no primary lesion was apparent. After resection and anastomosis of the perforated small bowel, chemotherapy was performed. The patient began chemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA-CO) for 9 cycles. When the 4th cycle of chemotherapy was finished, β-human chorionic gonadotropin (hCG) level was normalized and follow-up computed tomography scans showed regression of the liver metastasis and small bowel lesion and significantly decreased lung metastasis. After 9 cycles of chemotherapy were completed, the patient showed complete response. If patients have high β-hCG of unknown origin and suspected panperitonitis, which are suspicious of choriocarcinoma metastasis to small bowel, the pathologic findings are important. It is essential to confirm the histopathologic diagnosis postoperatively. Choriocarcinoma can spread to various organs and show aggressive manifestations. Therefore, we should be aware of possible metastatic sites and remain alert to its diagnosis.

  7. Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy

    NARCIS (Netherlands)

    de Jonge, M. E.; Mathôt, R. A. A.; Dalesio, O.; Huitema, A. D. R.; Rodenhuis, S.; Beijnen, J. H.

    2002-01-01

    Reversible alopecia is a commonly observed, important and distressing complication of chemotherapy. Permanent alopecia, however, is rare after standard-dose therapy, but has occasionally been observed after high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC). We evaluated

  8. 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.

  9. 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.

  10. Cardioprotective effect of curcumin and piperine combination against cyclophosphamide-induced cardiotoxicity

    OpenAIRE

    Chakraborty, Manodeep; Bhattacharjee, Ananya; Kamath, Jagadish Vasudev

    2017-01-01

    Objective: Curcumin is a well-established cardioprotective phytoconstituent, but the poor bioavailability associated with it is always a matter of therapeutic challenge. The present study was undertaken to increase the therapeutic efficacy of curcumin by combining with bio-enhancer like piperine against cyclophosphamide (CP)-induced cardiotoxicity in rats. Materials and Methods: Rats (n = 8) were treated with curcumin (200 mg/kg, p.o.) alone and different dose combination of curcumin (100,...

  11. Fever after peripheral blood stem cell infusion in haploidentical transplantation with post-transplant cyclophosphamide.

    Science.gov (United States)

    Arango, Marcos; Combariza, Juan F

    2017-06-01

    Noninfection-related fever can occur after peripheral blood stem cell infusion in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide. The objective of this study was to analyze the incidence of fever and characterize some clinical features of affected patients. A retrospective case-series study with 40 patients who received haploidentical hematopoietic stem cell transplantation was carried out. Thirty-three patients (82.5%) developed fever; no baseline characteristic was associated with its development. Median time to fever onset was 25.5h (range, 9.5-100h) and median peak temperature was 39.0°C (range, 38.1-40.5°C). Not a single patient developed hemodynamic or respiratory compromise that required admission to the intensive care unit. Fever was not explained by infection in any case. Ninety-one percent of the febrile episodes resolved within 96h of cyclophosphamide administration. No significant difference in overall survival, event-free survival, or graft versus host disease-free/relapse-free survival was found in the group of febrile individuals after peripheral blood stem cell infusion. Fever after peripheral blood stem cell infusion in this clinical setting was common; it usually subsides with cyclophosphamide administration. The development of fever was not associated with an adverse prognosis. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

  12. 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.

  13. 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.

  14. Protective Effect of Intravesical Platelet-Rich Plasma on Cyclophosphamide-Induced Hemorrhagic Cystitis.

    Science.gov (United States)

    Ozyuvali, E; Yildirim, M E; Yaman, T; Kosem, B; Atli, O; Cimentepe, E

    2016-12-01

    Hemorrhagic cystitis (HC) is the most common urotoxic side effect of cyclophosphamide (CYP). Platelet rich plasma (PRP) plays an important role in wound healing and inflammatory responses. The aim of this study was to investigate the efficacy of intravesical PRP at treatment of interstitial cystitis (IC). Female rats (n=24) were used. IC was induced by intraperitoneal injection of cyclophosphamide (CYP). Rats were randomly allocated to one of four groups (n = 6 per group): a control group; a sham group with saline (75 mg/kg; i.p.) instead of CYP on day 1; a IC group, which was injected with CYP (150 mg/kg; i.p.) on day 1; and, a intravesical PRP‑treated group which was injected with CYP (150 mg/kg; i.p.) on day 1. On day 2, the rats in each group were sacrificed under anesthesia. Histological evaluation showed that bladder inflammation in CYP‑treated rats was not suppressed by PRP. CYP administration induced severe IC with marked edema, hemorrhage and inflammation in CYP and CYP+PRP groups, but PRP was not found to be effective to decrease these effects. The application of PRP could not reverse the histopathological changes in rats that had interstitial cystitis due to the cyclophosphamide injection.

  15. Prevention of cyclophosphamide-induced hemorrhagic cystitis by resveratrol: a comparative experimental study with mesna.

    Science.gov (United States)

    Keles, Ibrahim; Bozkurt, Mehmet Fatih; Cemek, Mustafa; Karalar, Mustafa; Hazini, Ahmet; Alpdagtas, Saadet; Keles, Hikmet; Yildiz, Turan; Ceylan, Cavit; Buyukokuroglu, Mehmet Emin

    2014-12-01

    Hemorrhagic cystitis (HC) is the most common urotoxic side effect of cyclophosphamide (CP). The aim of this study was to compare the classical efficacy of mesna (2-mercaptoethane sulfonate sodium) with three different doses of resveratrol (RES) on cyclophosphamide-induced HC in rats. Forty-six male Sprague-Dawley rats were divided into six groups. Group 1 served as a negative control (sham). Five groups received a single dose of cyclophosphamide (150 mg/kg) intraperitoneally at the same time. Groups 2, 3, 4, 5, and 6 received only CP, CP + 20 mg/kg RES, CP + 40 mg/kg RES, CP + 80 mg/kg RES, and CP + classical protocol of three doses of mesna (30 mg/kg three times), respectively. Antioxidants, cytokines, and malondialdehyde levels were measured in all groups. In addition, histopathological alterations in tissues were examined. CP administration induced severe HC with marked edema, hemorrhage, and inflammation in group 2. RES 20 mg/kg showed meaningful protection against bladder damage compared to the control group. It was seen that RES 40 mg/kg gave weaker protection but RES 80 mg/kg was not found to be effective. In conclusion, marked bladder protection was found in 20 and 40 mg/kg RES applications compared to the control group, but this protection was weaker than with mesna.

  16. Efficacy and survival associated with cystoscopy and clot evacuation for radiation or cyclophosphamide induced hemorrhagic cystitis.

    Science.gov (United States)

    Kaplan, Joshua R; Wolf, J Stuart

    2009-02-01

    We assessed the outcome of patients with hemorrhagic cystitis severe enough to require cystoscopy and clot evacuation. We retrospectively evaluated the records of 33 patients with cyclophosphamide or radiation induced hemorrhagic cystitis treated with cystoscopy. Mean followup of living patients was 76 months. Of 33 patients 20 (61%) had resolution of hematuria after single cystoscopy unrelated to hemorrhagic cystitis etiology. Only 4 of 11 patients (36%) had resolution after 2 or more cystoscopies, and all were in the radiation induced hemorrhagic cystitis group (4 of 6, 67%) with none in the cyclophosphamide induced hemorrhagic cystitis group (0 of 5, p = 0.02). Hematuria was refractory to cystoscopy in 9 patients and ileal conduits were created in 4. Kaplan-Meier overall survival at 1, 2 and 5 years was 58%, 51% and 43%, respectively, with survival tending to be worse in patients who received cyclophosphamide for bone marrow transplantation induction. Of the 18 deaths 3 were due to complications of hemorrhagic cystitis, 13 were due to the disease underlying the hemorrhagic cystitis and 2 were unrelated. The response of hemorrhagic cystitis to single cystoscopy and clot evacuation is reasonable but response to subsequent cystoscopy (unless the hemorrhagic cystitis is radiation induced) is less likely, so alternate interventions should be considered if hematuria does not resolve after initial cystoscopy. Patients with hemorrhagic cystitis requiring cystoscopy have a poor prognosis even if hematuria resolves, although most deaths are related to the disease underlying the hemorrhagic cystitis rather than its direct result.

  17. Nephroprotective effect of Murraya koenigii on cyclophosphamide induced nephrotoxicity in rats.

    Science.gov (United States)

    Mahipal, Patel; Pawar, Rajesh Singh

    2017-08-01

    To evaluate the nephroprotective effect of defatted methanolic extract and aqueous extract of Murraya koenigii (M. koenigii) against cyclophosphamide drug. Nephrotoxicity was induced by cyclophosphamide in 7 days at 150 mg/kg body weight through intraperitoneal route in rat model. Nephroprotective activity of M. koenigii extract (100 mg/kg and 200 mg/kg in intraperitoneal route) was measured, including nephrological source, oxidative stress parameters like superoxide dismutase, glutathione, the lipid peroxide and in vivo assay like blood urea nitrogen, creatinine were determined and analyzed by One way analysis of variance followed by Tukey's test. The study result showed that important phytochemicals such as carbohydrates, flavonoids, tannin, alkaloids, glycosides, protein and steroids were found to be present in the extract of M. koenigii. The renal function markers like blood urea nitrogen and creatinine level were found to be decreased significantly by M. koenigii extract treatment. A significant difference was found to be at P koenigii extract against cyclophosphamide induced nephrotoxicity. Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

  18. 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.

  19. Coffea arabica Seed Extract Stimulate the Cellular Immune Function and Cyclophosphamide-induced Immunosuppression in Mice

    Science.gov (United States)

    Rafiul Haque, Mohammad; Ansari, Shahid Hussain; Rashikh, Azhar

    2013-01-01

    In this study, we investigate the immunostimulatory effects of alcoholic extract of the coffee seed on cell-mediated immune response and cyclophosphamide-induced (CP) immunosuppressed mice. The assessment of cellular immune function was carried out by the measurement of delayed-type hypersensitivity (DTH) response. According to the literature survey, cyclophosphamide has only suppressing effect on the lymphoid organ, white blood cell (WBC) and other parts of humoral immunity. Humoral immunity was assessed by the hemagglutination antibody titre. Mice were treated with three doses of extract (50, 150 and 250 mg/Kg body weight per os). Relative organ weight and WBC counts were also studied in these animals. At doses of 50 and 150, a significant increase (p < 0.05) in relative organ weight of spleen and thymus was observed but there was no effect on kidney and liver weights. WBC counts was also increased significantly (p < 0.001) in all doses of the plant extract. Coffea arabica extract elicited a significant (p < 0.001) increase in the DTH response at doses of 50 and 150 mg/Kg, but the change at higher dose of 250 mg/Kg was not statistically significant. In the HT test, plant extract also showed modulatory effect at all doses groups. Over all, coffee seed showed the stimulatory effect on cellular immune function and cyclophosphamide induced immunosuppression in mice. PMID:24250577

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

    Science.gov (United States)

    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.

  1. 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.

  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...

  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

    2012-01-01

    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...

  4. Determination of exposure of dispensary drug preparers to cyclophosphamide by passive sampling and liquid chromatography with tandem mass spectrometry.

    Science.gov (United States)

    Wakui, Nobuyuki; Ookubo, Tetuo; Iwasaki, Yusuke; Ito, Rie; Mitui, Miyuki; Yano, Yuichi; Saito, Koichi; Nakazawa, Hiroyuki

    2013-03-01

    To determine cyclophosphamide exposure to preparers during tablet crushing and subsequent handling by analyzing indoor air collected using a high-performance volatile organic compounds-solvent desorption (VOC-SD) passive air sampler. The passive sampler was taped to the mask over the mouth of the preparer and indoor air was collected during crushing and preparation of cyclophosphamide tablets (Endoxan®). After collection, the carbon molecular sieve adsorbent of the passive sampler was placed in a centrifuge tube, and 1 mL of carbon disulfide was used to elute cyclophosphamide from the adsorbent. Liquid-liquid extraction with 1 mL of water was performed, and the aqueous phase was used as the test solution. Cyclophosphamide concentration was determined by liquid chromatography with ultraviolet and tandem mass spectrometry detection. Cyclophosphamide concentration was detected in the range of 7.6-157.7 ng/sampler. Our results showed that low-level exposure occurred near the mouth of the preparer, which could present risks for long-term exposure, especially if combined with multiple toxic drug exposures. The anticancer drug monitoring methodology described here is a simple exposure assessment that can be used to ensure the safety of hospital pharmacy tablet preparers. Furthermore, since the anticancer drug exposure risk is very high for preparers, preparation should be in hood or with face mask.

  5. 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.

  6. Bone marrow mesenchymal stem cell repair of cyclophosphamide-induced ovarian insufficiency in a mouse model

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    Badawy A

    2017-06-01

    Full Text Available Ahmed Badawy,1 Mohamed A Sobh,2 Mohamed Ahdy,3 Mohamed Sayed Abdelhafez1 1Department of Obstetrics and Gynecology, 2Department of Internal Medicine, 3Department of Clinical Pharmacology, Mansoura University, Mansoura, Egypt Objective: Attempting in vivo healing of cyclophosphamide-induced ovarian insufficiency in a mouse model using bone marrow mesenchymal stem cells (BMMSCs.Methods: Female BALB/c white mice were used to prepare a model for premature ovarian failure by single intraperitoneal injection of cyclophosphamide (80 mg/kg. Ten mice were injected with BMMSCs and then sacrificed after 21 days for morphometric evaluation of the ovaries. Hormonal profile was evaluated while mice were being sacrificed. Another 10 mice were left for natural breeding with male mice, and 5 of these were injected with BMMSCs. Oocyte-like structures were obtained from 3 mice and were subjected to in vitro fertilization/intracytoplasmic sperm injection.Results: Morphometric analysis of the ovaries demonstrated the presence of newly formed primordial follicles. Contribution of MSCs to the formation of these follicles was proven by a labeling technique. There was a drop in estradiol and rise in follicle-stimulating hormone levels, followed by resumption of the hormonal levels to near normal 21 days after MSCs therapy. The 5 mice that were injected with MSCs became pregnant after natural breeding. Fertilization and further division was reported in 5 oocytes subjected to intracytoplasmic sperm injection, but division did not continue.Conclusion: From this proof-of-concept trial, we can say that healing of damaged ovaries after chemotherapy in mice is possible using in vivo therapy with BMMSCs. This should open the gate for a series of animal studies that test the possibility of in vitro maturation of germinal epithelium of the ovary into mature oocytes. Keywords: cyclophosphamide, stem cell, POF, ovarian insufficiency

  7. Cyclophosphamide-induced agenesis of cerebral aqueduct resulting in hydrocephalus in mice.

    Science.gov (United States)

    Prakash; Singh, Gajendra; Singh, Sukh Mahendra

    2007-07-01

    The present work was undertaken to reveal the mechanism of cerebral aqueduct agenesis found to result in hydrocephalus following intrauterine exposure to model teratogen, cyclophosphamide, in murine fetuses. A single dose of 10-mg/kg body weight cyclophosphamide was injected intaperitoneally to pregnant mice on day 10, 11 or 12 of gestation. Fetuses were collected through abdominal incision on day 18 and studied for various malformations of brain and cranium including hydrocephalus. Incomplete development and failure of canalization of the cerebral aqueduct were detected when serial sections of brain in coronal and transverse planes were studied under the microscope. Biotechnological investigations such as % DNA fragmentation, % viable cell count and cell proliferation assay were carried out on brain cells for further studies. Agenesis and non-canalization of the cerebral aqueduct resulted in increased pressure of CSF, which led to rupture of the aqueduct complicated by leakage and accumulation of CSF in brain substance forming a cavity containing CSF parallel and lateral to the unopened part of the cerebral aqueduct. Incomplete development along with non-canalization of the cerebral aqueduct resulted in blockage of CSF flow through the ventricles that manifest as internal hydrocephalus. External hydrocephalus on the other hand was detected where the CSF accumulated in the cavity formed inside the brain substance and established communication with the CSF in the subarachnoid space. Cyclophosphamide induced inhibition of mitosis and cell differentiation of ependymal cells reflecting a decreased % viable cell count and cell proliferation assay along with augmentation of apoptosis of brain cells quantified as increased % DNA fragmentation count, which were identified as the contributing factors underlying the agenesis and incomplete development of the cerebral aqueduct. The study also suggests that cell survival, proliferation, migration or differentiation of

  8. 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.

  9. 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.

  10. Superiority of cisplatin or carboplatin in combination with teniposide and vincristine in the induction chemotherapy of small-cell lung cancer. A randomized trial with 5 years follow up

    DEFF Research Database (Denmark)

    Lassen, U; Kristjansen, P E; Osterlind, K

    1996-01-01

    PURPOSE: The introduction of platinum compounds and epipodophyllotoxins in combination with vincristine as induction chemotherapy in small-cell lung cancer (SCLC) was investigated in order to: (1) compare the efficacy of cisplatin with that of carboplatin in combination with teniposide and vincri......PURPOSE: The introduction of platinum compounds and epipodophyllotoxins in combination with vincristine as induction chemotherapy in small-cell lung cancer (SCLC) was investigated in order to: (1) compare the efficacy of cisplatin with that of carboplatin in combination with teniposide...... and vincristine as inducers of remission over three cycles; (2) compare the toxicity pattern of carboplatin and of cisplatin when given in combination regimens; and (3) compare a chemotherapeutic regimen consisting of three alternating combinations with that of regimens consisting of four alternating combinations....... PATIENTS AND METHODS: From November 1985 to September 1991, 484 consecutive, previously untreated patients with SCLC, performance status 0-4, entered a three armed randomized trial with three cycles of cisplatin (arm I) or carboplatin (arm II) in combination with teniposide and vincristine alternating...

  11. Cyclophosphamide versus methylprednisolone for the treatment of neuropsychiatric involvement in systemic lupus erythematosus.

    Science.gov (United States)

    Trevisani, V F; Castro, A A; Neves Neto, J F; Atallah, A N

    2000-01-01

    Neuropsychiatric involvement in systemic lupus erythematosus is complex and several clinical presentations are related to this disease such as: convulsions, chronic headache, transverse myelitis, vascular brain disease, psychosis and neural cognitive dysfunction. To assess the efficacy and safety of cyclophosphamide and methylprednisolone in the treatment of neuropsychiatric manifestations of systemic lupus erythematosus on mortality and side effects. We searched EMBASE, LILACS, Cochrane Controlled Trials Register and MEDLINE up to and including December 1999, additional articles were sought through handsearching in relevant journals, using the search strategy described in the Cochrane Handbook [Dickersin 1994]. There were no language restrictions. All randomized controlled trials which compared cyclophosphamide to methylprednisolone were to be included. Patients of any age and gender were included if they fulfilled the criterion of the American Rheumatology Association for the diagnosis of systemic lupus erythematosus and presented with any one of the following neuropsychiatric events; convulsions, organic brain syndrome; cranial neuropathy. Outcome measures included the following: a) Overall mortality (primary event); b) Motor and psychiatric deficit (primary event); c) Clinical improvement (secondary event). The analysis planned was to do the following: Data would be independently extracted by the two reviewers and cross-checked. The methodological quality of each trial would be assessed by the same two reviewers. Details of the randomisation (generation and concealment), blinding, and the number of patients lost on follow-up would be recorded. The results of each RCT would be summarised on an intention-to-treat basis in 2 x 2 tables for each outcome. External validity would be defined by characteristics of the participants, the interventions and the outcomes. If appropriate, RCTs would be stratified based on control group and category of disease in accordance

  12. Cyclophosphamide 'pulses' in chronic progressive multiple sclerosis. A preliminary clinical trial.

    Science.gov (United States)

    Myers, L W; Fahey, J L; Moody, D J; Mickey, M R; Frane, M V; Ellison, G W

    1987-08-01

    To our knowledge, this is the first clinical trial in multiple sclerosis (MS) demonstrating the feasibility of directing immunomodulating therapy by monitoring immunologic results. Cyclophosphamide was administered at monthly intervals, escalating the dose until there was a significant reduction in both the number of blood B lymphocytes and helper/inducer (CD4) T cells of 14 patients with chronic progressive MS. The frequency and severity of adverse effects led us to conclude that the regimen is too toxic for the long-term treatment of patients with MS.

  13. [Reconstitution of cyclophosphamide-induced, impaired function of the immune system in animal models].

    Science.gov (United States)

    Artym, Jolanta

    2003-01-01

    Cyclophosphamide (CY) is an alkylating agent used in chemotherapy of tumors and autoimmune disorders. The drug causes a large number of side-effects including deep, transient lymphopenia and neutropenia, thus rendering the immune system susceptible to infections. In this review we focus on the effects of CY on the haematopoetic system and the immune response in rodents. In addition, we present approaches aimed at reconstitution of lympho- and myelopoiesis using a spectrum of immunotropic factors including: thymic hormones, cytokines, low-molecular weight compounds, bacterial products and lactoferrin.

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

    Science.gov (United States)

    Wang, Ching-Chia; Weng, Te-I; Lu, Meng-Yao; Yang, Rong-Sen; Lin, Kai-Hsin; Wu, Mei-Hwan; Liu, Shing-Hwa

    2015-08-01

    Hemorrhagic cystitis is a common complication with chemotherapeutic alkylating agents. We investigated the possible prognostic factors of cyclophosphamide-induced hemorrhagic cystitis in children. Medical records of children (hemorrhagic cystitis were collected retrospectively from January 2000 to December 2010 in a tertiary care center. We also prospectively enrolled children (hemorrhagic cystitis than those who did not receive BMT (p hemorrhage cystitis, was significantly lower after the development of hemorrhagic cystitis (p 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. Copyright © 2013. Published by Elsevier B.V.

  15. Capacity buffer of the saliva in children and adolescents with cancer: Variations induced by the administration of metotrexate or cyclophosphamide.

    Science.gov (United States)

    Rojas-Morales, Thais; Lugo, Zulecnys; Santana, Yrma; Navas, Rita; Zambrano, Olga; Viera, Ninoska; García, Isaura

    2005-07-01

    To determine the variations in the levels of capacity buffer of the saliva in children and adolescents with cancer that receiving Metotrexate or cyclophosphamide. A clinical, random-controlled assay was carried out. The sample was composed by 24 children, ages between 2 and 16 years, with diagnostic of Leukemia and Lymphomas attending to The Autonomous Service of University Hospital of Maracaibo and Hospital of Pediatric Specialties. Two groups were conformed to which a sample of saliva was taken before and after the chemotherapy; twelve patients were randomly placed in the G1: patient receiving Metotrexate and twelve in the G2: patient receiving cyclophosphamide. In order to determine the capacity buffer, the CRT Buffer IVOCLAR VIVADENT was used. The capacity salivary buffer did not show significant differences before and after the administration of the cytostatic agents studied. In this study, the Metotrexate or cyclophosphamide administration does not modify the salivary buffer capacity in pediatric patient with cancer.

  16. Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome.

    Science.gov (United States)

    Gulati, Ashima; Sinha, Aditi; Gupta, Aarti; Kanitkar, Madhuri; Sreenivas, Vishnubhatla; Sharma, Jyoti; Mantan, Mukta; Agarwal, Indira; Dinda, Amit K; Hari, Pankaj; Bagga, Arvind

    2012-11-01

    There are limited data on the relative efficacy and safety of calcineurin inhibitors and alkylating agents for idiopathic steroid-resistant nephrotic syndrome in children. To clarify this, we compared tacrolimus and intravenous cyclophosphamide therapy in a multicenter, randomized, controlled trial of 131 consecutive pediatric patients with minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis, stratified for initial or late steroid resistance. Patients were randomized to receive tacrolimus for 12 months or 6-monthly infusions of intravenous cyclophosphamide with both arms receiving equal amounts of alternate-day prednisolone. The primary outcome of complete or partial remission at 6 months, based on spot urine protein to creatinine ratios, was significantly higher in children receiving tacrolimus compared to cyclophosphamide (hazard ratio 2.64). Complete remission was significantly higher with tacrolimus (52.4%) than with cyclophosphamide (14.8%). The secondary outcome of sustained remission or steroid-sensitive relapse of nephrotic syndrome at 12 months was significantly higher with tacrolimus than cyclophosphamide. Treatment withdrawal was higher with cyclophosphamide, chiefly due to systemic infections. Compared to cyclophosphamide, 3 patients required treatment with tacrolimus to achieve 1 additional remission. Thus, tacrolimus and prednisolone are effective, safe, and preferable to cyclophosphamide as the initial therapy for patients with steroid-resistant nephrotic syndrome.

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

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    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.

  18. 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

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    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.

  19. 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.

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

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    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.

  1. 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

  2. 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.

  3. Crataegus monogyna aqueous extract ameliorates cyclophosphamide-induced toxicity in rat testis: stereological evidences.

    Science.gov (United States)

    Jalali, Ali Shalizar; Hasanzadeh, Shapour; Malekinejad, Hassan

    2012-01-01

    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.

  4. 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.

  5. Fucoidan and Fucosylated Chondroitin Sulfate Stimulate Hematopoiesis in Cyclophosphamide-Induced Mice

    Directory of Open Access Journals (Sweden)

    Natalia Anisimova

    2017-09-01

    Full Text Available Application of cytostatics in cancer patients’ chemotherapy results in a number of side effects, including the inhibition of various parts of hematopoiesis. Two sulfated polysaccharides, fucoidan from the seaweed Chordaria flagelliformis (PS-Fuc and fucosylated chondroitin sulfate from the sea cucumber Massinium magnum (PS-FCS, were studied as stimulators of hematopoiesis after cyclophosphamide immunosuppression in mice. Recombinant granulocyte colony-stimulating factor (r G-CSF was applied as a reference. Both tested polysaccharides PS-Fuc and PS-FCS have a similar activity to r G-CSF, causing pronounced neutropoiesis stimulation in animals with myelosuppression induced by cyclophosphamide (CPh. Moreover, these compounds are also capable to enhance thrombopoiesis and erythropoiesis. It should be noted that PS-FCS demonstrated a greater activity than r G-CSF. The results indicate the perspective of further studies of PS-Fuc and PS-FCS, since these compounds can be considered as potentially promising stimulators of hematopoiesis. Such drugs are in demand for the accompanying treatment of cancer patients who suffer from hematological toxicity during chemo and/or radiation therapy.

  6. [Evaluation of acute cardiotoxicity from the combination cyclophosphamide-mitoxantrone-5-fluorouracil (CMF) with Holter ECG].

    Science.gov (United States)

    Doria, G; Cangemi, F; Tosto, A; Platania, F; Circo, A; Motta, S; Tralongo, P; Aiello, R A; Failla, G

    1990-05-01

    By making use of a twenty-four hour Holter monitoring, it as been possible to compute the acute cardiotoxicity of the cyclophosphamide + mitoxantrone + 5-fluorouracil (CNF) association in twenty oncologic patients (pts) each of whom being immune from organic cardiopathy emerging clinically and at their first cycle of chemotherapy. The following parameters have been computed: meaningful changes in the heart frequency; premature atrial and ventricular depolarizations, both as a first appearance and as a clear growth in the number; the ST dislocation entity; malignant ventricular arrhythmias. The administration of CNF at the doses of: 600 mg/m2 of cyclophosphamide, 12 mg/m2 of mitoxantrone and 600 mg/m2 of 5-fluorouracil , has caused a meaningful increase in the heart frequency on 6 pts (30%), an increase of premature atrial depolarization on 4 pts (20%) with an appearance ex novo on 2 pts (10%), an increase of premature ventricular depolarization, without any passing to superior Lown classes, on 2 pts (10%) with an appearance ex novo on 3 pts (15%). Although the results in the study point out a frequency percentage of simple hyperkinetic arrhythmias equal to the 55%, the lack of more serious hyperkinetic arrhythmias and of intense disorders of ventricular repolarization testified to a synergic effect as a determining factor on the acute cardiotoxicity of the previously discussed association, in our opinion.

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

    Science.gov (United States)

    Inui, Naoki

    2017-05-01

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

  8. Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage

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    Jie Deng

    2018-04-01

    Full Text Available Oxidative DNA damage in bone marrow cells is the main side effect of chemotherapy drugs including cyclophosphamide (CTX. However, not all antioxidants are effective in inhibiting oxidative DNA damage. In this study, we report the beneficial effect of carnosine (β-alanyl-l-histidine, a special antioxidant with acrolein-sequestering ability, on CTX-induced bone marrow cell suppression. Our results show that carnosine treatment (100 and 200 mg/kg, i.p. significantly inhibited the generation of reactive oxygen species (ROS and 8-hydroxy-2′-deoxyguanosine (8-oxo-dG, and decreased chromosomal abnormalities in the bone marrow cells of mice treated with CTX (20 mg/kg, i.v., 24 h. Furthermore, carnosine evidently mitigated CTX-induced G2/M arrest in murine bone marrow cells, accompanied by reduced ratios of p-Chk1/Chk1 and p-p53/p53 as well as decreased p21 expression. In addition, cell apoptosis caused by CTX was also suppressed by carnosine treatment, as assessed by decreased TUNEL-positive cell counts, down-regulated expressions of Bax and Cyt c, and reduced ratios of cleaved Caspase-3/Caspase-3. These results together suggest that carnosine can protect murine bone marrow cells from CTX-induced DNA damage via its antioxidant activity. Keywords: Carnosine, Cyclophosphamide, Oxidative DNA damage, Sister chromatid exchange, Apoptosis, Cell cycle arrest

  9. Targeting human c-Myc promoter duplex DNA with actinomycin D by use of multi-way analysis of quantum-dot-mediated fluorescence resonance energy transfer

    DEFF Research Database (Denmark)

    Gholami, Somayeh; Kompany Zare, Mohsen

    2013-01-01

    of concentration profiles and pure spectra for all species, including non-fluorophores. The hard modeling approach was also used for determination of equilibrium constants for the hybridization and intercalation equilibria, using nonlinear fit data analysis. The intercalation constant 3.6 x 10(6) mol(-1) L...

  10. Human p53 interacts with the elongating RNAPII complex and is required for the release of actinomycin D induced transcription blockage

    NARCIS (Netherlands)

    Borsos, B.N. (Barbara N.); Huliák, I. (Ildikó); Majoros, H. (Hajnalka); Ujfaludi, Z. (Zsuzsanna); Gyenis, A. (Ákos); Pukler, P. (Peter); Boros, I.M. (Imre M.); Pankotai, T. (Tibor)

    2017-01-01

    textabstractThe p53 tumour suppressor regulates the transcription initiation of selected genes by binding to specific DNA sequences at their promoters. Here we report a novel role of p53 in transcription elongation in human cells. Our data demonstrate that upon transcription elongation blockage, p53

  11. 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.

  12. Cyclophosphamide Injection

    Science.gov (United States)

    ... the kidneys) in children whose disease has not improved, has gotten worse, or has come back after ... if you have previously received treatment with other chemotherapy medications or if you have had x-rays ...

  13. Effects of cyclosporin A and cyclophosphamide on Peyer's patches in rat, exposed in utero and neonatally or during adult age

    NARCIS (Netherlands)

    Kuper, C.F.; Zijverden, M. van; Klaassen, C.; Tegelenbosch-Schouten, M.; Wolterbeek, A.P.M.

    2007-01-01

    The effects of cyclosporin A (CY) and cyclophosphamide (CPS) on Peyer's patches (PP) were studied in Wistar rats, exposed in utero and neonatally or during adult age. In one study, pregnant dams received 5 or 15 mg/kg bw/day CY from gestation day 6 to day 21 of lactation. In two other studies,

  14. Effect of Hydroalcoholic Extract of Cinnamon on the Pituitary-Gonadal Axis in Adult Male Rats under Chemotherapy by Cyclophosphamide

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    Habibollah Johari

    2014-03-01

    Full Text Available Background: Cyclophosphamide chemotherapy is used as anti cancer drug and weakening immune system for adult widely. As there are inadequate information, so we are to examine possible effect of hydro alcoholic extract of cinnamon on the pituitary - gonadal axis in adult male rats chemotherapy drug by cyclophosphamide. Materials and Methods: Thirty five male Wistar rats divided into 5 groups of 7 including control, observer, and experiments 1, 2, 3, 4 and 5 respectively. The control group received no treatment while observer group were injected 2.0 mm of distilled water (solvent intraperitoneally. The experimental mice 1, 2 and 3 were intraperitoneally injected 5 mg/kg cyclophosphamide drug with 50, 100 and 200 mg/kg fed by gavage either cinnamon extract. Results: The weight of the rats in the experimental groups 1, 2, 3 and 4 were significantly lower than the control group (p=0.01. Right and left testicular weight in experimental groups 2 and 3 than in group 4 was significantly increased in groups 1 and 4 showed a significant decrease compared to the control group (p=0.01. Hormones LH, FSH and testosterone increased significantly in groups 2 and 3 than in group 4 showed the (p=0.05. 5 experimental groups showed significant increase in FSH compared with controls (p=0.05. Conclusion: This study showed that cyclophosphamide has a destructive effect on testis and secretion of sex hormones in male rats and hence effect of cinnamon improves it to some extent.

  15. Mesna and furosemide for prevention of cyclophosphamide-induced sterile haemorrhagic cystitis in dogs--a retrospective study.

    Science.gov (United States)

    Laberke, S; Zenker, I; Hirschberger, J

    2014-03-08

    Sterile haemorrhagic cystitis (SHC) is a possible side effect of cyclophosphamide which can severely impact quality of life. Mesna and diuresis are effective in human medicine to prevent SHC. The aim of the present study was to compare the efficacy of mesna versus diuresis with furosemide in preventing SHC in dogs treated with cyclophosphamide within a multidrug chemotherapy induction protocol for malignant lymphoma. Medical records of dogs treated at the Clinic of Small Animal Medicine, Munich, between 1997 and 2009 were analysed retrospectively. Of the 131 dogs included, 33 received no prophylaxis (group 1), 43 received mesna (group 2), and 55 received furosemide (group 3). Age, gender, breed, bodyweight, body surface area, dose and application method of cyclophosphamide, and the method of SHC prophylaxis were compared between dogs with and without SHC. Six dogs (4.6 per cent) developed SHC. The incidence of SHC in groups 1, 2 and 3 was 4/33 (12.1 per cent), 1/43 (2.3 per cent), and 1/55 (1.8 per cent), respectively. Dogs receiving either mesna or furosemide were significantly less likely to develop SHC (P=0.03). Otherwise no significant differences were found. In conclusion, this study demonstrates the efficacy and the medical indication of mesna and furosemide for prevention of cyclophosphamide-induced SHC.

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

    Energy Technology Data Exchange (ETDEWEB)

    Manda, K.; Bhatia, A. L.

    2004-07-01

    Clinical studies have demonstrated an altered pineal function in cancer patients. Owing to the document antineoplastic activity of the pineal gland, these anomalies could have a prognostic significance. This study was carried out to monitor the effect of higher blood levels of melatonin, the most important pineal hormone, which could be applied in relation to the response to chemotherapy in human neoplasms. Cyclophosphamide is a commonly used chemotherapeutic drug and well-known mutagen and clastogen. It is an alkylating agent, producing highly active carbonium ion, which the extremely electron-rich area of the nucleic acids and proteins. The present study aimed to investigate the protective effect of melatonin against cyclophosphamide induced oxidative stress in mice tissues. Lipid perioxidation. Reduced glutathione (GSH), Glutathione disulphide (GSSG), Glutathione peroxidase (GSH-Px) and serum phosphatase level taken as endpoints. Twenty days oral administration with melatonin (0.25 mg/Kg body weight) followed by an acute treatment with cyclophosphamide (75 mg/kg b. w.) inhibited the radiomimetic drug-induced augmented level of lipid peroxidation, Blood GSSG and acid phosphatase. Cyclophosphamide induced depletion in the level of GSH, GSH-Px and alkaline phosphatase is ameliorated significantly by melatonin administration. The findings support the results showing melatonin as a free radical scavenger, and singlet oxygen quencher. Results clearly indicate the antioxidative properties of melatonin against the radiomimetic drug which could be effectively used selectively for the protection of normal tissue during chemotherapy. (Author) 34 refs.

  17. 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

    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

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

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    Huijts Charlotte M

    2011-11-01

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

  19. 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

  20. The Ethanol Extract of the Inner Bark of Caesalpinia pyramidalis (Tul. Reduces Urinary Bladder Damage during Cyclophosphamide-Induced Cystitis in Rats

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    Janaína P. Moraes

    2013-01-01

    Full Text Available Hemorrhagic cystitis (HC is a common side effect of cyclophosphamide therapy, which deserves new therapeutic strategies, such as those based on natural products. The ethanol extract of the inner bark of Caesalpinia pyramidalis (Tul. (EECp possesses anti-inflammatory, antinociceptive, and antioxidant activities as previously showed by our group. We have investigated the effect of EECp on the cyclophosphamide-induced HC. Cystitis was induced in male Wistar rats by the injection of cyclophosphamide. These animals were pretreated with EECp (100–400 mg/kg, vehicle, or mesna. Myeloperoxidase activity and malondialdehyde formation were measured in urinary bladder and other tissues. Bladder edema and histopathological alterations and serum nitric oxide metabolites concentration NOx- were also evaluated. Treatment with EECp (100–400 mg/kg or mesna impaired the increase of myeloperoxidase activity in urinary bladder and the serum NOx- induced by cyclophosphamide but did not reduce edema in this tissue, as did mesna. Total histological score was reduced by EECp (100 mg/kg. Lung myeloperoxidase activity, which was increased by cyclophosphamide, was decreased significantly by EECp (400 mg/kg. EECp also diminished the malondialdehyde formation in bladder, lung, and spleen, although these parameters were not affected by cyclophosphamide. These results indicate that EECp reduced urinary bladder damage during cyclophosphamide-induced HC in rats.

  1. The Ethanol Extract of the Inner Bark of Caesalpinia pyramidalis (Tul.) Reduces Urinary Bladder Damage during Cyclophosphamide-Induced Cystitis in Rats

    Science.gov (United States)

    Moraes, Janaína P.; Pereira, Denyson S.; Matos, Alexandre S.; Santana, Danielle G.; Santos, Cliomar A.; Estevam, Charles S.; Fakhouri, Ricardo; de Lucca Junior, Waldecy; Camargo, Enilton A.

    2013-01-01

    Hemorrhagic cystitis (HC) is a common side effect of cyclophosphamide therapy, which deserves new therapeutic strategies, such as those based on natural products. The ethanol extract of the inner bark of Caesalpinia pyramidalis (Tul.) (EECp) possesses anti-inflammatory, antinociceptive, and antioxidant activities as previously showed by our group. We have investigated the effect of EECp on the cyclophosphamide-induced HC. Cystitis was induced in male Wistar rats by the injection of cyclophosphamide. These animals were pretreated with EECp (100–400 mg/kg), vehicle, or mesna. Myeloperoxidase activity and malondialdehyde formation were measured in urinary bladder and other tissues. Bladder edema and histopathological alterations and serum nitric oxide metabolites concentration NOx − were also evaluated. Treatment with EECp (100–400 mg/kg) or mesna impaired the increase of myeloperoxidase activity in urinary bladder and the serum NOx − induced by cyclophosphamide but did not reduce edema in this tissue, as did mesna. Total histological score was reduced by EECp (100 mg/kg). Lung myeloperoxidase activity, which was increased by cyclophosphamide, was decreased significantly by EECp (400 mg/kg). EECp also diminished the malondialdehyde formation in bladder, lung, and spleen, although these parameters were not affected by cyclophosphamide. These results indicate that EECp reduced urinary bladder damage during cyclophosphamide-induced HC in rats. PMID:24348180

  2. 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

  3. Phase I and extension study of clofarabine plus cyclophosphamide in patients with relapsed/refractory acute lymphoblastic leukemia.

    Science.gov (United States)

    Faderl, Stefan; Balakrishnan, Kumudha; Thomas, Deborah A; Ravandi, Farhad; Borthakur, Gautam; Burger, Jan; Ferrajoli, Alessandra; Cortes, Jorge; O'Brien, Susan; Kadia, Tapan; Feliu, Jennie; Plunkett, William; Gandhi, Varsha; Kantarjian, Hagop M

    2014-06-01

    Clofarabine is a nucleoside analogue with activity in children with acute lymphoblastic leukemia (ALL). Based on the hypothesis that clofarabine inhibits DNA repair after exposure to DNA-damaging agents, we designed a phase I and extension study to evaluate the combination of clofarabine and cyclophosphamide in adult patients with relapsed/refractory ALL. The continual reassessment method (CRM) was used to define the maximum tolerated dose (MTD). Fifty patients with a median age of 30 years (range, 21-72 years) were enrolled, 30 of whom were part of the phase I group. Clofarabine 40 mg/m(2) intravenously daily × 3 days and cyclophosphamide 200 mg/m(2) intravenously every 12 hours × 3 days were established as the MTDs. Dose limiting toxicity (DLT) included 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 (CRp). Three responses occurred in patients with primary refractory disease. Early mortality (< 30 days) was 6%. The median duration of response was 69 days (range, 5-315 days). Median overall survival was about 3 months. Compared with day 1 (cyclophosphamide alone), H2AX phosphorylation was increased on day 2 when clofarabine and cyclophosphamide were administered as a couplet (n = 8). The combination of clofarabine plus cyclophosphamide at the doses used in this study 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Incidence of sterile hemorrhagic cystitis in tumor-bearing dogs concurrently treated with oral metronomic cyclophosphamide chemotherapy and furosemide: 55 cases (2009-2015).

