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Sample records for radiation cyclophosphamide busulfan

  1. OUTCOMES FOLLOWING HCT USING FLUDARABINE, BUSULFAN AND THYMOGLOBULIN: A MATCHED COMPARISON TO ALLOGENEIC TRANSPLANTS CONDITIONED WITH BUSULFAN AND CYCLOPHOSPHAMIDE

    PubMed Central

    Bredeson, Christopher N.; Zhang, Mei-Jie; Agovi, Manza-A.; Bacigalupo, Andrea; Bahlis, Nizar J.; Ballen, Karen; Brown, Christopher; Chaudhry, M. Ahsan; Horowitz, Mary M.; Kurian, Seira; Quinlan, Diana; Muehlenbien, Catherine E.; Russell, James A.; Savoie, Lynn; Rizzo, J. Douglas; Stewart, Douglas A.

    2012-01-01

    We have reported a lower incidence of acute graft versus host disease (aGVHD) with a novel conditioning regimen using low dose rabbit anti-thymocyte globulin (TG, Thymoglobulin) with fludarabine and intravenous busulfan (FluBuTG). To assess further this single center experience, we performed a retrospective matched pair analysis comparing outcomes of adult patients transplanted using the FluBuTG conditioning regimen with matched controls from patients reported to the CIBMTR receiving a first allogeneic hematopoietic stem cell transplant (HCT) after standard oral busulfan and cyclophosphamide (BuCy). 120 cases and 215 matched controls were available for comparison. Patients receiving FluBuTG had significantly less treatment related mortality (12% vs 34%, p<0.001) and grades II–IV aGVHD (15% vs 34% p<0.001) compared to BuCy patients. The risk of relapse was higher in the FluBuTG patients (42% vs 20%, p<0.001). The risks of chronic GVHD (cGVHD) and disease free survival (DFS) were similar in the cases and controls. These results suggest that the novel regimen FluBuTG decreases the risk of aGVHD and transplant mortality after HLA-identical sibling HCT, but is associated with an increased risk of relapse, resulting in similar DFS. Whether these conditioning regimens may be more suitable for specific patient populations based on relapse risk requires testing in prospective randomized trials. PMID:18721762

  2. Comparison of Outcomes of Allogeneic Transplantation for CML with Cyclophosphamide in Combination with Intravenous Busulfan, Oral Busulfan or TBI

    PubMed Central

    Copelan, Edward A.; Avalos, Belinda; Ahn, Kwang Woo; Zhu, Xiaochun; Gale, Robert Peter; Grunwald, Michael R.; Hamadani, Mehdi; Hamilton, Betty K.; Hale, Gregory A.; Marks, David I.; Waller, Edmund K.; Savani, Bipin N.; Costa, Luciano J.; Ramanathan, Muthalagu; Cahn, Jean-Yves; Khoury, H. Jean; Weisdorf, Daniel J.; Inamoto, Yoshihiro; Kamble, Rammurti T.; Schouten, Harry C.; Wirk, Baldeep; Litzow, Mark R.; Aljurf, Mahmoud D.; van Besien, Koen W.; Ustun, Celalettin; Bolwell, Brian J.; Bredeson, Christopher N.; Fasan, Omotayo; Ghosh, Nilanjan; Horowitz, Mary M.; Arora, Mukta; Szer, Jeffrey; Loren, Alison W.; Alyea, Edwin P.; Cortes, Jorge; Maziarz, Richard T.; Kalaycio, Matt E.; Saber, Wael

    2014-01-01

    Cyclophosphamide in combination with busulfan (Bu) or total body irradiation (TBI) are the most commonly used myeloablative conditioning regimens in patients with Chronic Myeloid Leukemia (CML). We used data from the Center for International Bone Marrow Transplantation Research to compare outcomes in adults who underwent hematopoietic cell transplantation for CML in first chronic phase following myeloablative conditioning with cyclophosphamide (Cy) in combination with TBI, oral Bu or intravenous (IV) Bu. Four hundred thirty-eight adults received human leukocyte antigen (HLA)-matched sibling grafts and 235 received well-matched grafts from unrelated donors from 2000 through 2006. Important differences existed between the groups in distribution of donor relation, exposure to tyrosine kinase inhibitors and year of transplantation. In multivariate analysis, relapse occurred less frequently among patients receiving IV Bu compared to TBI (RR=0.36; P=0.022) or oral Bu (RR=0.39; P=0.028), but non-relapse mortality and survival were similar. A significant interaction was detected between donor relation and the main effect in leukemia-free survival (LFS). Among recipients of HLA-identical sibling grafts, but not URD grafts, LFS was better in patients receiving IV (RR=0.53; P=0.025) or oral Bu (RR=0.64; P=0.017) compared to TBI. In CML in first chronic phase, Cy in combination with IV Bu was associated with less relapse than TBI or oral Bu. LFS was better following IV or oral Bu compared to TBI. PMID:25528388

  3. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning

    PubMed Central

    Brazauskas, Ruta; Rizzo, J. Douglas; Sobecks, Ronald M.; Wang, Zhiwei; Horowitz, Mary M.; Bolwell, Brian; Wingard, John R.; Socie, Gerard

    2011-01-01

    Risks of secondary solid cancers among allogeneic hematopoietic cell transplant (HCT) recipients who receive conditioning without total body irradiation are not well known. We evaluated the incidence and risk factors for solid cancers after HCT using high-dose busulfan-cyclophosphamide conditioning in 4318 recipients of first allogeneic HCT for acute myeloid leukemia in first complete remission (N = 1742) and chronic myeloid leukemia in first chronic phase (N = 2576). Our cohort represented 22 041 person-years at risk. Sixty-six solid cancers were reported at a median of 6 years after HCT. The cumulative-incidence of solid cancers at 5 and 10 years after HCT was 0.6% and 1.2% among acute myeloid leukemia and 0.9% and 2.4% among chronic myeloid leukemia patients. In comparison to general population incidence rates, HCT recipients had 1.4× higher than expected rate of invasive solid cancers (95% confidence interval, 1.08-1.79, P = .01). Significantly elevated risks were observed for tumors of the oral cavity, esophagus, lung, soft tissue, and brain. Chronic graft-versus-host disease was an independent risk factor for all solid cancers, and especially cancers of the oral cavity. Recipients of allogeneic HCT using busulfan-cyclophosphamide conditioning are at risk for developing solid cancers. Their incidence continues to increase with time, and lifelong cancer surveillance is warranted in this population. PMID:20926773