    Science.gov (United States)

    Chan, Catherine M; Frimberger, Angela E; Moore, Antony S

    2016-12-15

    OBJECTIVE To determine the incidence of sterile hemorrhagic cystitis (SHC) in tumor-bearing dogs concurrently treated with oral metronomic cyclophosphamide chemotherapy and furosemide. DESIGN Retrospective case series. ANIMALS 55 dogs. PROCEDURES Record databases of 2 specialty practices were searched to identify dogs treated with oral metronomic cyclophosphamide chemotherapy in conjunction with furosemide for a minimum of 28 days between January 2009 and December 2015. Information extracted from the records included signalment, tumor diagnosis, cyclophosphamide and furosemide dosages, and concurrent medications. Confirmed SHC was defined as the presence of gross or microscopic hematuria and clinical signs associated with lower urinary tract disease in the absence of infection or neoplasia of the urinary tract; the definition for suspected SHC was the same, except the absence of infection or neoplasia of the urinary tract was not confirmed. RESULTS Cyclophosphamide dosage varied from 6.5 to 18.6 mg/m 2 once daily to 6.3 to 49.2 mg/m 2 every other day. Median duration of cyclophosphamide administration was 272 days (range, 28 to 1,393 days). Median cumulative dose of cyclophosphamide administered was 2,898 mg/m 2 (range, 224 to 14,725 mg/m 2 ). Median furosemide dose was 1.4 mg/kg (0.64 mg/lb). Confirmed or suspected SHC was identified in 2 of 55 (3.6%) dogs. Cyclophosphamide administration was discontinued for the dog with confirmed SHC but not the dog with suspected SHC. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that oral administration of furosemide in conjunction with oral metronomic cyclophosphamide chemotherapy was associated with a low incidence of SHC, which suggested that furosemide may protect against cyclophosphamide-induced SHC.

  5. Radiation effect studies on anticancer drugs, cyclophosphamide and doxorubicin for radiation sterilization

    Science.gov (United States)

    Varshney, L.; Dodke, P. B.

    2004-12-01

    Two anticancer drugs, cyclophosphamide (CPH) and doxorubicin hydrochloride (DOXO), in powder form were exposed to a range of doses of 60Co gamma and electron beam radiation to study the effects of ionizing radiation. Pharmacopoeia tests, discolouration, degradation products, effect of irradiation temperature and dose rate were investigated. CPH undergoes less than 2% degradation at 30 kGy. Chromatographic studies revealed formation of several trace level degradation products, discolouration and free radicals in the irradiated CPH. N, N-bis (2-chloroethyl) group in the molecule is particularly sensitive to radiation degradation. Irradiation to 5 kGy at low temperature (77 K) did not result in significant changes. DOXO was observed to be quite radiation resistant and did not undergo significant changes in its physico-chemical properties and degradation product profile. It can be radiation sterilized at normal sterilization dose of 25 kGy.

  6. 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.

  7. Synergistic immunostimulating activity of pidotimod and red ginseng acidic polysaccharide against cyclophosphamide-induced immunosuppression.

    Science.gov (United States)

    Du, Xiao Fei; Jiang, Cheng Zhe; Wu, Chun Fu; Won, Eun Kyung; Choung, Se Young

    2008-09-01

    We investigated the synergistic effect of combined treatment with red ginseng acidic polysaccharide (RGAP) from Panax ginseng C.A. Meyer and pidotimod in cyclophosphamide-treated mice. The combination of pidotimod and RGAP restored concanavalin A-induced splenic T cell proliferation and LPS-stimulated B cell proliferation significantly. The production of nitric oxide from peritoneal macrophages was increased by the combinations. NK cell activity was increased by RGAP alone or in combination with pidotimod. A synergistic increase in the level of serum IL-12 and interferongamm was observed when the combination of the two was used. RGAP alone or in combination with pidotimod modulated the level of serum C-reactive protein to a near-normal level. These results indicate that combinations of pidotimod and RGAP are synergistic and suggest that combination therapy using pidotimod and RGAP for improving immune activity may provide an additional benefit over the use of the two drugs by themselves.

  8. Steady improvement of prothrombin levels after cyclophosphamide therapy in pediatric lupus anticoagulant hypoprothrombinemia syndrome (LAHPS).

    Science.gov (United States)

    Taddio, Andrea; Brescia, Annemarie C; Lepore, Loredana; Rose', Carlos D

    2007-12-01

    Lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) is a rare acquired disorder associated with several different conditions but mostly with systemic lupus erythematosus (SLE). LAHPS probably results from the presence of anti-Factor II antibodies, which usually counterbalance the prothrombotic effect of the lupus anticoagulant (LAC). In fact, Factor II deficiency in SLE is invariably associated with the presence of LAC. No consensus exists for the treatment of LAHPS. Corticosteroids, with or without the addition of vitamin K or blood products, have been a successful first-line treatment. Immunoglobulin (IVIG) treatment has been shown to be effective in the setting of acute bleeding. However, in some patients, conservative treatment is not enough to control bleeding, and the addition of immunosuppressive therapy, usually azathioprine, is needed. In our patients, Factor II deficiency reappeared after tapering steroids. Both children achieved normal Factor II levels with cyclophosphamide. This effect was long-lasting, a phenomenon that has not been documented in children prior to this report.

  9. Chronic hematuria and localized bladder damage following combined cyclophosphamide and local radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Kende, G.; Wajsman, Z.; Thomas, P.R.M.; Freeman, A.I.

    1979-01-01

    A 13-year-old white male had Ewing sarcoma of the right pubic and ischial bones. Initial therapy consisted of 5400 rads in seven weeks to the right side of the pelvis and 14 intravenous injections of cyclophosphamide (Cytoxan, CTX) at 500 mg/m/sup 2/; BCNU and Adriamycin maintenance therapy continued for a total of two years. He has now been disease-free for five years. Three months following the completion of the right pelvic radiotherapy (RT), while on intravenous CTX, severe hematuria appeared, which subsided, but at present he has continuous microscopic hematuria, as well as periodic episodes of gross hematuria. Serial cystocopies initially revealed thickening and hemorrhagic and edematous changes on the right (irradiated) side of the bladder, and recent multiple telangiectatic patches have been demonstrated as a late healing phase. This case demonstrates the additive toxicity to the bladder of CTX and RT, illustrating that the hemorrhagic cystitis can be extremely protracted lasting five years.

  10. Repeated Cold Stress Reduces Cyclophosphamide-Induced Cystitis/Bladder Pain and Macrophage Activity in Mice.

    Science.gov (United States)

    Tsubota, Maho; Miyamoto, Tomoyoshi; Hiruma, Saki; Saeki, Haruka; Miyazaki, Takaya; Sekiguchi, Fumiko; Funakami, Yoshinori; Kawabata, Atsufumi

    2017-01-01

    We examined the effect of repeated cold (RC) stress on cyclophosphamide (CPA)-induced cystitis/bladder pain in mice, in relation to macrophage activity. CPA, given i.p. at 400 mg/kg, caused bladder pain symptoms accompanying cystitis in both unstressed and RC-stressed mice, which were prevented by the macrophage inhibitor minocycline. A low dose, that is, 200 mg/kg, of CPA still produced bladder pain symptoms in unstressed but not RC-stressed mice. Lipopolysaccharide-induced cytokine production in peritoneal macrophages from RC-stressed mice was less than that from unstressed mice. Thus, RC stress appears to reduce CPA-induced bladder pain in mice, which may be associated with the decreased macrophage activity. © 2017 S. Karger AG, Basel.

  11. L-Carnitine Protect against Cyclophosphamide Induced Skeletal and Neural Tube Malformations in Rat Fetuses.

    Science.gov (United States)

    Khaksary Mahabady, Mahmood; Najafzadeh Varzi, Hossein; Zareyan Jahromi, Saeedeh

    2015-11-01

    Cyclophosphamide (CP) is a mustard alkylating agent used in the treatment of a number of neoplastic diseases and as an immunosuppressant for the prevention of xenograft rejection. There are many reports that the teratogenic effects of cyclophosphamide can be prevented by application of antioxidant drugs and stimulation of the maternal immune system. Also, there is some evidence that L-carnitine is antioxidant. Therefore, in this study, the prophylactic effect of L-carnitine on teratogenic effects of CP was evaluated. This study was performed on 31 pregnant rats divided into 5 groups. Control group received normal saline and test groups received L-carnitine (500 mg/kg), CP (15 mg/kg), CP (15 mg/kg) plus L-carnitine (250 mg/kg) and CP (15 mg/kg) plus L-carnitine (500 mg/kg) intraperitoneally at 9th day of gestation. Fetuses were collected at 20th day of gestation and after determination of weight and length; they were stained by Alizarin red-Alcian blue method. Cleft palate, spina bifida, and exencephaly incidence were 55.55%, 33.34% and 27.77% in fetuses of mice that received only CP. Cleft palate, spina bifida, exencephaly incidence were 21.42%, 4.76% and 9.52% in the group which received CP plus L-carnitine (250 mg/kg), respectively. However, cleft palate, spina bifida, and exencephaly incidence were 8%, 0% and 8% range in the group received CP plus L-carnitine (500 mg/kg), respectively. In addition, skeletal anomalies incidence including limbs, vertebrae, and sternum defects were decreased by L-carnitine. The mean of weight and length of animals' fetuses received L-carnitine were significantly greater than those received only CP. In conclusion, L-carnitine significantly decreased teratogenicity induced by CP; but this subject needs more detailed evaluation.

  12. Fullerene C60 nanoparticles ameliorated cyclophosphamide-induced acute hepatotoxicity in rats.

    Science.gov (United States)

    Elshater, Abd-Elraheim A; Haridy, Mohie A M; Salman, Muhammad M A; Fayyad, Asmaa S; Hammad, Seddik

    2017-10-25

    Cyclophosphamide (CP), a chemotherapeutic agent, induces hepatotoxicity as one of its side effects. Therefore, the aim of the present study is to investigate the potential hepatoprotective effects of fullerene C60 nanoparticles (C60) against the high toxic dose of CP. Twenty five albino rats were randomly assigned to 5 groups (n=5 per group). Group 1 served as a control. Group 2 received 200mg/kg of CP once intraperitoneally, while group 3 treated with the same CP dose plus C60 (4mgkg, orally) daily for 10days. Group 4 exposed CP and ZnCl2 (4mgkg, orally) daily for 10days. Group 5 exposed to CP and co-treated with C60 and ZnCl2. One day after last treatment, blood and livers were collected for hematological, biochemical and histopathological investigations. C60 normalized significantly RBCs, HB, PCV, WBCs and platelets numbers compared to CP-exposed rats. Moreover, liver enzymes namely ALT, AST and ALP revealed that CP elevated their levels and C60 significantly (pC60 treatment. In addition, antioxidant systems e.g. GSH, CAT and SOD were depleted from liver tissue due to CP toxicity these were recovered by C60 administration. The hepatoprotective effects of C60 on tested parameters were comparable with ZnCl2 and neither additive nor synergistic effect was observed. Histopathogically, severe liver degeneration was recorded after CP treatment, however, only mild changes were observed after C60 administration. Our data suggest that C60 improves both blood and hepatic parameters altered by cyclophosphamide-induced toxicities. The current study is of clinical relevance particularly, application of C60 as a monotherapy or in combination to ameliorate the CP side effects in cancer-treated patients. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  13. Chemoprotective effect of Crataegus monogyna aqueous extract against cyclophosphamide-induced reproductive toxicity

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    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.

  14. Spectral heart rate variability in rats with cyclophosphamide-induced hemorrhagic cystitis treated with cyclooxygenase inhibitors.

    Science.gov (United States)

    Dobrek, Łukasz; Baranowska, Agnieszka; Ciesielczyk, Katarzyna; Thor, Piotr J

    2015-01-01

    The pathogenesis of cyclophosphamide-induced hemorrhagic cystitis (CP-HC) is complex, involving the im- pact of many systemically and locally released agents on autonomic nervous system (ANS) activity, that affects bladder functioning. The purpose of our study was to provide an indirect evaluation of ANS functional status in experimental CP-HC model, involving prostaglandin synthesis block resulting from administration of cyclooxygenase inhibitors. The ANS activity was estimated through the spectral analysis of heart rate variability (HRV) in CP-HC rats divided into three study groups: 1-control, 2-treated with meloxicam (MLX) that preferentially blocks COX-2, and 3-treated with piroxicam (PRX) that inhibits COX1 and 2 activity. In animals treated either with MLX or PRX, the percent distribution of the spectrum in relation to components of very low (VLF) and low (LF) frequency was not different from the control group. PRX-treated group displayed nearly two times lower percent share of the high frequency (HF) component compared to the control. Moreover, an increase of the normalized LF (nLF) value with simultaneous reduction of the normalized HF (nHF) value were noted in PRX-treated rat with no change of these parameters for MLX-treated rats. The HRV analysis in CP-HC rats receiving PRX, indicated a functional reorganization manifested by reduced parasym- pathetic activity and increased sympathetic tonus. A partial prostaglandin synthesis block caused by COX-2 inhibitor (meloxicam) caused no significant changes of evaluated HRV parameters compared to the control. Assessing functional changes of the ANS caused by prostaglandin synthesis block it should be stated that prostaglandins synthesized by the constitutive COX-1 isoform seem to maintain the parasympathetic activity, which may be associated with the cholinergic anti-inflammatory pathway and resolution of inflammation in course of cyclophosphamide-induced cystitis.

  15. Outcome of dexamethasone-cyclophosphamide pulse therapy in pemphigus: a case series.

    Science.gov (United States)

    Kandan, Sakthi; Thappa, Devinder Mohan

    2009-01-01

    Pemphigus disorders are a group of serious and potentially life-threatening diseases affecting skin and/or mucus membranes. Dexamethasone-cyclophosphamide pulse (DCP) therapy has shown promising results in the management of these diseases. The objective of the study was to assess the outcome of DCP therapy in pemphigus. Pemphigus patients who had been treated with DCP therapy from 2001 to 2008 were prospectively and retrospectively analyzed. A total of 65 pemphigus patients were enrolled. Male to female ratio was 1 : 1.82. Mean age of patients was 44.65 +/- 11.85 years with a range of 14 to 73 years. Thirty two patients completed phase I, of which 28 (9 in phase II, 7 in phase III and 12 in phase III) were maintaining remission and four patients relapsed. Relapse was observed only in patients who discontinued or took irregular treatment. Six patients were declared cured of disease. Five patients died during phase I. Dexamethasone-cyclophosphamide pulse therapy is not absolutely free from adverse effects. Most of the immediate side effects were expected, tolerable and did not pose any problem in continuing treatment. There was a slight increased incidence of weight gain, hypertension, diabetes mellitus, cataract and Cushingoid habitus, since most of our patients also received additional daily oral steroids. Also, there was a high incidence of secondary pyogenic infections of skin lesions and oral candidiasis during phase I. Staphylococcus aureus was the commonest bacteria isolated from the pus of skin lesions. Most of the alterations in laboratory parameters were transitory or correctable, and did not pose a problem in continuing therapy. DCP therapy was found to be effective in inducing and maintaining remission in pemphigus, provided the patients receive regular and complete treatment.

  16. Outcome of dexamethasone-cyclophosphamide pulse therapy in pemphigus: A case series

    Directory of Open Access Journals (Sweden)

    Kandan Sakthi

    2009-01-01

    Full Text Available Background: Pemphigus disorders are a group of serious and potentially life-threatening diseases affecting skin and/or mucus membranes. Dexamethasone−cyclophosphamide pulse (DCP therapy has shown promising results in the management of these diseases. Aims: The objective of the study was to assess the outcome of DCP therapy in pemphigus. Methods: Pemphigus patients who had been treated with DCP therapy from 2001 to 2008 were prospectively and retrospectively analyzed. Results: A total of 65 pemphigus patients were enrolled. Male to female ratio was 1 : 1.82. Mean age of patients was 44.65 ± 11.85 years with a range of 14 to 73 years. Thirty two patients completed phase I, of which 28 (9 in phase II, 7 in phase III and 12 in phase III were maintaining remission and four patients relapsed. Relapse was observed only in patients who discontinued or took irregular treatment. Six patients were declared cured of disease. Five patients died during phase I. Dexamethasone−cyclophosphamide pulse therapy is not absolutely free from adverse effects. Most of the immediate side effects were expected, tolerable and did not pose any problem in continuing treatment. There was a slight increased incidence of weight gain, hypertension, diabetes mellitus, cataract and Cushingoid habitus, since most of our patients also received additional daily oral steroids. Also, there was a high incidence of secondary pyogenic infections of skin lesions and oral candidiasis during phase I. Staphylococcus aureus was the commonest bacteria isolated from the pus of skin lesions. Most of the alterations in laboratory parameters were transitory or correctable, and did not pose a problem in continuing therapy. Conclusions: DCP therapy was found to be effective in inducing and maintaining remission in pemphigus, provided the patients receive regular and complete treatment.

  17. 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

  18. 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.

  19. The Pharmacogenomic Association of Fc gamma Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

    NARCIS (Netherlands)

    Cartin-Ceba, Rodrigo; Indrakanti, Divya; Specks, Ulrich; Stone, John H.; Hoffman, Gary S.; Kallenberg, Cees G. M.; Langford, Carol A.; Merkel, Peter A.; Spiera, Robert F.; Monach, Paul A.; St. Clair, E. William; Seo, Philip; Tchao, Nadia K.; Ytterberg, Steven R.; Brunetta, Paul G.; Song, Huijuan; Birmingham, Dan; Rovin, Brad H.; Grp, RAVE-Immune Tolerance Network Res

    Objective The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide

  20. First-line trastuzumab plus epirubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety and efficacy data from the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial.

    Science.gov (United States)

    Untch, Michael; Muscholl, Michael; Tjulandin, Sergei; Jonat, Walter; Meerpohl, Hans-Gerd; Lichinitser, Mikhail; Manikhas, Alexey G; Coumbos, Alexandra; Kreienberg, Rolf; du Bois, Andreas; Harbeck, Nadia; Jackisch, Christian; Müller, Volkmar; Pauschinger, Matthias; Thomssen, Christoph; Lehle, Michaela; Catalani, Olivier; Lück, Hans-Joachim

    2010-03-20

    A high incidence of congestive heart failure (CHF) has been observed in patients with metastatic breast cancer (MBC) receiving doxorubicin-based chemotherapy and trastuzumab. The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial evaluated trastuzumab plus cyclophosphamide and the less cardiotoxic anthracycline epirubicin. This prospective trial combined a phase I dose-finding stage with a phase II randomized stage. In total, 120 patients with human epidermal growth factor receptor 2 (HER2) -positive MBC and adequate cardiac function received first-line trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg every week) plus cyclophosphamide (600 mg/m(2)) and either epirubicin 60 mg/m(2) (HEC-60) or 90 mg/m(2) (HEC-90) for six cycles, followed by trastuzumab monotherapy until progression. Sixty patients with HER2-negative disease received epirubicin (90 mg/m(2)) and cyclophosphamide (EC-90) alone. The primary end point was dose-limiting cardiotoxicity (DLC). Incidence of DLC was 5.0%, 1.7%, and 0% in the HEC-90, HEC-60, and EC-90 arms, respectively. All DLC events were manageable. There were no cardiac-related deaths. Other adverse-event profiles were comparable across the three arms, except febrile neutropenia, which was reported in 10% of the HEC-90 arm compared with 3% of the other arms. Tumor response rates were 57%, 60%, and 25% in the HEC-60, HEC-90, and EC-90 arms, respectively; median time to progression was 12.5, 10.1, and 7.6 months, respectively. The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.

  1. Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: L-NAME, L-arginine, stable gastric pentadecapeptide BPC 157.

    Science.gov (United States)

    Luetic, Krešimir; Sucic, Mario; Vlainic, Josipa; Halle, Zeljka Belosic; Strinic, Dean; Vidovic, Tinka; Luetic, Franka; Marusic, Marinko; Gulic, Sasa; Pavelic, Tatjana Turudic; Kokot, Antonio; Seiwerth, Ranka Serventi; Drmic, Domagoj; Batelja, Lovorka; Seiwerth, Sven; Sikiric, Predrag

    2017-04-01

    We revealed a new point with cyclophosphamide (150 mg/kg/day intraperitoneally for 7 days): we counteracted both rat stomach and duodenal ulcers and increased NO- and MDA-levels in these tissues. As a NO-system effect, BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once a day or in drinking water, till the sacrifice) attenuated the increased NO- and MDA-levels and nullified, in rats, severe cyclophosphamide-ulcers and even stronger stomach and duodenal lesions after cyclophosphamide + L-NAME (5 mg/kg intraperitoneally once a day). L-arginine (100 mg/kg intraperitoneally once a day not effective alone) led L-NAME-values only to the control values (cyclophosphamide + L-NAME + L-arginine-rats). Briefly, rats were sacrificed at 24 h after last administration on days 1, 2, 3, or 7, and assessment included sum of longest lesions diameters (mm) in the stomach and duodenum, oxidative stress by quantifying thiobarbituric acid reactivity as malondialdehyde equivalents (MDA), NO in stomach and duodenal tissue samples using the Griess reaction. All these parameters were highly exaggerated in rats who underwent cyclophosphamide treatment. We identified high MDA-tissue values, high NO-tissue values, ulcerogenic and beneficial potential in cyclophosphamide-L-NAME-L-arginine-BPC 157 relationships. This suggests that in cyclophosphamide damaged rats, NO excessive release generated by the inducible isozyme, damages the vascular wall and other tissue cells, especially in combination with reactive oxygen intermediates, while failing endothelial production and resulting in further aggravation by L-NAME which was inhibited by L-arginine. Finally, BPC 157, due to its special relations with NO-system, may both lessen increased MDA- and NO-tissues values and counteract effects of both cyclophosphamide and L-NAME on stomach and duodenal lesions.

  2. 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.

  3. 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.

  4. Radiation recall dermatitis, panniculitis, and myositis following cyclophosphamide therapy: histopathologic findings of a patient affected by multiple myeloma.

    Science.gov (United States)

    Borroni, Giovanni; Vassallo, Camilla; Brazzelli, Valeria; Martinoli, Sara; Ardigò, Marco; Alessandrino, Paolo Emilio; Borroni, Riccardo Giovanni; Franchini, Pietro

    2004-06-01

    Radiation recall dermatitis is one of the skin sequelae that may affect oncology patients. It occurs in a previously irradiated field, when subsequent chemotherapy is given. The eruption may be elicited by chemotherapy, even several months after radiotherapy. Its mechanism is poorly understood, and the histopathologic findings have received, to date, only sketchy descriptions. A 55-year-old male affected by multiple myeloma received radiation therapy both on his left coxofemoral area, and lumbar region (D11-L1). After cyclophosphamide administration, he developed 2 well defined square-shaped, infiltrated erythematoviolaceous plaques in the prior irradiated fields. Histopathologic findings revealed a diffusely fibrosclerosing process, involving deep dermis, hypodermis, as well as the underlying muscle, while sparing the epidermis and superficial-mid dermis. Histopathology was indistinguishable from deep radio-dermatitis, panniculitis, and myositis. This is the first case providing clear evidence of the causative role of cyclophosphamide in inducing a cutaneous and subcutaneous radiation recall reaction.

  5. 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

  6. Attenuation of cyclophosphamide-induced neurotoxicity in rat by yellow dye extract from root of Brimstone tree (Morinda lucida).

    Science.gov (United States)

    Oboh, Ganiyu; Akomolafe, Toyin L; Adefegha, Stephen A; Adetuyi, Abayomi O

    2012-09-01

    Cyclophosphamide is an anticancer and immunosuppressant drug that induces reactive oxygen species (ROS) production, so causing malondialdehyde (MDA) production, which is toxic to cells. This study therefore sought to assess the antioxidant and the protective effect of dietary inclusion (0.5 and 1.0%) of yellow dye from root of Brimstone tree (used to enhance the sensory quality of foods and in folk medicine) on cyclophosphamide-induced oxidative stress in brain. Wistar strain albino rats were placed on diet containing 0.5 and 1.0% yellow dye preparation from root of Brimstone tree for 14 days. Intraperitoneal administration of cyclophosphamide (75 mg/kg of body weight) 24 h before the termination of the experiment caused a significant (P<0.05) increase in the brain malondialdehyde (MDA) content (147.2%) and serum activities of aspartate aminotransferase (AST) (21.7 UI/l), alanine amino-transferase (ALT) (29.6 UI/l), alkaline phosphatase (43.8 UI/l) and total bilirubin (1.7 mg/dl). However, there was a significant decrease (P<0.05) in the MDA of content of the brain and serum enzyme activities, in those rats fed diet containing the yellow dye in a dose dependent manner. The inhibition of oxidative stress in brain and serum enzymes and metabolites by the dye could be attributed to its high total phenol content and antioxidant activity as typified by its reducing power, free-radical scavenging ability, Fe(II) chelating ability and inhibition of lipid peroxidation. Therefore, dietary inclusion of the yellow dye from root of Brimstone tree could prevent cyclophosphamide-induced oxidative stress in brain and the associated toxicity to the liver. Copyright © 2010 Elsevier GmbH. All rights reserved.

  7. Biological and environmental monitoring of occupational exposure to cyclophosphamide in industry and hospitals.

    Science.gov (United States)

    Sorsa, M; Pyy, L; Salomaa, S; Nylund, L; Yager, J W

    1988-03-01

    The aims of the study were to clarify potential exposure situations to anticancer agents during industrial processing, drug manufacture and hospital administration, using cyclophosphamide (CP) as the model compound. CP is considered an animal and human carcinogen, and it is shown to be an indirect mutagen in various test systems using several genetic endpoints. Environmental monitoring was performed by collecting ambient air samples during the different processing and handling stages. Both stationary and personal sampling was used. CP was analyzed by liquid chromatography (HPLC) and mass spectrometry (MS). The process materials and intermediates were also analyzed for genotoxic activity using the Ames test and SCE induction in CHO cells as endpoints. Biological monitoring studies were performed on 147 persons representing 5 groups of workers, control subjects and patients. In the experimental part of the project, the intermediates in the CP manufacturing process, CP I (nor-nitrogen mustard) and CP II (phosphoroxydichloride mustard) were found directly active in the 2 genotoxicity tests. These findings led to improvements in work hygiene when handling CP I and CP II in the process. The CP measurements showed that the highest potential-exposure sites occurred during specific operations of the process, e.g., during emptying of the drying drum and during tablet mass preparation (the range of CP concentrations in air was 0.16-0.49 mg/m3). The correlation between indirect genotoxicity and chemical analyses of the ambient air samples was good, revealing the activity to be due to cyclophosphamide. However, the air samples were found mutagenic without metabolic activation also in the beginning of the process; this is obviously due to CP II particles in the ambient air, since no CP was detected chemically. The personal protection of workers in the plant collaborating in the study is efficient and the production unit is equipped with the best available techniques to protect

  8. Ozone-induced loss of neuronal M{sub 2} muscarinic receptor function is prevented by cyclophosphamide

    Energy Technology Data Exchange (ETDEWEB)

    Gambone, L.M.; Elbon, C.L.; Fryer, A.D. [Johns Hopkins Univ., Baltimore, MD (United States)

    1994-09-01

    The authors tested the hypothesis that inflammatory cells mediate the loss of neuronal M{sub 2} muscarinic receptors in the lung after ozone exposure. Pathogen-free guinea pigs treated with cyclophosphamide (30 mg {center_dot} kg{sup {minus}1} {center_dot} day{sup {minus}1} ip for 7 days) before exposure to ozone were compared with untreated ozone-exposed animals. This dose of cyclophosphamide significantly reduced leukocytes in peripheral blood and bronchoalveolar lavage fluid. Twenty-four hours after ozone, muscarinic receptor function was tested in anesthetized animals. In air-exposed guinea pigs, vagally induced bronchoconstriction was attenuated by the muscarinic agonist pilocarpine (0.1-100 {mu}g/kg iv) and potentiated by the selective M{sub 2} antagonist gallamine (0.1-10 mg/kg iv), indicating that the neuronal M{sub 2} muscarinic receptors were functioning. These responses were significantly reduced after ozone, indicating loss of neuronal M{sub 2} muscarinic receptor function. However, in those animals treated with cyclophosphamide, M{sub 2} muscarinic receptor function was not altered by ozone. These data suggest that ozone-induced loss of neuronal muscarinic receptor function is mediated via inflammatory cells and that the link between ozone-induced hyperresponsiveness and inflammation may be the neuronal M{sub 2} muscarinic receptor. 27 refs., 9 figs.

  9. 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.

  10. 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.

  11. Secondary Exposure of Family Members to Cyclophosphamide After Chemotherapy of Outpatients With Cancer: A Pilot Study.

    Science.gov (United States)

    Yuki, Michiko; Ishida, Takashi; Sekine, Satoko

    2015-11-01

    To measure the total amount of cyclophosphamide (CPA) excreted in the urine of patients with cancer and their cohabitating family members seven days after CPA administration. Biological monitoring.
. Home setting with outpatients receiving chemo-therapy. 8 patients administered CPA, 10 cohabitating family members, and 10 control participants. During the first seven days after CPA administration, urine samples were collected from the participants. The samples were analyzed for the unchanged form of CPA using gas chromatography in tandem with mass spectroscopy. CPA levels
. CPA was detected in 112 of 276 patient urine samples. The last sample containing detectable CPA levels was collected after more than 48 hours in 63% of the patients, with a maximum length of five days post-treatment. In addition, 243 urine samples were collected from family members, and CPA was detected in the samples of five family members (17-252 ng per member). CPA was not detected in any control participants. These findings indicate that family members in close contact with patients receiving CPA are at high risk for drug exposure as many as seven days post-treatment
. Nurses should educate patients and their family members about preventing exposure to antineoplastic drugs in the home setting.


  12. Clinical Predictors of Response to Prednisone Plus Cyclophosphamide in Patients with Idiopathic Membranous Nephropathy.

    Science.gov (United States)

    Li, Shu; Wang, Ling; Zhang, Minfang; Zhou, Wenyan; Fang, Wei; Wang, Qin; Qi, Chaojun; Mou, Shan; Shao, Xinghua; Ni, Zhaohui

    2017-01-01

    Complete remission (CR) and partial remission (PR) are beneficial to the long-term outcome of patients with idiopathic membranous nephropathy (iMN). However, we are lacking in studies that evaluate the clinical predictors of response to treatment with prednisone plus cyclophosphamide (CP). The objectives of the study are to identify clinical factors that could predict clinical remission or relapse in patients with iMN who were treated with prednisone plus i.v. CP therapy. This retrospective study recruited a total of 102 eligible patients diagnosed with biopsy-proven iMN between January 2010 and December 2013 in our center. All subjects were treated with prednisone plus i.v. CP for at least 6 months. Primary outcome was remission, including both CR and PR. Demographic data and clinical data at baseline and month 3 of treatment with CP were assessed. The proportion of patients with remission (both CR and PR) was 82.4%, over an average follow-up duration of 15 (10-27.5) months. Fifty-two of them experienced a CR. Baseline proteinuria and the reduction of proteinuria at month 3 of CP treatment were independent predictors of remission (p 150, p proteinuria at baseline and high reduction of proteinuria at month 3 of treatment with CP were more likely to achieve remission and CR. The presence of only a PR may act as a useful predictor of relapse after completion of CP therapy. © 2016 S. Karger AG, Basel.

  13. The Effects of Tempol on Cyclophosphamide-Induced Oxidative Stress in Rat Micturition Reflexes

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    Eric J. Gonzalez

    2015-01-01

    Full Text Available We hypothesized that cyclophosphamide- (CYP- induced cystitis results in oxidative stress and contributes to urinary bladder dysfunction. We determined (1 the expression of oxidative stress markers 3-nitrotyrosine (3-NT, reactive oxygen species (ROS/reactive nitrogen species (RNS, inflammatory modulators, neuropeptides calcitonin gene-related peptide (CGRP, substance P (Sub P, and adenosine triphosphate (ATP that contribute to the inflammatory process in the urinary tract and (2 the functional role of oxidative stress in urinary bladder dysfunction with an antioxidant, Tempol, (1 mM in drinking water combined with conscious cystometry. In CYP-treated (4 hr or 48 hr; 150 mg/kg, i.p. rats, ROS/RNS and 3-NT significantly (P≤0.01 increased in urinary bladder. CYP treatment increased ATP, Sub P, and CGRP expression in the urinary bladder and cystometric fluid. In CYP-treated rats, Tempol significantly (P≤0.01 increased bladder capacity and reduced voiding frequency compared to CYP-treated rats without Tempol. Tempol significantly (P≤0.01 reduced ATP expression, 3-NT, and ROS/RNS expression in the urinary tract of CYP-treated rats. These studies demonstrate that reducing oxidative stress in CYP-induced cystitis improves urinary bladder function and reduces markers of oxidative stress and inflammation.

  14. Myeloablative Conditioning with PBSC Grafts for T Cell-Replete Haploidentical Donor Transplantation Using Posttransplant Cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Scott R. Solomon

    2016-01-01

    Full Text Available Relapse is the main cause of treatment failure after nonmyeloablative haploidentical transplant (haplo-HSCT. In an attempt to reduce relapse, we have developed a myeloablative (MA haplo-HSCT approach utilizing posttransplant cyclophosphamide (PT/Cy and peripheral blood stem cells as the stem cell source. We summarize the results of two consecutive clinical trials, using a busulfan-based (n=20 and a TBI-based MA preparative regimen (n=30, and analyze a larger cohort of 64 patients receiving MA haplo-HSCT. All patients have engrafted with full donor chimerism and no late graft failures. Grade III-IV acute GVHD and moderate-severe chronic GVHD occurred in 23% and 30%, respectively. One-year NRM was 10%. Predicted three-year overall survival, disease-free survival, and relapse were 53%, 53%, and 26%, respectively, in all patients and 79%, 74%, and 9%, respectively, in patients with a low/intermediate disease risk index (DRI. In multivariate analysis, DRI was the most significant predictor of survival and relapse. Use of TBI (versus busulfan had no significant impact on survival but was associated with significantly less BK virus-associated hemorrhagic cystitis. We contrast our results with other published reports of MA haplo-HSCT PT/Cy in the literature and attempt to define the comparative utility of MA haplo-HSCT to other methods of transplantation.

  15. Oral administration of vitamin C and histidine attenuate cyclophosphamide-induced hemorrhagic cystitis in rats.

    Science.gov (United States)

    Farshid, Amir Abbas; Tamaddonfard, Esmaeal; Ranjbar, Sepideh

    2013-01-01

    Cyclophosphamide (CP), a widely used antineoplastic drug causes hemorrhagic cystitis (HC) mainly via induction of oxidative stress. Both vitamin C and histidine have antioxidant properties. The present study aimed to investigate the effects of oral (p.o.) administration of vitamin C and histidine on the CP-induced HC in rats. The animals were divided into two major groups I and II with four subgroups (a, b, c, and d) in each. Groups I and II were treated with intraperitoneal (i.p.) injections of normal saline and CP (200 mg/kg), respectively, thereafter, normal saline, vitamin C (200 mg/kg), histidine (200 mg/kg) and vitamin C plus histidine were p.o. administered in subgroups a, b, c, and d, respectively, three times (2, 6, and 24 h) after i.p. injections of normal saline and CP. Blood samples were assayed for total antioxidant capacity (TAC) and malondialdehyde (MDA) levels. Histopathological changes of bladder wall were investigated. The decreased TAC and increased MDA levels of plasma and the severity of hemorrhages, congestion, edema, and leukocyte infiltration of bladder induced by CP were recovered with vitamin C and histidine treatments. Combined treatment with vitamin C and histidine showed a potentiation effect. The results indicated that vitamin C and histidine attenuated the CP-induced HC by reducing of free radical-induced toxic effects.

  16. 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.

  17. Chemoprotective and immunomodulatory effect of Acacia nilotica during cyclophosphamide induced toxicity.

    Science.gov (United States)

    Ahmad, Sabrina; Mika, Denish; Guruvayoorappan, C

    2012-01-01

    Most of the synthetic chemotherapeutic agents used today are immunosuppressant and lead to numerous side effects. Plant based immunomodulators are employed as supportive therapy to counteract the undesirable side effects of chemotherapy. In the present study, the immunomodulatory and chemoprotective effect of methanolic extract of Acacia nilotica was investigated in mice. Intraperitoneal administration of the extract was found to significantly increase the Total WBC count, bone marrow cellularity and alpha-esterase positive cells. Cyclophosphamide is a chemotherapeutic drug and induces acute myelosuppression but treatment with the extract was beneficial in ameliorating chemically induced toxicity. The administration of the extract considerably increased the Total WBC count (6800 +/- 733.9 cells/cm2), bone marrow cellularity (43.6 x 10(5) +/- 14.33 cells/femur) and alpha-esterase positive cells (808.6 +/- 8.57 cells/4000 cells) in CTX treated mice when compared to CTX alone treated control mice. Weight of lymphoid organs such as spleen and thymus reduced by CTX were enhanced by treatment with Acacia nilotica extract. It can be concluded that the extract possess immunostimulatory properties.

  18. Effect of Brahma Rasayana on antioxidant systems and cytokine levels in mice during cyclophosphamide administration.

    Science.gov (United States)

    Rekha, P S; Kuttan, G; Kuttan, R

    2001-06-01

    Intraperitoneal administration of cyclophosphamide (CTX) 25 mg/kg.b.wt. dose/mouse for 10 days was found to suppress the tissue and serum level of reduced glutathione (GSH), blood glutathione peroxidase (GPX) and tissue levels of superoxide dismutase (SOD) and catalase (CAT). Tissue levels of glutathione reductase (GR) and glutathione-S-transferase (GST) were unaltered by CTX treatment while serum and tissue lipid peroxide levels were significantly increased. Oral administration of Brahma Rasayana BR-50 mg/dose/mouse for 10 days and 30 days significantly enhanced the tissue levels of SOD, CAT, GST, GPX, serum and tissue GSH and significantly reduced the serum and tissue lipid peroxidation. BR treatment was also found to enhance the serum cytokine level of interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and granulocyte macrophage-colony stimulating factor (GM-CSF) in normal and CTX treated mice. The results are indicative of the use of BR to reduce the oxidant stress induced by CTX treatment and its effect in cellular function.

  19. 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. © The Author(s) 2015.

  20. Dietary Chlorella vulgaris Ameliorates Altered Immunomodulatory Functions in Cyclophosphamide-Induced Immunosuppressive Mice

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    Dai Cheng

    2017-07-01

    Full Text Available Based on the well-known toxicity of cyclophosphamide (CYP on the immune system, this research investigated the modulating effects of the long-term dietary Chlorella vulgaris (CV supplementation on the immunosuppression induced by CYP in mice, in order to provide a novel dietary design to mitigate the side effects of CYP therapy. Control, CYP-treated, CYP + CV (6%, CYP + CV (12% and CYP + CV (24% were used for 6 weeks, CV supplement in diet recovered the significantly reduced immunological function in CYP treated mice. As CV may have a modulating function through the inducible expression of cytokines, we assayed the expressions of interleukin-2 (IL-2, interleukin-12 (IL-12, tumor necrosis factor-α (TNF-α and interferon-γ (IFN-γ. Our results suggested that CYP significantly reduced the lymphocytes proliferation and phagocytic activities of macrophages, and stimulated the production of IL-2, IL-12, TNF-α and IFN-γ and that this impairment has been successfully adjusted by CV supplementation. Treatment with the algae also enhanced the natural killer (NK cells cytotoxicity, and ameliorate histological changes of the spleen in CYP-treated mice. Therefore, as we found in this study, a diet supplemented with whole CV has beneficial effects on CVP-induced immunosuppression, through its immunomodulatory potential.

  1. Cyclophosphamide-induced bacterial translocation in Escherichia coli C25-monoassociated specific pathogen-free mice.

    Science.gov (United States)

    Nakayama, M; Itoh, K; Takahashi, E

    1997-01-01

    The kinetics of bacterial translocation (BTL) from the intestine to the mesenteric lymph nodes (MLN) and the number of peripheral white blood cells (WBC), macrophages in Peyer's patches (PP) and M-cells on the surface of cecal PP after cyclophosphamide (CY) injection were examined in penicillin-G and streptomycin sulfate decontaminated and Escherichia coli C25-monoassociated specific pathogen-free mice. WBC are counted to confirm the immunological state of the mice. Until 8 days after CY injection, the number of WBC, bacteria in MLN and macrophages in PP decreased, but then significantly increased on day 14. The levels again decreased to the control levels on day 16. Although the number of M-cells decreased up to day 8, it did not return to the control level on day 16. These results indicate that BTL is stimulated in an immunopotentiated state after CY injection, and this phenomenon may be closely related to the number of macrophages in the blood and PP.

  2. 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

  3. Cyclophosphamide-induced male subfertility in mice: An assessment of the potential benefits of Maca supplement.

    Science.gov (United States)

    Onaolapo, A Y; Oladipo, B P; Onaolapo, O J

    2017-10-18

    Effects of Lepidium meyenii (Maca) on cyclophosphamide (CYP)-induced gonadal toxicity in male mice were investigated. Mice were assigned to six treatment groups: Vehicle control, CYP control, CYP plus oral Maca (500 or 1,000 mg/kg), and oral Maca (500 or 1,000 mg/kg). CYP was administered via the intraperitoneal route (days 1-2), while vehicle or Maca were administered daily for 28 days. On day 28, half of the animals in each group were either sacrificed or paired with age-matched females for fertility assessment. Plasma testosterone assay, sperm analysis and assessment of tissue antioxidant/morphological status were also carried out. CYP administration was associated with oxidative stress, subfertility and morphometric/morphological indices of gonadal injury, while administration of Maca mitigated CYP-induced gonadal toxicity and subfertility. This study shows that Maca is beneficial in the mitigation of CYP-induced male gonadal insufficiency and/or testicular morphological changes; however, further studies will be needed to ascertain its usability for this purpose in humans. © 2017 Blackwell Verlag GmbH.