  4. Etoposide in combination with cyclophosphamide and total body irradiation or busulfan as conditioning for marrow transplantation in adults and children

    SciTech Connect

    Spitzer, T.R.; Ortlieb, M.; Tefft, M.C.; Torrisi, J.; Cahill, R.; Deeg, H.J. ); Peters, C.; Gadner, H. ); Urban, C. )

    1994-04-30

    In an attempt to intensify conditioning therapy for bone marrow transplantation of hematologic malignancies, a retrospective three center evaluation of escalating doses of etoposide added to cyclophosphamide and either total body irradiation or busulfan was undertaken. Seventy-six patients who received etoposide (25-65 mg/kg) added to cyclophosphamide (60-120 mg/kg) and either total body irradiation (12.0-13.2 Gy) or busulfan (12-16 mg/kg) were evaluable for toxicity. Fifty-one of the evaluable patients received allogeneic transplants, while twenty-six received autologous transplants. A comparative analysis of toxicities according to conditioning regimen, donor source and etoposide dose was made. Similar toxicities were observed among the treatment groups with the exception of more frequent skin (p = 0.03) and life threatening hepatic toxicities (p = 0.01) in the busulfan treated patients. Life threatening or fatal toxicities were not influenced by donor source, either when analyzed by treatment group or etoposide dose. Etoposide at a dose of 60-65 mg/kg in combination with TBI and cyclophosphamide was associated with a significantly increased incidence of life threatening or fatal toxicities compared with a combination using a dose of 25-50 mg/kg (15 of 24 vs. 5 of 20; p = 0.013). The maximally tolerated dose of etoposide in combination with busulfan and cyclophosphamide cannot be definitively established in this analysis in part due to the heterogeneity of the patient population and treatment schemes. Although toxicities with bone marrow transplant preparative regimens containing etoposide in combination with cyclophosphamide and total body irradiation or busulfan were frequently severe, treatment related mortality risk was believed to be acceptably low. 27 refs., 3 tabs.

  5. Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes

    PubMed Central

    Rezvani, Andrew R.; McCune, Jeannine S.; Storer, Barry E.; Batchelder, Ami; Kida, Aiko; Deeg, H. Joachim; McDonald, George B.

    2013-01-01

    Targeted busulfan/cyclophosphamide (TBU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from TBU/CY to CY/TBU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/TBU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800–900 ng/mL. CY/TBU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to TBU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with TBU/CY for the same indications. In patients with myelofibrosis, CY/TBU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after TBU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/TBU cohort (2% vs. 13%, p=0.01). CY/TBU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/TBU is superior to TBU/CY as conditioning for patients with myelofibrosis. PMID:23583825

  6. Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide*

    PubMed Central

    Jiang, Yan; Zhao, Jing; Qi, Hui-jing; Li, Xiao-lin; Zhang, Shi-rong; Song, Daniel W.; Yu, Chi-yang; Gao, Jian-gang

    2013-01-01

    Busulfan/cyclophosphamide (Bu/Cy) conditioning regimen has been widely used to treat cancer patients, while their effects on major internal organs in females are not fully understood. We treated female mice with Bu/Cy, and examined the histopathology of major internal organs on Day 30 after the treatment. The results show that Bu/Cy treatment affected the ovaries most extensively, while it had less effect on the spleen, lungs, and kidneys, and no effect on the heart, liver, stomach, and pancreas. To better understand the effect of Bu/Cy on the ovaries, we counted follicles, and determined the levels of ovarian steroids. The Bu/Cy-treated mice showed a reduction of primordial and primary follicles (P<0.01) on Day 30 and a marked loss of follicles at all developmental stages (P<0.01) on Day 60. Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%, respectively. Thus, there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice; this is a profile similar to what is found in women with premature ovarian failure (POF). The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF. PMID:23549849

  7. Therapeutic drug monitoring for either oral or intravenous busulfan when combined with pre- and post-transplantation cyclophosphamide

    PubMed Central

    Lombardi, Lindsey R.; Kanakry, Christopher G.; Zahurak, Marianna; Durakovic, Nadira; Bolaños-Meade, Javier; Kasamon, Yvette L.; Gladstone, Douglas E.; Matsui, William; Borrello, Ivan; Huff, Carol Ann; Swinnen, Lode J.; Brodsky, Robert A.; Ambinder, Richard F.; Fuchs, Ephraim J.; Rosner, Gary L.; Jones, Richard J.; Luznik, Leo

    2016-01-01

    Busulfan (Bu)/cyclophosphamide (Cy) is a standard conditioning platform for allogeneic transplantation. We developed a strategy separating the Cy into two pre/post-transplantation doses (PTCy), providing myeloablative conditioning and single-agent graft-versus-host disease (GVHD) prophylaxis. We investigated the impact of Bu route on treatment-related toxicity for 131 consecutive adult patients. Busulfan was administered in four daily divided doses either orally (n = 72) or intravenously (n = 59) with pharmacokinetics on the first-dose and as necessary on subsequent doses to achieve a target area-under-the-concentration-curve (AUC) of 800–1400 µmol*min/L per dose. BuCy/PTCy with pharmacokinetics is well-tolerated with low treatment-related toxicity. Hepatic veno-occlusive disease incidence was 6% with two fatal events. Bu administration route in the context of BuCy/PTCy did not statistically impact hepatotoxicity, GVHD, relapse, disease-free survival, or overall survival. The BuCy/PTCy platform has a low incidence of treatment-related toxicity, including hepatotoxicity, in hematologic malignancies when using pharmacokinetics for a target AUC of 800–1400 µmol*min/L, irrespective of Bu administration route. PMID:26292764

  8. Daily Weight-Based Busulfan with Cyclophosphamide and Etoposide Produces Comparable Outcomes to Four-Times-Daily Busulfan Dosing for Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.