  4. 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.

  5. 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.

  6. Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis.

    Science.gov (United States)

    Radhakrishnan, Jai; Moutzouris, Dimitrios-Anestis; Ginzler, Ellen M; Solomons, Neil; Siempos, Ilias I; Appel, Gerald B

    2010-01-01

    Class V lupus nephritis (LN) occurs in one-fifth of biopsy-proven cases of systemic lupus erythematosus. To study the effectiveness of treatments in this group of patients, we pooled analysis of two large randomized controlled multicenter trials of patients with diverse ethnic and racial background who had pure class V disease. These patients received mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) as induction therapy for 24 weeks, with percentage change in proteinuria and serum creatinine as end points. Weighted mean differences, pooled odds ratios, and confidence intervals were calculated by using a random-effects model. A total of 84 patients with class V disease were divided into equal groups, each group had comparable entry variables but one received MMF and one received IVC. Within these groups, 33 patients on MMF and 32 patients on IVC completed 24 weeks of treatment. There were no differences between the groups in mean values for the measured end points. Similarly, no difference was found regarding the number of patients who did not complete the study or who died. In patients with nephrotic syndrome, no difference was noted between those treated with MMF and IVC regarding partial remission or change in urine protein. Hence we found that the response to MMF as induction treatment of patients with class V LN appears to be no different from that to IVC.

  7. RM-11, an isoxazole derivative, accelerates restoration of the immune function in mice treated with cyclophosphamide.

    Science.gov (United States)

    Zimecki, Michał; Artym, Jolanta; Ryng, Stanisław; Obmińska-Mrukowicz, Bozena

    2008-01-01

    The aim of this study was to evaluate efficacy of an isoxazole derivative RM11 to accelerate reconstitution of selected immune activities in cyclophosphamide (CP)-immunocompromised mice. We demonstrated that administration of fifteen 10 mug intraperitoneal doses of RM11, following a sublethal (200 mug/kg) dose of CP, significantly stimulated the number of antibody-forming cells (AFC) to sheep erythrocytes (SRBC) as determined 35 days after the CP treatment. Similarly, treatment of the CP-injected mice with 7 doses of RM11 significantly enhanced generation of delayed type hypersensitivity (DTH) to ovalbumin (OVA). Moreover, in that model, the treatment of mice with RM11 accelerated the process of myelopoiesis. RM11 also counteracted the suppressive action of methotrexate (MTX) in the in vitro model of the humoral immune response to SRBC. The phenotypic studies with fluorocytometer revealed that intraperitoneal 10 mug dose of RM11 significantly elevated the percentage of mature (CD3(+), CD4(+) and CD8(+)) T cells in the spleen and down-regulated the content of CD19(+) cells. We conclude that RM11 may be of potential therapeutic value in restoration of the immune status in patients undergoing chemotherapy.

  8. Blueberry Anthocyanins-Enriched Extracts Attenuate Cyclophosphamide-Induced Cardiac Injury.

    Science.gov (United States)

    Liu, Yunen; Tan, Dehong; Shi, Lin; Liu, Xinwei; Zhang, Yubiao; Tong, Changci; Song, Dequn; Hou, Mingxiao

    2015-01-01

    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.

  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. 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. 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.

  12. Chemoprotective effect of vitamin E in cyclophosphamide-induced hepatotoxicity in rats.

    Science.gov (United States)

    Cuce, Gokhan; Çetinkaya, Seda; Koc, Tugba; Esen, Hacı Hasan; Limandal, Cisem; Balcı, Tevfik; Kalkan, Serpil; Akoz, Mehmet

    2015-05-05

    Cyclophosphamide (CP) has a range of adverse effects on liver tissue in humans and animals. Administering an antioxidant with CP might reduce such side effects. Therefore, we examined the role of vitamin E in CP-induced liver toxicity in rats. Male Wistar albino rats were divided into four groups, each of seven rats: control, CP only, CP + vitamin E, and vitamin E only groups. The rats were administered treatments intraperitoneally for 7 days. Then the serum malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels were determined while the livers were removed, tissue was prepared using routine histological procedures, sections were stained using hematoxylin and eosin, and the terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) method was applied. Histopathologically, CP caused hydropic degeneration, necrosis, pleomorphism, and mitotic activity. The number of TUNEL-positive cells and the MDA and ALT levels were significantly higher in the CP group. The antioxidant effects of vitamin E significantly decreased the number of TUNEL-positive cells and the ALT and MDA levels, and normalized the liver histopathology. CP induces apoptosis, has toxic effects on liver tissue, and changes the histological structure. The administration of vitamin E prevented the liver tissue damage caused by CP. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Ethyl Pyruvate Ameliorates The Damage Induced by Cyclophosphamide on Adult Mice Testes

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    Zahra Bakhtiary

    2016-05-01

    Full Text Available Background: Cyclophosphamide (CP is a chemotherapy drug which causes deleterious effects on testicular tissue and increases free radicals in the body. The aim of this study is to investigate the protective effects of ethyl pyruvate (EP on testicular improvement in CP treated animals. Materials and Methods: In this experimental study, 15 male mice (6-8 weeks were divided into 3 groups. The control group received normal saline (0.1 ml/day, intraperitoneal (IP, CP group received CP (15 mg/kg/week, IP, and the CP+EP group received EP (40 mg/kg/day, IP plus CP. After 35 days, we assessed serum total antioxidant capacity (TAC along with histomorphometric and histochemical analyses of the testicles. Results: The mean thickness of the germinal epithelium, diameter of seminiferous tubules, and the number of Leydig cells in the CP+EP group were higher than those of the CP group (P<0.05. The number of the mast cells in the CP+EP group significantly reduced compared with the CP group (P<0.05. Alkaline phosphatase (ALP, periodic acid-schiff (PAS positive reactions and lipid granules in cytoplasm of the Leydig cells in the CP group increased compared with the other groups (P<0.05. TAC in the CP group significantly reduced compared with the other groups (P<0.05. Conclusion: This study showed the ability of EP to reduce the destructive side effects of CP in the adult mice reproductive system.

  14. Effect of cyclophosphamide on infections produced by Escherichia coli of high and low virulence in chickens.

    Science.gov (United States)

    Nakamura, K; Imada, Y; Abe, F

    1987-01-01

    The effect of cyclophosphamide (Cy) on infections caused by Escherichia coli strains of high (Expt 1) and low (Expt 2) virulence was examined in 4-week-old specified-pathogen-free chickens. In Expt 1 the mortalities of Cy-treated and non-treated chickens given 5 x 10(7) cfu of a strain of E. coli of high virulence were both 100%. In the groups given 5 x 10(5) cfu, the mortality of Cy-treated chickens was 90% and that of non-treated chickens was 10%. In Expt 2 the groups given 1 x 10(9) cfu of an E. coli strain of low virulence showed a mortality of 30% when treated with Cy and 0% when non-treated. The chickens given 5 x 10(7) or 5 x 10(5) cfu showed no mortality, clinical signs or histological lesions. Cy-treated chickens showed severe hypoplasia of granulopoiesis in the bone marrow. Haematological examination of Cy-treated chickens revealed leukopenia, especially lymphopenia, and thrombocytopenia. This study suggests that Cy treatment may enhance infection caused by E. coli strain of high virulence and manifest signs of infection caused by E. coli strain of low virulence in the chickens.

  15. Viscum album L. extract and quercetin reduce cyclophosphamide-induced cardiotoxicity, urotoxicity and genotoxicity in mice.

    Science.gov (United States)

    Sekeroğlu, Vedat; Aydin, Birsen; Sekeroğlu, Zülal Atli

    2011-01-01

    Possible protective effects of a methanolic extract of Viscum album (VA) and quercetin (QE) against cyclophosphamide (CP) induced cardiotoxicity, urotoxicity and genotoxicity in mice were evaluated. Mice were administered orally VA (250 mg/kg/day) and QE (50 mg/kg/day) for 10 days alone or in combination with CP. After the same doses of VA and QE given for 7 days, rats were intraperitoneally administered CP (40 mg/kg) on days 8 and 9 of the experiment. Cardiotoxic, urotoxic and genotoxic effects were examined in serum, heart, bladder and bone marrow. Significant decreases in the levels of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase), glutathione-S-transferases, reduced glutathione and mitotic index were observed. QE completely and VA partly ameliorated almost of all the examined parameters when given together with CP. Higher total nitrate/nitrite levels were observed in the myocardial tissue treated with QE and VA in combination with CP. In addition, the pre-treatment with VA and QE together with CP significantly decreased chromosome aberrations and aberrant cells compared to CP alone. Results from the current study suggest that QE and VA supplementation attenuates CP induced cardiotoxicity, urotoxicity and genotoxicity through a mechanism related to their ability to decrease oxidative stress and inflammation, and at least in part to its protective effects on the cardiovascular system. In addition, VA and QE may play a role in reducing cytogenotoxicity induced by anti-neoplastic drugs during cancer chemotherapy.

  16. Multivariate optimization of solvent bar microextraction combined with HPLC-UV for determination of trace amounts of vincristine in biological fluids.

    Science.gov (United States)

    Kiani, Mahsa; Qomi, Mahnaz; Hashemian, Farshad; Rajabi, Mehdi

    2017-10-29

    In the current work, an efficient method named solvent bar microextraction-high performance liquid chromatography-UV detection (HPLC-UV) was developed for preconcentration and determining the trace amount of vincristine (VCR) in biological samples such as plasma and urine. Briefly, VCR was extracted from an aqueous sample with pH 10.7 (donor phase) into 1-octanol as the supported liquid membrane (SLM) which is inserted into the pores of the hollow fiber and followed by back extraction into an aqueous receiving phase (pH=3.1). Studying the factors affecting the extraction performance in order to achieve a high extraction efficiency, requires the design of experiments (DOE) approach. In this regards, diverse factors' effects including the pH value of donor and acceptor phases, extraction time, extraction temperature, stirring rate and salt content of the donor phase were considered. The optimum experimental condition was as following: pH of the source phase, 10.7; pH of the receiving phase, 3.1; stirring rate, 1000rpm; extraction temperature, 51°C; extraction time, 60min and 11.3% w/v NaCl in the sample solution. Under the optimal; extraction condition, a favorable preconcentration factor equal to 98.5 was achieved. The linearity range was obtained in the domain of 0.05-5mgL-1. The limits of detection and quantification were 0.015 and 0.05mgL-1. Within-day and between-day RSDs of the proposed SBME method were 4.1% and 12.5%, respectively. Finally, the applicability of the implemented SBME method was evaluated by the extraction and quantification of VCR from biological samples such as urine and plasma and satisfactory results were obtained. Copyright © 2017. Published by Elsevier B.V.

  17. Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma.

    Science.gov (United States)

    Lokhorst, H M; Sonneveld, P; Cornelissen, J J; Joosten, P; van Marwijk Kooy, M; Meinema, J; Nieuwenhuis, H K; van Oers, M H; Richel, D J; Segeren, C N; Veth, G; Verdonck, L F; Wijermans, P W

    1999-02-01

    We performed a phase II study to test the efficacy and feasibility of induction therapy with vincristine, adriamycin and dexamethasone (VAD) and intermediate-dose melphalan, 70 mg/m2 (IDM), to autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma (MM). A total of 77 patients received two cycles of VAD (n = 62) and/or two cycles of i.v. IDM 70 mg/m2 (n = 15) combined with G-CSF. PBSC were harvested after the first IDM, successfully in 87% of patients. Patients with a response to induction received myeloablative therapy with PBSCT (n = 50) followed by IFN maintenance or allo-BMT (n = 11). Seventy-two per cent of patients achieved a response after VAD which increased to 85% after IDM. Of patients who received PBSCT and allo-BMT, 24% and 45% achieved CR, respectively. Toxicity of induction consisted mainly of bone marrow suppression after IDM (median 8 days) with prolonged aplasia in 11% of patients after the second IDM. Only six infections WHO grade 3 occurred during induction. Treatment-related mortality of PBSCT and allo-BMT was 6% and 18%, respectively. Median time of follow-up is 44 months, and 50% of patients after PBSCT and 60% of patients after allo-BMT are still in remission. Survival rates of all patients were 82%, 75% and 63%, and for transplanted patients 86%, 79% and 68% after 12, 24 and 36 months. Well known prognostic factors, including alpha-IFN maintenance after PBSCT, were not significant for response or survival although patients in CR after allo-BMT had a strong tendency for better outcome. VAD/IDM is an effective and safe induction therapy for autologous and allogeneic stem cell transplantation. Based on these observations a phase III trial was started in October 1995 comparing IFN maintenance with PBSCT and allo-BMT after response to induction with VAD and IDM.

  18. Extended Tumor Control after Dendritic Cell Vaccination with Low-Dose Cyclophosphamide as Adjuvant Treatment in Patients with Malignant Pleural Mesothelioma.

    Science.gov (United States)

    Cornelissen, Robin; Hegmans, Joost P J J; Maat, Alexander P W M; Kaijen-Lambers, Margaretha E H; Bezemer, Koen; Hendriks, Rudi W; Hoogsteden, Henk C; Aerts, Joachim G J V

    2016-05-01

    We demonstrated previously that autologous tumor lysate-pulsed dendritic cell-based immunotherapy in patients with malignant pleural mesothelioma is feasible, well-tolerated, and capable of inducing immunologic responses against tumor cells. In our murine model, we found that reduction of regulatory T cells with metronomic cyclophosphamide increased the efficacy of immunotherapy. To assess the decrease in number of peripheral blood regulatory T cells during combination therapy of low-dose cyclophosphamide and dendritic cell immunotherapy and determine the induction of immunologic responses with this treatment in patients with mesothelioma. Ten patients with malignant pleural mesothelioma received metronomic cyclophosphamide and dendritic cell-based immunotherapy. During the treatment, peripheral blood mononuclear cells were analyzed for regulatory T cells and immunologic responses. Administration of dendritic cells pulsed with autologous tumor lysate combined with cyclophosphamide in patients with mesothelioma was safe, the only side effect being moderate fever. Dendritic cell vaccination combined with cyclophosphamide resulted in radiographic disease control in 8 of the 10 patients. Overall survival was promising, with 7 out of 10 patients having a survival of greater than or equal to 24 months and two patients still alive after 50 and 66 months. Low-dose cyclophosphamide reduced the percentage of regulatory T cells of total CD4 cells in peripheral blood from 9.43 (range, 4.34-26.10) to 4.51 (range, 0.27-10.30) after 7 days of cyclophosphamide treatment (P = 0.02). Consolidation therapy with autologous tumor lysate-pulsed dendritic cell-based therapy and simultaneously reducing the tumor-induced immune suppression is well-tolerated and shows signs of clinical activity in patients with mesothelioma. Clinical trial registered with www.clinicaltrials.gov (NCT 01241682).

  19. Pediatric rhabdomyosarcomas and nonrhabdomyosarcoma soft tissue sarcoma

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    Agarwala Sandeep

    2006-01-01

    Full Text Available Tumors arising from the soft tissues are uncommon in children, accounting for about 6% of all childhood malignancies. More than half (53% of these originate from the striated muscles and are called rhabdomyosarcomas (RMS the remaining are nonrhabdomyosarcoma soft tissue sarcomas (NRSTS. Almost two-thirds of RMS cases are diagnosed in children < 6 years of age. They can arise at varied locations like the head and neck region, genitourinary tract, extremities, trunk and retroperitoneum. Pathologically RMS is now classified as superior, intermediate and poor outcome histologies. For stratification of treatment and also comparison of results the RMS are now staged both by the clinical grouping and the TNM staging systems. The ultimate outcome depends on the site, extent of disease and histology. Currently, approximately 70% of the patients survive for 5 years or more and are probably cured. This is credited to the use of multi-modal, risk-adapted therapy, refinements in tumor grouping and better supportive care which has emerged out of cooperative studies like Intergroup Rhabdomyosarcoma Study (IRS and the International Society of Pediatric Oncology studies (SIOP. The treatment involves chemotherapy, radiotherapy and organ/function preserving surgery. The gold standard chemotherapy is still vincristine, actinomycin D and cyclophosphamide (VAC regime with high doses of intensity bone marrow rescue with colony stimulating factors. The NRSTS are rare and of heterogenous histologies and so it has been difficult to arrive at a treatment strategy for these. What is definitely understood is that these are usually immature and poorly differentiated tumors that respond poorly to chemotherapy and so surgical resection forms the mainstay of treatment with adjuvant radiotherapy and chemotherapy to prevent local recurrences. In all likelihood, the molecular analysis of RMS will further refine current classification schemes and knowledge of genetic features of

  20. Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice.

    Science.gov (United States)

    Sheweita, Salah A; El-Hosseiny, Lobna S; Nashashibi, Munther A

    2016-01-01

    Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn't change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared

  1. Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice

    Science.gov (United States)

    Sheweita, Salah A.; El-Hosseiny, Lobna S.; Nashashibi, Munther A.

    2016-01-01

    Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn’t change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared

  2. Comparing cisplatin-based combination chemotherapy with EMA/CO chemotherapy for the treatment of high risk gestational trophoblastic neoplasia

    NARCIS (Netherlands)

    Lybol, C.; Thomas, C.M.G.; Blanken, E.A.; Sweep, F.C.; Verheijen, R.H.; Westermann, A.M.; Boere, I.A.; Reyners, A.K.; Massuger, L.F.A.G.; Hoesel, R.Q. van; Ottevanger, P.B.

    2013-01-01

    BACKGROUND: Cisplatin-based chemotherapy (etoposide 100mg/m(2) days 1-5, methotrexate 300mg/m(2) day 1, cyclophosphamide 600mg/m(2) day 1, actinomycin D 0.6mg/m(2) day 2 and cisplatin 60mg/m(2) day 4, EMACP) was compared to EMA/CO (etoposide 100mg/m(2) days 1-2, methotrexate 300mg/m(2) day 1 and

  3. Comparing cisplatin-based combination chemotherapy with EMA/CO chemotherapy for the treatment of high risk gestational trophoblastic neoplasia

    NARCIS (Netherlands)

    Lybol, C.; Thomas, C. M. G.; Blanken, E. A.; Sweep, F. C. G. J.; Verheijen, R. H.; Westermann, A. M.; Boere, I. A.; Reyners, A. K. L.; Massuger, L. F. A. G.; van Hoesel, R. Q. G. C. M.; Ottevanger, P. B.

    2013-01-01

    Background: Cisplatin-based chemotherapy (etoposide 100 mg/m(2) days 1-5, methotrexate 300 mg/m(2) day 1, cyclophosphamide 600 mg/m(2) day 1, actinomycin D 0.6 mg/m(2) day 2 and cisplatin 60 mg/m(2) day 4, EMACP) was compared to EMA/CO (etoposide 100 mg/m(2) days 1-2, methotrexate 300 mg/m(2) day 1

  4. Comparing cisplatin-based combination chemotherapy with EMA/CO chemotherapy for the treatment of high risk gestational trophoblastic neoplasia

    NARCIS (Netherlands)

    Lybol, C.; Thomas, C. M. G.; Blanken, E. A.; Sweep, F. C. G. J.; Verheijen, R. H.; Westermann, A. M.; Boere, I. A.; Reyners, A. K. L.; Massuger, L. F. A. G.; van Hoesel, R. Q. G. C. M.; Ottevanger, P. B.

    Background: Cisplatin-based chemotherapy (etoposide 100 mg/m(2) days 1-5, methotrexate 300 mg/m(2) day 1, cyclophosphamide 600 mg/m(2) day 1, actinomycin D 0.6 mg/m(2) day 2 and cisplatin 60 mg/m(2) day 4, EMACP) was compared to EMA/CO (etoposide 100 mg/m(2) days 1-2, methotrexate 300 mg/m(2) day 1

  5. [Efficacy and safety of cyclophosphamide as a sequential immunotherapy drug for anti-N-methyl-D-aspartate receptor encephalitis in children].

    Science.gov (United States)

    Zhu, Wei-Wen; Liao, Wei-Ping; Yi, Yong-Hong; Song, Xing-Wang

    2017-06-01

    To evaluate the efficacy and safety of cyclophosphamide as a second-line drug in the treatment of children with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Six children with anti-NMDAR encephalitis, who showed poor response to steroids and intravenous immunoglobulin, were given cyclophosphamide as a second-line immunotherapy. Follow-up was performed to evaluate the efficacy and safety of cyclophosphamide. After first-line immunotherapy for 1-4 weeks, the six patients had reduced psychiatric symptoms, seizures, and involuntary movements; three patients had an improved level of consciousness and were able to make simple conversations. However, all the patients still showed slow response, as well as cortical dysfunction symptoms such as aphasia, alexia, agraphia, acalculia, apraxia, and movement disorders. The six patients continued to receive cyclophosphamide as a sequential therapy. They were able to answer simple questions 7 days after treatment. Three school-aged patients were able to make simple calculation, had greatly improved reading and writing ability, and almost recovered self-care ability 2-3 weeks later. The cognitive function of the six patients was almost restored to the level before the onset of disease, and their living ability returned to normal 2-3 months later. During the treatment period, there were no adverse reactions or abnormal results of routine blood test and liver and kidney function tests. Children with anti-NMDAR encephalitis should be given appropriate immunotherapy as soon as possible. Cyclophosphamide as a sequential therapy has good efficacy and safety.

  6. Protective effect of L-carnitine in cyclophosphamide-induced germ cell apoptosis*

    Science.gov (United States)

    Zhu, Bin; Zheng, Yan-fei; Zhang, Yue-ying; Cao, Yun-song; Zhang, Lei; Li, Xin-gang; Liu, Teng; Jiao, Zhao-zhu; Wang, Qi; Zhao, Zhi-gang

    2015-01-01

    Cyclophosphamide (CP) is a widely used anti-cancer agent; however, it can also induce serious male infertility. There are currently no effective drugs to alleviate this side-effect. L-Carnitine has been used to treat male infertility, but whether it can be used to protect against CP-induced male infertility is still unclear. This study aims to explore the effect and mechanism of L-carnitine in male infertility induced by CP. CP was used to establish an animal model. After three weeks of treatment, rats were sacrificed and testis and serum were harvested for further evaluation. Testosterone and estrogen levels were measured by enzyme-linked immunosorbent assay (ELISA). Testicular injury was examined by hematoxylin and eosin (H & E) staining, and germ-cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The expression of LC3 and Beclin-1 was examined by immunohistochemistry, Western blot, and real-time polymerase chain reaction (PCR), respectively. Compared with the CP group, L-carnitine significantly increases sperm motility, viability, and testosterone level (PL-carnitine treatment can significantly up-regulate the LC3-II and Beclin-1 expression in the CP+L-carnitine group when compared with the control group (PL-carnitine can effectively retard cell apoptosis in the CP+L-carnitine group. In conclusion, L-carnitine contributes to the inhibition of cell apoptosis and the modulation of autophagy in protecting CP-induced testicular injury. These results suggest the applicability of L-carnitine in the treatment of male infertility. PMID:26365120

  7. Protective effect of L-carnitine in cyclophosphamide-induced germ cell apoptosis.

    Science.gov (United States)

    Zhu, Bin; Zheng, Yan-fei; Zhang, Yue-ying; Cao, Yun-song; Zhang, Lei; Li, Xin-gang; Liu, Teng; Jiao, Zhao-zhu; Wang, Qi; Zhao, Zhi-gang

    2015-09-01

    Cyclophosphamide (CP) is a widely used anti-cancer agent; however, it can also induce serious male infertility. There are currently no effective drugs to alleviate this side-effect. L-Carnitine has been used to treat male infertility, but whether it can be used to protect against CP-induced male infertility is still unclear. This study aims to explore the effect and mechanism of L-carnitine in male infertility induced by CP. CP was used to establish an animal model. After three weeks of treatment, rats were sacrificed and testis and serum were harvested for further evaluation. Testosterone and estrogen levels were measured by enzyme-linked immunosorbent assay (ELISA). Testicular injury was examined by hematoxylin and eosin (H & E) staining, and germ-cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The expression of LC3 and Beclin-1 was examined by immunohistochemistry, Western blot, and real-time polymerase chain reaction (PCR), respectively. Compared with the CP group, L-carnitine significantly increases sperm motility, viability, and testosterone level (PL-carnitine treatment can significantly up-regulate the LC3-II and Beclin-1 expression in the CP+L-carnitine group when compared with the control group (PL-carnitine can effectively retard cell apoptosis in the CP+L-carnitine group. In conclusion, L-carnitine contributes to the inhibition of cell apoptosis and the modulation of autophagy in protecting CP-induced testicular injury. These results suggest the applicability of L-carnitine in the treatment of male infertility.

  8. Flavonoid fraction of Cajanus cajan prohibited the mutagenic properties of cyclophosphamide in mice in vivo.

    Science.gov (United States)

    Abo-Zeid, Mona A M; Abdel-Samie, Negm S; Farghaly, Ayman A; Hassan, Emad M

    2018-02-01

    Cajanus cajan (L.) is a Pigeon pea cultivated in tropical and subtropical areas. It contains many bioactive components. The present study aimed to assess the antimutagenic efficacy of a flavonoid fraction of Cajanus cajan (FFCC) to reduce cytotoxicity and genotoxicity induced by cyclophosphamide (CP). We assessed genotoxic and cytotoxic effects using chromosome aberration, in mouse bone-marrow cells and spermatocytes, cell viability and DNA damage, in mouse bone-marrow cells. Animals received FFCC at concentrations 50,100 and 200 mg/kg b wt by oral gavage, and injected simultaneously with CP (20 mg/kg b wt) for 24 h. The results revealed that FFCC was safe and its effect was normal compared to control group. Moreover, we observed significant inhibition of CP-induced chromosome abnormalities in both, somatic and germ, cells (p ≪ 0.05) after concurrent administration of different concentrations of FFCC and CP. FFCC reduced chromosome aberrations by 14.29%, 25.21% and 28.57% in somatic cells, and 25.35%, 35.21% and 49.29% in germ cells after simultaneous treatment with CP respectively. Additionally, FFCC improved the cell viability of bone-marrow cells in a concentration-dependent manner when administered concurrently with CP. Similarly, FFCC diminished DNA damage (p ≪ 0.05) in CP-treated animals. The inhibitory index of tail DNA (%) reached 90.6% at the highest concentration of FFCC when administered simultaneously with CP. In conclusion, the flavonoid extract improved cell viability and protected animal cells from the cytotoxic and genotoxic effects exhibited by CP. Cajanus cajan flavonoids might contain the antioxidant bioactivity that effectively lessened chromosome aberrations and DNA damage induced by mutagenic agents. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Protective Effect of Kolaviron on Cyclophosphamide-Induced Cardiac Toxicity in Rats.

    Science.gov (United States)

    Omole, Joseph Gbenga; Ayoka, Oladele Abiodun; Alabi, Quadri Kunle; Adefisayo, Modinat Adebukola; Asafa, Muritala Abiola; Olubunmi, Babalola Olusegun; Fadeyi, Benson Akinloye

    2018-01-01

    Cyclophosphamide (CP) is a nitrogen mustard alkylating drug used for the treatment of chronic and acute malignant lymphomas, myeloma, leukemia, neuroblastoma, adenocarcinoma, retinoblastoma, breast carcinoma, and immunosuppressive therapy. Despite its vast therapeutic uses, it is known to cause severe cardiac toxicity. Kolaviron (KV), a Garcinia kola seed extract containing a mixture of flavonoids, is reputed for its antioxidant and membrane stabilizing properties. This study investigated the protective effect of KV on CP-induced cardiotoxicity in rats. Thirty rats were used, and they were divided into 6 groups of 5 rats each. Group I received 2 mL/kg propylene glycol orally for 14 days; group II received CP (50 mg/kg/d, intraperitoneally [i.p.]) for 3 days; groups III and IV received 200 and 400 mg/kg/d KV, respectively, orally for 14 days and groups V and VI were pretreated with 200 and 400 mg/kg/d KV, respectively, orally for 14 days followed by CP (50 mg/kg/d, i.p.) for 3 days. CP treatment resulted in a significantly lower food consumption and body weight in rats. The lactate dehydrogenase and creatine kinase enzymes in cardiac tissues of rats treated with CP were significantly higher. In cardiac tissues, 3-day doses of CP resulted in significantly higher heart weight, cardiac troponin I, myeloperoxidase, malondialdehyde, hydrogen peroxide and lower superoxide dismutase, catalase, glutathione peroxidase activities, and reduced glutathione levels. Histological examination of cardiac tissues showed sign of necrosis of myocardium after CP treatment. However, administration of KV at 200 and 400 mg/kg for 14 days prior to CP treatment, increase food consumption, body weight, and attenuates the biochemical and histological changes induced by CP. These results revealed that KV attenuates CP-induced cardiotoxicity by inhibiting oxidative stress and preserving the activity of antioxidant enzymes.

  10. Ameliorative effect of propolis against cyclophosphamide-induced toxicity in mice.

    Science.gov (United States)

    El-Naggar, Sabry A; Alm-Eldeen, Abeer A; Germoush, Mousa O; El-Boray, Kamal F; Elgebaly, Hassan A

    2015-02-01

    Cyclophosphamide (CTX) is a common anticancer agent used for the treatment of several malignancies. However, upon treatment, it induces severe toxicity due to its oxidative stress capability. Propolis, a natural product collected by honey bees, has shown several biological activities, such as free radical scavenging and antioxidant agent. This study elucidates the protective effects of propolis against CTX-induced changes in mice. Forty-eight male Swiss albino mice were divided into four groups; group 1 was intraperitoneally (i.p.) injected with 200 µL of phosphate buffer saline (PBS), group 2 was injected with 100 mg/kg/d propolis, group 3 was injected with a single dose of CTX (200 mg/kg), and group 4 was injected with a single dose of CTX (200 mg/kg) followed by propolis (100 mg/kg) for 7 consecutive days. After 12 d, mice were bled and then sacrificed to analyze the hematological, biochemical, and histological parameters. The results indicated that CTX-injected mice showed an increase in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine and a decrease in the total number of white blood cells (WBCs) and platelets. Moreover, dramatically changes in the histological architectures of the liver and kidney were observed. The mice that were injected with CTX/propolis showed an improvement in the levels of ALT, AST, urea, creatinine, WBCs, and platelets. Moreover, the histological picture of the liver and kidney was significantly improved. In conclusion, propolis might be considered an effective agent in ameliorating the toxicity resulted from CTX treatment.

  11. Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation.

    Science.gov (United States)

    Xie, H-J; Yasar, U; Lundgren, S; Griskevicius, L; Terelius, Y; Hassan, M; Rane, A

    2003-01-01

    The role of polymorphic CYP2B6 in cyclophosphamide (CPA) bioactivation was investigated in human liver microsomes. A total of 67 human liver specimens were first genotyped with respect to the CYP2B6*5 and CYP2B6*6 variant alleles. CYP2B6 apoprotein levels in 55 liver microsomal preparations were assessed by immunoblotting. 4-Hydroxy-CPA and hydroxy-bupropion were quantified by using HPLC and LC-MS, respectively. 7-Ethoxy-4-trifluoromethyl coumarin O-deethylase activity was measured fluorometrically. The frequencies of CYP2B6*5 and CYP2B6*6 mutant alleles were 9.0 and 16.4%, respectively. CYP2B6 protein expression was detected in 80% of the samples, with a large variation (0.003-2.234, arbitrary units). There was a high correlation between CYP2B6 apoprotein content and CPA 4-hydroxylation (n=55, r=0.81, P<0.0001). When based on the CYP2B6 apoprotein levels, the *6 carriers had significantly higher CPA 4-hydroxylation (P<0.05). CPA 4-hydroxylation also correlated significantly with other CYP2B6-specific reactions (n=20, P<0.0001). V(max) and K(m) for CPA 4-hydroxylation in recombinant CYP2B6 enzyme were 338 nmol/min/nmol enzyme and 1.4 mM, respectively. CYP2B6 showed much higher in vitro intrinsic clearance than previously observed in recombinant CYP2C19 and CYP2C9 variants in yeast expression system. Our results demonstrate that the polymorphic CYP2B6 is a major enzyme in the bioactivation of CPA. Moreover, we identified a strong impact of CYP2B6*6 on CPA 4-hydroxylation.

  12. Ifosfamide, epirubicin, and etoposide (IEV) mobilize peripheral blood stem cells more efficiently than cyclophosphamide/etoposide.

    Science.gov (United States)

    Hart, Christina; Blank, Christian; Krause, Stefan W; Andreesen, Reinhard; Hennemann, Burkhard

    2007-08-01

    High-dose chemotherapy with autologous stem cell support is an effective treatment in advanced multiple myeloma. In this study, we compare chemotherapy with ifosfamide, epirubicin, and etoposide (IEV) or cyclophosphamide and etoposide (CE) in 47 patients with multiple myeloma with regard to stem cell mobilization, toxicity, and tumor response. The proportion of patients reaching the threshold of >6 x 10(6) CD34+ cells/kg body weight was significantly higher in the IEV group (97% vs 71%), and more CD34+ cells (10 x 10(6) vs 3.5 x 10(6) cells/kg; p = 0.002) could be collected by the first leukapheresis associated with less leukaphereses needed. Non-hematopoietic side effects were mild with nausea being more frequent after IEV treatment (30% vs 7%). Grade 3/4 neutropenia (thrombocytopenia) occurred in 89 and 100% (55 and 44%) of the patients. There was one treatment-related death due to septic shock in the IEV group. Grade 3/4 anemia was more frequent in the IEV group (19% vs 0%). Forty-two percent (IEV) and 50% (CE) received inpatient treatment for neutropenic fever. In 20 and 7% of the patients, a partial response was observed after IEV and CE. However, the overall response rate (complete response and partial tumor response) after mobilization and tandem high-dose chemotherapy was 75% after IEV and 78% after CE and, thus, independent of the mobilization. In summary, both treatment protocols can readily be used for the mobilization of peripheral blood stem cells with comparable major toxicities and similar tumor response rates. However, the efficiency of the stem cell mobilization was significantly higher after IEV treatment.

  13. Intravenous Cyclophosphamide and Plasmapheresis in Dialysis-Dependent ANCA-Associated Vasculitis

    Science.gov (United States)

    Pepper, Ruth J.; Chanouzas, Dimitrios; Tarzi, Ruth; Little, Mark A.; Casian, Alina; Walsh, Michael; Pusey, Charles D.; Harper, Lorraine

    2013-01-01

    Summary Background and objectives Induction therapy with oral cyclophosphamide (CYP) has been a mainstay of treatment in patients with severe renal failure secondary to ANCA-associated vasculitis (AAV). Recent evidence proposes using pulsed intravenous CYP in less severe disease to minimize adverse events. It is unclear if this can be translated to those with dialysis-dependent renal insufficiency. Design, setting, participants, & methods All AAV patients presenting between 2005 and 2010 requiring dialysis at presentation were retrospectively analyzed. Patients were treated with plasma exchange, corticosteroids, and intravenous CYP. Rate of dialysis independence at 3 and 12 months and adverse effects were assessed and compared with the outcome of the plasmapheresis, prednisolone, and oral CYP arm of the randomized MEPEX (methylprednisolone versus plasma exchange) trial. Results Forty-one patients were included. At 3 months, 3 (7.3%) patients had died on dialysis, 12 (29.3%) remained dialysis dependent, and 26 (63.4%) were dialysis independent (creatinine, 2.5 mg/dl; GFR, 26 ml/min per 1.73 m2). Four patients subsequently reached ESRD at a median time of 83 days. Thirty-seven (90%) patients reached 1 year follow-up, 13 (35%) remained dialysis dependent, and 24 (65%) had independent renal function. Eleven patients (27%) had episodes of leukopenia (white cell count dialysis-dependent cohort treated with plasmapheresis in the MEPEX study in which 51% were alive with independent renal function at 1 year. Conclusions Intravenous CYP used with corticosteroids and plasmapheresis may be an effective alternative to oral CYP in patients with dialysis-dependent AAV. PMID:23160261

  14. Fludarabine, cyclophosphamide, and multiple-dose rituximab as frontline therapy for chronic lymphocytic leukemia.

    Science.gov (United States)

    Short, Nicholas J; Keating, Michael J; Wierda, William G; Faderl, Stefan; Ferrajoli, Alessandra; Estrov, Zeev; Smith, Susan C; O'Brien, Susan M

    2015-11-01

    Fludarabine, cyclophosphamide, and rituximab (FCR) result in durable responses in patients with previously untreated chronic lymphocytic leukemia (CLL). Previous reports have suggested that in patients with relapsed CLL, a dose-intensified rituximab regimen increases response rates in comparison with standard-dose rituximab. It is unknown whether rituximab intensification of the FCR regimen will result in improved response rates and patient outcomes in patients with previously untreated CLL. A single-arm study was conducted to evaluate the safety and efficacy of a modified FCR regimen with multiple-dose rituximab (FCR3) in 65 patients with previously untreated CLL. The results were compared with those for a historical cohort treated with FCR. The overall response rate to FCR3 was 97%, with 75% of the patients achieving a complete remission. Minimal residual disease negativity was achieved for 62% of the patients according to flow cytometry. The median time to progression (TTP) was 81 months, and the median overall survival (OS) was not reached, with 58% of the patients still alive at a median survivor follow-up of 9.7 years. Grade 3 or 4 neutropenia, grade 3 or 4 thrombocytopenia, and major infections were observed with 45%, 5%, and 1.9% of the FCR3 courses, respectively. Therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute myelogenous leukemia (t-AML) developed in 7 patients (11%; P < .01 vs the historical FCR cohort). In patients with previously untreated CLL, FCR3 resulted in response rates, TTP, and OS similar to those of a historical cohort of patients treated with FCR. FCR3 was associated with an increased incidence of t-MDS/t-AML. © 2015 American Cancer Society.

  15. Myelosuppression After Frontline Fludarabine, Cyclophosphamide, and Rituximab in Patients With Chronic Lymphocytic Leukemia

    Science.gov (United States)

    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

  16. 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.

  17. Protective effects of Origanum vulgare ethanol extract against cyclophosphamide-induced liver toxicity in mice.

    Science.gov (United States)

    Habibi, Emran; Shokrzadeh, Mohammad; Chabra, Aroona; Naghshvar, Farshad; Keshavarz-Maleki, Razieh; Ahmadi, Amirhossein

    2015-01-01

    Abstract Context: Despite its wide clinical use, cyclophosphamide (CP), an alkylating chemotherapeutic agent, possesses many adverse effects, including hepatotoxicity. Because Origanum vulgare L. (Lamiaceae) has antioxidative properties, it might protect against above-mentioned damage. This study evaluated the protective effects of O. vulgare extract on CP-induced liver toxicity. Mice were pretreated with aerial parts of O. vulgare ethanolic extract (intraperitoneally) at doses of 50, 100, 200, and 400 mg/kg for 7 consecutive days before the administration of a single 200 mg/kg intraperitoneal dose of CP 1 h after the last injection of O. vulgare. After 24 h, animals were anesthetized, blood samples and hepatic tissues were collected and used for biochemical and histological examination. Serum levels of hepatic markers were increased after CP treatment but restored in the O. vulgare-pretreated groups. The serum ALT, AST, and ALP of the CP group were 196.49 ± 3.82, 143.78 ± 4.79, and 203.18 ± 3.81 IU/l, respectively. However, pretreatment with 400 mg/kg O. vulgare significantly decreased the serum ALT, AST, and ALP to 52.49 ± 2.18, 44.78 ± 2.06, and 65.62 ± 1.73 IU/l, respectively (p < 0.001). Histological examinations also confirmed the protective effects of O. vulgare against CP-induced liver toxicity. Our results reveal that O. vulgare with high amount of flavonoids and phenolic compounds induces potent hepatoprotective mechanisms against CP. Therefore, O. vulgare might help defend the body against the side effects, particularly hepatic damages induced by chemotherapeutic agents.

  18. Efficacy of Rosmarinus officinalis leaves extract against cyclophosphamide-induced hepatotoxicity.

    Science.gov (United States)

    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.

  19. 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.

  20. Normalization of peripheral blood cell composition by lactoferrin in cyclophosphamide-treated mice.

    Science.gov (United States)

    Artym, Jolanta; Zimecki, Michał; Kruzel, Marian

    2004-03-01

    Cyclophosphamide (CP) is used in the treatment of autoimmune disorders and leukemia. The compound induces severe leuko- and neutropenia. Lactoferrin (LF) is a protein which plays a role in the innate immunity. In this study we evaluated the usefulness of LF in reversing CP-induced lympho- and neutropenia in mice. CBA mice were treated with CP (350 mg/kg body weight, intraperitoneally) and given LF as a 0.5% addition to drinking water. Alternatively, LF was administered orally (seven doses, 1 mg each) on alternate days following CP injection. Control groups received CP or LF only. Blood samples were taken before treatment and on days 4, 8, 15 and 22 following CP injection to determine leukocytosis and cell types in blood smears. Mice treated with CP showed severe leukopenia, strong eosinophilia (day 4), and an altered lymphocyte/neutrophil ratio (days 8-22). Treatment of mice with LF for 21 days partially normalized the cell composition in CP-treated mice (increased percentage of lymphocytes and decreased eosinophil content). The content of leukocytes increased upon LF treatment on days 4, 8, 15 and 22 (by 36.8, 39.5, 72 and 70.7%, respectively). More importantly, LF partly normalized the neutrophil and lymphocyte composition on day 22 (neutrophils: 29.2% in control mice, 50.6% in CP-treated, and 39.16% in CP/LF-treated; lymphocytes: 66.18% in control mice, 35% in CP-treated and 48.8% in CP/LF-treated). Administration of LF alone did not change the cell numbers or composition. LF given orally to CP-immunocompromised mice accelerates reconstitution of lymphopoiesis and myleopoiesis.

  1. Cardioprotective Effect of Selenium Against Cyclophosphamide-Induced Cardiotoxicity in Rats.

    Science.gov (United States)

    Gunes, Sibel; Sahinturk, Varol; Karasati, Pinar; Sahin, Ilknur Kulcanay; Ayhanci, Adnan

    2017-05-01

    The objective of this study is to evaluate the possible protective effects of selenium (Se) against cyclophosphamide (CP)-induced acute cardiotoxicity in rats. A total of 42 male Spraque-Dawley rats were divided into six groups (n = 7). Rats in the first group were served as control. Rats in the second group received CP (150 mg/kg) at the sixth day of experiment. Animals in the third and fourth groups were treated with only 0.5 and 1 mg/kg Se respectively for six consecutive days. Rats in the fifth and sixth groups received respective Se doses (0.5 or 1 mg/kg) for 6 days and then a single dose of CP administered on the sixth day. On day 7, the animals were sacrificed; blood samples were collected to measure malondialdehyde (MDA), glutathione (GSH), lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and ischemia-modified albumin (IMA) levels. Heart tissues were processed routinely and tissue sections were stained with H + E for light microscopic examination. In the CP-treated rats MDA, LDH, CK-MB, and IMA serum levels increased, while GSH levels decreased. Microscopic evaluation showed that tissue damage was conspicuously lower in CP plus Se groups. Moreover, 1 mg/kg Se was more protective than 0.5 mg/kg Se as indicated by histopathological and biochemical values. In conclusion, Se is suggested to be a potential candidate to ameliorate CP-induced cardiotoxicity which may be related to its antioxidant activity.

  2. The protective effect of Moringa oleifera leaves against cyclophosphamide-induced urinary bladder toxicity in rats.

    Science.gov (United States)

    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

  3. 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.

  4. Cardioprotective effect of curcumin and piperine combination against cyclophosphamide-induced cardiotoxicity.

    Science.gov (United States)

    Chakraborty, Manodeep; Bhattacharjee, Ananya; Kamath, Jagadish Vasudev

    2017-01-01

    Curcumin is a well-established cardioprotective phytoconstituent, but the poor bioavailability associated with it is always a matter of therapeutic challenge. The present study was undertaken to increase the therapeutic efficacy of curcumin by combining with bio-enhancer like piperine against cyclophosphamide (CP)-induced cardiotoxicity in rats. Rats ( n = 8) were treated with curcumin (200 mg/kg, p.o.) alone and different dose combination of curcumin (100, 50, 25 mg/kg, p.o.) and piperine (20 mg/kg, p.o.) for 10 days. All the treated groups were subjected to CP (200 mg/kg, i.p.) toxicity on day 1. Twenty-four hours after the last treatment, the effects were evaluated by changes in electrocardiographic (ECG) parameters, serum biomarkers, lipid profile, tissue antioxidants, and histopathological examination. Serum and tissue homogenate parameters were measured by semi-autoanalyzer and spectrophotometer, respectively. Results obtained were assessed by one-way analysis of variance followed by Tukey-Karmer multiple comparison test. Incorporation of piperine with the doses of 50 and 25 mg/kg with curcumin exhibited significant beneficial effect compared to curcumin alone-treated group. The best effective group was a combination of curcumin 50 mg/kg with piperine 20 mg/kg which showed extremely significant ( P curcumin alone-treated group. From this study, it can be concluded that a novel dose combination of curcumin (50 mg/kg) with piperine (20 mg/kg) exhibited profound cardioprotection compared to curcumin (200 mg/kg) alone-treated group.

  5. 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.

  6. 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.

  7. Effect of cyclophosphamide on the solid form of mannitol during lyophilization.

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    Patel, Krupaliben; Munjal, Bhushan; Bansal, Arvind K

    2017-04-01

    Mannitol is a commonly used bulking agent in lyophilized formulations. It can crystallize into multiple solid forms during lyophilization thereby exhibiting phase heterogeneity and variability in product performance. In this manuscript, we studied the effect of cyclophosphamide (CPA), an anticancer drug, on the solid form of mannitol during lyophilization from aqueous solutions. Freeze-concentration studies were performed in the DSC while lyophilization was performed in a lab scale freeze dryer. DSC experiments revealed two-stage crystallization of mannitol (1.5% w/v) during freeze-concentration, evident as two distinct exothermic events (at -18.2°C and -30°C) in the cooling curve. This was complemented by two eutectic melting endotherms in the subsequent heating curve. Addition of CPA (4.0% w/v) completely inhibited the exotherm at -18.2°C, but enhanced the enthalpy of exotherm at -30°C by five folds. Likewise, only one eutectic melting endotherm was observed in the subsequent heating curve. Lyophilization of the solution containing only mannitol, yielded a mixture of β- (major) and δ- (minor) polymorphs of mannitol. However, in the presence of CPA, only δ-polymorph was observed in the lyophilized sample. This selective favoring of the metastable δ-polymorph over the stable β-polymorph, was explained by altered freezing kinetics of the solution in presence of CPA. The study provides mechanistic insights into solute crystallization behaviour during lyophilization of multi-component systems. Copyright © 2017. Published by Elsevier B.V.

  8. 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.

  9. 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

  10. Risk Factors for Early-Onset Peripheral Neuropathy Caused by Vincristine in Patients With a First Administration of R-CHOP or R-CHOP-Like Chemotherapy

    Science.gov (United States)

    Okada, Naoto; Hanafusa, Takeshi; Sakurada, Takumi; Teraoka, Kazuhiko; Kujime, Toshihide; Abe, Masahiro; Shinohara, Yasuo; Kawazoe, Kazuyoshi; Minakuchi, Kazuo

    2014-01-01

    Background Peripheral neuropathy is a well-known side effect of vincristine (VCR), a microtubule inhibitor used for R-CHOP or R-CHOP-like (namely R-CVP and R-THP-COP) regimens. Previous studies have shown that both the total dose of VCR and the number of treatment cycles are related to the incidence of VCR-induced peripheral neuropathy (VIPN). However, VIPN will also occur during the first treatment cycle regardless of the total dose of VCR or number of treatment cycles (early-onset VIPN). There is little information about early-onset VIPN, and it is difficult to predict. The present study’s goal was to identify risk factors for early-onset VIPN. Methods We analyzed the case records of patients who had their first administration of an R-CHOP or R-CHOP-like regimen between April 2008 and August 2013 at Tokushima University Hospital in Tokushima, Japan. To identify the risk factors for early-onset VIPN, we performed univariate and multivariate logistic regression analyses. Results Forty-one patients underwent an R-CHOP or R-CHOP-like regimen for the first time at Tokushima University Hospital between April 2008 and August 2013, and 14 patients had grade 1 or higher early-onset VIPN. A univariate analysis revealed that age, the dose of VCR and the concomitant use of aprepitant appeared to be the risk factors of early-onset VIPN. In our calculation using receiver-operator characteristics curves, the cut-off value for patient age was 65 years and that of the dose of VCR was 1.9 mg. A multivariate analysis revealed that VCR dose ≥ 1.9 mg and the concomitant use of the antiemetic aprepitant were independent risk factors for early-onset VIPN. Conclusions Our present study showed that the patients who had VCR dose ≥ 1.9 mg and the concomitant use of aprepitant had the risk for early-onset VIPN. This suggests that it is important to use aprepitant in light of the risk of early-onset VIPN and the benefit of aprepitant’s antiemetic effect in R-CHOP and R

  11. Influence of etoposide and cyclophosphamide on the efficacy of cloxacillin and erythromycin in an experimental staphylococcal infection.

    Science.gov (United States)

    Calame, W; van der Waals, R; Mattie, H; van Furth, R

    1989-01-01

    The effect of monocytopenia and granulocytopenia on the outgrowth of Staphylococcus aureus as well as on antibiotic efficacy was studied in an experimental thigh infection in mice. Pretreatment with etoposide reduced monocyte numbers in blood to 14% and those of granulocytes to 54% at the time of infection. Monocytopenia did not affect the proliferation of bacteria in the infected thigh or the reduction of bacterial numbers after treatment with cloxacillin or erythromycin. Pretreatment with cyclophosphamide reduced monocyte numbers to 15% and granulocyte numbers to 3%. This resulted in a marked increase in the number of bacteria at the site of infection and a decrease in the efficacy of antibiotic treatment. PMID:2764550

  12. 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; Iversen, Trine Zeeberg

    2016-01-01

    melanoma (MM). In addition, clinical and immunological effect of the treatment was evaluated.  Experimental design: Twenty-two patients were enrolled and treated with six cycles of cyclophosphamide 50 mg orally bi-daily for a week every second week (day 1–7). During the six cycles patients received...... and nine patients achieved stable disease. In three patients minor tumor regression was observed. By IFNγ ELISpot and proliferation assay immune responses were seen in 6/17 and 4/17 patients, respectively; however, no correlation with clinical response was found. The percentage of Tregs was unchanged...

  13. Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide

    NARCIS (Netherlands)

    Ekhart, Corine; Doodeman, Valerie D.; Rodenhuis, Sjoerd; Smits, Paul H. M.; Beijnen, Jos H.; Huitema, Alwin D. R.

    2008-01-01

    PURPOSE: The anticancer agent, cyclophosphamide, is metabolized by cytochrome P450 (CYP), glutathione S-transferase (GST) and aldehyde dehydrogenase (ALDH) enzymes. Polymorphisms of these enzymes may affect the pharmacokinetics of cyclophosphamide and thereby its toxicity and efficacy. The purpose

  14. [Effect of epsilon-aminocaproic acid, cyclophosphamide and their combination on the growth of autochthonous sarcomas of mice induced by benzo(a)pyrene].

    Science.gov (United States)

    Anikin, I V; Tyndyk, M L; Zabezhinskiĭ, M A; Popovich, I G; Anisimov, V N; Pliss, G B

    2014-01-01

    Antifibrinolytic drug epsilon-aminocaproic acid as a therapeutic form (5% solution in saline) was tested for antitumor activity in the autochthonous subcutaneous tumors of mice, induced by benzo (a) pyrene, in monotherapy mode (instead animals received drinking water) and in combination with cyclophosphamide, which was administered once intraperitoneally in the dose of 200 mg/kg. In the control groups, treated with drinking water and saline solution instead of water, there was no stabilization and reduction in tumor volume, while in the groups receiving epsilon-aminocaproic acid, cyclophosphamide and their combination statistically significantly in comparison with the control groups there was increased the proportion of tumors with not changed or reduced volume; epsilon-aminocaproic acid enhanced the antitumor effect of cyclophosphamide. The data obtained are for further study of the antitumor effect of epsilon-aminocaproic acid.

  15. Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer: review of the literature.

    Science.gov (United States)

    Nelius, T; Rinard, K; Filleur, S

    2011-10-01

    Castration-refractory prostate cancer remains a therapeutic challenge even after introduction of docetaxel as first-line treatment. Castration-refractory prostate cancer cannot be cured by any available therapeutic option, and chemotherapy still needs to be considered palliative. The survival benefit is modest, and treating physicians are searching for alternative treatment options. Despite new drugs currently under investigation, some conventional and well known chemotherapeutic drugs are experiencing a renaissance. The development of anti-angiogenic approaches in cancer treatment has led to the development of metronomic dosing of conventional chemotherapeutic drugs including cyclophosphamide. The intention of this review is to evaluate the efficacy and toxicity of oral/metronomic cyclophosphamide in the treatment of patients with castration-refractory prostate cancer. A comprehensive literature search was performed in different databases using various key words. Relevant articles and references between 1962 and 2010 were reviewed and analyzed for data regarding the association between oral cyclophosphamide treatment and prostate cancer. Oral cyclophosphamide is active in the treatment for castration-refractory prostate cancer even in patients treated with previous chemotherapy including docetaxel. It yields symptomatic and objective remissions. The side effects are usually grade 1-2 and easy to manage. Grade three to four side effects are less common. Oral cyclophosphamide treatment for patients with castration-refractory prostate cancer deserves more attention and validation, and warrants further testing of various treatment combinations. Given the fact that castration-refractory prostate cancer includes an extremely heterogeneous group of patients with variability of tumor growth rates, the combination of cyclophosphamide with other active agents such as angiogenesis inhibitors and immunomodulatory compounds need to be explored. Copyright © 2010 Elsevier Ltd

  16. 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.

  17. 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.

  18. Protective effects of silymarin and curcumin on cyclophosphamide-induced cardiotoxicity.

    Science.gov (United States)

    Avci, H; Epikmen, E T; Ipek, E; Tunca, R; Birincioglu, S S; Akşit, H; Sekkin, S; Akkoç, A N; Boyacioglu, M

    2017-06-14

    Cyclophosphamide (CP) is a potent anticancer agent; its clinical use is limited due to its marked cardiotoxicity. The present study was aimed at evaluating the cardioprotective effects of silymarin (SLY) and curcumin (CUR), which have strong antioxidant properties, against the toxic effects of high-dose CP on the heart of rats. A total of 36 adult Wistar albino female rats were randomly divided into six groups. Group I (control group; nothing was administered), Group II (CP group; 30mg/kg/day CP was administered intraperitoneally to each animal for seven days), Group III (SLY group; 100mg/kg/day SLY by gavage for 14 days), Group IV (CUR group; 100mg/kg/day CUR by gavage for 14 days), Group V (SLY+CP group; 100mg/kg/day SLY by gavage for 14days plus 30mg/kg/day CP intraperitoneally starting from the seventh day) and Group VI (CUR+CP group; 100mg/kg/day CUR by gavage for 14days plus 30mg/kg/day CP intraperitoneally starting from the seventh day). Biochemical, histopathological and immunohistochemical methods were utilised for evaluation of the cardiotoxicity. The result showed that an increase in heart MDA and DNA fragmentation levels were detected while significant decreases were seen in SOD levels in CP alone group when compared to the other groups. CP caused severe damage in the histopathological status of heart tissue including intersititial oedema, haemorrhage, degeneration and necrosis in muscle fibrils and perinuclear vacuolization. A significant increase in the percentage of TUNEL-positive cells and γH2AX protein expression was detected in the CP-treated group compared to the control and other treated groups. There was significant increase in the percentage of caspase 3-positive cells and decrease in the percentage of Bcl-2 positive cells in the CP group compared to the control group and other treated groups. However, a significant decrease in the percentage of cTnI and cTnT immunoreactivity was also observed in the CP-treated group compared to the control

  19. [Neoadjuvant chemotherapy using epirubicin, cyclophosphamide and fluorouracil: neutropenia and elevation of transaminase, and their management].

    Science.gov (United States)

    Wang, Xinguang; Fan, Tie; Fan, Zhaoqing; Wang, Tianfeng; Xie, Yuntao; Li, Jinfeng; Ouyang, Tao

    2015-03-01

    To retrospectively investigate the incidence of severe neutropenia and elevation of transaminase during neoadjuvant chemotherapy using epirubicin, cyclophosphamide and fluorouracil in breast cancer patients. From January 2011 to December 2012, 303 consecutive breast cancer patients with complete treatment data treated in our department were included in this analysis. All patients received neoadjuvant chemotherapy with equal dose of EPI (100 mg/m(2)) administered every 3 weeks for 4 cycles before surgery. 200 patients (66.0%) experienced at least one episode of grade 3/4 neutropenia/leukopenia, among them 176 patients experienced their first episode after the first cycle. Febrile neutropenia (FN) occurred in 13 patients for 14 episodes. Elevation of transaminase occurred in a total of 46 patients (15.2%), among them, grade 2 or higher elevation occurred in 15 patients (5.0%). Three blood test plans were adopted to monitor the patients during chemotherapy: (1) Routine blood count repeated every week; (2) Routine blood count before and on day 10 of each chemotherapy episode; (3) Routine blood count before and on day 7, 10 and 14 of each chemotherapy episode. The number of patients whose chemotherapy was delayed due to 3/4 neutropenia/leucopenia in each blood test plan was 3 (5.0%), 7 (3.9%) and 2 (3.2%), respectively. The number of patients with febrile neutropenia (FN) in each blood test plan was 2 (3.3%), 8 (4.4%) and 3 (4.8%), respectively. No statistically significant difference in treatment delay or the incidence of FN was observed among different blood test plans. No statistically significant difference in the incidence of grade 3/4 neutropenia/leukopenia or grade 2 or higher transaminase elevation was observed among different 5-Fu regimens. During neoadjuvant chemotherapy using FE100 C, Fci E100 C or E100 C for breast cancer patients without routine prophylactic G-CSF, the incidence of grade 3/4 neutropenia/leukopenia is 66.0%. With the patient management plan

  20. Enhanced clearance of Escherichia coli and Staphylococcus aureus in mice treated with cyclophosphamide and lactoferrin.

    Science.gov (United States)

    Artym, Jolanta; Zimecki, Michal; Kruzel, Marian L

    2004-09-01

    Previous studies on cyclophosphamide (CP)-immunocompromised mice showed accelerated reconstitution of immune system function following oral treatment with lactoferrin (LF). The aim of this investigation was to evaluate the ability of mice, treated with a sublethal dose of CP and given LF, to combat bacterial infections. Mice were injected with a single, intraperitoneal dose of CP (350 mg/kg body weight). One group of CP-treated mice was also given LF in drinking water (0.5% solution) for 14 days. Untreated and LF-treated mice served as controls. On day 15 following CP administration, mice were infected intravenously with 10(8) Escherichia coli or 5 x 10(7) Staphylococcus aureus. Twenty-four hours later, the number of colony-forming units (CFU) in spleens and livers were determined. Phenotypic analysis of blood leukocytes was determined, as well as the ability of splenic and peritoneal cells to produce IL-6 spontaneously and in the presence of lipopolysaccharide (LPS). Treatment with CP, or with CP and LF, led to profound reduction of E. coli CFU in the liver and the spleen; treatment with LF alone had significant inhibitory effects on organ enumerated CFU. S. aureus CFUs were also significantly reduced in spleens of mice treated with CP or CP/LF and, to a lesser degree, after LF alone. These effects were also significantly reduced in the livers. Analysis of blood cellular phenotype revealed total number of peripheral leukocytes was lower in the CP-treated group (52.6%) but not significantly different from control values in CP/LF and LF-treated groups (90.7% and 104.6%, respectively). Conversely, percentage of blood neutrophils was markedly elevated in CP and CP/LF groups--62% and 42.5% vs. 18.4% in controls. These findings were accompanied by production of IL-6 by splenic and peritoneal cells which was significantly increased in CP- and CP/LF-treated groups. It was concluded that the increased clearance of bacteria in the organs of mice treated with CP and CP

  1. An evaluation of the mode of action framework for mutagenic carcinogens case study: Cyclophosphamide.

    Science.gov (United States)

    McCarroll, Nancy; Keshava, Nagalakshmi; Cimino, Michael; Chu, Margaret; Dearfield, Kerry; Keshava, Channa; Kligerman, Andrew; Owen, Russell; Protzel, Alberto; Putzrath, Resha; Schoeny, Rita

    2008-03-01

    In response to the 2005 revised US Environmental Protection Agency (EPA) Cancer Guidelines, a Risk Assessment Forum's Technical Panel has devised a strategy in which genetic toxicology data combined with other information are assessed to determine whether a carcinogen operates through a mutagenic mode of action (MOA). This information is necessary for EPA to decide whether age-dependent adjustment factors (ADAFs) should be applied to the cancer risk assessment. A decision tree has been developed as a part of this approach and outlines the critical steps for analyzing a compound for carcinogenicity through a mutagenic MOA (e.g., data analysis, determination of mutagenicity in animals and in humans). Agents, showing mutagenicity in animals and humans, proceed through the Agency's framework analysis for MOAs. Cyclophosphamide (CP), an antineoplastic agent, which is carcinogenic in animals and humans and mutagenic in vitro and in vivo, was selected as a case study to illustrate how the framework analysis would be applied to prove that a carcinogen operates through a mutagenic MOA. Consistent positive results have been seen for mutagenic activity in numerous in vitro assays, in animals (mice, rats, and hamsters) and in humans. Accordingly, CP was processed through the framework analysis and key steps leading to tumor formation were identified as follows: metabolism of the parent compound to alkylating metabolites, DNA damage followed by induction of multiple adverse genetic events, cell proliferation, and bladder tumors. Genetic changes in rats (sister chromatid exchanges at 0.62 mg/kg) can commence within 30 min and in cancer patients, chromosome aberrations at 35 mg/kg are seen by 1 hr, well within the timeframe and tumorigenic dose range for early events. Supporting evidence is also found for cell proliferation, indicating that mutagenicity, associated with cytotoxicity, leads to a proliferative response, which occurs early (48 hr) in the process of tumor induction

  2. 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.

  3. The influence of montelukast on the autonomic nervous system activity in rats with cyclophosphamide-induced hemorrhagic cystitis

    Directory of Open Access Journals (Sweden)

    Dobrek Lukasz

    2015-09-01

    Full Text Available The complex pathogenesis of cyclophosphamide-induced hemorrhagic cystitis involves arachidonic acid-derived inflammatory mediators, among them leukotrienes. Montelukast, a leukotriene receptor antagonist, is reported to exert an alleviatory effect in the course of cystitis associated with overactive bladder symptoms. The aim of this study was to verify whether the effect of montelukast is also associated with its influence on autonomic activity. The experiment included 20 rats with cyclophosphamide-induced hemorrhagic cystitis (75 mg/kg, four doses every second day, among them, 10 treated with oral montelukast (10 mg/kg for 8 days and 10 controls. Time and frequency domain analyses of heart rate variability (HRV were conducted in all the rats as an indirect measure of their autonomic activity. The montelukast-treated animals showed an increase in root mean square of successive differences (rMSSD, as well as an increase in HRV spectrum total power (TP and power of very low (VLF spectral component. This suggests that due to its anti-inflammatory and its anti-leukotriene effect, montelukast improves overall autonomic activity, with no preferential influence on either the sympathetic or parasympathetic part. Furthermore, the increase in VLF corresponds to attenuation of inflammatory response. In conclusion, this study showed that aside from its antagonistic effect on leukotriene receptors, montelukast can also modulate autonomic activity.

  4. 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.

  5. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients

    NARCIS (Netherlands)

    Waal, de Esther G. M.; de Munck, Linda; Hoogendoorn, Mels; Woolthuis, Gerhard; van der Velden, Annette; Tromp, Yvonne; Vellenga, Edo; Hovenga, Sjoerd

    2015-01-01

    Combination therapy for longer periods but at low dose might be an effective and tolerable manner to treat patients with relapsed multiple myeloma (MM). We used bortezomib, dexamethasone and low-dose oral cyclophosphamide as an induction regimen, followed by 1 year of maintenance consisting of

  6. 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

    pronounced in patients older than 65 years. INTERPRETATION: The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects. FUNDING: Roche Pharma...

  7. 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

  8. A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

    Science.gov (United States)

    González-Fierro, Aurora; de la Cruz-Hernández, Erick; Revilla-Vázquez, Alma; Chávez-Blanco, Alma; Trejo-Becerril, Catalina; Pérez-Cárdenas, Enrique; Taja-Chayeb, Lucia; Bargallo, Enrique; Villarreal, Patricia; Ramírez, Teresa; Vela, Teresa; Candelaria, Myrna; Camargo, Maria F.; Robles, Elizabeth; Dueñas-González, Alfonso

    2006-01-01

    Background 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. Methodology 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. Main Findings 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. Conclusions Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well

  9. Use of laser photomodulation in the evolution of oral mucositis associated to cyclophosphamide, methotrexate, 5-fluouracil - CMF in 5 fluouracil + adriamycin + cyclophosphamide - FAC chemotherapy protocols in patients with breast cancer

    Science.gov (United States)

    de Fátima Lima Ferreira, Maria; de Carvalho, Fabiola Bastos; de Oliveira, Susana C. P. S.; Monteiro, Juliana S. C.; Santos, Gustavo M. P.; Gesteira, Maria F. M.; Maia, Tereza Cristina Teixeira; Pinheiro, Antônio L. B.

    2013-03-01

    The aim of this study was to evaluate the efficacy of the laser photobiomodulation (FBML) in prevention and treatment of oral mucositis induced by chemotherapy protocols CMF (cyclophosphamide, methotrexate, 5-Fluouracil) and FAC (5 Fluouracil + Adriamycin + Cyclophosphamide) in cancer patients breast. We selected 28 patients treated at the Center for High Complexity (CACON), who underwent 6 cycles of 21 days of treatment, with diagnosis of infiltrating ductal carcinoma (ICD C50.9). Were randomly divided into three groups: Group A - eight patients (Protocol FAC + Dental protocol of CACON + Laser), Group B - 6 patients (Protocol CMF + Dental protocol of CACON + Laser), Group C - was divided into two sub-groups: Group C1 with 8 patients (Control Group 1: FAC + Dental protocol o CACON) and group C2 with 6 patients (control group 2: Protocol CMF + Dental protocol of CACON). Patients in Group A and B were use of preventive FBML 24 hours before the start of chemotherapy cycle, then every 48 hours and was extended up to one week following completion of chemotherapy. The groups A and B, presented oral mucositis grade 0 (64.29%) p = 0.07, grade I (7.14%), grade II (14.29%), grade III (7.14 %), grade IV (7.14%) compared to group C, who presented mucositis grade 0 (35.71%) in the initial evaluation with p = 0.10, grade I (21.43%), grade II (28.57%), grade III (14.29%), grade IV (0.00%), patients who used the FBML as a preventive and therapeutic showed a reduction and pain relief in 42.86%. It is concluded that the low power laser when used preventively or as therapy and showed immediate relief of pain and accelerate tissue repair.

  10. Cyclophosphamide, alvocidib (flavopiridol), and rituximab, a novel feasible chemoimmunotherapy regimen for patients with high-risk chronic lymphocytic leukemia.

    Science.gov (United States)

    Stephens, Deborah M; Ruppert, Amy S; Maddocks, Kami; Andritsos, Leslie; Baiocchi, Robert; Jones, Jeffrey; Johnson, Amy J; Smith, Lisa L; Zhao, Yuan; Ling, Yonghua; Li, Junan; Phelps, Mitch A; Grever, Michael R; Byrd, John C; Flynn, Joseph M

    2013-10-01

    Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study, we combined cyclophosphamide, alvocidib and rituximab (CAR) in a schema designed to mitigate tumor lysis syndrome (TLS) seen previously with alvocidib. Nine nucleoside analog-naïve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Progressive multifocal encephalopathy after cyclophosphamide in granulomatosis with polyangiitis (Wegener) patients: case report and review of literature.

    Science.gov (United States)

    Pugnet, G; Pagnoux, C; Bézanahary, H; Ly, K H; Vidal, E; Guillevin, L

    2013-01-01

    Progressive multifocal encephalopathy (PML) is a rare demyelinating disorder targeting the central nervous system and resulting from JC virus reactivation. PML occurs in patients immunocompromised because of haematological malignancies, HIV infection or treatment with cytotoxic drugs. Herein, we describe PML occurring in 2 granulomatosis with polyangiitis (Wegener) patients treated with steroids and cyclophosphamide. The outcome was progressively favourable after immunosuppressant discontinuation for 1 patient and fatal for the other. Four previously reported GPA patients developed PML in the course of their disease. One of them improved gradually after immunosuppressant withdrawal. PML should be strongly suspected whenever unusual central neurological manifestations appear in this context. No effective treatment is available, but immunosuppressants should be discontinued if possible.

  12. 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.

  13. Case of Steven-Johnson Syndrome in a male with breast cancer secondary to docetaxel/cyclophosphamide therapy.

    Science.gov (United States)

    Jarrett, Benjamin; Ghazala, Sehem; Chao, Joseph; Chaudhary, Sachin

    2016-11-15

    The mortality rate for Stevens-Johnson syndrome (SJS) is estimated to be ∼12% and for toxic epidermal necrolysis (TEN) it is around 30%. It continues to be a severe life-threatening drug reaction. We present a 60-year-old Caucasian man with a medical history significant for breast cancer status post mastectomy and chemotherapy with docetaxel and cyclophosphamide who presented with severe mucositis and a progressing skin rash consistent with SJS. He was started on high-dose corticosteroids and IVIG but continued to have worsening mucosal ulcerations and severe bleeding from the oral, conjunctival and genital mucosa. He underwent several rounds of plasmapheresis and additional high-dose steroids with mild improvement in the mucocutaneous manifestations. He subsequently developed respiratory failure, which required mechanical ventilation, as well as disseminated intravascular coagulation, diffuse alveolar haemorrhage, with Pneumocystis jirovecii pneumonia which led to his demise on hospital day 15. 2016 BMJ Publishing Group Ltd.

  14. 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.

  15. Randomized parallel study of doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer.

    Science.gov (United States)

    Diéras, Véronique; Fumoleau, Pierre; Romieu, Gilles; Tubiana-Hulin, Michèle; Namer, Moïse; Mauriac, Louis; Guastalla, Jean-Paul; Pujade-Lauraine, Eric; Kerbrat, Pierre; Maillart, Philippe; Pénault-Llorca, Frédérique; Buyse, Marc; Pouillart, Pierre

    2004-12-15

    This randomized, noncomparative, parallel-group study was designed to evaluate the pathologic complete response (pCR) rate of combined doxorubicin plus paclitaxel (AP) and doxorubicin plus cyclophosphamide (AC) as neoadjuvant chemotherapy in patients with previously untreated breast cancer who were unsuitable for conservative surgery. A total of 200 patients with T2-3, N0-1, M0 disease were randomly assigned in a 2:1 ratio to receive preoperative chemotherapy with either doxorubicin 60 mg/m(2) plus paclitaxel 200 mg/m(2) as a 3-hour infusion (AP) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (AC) every 3 weeks for 4 courses followed by surgery. A pCR (eradication of invasive carcinoma in tumor and in axillary lymph nodes) was found in 16% and 10% of patients in the AP and AC arms, respectively, by study center pathologists, and in 8% and 6% of patients, respectively, by independent pathologists. Patients with pCRs tended to have unifocal disease, tumors with negative hormonal receptor status, and less differentiation (Scarff, Bloom, and Richardson scale grade 3). Breast-conserving surgery was performed in 58% and 45% of patients in the AP and AC arms, respectively. An objective clinical response was achieved in 89% of patients in the AP arm and 70% in the AC arm. At a median follow-up of 31 months, disease-free survival (DFS) was higher in patients who reached pCR versus those without pCR (91% v 70%). The encouraging pathologic and clinical responses of patients with breast cancer after neoadjuvant chemotherapy with doxorubicin plus paclitaxel warrant additional investigation of paclitaxel in the neoadjuvant setting of breast cancer management.

  16. 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.

  17. Incidence of sterile hemorrhagic cystitis in dogs receiving cyclophosphamide orally for three days without concurrent furosemide as part of a chemotherapeutic treatment for lymphoma: 57 cases (2007-2012).

    Science.gov (United States)

    Best, Matthew P; Fry, Darren R

    2013-10-01

    To evaluate the incidence of sterile hemorrhagic cystitis (SHC) and other adverse effects in dogs following oral administration of the single-day, maximum-tolerated dose (MTD) of cyclophosphamide divided over 3 days as part of a multiagent chemotherapy protocol for treatment of lymphoma without concurrent administration of furosemide. Retrospective case series. 57 dogs. Medical records were reviewed to identify dogs with lymphoma that underwent the described cyclophosphamide treatment. Information was obtained regarding signalment, lymphoma stage, concurrent diseases, cyclophosphamide doses administered, adverse effects (including SHC), remission rates, and outcomes. The incidence of SHC was compared with that of literature-derived historical control groups that received the MTD of cyclophosphamide as a single, 1-day dose with or without furosemide treatment. None of the 57 dogs developed SHC during the study period. Forty-seven of 57 (82%) dogs had complete remission of lymphoma. Other adverse effects were uncommon and self-limiting; no dogs had myelosuppression, and only 5 had mild gastrointestinal effects. Incidence of SHC was significantly lower than that reported for historical control dogs that received cyclophosphamide as a single dose without furosemide (24/219) and was not significantly different from that for historical control dogs that received cyclophosphamide as a single dose with furosemide (2/139). No dogs in this study had SHC following oral administration of the single-day MTD of cyclophosphamide divided over a 3-day period without furosemide administration. Further research is needed to confirm whether this method of cyclophosphamide administration is equivalent or superior to the current single-dose administration method.

  18. 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.

  19. [Drug patch tests in the investigation of a fixed drug eruption subsequent to 2 courses of cyclophosphamide in combination with mesna].

    Science.gov (United States)

    Delaigue, S; Boye, T; Pasquine, C; Guetta, K; Alla, P; Ponte-Astoul, J; Morand, J-J

    2015-01-01

    When fixed drug eruption occurs following use of cyclophosphamide and mesna, it is difficult to establish which drug is responsible. We report a new case of patch tests that resulted in withdrawal of mesna and enabled continued treatment with cyclophophamide. A 57-year-old female patient with multiple sclerosis presented increasingly severe cutaneous lesions after successive courses of cyclophosphamide. Twenty-four hours after her latest treatment, she presented at the ER with a worse eruption than those to date and including facial lesions. The clinical diagnosis was a fixed drug eruption, and patch tests for mesna one month later were positive. Fixed drug eruption always occurs after recurrent treatment and the investigation must be precise. Patch tests may be used to determine which drug could be responsible. The most conclusive test comprises withdrawal of the incriminated drug with no further signs of drug eruption on resumption of the other medication. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  20. 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. Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  1. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

    DEFF Research Database (Denmark)

    Vangsted, A. J.; Soeby, K.; Klausen, T.W.

    2010-01-01

    Background: The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored....... The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion), *6, and CYP2D6 gene duplication. Results: In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment....... We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. Conclusion...

  2. A comparison of busulphan versus total body irradiation combined with cyclophosphamide as conditioning for autograft or allograft bone marrow transplantation in patients with acute leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Ringden, O. [Huddinge Hospital, Stockholm (Sweden). Dept. of Clinical Immunology; Labopin, M.; Gorin, N.C. [Hopital Saint-Antoine, Paris (France). Centre International Greffes de Moelle; Tura, S. [Orsola University Hospital, Bologna (Italy); Arcese, W. [University `La Sapienza`, Rome (Italy). Haematology; Iriondo, A. [Hospital National, Santander (Spain); Zittoun, R. [Hotel-Dieu, Paris (France). Service d`Hematologie; Sierra, J. [Hospital Clinic, Barcelona (Spain)

    1996-06-01

    We retrospectively compared the outcome in patients in the EBMT database transplanted for acute leukaemia from January 1987 to January 1994 who received busulphan and cyclophosphamide (BU/CY) as a pretransplant regimen versus those who received cyclophosphamide and total-body irradiation (CY-TBI). The patients were matched for type of transplant (autologous bone marrow transplantation (ABMT) versus allogenic (BMT)), diagnosis (acute lymphoblast leukaemia (ALL) ora cute myeloid leukaemia (AML)), status (early first complete remission, CR-1) versus intermediate (second or later remission, first relapse), age, FAB classification for AML, prevention of graft-versus-host disease and year of transplantation. BU/CY and CY/TBI as pretransplant regimens gave similar results in all situations, except ABMT for ALL intermediate stages with more than 2 years from diagnosis to transplantation, where a lower RI and a higher LFS were associated with CY/TBI. (author).

  3. A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas

    Energy Technology Data Exchange (ETDEWEB)

    Press, O. W.(Fred Hutchinson Cancer Research Center); Eary, Janet F.(Fred Hutchinson Cancer Research Center); Gooley, T; Gopal, A K.; Liu, Stephen (Fred Hutchinson Cancer Research Center, Seattle, WA); Rajendran, Joseph G.(UNIVERSITY OF WASHINGTON); Maloney, David G.; Petersdorf, Stephen; Bush, Sharon A.; Durack, L. D.(Fred Hutchinson Cancer Research Center); Martin, P J.(Fred Hutchinson Cancer Center); Fisher, Darrell R.(BATTELLE (PACIFIC NW LAB)); Wood, Brent; Borrow, James W.(First Hill Diagnostic Imaging, Richland, WA); Porter, Bruce (First Hill Diagnostic Imaging, Richland, WA); Smith, Justin P.(First Hill Diagnostic Imaging, Richland, WA); Matthews, D. C.(Fred Hutchinson Cancer Research Center); Appelbaum, F. R.(Fred Hutchinson Cancer Research Center); Bernstein, I. D.(Fred Hutchinson Cancer Research Center)

    1999-11-01

    Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 (I-131)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg I-131-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of I-131 calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total -body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of I-131-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.

  4. 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 Medicine, UCLA, Department of Biostatistics and Pathology, Los Angeles (United States); Lynch, David A. [National Jewish Health, Radiology Department, Denver, CO (United States); Strollo, Diane C. [UPMC Presbyterian, Radiology Department, Pittsburgh, PA (United States); Kleerup, Eric; Tashkin, Donald P. [David Geffen School of Medicine, UCLA, Department of Med-Pul and Critical Care, Los Angeles, CA (United States); Chong, Daniel; Shah, Sumit K.; Ahmad, Shama; Abtin, Fereidoun; Goldin, Jonathan G. [David Geffen School of Medicine, UCLA, Department of Radiological Sciences, Los Angeles, CA (United States)

    2011-12-15

    The Scleroderma Lung Study showed the efficacy of cyclophosphamide in modestly improving the forced vital capacity (FVC) compared with placebo over 1 year. Using changes in texture-based scores that quantify lung fibrosis as the percentage involvement of reticulation patterns, the effectiveness of cyclophosphamide was re-assessed by examining its impact on quantitative lung fibrosis (QLF). Axial HRCT images were acquired (1-mm slice thickness, 10-mm increments) in the prone position at inspiration. A validated model for quantifying interstitial disease patterns was applied to images from 83 subjects at baseline and 12 months. Scores were calculated for six zones (upper, mid, lower of the right/left lung) and the whole lung. Average changes were compared. Correlations were performed between QLF and physiological and clinical scores. From the most severe zones identified at baseline, QLF scores decreased by 2.6% in the cyclophosphamide group, whereas they increased by 9.1% in the placebo group, leading to {proportional_to}12% difference (p = 0.0027). Between-treatment difference in whole lung QLF was {proportional_to}5% (p = 0.0190). Significant associations were observed between changes in QLF and FVC (r = -0.33), dyspnea score (r = -0.29), and consensus visual score (p = 0.0001). QLF scores provide an objective quantitative tool for assessing treatment efficacy in scleroderma-related interstitial lung disease. (orig.)

  5. Role of {sup 18}F-FDG PET-CT in monitoring the cyclophosphamide induced pulmonary toxicity in patients with breast cancer - 2 Case Reports

    Energy Technology Data Exchange (ETDEWEB)

    Taywade, Sameer Kamalakar; Kumar, Rakesh; Bhethanabhotla, Sainath; Bal, Chandrasekhar [A.I.I.M.S, New Delhi (India)

    2016-09-15

    Drug induced pulmonary toxicity is not uncommon with the use of various chemotherapeutic agents. Cyclophosphamide is a widely used chemotherapeutic drug in the treatment of breast cancer. Although rare, lung toxicity has been reported with cyclophosphamide use. Detection of bleomycin induced pulmonary toxicity and pattern of {sup 18}F-fluorodeoxyglucose ({sup 18}F-FDG) uptake in lungs on fluorodeoxyglucose positron emission tomography-computed tomography ({sup 18}F-FDG PET-CT) has been elicited in literature in relation to lymphoma. However, limited data is available regarding the role of {sup 18}F-FDG PET-CT in monitoring drug induced pulmonary toxicity in breast cancer. We here present two cases of cyclophosphamide induced drug toxicity. Interim {sup 18}F-FDG PET-CT demonstrated diffusely increased tracer uptake in bilateral lung fields in both these patients. Subsequently there was resolution of lung uptake on {sup 18}F-FDG PET-CT scan post completion of chemotherapy. These patients did not develop significant respiratory symptoms during chemotherapy treatment and in follow up.

  6. Effects of β-glucan polysaccharide revealed by the dominant lethal assay and micronucleus assays, and reproductive performance of male mice exposed to cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Rodrigo Juliano Oliveira

    2014-01-01

    Full Text Available β-glucan is a well-known polysaccharide for its chemopreventive effect. This study aimed to evaluate the chemopreventive ability of β-glucan in somatic and germ cells through the dominant lethal and micronucleus assays, and its influence on the reproductive performance of male mice exposed to cyclophosphamide. The results indicate that β-glucan is capable of preventing changes in DNA in both germ cells and somatic ones. Changes in germ cells were evaluated by the dominant lethal assay and showed damage reduction percentages of 46.46% and 43.79% for the doses of 100 and 150 mg/kg. For the somatic changes, evaluated by micronucleus assay in peripheral blood cells in the first week of treatment, damage reduction percentages from 80.63-116.32% were found. In the fifth and sixth weeks, the percentage ranged from 10.20-52.54% and -0.95-62.35%, respectively. Besides the chemopreventive efficiency it appears that the β-glucan, when combined with cyclophosphamide, is able to improve the reproductive performance of males verified by the significant reduction in rates of post-implantation losses and reabsorption in the mating of nulliparous females with males treated with cyclophosphamide.