    PubMed

    Hill, Brian T; Rybicki, Lisa; Carlstrom, Kelley D; Jagadeesh, Deepa; Gerds, Aaron; Hamilton, Betty; Liu, Hien; Dean, Robert; Sobecks, Ronald; Pohlman, Brad; Andresen, Steven; Kalaycio, Matt; Bolwell, Brian J; Majhail, Navneet S

    2016-09-01

    High-dose busulfan (Bu) is an integral component of commonly used preparative regimens for both allogeneic and autologous transplantation. There is significant interest in comparing the efficacy and toxicity of administering Bu every 6 (Bu6) or every 24 hours (daily Bu). To facilitate a therapeutic dose-monitoring protocol, we transitioned from Bu6 to daily Bu dosing for patients with Hodgkin and non-Hodgkin lymphoma undergoing autologous stem cell transplantation (ASCT). Here, we retrospectively review outcomes of 400 consecutive eligible lymphoma patients who underwent ASCT from 2007 to 2013 with high-dose busulfan (Bu), cyclophosphamide (Cy), and etoposide (E). Bu was given at a fixed dose of either .8 mg/kg every 6 hours for 14 doses for 307 patients or a fixed dose of 2.8 mg/kg every 24 hours for 4 doses (days -9 through -6) for 93 patients who underwent transplantation after the transition from Bu6 to daily Bu was made. Toxicity was assessed using pulmonary and liver function tests (LFT) at specified time points before and after ASCT. Baseline patient and disease characteristics of patients dosed with Bu6 and daily Bu were similar. There was no significant difference in forced expiratory volume in 1 second or diffusing capacity of the lungs for carbon monoxide before and after transplantation in the Bu6 versus daily Bu cohorts. Changes in LFTs with daily Bu were not significantly different than those with Bu6. There were no differences in relapse, nonrelapse mortality, progression-free survival, or overall survival between Bu6 and Bu 24 administration schedules in univariable or multivariable analysis (P ≥ .34). For a subset of 23 patients who had first-dose Bu levels measured, we observed significant variation in an median estimated cumulative area under the curve (AUC) of 17,568 µM-minute (range, 12,104 µM-23,084 µM-minute). In conclusion, daily Bu with Cy/E is more convenient than Bu6, has equivalent outcomes, and results in no increase

  9. Comparative Analysis of Busulfan and Cyclophosphamide versus Cyclophosphamide and Total Body Irradiation in Full Intensity Unrelated Marrow Donor Transplantation for Acute Myelogenous Leukemia, Chronic Myelogenous Leukemia and Myelodysplasia

    PubMed Central

    Uberti, Joseph P.; Agovi, Manza-A.; Tarima, Sergey; Haagenson, Michael; Gandham, Sharavi; Anasetti, Claudio; Baker, K. Scott; Bolwell, Brian J.; Bornhauser, Martin; Chan, Ka Wah; Copelan, Edward; Davies, Stella M.; Finke, Juergen; Hale, Gregory A.; Kollman, Craig; McCarthy, Philip L.; Ratanatharathorn, Voravit; Ringdén, Olle; Weisdorf, Daniel J.; Rizzo, J. Douglas

    2011-01-01

    We retrospectively compared clinical outcomes in 1593 T-repleted URD marrow transplant recipients with AML, MDS and CML who received myeloablative conditioning regimens of either busulfan and cyclophosphamide (BuCy), standard-dose Cy/TBI (1,000-1,260 cGy) or high-dose Cy/TBI (1,320-1,500 cGy). Subjects were drawn from patients transplanted between 1991 and 1999 facilitated by the National Marrow Donor Program (NMDP). Patients who received high-dose Cy/TBI regimens were slightly younger, more likely to receive a mismatched transplant and to have intermediate or advanced disease compared to patients in the BuCy or standard-dose TBI group. Neutrophil recovery was significantly higher in the standard dose CY/TBI group compared to the high-dose Cy/TBI or BuCy group. Patients who received the high-dose Cy/TBI regimen had an increased risk of developing grade III-IV aGVHD when compared to the control group who received BuCy (p=0.011). Overall survival (OS), disease free survival (DFS), transplant-related mortality (TRM) and relapse were not significantly different between any of the regimens. We conclude that BuCy, standard-dose and high dose Cy/TBI regimens have equivalent efficacy profiles for OS, DFS, TRM and relapse risk in patients undergoing T-replete URD marrow transplantation for AML, CML and MDS. PMID:20400989

  10. 131I-Anti-CD45 Antibody Plus Busulfan and Cyclophosphamide before Allogeneic Hematophoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia in First Remission

    SciTech Connect

    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 comparison between regimens containing chemotherapy alone (busulfan and cyclophosphamide) and chemotherapy (V. RAPID) plus total body irradiation on marrow engraftment following allogeneic bone marrow transplantation.

    PubMed

    Reynolds, M; McCann, S R

    1989-10-01

    The effect of two conditioning regimens given prior to allogeneic bone marrow transplantation (BMT) on the kinetics of engraftment were compared. 5 patients received busulfan and cyclophosphamide: 7 patients received daunorubicin, vincristine, cytosine arabinoside, methylprednisone and VM-26 plus total body irradiation (TBI). Bone marrow progenitors (BFU-E, CFU-E, CFU-GM, CFU-F) were assayed up to 3 months post-BMT. All progenitors were severely depressed in spite of peripheral blood recovery. There was no stromal recovery in any adult patient post-BMT. There was no significant difference in time to engraftment, or colony forming units, or between patients conditioned with chemotherapy alone or chemotherapy plus TBI. We were unable to detect effects of graft-versus-host disease or cytomegalic viral infection on bone marrow progenitors or peripheral blood recovery in this study. PMID:2684682

  12. Cyclophosphamide

    MedlinePlus

    Cyclophosphamide is used alone or in combination with other medications to treat Hodgkin's lymphoma (Hodgkin's disease) and ... organs where eggs are formed), and breast cancer. Cyclophosphamide is also used to treat nephrotic syndrome (a ...

  13. Bone marrow transplantation from matched related donors for patients with Fanconi anemia using low-dose busulfan and cyclophosphamide as conditioning.

    PubMed

    Torjemane, L; Ladeb, S; Ben Othman, T; Abdelkefi, A; Lakhal, A; Ben Abdeladhim, A

    2006-04-01

    Seventeen patients with Fanconi anemia (FA) underwent allogeneic bone marrow transplantation (BMT) from matched related donors (MRD) between January 1999 and June 2003. Median age at BMT was 11 years. Conditioning regimen consisted of low-dose cyclophosphamide (CY; 40 mg/kg) and busulfan (BU; 6 mg/kg) with the addition of lymphoglobulin (20 mg/kg) in two patients. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A (CsA) and methotrexate (MTX; 5 mg/m(2) at day 1, 3, 6). All patients engrafted (for an absolute neutrophil count >0.5 x 10(9)/L) after a median time of 12 days (range 10-16 days). Fourteen patients (82%) had sustained grafts, whereas three others (18%) rejected grafts between day +39 and +80 after transplantation. Two of them are still alive after successful second PBSC transplantation and one died. Acute and chronic GVHD occurred in 23% and 13% of patients, respectively. With a median follow-up of 16 months (range 3-53 months), survival rate was 72% and Karnofsky score was at least 90%. The low-dose BU/CY regimen, in FA patients allografted from an HLA-matched related donor, allowed engraftment with relative low toxicity. Early graft failure (GF) remains a problem and may require modification of this regimen. PMID:16333862

  14. Once Daily IV Busulfan and Fludarabine (IV Bu-Flu) Compares Favorably with IV Busulfan and Cyclophosphamide (IV BuCy2) as Pretransplant Conditioning Therapy in AML/MDS

    PubMed Central

    Andersson, Borje S.; de Lima, Marcos; Thall, Peter F.; Wang, Xuemei; Couriel, Daniel; Korbling, Martin; Roberson, Soonja; Giralt, Sergio; Pierre, Betty; Russell, James A.; Shpall, Elizabeth J.; Jones, Roy B.; Champlin, Richard E.

    2009-01-01

    Summary We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with IV busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. 67 patients received BuCy2 and subsequently 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these non-randomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 vs. 39 years, p< 0.01), more often had unrelated donors (47.3% vs. 20.9%, p< 0.0003), and had shorter median follow-up (39.7 vs. 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome (“period” effects), 78 AML patients receiving Melphalan-Flu (“MF”), treated in parallel during this time (1997 to 2004) were used to estimate the period effect; The MF patients’ outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in CR1 had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, while CR1 patients younger than age 41 had a 3-year EFS of 89%. These results support replacing BuCy±ATG with Bu-Flu±rabbit-ATG, and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1. PMID:18489993

  15. Cyclophosphamide

    MedlinePlus

    ... cancer (cancer that begins in the female reproductive organs where eggs are formed), and breast cancer. Cyclophosphamide ... This branded product is no longer on the market. Generic alternatives may be available.

  16. Busulfan Injection

    MedlinePlus

    ... cancer cells in preparation for a bone marrow transplant. Busulfan is in a class of medications called ... a total of 16 doses) before bone marrow transplant.Busulfan injection may cause seizures during therapy with ...

  17. Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes.

    PubMed

    Flowers, Christopher R; Costa, Luciano J; Pasquini, Marcelo C; Le-Rademacher, Jennifer; Lill, Michael; Shore, Tsiporah B; Vaughan, William; Craig, Michael; Freytes, Cesar O; Shea, Thomas C; Horwitz, Mitchell E; Fay, Joseph W; Mineishi, Shin; Rondelli, Damiano; Mason, James; Braunschweig, Ira; Ai, Weiyun; Yeh, Rosa F; Rodriguez, Tulio E; Flinn, Ian; Comeau, Terrance; Yeager, Andrew M; Pulsipher, Michael A; Bence-Bruckler, Isabelle; Laneuville, Pierre; Bierman, Philip; Chen, Andy I; Kato, Kazunobu; Wang, Yanlin; Xu, Cong; Smith, Angela J; Waller, Edmund K

    2016-07-01

    Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM. PMID:27040394

  18. Pharmacokinetic-directed high-dose busulfan combined with cyclophosphamide and etoposide results in predictable drug levels and durable long-term survival in lymphoma patients undergoing autologous stem cell transplantation.

    PubMed

    Zhang, Hongzheng; Graiser, Michael; Hutcherson, Donald A; Dada, M Olufemi; McMillan, Stephanie; Ali, Zahir; Flowers, Christopher R; Waller, Edmund K

    2012-08-01

    The clinical advantage of pharmacokinetic (PK)-directed-based dosing on intravenous (i.v.) versus oral busulfan-related toxicity and survival remains unclear. We performed a retrospective cohort study of sequential cohorts of patients comparing PK-directed oral and i.v. busulfan-based conditioning regimens in lymphoma patients undergoing autologous hematopoietic cell transplantation (ASCT). Patients received oral (n = 95), every 6 hours i.v. (IV16, n = 113), or once-daily i.v. (IV4, n = 86) busulfan, cyclophosphamide, and etoposide. PK-directed dosing was performed to achieve a predefined target area under the curve (AUC) of 20,000 μM-min (range: 18,400-21,600 μM-min). PK-directed dose adjustments markedly reduced the number of patients in the oral group with total AUC higher than the targeted AUC range, and reduced the variations of total AUC values in all patient groups. One hundred-day mortality was 2.1%, 3.6%, and 3.5% for oral, IV16, and IV4 cohorts, respectively. Five-year overall survival (OS) was 57% (95% confidence interval [CI] 45%-66%) and 64% (95% CI 53%-73%) for patients who received oral and i.v. busulfan, respectively. Both multivariable and instrumental variable analyses indicated the route of delivery had no significant impact on OS, whereas refractory disease and age ≥55 were significantly associated with poorer OS. In lymphoma patients undergoing ASCT, PK-directed i.v. or oral busulfan-based conditioning regimens have comparable toxicity and OS. PMID:22370160

  19. PHASE II TRIAL OF GVHD PROPHYLAXIS WITH POST-TRANSPLANTATION CYCLOPHOSPHAMIDE FOLLOWING REDUCED-INTENSITY BUSULFAN/FLUDARABINE (BU/FLU) CONDITIONING FOR HEMATOLOGICAL MALIGNANCIES