  7. Topotecan plus cyclophosphamide as maintenance chemotherapy for children with high-risk neuroblastoma in complete remission: short-term curative effects and toxicity.

    Science.gov (United States)

    Feng, Chen; Tang, Suoqin; Wang, Jianwen; Liu, Ying; Yang, Guang

    2013-08-01

    To evaluate chemotherapy-related toxicity and the short-term efficacy of topotecan and cyclophosphamide as maintenance chemotherapy for stage IV neuroblastoma in complete remission. The clinical data of 16 children with stage IV neuroblastoma received 3 cycles of maintenance chemotherapy with topotecan (0.75 mg·m(-2)·day(-1), infused on days 0-4) and cyclophosphamide 250 mg·m(-2)·day(-1), infused on days 0-4). The two-year event-free survival after complete remission was recorded and the chemotherapy-related toxicities were evaluated according to the Common Terminology Criteria for Adverse Events of the National Cancer Institute. The most common chemotherapy-related toxicity was bone marrow suppression and suppressions of neutrophils, hemoglobin and platelets, which occurred in all the patients mostly of grade III and IV. All the patients experienced episodes of infections, which were controlled effectively with antibiotics. Impairment of gastrointestinal and liver functions in these cases was mostly mild (grade I and II) and recovered after corresponding treatments. None of the patients exhibited damages in the nervous system or the renal or cardiac functions. After complete remission, the two-year event-free survival rate of these patients was 68.75% (11/16). Topotecan plus cyclophosphamide for maintenance chemotherapy can be effective and relative safe for stage IV neuroblastoma in complete remission, thus giving a chance to those patients who choose not to have stem cell transplantation.

  8. Cyclophosphamide-based stem cell mobilization in relapsed multiple myeloma patients: A subgroup analysis from the phase III trial ReLApsE.

    Science.gov (United States)

    Baertsch, Marc-Andrea; Schlenzka, Jana; Lisenko, Katharina; Krzykalla, Julia; Becker, Natalia; Weisel, Katja; Noppeney, Richard; Martin, Hans; Lindemann, Hans W; Haenel, Mathias; Nogai, Axel; Scheid, Christof; Salwender, Hans; Fenk, Roland; Graeven, Ullrich; Reimer, Peter; Schmidt-Hieber, Martin; Goerner, Martin; Schmidt-Wolf, Ingo G H; Klein, Stefan; Ho, Anthony D; Goldschmidt, Hartmut; Wuchter, Patrick

    2017-07-01

    Analysis of the efficiency and toxicity of cyclophosphamide-based stem cell mobilization in patients with relapsed multiple myeloma (RMM). Peripheral blood stem cells (PBSCs) were mobilized with high dose cyclophosphamide (2 g/m2 daily on days 1 and 2) and G-CSF plus pre-emptive/rescue plerixafor in RMM patients (first to third relapse) treated within the ReLApsE trial of the German-Speaking Myeloma Multicenter Group (GMMG). Mobilization was initiated with high-dose cyclophosphamide (HD-CY) and G-CSF in 30 patients. Fifteen patients received additional pre-emptive/rescue administration of plerixafor. Stem cell collection was successful (≥2×106 CD34+ cells per kg bw) in 77% (23/30 patients). Patients with prior high-dose melphalan collected a significantly lower median total number of PBSCs than patients without prior high-dose melphalan (3.3×106 vs 17×106 CD34+ cells/kg bw). Toxicity of HD-CY was frequent with 12 serious adverse events (SAE) in 37% of patients (11/30 patients). Infections accounted for the majority of SAE reports. In two patients, SAEs were lethal (septic shock). These data proof feasibility of PBSC collection at relapse but emphasize the importance of collection and storage of additional PBSC transplants during first-line treatment when mobilization is more efficient and less toxic. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Cuscuta chinensis Ameliorates Immunosuppression and Urotoxic Effect of Cyclophosphamide by Regulating Cytokines - GM-CSF and TNF-Alpha.

    Science.gov (United States)

    Raju, Nidhi; Sakthivel, Kunnathur Murugesan; Kannan, Narayanan; Vinod Prabhu, Venugopal; Guruvayoorappan, Chandrasekaran

    2015-06-01

    Cancer is the leading cause of death worldwide. Cyclophosphamide (CTX) is commonly used as anticancer drug which causes toxicity by its reactive metabolites such as acroline and phosphoramide mustard. In this study, Cuscuta chinensis (C. chinensis) (family: Convolvulaceae) was assessed for ability to restore mice against CTX-induced toxicity. Coadministration of C. chinensis extract (10 mg/kg BW, IP, daily) for ten consecutive days reduced CTX-induced (25 mg/kg BW, IP, daily) toxicity. Treatment with C. chinensis extract significantly (p < 0.01) increased the relative organ weight and body weight. Moreover, administration of C. chinensis extract significantly increased bone marrow cellulatity and α-esterase activity in CTX-treated mice which suggested its protective role on the hematopoietic system. The GSH content was drastically reduced by CTX administration in urinary bladder which was enhanced by treatment with C. chinensis extract, indicating that preventing acroline-mediated tissue damage or cell toxicity and also the extract decreased the urinary bladder nitric oxide (NO) level which proves recovery over urinary tract injury associated with CTX treatment. The administration of C. chinensis extract decreased serum urea, creatinine, and bilirubin levels when compared to CTX-alone-treated group. Histopathological analysis of the urinary bladder of CTX-alone-treated group showed necrotic damage whereas the C. chinensis-treated group showed normal bladder architecture. The above data clearly demonstrates chemoprotective role of C. chinensis against CTX-induced toxicities by regulating antioxidant and inflammatory mediators.

  10. Enhancement of cyclophosphamide-induced antitumor effect by a novel polysaccharide from Ganoderma atrum in sarcoma 180-bearing mice.

    Science.gov (United States)

    Li, Wenjuan; Nie, Shaoping; Chen, Yi; Wang, Yuanxing; Li, Chang; Xie, Mingyong

    2011-04-27

    The aim of this study was to investigate the enhancement of Ganoderma atrum polysaccharide (PSG-1) on cyclophosphamide (CTX)-induced antitumor effect in sarcoma 180 (S-180)-bearing mice. Results showed that both CTX and PSG-1 delayed tumor growth and resulted in tumor apoptosis. The combined regimen was superior to either modality alone. Moreover, the combined treatment-induced apoptosis was mediated via mitochondrial pathway, as evidenced by alterations of Bcl-2 family proteins, loss of mitochondrial membrane potential (Δψ(m)), cytochrome c release, and caspases activation. Our results also showed that thymus and spleen indexes, lymphocytes proliferation, and concentrations of cytokine in the CTX group were decreased, which were alleviated by PSG-1. Additionally, the combined treatment ameliorated oxidative stress as compared with CTX alone. Taken together, we conclude that PSG-1 improved the antitumor effect of CTX, possibly in part mediated by enhancing the induction of apoptosis via mitochondrial pathways, activating host immune function, and modifying the redox system in S-180-bearing mice.

  11. Effects of whole body x-irradiation and cyclophosphamide treatment on induction of macrophage tumoricidal function in mice

    Energy Technology Data Exchange (ETDEWEB)

    Schultz, R.M.; Pavlidis, N.A.; Chirigos, M.A.; Weiss, J.F.

    1978-07-01

    The influence of whole-body x irradiation (200 to 800 R) and subcutaneous cyclophosphamide (CY) treatment (150 to 500 mg/kg) was studied on the ability of adjuvants to induce cytotoxic macrophages in vivo. Surprisingly, radiation or CY therapy alone produced growth inhibitory macrophages whose function peaked within 2 days after treatment. When adjuvants such as Bacillus Calmette Guerin (BCG), pyran copolymer, or glucan were administered ip within 2 hr after sublethal (600 R) x irradiation, adjuvant-induced cytotoxic function was depressed but not ablated. In addition, when noninduced peritoneal macrophages were obtained 6 days after lethal (800 R) x irradiation, their ability to be activated in vitro by lymphokine or fibroblast-derived interferon preparations was only slightly depressed at all concentrations of inducer tested. When BCG, pyran, or glucan was administered ip concurrently with sc CY treatment, only the ability of BCG to activate macrophages was markedly reduced, indicating separate mechanisms for the induction of tumoricidal macrophages. A better understanding of the interaction of chemotherapeutic and/or radiation regimens with adjuvants which affect macrophage function may be instrumental to rationalized immunotherapy protocols.

  12. Micronucleated Erythrocytes in Peripheral Blood from Neonate Rats Exposed by Breastfeeding to Cyclophosphamide, Colchicine, or Cytosine-Arabinoside

    Directory of Open Access Journals (Sweden)

    Belinda C. Gómez-Meda

    2016-01-01

    Full Text Available Genotoxic exposure to chemical substances is common, and nursing mothers could transmit harmful substances or their metabolites to their offspring through breast milk. We explored the possibility of determining genotoxic effects in the erythrocytes of breastfeeding rat pups whose mothers received a genotoxic compound while nursing. Ten groups of female rats and five pups per dam were studied. The control group received sterile water, and the experimental groups received one of three different doses of cyclophosphamide, colchicine, or cytosine-arabinoside. Blood smears were prepared from samples taken from each dam and pup every 24 h for six days. There were increased numbers of micronucleated erythrocytes (MNEs and micronucleated polychromatic erythrocytes (MNPCEs in the samples from pups in the experimental groups (P<0.02 and increased MNPCE frequencies in the samples from the dams (P<0.05. These results demonstrate the vertical transmission of the genotoxic effect of the compounds tested. In conclusion, assessing MNEs in breastfeeding neonate rats to assess DNA damage may be a useful approach for identifying genotoxic compounds and/or cytotoxic effects. This strategy could help in screening for therapeutic approaches that are genotoxic during the lactation stage and these assessments might also be helpful for developing preventive strategies to counteract harmful effects.

  13. Micronucleated Erythrocytes in Peripheral Blood from Neonate Rats Exposed by Breastfeeding to Cyclophosphamide, Colchicine, or Cytosine-Arabinoside

    Science.gov (United States)

    Bañales-Martínez, Luis R.; Lemus-Varela, María de Lourdes; Trujillo, Xóchitl; Sánchez-Parada, María G.; Armendáriz-Borunda, Juan; Zúñiga-González, Guillermo M.

    2016-01-01

    Genotoxic exposure to chemical substances is common, and nursing mothers could transmit harmful substances or their metabolites to their offspring through breast milk. We explored the possibility of determining genotoxic effects in the erythrocytes of breastfeeding rat pups whose mothers received a genotoxic compound while nursing. Ten groups of female rats and five pups per dam were studied. The control group received sterile water, and the experimental groups received one of three different doses of cyclophosphamide, colchicine, or cytosine-arabinoside. Blood smears were prepared from samples taken from each dam and pup every 24 h for six days. There were increased numbers of micronucleated erythrocytes (MNEs) and micronucleated polychromatic erythrocytes (MNPCEs) in the samples from pups in the experimental groups (P < 0.02) and increased MNPCE frequencies in the samples from the dams (P < 0.05). These results demonstrate the vertical transmission of the genotoxic effect of the compounds tested. In conclusion, assessing MNEs in breastfeeding neonate rats to assess DNA damage may be a useful approach for identifying genotoxic compounds and/or cytotoxic effects. This strategy could help in screening for therapeutic approaches that are genotoxic during the lactation stage and these assessments might also be helpful for developing preventive strategies to counteract harmful effects. PMID:28018917

  14. Potential urinary biomarkers of nephrotoxicity in cyclophosphamide-treated rats investigated by NMR-based metabolic profiling.

    Science.gov (United States)

    Lim, Sa Rang; Hyun, Sun-Hee; Lee, Seul Gi; Kim, Jin-Young; Kim, So-Hyun; Park, Sang-Jin; Moon, Kyoung-Sik; Sul, Donggeun; Kim, Dong Hyun; Choi, Hyung-Kyoon

    2017-03-01

    The anticancer-drug cyclophosphamide (CP) is known to have nephrotoxicity. The aim of this study was to identify urinary biomarkers indicating CP-induced nephrotoxicity. We investigated the urine metabolic profiles using nuclear magnetic resonance spectrometry of rats administered with single high-doses of CP (0, 30, and 100 mg/kg body weight) and daily low-doses over a 4-week period (0, 1, 3, and 10 mg/kg body weight). Among 18 identified urinary metabolites, 2-oxoglutarate, citrate, hippurate, formate, valine, and alanine for short-term and 2-oxoglutarate, citrate, hippurate, isoleucine, leucine, allantoin, valine, and lysine for long-term were selected as potential biomarkers. Pathway-enrichment analysis suggested that the urinary metabolism of CP is related to valine, leucine, and isoleucine biosynthesis; taurine and hypotaurine metabolism; glyoxylate and dicarboxylate metabolism; citrate cycle; and alanine, aspartate, and glutamate metabolism, with high pathway impact. The potential biomarkers obtained in this study could be used to monitor CP-induced nephrotoxicity relative to dose and treatment time. © 2016 Wiley Periodicals, Inc.

  15. The Quinovic Acid Glycosides Purified Fraction from Uncaria tomentosa Protects against Hemorrhagic Cystitis Induced by Cyclophosphamide in Mice

    Science.gov (United States)

    Dietrich, Fabrícia; Pietrobon Martins, Jerônimo; Kaiser, Samuel; Madeira Silva, Rodrigo Braccini; Rockenbach, Liliana; Albano Edelweiss, Maria Isabel; Ortega, George González; Morrone, Fernanda Bueno; Campos, Maria Martha; Battastini, Ana Maria Oliveira

    2015-01-01

    Uncaria tomentosa is widely used in folk medicine for the treatment of numerous diseases, such as urinary tract disease. Hemorrhagic cystitis (HE) is an inflammatory condition of the bladder associated with the use of anticancer drugs such as cyclophosphamide (CYP). Sodium 2-mercaptoethanesulfonate (Mesna) has been used to prevent the occurrence of HE, although this compound is not effective in established lesions. It has been demonstrated that the purinergic system is involved in several pathophysiological events. Among purinergic receptors, P2X7 deserves attention because it is involved in HE induced by CYP and, therefore, can be considered a therapeutic target. The objective of this study was to investigate the potential therapeutic effect of the quinovic acid glycosides purified fraction (QAPF) from U. tomentosa in the mouse model of CYP-induced HE. Pretreatment with QAPF not only had a protective effect on HE-induced urothelial damage (edema, hemorrhage and bladder wet weight) but was also able to control visceral pain, decrease IL-1β levels and down-regulates P2X7 receptors, most likely by inhibit the neutrophils migration to the bladder. This research clearly demonstrates the promising anti-inflammatory properties of QAPF, supporting its use as complementary therapy. QAPF represents a promising therapeutic option for this pathological condition. PMID:26154141

  16. Rituximab, cladribine and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial.

    Science.gov (United States)

    Robak, Tadeusz; Blonski, Jerzy; Skotnicki, Aleksander Bartłomiej; Piotrowska, Magdalena; Wróbel, Tomasz; Rybka, Justyna; Kłoczko, Janusz; Bołkun, Łukasz; Budziszewska, Bożena Katarzyna; Walczak, Urszula; Uss, Anatoly; Fidecka, Marta; Smolewski, Piotr

    2018-02-10

    PALG CLL4 is the first, randomized, phase IIIb study with cladribine, cyclophosphamide and rituximab (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients. The induction treatment consisted of six RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm. In the intention-to-treat population, 97 patients completed the induction phase with an overall response rate (ORR) of 73.2% (CR 22.7%, PR 50.5%). Subsequently, 66 patients were randomized into the rituximab maintenance arm (n=33) or the observational arm (n=33). CR rates were 57.1% in the maintenance group vs 50% in the observational group. PFS was significantly longer in the rituximab maintenance vs the observational arm (p=0.028). The multivariate Cox model indicated that del17p (p=0.006) and elevated beta-2-microglobulin (p=0.015) significantly increased the hazard ratio (HR) of progression, whereas the presence of CD38 (p=0.013) significantly decreased it; maintenance therapy with rituximab (pmaintenance therapy with rituximab in previously untreated patients with CLL. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  17. The Quinovic Acid Glycosides Purified Fraction from Uncaria tomentosa Protects against Hemorrhagic Cystitis Induced by Cyclophosphamide in Mice.

    Science.gov (United States)

    Dietrich, Fabrícia; Pietrobon Martins, Jerônimo; Kaiser, Samuel; Madeira Silva, Rodrigo Braccini; Rockenbach, Liliana; Albano Edelweiss, Maria Isabel; Ortega, George González; Morrone, Fernanda Bueno; Campos, Maria Martha; Battastini, Ana Maria Oliveira

    2015-01-01

    Uncaria tomentosa is widely used in folk medicine for the treatment of numerous diseases, such as urinary tract disease. Hemorrhagic cystitis (HE) is an inflammatory condition of the bladder associated with the use of anticancer drugs such as cyclophosphamide (CYP). Sodium 2-mercaptoethanesulfonate (Mesna) has been used to prevent the occurrence of HE, although this compound is not effective in established lesions. It has been demonstrated that the purinergic system is involved in several pathophysiological events. Among purinergic receptors, P2X7 deserves attention because it is involved in HE induced by CYP and, therefore, can be considered a therapeutic target. The objective of this study was to investigate the potential therapeutic effect of the quinovic acid glycosides purified fraction (QAPF) from U. tomentosa in the mouse model of CYP-induced HE. Pretreatment with QAPF not only had a protective effect on HE-induced urothelial damage (edema, hemorrhage and bladder wet weight) but was also able to control visceral pain, decrease IL-1β levels and down-regulates P2X7 receptors, most likely by inhibit the neutrophils migration to the bladder. This research clearly demonstrates the promising anti-inflammatory properties of QAPF, supporting its use as complementary therapy. QAPF represents a promising therapeutic option for this pathological condition.

  18. Omega-3 fatty acids are able to modulate the painful symptoms associated to cyclophosphamide-induced-hemorrhagic cystitis in mice.

    Science.gov (United States)

    Freitas, Raquel D S; Costa, Kesiane M; Nicoletti, Natália F; Kist, Luiza W; Bogo, Maurício R; Campos, Maria M

    2016-01-01

    This study investigated the effects of the long-term dietary fish oil supplementation or the acute administration of the omega-3 fatty acid docosahexaenoic acid (DHA) in the mouse hemorrhagic cystitis (HC) induced by the anticancer drug cyclophosphamide (CYP). HC was induced in mice by a single CYP injection (300mg/kg ip). Animals received four different diets containing 10% and 20% of corn or fish oil, during 21days. Separated groups received DHA by ip (1μmol/kg) or intrathecal (i.t.; 10μg/site) routes, 1h or 15min before CYP. The behavioral tests (spontaneous nociception and mechanical allodynia) were carried out from 1h to 6h following CYP injection. Bladder inflammatory changes, blood cell counts and serum cytokines were evaluated after euthanasia (at 6h). Immunohistochemistry analysis was performed for assessing spinal astrocyte and microglia activation or GPR40/FFAR1 expression. Either fish oil supplementation or DHA treatment (ip and i.t.) markedly prevented visceral pain, without affecting CYP-evoked bladder inflammatory changes. Moreover, systemic DHA significantly prevented the neutrophilia/lymphopenia caused by CYP, whereas this fatty acid did not significantly affect serum cytokines. DHA also modulated the spinal astrocyte activation and the GPR40/FFAR1 expression. The supplementation with fish oil enriched in omega-3 fatty acids or parenteral DHA might be interesting nutritional approaches for cancer patients under chemotherapy schemes with CYP. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Preventive measures for cyclophosphamide-related hemorrhagic cystitis in blood and bone marrow transplantation: an Italian multicenter retrospective study.

    Science.gov (United States)

    Gonella, Silvia; di Pasquale, Tania; Palese, Alvisa

    2015-02-01

    Hemorrhagic cystitis (HC) is a troublesome and potentially life-threatening complication of bone marrow transplantation (BMT). HC can appear within a few hours after chemotherapy or after weeks or months. Early-onset HC (EOHC) is usually associated with the conditioning regimen. The main aim of this study was to describe the incidence of EOHC in patients undergoing BMT regimens including high-dose cyclophosphamide (CY) and the effects of the main preventive measures adopted in Italian nursing practice. The authors retrospectively analyzed the clinical records of 158 Italian patients who underwent BMT from 2006-2008. Thirty-one patients (19.6%) developed EOHC. One hundred and forty-seven patients (93%) given high-dose CY were treated with hyperhydration combined with 2-mercaptoethane sulphonate (mesna) and diuresis alkalinization, and only 51 (32.3%) patients were preventively catheterized and received continuous bladder irrigation (CBI). By univariate analysis, prophylactic urethral catheterization and CBI did not decrease EOHC incidence questioning if these measures were to be routinely recommended. Previous studies showed increased discomfort and urinary tract infection in catheterized patients; therefore, nurses may fulfill an important role in balancing the benefits and harms of preventive catheterization and CBI in patients who received BMT conditioning including high-dose CY.

  20. Inhibitory effect of cyclophosphamide on the biosynthesis of a perchloro-soluble protein fraction of ehrlich ascites carcinoma cells

    Directory of Open Access Journals (Sweden)

    R. Raposo Abreu

    1973-01-01

    Full Text Available The perchloro-soluble mucroptotein fraction was determined in the cells of Ehrlich ascites carcinoma on the 10th and 12th days post-inoculation of the tumor. After 3 days of a single subcutaneous dose of cyclophosphamide (200 mg/kg the mucoprotein levels were found considerable lower. This difference was highly significant statistically.Foi determinada a fração mucoproteica percloro-solúvel nas células do carcinoma ascítico de Ehrlich, no 10º e 12º dias após a inoculação do tumor. Nos camundongos injetados com uma única dose subcutânea de ciclofosfamida (200 mg/kg os níveis desta fração foram encontrados consideravelmente mais baixos. A análise estatística demonstrou que as diferenças observadas entre os animais controles e os tratados com ciclofosfamida foram altamente significativas.

  1. Efficiency of Coleus aromaticus extract in modifying cyclophosphamide and mitomycin-C induced clastogenicity in mouse bone marrow cells.

    Science.gov (United States)

    Prasad, Shyama; Naik, Prashantha; Vijayalaxmi, K K

    2002-09-01

    The anticlastogenic potency of the ethanolic extract of a medicinal plant, C. aromaticus was investigated by taking bone marrow chromosomal aberration assay and micronucleus (MN) test as the test parameters. Swiss albino mice were fed orally with different doses (10,15, 25, 50 and 100 mg/kg body weight) of ethanolic extract for 7 days and on the 7th day, two doses each of anticancer drugs cyclophosphamide (CP; 25 and 50 mg/kg body weight) and mitomycin-C (MMC; 4 and 8 mg/kg body weight) were injected, ip, to different groups of animals. Bone marrow MN preparations were made at 24 and 48 hr time intervals. Coleus extract reduced CP and MMC induced MN and lower doses of the extract were found to be more effective than higher doses. The effective doses of extract in MN test were selected to study the anticlastogenic effects against CP (25 and 50 mg/kg body weight) and MMC (2 and 4 mg/kg body weight) induced chromosomal aberrations. The results indicate the protective effect of C. aromaticus against CP and MMC induced cytogenetic damage.

  2. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes.

    Science.gov (United States)

    Benjamini, Ohad; Jain, Preetesh; Trinh, Long; Qiao, Wei; Strom, Sara S; Lerner, Susan; Wang, Xuemei; Burger, Jan; Ferrajoli, Alessandra; Kantarjian, Hagop; O'Brien, Susan; Wierda, William; Estrov, Zeev; Keating, Michael

    2015-06-01

    Patients with chronic lymphocytic leukemia (CLL) are known to have an increased incidence of second cancers, but the contribution of commonly used frontline therapies to the incidence of second cancers is unclear. We report on the characteristics, incidence, outcomes and factors associated with second cancers in 234 patients receiving fludarabine, cyclophosphamide and rituximab (FCR) based regimens in the frontline setting. The risk of second cancers was 2.38 times higher than the expected risk in the general population. Ninety-three patients (40%) had other cancers before and 66 patients (28%) after FCR. Rates of therapy related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) were high, while solid tumors were not increased. Overall survival of patients with second cancers after frontline FCR was shorter (median of 4.5 years) compared to patients with and without prior cancers. Second cancer risk after frontline FCR is mainly due to high rates of t-AML/MDS and RT, and as speculated the survival of affected patients is shorter.

  3. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab).

    Science.gov (United States)

    Tam, Constantine S; O'Brien, Susan; Plunkett, William; Wierda, William; Ferrajoli, Alessandra; Wang, Xuemei; Do, Kim-Anh; Cortes, Jorge; Khouri, Issa; Kantarjian, Hagop; Lerner, Susan; Keating, Michael J

    2014-11-13

    Although fludarabine, cyclophosphamide, and rituximab (FCR) together are established as a standard first-line treatment of younger patients with chronic lymphocytic leukemia (CLL), there is little information to guide the management of patients with CLL refractory to, or who have relapsed after, receiving frontline FCR treatment. To define optimal salvage strategy and identify patients unsuitable for retreatment with FCR, we examined the survival and treatment outcome of 300 patients enrolled in a phase 2 study of FCR. After a median 142 months of follow-up, 156 patients developed progressive CLL, with a median survival of 51 months after disease progression. The duration of first remission (REM1) was a key determinant of survival after disease progression and first salvage. Patients with a short REM1 (<3 years) had a short survival period, irrespective of salvage therapy received; these patients have high unmet medical needs and are good candidates for investigation of novel therapies. In patients with a long REM1 (≥3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care. © 2014 by The American Society of Hematology.

  4. Crocin, a dietary colorant, mitigates cyclophosphamide-induced organ toxicity by modulating antioxidant status and inflammatory cytokines.

    Science.gov (United States)

    Jnaneshwari, Sadashivaiah; Hemshekhar, Mahadevappa; Santhosh, Martin Sebastin; Sunitha, Kabburahalli; Thushara, Rammohan; Thirunavukkarasu, Chinnasamy; Kemparaju, Kempaiah; Girish, Kesturu Subbaiah

    2013-04-01

    This study investigated the protective efficacy of crocin against hepatotoxicity induced by cyclophosphamide (CP) in Wistar rats. The experimental rats were treated with crocin orally at a dose of 10 mg/kg for 6 consecutive days after the administration of a single intraperitoneal dose of CP (150 mg/kg). The ameliorative effect of crocin on organ toxicity was studied by evaluating oxidative stress enzymes, inflammatory cytokines and histological sections. A single intraperitoneal CP injection significantly elevated endogenous reactive oxygen species and oxidation of lipids and proteins, which are the hallmarks of oxidative damage in liver and serum. In consequence, the primary defensive reduced glutathione, total thiol and antioxidant enzymes such as superoxide dismutase, catalase, glutathione-S-transferase and glutathione peroxidase, were significantly reduced. In addition, liver and serum aspartate aminotransferase and alanine aminotransferase along with acid and alkaline phosphatase were considerably increased. Oral administration of crocin significantly rejuvenated all the above altered markers to almost normal state. The protective efficacy of crocin was further supported by the histological assessment and restoration of CP-induced inflammatory cytokines and enzyme levels compared with the control drug. The results obtained suggest the protective nature of crocin against CP-induced oxidative damage/inflammation and organ toxicity. © 2013 The Authors. JPP © 2013. Royal Pharmaceutical Society.

  5. Efficacy of Scalp Cooling in Preventing Chemotherapy-Induced Alopecia in Breast Cancer Patients Receiving Adjuvant Docetaxel and Cyclophosphamide Chemotherapy.

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    Cigler, Tessa; Isseroff, Devora; Fiederlein, Barbara; Schneider, Sarah; Chuang, Ellen; Vahdat, Linda; Moore, Anne

    2015-10-01

    Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of many chemotherapy agents. The TC (docetaxel [Taxotere] and cyclophosphamide) chemotherapy regimen is typically associated with complete alopecia. Scalp cooling with cold caps has been reported to minimize or prevent CIA. We conducted a prospective study to assess efficacy of scalp cooling in preventing CIA among women receiving adjuvant TC chemotherapy for breast cancer. Women at the Weill Cornell Breast Center who independently elected to use scalp cooling with cold caps during adjuvant TC chemotherapy were asked to participate. Degree of hair loss was assessed by a single practitioner using Dean's alopecia scale (grade 1/excellent [ 75% hair loss]), by digital photographs, and by patient self-report of hair thinning or the need to wear a wig/head covering, or both. Assessments were made before each chemotherapy treatment and at follow-up visits between 3 weeks and 3 months after completion of chemotherapy. Of 20 evaluable patients, 10% reported a need to wear a wig/head covering at the follow-up visit. Dean's alopecia score was excellent for 65% of patients, good for 25% of patients, and moderate or poor for 10% of patients. The majority of patients reported hair thinning after every chemotherapy cycle. No patient discontinued therapy because of an intolerance to cold caps. Scalp cooling with cold caps appears to be effective in preventing CIA among the majority of women undergoing treatment with TC chemotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. An ethanol extract of Origanum vulgare attenuates cyclophosphamide-induced pulmonary injury and oxidative lung damage in mice.

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    Shokrzadeh, Mohammad; Ahmadi, Amirhossein; Chabra, Aroona; Naghshvar, Farshad; Salehi, Fatemeh; Habibi, Emran; Haghi-Aminjan, Hamed

    2014-10-01

    Injury to normal tissues is the major limiting side effect of using cyclophosphamide (CP), an antineoplastic alkylating compound. This study was undertaken to evaluate the protective effect of an extract of Origanum vulgare L. (Lamiaceae), an antioxidative medicinal plant, against CP-induced oxidative lung damage in mice. Mice were pre-treated with various doses of O. vulgare extract (50, 100, 200, and 400 mg/kg) for 7 consecutive days followed by an injection with CP (200 mg/kg b.w.) One hour after the injection of O. vulgare on the last day, mice were injected with CP; 24 h later, they were euthanized, their lungs were immediately removed, and biochemical and histological studies were conducted. A single dose of CP markedly altered the levels of several biomarkers associated with oxidative stress in lung homogenates. Pretreatment with O. vulgare significantly reduced the levels of lipid peroxidation and attenuated the alterations in glutathione content and superoxide dismutase activity induced by CP in lung tissue. In addition, O. vulgare effectively alleviated CP-induced histopathological changes in lung tissue. Our results revealed that O. vulgare protects lung tissues from CP-induced pulmonary damage and suggest a role for oxidative stress in the pathogenesis of lung disease produced by CP. Because O. vulgare has been extensively used as an additive agent and is regarded as safe, it may be used concomitantly as a supplement for reducing lung damage in patients undergoing chemotherapy.

  7. The Mitigating Effect of Citrullus colocynthis (L. Fruit Extract against Genotoxicity Induced by Cyclophosphamide in Mice Bone Marrow Cells

    Directory of Open Access Journals (Sweden)

    Mohammad Shokrzadeh

    2013-01-01

    Full Text Available Possible genoprotective effect of Citrullus colocynthis (L. (CCT fruits extract against cyclophosphamide- (CP-induced DNA damage in mice bone marrow cells was evaluated using micronucleus assay, as an index of induced chromosomal damage. Mice were preadministered with different doses of CCT via intraperitoneal injection for 7 consecutive days followed by injection with CP (70 mg/kg b.w. 1 hr after the last injection of CCT. After 24 hr, mice were scarified to evaluate the frequency of micronucleated polychromatic erythrocytes (MnPCEs. In addition, the number of polychromatic erythrocytes (PCEs among 1000 normochromatic erythrocytes (NCEs per animal was recorded to evaluate bone marrow. Pretreatment with CCT significantly reduced the number of MnPCEs induced by CP in bone marrow cells (P<0.0001. At 200 mg/kg, CCT had a maximum chemoprotective effect and reduced the number of MnPCEs by 6.37-fold and completely normalized the mitotic activity. CCT also led to marked proliferation and hypercellularity of immature myeloid elements after mice were treated with CP and mitigated the bone marrow suppression. Our study revealed that CCT has an antigenotoxic effect against CP-induced oxidative DNA damage in mice. Therefore, it could be used concomitantly as a supplement to protect people undergoing chemotherapy.

  8. Effects of lactoferrin on IL-6 production by peritoneal and alveolar cells in cyclophosphamide-treated mice.

    Science.gov (United States)

    Artym, J; Zimecki, M; Kruzel, M L

    2004-04-01

    Previous studies have shown that oral treatment with lactoferrin (LF) restores the immune response in cyclophosphamide (CP) immunocompromised mice. The aim of the present investigation was to determine the regulatory ability of LF on the production of interleukin 6 (IL-6) in peritoneal and alveolar cells, derived from CP-treated mice. CBA mice were injected with a single, intraperitoneal (i.p.) dose of CP (350 mg/kg body weight) followed by LF administered in drinking water (0.5% solution) for 21 days. The control counterparts were given water. Peritoneal and alveolar cells were isolated from mice and the production of IL-6, both spontaneous and lipopolysaccharide (LPS) induced, was determined in 24h cell cultures using a bioassay. The results showed increased production of IL-6 in both CP-treated mice and in mice given, in addition, LF. The administration of LF alone led also to an increase in IL-6 production by the cell cultures. Intravenous (i.v.) administration of LPS resulted in a significant increase in IL-6 serum levels in CP and CP/LF but not in LF-treated mice. Analysis of cell type composition in the peritoneal cavity revealed a strong increase in mastocyte and neutrophil content in CP and CP/LF-treated groups. Our findings suggest that enhanced IL-6 production in CP and CP/LF-treated mice may contribute to reconstitution of immune system function in immunocompromised mice.

  9. Ethanolic extract of Moringa oleifera Lam. leaves protect the pre-pubertal spermatogonial cells from cyclophosphamide-induced damage.

    Science.gov (United States)

    Nayak, Guruprasad; Honguntikar, Sachin D; Kalthur, Sneha Guruprasad; D'Souza, Antony Sylvan; Mutalik, Srinivas; Setty, Manjunath M; Kalyankumar, Raksha; Krishnamurthy, Hanumanthappa; Kalthur, Guruprasad; Adiga, Satish Kumar

    2016-04-22

    Moringa oleifera Lam. is widely cultivated in Asian and African countries for its medicinal and dietary significance. The leaves are highly nutritious and are known to possess various biological activities. Pre-pubertal Swiss albino male mice were injected with single dose of cyclophosphamide (CP, 200mg/kg body weight) or ethanolic extract of Moringa oleifera leaves (MOE, 100mg/kg body weight) intraperitoneally. In combination group, MOE was administered 24h prior to CP injection. CP induced a significant decrease in testicular weight (p<0.01) and depletion of germ cells (p<0.001) and higher level of DNA damage (p<0.001) compared to control. The expression of P53, Bax, Cytochrome C (Cyt C) was increased while there was a decrease in the expression of Bcl2, c-Kit and Oct4. Administration of MOE 24h prior to CP treatment ameliorated the depletion (p<0.001), DNA damage (p<0.001) and apoptosis (p<0.01) of germ cells induced by CP. The mitigating effect of MOE appears to be mediated by up-regulating the expression of c-Kit and Oct4 transcripts in P53-independent manner. MOE protects the spermatogonial cells from CP-induced damage by modulating the apoptotic response elicited by CP and therefore can be considered as an efficient method of male fertility preservation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Sperm abnormalities induced by pre-pubertal exposure to cyclophosphamide are effectively mitigated by Moringa oleifera leaf extract.

    Science.gov (United States)

    Nayak, G; Vadinkar, A; Nair, S; Kalthur, S G; D'Souza, A S; Shetty, P K; Mutalik, S; Shetty, M M; Kalthur, G; Adiga, S K

    2016-03-01

    Moringa oleifera L. is a medicinal plant with potential antioxidant property. This study was aimed at investigating the chemoprotective effect of Moringa oleifera leaf extract (MOE) on cyclophosphamide (CP)-induced testicular toxicity. Two-week-old male Swiss albino mice were intraperitoneally injected with phosphate-buffered saline, 50 mg kg(-1) of CP and 25 mg kg(-1) of MOE. In combination treatment, mice were injected with 25 mg kg(-1) of MOE 24 h prior to CP injection, 24 h prior and post-CP injection and 24 h post-CP injection for 5 consecutive days (10 mg kg(-1) ). Six weeks later, mice were sacrificed to assess epididymal sperm parameters. MOE alone did not have any significant effect on sperm parameters. However, acute injection of CP resulted in significant decline in motility (P < 0.001), increase in head abnormality (P < 0.01) and DNA damage (P < 0.05). Combining MOE with CP increased the sperm density, motility and reduced head defect and DNA damage, irrespective of the schedule and dosage of MOE. Administration of MOE prior to CP significantly elevated the level of superoxide dismutase and catalase with concomitant decrease in lipid peroxidation in the testicular tissue. In conclusion, MOE may have potential benefit in reducing the loss of male gonadal function following chemotherapy. © 2015 Blackwell Verlag GmbH.

  11. Evaluation of immunostimulant activity and chemoprotective effect of mangrove Rhizophora apiculata against cyclophosphamide induced toxicity in BALB/c mice.

    Science.gov (United States)

    Vinod Prabhu, V; Guruvayoorappan, C

    2012-08-01

    Chemotherapeutic drugs available today are immunosuppressant, cytotoxic and with variety of side effects in cancer chemotherapy. Plant based immunomodulators are often an auxiliary therapy to overcome the repulsive effects of cytotoxic chemotherapeutic agents and to restore immunity with normal health. Mangroves Rhizophora apiculata (R. apiculata) extract was found to protect mice from cyclophosphamide (CTX) induced leukopenia. The leukocyte counts in the R. apiculata extract treated animals was significantly increased (10425 ± 163 mm³) where the control group shows no significant increase (7855 ± 282 mm³). The leukocytes count in CTX induced group treated with R. apiculata extract shows significant increase (5235 ± 303 mm³) when compared with CTX induced group (3416 ± 172 mm³) on the same day. The hemoglobin level of CTX induced group treated with R. apiculata extract shows increase in the level compared with the CTX induced animals. The bone marrow cellularity and α-esterase activity was also significantly higher compared to normal group and CTX induced group. Moreover, R. apiculata extract prevented the loss of organ weight and is increased the organ weight in treated animals. This indicates the efficiency of R. apiculata extract as an effective immunostimulant and better chemoprotectant against CTX induced toxicity in BALB/c mice.

  12. Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARγ and abrogation of oxidative stress and inflammation.

    Science.gov (United States)

    Mahmoud, Ayman M

    2014-09-01

    The most important reason for the non-approval and withdrawal of drugs by the Food and Drug Administration is hepatotoxicity. Therefore, this study was undertaken to evaluate the protective effects of hesperidin against cyclophosphamide (CYP)-induced hepatotoxicity in Wistar rats. The rats received a single intraperitoneal dose of CYP of 200 mg/kg body mass, followed by treatment with hesperidin, orally, at doses of 25 and 50 mg/kg for 11 consecutive days. CYP induced hepatic damage, as evidenced by the significantly elevated levels of serum pro-inflammatory cytokines, serum transaminases, liver lipid peroxidation, and nitric oxide. As a consequence, there was reduced glutathione content, and the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, were markedly reduced. In addition, CYP administration induced a considerable downregulation of peroxisome proliferator activated receptor gamma (PPARγ) and upregulation of nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) mRNA expression. Hesperidin, in a dose-dependent manner, rejuvenated the altered markers to an almost normal state. In conclusion, hesperidin showed a potent protective effect against CYP-induced oxidative stress and inflammation leading to hepatotoxicity. The study suggests that hesperidin exerts its protective effect against CYP-induced hepatotoxicity through upregulation of hepatic PPARγ expression and abrogation of inflammation and oxidative stress.

  13. The Quinovic Acid Glycosides Purified Fraction from Uncaria tomentosa Protects against Hemorrhagic Cystitis Induced by Cyclophosphamide in Mice.

    Directory of Open Access Journals (Sweden)

    Fabrícia Dietrich

    Full Text Available Uncaria tomentosa is widely used in folk medicine for the treatment of numerous diseases, such as urinary tract disease. Hemorrhagic cystitis (HE is an inflammatory condition of the bladder associated with the use of anticancer drugs such as cyclophosphamide (CYP. Sodium 2-mercaptoethanesulfonate (Mesna has been used to prevent the occurrence of HE, although this compound is not effective in established lesions. It has been demonstrated that the purinergic system is involved in several pathophysiological events. Among purinergic receptors, P2X7 deserves attention because it is involved in HE induced by CYP and, therefore, can be considered a therapeutic target. The objective of this study was to investigate the potential therapeutic effect of the quinovic acid glycosides purified fraction (QAPF from U. tomentosa in the mouse model of CYP-induced HE. Pretreatment with QAPF not only had a protective effect on HE-induced urothelial damage (edema, hemorrhage and bladder wet weight but was also able to control visceral pain, decrease IL-1β levels and down-regulates P2X7 receptors, most likely by inhibit the neutrophils migration to the bladder. This research clearly demonstrates the promising anti-inflammatory properties of QAPF, supporting its use as complementary therapy. QAPF represents a promising therapeutic option for this pathological condition.

  14. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951.