    PubMed Central

    Alousi, Amin M.; Brammer, Jonathan E.; Saliba, Rima M.; Andersson, Borje; Popat, Uday; Hosing, Chitra; Jones, Roy; Shpall, Elizabeth J; Khouri, Issa; Qazilbash, Muzaffar; Nieto, Yago; Shah, Nina; Ahmed, Sairah; Oran, Betul; Atrash, Gheath Al; Ciurea, Stefan; Kebriaei, Partow; Chen, Julianne; Rondon, Gabriela; Champlin, Richard

    2016-01-01

    GVHD-prophylaxis with post-transplant cyclophosphamide (CY) following ablative HLA-matched bone marrow (BM) transplantation has been reported to have comparable rates of acute GVHD with an apparent reduction in chronic GVHD and infections. We conducted a phase II trial of post-CY following reduced-intensity conditioning (RIC) using intravenous busulfan (AUC of 4,000 micromolar-minutes), Fludarabine (40mg/m2) for 4 days and CY 50mg/kg on days +3 and +4 following BM or peripheral blood (PB) transplants from matched related (MRD) or unrelated donors (MUD). MUD- recipients received anti-thymocyte globulin (ATG); however, a later amendment removed ATG. 49 patients were treated (AML/MDS: 82%). Median age was 62 years (range, 39–72). Fifteen patients received a MRD (9 PB/6 BM); 34 had a MUD (2 PB/32 BM). The cumulative incidence of grade II–IV, III–IV acute and chronic GVHD was 58%, 22% and 18%. A matched-cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II–IV (46% versus 19%, HR=2.8, p=0.02) and treatment-related mortality (HR 3.3, p=0.035) and worse overall survival (HR=1.9, p=0.04) with post-Cy. The incidence of chronic GVHD and CMV reactivation did not differ. This study suggests that post-transplant CY should not be used as sole GVHD-prophylaxis following a RIC transplant from HLA matched donors. PMID:25667989

  20. Phase II Trial of Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide after Reduced-Intensity Busulfan/Fludarabine Conditioning for Hematological Malignancies.

    PubMed

    Alousi, Amin M; Brammer, Jonathan E; Saliba, Rima M; Andersson, Borje; Popat, Uday; Hosing, Chitra; Jones, Roy; Shpall, Elizabeth J; Khouri, Issa; Qazilbash, Muzaffar; Nieto, Yago; Shah, Nina; Ahmed, Sairah; Oran, Betul; Al Atrash, Gheath; Ciurea, Stefan; Kebriaei, Partow; Chen, Julianne; Rondon, Gabriela; Champlin, Richard E

    2015-05-01

    Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (CY) after ablative HLA-matched bone marrow (BM) transplantation has been reported to have comparable rates of acute GVHD with an apparent reduction in chronic GVHD and infections when compared to historical prophylaxis with a calcineurin-inhibitor (CNI) and methotrexate (MTX). We conducted a phase II trial of post-transplantation CY (post-CY) after reduced-intensity conditioning (RIC) using intravenous busulfan (area under the curve of 4000 micromolar minute), fludarabine (40 mg/m(2)) for 4 days, and CY 50 mg/kg on days +3 and +4 after BM or peripheral blood (PB) transplantations from matched related (MRD) or unrelated donors (MUD). MUD recipients received antithymocyte globulin (ATG); however, a later amendment removed ATG. Forty-nine patients were treated (acute myeloid leukemia/myelodysplastic syndrome, 82%). Median age was 62 years (range, 39 to 72). Fifteen patients received an MRD (9 PB/6 BM); 34 had a MUD (2 PB/32 BM). The cumulative incidence of grade II to IV acute GVHD, III to IV acute GVHD, and chronic GVHD was 58%, 22%, and 18%, respectively. A matched cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II to IV (46% versus 19%; hazard ratio [HR], 2.8; P = .02) and treatment-related mortality (HR, 3.3; P = .035) and worse overall survival (HR, 1.9; P = .04) with post-CY. The incidence of chronic GVHD and CMV reactivation did not differ. This study suggests that post-CY should not be used as sole GVHD prophylaxis after a RIC transplantation from HLA-matched donors. PMID:25667989

  1. Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases

    PubMed Central

    Soussain, Carole; Choquet, Sylvain; Fourme, Emmanuelle; Delgadillo, Daniel; Bouabdallah, Krimo; Ghesquières, Hervé; Damaj, Gandhi; Dupriez, Brigitte; Vargaftig, Jacques; Gonzalez, Alberto; Houillier, Caroline; Taillandier, Luc; Hoang-Xuan, Khê; Leblond, Véronique

    2012-01-01

    Background Relapsing primary central nervous system lymphoma carries a poor prognosis when treated with conventional chemotherapy with a one-year overall survival of 25-40%. Encouraging results have been shown with intensive chemotherapy followed by autologous hematopoietic stem cell rescue. We report the results of a large multicenter retrospective analysis of intensive chemotherapy followed by hematopoietic stem cell rescue in immunocompetent adult patients with primary central nervous system lymphoma or intraocular lymphoma after the failure of high-dose methotrexate-based treatment. Design and Methods Patients were included if they received intensive chemotherapy with a combination of thiotepa, busulfan and cyclophosphamide. Seventy-nine patients (median age 52.4 years, range 23-67 years) were identified. All of the patients except 5 received a salvage treatment after the failure of high-dose methotrexate. After salvage treatment and just before intensive chemotherapy followed by hematopoietic stem cell rescue, 32 patients were in complete response, 26 patients were in partial response, 2 patients had stable disease and 19 patients had progressive disease. Results With a median follow up of 56 months, the 5-year overall survival probability was 51% in the whole population and 62% among patients who were chemosensitive to the salvage treatment. The 5-year event-free survival probability was 37.8% in the whole population and 43.7% in the chemosensitive subpopulation. Neurocognitive assessments in a subset of patients suggest no evidence of intensive chemotherapy-induced neurocognitive decline. Conclusions Thiotepa, busulfan and cyclophosphamide-based intensive chemotherapy is an effective treatment for refractory and recurrent primary central nervous system lymphoma in chemosensitive patients up to 65 years of age. The role of intensive chemotherapy followed by hematopoietic stem cell rescue in chemorefractory patients needs to be more accurately defined. PMID

  2. Busulfan kinetics.

    PubMed

    Ehrsson, H; Hassan, M; Ehrnebo, M; Beran, M

    1983-07-01

    Busulfan kinetics were studied in patients with chronic myelocytic leukemia after oral doses of 2, 4, and 6 mg. The plasma concentration-time data could be fitted to a zero-order absorption one-compartment open model. The elimination rate constant averaged 0.27 +/- 0.05 hr-1 (SD). The plasma AUC was linearly related to the dose. The lag time for the start of absorption, the time absorption ends, and the absorption rate constant showed some interindividual variations. About 1% of busulfan is excreted unchanged in urine over 24 hr. PMID:6574831

  3. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation.

    PubMed

    Sanders, J E; Hawley, J; Levy, W; Gooley, T; Buckner, C D; Deeg, H J; Doney, K; Storb, R; Sullivan, K; Witherspoon, R; Appelbaum, F R

    1996-04-01

    Patients successfully treated with a marrow transplant often have concerns about fertility and pregnancy. This study was performed to determine pregnancy outcome among patients who had received high-dose chemotherapy alone or with total-body irradiation (TBI) and marrow transplantation for aplastic anemia or hematologic malignancy. Records of 1,326 postpubertal and 196 prepubertal patients currently more than 12 years of age after marrow transplant in Seattle from August 1971 to January 1992 were reviewed to determine the patients with normal gonadal function and pregnancies. Among 708 postpubertal women, 110 recovered normal ovarian function and 32 became pregnant. In addition, nine formerly prepubertal girls with normal gonadal function became pregnant. Among 618 postpubertal men, 157 recovered testicular function and partners of 33 became pregnant. An additional two formerly prepubertal men had partners who became pregnant. Forty-one female patients and partners of 35 male patients had 146 pregnancies after transplant. All 76 patients responded to a questionnaire requesting pregnancy history, outcome, infant birth weight, and congenital anomalies information for all clinically recognized pregnancies. There were 115 live births among 146 (79%) pregnancies. Spontaneous abortion terminated four of 56 (7%) pregnancies for 28 female cyclophosphamide (CY) recipients and six of 16 (37%) pregnancies for 13 TBI recipients (P = .02). Partners of 28 male CY recipients had four of 62 (6.4%) pregnancies terminate with spontaneous abortion, but there were no spontaneous abortions among eight pregnancies of five TBI recipients' partners. Preterm delivery occurred for eight of 44 (18%) and five of eight (63%) live births for 24 CY and eight TBI female recipients (P = .01). This 25% incidence among all female patient pregnancies is higher than the expected incidence of 8% to 10% (P = .0001). The 13 preterm deliveries resulted in 10 low birth weight ([LBW] 1.8 to 2.24 kg) and

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

    NASA Astrophysics Data System (ADS)

    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.

  5. Randomized trial of two different conditioning regimens for bone marrow transplantation in thalassemia--the role of busulfan pharmacokinetics in determining outcome.

    PubMed

    Chandy, M; Balasubramanian, P; Ramachandran, S V; Mathews, V; George, B; Dennison, D; Krishnamoorthy, R; Srivastava, A

    2005-11-01

    In total, 94 patients with homozygous beta thalassemia were randomized to two different conditioning regimens: busulfan 600 mg/m2 + cyclophosphamide 200 mg/kg or busulfan 16 mg/kg + cyclophosphamide 200 mg/kg and antilymphocyte globulin (47 in each group), for bone marrow transplantation, to see whether increased myeloablation or increased immunosuppression would reduce rejection. Busulfan pharmacokinetics in determining outcome was evaluated. There was no significant difference in engraftment, graft-versus-host disease, rejection, and overall and disease-free survival in the two groups. Systemic exposure to busulfan was significantly higher in the 600 mg/m2 group, but in both groups there was a wide interindividual variation in the busulfan kinetics. Six patients rejected the graft, two in the busulfan 600 mg group and four in busulfan 16 mg group (P = 0.677 CI -0.17, 0.07), but in five patients (pharmacokinetic data not available in one patient) who rejected the graft busulfan first dose trough level (C(min)-1) was below 150 ng/ml while it was above this level in the 66 of 68 patients with successful engraftment (P < or = 0.001). This randomized trial shows that rejection is influenced by busulfan levels and suggests that monitoring of busulfan levels and dose adjustment based on first-dose kinetics may reduce the risk of rejection. PMID:16151422

  6. Relationship of plasma pharmacokinetics of high-dose oral busulfan to the outcome of allogeneic bone marrow transplantation in children with thalassemia.

    PubMed

    Pawlowska, A B; Blazar, B R; Angelucci, E; Baronciani, D; Shu, X O; Bostrom, B

    1997-12-01

    We analyzed plasma pharmacokinetics of busulfan in 64 children and young adults (age 2.8-26; median 11 years) with homozygous beta-thalassemia transplanted with bone marrow from HLA-identical sibling donors. A uniform conditioning regimen was employed, using busulfan 14 or 16 mg/kg in 12 divided doses, and cyclophosphamide 120 or 200 mg/kg. Three sets of parameters were examined in this homogenous patient population: (1) factors that affect the plasma kinetics of busulfan, such as age and pre-transplant liver status defined by liver function tests, ferritin levels and liver biopsy; (2) busulfan-related toxicity: occurrence of veno-occlusive disease, seizures and idiopathic interstitial pneumonitis; and (3) the relationship between busulfan exposure and transplant outcome: engraftment delay or rejection, aplasia, occurrence of mixed chimeras and mortality. Kinetic analysis of first and 10th dose (using area under the curve (AUC), maximum and minimum concentration) as comparable, showing no sign of accumulation or decline in busulfan plasma levels over time. Age and liver status did not influence busulfan metabolism. No relationship was found between busulfan exposure and toxicities or transplant outcome. We conclude that busulfan monitoring is not predictive in children and young adults with homozygous beta-thalassemia receiving busulfan and high-dose cyclophosphamide along with histocompatable sibling donor marrow. PMID:9422469