    Science.gov (United States)

    De Moerloose, Barbara; Suciu, Stefan; Bertrand, Yves; Mazingue, Françoise; Robert, Alain; Uyttebroeck, Anne; Yakouben, Karima; Ferster, Alice; Margueritte, Geneviève; Lutz, Patrick; Munzer, Martine; Sirvent, Nicolas; Norton, Lucilia; Boutard, Patrick; Plantaz, Dominique; Millot, Frederic; Philippet, Pierre; Baila, Liliana; Benoit, Yves; Otten, Jacques

    2010-07-08

    The European Organisation for Research and Treatment of Cancer 58951 trial for children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) addressed 3 randomized questions, including the evaluation of dexamethasone (DEX) versus prednisolone (PRED) in induction and, for average-risk patients, the evaluation of vincristine and corticosteroid pulses during continuation therapy. The corticosteroid used in the pulses was that assigned at induction. Overall, 411 patients were randomly assigned: 202 initially randomly assigned to PRED (60 mg/m(2)/d), 201 to DEX (6 mg/m(2)/d), and 8 nonrandomly assigned to PRED. At a median follow-up of 6.3 years, there were 19 versus 34 events for pulses versus no pulses; 6-year disease-free survival (DFS) rate was 90.6% (standard error [SE], 2.1%) and 82.8% (SE, 2.8%), respectively (hazard ratio [HR] = 0.54; 95% confidence interval, 0.31-0.94; P = .027). The effect of pulses was similar in the PRED (HR = 0.56) and DEX groups (HR = 0.59) but more pronounced in girls (HR = 0.24) than in boys (HR = 0.71). Grade 3 to 4 hepatic toxicity was 30% versus 40% in pulses versus no pulses group and grade 2 to 3 osteonecrosis was 4.4% versus 2%. For average-risk patients treated according to Berlin-Frankfurt-Muenster-based protocols, pulses should become a standard component of therapy.

  15. A randomized double blind control trial comparing filgrastim and pegfilgrastim in cyclophosphamide peripheral blood hematopoietic stem cell mobilization.

    Science.gov (United States)

    Kuan, Jew-Win; Su, Anselm-Ting; Wong, Shu-Ping; Sim, Xavier Yoon-Han; Toh, See-Guan; Ong, Tee-Chuan; Rajasuriarr, Jay-Suria; Lim, Su-Hong; Guan, Yong-Khee; Liew, Hong-Keng; Liew, Pek-Kuen; Tan, Jerome Tsen-Chuen; Kori, Ahlam-Naila; Cheng, Yuin-Yin; Tan, Sen-Mui; Chang, Kian-Meng

    2015-10-01

    There are few randomized trials comparing filgrastim and pegfilgrastim in peripheral blood stem cell mobilization (PBSCM). None of the trials studied the effects of the timing of pegfilgrastim administration on the outcomes of mobilization. We conducted a randomized triple blind control trial comparing the outcomes of filgrastim 5 µg/kg daily from day 3 onwards, 'early' pegfilgrastim 6 mg on day 3 and 'delayed' pegfilgrastim 6 mg on day 7 in cyclophosphamide PBSCM in patients with no previous history of mobilization. Peripheral blood (PB) CD34+ cell count was checked on day 8 and day 11 onward. Apheresis was started when PB CD34+ ≥ 10/µl from day 11 onward. The primary outcome was the successful mobilization rate, defined as cumulative collection of ≥ 2 × 10(6)/kg CD34+ cells in three or less apheresis. The secondary outcomes were the day of neutrophil and platelet engraftment post transplantation. There were 156 patients randomized and 134 patients' data analyzed. Pegfilgrastim 6 mg day 7 produced highest percentage of successful mobilization, 34 out of 48 (70.8%) analyzed patients, followed by daily filgrastim, 28 out of 44 (63.6%) and day 3 pegfilgrastim, 20 out of 42 (47.6%) (p = 0.075). Pegfilgrastim day 7 and daily filgrastim reported 1.48 (p = 0.014) and 1.49 (p = 0.013) times higher successful mobilization rate respectively as compared to pegfilgrastim day 3 after adjusting for disease, gender and exposure to myelotoxic agent. Multiple myeloma patients were three times more likely to achieve successful mobilization as compared to acute leukemia or lymphoma patients. Pegfilgrastim avoided the overshoot of white cells compared to filgrastim. There was no difference in the duration of both white cells and platelet recovery post transplantation between the three interventional arms. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Pharmacological and histopathological study of cyclophosphamide-induced hemorrhagic cystitis - comparison of the effects of dexamethasone and Mesna

    Directory of Open Access Journals (Sweden)

    M.M. Morais

    1999-10-01

    Full Text Available Chemotherapy with oxazaphosphorines, such as cyclophosphamide (CYP, is often limited by unacceptable urotoxicity. Without uroprotection, hemorrhagic cystitis (HC becomes dose-limiting. To compare the uroprotective efficacy of classical 2-mercaptoethanesulfonic acid (Mesna treatment with dexamethasone in CYP-induced HC, male Wistar rats (150-200 g; N = 6 in each group were treated with saline or Mesna (40 mg/kg, ip immediately and 4 and 8 h after ip administration of CYP (200 mg/kg. One, 2 or 3 doses of Mesna were replaced with dexamethasone (1 mg/kg, ip. The animals were sacrificed 24 h later. Cystitis was evaluated by determining the changes in bladder wet weight (BWW and by macroscopic and microscopic analysis. CYP treatment induced a marked increased in BWW (162%, P<0.05, which was significantly inhibited by treatment with 3 doses of Mesna (P<0.05; 80%. The replacement of 1 or 2 doses of Mesna with dexamethasone reduced the increase in BWW by 83.3 and 95%, respectively. Macroscopic analysis of the bladder of rats with CYP-induced HC showed severe edema and hemorrhage, confirmed by microscopic analysis, that also showed mucosal erosion, inflammatory cell infiltration and ulcerations. The replacement of 1 or 2 doses of Mesna with dexamethasone inhibited the CYP-induced increase in BWW and almost abolished the macroscopic and microscopic alterations, with no significant difference between the effects of Mesna and dexamethasone, indicating that both drugs were efficient in blocking HC. However, although the replacement of all Mesna doses with dexamethasone reduced the edema, it did not prevent HC, suggesting that Mesna is necessary for the initial uroprotection.

  17. Protective Effect of Thymoquinone against Cyclophosphamide-Induced Hemorrhagic Cystitis through Inhibiting DNA Damage and Upregulation of Nrf2 Expression.

    Science.gov (United States)

    Gore, Prashant R; Prajapati, Chaitali P; Mahajan, Umesh B; Goyal, Sameer N; Belemkar, Sateesh; Ojha, Shreesh; Patil, Chandragouda R

    2016-01-01

    Cyclophosphamide (CYP) induced hemorrhagic cystitis is a dose-limiting side effect involving increased oxidative stress, inflammatory cytokines and suppressed activity of nuclear factor related erythroid 2-related factor (Nrf2). Thymoquinone (TQ), an active constituent of Nigella sativa seeds, is reported to increase the expression of Nrf2, exert antioxidant action, and anti-inflammatory effects in the experimental animals. The present study was designed to explore the effects of TQ on CYP-induced hemorrhagic cystitis in Balb/c mice. Cystitis was induced by a single intraperitoneal injection of CYP (200 mg/kg). TQ was administered intraperitoneally at 5, 10 and 20 mg/kg doses twice a day, for three days before and three days after the CYP administration. The efficacy of TQ was determined in terms of the protection against the CYP-induced histological perturbations in the bladder tissue, reduction in the oxidative stress, and inhibition of the DNA fragmentation. Immunohistochemistry was performed to examine the expression of Nrf2. TQ protected against CYP-induced oxidative stress was evident from significant reduction in the lipid peroxidation, restoration of the levels of reduced glutathione, catalase and superoxide dismutase activities. TQ treatment significantly reduced the DNA damage evident as reduced DNA fragmentation. A significant decrease in the cellular infiltration, edema, epithelial denudation and hemorrhage were observed in the histological observations. There was restoration and rise in the Nrf2 expression in the bladder tissues of mice treated with TQ. These results confirm that, TQ ameliorates the CYP-induced hemorrhagic cystitis in mice through reduction in the oxidative stress, inhibition of the DNA damage and through increased expression of Nrf2 in the bladder tissues.

  18. Hemostatic Efficacy and Histopathological Effects of Ankaferd Blood Stopper in an Experimental Rat Model of Cyclophosphamide-induced Hemorrhagic Cystitis.

    Science.gov (United States)

    Kilic, Ozcan; Akand, Murat; Karabagli, Pinar; Piskin, Mehmet Mesut

    2016-08-01

    To evaluate the hemostatic efficacy and histopathological effects of Ankaferd Blood Stopper (ABS) in an experimental rat model of cyclophosphamide-induced (CYP) hemorrhagic cystitis (HC). Forty male Sprague-Dawley rats were included in the study. Firstly, 10 rats were divided equally into 2 groups where the first group was administered only an intraperitoneal (i.p.) injection of normal saline to constitute the negative control group (CON). The remaining 5 rats were administered only a single i.p. injection of CYP (without any further treatment) for induction of HC to constitute the positive control group (HC). Subsequently, the remaining 30 rats, which also received i.p. CYP for induction of HC, were divided into 3 groups to which intravesical saline (SAL group), epinephrine (EPN group), and ABS (ANK group) were administered for 3 consecutive days. Ten days after the third instillation, cystectomy was performed for histopathological examination. Specimens were evaluated for presence of congestion, edema, necrosis, ulceration, and regenerated epithelium, and scores were given for each parameter according to the severity. No statistically significant difference was observed for congestion, edema, necrosis, and ulceration between HC-SAL, and also between CON-ANK groups (all P values >.05). There was a significant difference for total scores between EPN and ANK groups (P = .009). There was statistically significant difference for regenerating epithelium between CON-EPN, CON-ANK, HC-ANK, and SAL-ANK groups. Intravesical administration of ABS is at least as efficacious as EPN in terms of congestion, edema, necrosis, and ulceration. Moreover, ABS can be considered as a better option in inducing regenerating epithelium than EPN. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Oral glutamine attenuates cyclophosphamide-induced oxidative stress in the bladder but does not prevent hemorrhagic cystitis in rats.

    Science.gov (United States)

    Abraham, Premila; Isaac, Bina; Ramamoorthy, Hemalatha; Natarajan, Kasthuri

    2011-06-01

    Cyclophosphamide (CP) is widely used in the treatment of cancer and non-malignant disease states such as rheumatoid arthritis. Hemorrhagic cystitis is a major dose-limiting side effect of CP. The incidence of this side effect is related to the dosage and can be as high as 75%. Elimination of the side effects of CP can lead to better tolerance of the drug, and a more efficient therapy can be achieved for patients in need of CP treatment. Several studies have demonstrated that oxidative stress and neutrophil infiltration play important roles in CP-induced bladder damage. Glutamine is utilized under clinical conditions for preventing chemotherapeutic drug-induced side effects, based on its ability to attenuate oxidative stress. The aim of the study is to verify whether glutamine prevents CP-induced oxidative stress and bladder damage using a rat model. Adult male rats were administered 150 mg/kg body weight of CP intraperitoneally. Glutamine pretreated rats were administered 1 g/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 urinary bladders were removed and used for light microscopic and biochemical studies. The markers of oxidative stress including malondialdehyde content, protein carbonyl content, protein thiol, and myeloperoxidase activity, a marker of neutrophil infiltration, were measured in bladder homogenates. CP treatment induced hemorrhagic cystitis in the rats. Pretreatment with glutamine significantly reduced CP-induced lipid peroxidation (p hemorrhagic cystitis, although it prevents CP-induced oxidative stress and neutrophil infiltration significantly. It is therefore necessary to clarify the utility of glutamine as a chemoprotective agent before it is recommended in the market as a nutrient supplement.

  20. Protective Effect of Carvacrol Against Oxidative Stress and Heart Injury in Cyclophosphamide-Induced Cardiotoxicity in Rat

    Directory of Open Access Journals (Sweden)

    Songul Cetik

    2015-08-01

    Full Text Available Possible protective effects of carvacrol (Car against cyclophosphamide (CP-induced cardiotoxicity was examined in this study. Experimental groups of the rats were randomly divided into 13 groups,each including seven animals: Group 1 (control treated with saline; groups 2, 3, and 4 treated with 50, 100, or 150 mg/kg of CP, respectively; group 5 treated with 0.5 mL olive oil; groups 6 and 7 treated with 5.0 and 10 mg/kg of Car, respectively; groups 8, 9, or 10 treated with respective CP plus 5.0 mg/kg of Car; and groups 11, 12, or 13 treated with respective CP plus 10 mg/kg of Car. Serum alanine transaminase (ALT,aspartat transaminase (AST, lactate dehydrogenase (LDH, malondialdehyde (MDA,creatine kinase-MB (CK-MB, total oxidant state (TOS, oxidative stress index (OSI, and levels were high only in the CP groups. There was a dose-dependence on the CP-induced cardiotoxicity. Hemorrhage, inflammatory cell infiltration and the separation of the muscle fibers in the heart tissue supported the biochemical data. With 5.0 and 10 mg/kg Car, there was an important decrease in the CP toxicity and this was related to the oxidative and nitrosative stress in the CP-induced cardiotoxicity. Reduced inflammation and lipid peroxidation in the heart tissue and increase of serum glutathione (GSH and total antioxidant capacity (TAS levels were found when carvacrol was applied. Based on these findings, it could be proposed that Car was a strong candidate in preventing the CP-induced cardiotoxicity but further clinical studies should be done in order to verify its application on humans.

  1. Immunostimulant and chemoprotective effect of vivartana, a polyherbal formulation against cyclophosphamide induced toxicity in swiss albino mice.

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    Gnanasekaran, Sadhana; Sakthivel, Kunnathur Murugesan; Chandrasekaran, Guruvayoorappan

    2017-09-01

    The aim of the study is to develop a technology for cost effective immunomodulator from natural products to combat adverse effects during cancer chemotherapy. In the present study, the immunomodulatory efficacy of Vivartana, a poly herbal formulation in immunosuppressed animal model induced by cyclophosphamide (CTX) and its comparison with standard herbal immunostimulators Chyawanprash and Brahma Rasayana was investigated. The effect of Vivartana (500 mg/kg.bw) (p.o.), Chyawanprash (20 mg/kg.bw) (p.o.) and Brahma Rasayana (20 mg/kg.bw) (p.o.) on hematological parameters, relative organ weight, Bone marrow cellularity and α-esterase activity were determined in Swiss albino mice by using the standard methods. Among the herbal formulations Vivartana showed the maximum number of leukocytes (13150 cells/mm3) on the 15th day. The leukocyte count in Vivartana treated CTX induced group shows significant increase (5375 cells/mm3) when compared with CTX alone induced group (3358 cells/mm3) on the same day. The Vivartana treated CTX induced group shows increase in the hemoglobin level compared with the CTX induced group. Moreover, Vivartana treatment prevented the loss of organ weight in the CTX induced group by the enhancement of spleenocytes on the 7th day and thymocytes on the 11th day. Similarly the lowered bone marrow cellularity and number of α-esterase positive cells in CTX induced group were restored in the Vivartana treatment. Treatment with vivartana also exhibits hepatoprotective activity by regulating the SGOT and SGPT levels in CTX induced group. The study indicates that Vivartana has the considerable potential as an immunostimulant and chemoprotectant against CTX induced immunosuppression in Swiss albino mice.

  2. Comparison of voiding function and nociceptive behavior in two rat models of cystitis induced by cyclophosphamide or acetone

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    Saitoh, Chikashi; Yokoyama, Hitoshi; Chancellor, Michael B.; de Groat, William C.; Yoshimura, Naoki

    2009-01-01

    Aims Nociceptive behavior and its relationship with bladder dysfunction were investigated in two cystitis models, which were induced by intraperitoneal (ip) injection of cyclophosphamide (CYP) or intravesical instillation of acetone, using freely moving, non-catheterized conscious rats. Methods Female Sprague-Dawley rats were used. Cystitis was induced by ip injection of CYP (100 and 200mg/kg) or intravesical instillation of acetone (10, 30 and 50%) via a polyethylene catheter temporarily inserted into the bladder through the urethra. Then the incidence of nociceptive behavior (immobility with decreased breathing rates) was scored. Voided urine was collected simultaneously and continuously to measure bladder capacity. The plasma extravasation in the bladder was quantified by an evans blue (EB) dye leakage technique. Results CYP (100mg/kg, ip) induced nociceptive behavior without affecting bladder capacity or EB concentration in the bladder. A higher dose of CYP (200mg/kg, ip) decreased bladder capacity and increased EB levels as well as nociceptive behavior. In contrast, intravesical instillation of acetone (30%) decreased bladder capacity and increased EB levels, but evoked nociceptive behavior less frequently compared with CYP-treated animals. In capsaicin pretreated rats, nociceptive behavior induced by CYP or acetone was reduced; however, the overall effects of CYP or acetone on bladder capacity and bladder EB levels were unaffected. Conclusions These results suggest that there is a difference in the induction process of nociceptive behavior and small bladder capacity after two different types of bladder irritation and that C-fiber sensitization is more directly involved in pain sensation than reduced bladder capacity. PMID:19618450

  3. Genoprotective effects of Origanum vulgare ethanolic extract against cyclophosphamide-induced genotoxicity in mouse bone marrow cells.

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    Habibi, Emran; Shokrzadeh, Mohammad; Ahmadi, Amirhossein; Chabra, Aroona; Naghshvar, Farshad; Keshavarz-Maleki, Razieh

    2015-01-01

    Cyclophosphamide (CP), an alkylating chemotherapeutic agent, can bind DNA, causing chromosome breaks, micronucleus (Mn) formation, and cell death. Because Origanum vulgare L. (Lamiaceae) has antioxidative properties, it might protect against DNA damage. The genoprotective effect of O. vulgare ethanolic extract against CP-induced genotoxicity in mouse bone marrow cells was evaluated using a Mn assay. Mice were pre-treated with aerial parts of O. vulgare ethanolic extract at different doses (50, 100, 200, or 400 mg/kg) for 7 d. One hour after the last administration of O. vulgare, animals were injected with CP at 200 mg/kg. After 24 h, the bone marrow cells of both femurs were flushed and the frequency of MnPCEs was evaluated to measure the chromosomal damages. In addition, the number of PCEs per 1000 NCEs in each animal was recorded to evaluate the bone-marrow suppression; mitotic activity was calculated as [PCE/(PCE + NCE)] × 100 to assess the cell division. At 400 mg/kg, O. vulgare displayed its maximum protective effect, reduced the number of MnPCEs from 10.52 ± 1.07 for CP group to 2.17 ± 0.26 and completely normalized the mitotic activity (p Origanum vulgare also led to significant proliferation and hypercellularity of immature myeloid elements after the mice were treated with CP, mitigating the bone marrow suppression. Origanum vulgare ethanolic extract exerts a potent genoprotective effect against CP-induced genotoxicity in mice bone marrow, which might be possibly due to the scavenging of free radicals during oxidative stress conditions.

  4. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial.

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    Brown, Jennifer R; O'Brien, Susan; Kingsley, C Daniel; Eradat, Herbert; Pagel, John M; Lymp, James; Hirata, Jamie; Kipps, Thomas J

    2015-04-30

    Obinutuzumab is a type 2, glycoengineered, anti-CD20 antibody recently approved with chlorambucil for the initial therapy of chronic lymphocytic leukemia (CLL). In this nonrandomized, parallel-cohort, phase 1b, multicenter study, we explored the safety and preliminary efficacy of obinutuzumab-bendamustine (G-B) or obinutuzumab fludarabine cyclophosphamide (G-FC) for the therapy of previously untreated fit patients with CLL. Patients received up to 6 cycles of G-B (n = 20) or G-FC (n = 21). The primary end point was safety, with infusion-related reactions (88%, grade 3-4 20%) being the most common adverse event and grade 3-4 neutropenia in 55% on G-B and 48% on G-FC. Mean cycles completed were 5.7 for G-B and 5.1 for G-FC, with 2 and 7 early discontinuations, respectively. The objective response rate (ORR) for G-B was 90% (18/20) with 20% complete response (CR) and 25% CR with incomplete marrow recovery (CRi). The ORR for G-FC was 62% (13/21), with 10% CR and 14% CRi, including 4 patients not evaluable. With a median follow-up of 23.5 months in the G-B cohort and 20.7 months in the G-FC cohort, no patient has relapsed or died. We conclude that obinutuzumab with either B or FC shows manageable toxicity and has promising activity. This study was registered at www.clinicaltrials.gov as #NCT01300247. © 2015 by The American Society of Hematology.

  5. Immune function in cyclophosphamide-treated mice is restored by the T-cell-tropic isoxazole derivative R-13.

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    Zimecki, Michał; Artym, Jolanta; Kocięba, Maja; Obmińska-Mrukowicz, Bożena; Mączyński, Marcin; Ryng, Stanisław

    2015-01-01

    Reconstitution of the immune function in chemotherapy patients will lead to decreases in post-operative complications. A preliminary investigation showed that an isoxazole derivative R-13 (3,5-dimethyl-isoxazole[5,4-e]8H-triazepin-4-one) hydrochloride, given in a single oral dose to normal mice, induced significant increases in the content of CD4(+) cells in the spleens and lymph nodes. That observation prompted the authors to assess the immune reconstituting effects of R-13 in mice pre-treated with cyclophosphamide (CP). Mice were given intraperitoneally (IP) a sublethal dose of CP (200 mg/kg) and then R-13 (as 20 µg IP doses, every 3 days post-CP treatment). Control mice, not treated with CP, received R-13 or the vehicle (DMSO in appropriate dilution). Blood leukocyte and splenocyte numbers, blood cell type levels, splenocyte spontaneous and ConA-induced proliferation, and delayed-type hypersensitivity (DTH) to ovalbumin (OVA) were investigated on day 15 post-CP treatment and five R-13 doses. The humoral immune response (antibody-forming cell development to sheep erythrocytes) was measured 30 days post-CP treatment and 10 R-13 doses. In CP-treated mice, five dosings with R-13 led to increases in numbers of splenocytes and blood leukocytes, as well as in spontaneous and ConA-induced splenocyte proliferation, relative to levels in mice that received only CP 15 days earlier. Blood analysis revealed decreases in neutrophil and eosinophil contents and an increased appearance of lymphocyte immature forms in all mice that received the R-13. Both cell-mediated responses to OVA and humoral immune response to sheep erythrocytes in CP-treated hosts were restored. Based on the data here, it is concluded that R-13 may be of potential value for reconstitution of the immune function of chemotherapy patients.

  6. Protective effect of gonadotropin-releasing hormone analog on the ovarian reserve in rats receiving cyclophosphamide treatment

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    Gui T

    2015-03-01

    Full Text Available Ting Gui,1,* Guangwen Yuan,2,* Keng Shen,1 Dongyan Cao,1 Jiaxin Yang,1 Ming Wu,1 Jinghe Lang11Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, 2Department of Gynecologic Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People’s Republic of China*These authors contributed equally to this workObjective: The aim of the study reported here was to investigate the protective effect of gonadotropin-releasing hormone analog (GnRHa against cyclophosphamide (CTX-induced gonadotoxicity.Methods: Eighty Fischer 344 rats were divided randomly into four groups (20 per group. One group received normal saline, one GnRHa, one CTX, and one GnRHa+CTX. Several parameters were used to observe the ovarian reserve, including ovary weight, follicle number and diameter, concentrations of estradiol (E2 and follicle-stimulating hormone (FSH, and expressions of sex hormone receptors.Results: When treatment was finished, the number of small follicles in the GnRHa+CTX group was significantly higher than in the CTX-alone group. Thirty days after treatment, the ovary weight, percentage of small follicles, mean follicular diameter, and serum concentrations of E2 and FSH in the GnRHa+CTX group all recovered, approaching normal levels. Sex hormone receptors did not show significant differences between the four groups.Conclusion: Combination treatment with GnRHa could prevent CTX-induced damage to ovarian reserve.Keywords: gonadotoxicity, ovarian reserve, GnRHa, CTX, premature ovarian failure

  7. Protective effect of mirtazapine and hesperidin on cyclophosphamide-induced oxidative damage and infertility in rat ovaries.

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    Khedr, Naglaa Fathi

    2015-12-01

    Cyclophosphamide (CP) causes infertility due to ovarian toxicity. The toxicity mechanism suggests oxidative stress. We assessed whether mirtazapine (MTZ) and hesperidin (HSP) could promote ovarian protection against damage due to CP chemotherapy. Female Wistar rats aged 14 weeks were used. Animals were divided into four groups: control vehicle group (n = 8); CP group (n = 8, rats received 150 mg/kg of CP, single intraperitoneal [i.p.] injection); CP + MTZ group (n = 8, rats received same dose of CP + 30 mg/kg of MTZ, orally, daily); and HSP + CP group (n = 8, rats received same dose of CP + 100 mg/kg of HSP, orally, daily). After eight days of medication, ovaries were removed and ovarian toxicity was assessed by counting follicles and corpora lutea. Nitric oxide (NO) and malondialdehyde (MDA) levels, myeloperoxidase (MPO), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities were estimated in ovarian tissue. NO level, MDA level, and MPO activity were increased (P < 0.001), while, GPx and SOD activities were lowered significantly (P < 0.001) in CP-treated group compared with control vehicle. In addition, ovulation, number of follicles, and ovarian weight were reduced by CP treatment. On the contrary, rats pretreated with MTZ and HSP showed significant decrease in NO, MDA levels, and MPO activity, while, activities of SOD and GPx were increased (P < 0.001). Oxidative stress induced by CP in the rat ovary causes infertility in the female rats. HSP and MTZ could reverse this effect and provide protection of fertility against CP-induced toxicity. © 2015 by the Society for Experimental Biology and Medicine.

  8. Uso da ciclofosfamida em modelo de imunodepressão experimental em ovinos Ovine experimental immunosuppression using cyclophosphamide

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    Maurício Garcia

    2004-09-01

    Full Text Available A ciclofosfamida (CY foi usada para avaliar o efeito no sistema imune de ovinos. Carneiros adultos castrados foram divididos em 3 grupos, com 6 animais cada. Os Grupos I (dia 0 e II (dia 1 foram tratados com a CY (40 mg/kg, dose única, IV, e o Grupo III não foi tratado, permanecendo como controle. Todos os grupos foram imunizados no dia 0 com a vacina B19 contra a brucelose. No dia 6, todos animais foram sangrados e foi realizado o teste de soro-aglutinação para detecção de anticorpos anti-brucella. Foram também realizadas, diariamente durante 7 dias, contagens de linfócitos sangüíneos e dosagens de gamaglobulinas séricas por eletroforese. Os resultados encontrados mostraram uma diminuição estatística da resposta imune. Foram encontrados, nos Grupos I e II, baixos títulos de anticorpos anti-brucella, além de linfopenia e hipogamaglo-bulinemia. Uma alta mortalidade (40% foi encontrada nos animais tratados.Cyclophosphamide (CY was used to evaluate the effect on the immune system of sheep. Castred adult rams were divided into 3 groups, with 6 animals each one. Group I (day 0 and Group II (day 1 were treated with CY (40 mg/kg, single dose, IV, and Group III was not treated and remained as control. All groups were immunized on day 0 with B19 brucellosis vaccine. On day 6, all animals were bled and serum agglutination test for brucellosis antibodies detection was performed. During 7 days blood lymphocyte counts and electrophoresis gammaglobulin dosage were daily performed. The results showed statistical decrease of immune response. Low serum titers of brucellosis antibodies were found in Groups I and II, and lymphopenia and hypogammaglobulinemia were also found in these groups. A high mortality rate (40% occurred in the treated animals.

  9. Protective effect of enterosgel on rat liver lysosomes during cytostatic treatment.

    Science.gov (United States)

    Grek, O R; Mishenina, S V; Pupyshev, A B

    2002-10-01

    Polychemotherapy with a complex of cytostatics (cyclophosphamide, doxorubicin, vincristine, prednisolone) induces progressive damage to hepatocyte membranes, which manifested in labilization of lysosomes and activation of lysosomal enzymes and serum transaminases. Enterosgel stabilized liver lysosomes and reduced manifestation of hepatocyte cytolysis.

  10. Novel Combination Chemotherapy for Localized Ewing Sarcoma

    Science.gov (United States)

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

  11. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS).

    Science.gov (United States)

    Hájek, R; Masszi, T; Petrucci, M T; Palumbo, A; Rosiñol, L; Nagler, A; Yong, K L; Oriol, A; Minarik, J; Pour, L; Dimopoulos, M A; Maisnar, V; Rossi, D; Kasparu, H; Van Droogenbroeck, J; Yehuda, D B; Hardan, I; Jenner, M; Calbecka, M; Dávid, M; de la Rubia, J; Drach, J; Gasztonyi, Z; Górnik, S; Leleu, X; Munder, M; Offidani, M; Zojer, N; Rajangam, K; Chang, Y-L; San-Miguel, J F; Ludwig, H

    2017-01-01

    This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

  12. Involvement of interleukin-6-regulated nitric oxide synthase in hemorrhagic cystitis and impaired bladder contractions in young rats induced by acrolein, a urinary metabolite of cyclophosphamide.

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    Wang, Ching-Chia; Weng, Te-I; Wu, En-Ting; Wu, Mei-Hwan; Yang, Rong-Sen; Liu, Shing-Hwa

    2013-01-01

    Hemorrhagic cystitis is a common complication in children receiving cyclophosphamide, a chemotherapeutic alkylating agent. Acrolein is a urinary metabolite from cyclophosphamide and can induce hemorrhagic cystitis. Here, we investigated the effects and mechanisms of acrolein by intravesical instillation on urinary bladder muscle contractions and pathological alterations in rats. Acrolein instillation significantly increased the muscle contractions of rat bladder detrusor after 1 and 6 h but markedly decreased detrusor contractions after 24 h. Acrolein increased phosphorylated protein kinase C (pan-PKC) expressions in bladders after 1 and 6 h but inhibited it after 24 h. Inducible nitric oxide (NO) synthase (iNOS) protein expressions were markedly induced in bladders 24 h after acrolein treatment. Twenty-four-hour acrolein instillation increased the levels of nitrite/nitrate and interleukin-6 (IL-6) in the urinary bladder. The iNOS inhibitors significantly inhibited the acrolein-increased nitrite/nitrate levels, but not IL-6 levels. IL-6-neutralizing antibodies effectively inhibited the acrolein-increased NOx levels. The increased detrusor contractions by 1-h acrolein treatment were significantly reversed by the PKC inhibitor RO32-0432, and the decreased detrusor contractions by 24-h acrolein treatment were significantly reversed by the iNOS inhibitor and IL-6-neutralizing antibody. Both the iNOS inhibitor and IL-6-neutralizing antibody effectively reversed the increased iNOS expression, decreased PKC phosphorylation, increased bladder weight, and hemorrhagic cystitis in rats 24 h after acrolein treatment. Taken together, these results suggest that an IL-6-regulated iNOS/NO signaling pathway participates in the acrolein-triggered detrusor contraction inhibition and hemorrhagic cystitis. These findings may help us to find a new strategy to treat cyclophosphamide-induced hemorrhagic cystitis.

  13. Non-invasive Imaging of Sendai Virus Infection in Pharmacologically Immunocompromised Mice: NK and T Cells, but not Neutrophils, Promote Viral Clearance after Therapy with Cyclophosphamide and Dexamethasone.

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    Mostafa, Heba H; Vogel, Peter; Srinivasan, Ashok; Russell, Charles J

    2016-09-01

    In immunocompromised patients, parainfluenza virus (PIV) infections have an increased potential to spread to the lower respiratory tract (LRT), resulting in increased morbidity and mortality. Understanding the immunologic defects that facilitate viral spread to the LRT will help in developing better management protocols. In this study, we immunosuppressed mice with dexamethasone and/or cyclophosphamide then monitored the spread of viral infection into the LRT by using a noninvasive bioluminescence imaging system and a reporter Sendai virus (murine PIV type 1). Our results show that immunosuppression led to delayed viral clearance and increased viral loads in the lungs. After cessation of cyclophosphamide treatment, viral clearance occurred before the generation of Sendai-specific antibody responses and coincided with rebounds in neutrophils, T lymphocytes, and natural killer (NK) cells. Neutrophil suppression using anti-Ly6G antibody had no effect on infection clearance, NK-cell suppression using anti-NK antibody delayed clearance, and T-cell suppression using anti-CD3 antibody resulted in no clearance (chronic infection). Therapeutic use of hematopoietic growth factors G-CSF and GM-CSF had no effect on clearance of infection. In contrast, treatment with Sendai virus-specific polysera or a monoclonal antibody limited viral spread into the lungs and accelerated clearance. Overall, noninvasive bioluminescence was shown to be a useful tool to study respiratory viral progression, revealing roles for NK and T cells, but not neutrophils, in Sendai virus clearance after treatment with dexamethasone and cyclophosphamide. Virus-specific antibodies appear to have therapeutic potential.

  14. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

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    Vogel Ulla

    2010-08-01

    Full Text Available Abstract Background The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment. Methods Data was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion, *6, and CYP2D6 gene duplication. Results In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. Conclusion There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome.

  15. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951

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    Suciu, Stefan; Bertrand, Yves; Mazingue, Françoise; Robert, Alain; Uyttebroeck, Anne; Yakouben, Karima; Ferster, Alice; Margueritte, Geneviève; Lutz, Patrick; Munzer, Martine; Sirvent, Nicolas; Norton, Lucilia; Boutard, Patrick; Plantaz, Dominique; Millot, Frederic; Philippet, Pierre; Baila, Liliana; Benoit, Yves; Otten, Jacques

    2010-01-01

    The European Organisation for Research and Treatment of Cancer 58951 trial for children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) addressed 3 randomized questions, including the evaluation of dexamethasone (DEX) versus prednisolone (PRED) in induction and, for average-risk patients, the evaluation of vincristine and corticosteroid pulses during continuation therapy. The corticosteroid used in the pulses was that assigned at induction. Overall, 411 patients were randomly assigned: 202 initially randomly assigned to PRED (60 mg/m2/d), 201 to DEX (6 mg/m2/d), and 8 nonrandomly assigned to PRED. At a median follow-up of 6.3 years, there were 19 versus 34 events for pulses versus no pulses; 6-year disease-free survival (DFS) rate was 90.6% (standard error [SE], 2.1%) and 82.8% (SE, 2.8%), respectively (hazard ratio [HR] = 0.54; 95% confidence interval, 0.31-0.94; P = .027). The effect of pulses was similar in the PRED (HR = 0.56) and DEX groups (HR = 0.59) but more pronounced in girls (HR = 0.24) than in boys (HR = 0.71). Grade 3 to 4 hepatic toxicity was 30% versus 40% in pulses versus no pulses group and grade 2 to 3 osteonecrosis was 4.4% versus 2%. For average-risk patients treated according to Berlin-Frankfurt-Muenster–based protocols, pulses should become a standard component of therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728. PMID:20407035

  16. Effects of low dose pre-irradiation on hepatic damage and genetic material damage caused by cyclophosphamide.

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    Yu, H-S; Song, A-Q; Liu, N; Wang, H

    2014-01-01

    Cyclophosphamide (CTX) can attack tumour cells, but can also damage the other cells and microstructures of an organism at different levels, such as haematopoietic cells, liver cells, peripheral lymphocyte DNA, and genetic materials. Low dose radiation (LDR) can induce general adaptation reaction. In this study, we explore the effects of low dose radiation on hepatic damage and genetic material damage caused by CTX. Mice were implanted subcutaneously with S180 cells in the left groin (control group excluded). On days 8 and 11, mice of the LDR and LDR+CTX groups were given 75 mGy of whole-body γ-irradiation; whereas mice of the CTX and LDR+CTX groups were injected intraperitoneally with 3.0 mg of CTX. All mice were sacrificed on day 13. DNA damage of the peripheral lymphocytes, alanine aminotransferase (ALT) activity, total protein (TP), albumin (ALB) of the plasma, malonyl-dialdheyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity of the hepatic homogenate, and micronucleus frequency (MNF) of polychromatoerythrocytes in the bone marrow were analysed. The control group had the lowest MDA content and the highest SOD and GSH-PX activity, whereas the CTX group had the highest MDA content and the lowest SOD and GSH-PX activity. Compared with the CTX group, the MDA content decreased significantly (p 0.05). Pre-chemotherapeutic LDR can induce the activities of anti-oxidative enzymes and promote the elimination of free radicles to alleviate the damaging effects of oxidative stress to hepatic tissue caused by high-dose CTX. At the same time, LDR has no obvious effect on the ALT activity of plasma, but may have protective effect on the protein synthesis function of the liver. High-dose CTX chemotherapy can cause DNA damage of peripheral lymphocytes; however, LDR before chemotherapy may have certain protective effect on DNA damage. Moreover, CTX has potent mutagenic effect; however, LDR may have no protective effect against the genetic

  17. Impact of rituximab on immunoglobulin concentrations and B cell numbers after cyclophosphamide treatment in patients with ANCA-associated vasculitides.

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    Nils Venhoff

    Full Text Available OBJECTIVE: To assess the impact of immunosuppressive therapy with cyclophosphamide (CYC and rituximab (RTX on serum immunoglobulin (Ig concentrations and B lymphocyte counts in patients with ANCA-associated vasculitides (AAVs. METHODS: Retrospective analysis of Ig concentrations and peripheral B cell counts in 55 AAV patients. RESULTS: CYC treatment resulted in a decrease in Ig levels (median; interquartile range IQR from IgG 12.8 g/L (8.15-15.45 to 9.17 g/L (8.04-9.90 (p = 0.002, IgM 1.05 g/L (0.70-1.41 to 0.83 g/L (0.60-1.17 (p = 0.046 and IgA 2.58 g/L (1.71-3.48 to 1.58 g/L (1-31-2.39 (p = 0.056 at a median follow-up time of 4 months. IgG remained significantly below the initial value at 14.5 months and 30 months analyses. Subsequent RTX treatment in patients that had previously received CYC resulted in a further decline in Ig levels from pre RTX IgG 9.84 g/L (8.71-11.60 to 7.11 g/L (5.75-8.77; p = 0.007, from pre RTX IgM 0.84 g/L (0.63-1.18 to 0.35 g/L (0.23-0.48; p<0.001 and from pre RTX IgA 2.03 g/L (1.37-2.50 to IgA 1.62 g/L (IQR 0.84-2.43; p = 0.365 14 months after RTX. Treatment with RTX induced a complete depletion of B cells in all patients. After a median observation time of 20 months median B lymphocyte counts remained severely suppressed (4 B-cells/µl, 1.25-9.5, p<0.001. Seven patients (21% that had been treated with CYC followed by RTX were started on Ig replacement because of severe bronchopulmonary infections and serum IgG concentrations below 5 g/L. CONCLUSIONS: In patients with AAVs, treatment with CYC leads to a decline in immunoglobulin concentrations. A subsequent RTX therapy aggravates the decline in serum immunoglobulin concentrations and results in a profoundly delayed B cell repopulation. Surveying patients with AAVs post CYC and RTX treatment for serum immunoglobulin concentrations and persisting hypogammaglobulinemia is warranted.

  18. Probucol Attenuates Cyclophosphamide-induced Oxidative Apoptosis, p53 and Bax Signal Expression in Rat Cardiac Tissues

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    Yousif A. Asiri

    2010-01-01

    Full Text Available Cyclophosphamide (CP is a widely used drug in cancer chemotherapy and immunosuppression, which could cause toxicity of the normal cells due to its toxic metabolites. Probucol, a cholesterol-lowering drug, acts as potential inhibitor of DNA damage and shows to protect against doxorubicin-induced cardiomyopathy by enhancing the endogenous antioxidant system including glutathione peroxidase, catalase and superoxide dismutase. This study examined the possible protective effects of probucol, a lipid-lowering compound with strong antioxidant properties, against CPinduced cardiotoxicity. This objective could be achieved through studying the gene expression-based on the possible protective effects of probucol against CP-induced cardiac failure in rats. Adult male Wistar albino rats were assigned into four treatment groups: Animals in the first (control and second (probucol groups were injected intraperitoneally with corn oil and probucol (61 mg/kg/day, respectively, for two weeks. Animals in the third (CP and fourth (probucol plus CP groups were injected with the same doses of corn oil and probucol (61 mg/kg/day, respectively, for one week before and one week after a single dose of CP (200 mg/kg, I.P.. The p53, Bax, Bcl2 and oxidative genes signal expression were measured by real time PCR. CP-induced cardiotoxicity was clearly observed by a significant increase in serum creatine phosphokinase isoenzyme (CK-MB (117%, lactate dehydrogenase (LDH (64%, free (69% and esterified cholesterol (42% and triglyceride (69% compared to control group. In cardiac tissues, CP significantly increases the mRNA expression levels of apoptotic genes, p53 with two-fold and Bax with 1.6-fold, and decreases the anti-apoptotic gene Bcl2 with 0.5-fold. Moreover, CP caused downregulation of antioxidant genes, glutathione peroxidase, catalase, and superoxide dismutase and increased the lipid peroxidation and decreased adenosine triphosphate (ATP (40% and ATP/ADP (44% in cardiac

  19. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer

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    Orlando Laura

    2006-09-01

    Full Text Available Abstract Background HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX and methotrexate (MTX in metastatic breast cancer (MBC. Methods Between April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week and CTX (50 mg daily (CM. Results The 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts, and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts, liver (14 pts, bone (12 pts, lymph nodes (8 pts, central nervous system (CNS (9 pts. We observed 4 partial remission (PR (18%, 95% CI 5–40%, 10 stable disease (SD (46%, 95% CI 24–68%, and 8 PD (36%, CI 17–59%. The clinical benefit (RP plus RC plus SD for ≥ 24 weeks in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24–68% and 27% (95% CI, 6–61%, respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively. Overall clinical toxicity was generally mild. Grade ≥2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively. Conclusion The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this

  20. Antitumor activity of mixed heat shock protein/peptide vaccine and cyclophosphamide plus interleukin-12 in mice sarcoma

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    Sui Xiang

    2011-02-01

    Full Text Available Abstract Background The immune factors heat shock protein (HSP/peptides (HSP/Ps can induce both adaptive and innate immune responses. Treatment with HSP/Ps in cancer cell-bearing mice and cancer patients revealed antitumor immune activity. We aimed to develop immunotherapy strategies by vaccination with a mixture of HSP/Ps (mHSP/Ps, HSP60, HSP70, Gp96 and HSP110 enhanced with cyclophosphamide (CY and interleukin-12 (IL-12. Methods We extracted mHSP/Ps from the mouse sarcoma cell line S180 using chromatography. The identity of proteins in this mHSP/Ps was assayed using SDS-PAGE and Western blot analysis with antibodies specific to various HSPs. BALB/C mice bearing S180 cells were vaccinated with mHSP/Ps ×3, then were injected intraperitoneally with low-dose CY and subcutaneously with IL-12, 100 μg/day, ×5. After vaccination, T lymphocytes in the peripheral blood were analyzed using FACScan and Cytotoxicity (CTL was analyzed using lactate dehydrogenase assay. ELISPOT assay was used to evaluate interferon γ (IFN-γ, and immune cell infiltration in tumors was examined in the sections of tumor specimen. Results In mice vaccinated with enhanced vaccine (mHSP/Ps and CY plus IL-12, 80% showed tumor regression and long-term survival, and tumor growth inhibition rate was 82.3% (30 days, all controls died within 40 days. After vaccination, lymphocytes and polymorphonuclear leukocytes infiltrated into the tumors of treated animals, but no leukocytes infiltrated into the tumors of control mice. The proportions of natural killer cells, CD8+, and interferon-γ-secreting cells were all increased in the immune group, and tumor-specific cytotoxic T lymphocyte activity was increased. Conclusions In this mice tumor model, vaccination with mHSP/Ps combined with low-dose CY plus IL-12 induced an immunologic response and a marked antitumor response to autologous tumors. The regimen may be a promising therapeutic agent against tumors.