  7. A rapid & sensitive liquid chromatography- tandem mass spectrometry method for the quantitation of busulfan levels in plasma & application for routine therapeutic monitoring in haematopoietic stem cell transplantation

    PubMed Central

    Desire, Salamun; Mohanan, Ezhil Pavai; George, Biju; Mathews, Vikram; Chandy, Mammen; Srivastava, Alok; Balasubramanian, Poonkuzhali

    2013-01-01

    Background & objectives: Busulfan (Bu) in combination with cyclophosphamide is widely used in myeloablative conditioning regimen prior to haematopoietic stem cell transplantation (HSCT). Its narrow therapeutic range and toxic side effects at high systemic exposure and graft rejection at low exposure emphasize the need for busulfan dose optimization using targeted dose adjustment prior to HSCT. We report here a rapid and sensitive method to quantitate busulfan plasma levels in patients receiving busulfan as part of pre-transplant conditioning. Methods: The method involves simple protein precipitation of the plasma followed by analysis using a high performance liquid chromatography (HPLC) with tandem mass spectrometry - electrospray ionization technique (LC-ESI MS/MS) in positive ionization mode and quantified using multiple reaction monitoring (MRM). Deuterated busulfan (d8-busulf`an) was used as the internal standard. Results: The method was linear for the concentration ranging from 0 to 4000 ng/ml of busulfan with a limit of detection of 2 ng/ml and limit of quantitation of 5 ng/ml. The assay was accurate for serial concentrations of Bu in plasma for five consecutive days and the CV was less than 10 per cent. Conclusion: Using this rapid and sensitive method, busulfan levels were targeted and subsequent doses adjusted at our center in 26 patients receiving high dose busulfan in combination with cyclophosphamide or fludarabine. PMID:23703347

  8. Solid tumor models for the assessment of different treatment modalities: XVI. Sequential combined modality (Cyclophosphamide-Radiation) therapy

    SciTech Connect

    Looney, W.B.; Ritenour, E.R.; Hopkins, H.A.

    1981-03-01

    A tumor cure rate of 60% was realized when three series of combined radiation (1500 rads) and cyclophosphamide (150 mg/kg) doses were given sequentially to rats with hepatoma 3924A and the time between modalities held constant at 7 days. This sequence was previously shown to enhance tumor sensitivity and diminish host toxicity. The first series was given on days 0 and 7; second, days 14 and 21; and third, days 28 and 35. The cure rate was reduced to 10% when the time of the second series was increased from 14 to 32 days (first series, days 0 and 7; second, days 32 and 39; and third, days 63 and 70). No cures were obtained when the time of the second series of combined cyclophosphamide and radiation was further increased from 14 to 40 days; however, this treatment schedule resulted in at least a threefold increase in life span over controls of 30 +/- 1 days. Two and three single 1500 rad doses of radiation given 14 to 40 days apart produced skin changes within accepted limits of normal tissue tolerance. No major long-term hematological changes in peripheral blood and bone marrow have been demonstrated to date following two and three courses of cyclophosphamide given 14 to 40 days apart. Experimental results indicate that the frequency and dosage of cyclophosphamide and radiation used are within clinically acceptable doses and scheduling.

  9. Interactions of radiation and 5-fluorouracil, cyclophosphamide or methotrexate in intestinal crypt cells

    SciTech Connect

    von der Maase, H.

    1984-01-01

    The interactions of radiation and 5-fluorouracil (5-FU), cyclophosphamide (CTX), or methotrexate (MTX) in mouse jejunal crypt cells were studied using the microcolony survival assay. 5-FU given from 48 hr before to 24 hr after irradiation resulted in an almost constant, increased cell kill except at injection 6 hr after irradiation, which resulted in a more pronounced effect. CTX enhanced the radiation effect only when given simultaneously with or up to 3 hr after irradiation. The effect of MTX, extremely dependent on the sequence and interval between drug administration and irradiation, was most prominent when administered 1 hr before irradiation. At this drug-radiation interval, the D/sub 0/ surprisingly increased by a factor of 2.4, whereas MTX 15 min before irradiation displaced the survival curve to the left without changing the D/sub 0/. The influence of MTX on the radiation response disappeared when the drug was given either 96 hr before or 3 hr after irradiation.

  10. Cyclophosphamide Injection

    MedlinePlus

    Cyclophosphamide is used alone or in combination with other medications to treat Hodgkin's lymphoma (Hodgkin's disease) and ... organs where eggs are formed), and breast cancer. Cyclophosphamide is also used to treat nephrotic syndrome (a ...

  11. Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation.

    PubMed

    Poonkuzhali, B; Chandy, M; Srivastava, A; Dennison, D; Krishnamoorthy, R

    2001-03-01

    Busulfan, at a dose of 16 mg/kg, is widely used in combination with cyclophosphamide as a conditioning regimen for patients undergoing bone marrow transplantation. Wide interindividual variation in busulfan kinetics and rapid clearance of the drug have been reported, especially in children. Some of the factors contributing to interpatient variability have been identified. They include circadian rhythms, age, disease, drug interaction, changes in hepatic function, and busulfan bioavailability. In this study, we demonstrate that hepatic glutathione S-transferase (GST) activity correlates negatively with busulfan maximum and minimum concentrations (Pearson's correlation r = -0.74 and -0.77, respectively) and positively with busulfan clearance (Pearson's correlation r = 0.728) in children with thalassemia major in the age range of 2 to 15 years. We also found that plasma alpha GST levels were 5 to 10 times higher in patients with thalassemia than in normal controls and age-matched leukemic patients, either reflecting extensive liver damage, elevated expression of the enzyme, or both in thalassemic patients. Plasma alpha GST concentrations showed a similar correlation with busulfan kinetic parameters to that observed for hepatic GST. The status of hepatic GST activity accounts, at least in part, for the observed interindividual variation in busulfan kinetics, while the observed association with plasma alpha GST is difficult to explain at present. PMID:11181493

  12. Cyclophosphamide Injection

    MedlinePlus

    ... cancer (cancer that begins in the female reproductive organs where eggs are formed), and breast cancer. Cyclophosphamide ... This branded product is no longer on the market. Generic alternatives may be available.