  1. Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia in Ukraine

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    Mandrik O

    2015-08-01

    Full Text Available Olena Mandrik,1 Isaac Corro Ramos,2 Saskia Knies,1,3 Maiwenn Al,1,2 Johan L Severens1,2 1Institute of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, the Netherlands; 2Institute of Medical Technology Assessment (iMTA, Erasmus University Rotterdam, Rotterdam, the Netherlands; 3National Health Care Institute, Diemen, the Netherlands Abstract: The aim of this study was to assess the cost-effectiveness, from a health care perspective, of adding rituximab to fludarabine and cyclophosphamide scheme (FCR versus FC for treatment-naïve and refractory/relapsed Ukrainian patients with chronic lymphocytic leukemia. A decision-analytic Markov cohort model with three health states and 1-month cycle time was developed and run within a life time horizon. Data from two multinational, prospective, open-label Phase 3 studies were used to assess patients' survival. While utilities were generalized from UK data, local resource utilization and disease-associated treatment, hospitalization, and side effect costs were applied. The alternative scenario was performed to assess the impact of lower life expectancy of the general population in Ukraine on the incremental cost-effectiveness ratio (ICER for treatment-naïve patients. One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the robustness of the results. The ICER (in US dollars of treating chronic lymphocytic leukemia patients with FCR versus FC is US$8,704 per quality-adjusted life year gained for treatment-naïve patients and US$11,056 for refractory/relapsed patients. When survival data were modified to the lower life expectancy of the general population in Ukraine, the ICER for treatment-naïve patients was higher than US$13,000. This value is higher than three times the current gross domestic product per capita in Ukraine. Sensitivity analyses have shown a high impact of rituximab costs and a moderate impact of differences in utilities on the ICER

  2. Resistance to the induction of EAE in AO rats: its prevention by the pre-treatment with cyclophosphamide or low dose of irradiation

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    Mostarica-Stojkovic, M.; Petrovic, M.; Lukic, M.L. (Belgrade Univ. (Yugoslavia). Medicinski Fakultet; Inst. for Biological Research, Belgrade (Yu). Lab. for Cellular Immunology)

    1982-11-01

    Susceptibility to the induction of experimental allergic encephalomyelitis (EAE) was compared in AO, DA and Lewis strain of rats. As evaluated by clinical and histological criteria, AO rats exhibited significantly lower susceptibility to EAE induced with guinea-pig spinal cord (GPSC) tissue and complete resistance to the encephalitogenic challenge with rat myelin basic protein (BP) irrespective of antigen dose and adjuvant used. AO rats pre-treated with BP + Freund's incomplete adjuvant became completely unresponsive to the induction of EAE with GPSC + Freund's complete adjuvant (FCA) indicating that they do possess cells sensitive to some antigenic determinants of rat BP. In order to test whether the resistance to EAE is due to an active suppression, low dose of irradiation (300 rad) and cyclophosphamide (20 mg/kg) was applied prior to the induction of EAE. Selective depletion of radiosensitive cells facilitated the induction of EAE. Similarly cyclophosphamide given 2 days prior to BP + FCA completely abrogated the resistance to EAE induction. Thus, it appears that the inability of BP + FCA to produce EAE in AO rats is due to the disproportionate activation of suppressor cells.

  3. Inhibition of cyclophosphamide-induced oxidative stress in rat brain by polar and non-polar extracts of Annatto (Bixa orellana) seeds.

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    Oboh, Ganiyu; Akomolafe, Toyin L; Adefegha, Stephen A; Adetuyi, Abayomi O

    2011-03-01

    Annatto (Bixa orellana) seeds are widely distributed throughout the Tropics and have been used to provide both colour and flavour to food. This study sought to assess the ability of dietary inclusion of polar (water) and non-polar (chloroform) extracts of Annatto (B. orellana) seeds on cyclophosphamide-induced oxidative stress in rat brain. The total phenol content and antioxidant activities of polar (water) and non-polar (chloroform) extracts of Annatto seeds were determined in vitro and in vivo. The results of the study showed that intraperitoneal administration of cyclophosphamide (75 mg/kg of body weight) caused a significant increase (Pnon-polar extract had significantly higher inhibitory effects on the elevated MDA production in brain and serum liver function markers. This higher protective effect of the non-polar extract could be attributed to its higher antioxidant properties as typified by its significantly higher (Pnon-polar extract is a better protectant. Copyright © 2010 Elsevier GmbH. All rights reserved.

  4. Phase I/II clinical trial of encapsulated, cytochrome P450 expressing cells as local activators of cyclophosphamide to treat spontaneous canine tumours.

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    Monika Michałowska

    Full Text Available Based upon promising preclinical studies, a clinical trial was performed in which encapsulated cells overexpressing cytochrome P450 enzyme isoform 2B1 were implanted around malignant mammary tumours arising spontaneously in dogs. The dogs were then given cyclophosphamide, one of the standard chemotherapeutic agents used for the treatment of mammary tumours. The dogs were assessed for a number of clinical parameters as well as for reduction in tumour size. The treatment was well tolerated with no evidence of adverse reactions or side effects being associated with the administration of the encapsulated cells. Reductions in tumour size of more than 50% were observed for 6 out of the 11 tumours analysed while 5 tumours showing minor responses, i.e. stable disease. In contrast, the tumours that received cyclophosphamide alone showed only stable disease. Taken together, this data suggests that encapsulated cytochrome P450 expressing cells combined with chemotherapy may be useful in the local treatment of a number of dog mammary tumours and support the performance of further clinical studies to evaluate this new treatment.

  5. A case report of treating a high-risk gestational trophoblastic disease (GTD

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    Zhi Hao Liew

    2017-12-01

    Full Text Available Background: GTD developing after a normal pregnancy is reported in 25% of patients and it is usually choriocarcinoma. It occurs in approximately 5 per 100,000 pregnancies in Southeast Asia. Case: A 34 year-old Malay lady, gravida 4 para 4+0 presented with vaginal bleeding in two weeks after the delivery of her fourth child who was born as full term through LSCS. She admitted to hospital and underwent Suction and curettage. The histopathology came back as choriocarcinoma. On post-op day 7, she developed massive hemoperitoneum due to uterine perforation caused by tumour rupture. Therefore, total abdominal hysterectomy was performed. Post-surgery serum beta hCG was 209,320 IU/L. Thyroid function test was normal. Histopathology examination revealed choriocarcinoma at the fundus with haemorrhagic necrotic areas, infiltrating myometrial wall and right fallopian tube stump with serosal breach. CT imaging showed normal brain and multiple bilateral lung nodules in upper and lower lobes. She was given first cycle of EMA-CO (Etoposide, Methotrexate, Actinomycin D, Vincristine, Cyclophosphamid in view of high-risk choriocarcinoma with lungs metastasis, stage III with WHO prognostic scoring 11. Her pre-chemotherapy beta hCG was 263,753 IU/L which gradually went down and became less than 0.1 after cycle-5. CT scan was also normal. After that, another two more cycles of chemotherapy were proceeded. Therefore, she has completed seven cycles of chemotherapy in March 2016. She has been monitored under oncology follow-up for one year. Monthly βhCG was always normal until now without signs and symptoms of recurrence. Conclusion: Generally, high-risk GTDs are resistant to single agent chemotherapy and multiple chemotherapy regimens are necessary. Although this patient is a case of choriocarcinoma having high risk features, such as antecedent full-term pregnancy and pre-treatment beta-hCG of 263,753 IU/L (more than 100,000, she gained complete remission after seven

  6. Effect of the administration time of HS6101 on hematopoietic recovery in ICR mice injured by cyclophosphamide

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    Shuang XING

    2015-06-01

    Full Text Available Objective To explore the effect of the administration time of HS6101 on hematopoietic recovery in ICR mice injured by cyclophosphamide (CTX. Methods One hundred and three male ICR mice were divided into 4 groups: CTX control, HS6101 prevention, HS6101 treatment, and HS6101 prevention+treatment groups. CTX was intraperitoneally injected into the ICR mice at a dose of 100mg/(kg.d for three consecutive days to establish a chemotherapeutics-injured model. HS6101 at a dose of 27μg/mouse in 0.2ml was subcutaneously injected into the mice 1h before the first administration of CTX in HS6101-prevention group, 1h after the last administration of CTX in HS6101 treatment group, and both at 1h before the first administration and 1h after the last administration of CTX in HS6101 prevention + treatment group. Physiological saline was subcutaneously injected into the mice in CTX control group (0.2ml/mouse. 10μl peripheral blood was collected from the caudal vein for WBC, neutrophil lymphocyte, RBC and platelet counts on day -1, 3, 5, 7, 9, 11, 13, 15, 17 with the MEK-7222K cell analyzer, and the cell count was compared between HS6101 treatment mice and CTX control mice. Another 30 male ICR mice were used for bone marrow colony forming unit (CFU assay and bone marrow histopathological examination, and they were assigned into normal control, CTX control, HS6101 prevention, HS6101treatment and HS6101 prevention + treatment groups (each n=6. On the day 4 and day 9 after CTX injection, mice were sacrificed and bone marrow cells were collected from the left femur for mononuclear cell (MNC isolation. 1×104 MNCs were planted in 1.0ml mouse CFU culture medium M3434 and cultured in incubator with the temperature of 37℃, and 5% CO2 for 7 days. After that, granulocyte macrophage-colony-forming unit (GM-CFU, megakaryocyte colony forming unit (MK-CFU, mixture-colony-forming unit (Mix-CFU, burst-forming unit-erythroid (BFU-E and colony-forming unit-erythroid (CFU

  7. Long-lasting remission and successful treatment of acquired factor VIII inhibitors using cyclophosphamide in a patient with systemic lupus erythematosus.

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    Trotta, F; Bajocchi, G; La Corte, R; Moratelli, S; Sun, L Y

    1999-10-01

    Acquired deficiency of clotting factor VIII (FVIII) is a rare bleeding diathesis seldom encountered in systemic lupus erythematosus (SLE). Reduction of FVIII activity by autoantibodies can cause potentially life-threatening situations. Herein, an SLE patient with a positive lupus anticoagulant (LAC) test who abruptly developed metrorrhagia 4 yr after diagnosis is reported. Coagulation tests revealed FVIII activity reduced to 3% and a prolonged aPTT. FVIII inhibitor(s) were found to be as high as 3.0 Bethesda Units. Plasmapheresis, immunoglobulins, prednisolone and FVIII plasma concentrates induced the cessation of metrorrhagia, but the clotting tests were barely improved. One month later, extensive ecchymosis appeared and worsened, despite re-administration of the previous therapy. Pulse cyclophosphamide followed by oral administration was then started with normalization of coagulation parameters and long-lasting disease remission.

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

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

    2010-01-01

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

  9. Identification and Pharmacokinetics of Multiple Potential Bioactive Constituents after Oral Administration of Radix Astragali on Cyclophosphamide-Induced Immunosuppression in Balb/c Mice

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    Menghua Liu

    2015-03-01

    Full Text Available Radix Astragali (RA is one of the commonly-used traditional Chinese medicines (TCMs with an immunomodulatory effect confirmed in the clinic. In order to better understand the material basis for the therapeutic effects, this study was to investigate the absorbed components and their pharmacokinetic profile after oral administration of RA on cyclophosphamide-induced immunosuppression in Balb/c mice. As a result, 51 compounds in RA extract and 31 prototype compounds with nine metabolites were detected in mice plasma by the ultra-fast liquid chromatography (UFLC-DAD-Q-TOF-MS/MS method. The pharmacokinetic parameters of five main constituents, including calycosin-7-O-glucoside, ononin, calycosin, formononetin and astragaloside IV, were obtained using HPLC-MS/MS. These results offered useful information for research on the pharmacological mechanism of RA and for its further development.

  10. Severe Acute Hepatitis B in HBV-Vaccinated Partner of a Patient with Multiple Myeloma Treated with Cyclophosphamide, Bortezomib, and Dexamethasone and Autologous Stem Cell Transplant

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    Majed M. Almaghrabi

    2017-01-01

    Full Text Available Hepatitis B reactivation can occur with various forms of immunosuppression. Cyclophosphamide, Bortezomib, and Dexamethasone (CYBOR-D chemotherapy is commonly used for the treatment of multiple myeloma and has not been noted in guidelines to be causative in HBV reactivation. Indeed, current guidelines do not recommend providing antiviral prophylaxis to patients with prior HBV infection. We present a case of HBV reactivation as a result of CYBOR-D and autologous stem cell transplant which is complicated by the patient’s partner who developed acute hepatitis B. Our case highlights the need to review the role of antiviral prophylaxis for patients undergoing treatment of multiple myeloma and also the role of ensuring immunity for close contacts of these patients who may also be at risk.

  11. Early aggressive intra-venous pulse cyclophosphamide therapy for interstitial lung disease in a patient with systemic sclerosis. A case report.

    LENUS (Irish Health Repository)

    Peshin, R

    2009-06-01

    Interstitial lung disease is an important cause of mortality and morbidity in patients with systemic sclerosis (SSc). There are currently no recommended guidelines for management of these patients. This is probably due to the rarity of this condition, as well as clinical trials with only a small number of cases. There are published case report and case series along with the two main trials, viz. Scleroderma Lung Study and the Fibrosing Alveolitis Study, but again, there is no consensus on treatment protocols. In this report, we present a case of aggressive interstitial lung disease in a patient with SSc, which improved dramatically on treatment with intra-venous cyclophosphamide and high dose prednisolone therapy.

  12. Comparison of engraftment following different stem cell mobilization modalities in patients with multiple myeloma treated with a uniform induction regimen containing bortezomib, cyclophosphamide and dexamethasone.

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    Benyamini, Noam; Avivi, Irit; Dann, Eldad J; Zuckerman, Tsila; Lavi, Noa; Katz, Tami

    2017-03-01

    Bortezomib-based induction followed by autologous stem cell transplantation is a common treatment for multiple myeloma (MM). Stem cell (SC) mobilization with granulocyte-colony stimulating factor (G-CSF) alone has become an alternative to G-CSF combined with chemotherapeutic agents. This study aimed to compare the efficacy of the two mobilization modalities following induction with a uniform regimen containing bortezomib, cyclophosphamide and dexamethasone (VCD). We retrospectively evaluated results of SC mobilization using either G-CSF alone or combined with high-dose cyclophosphamide (HD-CY) in MM patients after VCD induction. The primary endpoints of the study were engraftment and mobilization-associated toxicity. Parameters of stem cell collection, transplantation and engraftment were assessed. Data of 92 patients were analyzed [56 (61%) mobilized with HD-CY + G-CSF and 36 (39%) with G-CSF only]. HD-CY + G-CSF provided a higher number of CD34 + cells (15.9 vs 8.1 × 10 6 /kg, p = 0.001) with fewer apheresis sessions. However, while no adverse events were observed in patients receiving G-CSF alone, nine patients (16%) receiving HD-CY + G-CSF developed neutropenic fever requiring hospitalization. Although a greater number of cells was transplanted following mobilization with HD-CY + G-CSF, neutrophil and platelet engraftment and duration of transplant-related hospitalization were similar in both cohorts. G-CSF alone provided a sufficient SC amount, without exposing patients to additional toxicity. While HD-CY + G-CSF resulted in a superior SC yield in MM patients induced with VCD, this advantage should be balanced against adverse effects of this mobilization regimen.

  13. Iridoid glycosides fraction from Picrorhiza kurroa attenuates cyclophosphamide-induced renal toxicity and peripheral neuropathy via PPAR-γ mediated inhibition of inflammation and apoptosis.

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    Sharma, Supriya; Sharma, Pallavi; Kulurkar, Pankaj; Singh, Damanpreet; Kumar, Dinesh; Patial, Vikram

    2017-12-01

    Picrorhiza kurroa Royle (Scrophulariaceae) is an important medicinal herb being widely used in variety of ailments. The present study was envisaged to evaluate the effects of iridoid glycosides enriched fraction (IGs) from Picrorhiza kurroa rhizome against cyclophosphamide (CP) -induced renal toxicity and peripheral neuropathy. Mice in different groups were pretreated with 25, 50 and 100 mg/kg; p.o. doses of IGs for 21 days, followed by cyclophosphamide intoxication for consecutive two days. Further, to identify the putative role of PPAR-γ receptors for the protective effect of IGs, an additional group of mice were pretreated with PPAR-γ antagonist BADGE (5 mg/kg; i.p.) followed by IGs (100 mg/kg; p.o.) for 21 days before CP intoxication. IGs pretreatment decreased the hyperalgesic responses toward acetone and heat in acetone drop and tail immersion tests. The abolition of intramyelin odema, cytoplasmic vacuolization and axonal degeneration of sciatic nerve were observed in IGs pretreated mice in a dose-dependent manner. IGs treatment also attenuated the altered serum biochemical markers for renal injury. Furthermore, the treatment prevented renal tubular swelling, granular degeneration and glomerular damage. The levels of IL-1β and TNFα in different group revealed the anti-inflammatory effect of IGs, which was further confirmed by improvement in altered expressions of NF-kB in kidney and sciatic serve. Bax/Bcl-2 expressions and caspase 3/9 activity in renal tissues showed the anti-apoptotic effect of IGs. IGs pretreatment also improved the PPAR-γ expression in the kidney tissues. All the observed protective effects of IGs were suppressed after pretreatment with BADGE. Present study concludes that IGs from Picrorhiza kurroa attenuates CP-induced renal toxicity and peripheral neuropathy via PPAR-γ -mediated pathways. Copyright © 2017 Elsevier GmbH. All rights reserved.

  14. Reconstitution of the cellular immune response by lactoferrin in cyclophosphamide-treated mice is correlated with renewal of T cell compartment.

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    Artym, Jolanta; Zimecki, Michal; Kruzel, Marian L

    2003-01-01

    Cyclophosphamide is an alkylating agent used to treat both malignant and non-malignant immune-mediated inflammatory disorders in humans. It is also known as a potent immunosuppressive drug in humans and experimental animals. The aim of this study was to evaluate the effects of oral administration of lactoferrin (LF) on cellular responses and reconstruction of the lymphocyte pool in mice treated with cyclophosphamide (CP). Twelve week-old CBA mice were given a single intraperitoneal (i.p.) dose of CP (400 mg/kg body weight), then were treated per os with seven doses of LF (1 mg/dose) on alternate days. We demonstrated that the magnitude of delayed type hypersensitivity to ovalbumin, strongly diminished by CP action, was reconstituted by LF. Oral LF treatment also resulted in partial recovery of Concanavalin A-induced splenocyte proliferation. Blood profile analysis revealed elevation of leukocytosis by LF in CP-treated mice (from 64.9 to 84.76% of the control value). LF also caused substantial restoration of the percentage of the lymphocyte population in circulating blood (from 43.4 to 60.2% of the control values). LF alone had no effect on the neutrophil/lymphocyte ratio in normal mice, however, the total number of leukocytes decreased by 23.25%. Furthermore, we showed that LF increased the cellularity of spleens isolated from CP-treated mice (from 53.2 to 78.8%) and the content of peritoneal and alveolar macrophages (elevations from 50.6 to 67.3% and from 65.2 to 83.6%, respectively). Lastly, using panning technique, we demonstrated that LF strongly elevated the pool of CD3+ T cells in normal and CP-immunocompromised mice and CD4+ T cell content. In conclusion, we showed for the first time that lactoferrin, given orally to CP-immunosuppressed mice, could reconstitute a T-cell mediated immune response by renewal of the T cell pool.

  15. Urinary IgG and α2-Macroglobulin Are Powerful Predictors of Outcome and Responsiveness to Steroids and Cyclophosphamide in Idiopathic Focal Segmental Glomerulosclerosis with Nephrotic Syndrome

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    Claudio Bazzi

    2013-01-01

    Full Text Available Objective. To assess whether high-molecular-weight proteins excretion predicts outcome and therapy-responsiveness in patients with FSGS and nephrotic syndrome. Research Design and Methods. Thirty-eight patients measured at biopsy fractional excretion of IgG (FEIgG and urinary α2-macroglobulin/creatinine ratio (α2m/C. Low and high risk groups were defined by cutoffs assessed by ROC analysis. In all patients first-line therapy was with steroids alone or in combination with cyclophosphamide. Results. α2m/C and FEIgG were correlated with segmental sclerosis (r=0.546; r=0.522. Twenty-three patients (61% entered Remission and 9 (24% progressed to ESRD. Comparing low and high risk groups, by univariate analysis remission was predicted by FEIgG (77% versus 25%, P=0.016 and α2m/C (81% versus 17%, P=0.007 and ESRD at best by FEIgG (0% versus 75%, P<0.0001 and α2m/C (4% versus 67%, P<0.0001. By multivariate analysis FEIgG was the only independent predictor of remission and α2m/C the most powerful predictor of ESRD. Low and high risk groups of FEIgG and α2m/C in combination had very high predictive value of sustained remission and ESRD in response to therapy. Conclusions. FEIgG and α2m/C are powerful predictors of outcome and responsiveness to steroids and cyclophosphamide; their predictive value, if validated in prospective studies, may be useful in clinical practice suggesting first-line alternative treatments in high risk patients.

  16. Adjuvant Docetaxel and Cyclophosphamide (DC with prophylactic granulocyte colony-stimulating factor (G-CSF on days 8 &12 in breast cancer patients: a retrospective analysis.

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    Rinat Yerushalmi

    Full Text Available PURPOSE: Four cycles of docetaxel/cyclophosphamide (DC resulted in superior survival than doxorubicin/cyclophosphamide in the treatment of early breast cancer. The original study reported a 5% incidence of febrile neutropenia (FN recommending prophylactic antibiotics with no granulocyte colony-stimulating factor (G-CSF support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events. We explored the use of growth factor (GF support on days 8 and 12 of the cycle with the original DC protocol. METHODS: Our study included all consecutive patients with stages I-II breast cancer who were treated with the DC protocol at the Institute of Oncology, Davidoff Center (Rabin Medical Center, Petah Tikva, Israel from April, 2007 to March, 2012. Patient, tumor characteristics, and toxicity were reported. RESULTS: In total, 123 patients received the DC regimen. Median age was 60 years, (range, 25-81 years. Thirty-three patients (26.8% were aged 65 years and older. Most of the women (87% adhered to the planned G-CSF protocol (days 8 &12. 96% of the patients completed the 4 planned cycles of chemotherapy. Six patients (5% had dose reductions, 6 (5% had treatment delays due to non-medical reasons. Thirteen patients (10.6% experienced at least one event of FN (3 patients had 2 events, all requiring hospitalization. Eight patients (6.5% required additional support with G-CSF after the first chemotherapy cycle, 7 because of FN and one due to neutropenia and diarrhea. IN CONCLUSION: Primary prophylactic G-CSF support on days 8 and 12 of the cycle provides a tolerable option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support.

  17. Removal of bowel aerobic gram-negative bacteria is more effective than immunosuppression with cyclophosphamide and steroids to decrease natural alpha-galactosyl IgG antibodies.

    Science.gov (United States)

    Mañez, R; Blanco, F J; Díaz, I; Centeno, A; Lopez-Pelaez, E; Hermida, M; Davies, H F; Katopodis, A

    2001-02-01

    Natural alpha-Galactosyl (Gal) antibodies play an important role in the rejection of pig xenografts by humans and Old World monkeys. In this study we investigate the efficacy of two different strategies to reduce the serum level of natural anti-Gal antibodies. On the one hand, removal of aerobic gram-negative bacteria from the intestinal flora, because anti-Gal antibodies appear to be produced as a result of the continuous sensitization by these microorganisms. On the other hand, we studied the effect on these antibodies of an immunosuppressive regimen of cyclophosphamide and steroids. Ten baboons were treated for three months with norfloxacin (Nor Group; n=6) or cyclophosphamide and steroids (CyP Group; n=4). A further four baboons did not receive any treatment (Control Group). Aerobic gram-negative bacteria became negative in stools of the Nor Group after two weeks of treatment, and remained undetectable until week 7. Thereafter, a gradual increase on the fecal concentration of aerobic gram-negative bacteria was observed despite the norfloxacin treatment. The mean anti-Gal IgG in the Nor Group gradually declined from week 4 to 9 to a mean of 62.7 +/- 18% of the baseline level, and during this period were significantly lower than in the CyP (Premoval of normal aerobic gram-negative bacteria from the intestinal flora is more effective than immunosuppression with CyP and steroids in reducing the level of natural anti-Gal antibodies, although there is no discernible effect on IgM antibodies.

  18. Cost-effectiveness analysis of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-positive breast cancer: modeling the downstream effects.

    Science.gov (United States)

    Au, Heather-Jane; Golmohammadi, Kamran; Younis, Tallal; Verma, Shailendra; Chia, Stephen; Fassbender, Konrad; Jacobs, Philip

    2009-04-01

    BCIRG 001 demonstrated prolonged disease-free (DFS) and overall survival (OS) but increased toxicity for adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) versus 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) in women with node positive breast cancer (BC). This study evaluates quality-adjusted survival and cost-effectiveness of adjuvant TAC versus FAC, taking downstream decisions and events into account, including palliative chemotherapy with taxanes. We developed a Markov model for a cohort of women with node positive BC eligible for adjuvant anthracyclines. Data input included clinical and resource utilization data collected prospectively from BCIRG 001. Treatment decisions and outcomes with disease recurrence were based on a systematic literature review with validity reviewed by a national panel of Canadian BC oncologists. Direct costs for resource utilization following Canadian practice patterns were included. Unit costs were obtained from provincial cost list and published drug list prices. Utility scores were derived from the literature. An incremental cost-effectiveness ratio (ICER) in cost per quality-adjusted life-years (QALY) gained for TAC versus FAC was calculated. For 1,000 women with node positive BC, the model showed that TAC would lead to a gain of 313 QALY (370 life years) at an additional cost of $5.8 Million Canadian dollars (Cdn) compared to FAC, over a 10-year time horizon. The ICER of TAC versus FAC was $18,505.54 Cdn per QALY gained. Sensitivity analyses supported the robustness of the model. By one-way sensitivity analyses of over 50 model variables, 95% of the cumulative ICER variation was from $6,000 to $28,000 Cdn/QALY. By multivariate Monte Carlo simulation, there was a 70% probability that the ICER would be under $50,000 CdN/QALY. For women with node positive BC, TAC improves DFS and OS compared to FAC and is a cost-effective adjuvant chemotherapy strategy.

  19. Cyclophosphamide leads to persistent deficits in physical performance and in vivo mitochondria function in a mouse model of chemotherapy late effects.

    Science.gov (United States)

    Crouch, Marie-Laure; Knowels, Gary; Stuppard, Rudolph; Ericson, Nolan G; Bielas, Jason H; Marcinek, David J; Syrjala, Karen L

    2017-01-01

    Fatigue is the symptom most commonly reported by long-term cancer survivors and is increasingly recognized as related to skeletal muscle dysfunction. Traditional chemotherapeutic agents can cause acute toxicities including cardiac and skeletal myopathies. To investigate the mechanism by which chemotherapy may lead to persistent skeletal muscle dysfunction, mature adult mice were injected with a single cyclophosphamide dose and evaluated for 6 weeks. We found that exposed mice developed a persistent decrease in treadmill running time compared to baseline (25.7±10.6 vs. 49.0±16.8 min, P = 0.0012). Further, 6 weeks after drug exposure, in vivo parameters of mitochondrial function remained below baseline including maximum ATP production (482.1 ± 48.6 vs. 696.2 ± 76.6, P = 0.029) and phosphocreatine to ATP ratio (3.243 ± 0.1 vs. 3.878 ± 0.1, P = 0.004). Immunoblotting of homogenized muscles from treated animals demonstrated a transient increase in HNE adducts 1 week after exposure that resolved by 6 weeks. However, there was no evidence of an oxidative stress response as measured by quantitation of SOD1, SOD2, and catalase protein levels. Examination of mtDNA demonstrated that the mutation frequency remained comparable between control and treated groups. Interestingly, there was evidence of a transient increase in NF-ĸB p65 protein 1 day after drug exposure as compared to saline controls (0.091±0.017 vs. 0.053±0.022, P = 0.033). These data suggest that continued impairment in muscle and mitochondria function in cyclophosphamide-treated animals is not linked to persistent oxidative stress and that alternative mechanisms need to be considered.

  20. Dose-response relationship in cyclophosphamide-treated B-cell lymphoma xenografts monitored with [{sup 18}F]FDG PET

    Energy Technology Data Exchange (ETDEWEB)

    Brepoels, Lieselot; Saint-Hubert, Marijke de; Mortelmans, Luc [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); Stroobants, Sigrid [University Hospital Antwerpen, Department of Nuclear Medicine, Edegem (Belgium); Verhoef, Gregor [University Hospital Gasthuisberg Leuven, Department of Hematology, Leuven (Belgium); Balzarini, Jan [KU Leuven, Department of Microbiology and Immunology, Leuven (Belgium); Mottaghy, Felix M. [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); Universitaetsklinikum der RWTH Aachen, Klinik fuer Nuklearmedizin, Aachen (Germany)

    2010-09-15

    Although [{sup 18}F]FDG PET can measure therapy response sooner and more accurately than morphological imaging techniques, there is still some debate as to whether [{sup 18}F]FDG uptake really reflects changes in the viable cell fraction. In this study changes in [{sup 18}F]FDG uptake were investigated in a lymphoma model at several time-points after treatment and with different doses of chemotherapy. Data were analysed in terms of several parameters. SCID mice were subcutaneously inoculated with 5 x 10{sup 6} Daudi cells in the right thigh. One group was not treated (control group). The other groups received cyclophosphamide 75 mg/kg (low-dose group), 125 mg/kg (medium-dose group) and 175 mg/kg (high-dose group) on day 0. Sequential [{sup 18}F]FDG small-animal PET ({mu}PET) scans were performed on days 0, 2, 6, 9, 13 and 16 after treatment. The mean and maximum standardized uptake value (SUV{sub mean} and SUV{sub max}), metabolic tumour volume (Vol{sub metab}) and total lesion glycolysis (TLG) were calculated. A significant decrease in [{sup 18}F]FDG uptake was observed on day 2 in the medium-dose and high-dose groups and on day 6 in the low-dose group, all preceding morphological changes. SUV{sub mean} and SUV{sub max} formed a plateau from day 6 to day 9, corresponding to the known influx of inflammatory cells. No obvious plateau was observed with TLG which was found to be the most sensitive parameter clearly differentiating the low-dose group from the medium- and high-dose groups early after therapy. [{sup 18}F]FDG uptake was able to reflect the dose-response relationship for cyclophosphamide. TLG was the best parameter for dose-related response assessment in this tumour model. (orig.)

  1. A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors.

    Science.gov (United States)

    Connor, Joseph P; Cristea, Mihaela C; Lewis, Nancy L; Lewis, Lionel D; Komarnitsky, Philip B; Mattiacci, Maria R; Felder, Mildred; Stewart, Sarah; Harter, Josephine; Henslee-Downey, Jean; Kramer, Daniel; Neugebauer, Roland; Stupp, Roger

    2013-01-15

    Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent. Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5-4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated. Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients. The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles.

  2. The influence of piroxicam, a non-selective cyclooxygenase inhibitor, on autonomic nervous system activity in experimental cyclophosphamide-induced hemorrhagic cystitis and bladder outlet obstruction in rats.

    Science.gov (United States)

    Dobrek, Łukasz; Baranowska, Agnieszka; Skowron, Beata; Thor, Piotr J

    2014-01-01

    Signs and symptoms of secondary overactive bladder (OAB) are observed both in course of infravesical obstruction of urine outflow in patients with benign prostatic hyperplasia, and as a result of development of hemorrhagic cystitis (HC) following administration of cyclophosphamide (CP). Non-steroidal antiinflammatory drugs (NSAIDs) alleviate symptoms of bladder overactivity reducing local synthesis of prostaglandins (PGs), but precise effects of those agents on functions of the autonomic nervous system (ANS) in course of OAB remain unknown. The purpose of this study was to evaluate the effect of piroxicam-induced prostaglandins (PGs) synthesis block on activity of the ANS in two experimental models of secondary OAB: bladder outlet obstruction (BOO) and cyclophosphamide-induced HC (CP-HC), by heart rate variability analysis (HRV). The experiment was performed on a group of rats with surgically induced 2-week BOO, and on a group of rats that were administered CP five times, with corresponding control groups. Study animals were given piroxicam (PRX) i.p. in two doses: 2 and 10 mg/kg b.w. In the BOO model, PRX in both doses revealed a trend for reduction of value of all non-normalized components of HRV. The lower PRX dose caused an increased nHF value, and PRX administered in the dose of 10 mg/kg b.w. caused an increase of the nLF value. In the CP-HC model, the lower PRX dose caused a trend for an increase of values of all non-normalized components, and the higher dose--for their decrease. Both doses of PRX in that model caused increase of the nLF value. Inhibition of PGs synthesis caused changes of ANS function in both models of OAB. Both in BOO and in CP-HC, PGs seem to be ANS-activating factors, responsible for maintenance of a high parasympathetic activity. In both models, inhibition of PGs synthesis with PRX administered at the dose of 10 mg/kg b.w. lead to functional reconstruction of ANS, with marked sympathetic predominance. That may contribute to reduction of

  3. Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group

    Science.gov (United States)

    Ray-Coquard, I; Paraiso, D; Guastalla, J-P; Leduc, B; Guichard, F; Martin, C; Chauvenet, L; Haddad-Guichard, Z; Lepillé, D; Orfeuvre, H; Gautier, H; Castera, D; Pujade-Lauraine, É

    2007-01-01

    ICON3 trial results have suggested that CAP and carboplatin–taxol regimens as first-line treatment of advanced ovarian cancer (AOC) yield similar survival. We explored the impact of increased dose of cyclophosphamide in a modified CAP regimen on the disease-free survival (DFS) and overall survival (OS) of AOC patients. From February 1994 to June 1997, 164 patients were randomised to receive six cycles every 3 weeks of either standard CEP (S) combining cyclophosphamide (C), 500 mg m−2, epirubicin (E) 50 mg m−2, and cisplatin (P) 75 mg m−2 or intensive CEP (I) with E and P at the same doses, but with (C) 1800 mg m−2 and filgrastim 5 μg kg−1 per day × 10 days. Response was evaluated at second-look surgery. Patient characteristics were well balanced. Except for grade 3–4 neutropaenia (S: 54%, I: 38% of cycles), Arm1 presented a significantly more important toxicity: infection requiring antibiotics, grade 3–4 thrombocytopaenia, anaemia, nausea-vomiting, diarrhoea, mucositis. Median follow-up was 84 months. DFS (15.9 vs 14.8 months) and OS (33 vs 30 months) were not significantly different between S and I (P>0.05). Increasing cyclophosphamide dose by more than 3 times with filgrastim support in the modified CAP regimen CEP induces more toxicity but not better efficacy in AOC. PMID:17923867

  4. The effect of Lychnis chalcedonica L. flavonoids on the development of tumors in mice and the effectiveness of treatment with cyclophosphamide

    Science.gov (United States)

    Zibareva, L. N.; Zueva, E. P.; Razina, T. G.; Amosova, E. N.; Krylova, S. G.; Lopatina, K. A.; Rybalkina, O. Y.; Badulina, A. A.; Safonova, E. A.; Babushkina, M. S.; Filonenko, E. S.; Galiulina, A. V.

    2015-11-01

    A complex of biologically active substances was obtained from Lychnis chalcedonica L. introduced in culture at the Siberian botanical garden of Tomsk State University. Earlier, bioactivities such as radioprotective, gemoreologic and antifungal, were identified, which were determined by the presence of phytoecdysteroids whose composition was studied. The antitumor action of flavonoids extracted from ethanol extract of Lychnis chalcedonica was identified in this study. They were partially identified using the HPLC method. A major component of this complex was detected, which likely determines the effect on the tumor. The influence of these polyphenol compounds was studied on three models of tumors: Lewis lung carcinoma, melanoma - B16 and cancer light - 67. As a result of experiments conducted on female mice of the C57BL/6 line it was discovered that the Lychnis chalcedonica flavonoids complex inhibits tumor growth in mice with melanoma B-16, and together with cyclophosphamide enhances the antitumor effect of cytostatic. Lychnis chalcedonica flavonoids, when given as an isolated injection to mice with Lewis lung carcinomas, prevent a deterioration of the level of gematocrit and hemoglobin in the peripheral blood.

  5. Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits.

    Science.gov (United States)

    Yang, Miyoung; Kim, Joong-Sun; Song, Myoung-Sub; Kim, Sung-Ho; Kang, Seong Soo; Bae, Chun-Sik; Kim, Jong-Choon; Wang, Hongbing; Shin, Taekyun; Moon, Changjong

    2010-05-01

    Cyclophosphamide (CYP) is an anti-neoplastic agent as well as an immunosuppressive agent. In order to elucidate the alteration in adult hippocampal function following acute CYP treatment, hippocampus-related behavioral dysfunction and changes in adult hippocampal neurogenesis in CYP-treated (intraperitoneally, 40 mg/kg) mice (8-10-week-old ICR) were analyzed using hippocampus-dependent learning and memory tasks (passive avoidance and object recognition memory test) and immunohistochemical markers of neurogenesis (Ki-67 and doublecortin (DCX)). Compared to the vehicle-treated controls, mice trained at 12h after CYP injection showed significant memory deficits in passive avoidance and the object recognition memory test. The number of Ki-67- and DCX-positive cells began to decrease significantly at 12h post-injection, reaching the lowest level at 24h after CYP injection; however, this reverted gradually to the vehicle-treated control level between 2 and 10 days. We suggest that the administration of a chemotherapeutic agent in adult mice interrupts hippocampal functions, including learning and memory, possibly through the suppression of hippocampal neurogenesis. Copyright 2010 Elsevier Inc. All rights reserved.

  6. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells.

    Science.gov (United States)

    Soo, Jaslyn Sian-Siu; Ng, Char-Hong; Tan, Si Hoey; Malik, Rozita Abdul; Teh, Yew-Ching; Tan, Boon-Shing; Ho, Gwo-Fuang; See, Mee-Hoong; Taib, Nur Aishah Mohd; Yip, Cheng-Har; Chung, Felicia Fei-Lei; Hii, Ling-Wei; Teo, Soo-Hwang; Leong, Chee-Onn

    2015-10-01

    Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.

  7. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with advanced breast cancer: long-term analysis of the previously published trial.

    Science.gov (United States)

    Jassem, Jacek; Pienkowski, Tadeusz; Pluzanska, Anna; Jelic, Svetislav; Gorbunova, Vera; Berzins, Juris; Nagykalnai, Thomas; Biganzoli, Laura; Aloe, Alessandra; Astier, Ludovic; Munier, Stephane

    2009-09-01

    The aim of this study was to perform an independent review of the efficacy data and to determine whether the efficacy difference observed in a phase III randomised clinical trial that compared doxorubicin plus paclitaxel (AT) versus fluorouracil/doxorubicin/cyclophosphamide (FAC) in first-line chemotherapy of metastatic breast cancer was maintained after a longer follow-up period. A blinded independent review of original radiological images and original case report forms (CRFs) was conducted by an expert radiologist and an expert medical oncologist, respectively. The analysis of the updated data included time to progression (TTP) and overall survival (OS). CRFs for all 267 patients randomised in the study were available for medical review. The results of the independent review were consistent with the original analysis. At a median follow-up of 69 months, the difference in median TTP and OS in favour of the AT arm remained significant (median TTP 8.1 vs. 6.2 months, (p = 0.036); OS 23.0 vs. 18.3 months, (p = 0.005), respectively). This blinded independent review and analysis of updated data confirmed the advantage for AT over FAC with regard to TTP and OS in patients with metastatic breast cancer.

  8. Benefits of Preventive Administration of Chlorella sp. on Visceral Pain and Cystitis Induced by a Single Administration of Cyclophosphamide in Female Wistar Rat.

    Science.gov (United States)

    Hidalgo-Lucas, Sophie; Rozan, Pascale; Guérin-Deremaux, Laetitia; Baert, Blandine; Violle, Nicolas; Saniez-Degrave, Marie-Hélène; Bisson, Jean-François

    2016-05-01

    Chlorella sp. is a green microalgae containing nutrients, vitamins, minerals, and chlorophyll. In some communities, Chlorella sp. is a traditional medicinal plant used for the management of inflammation-related diseases. In a rat model, ROQUETTE Chlorella sp. (RCs) benefits were investigated on visceral pain and associated inflammatory parameters related to cystitis both induced by cyclophosphamide (CYP). RCs was orally administered every day from day 1-16 (250 and 500 mg/kg body weight). Six hours after an intraperitoneal injection of 200 mg/kg body weight of CYP, body temperature, general behavior, food intake, and body weight were recorded. Twenty-four hours after CYP injection, rats were tested in two behavioral tests, an open field and the aversive light stimulus avoidance conditioning test, to evaluate the influence of pain on general activity and learning ability of rats. After euthanasia, bladders were weighed, their thickness was scored, and the urinary hemoglobin was measured. RCs orally administered at the two dosages significantly reduced visceral pain and associated inflammatory parameters related to cystitis both induced by CYP injection, and improved rat behavior. To conclude, RCs demonstrated beneficial effects against visceral pain and cystitis.

  9. The Natural Carotenoid Crocetin and the Synthetic Tellurium Compound AS101 Protect the Ovary against Cyclophosphamide by Modulating SIRT1 and Mitochondrial Markers

    Directory of Open Access Journals (Sweden)

    Giovanna Di Emidio

    2017-01-01

    Full Text Available Cancer therapies are associated with increased infertility risk due to accelerated reproductive aging. Oxidative stress (OS is a potential mechanism behind ovarian toxicity by cyclophosphamide (CPM, the most ovotoxic anticancer drug. An important sensor of OS is SIRT1, a NAD+-dependent deacetylase which regulates cellular defence and cell fate. This study investigated whether the natural carotenoid crocetin and the synthetic compound AS101 protect the ovary against CPM by modulating SIRT1 and mitochondrial markers. We found that the number of primordial follicles of female CD1 mice receiving crocetin plus CPM increased when compared with CPM alone and similar to AS101, whose protective effects are known. SIRT1 increased in CPM mouse ovaries revealing the occurrence of OS. Similarly, mitochondrial SIRT3 rose, whilst SOD2 and the mitochondrial biogenesis activator PGC1-α decreased, suggesting the occurrence of mitochondrial damage. Crocetin and AS101 administration prevented SIRT1 burst suggesting that preservation of redox balance can help the ovary to counteract ovarian damage by CPM. Decreased SIRT3 and increased SOD2 and PGC1-α in mice receiving crocetin or AS101 prior to CPM provide evidence for mitochondrial protection. Present results improve the knowledge of ovarian damage by CPM and may help to develop interventions for preserving fertility in cancer patients.

  10. A Comparison Study of the Effects of Echinacea purpurea Ethanolic Extract and Mesna on Cyclophosphamide-Induced Macroscopic Fetal Defects in Rats

    Directory of Open Access Journals (Sweden)

    Hossein Najafzadeh Varzi

    2009-03-01

    Full Text Available Objective(s There are some reports that the teratogenic effects of cyclophosphamide (CPA can be prevented by application of antioxidant drugs and stimulation of the maternal immune system. Echinacea purpurea extract is antioxidative and immunomodulator drug. Mesna (Sodium 2-mercaptoethane sulfonate is used for decreasing side effects of CPA, especially hemorrhagic cystitis. In this study, we compared the prophylactic effects of mesna and Echinacea extract on teratogenic effects of CPA. Materials and Methods This study was performed on 32 pregnant rats that were divided into 4 groups. The first group (control group received normal saline and the other groups received CPA (15 mg/kg intraperitoneally on 13th day of gestation. Mesna and E. purpurea extracts were administrated at doses of 100 and 400 mg/kg by IP injection, respectively, along with it and 12 hr later, after CPA injection. Rats were dissected on day 20 of gestation, embryos harvested and after determination of gross malformations they were stained by Alizarin red-Alcian blue method. ResultsCleft palate incidence was 38.46, 30.77 and 14.28% in fetuses of rats that received only CPA, CPA with mesna and CPA with Echinacea extract, respectively. In addition, skeletal anomalies incidence including limbs, vertebra, sternum, and scapula defects were decreased by Echinacea extract.ConclusionE. purpurea has significant effect on preventing CPA-induced malformations and better prophylactic effect than mesna on cases like CPA-induced cleft palate.

  11. Fludarabine, cyclophosphamide and antithymocyte globulin as total body irradiation-free conditioning for matched related and unrelated allogeneic stem cell transplantation in severe aplastic anemia

    Science.gov (United States)

    Anderlini, Paolo; Acholonu, Sandra; Okoroji, Grace-Julia; Bassett, Roland E.; Giralt, Sergio; Shpall, Elizabeth J; Qazilbash, Muzaffar; Popat, Uday; Worth, Laura; Champlin, Richard E.

    2014-01-01

    Twenty severe aplastic anemia (SAA) patients underwent allogeneic stem cell transplantation (allo-SCT) with fludarabine (FLU), cyclophosphamide and antithymocyte globulin from a matched related (n=7, age ≥ 40) or unrelated donor (n=13, any age). Median age was 34 years (range 1–59). Median time from diagnosis to allo-SCT was 12 months (range 2–244). Seventeen out of 19 evaluable patients engrafted (90%). There were two secondary graft failures (10%). Median time to neutrophil recovery was 15 days (range 8–30). Chimerism studies indicated ≥90% donor-derived engraftment in 16/19 evaluable patients (75%). Four out of 20 patients (20%) developed acute (grade II–IV) GVHD, and 6/16 evaluable patients (37%) developed chronic GVHD. We observed EBV reactivation and viremia in seven patients, which was successfully treated with rituximab in all but one instance (where it was self-limiting). Thirteen patients (62%) are alive (including eight of the last nine treated) with a median follow-up of 30 months (range 3–112). Seven patients expired (graft rejection n=1, GVHD n=1, multiorgan failure n=1, infection n=2, EBV post-transplant lymphoproliferative disorder/PTLD n=2). Total body irradiation-free, FLU-based conditioning for matched related and unrelated allo-SCT is feasible with high engraftment rates. EBV PTLD remains a drawback of this approach. PMID:20939697

  12. Establishment and assessment of a novel in vitro bio-PK/PD system in predicting the in vivo pharmacokinetics and pharmacodynamics of cyclophosphamide.

    Science.gov (United States)

    Tong, Shanshan; Sun, Hong; Xue, Caifu; Chen, Hanmei; Liu, Jing; Yang, Huiying; Zhou, Ning; Xiang, Xiaoqiang; Cai, Weimin

    2017-06-06

    1. A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro. 2. The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline. The metabolism and pharmacological effects of CP (5, 10 and 20 mM) were measured by HPLC and MTT assay. A mathematical model based on mass balance was used to predict the in vitro clearance of CP. In vivo clearance of CP was estimated by in vitro to in vivo extrapolations (IVIVE) and simulations using Simcyp® software. 3. The predicted in vivo clearance of CP at concentrations of 5, 10 and 20 mM was 11.36, 10.12 and 10.68 mL/min/kg, respectively, within two-fold differences compared with the reported 11.1 mL/min/kg. The survival ratio of effector cells during the metabolism and circulation of CP was significantly enhanced. 4. This system may serve as an alternative approach to predict in vivo metabolism, pharmacological effects and toxicity of drugs, ensuring an efficient drug screening process.

  13. Delayed erythropoiesis in irradiated rats grafted with syngeneic marrow: effects of cytotoxic drugs and iron-deficiency anemia. [Gamma radiation; cyclophosphamide; busulfan; dimethylmyleran

    Energy Technology Data Exchange (ETDEWEB)

    Rodday, P.; Bennett, M.; Vitalle, J.J.

    1976-09-01

    Erythropoiesis in spleens of lethally irradiated Lewis rats grafted with 4-35 x 10/sup 6/ syngeneic marrow cells was inhibited or delayed during the test period of 5 days; this was in marked contrast to observations in irradiated mice. The mechanism of this inhibition was the subject of this study. Pretreatment of recipients 9 days prior to irradiation with the cytotoxic drugs cyclophosphamide (CY), busulfan (BUS), or dimethylmyleran (DMM), or the induction of iron deficiency with anemia in recipients reversed this delayed erythropoiesis. However, neither iron-deficiency anemia nor pretreatment with BUS or DMM affected the ability of irradiated recipients to reject 20 to 50 x 10/sup 6/ allogeneic marrow cells. The administration of commercial preparations of erythropoietin to hosts stimulated erythropoiesis moderately. However, proliferation of syngeneic marrow cells was not enhanced when infused into lethally irradiated spontaneous hypertensive (SH) inbred-strain rats which have high levels of endogenous erythropoietin. Finally, plasma from irradiated rats treated with phenylhydrazine to produce severe anemia was rich in erythropoietin but failed to stimulate erythropoiesis in the cell transfer system. Two hypotheses are considered.

  14. The absolute percent deviation of IGHV mutation rather than a 98% cut-off predicts survival of chronic lymphocytic leukaemia patients treated with fludarabine, cyclophosphamide and rituximab.

    Science.gov (United States)

    Jain, Preetesh; Nogueras González, Graciela M; Kanagal-Shamanna, Rashmi; Rozovski, Uri; Sarwari, Nawid; Tam, Constantine; Wierda, William G; Thompson, Philip A; Jain, Nitin; Luthra, Rajyalakshmi; Quesada, Andres; Sanchez-Petitto, Gabriela; Ferrajoli, Alessandra; Burger, Jan; Kantarjian, Hagop; Cortes, Jorge; O'Brien, Susan; Keating, Michael J; Estrov, Zeev

    2018-01-01

    The degree of somatic hypermutation, determined as percent deviation of immunoglobulin heavy chain gene variable region sequence from the germline (IGHV%), is an important prognostic factor in chronic lymphocytic leukaemia (CLL). Currently, a cut-off of 2% deviation or 98% sequence identity to germline in IGHV sequence is routinely used to dichotomize CLL patients into mutated and unmutated groups. Because dissimilar IGHV% cut-offs of 1-5% were identified in different studies, we wondered whether no cut-off should be applied and IGHV% treated as a continuous variable. We analysed the significance of IGHV% in 203 CLL patients enrolled on the original frontline fludarabine, cyclophosphamide and rituximab (FCR) trial with a median of 10 years follow-up. Using the Cox Proportional Hazard model, IGHV% was identified as a continuous variable that is significantly associated with progression-free (PFS) and overall survival (OS) (P < 0·001). Furthermore, we validated this finding in 323 patients treated with FCR off-protocol and in the total cohort (n = 535). Multivariate analysis revealed a continuous trend. Higher IGHV% levels were incrementally associated with favorable PFS and OS in both FCR-treated cohorts (P < 0·001, both cohorts). Taken together, our data suggest that IGHV% is a continuous variable in CLL patients treated with FCR. © 2017 John Wiley & Sons Ltd.

  15. Protective effect of combined pumpkin seed and ginger extracts on sperm characteristics, biochemical parameters and epididymal histology in adult male rats treated with cyclophosphamide.

    Science.gov (United States)

    Aghaie, Somaieh; Nikzad, Hossein; Mahabadi, Javad Amini; Taghizadeh, Mohsen; Azami-Tameh, Abolfazl; Taherian, Aliakbar; Sajjadian, Seyyed Mohammad Sajjad; Kamani, Mehran

    2016-09-01

    Reproductive toxicity is one of the side effects of cyclophosphamide (CP) in cancer treatment. Pumpkin seeds and Zingiber officinale are natural sources of antioxidants. We investigated the possible protective effect of combined pumpkin seed and Zingiber officinale extracts on sperm characteristics, epididymal histology and biochemical parameters of CP-treated rats. Male adult Wistar rats were divided randomly into six groups. Group 1, as a control, received an isotonic saline solution injection intraperitoneally (IP). Group 2 were injected IP with a single dose of CP (100 mg/kg) once. Groups 3 and 4 received CP plus 300 and 600 mg/kg combined pumpkin seed and Zingiber officinale extract (50:50). Groups 5 and 6 received only 300 and 600 mg/kg combined pumpkin seed and Zingiber officinale extract. Six weeks after treatment, sperm characteristics, histopathological changes and biochemical parameters were assessed. In CP-treated rats, motile spermatozoa were decreased, and abnormal or dead spermatozoa increased significantly (P sperm parameters. Epididymal epithelium and fibromascular thickness were also improved in extract-treated rats compared to control or CP groups. Biochemical analysis showed that the administration of combined extracts could increase the total antioxidant capacity (TAC) level significantly in groups 3, 4, 5 and 6. Interestingly, the mixed extract could decrease most of the side effects of CP such as vacuolization and separation of epididymal tissue. Our findings indicated that the combined extracts might be used as a protective agent against CP-induced reproductive toxicity.

  16. Immune-enhancing effect of nanometricLactobacillus plantarumnF1 (nLp-nF1) in a mouse model of cyclophosphamide-induced immunosuppression.

    Science.gov (United States)

    Choi, Dae-Woon; Jung, Sun Young; Kang, Jisu; Nam, Young-Do; Lim, Seong-Il; Kim, Ki Tae; Shin, Hee Soon

    2017-11-15

    Nanometric Lactobacillus plantarum nF1 (nLp-nF1) is a biogenics consisting of dead L. plantarum pre-treated with heat and a nanodispersion process. In this study, we investigated the immune-enhancing effects of nLp-nF1 in vivo and in vitro . To evaluate the immunostimulatory effects of nLp-nF1, mice immunosuppressed by cyclophosphamide (CPP) treatment were administered with nLp-nF1. As expected, CPP restricted the immune response of mice, whereas oral administration of nLp-nF1 significantly increased total IgG in serum, and cytokine production [interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α)] in bone marrow cells. Furthermore, nLp-nF1 enhanced the production of splenic cytokines such as IL-12, TNF-α, and interferon gamma (IFN-γ). In vitro , nLp-nF1 stimulated the immune response by enhancing the production of cytokines such as IL-12, TNF-α, and IFN-γ. Moreover, nLp-nF1 given a food additive enhanced the immune responses when combined with various food materials on in vitro . These results suggest that nLp-nF1 could be used to strengthen the immune system and recover normal immunity in people with a weaker immune system, such as children, the elderly, and patients.

  17. Post-transplantation Cyclophosphamide and Sirolimus after Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-based Myeloablative Conditioning and Peripheral Blood Stem Cells.

    Science.gov (United States)

    Cieri, Nicoletta; Greco, Raffaella; Crucitti, Lara; Morelli, Mara; Giglio, Fabio; Levati, Giorgia; Assanelli, Andrea; Carrabba, Matteo G; Bellio, Laura; Milani, Raffaella; Lorentino, Francesca; Stanghellini, Maria Teresa Lupo; De Freitas, Tiago; Marktel, Sarah; Bernardi, Massimo; Corti, Consuelo; Vago, Luca; Bonini, Chiara; Ciceri, Fabio; Peccatori, Jacopo

    2015-08-01

    Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/μL of 41 days. Cumulative incidences of grade II to IV and III-IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth.

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    Robbert G van der Most

    Full Text Available BACKGROUND: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. METHODS AND FINDINGS: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-alpha/beta response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-gamma and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5 antibodies. CONCLUSION: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion.

  19. Cyclophosphamide-induced Down-Regulation of Uroplakin II in the Mouse Urinary Bladder Epithelium is Prevented by S-Allyl Cysteine.

    Science.gov (United States)

    Abdi, Sayed Aliul Hasan; Najmi, Abul Kalam; Raisuddin, Sheikh

    2016-12-01

    The alkylating anticancer drug, cyclophosphamide (CP), induces a number of toxic effects including haemorrhagic cystitis (HC) in the urinary bladder. Uroplakins are unique urinary transmembrane proteins of urothelium, which may become potential targets of CP metabolites and reactive free radicals. Natural compounds, especially those rich in thiols, have shown protective effects against CP-induced HC. In this study, we studied the modulatory effect of the thiol-rich compound S-allyl cysteine (SAC) on the mRNA level of uroplakin II by real-time polymerase chain reaction and expression of uroplakin II protein by immunoblotting. SAC (150 mg/kg) showed significant (p bladder. When compared with mercaptoethane sulphonic acid (mesna) (40 mg/kg), a known thiol-rich drug used in clinical application, SAC was found to be more efficacious in affording protection in urinary bladder tissues. Role of uroplakins in CP-induced urinary bladder toxicity has not been well investigated. This study demonstrated that uroplakins may be the potential target of toxic metabolites of CP and natural compounds such as SAC have the capacity to modulate their expression leading to reduced toxicity burden on the urinary bladder epithelium. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  20. Bone marrow transplantation for girls with aplastic anemia utilizing modified field of total lymphoid irradiation and cyclophosphamide; With emphasis on the field of pelvic cavity

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    Hanada, Ryoji; Kawakami, Tetsuo; Akuta, Naoko; Moriwaki, Kohichi; Kato, Shizue; Inaba, Toshiya; Hayashi, Yasuhide; Yamamoto, Keiko (Saitama Children' s Medical Center, Saitama (Japan))

    1990-12-01

    A preparative regimen for allogeneic bone marrow transplantation, consisting of total lymphoid irradiation (TLI) with 750 cGy and cyclophosphamide (CY), was used in five girls with aplastic anemia. All patients received bone marrow from HLA matched/mixed lymphocyte culture negative siblings. In our regimen the 'inverted Y' field to irradiate the pelvic nodes was modified, which did not include the whole pelvic cavity in an attempt to protect the ovaries from irradiation. Although some of the pelvic nodes was supported not to be irradiated in order to protect the ovaries, engraftment occurred in all five patients including four who had been transfused prior to transplantation. All five are alive from 47 days to 1378 days (median 285 days) after transplantation without tranplantation-associated complications. The calculated dose to the ovaries was sixteen percent of the entire dose of the regimen. Both of the two evaluable patients that had received tranplantation just before or during the puberty are developing normal sex maturity including menstruation. This study suggests that our preparative regimen is effective not only for engraftment of the donor marrow but also for protecting the ovaries from irradiation. (author).

  1. Distinction by concanavalin A agglutination between ulceration and repair of rat bladder epithelium induced by freezing or cyclophosphamide and the effect of sodium saccharin.

    Science.gov (United States)

    Suzuki, T; Hasegawa, R; Murasaki, G; Cohen, S M

    1984-01-01

    Agglutination of rat urinary bladder epithelial cells by concanavalin A (Con A) has been reported to be an early marker of bladder carcinogenesis. Ulceration of the bladder, induced by cyclophosphamide (CP) or freezing, followed by sodium saccharin in the diet results in the induction of bladder cancer. In the present studies, the agglutination of rat urinary bladder epithelial cells by Con A was shown to be increased during the regenerative hyperplasia following ulceration induced by i.p. CP injection, but it returned to normal levels by Day 21 when the preparative process was nearly complete. This effect correlated quantitatively with the dose of CP. However, if CP administration was followed by sodium saccharin in the diet beginning 14 days after the injection, the agglutinability of bladder cells by Con A persisted. In contrast, agglutination of bladder cells by Con A during regenerative hyperplasia following ulceration induced by freezing was not increased whether sodium saccharin was fed or not. These results indicate that Con A agglutination distinguishes between the regenerative hyperplasia induced by CP or freezing, even though either method followed by sodium saccharin in the diet results in bladder cancer in the rat.

  2. Increased expression of interleukin (IL-6 family members and receptors in urinary bladder with cyclophosphamide (CYP-induced bladder inflammation in female rats

    Directory of Open Access Journals (Sweden)

    Beatrice eGirard

    2011-02-01

    Full Text Available Recent studies suggest that JAK-STAT signaling pathways contribute to increased voiding frequency and referred pain of CYP-induced cystitis in rats. Potential upstream chemical mediator(s that may be activated by CYP-induced cystitis to stimulate JAK/STAT signaling are not known in detail. In these studies, members of the interleukin (IL-6 family of cytokines including, leukemia inhibitory factor (LIF, IL-6 and ciliary neurotrophic factor (CNTF and associated receptors, IL-6 receptor (R α, LIFR and gp130 were examined in the urinary bladder in control and CYP-treated rats. Cytokine and receptor transcript and protein expression and distribution were determined in urinary bladder after cyclophosphamide (CYP-induced cystitis using quantitative, real-time polymerase chain reaction (Q-PCR, western blotting and immunohistochemistry. Acute (4 hr; 150 mg/kg; i.p., intermediate (48 hr; 150 mg/kg; i.p. or chronic (75 mg/kg; i.p., once every 3 days for 10 days cystitis was induced in adult, female Wistar rats with CYP treatment. Q-PCR analyses revealed significant (p ≤ 0.01 CYP duration- and tissue- (e.g., urothelium, detrusor dependent increases in LIF, IL-6, IL-6Rα, LIFR and gp130 mRNA expression. Western blotting demonstrated significant (p ≤ 0.01 increases in IL-6, LIF and gp130 protein expression in whole urinary bladder with CYP treatment. CYP-induced cystitis significantly (p ≤ 0.01 increased LIF-immunoreactivity (IR in urothelium, detrusor, and suburothelial plexus whereas increased gp130-IR was only observed in urothelium and detrusor. These studies suggest that IL-6 and LIF may be potential upstream chemical mediators that activate JAK/STAT signaling in urinary bladder pathways.

  3. Upfront plerixafor plus G-CSF versus cyclophosphamide plus G-CSF for stem cell mobilization in multiple myeloma: efficacy and cost analysis study.

    Science.gov (United States)

    Afifi, S; Adel, N G; Devlin, S; Duck, E; Vanak, J; Landau, H; Chung, D J; Lendvai, N; Lesokhin, A; Korde, N; Reich, L; Landgren, O; Giralt, S; Hassoun, H

    2016-04-01

    Cyclophosphamide plus G-CSF (C+G-CSF) is one of the most widely used stem cell (SC) mobilization regimens for patients with multiple myeloma (MM). Plerixafor plus G-CSF (P+G-CSF) has demonstrated superior SC mobilization efficacy when compared with G-CSF alone and has been shown to rescue patients who fail mobilization with G-CSF or C+G-CSF. Despite the proven efficacy of P+G-CSF in upfront SC mobilization, its use has been limited, mostly due to concerns of high price of the drug. However, a comprehensive comparison of the efficacy and cost effectiveness of SC mobilization using C+G-CSF versus P+G-CSF is not available. In this study, we compared 111 patients receiving C+G-CSF to 112 patients receiving P+G-CSF. The use of P+G-CSF was associated with a higher success rate of SC collection defined as ⩾5 × 10(6) CD34+ cells/kg (94 versus 83%, P=0.013) and less toxicities. Thirteen patients in the C+G-CSF arm were hospitalized owing to complications while none in the P+G-CSF group. C+G-CSF was associated with higher financial burden as assessed using institutional-specific costs and charges (P<0.001) as well as using Medicare reimbursement rates (P=0.27). Higher rate of hospitalization, increased need for salvage mobilization, and increased G-CSF use account for these differences.

  4. High-dose cyclophosphamide followed by autologous peripheral blood progenitor cell transplantation improves the salvage treatment for persistent or sensitive relapsed malignant lymphoma

    Directory of Open Access Journals (Sweden)

    Baldissera R.C.

    2002-01-01

    Full Text Available Trials have demonstrated that high-dose escalation followed by autologous transplantation can promote better long-term survival as salvage treatment in malignant lymphomas. The aim of the present nonrandomized clinical trial was to demonstrate the role of high-dose cyclophosphamide (HDCY in reducing tumor burden and also to determine the effectiveness of HDCY followed by etoposide (VP-16 and methotrexate (MTX in Hodgkin's disease plus high-dose therapy with peripheral blood progenitor cell (PBPC transplantation as salvage treatment. From 1998 to 2000, 33 patients with a median age of 33 years (13-65 affected by aggressive non-Hodgkin's lymphoma (NHL (60.6% or persistent or relapsed Hodgkin's disease (39.4% were enrolled and treated using high dose escalation (HDCY + HDVP-16 plus HDMTX in Hodgkin's disease followed by autologous PBPC transplantation. On an "intention to treat" basis, 33 patients with malignant lymphomas were evaluated. The overall median follow-up was 400 days (40-1233. Thirty-one patients underwent autografting and received a median of 6.19 x 10(6/kg (1.07-29.3 CD34+ cells. Patients who were chemosensitive to HDCY (N = 22 and patients who were chemoresistant (N = 11 presented an overall survival of 96 and 15%, respectively (P<0.0001. Overall survival was 92% for chemosensitive patients and 0% for patients who were still chemoresistant before transplantation (P<0.0001. Toxicity-related mortality was 12% (four patients, related to HDCY in two cases and to transplant in the other two. HDCY + HDVP-16 plus HDMTX in only Hodgkin's disease followed by autologous PBPC proved to be effective and safe as salvage treatment for chemosensitive patients affected by aggressive NHL and Hodgkin's disease, with acceptable mortality rates related to sequential treatment.

  5. Phase II study of adjuvant docetaxel and carboplatin with/without doxorubicin and cyclophosphamide in triple negative breast cancer: a randomised controlled clinical trial

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    Safa Najafi

    2017-03-01

    Full Text Available Aim of the study: The aim of this trial was to compare overall survival (OS, disease-free survival (DFS, and toxicity of two adjuvant regimens in triple negative patients with Iranian ethnicity. Material and methods: In a phase II trial, patients with previously untreated triple negative breaststroke cancer were randomly assigned by using docetaxel 70 mg/m 2 and carboplatin AUC = 7 every three weeks with granulocyte colony-stimulating factor for sin courses (arm A or doxorubicin hydrochloride 60 mg/m 2 and cyclophosphamide 600 mg/m 2 every three weeks with G-CSF for four courses followed by docetaxel 70 mg/m 2 and carboplatin AUC = 7 every three weeks with G-CSF for four courses (arm B. Results : A total of 119 patients were randomly enrolled in our study (60 patients in Arm A and 59 patients in Arm B between 2011 and 2016. The mean follow-up was 40 months at the time of treatment analysis. The 2-year and 5-year DFS rates for Arm A were 92.7% vs. 85% and for Arm B were 82.6% vs. 64.4%. The 2-year and 5-year OS rates for Arm A were 96.5% vs. 91.7% and for Arm B were 90.5% vs. 81.3%. There was a significant correlation for DFS and OS in the two arms. There was no significant difference between adverse events with the two regimens. Conclusions : In our research, less progression was found with Arm A as compared to Arm B. Adding of anthracyclines such as doxorubicin hydrochloride did not increase OS and DFS in triple negative breast cancer (TNBC patients.

  6. Effects of Saw Palmetto Extract on Urodynamic Parameters, Bladder Muscarinic and Purinergic Receptors and Urinary Cytokines in Rats with Cyclophosphamide-Induced Cystitis.

    Science.gov (United States)

    Nasrin, Sweety; Masuda, Eiji; Kugaya, Haruna; Osano, Ayaka; Ito, Yoshihiko; Yamada, Shizuo

    2014-01-01

    To clarify the effect of saw palmetto extract (SPE), a phytotherapeutic agent, on urodynamic parameters, bladder muscarinic and purinergic receptors, and urinary cytokines in rats with cystitis induced by cyclophosphamide (CYP). Saw palmetto extract (60 mg/kg per day) was administered orally twice a day for 7 days to rats. The urodynamic parameters in CYP (150 mg/kg i.p.)-treated rats were monitored by a cystometric method under anesthesia. The muscarinic and purinergic receptors in the bladder and submaxillary gland were measured by radioreceptor assays using [N-methyl-(3) H] scopolamine chloride([(3) H]NMS) and αβ-methylene-ATP [2,8-(3) H] tetrasodium salt ([(3) H]αβ-MeATP), respectively. Urinary cytokines (interleukin-1β [IL-1β], IL-6 and L-17) were measured with enzyme linked immunosorbent assay kits. Micturition interval and micturition volume were significantly decreased and the frequency of micturition and basal pressure were significantly increased in the CYP-treated rats compared with sham-operated rats. Orally administered SPE significantly increased the micturition interval and micturition volume and decreased the frequency of micturition and basal pressure. The maximal number of sites (Bmax ) for the specific binding of [(3) H]NMS and [(3) H]αβ-MeATP was significantly decreased in the bladder. The decrease in receptors was attenuated by repeated treatment with SPE. An elevation in urinary cytokine (IL-1β and IL-17) levels were seen, and this increase was effectively suppressed by SPE treatment. Saw palmetto extract attenuates the alteration of urodynamic parameters, pharmacologically relevant receptors, and urinary cytokines in CYP-treated rats. Therefore, SPE may be a potential therapeutic agent for improving the clinical symptoms of cystitis. © 2013 Wiley Publishing Asia Pty Ltd.

  7. Protective specific immunity induced by cyclophosphamide plus tumor necrosis factor alpha combination treatment of EL4-lymphoma-bearing C57BL/6 mice.

    Science.gov (United States)

    Krawczyk, C M; Verstovsek, S; Ujházy, P; Maccubbin, D; Ehrke, M J

    1995-06-01

    A combination treatment protocol initiated 12 days after tumor injection, when the tumor was large, by administering cyclophosphamide (CY, 150 or 250 mg/kg) intraperitoneally followed by intravenous tumor necrosis factor alpha (TNF alpha, 1000 units injection) on days 13, 16, 18, 21, and 23, resulted in about 60% long-term survival (i.e., survival for at least 60 days) in the syngeneic C57BL/6 mouse/EL4 lymphoma model system. The establishment of a specific antitumor immune memory and its possible therapeutic relevance was verified by reinjecting 60-day survivors with EL4 cells; all 60-day survivors that had received the combination treatments rejected the implants and survived for a further 60 days. Thymic cellularity was reduced during treatment and its recovery appeared to correlate with long-term survival and immunity. Thymocytes from mice treated with the combination were found to express significant levels of specific anti-EL4 cytolytic activity following a 4-day stimulation culture with X-irradiated EL4 cells and low concentrations of interleukin-2. This response could not be generated with thymocytes from naive animals. In each case the effect seen with the combination of a moderate CY dose (150 mg/kg) with TNF alpha was better than that seen with either dose of CY alone and equal to or better than that seen with the higher dose of CY combined with TNF alpha. These results indicate that treatment with a single moderate dose of CY in combination with TNF alpha is effective against a large, established tumor in this murine model. Furthermore, all the long-term survivors induced by this treatment developed protective immunity against reimplanted tumor and demonstrated a long-term specific immune memory in the thymus.

  8. Combined protective effect of zinc oxide nanoparticles and melatonin on cyclophosphamide-induced toxicity in testicular histology and sperm parameters in adult Wistar rats

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    Fereshte Torabi

    2017-08-01

    Full Text Available Background: Cyclophosphamide (CP has been known as an anticancer drug with several side effects on various organs such as a male reproductive system that can cause infertility. Objective: To evaluate the possible combined effects of zinc oxide nanoparticles (nZno and melatonin (Mel on sperm parameters and histopathological changes of the testis in CP-treated rats. Materials and Methods: 42 adult male Wistar rats were divided into six groups. GI: control, GII: 60 mg/kg/wk CP, GIII and GIV, 10 mg/kg/wk Mel and 5mg/kg/wk nZno and GV: 5 mg/kg/wk nZno and 10 mg/kg/wk Mel were given 2 hr prior to CP injection, respectively,GVI: 5mg/kg/wk nZno and 10 mg/kg/wk Mel simultaneously. After 8 wk of treatment, rats were sacrificed and testis and epididymis were harvested for further evaluation. Results: The CP-treated group showed significant decreases in the body, testes and epididymis weights and sperm parameters (sperm count, viability, motility with an increase abnormal sperms when compared with the control (p<0.001, as well as many histological alterations included decreased diameters of seminiferous tubules and Johnsen’s Testicular Score (with degeneration, desquamation, multi-nucleated giant cell formation, whereas combined treatment (GV, showed more protective effects on CP-induced reproductive system damage compared with groups III or IV (p<0.001. Conclusion: These results suggest simultaneous administration of Mel and nZno have more effectively protections against CP-induced reproductive damage than Mel or nZno alone.

  9. Comparison of Cyclophosphamide Combined with Total Body Irradiation, Oral Busulfan, or Intravenous Busulfan for Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Mitsuhashi, Kenjiro; Kako, Shinichi; Shigematsu, Akio; Atsuta, Yoshiko; Doki, Noriko; Fukuda, Takahiro; Kanamori, Heiwa; Onizuka, Makoto; Takahashi, Satoshi; Ozawa, Yukiyasu; Kurokawa, Mineo; Inoue, Yoshiko; Nagamura-Inoue, Tokiko; Morishima, Yasuo; Mizuta, Shuichi; Tanaka, Junji

    2016-12-01

    We conducted a retrospective analysis to compare outcomes in adult patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) with conditioning regimens containing cyclophosphamide (CY) in combination with total body irradiation (TBI), oral busulfan (p.o. BU), or intravenous busulfan (i.v. BU). We used data for January 2000 to December 2012 from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We identified 2130 patients treated with TBI/CY (n = 2028), p.o. BU/CY (n = 60), or i.v. BU/CY (n = 42). Two-year overall survival (OS) and 2-year relapse-free survival rates were 69.0% and 62.1%, respectively, in the TBI/CY group, 55.9% and 54.2% in the p.o. BU/CY group, and 71.0% and 46.8% in the i.v. BU/CY group. In multivariate analysis, compared with TBI/CY, p.o. BU/CY, but not i.v. BU/CY, was associated with lower OS (hazard ratio [HR], 1.46; P = .047) and a higher incidence of sinusoidal obstruction syndrome (HR, 3.36; P = .030). No between-group differences were seen in the incidence of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), or chronic GVHD. We suggest that i.v. BU/CY might be a possible alternative allo-HCT conditioning regimen for adults with ALL who are not suitable for TBI. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  10. 131I-Anti-CD45 Antibody Plus Busulfan and Cyclophosphamide before Allogeneic Hematophoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia in First Remission

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    Pagel, John M.; Appelbaum, Frederick R.; Eary, Janet F.; Rajendran, Joseph G.; Fisher, Darrell R.; Gooley, Ted; Ruffner, Katherine; Nemecek, Eneida; Sickle, Eileen; Durack, Larry; Carreras, Jeanette; Horowitz, Mary; Press, Oliver W.; Gopal, Ajay K.; Martin, Paul J.; Bernstein, Irwin D.; Matthews, Dana C.

    2006-03-01

    In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a Phase I/II study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/ml) and cyclophosphamide (CY; 120 mg/kg). Fifty-two of 59 patients (88%) receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102-298 mCi 131I delivering an estimated 5.3-19 (mean 11.3) Gy to marrow, 17-72 (mean 29.7) Gy to spleen, and 3.5 Gy (n=4) to 5.25 Gy (n=42) to the liver. The estimated 3-year non-relapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared to those from 509 similar International Bone Marrow Transplant Registry patients transplanted using BU/CY alone. After adjusting for differences in age and cytogenetics-risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; p=.09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and Phase II results are sufficiently encouraging to warrant further study.

  11. A suicide gene therapy combining the improvement of cyclophosphamide tumor cytotoxicity and the development of an anti-tumor immune response.

    Science.gov (United States)

    Touati, Walid; Tran, Thi; Seguin, Johanne; Diry, Monique; Flinois, Jean-Pierre; Baillou, Claude; Lescaille, Geraldine; Andre, Francois; Tartour, Eric; Lemoine, Francois M; Beaune, Philippe; de Waziers, Isabelle

    2014-01-01

    Gene-directed enzyme prodrug therapy (GDEPT) consists in targeted delivery to tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. One of the major limitations of this strategy in clinical application was the poor prodrug activation capacity of suicide gene. We built a highly efficient suicide gene capable of bioactivating the prodrug cyclophosphamide (CPA) by fusing a CYP2B6 triple mutant with NADPH cytochrome P450 reductase (CYP2B6TM-RED). Expression of this fusion gene via a recombinant lentivirus (LV) vector converted resistant human (A549) and murine (TC1) pulmonary cell lines into CPA-susceptible cell lines. We tested the efficiency of our GDEPT strategy in C57Bl/6 immunocompetent mice, using TC1 cells expressing the HPV-16 E6/E7 oncoproteins. In mice bearing tumors composed only of TC1-CYP2B6TM-RED cells, four CPA injections (140 mg/Kg once a week) completely eradicated the tumors for more than two months. Tumors having only 25% of TC1-CYP2B6TM-RED cells were also completely eradicated by five CPA injections, demonstrating a major in vivo bystander effect. Moreover, surviving mice were rechallenged with parental TC1 cells. The tumors regressed spontaneously 7 days after cell inoculation or grew more slowly than in control naive mice due to a strong immune response mediated by anti-E7CD8(+)T cells. These data suggest that combining the CYPB6TM-RED gene with CPA may hold promise as a highly effective treatment for solid tumors in humans.

  12. Adenoviral delivery of pan-caspase inhibitor p35 enhances bystander killing by P450 gene-directed enzyme prodrug therapy using cyclophosphamide+

    Directory of Open Access Journals (Sweden)

    Doloff Joshua C

    2010-09-01

    Full Text Available Abstract Background Cytochrome P450-based suicide gene therapy for cancer using prodrugs such as cyclophosphamide (CPA increases anti-tumor activity, both directly and via a bystander killing mechanism. Bystander cell killing is essential for the clinical success of this treatment strategy, given the difficulty of achieving 100% efficient gene delivery in vivo using current technologies. Previous studies have shown that the pan-caspase inhibitor p35 significantly increases CPA-induced bystander killing by tumor cells that stably express P450 enzyme CYP2B6 (Schwartz et al, (2002 Cancer Res. 62: 6928-37. Methods To further develop this approach, we constructed and characterized a replication-defective adenovirus, Adeno-2B6/p35, which expresses p35 in combination with CYP2B6 and its electron transfer partner, P450 reductase. Results The expression of p35 in Adeno-2B6/p35-infected tumor cells inhibited caspase activation, delaying the death of the CYP2B6 "factory" cells that produce active CPA metabolites, and increased bystander tumor cell killing compared to that achieved in the absence of p35. Tumor cells infected with Adeno-2B6/p35 were readily killed by cisplatin and doxorubicin, indicating that p35 expression is not associated with acquisition of general drug resistance. Finally, p35 did not inhibit viral release when the replication-competent adenovirus ONYX-017 was used as a helper virus to facilitate co-replication and spread of Adeno-2B6/p35 and further increase CPA-induced bystander cell killing. Conclusions The introduction of p35 into gene therapeutic regimens constitutes an effective approach to increase bystander killing by cytochrome P450 gene therapy. This strategy may also be used to enhance other bystander cytotoxic therapies, including those involving the production of tumor cell toxic protein products.

  13. VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide

    Science.gov (United States)

    Orlandi, P; Fontana, A; Fioravanti, A; Di Desidero, T; Galli, L; Derosa, L; Canu, B; Marconcini, R; Biasco, E; Solini, A; Francia, G; Danesi, R; Falcone, A; Bocci, G

    2013-01-01

    Background: No data are available on the pharmacogenetics of metronomic chemotherapy in prostate cancer. The aim of this study was to evaluate the association between VEGF-A sequence variants and prostate-specific antigen (PSA) progression, progression-free survival (PFS) and overall survival (OS), in advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide (CTX), celecoxib and dexamethasone. Methods: Forty-three patients were enrolled, and genomic DNA was extracted. VEGF-A gene SNPs (−2578A/C, −634C/G, +936C/T) were analysed using TaqMan PCR assays. Hardy–Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated by Fisher's exact test. PFS and OS were analysed with GraphPad Prism software, using the product limit method of Kaplan and Meier, and comparing survival curves using both the log-rank test and the Gehan–Wilcoxon test. We used Bonferroni correction to account for multiple testing, and a two-tailed P-value of <0.017 was considered statistically significant. Results: Overall, 20 patients (46%) experienced a reduction in PSA levels from baseline and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. In non-responders, the −2578CC genotype was more frequent (18.60% vs 2.33% in responders; P=0.0212) whereas the −634CC genotype frequency was 22.73% vs 0% in responders (P=0.0485). With regard to PFS, patients harbouring the −634CC genotype had a median PFS of 2.2 months whereas patients with the genotype −634CG/GG had a median PFS of 6.25 months (P=0.0042). Conclusion: The −634CC genotype is significantly associated with a shorter PFS in patients treated with a metronomic CTX schedule. PMID:23860526

  14. Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia.

    Science.gov (United States)

    Strati, Paolo; Wierda, William; Burger, Jan; Ferrajoli, Alessandra; Tam, Constantine; Lerner, Susan; Keating, Michael J; O'Brien, Susan

    2013-11-01

    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. 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. 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%). 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 should encourage surveillance for

  15. A novel method for assessing bladder-related pain reveals the involvement of nerve growth factor in pain associated with cyclophosphamide-induced chronic cystitis in mice.