  13. Timed Sequential Busulfan and Post Transplant Cyclophosphamide for Allogeneic Transplantation

    ClinicalTrials.gov

    2016-08-05

    Other Diseases of Blood and Blood-forming Organs; Acute Myeloid Leukemia; Acute Lymphocytic Leukemia; Chronic Myeloid Leukemia; Chronic Lymphocytic Leukemia; Myelodysplastic Syndrome; Myeloproliferative Syndrome; Non-Hodgkins Lymphoma; Hodgkins Lymphoma; Multiple Myeloma

  14. Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation.

    PubMed

    Bostrom, Bruce; Enockson, Karen; Johnson, Amy; Bruns, Alyssa; Blazar, Bruce

    2003-01-01

    We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean +/- SD, 1.21 +/- 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4-12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis. PMID:12603688

  15. Cyclophosphamide (Cytoxan)

    MedlinePlus

    ... until the bladder can be evaluated by cystoscopy. Infertility Cyclophosphamide may cause infertility in both men and women who are treated ... many of cyclophosphamide’s side–effects, the risk of infertility appears to be related to the length of ...

  16. Interactions of radiation, cyclophosphamide and nimorazole in a C/sub 3/H mammary carcinoma in vivo

    SciTech Connect

    Zachariae, C.; Overgaard, J.

    1986-08-01

    The combined effect of adjuvant Cyclophosphamide (CTX) and the hypoxic radiosensitizer, Nimorazole (NIM), on the radiation response was studied in a C/sub 3/H mammary carcinoma in CDF1 mice. The effect of NIM and CTX alone or in combination without radiation was assessed by tumor growth delay measured by tumor growth time (TGT). Administration of CTX (100 mg/kg) increased the TGT from 5.2 days in untreated controls to 18.8 days. NIM (1000 mg/kg) had no effect on the TGT. The combined treatment with NIM given 4 hrs before CTX did not increase the TGT compared with CTX alone, which suggests that NIM does not potentiate CTX. The possible effect of an interaction between the therapeutic parameters was determined by administration of NIM, CTX, and radiation in different sequences to C/sub 3/H mammary tumor bearing mice. The drugs were administered as single doses before or after graded single doses of irradiation. The end point was the radiation dose required to achieve local tumor control in 50% of the mice (TCD50). The enhancement ratio (ER)--defined as TCD50 for radiation alone relative to TCD50 for radiation combined with drug--was 1.2 for CTX given either 15 min before or 4 hrs after radiation. NIM given 30 min before radiation showed an ER of 1.6; no enhancement was obtained when NIM was given after radiation. When NIM was given immediately after radiation, followed 4 hrs later by CTX, the ER was 1.2. However, applying NIM 30 min before radiation and CTX 3.5 hrs after radiation, the ER increased to 1.6. NIM given 30 min before, together with CTX given 15 min before radiation, showed an ER of 1.8. Data suggest: an improved tumor response may be expected when CTX is added to a radiation and hypoxic radiosensitizer treatment; improvement is attributable to an additive effect based on the chemotherapy response rather than to chemopotentiation by the hypoxic radiosensitizer.

  17. Clinical trials with cyclophosphamide and misonidazole combination for maintaining treatment after radiation therapy of lung carcinoma

    SciTech Connect

    Busutti, L.; Breccia, A.; Stagni, G.; Gattavecchia

    1984-09-01

    Fifteen patients with inoperable non oat cell lung carcinoma, who had already been treated with telecobalt therapy in the mediastinum-hilar region, were treated with continuing therapy with misonidazole (MISO) and cyclophosphamide (Cy). MISO was administered in single doses of 1000 mg/m/sup 2/ and 500 mg/m/sup 2/, orally. Cy was administered in single doses of 500 mg/m/sup 2/ and 250 mg/m/sup 2/, i.v. This treatment was given every 4 weeks. All patients (15/15) suffered from hyporexia, nausea and vomiting within 48 hours from administration; furthermore, 2 patients had hemoragic cystitis, 2 had peripheral neurotoxicity, 3 had fever, and 2 had serious nervous depression. Leukopenia occurred in all patients immediately after drug administration, although it was not present in any patient by the time of the next administration. This clinical trial was concluded in December 1981. The follow-up at 18 months shows 7/15 cases of relapse. Eight of 15 patients are alive with progression of disease from 8 to 18 months.

  18. Graft failure in children receiving HLA-mismatched marrow transplants with busulfan-containing regimens.

    PubMed

    Schultz, K R; Ratanatharathorn, V; Abella, E; Eisenbrey, A B; Karanes, C; Lum, L G; de Planque, M M; Uberti, J P; Ravindranath, Y; Sensenbrenner, L L

    1994-06-01

    Identifying risk factors that lead to graft failure may reduce morbidity and mortality after bone marrow transplantation (BMT) for hematologic malignancies. We evaluated engraftment of all patients with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and myelodysplastic syndrome (MDS) receiving an unmanipulated marrow allogeneic BMT at the Detroit Medical Center from 1987 to 1992 using a busulfan, cyclophosphamide +/- cytarabine preparative regimen. Three of 118 patients had graft failure (2.5%; (95% confidence interval (CI) 0.7%, 6.4%). Graft failure was high in patients < or = 15 years with 3 of 12 patients with failure (25.0%) compared with 0 of 106 patients > 15 years (p = 0.002). Failure to engraft was not seen in HLA-identical (related or unrelated) donor transplants (0 of 103) whereas 3 of 15 HLA-mismatched donors failed (p = 0.003). Patient diagnosis, locus of HLA-mismatch, cytarabine in the preparative regimen, marrow cell dose and the relative reactive index (RRI) were not significant factors. Altered busulfan kinetics secondary to young age was probably not a major factor since 8 of 8 HLA-identical donor transplants engrafted in children. These findings demonstrate that patients receiving an unmanipulated marrow graft using busulfan-containing regimens were at a high risk for graft failure only if they were < or = 15 years of age and had an HLA-mismatched donor. More immunosuppressive preparative regimens, possibly including total body irradiation, should be considered to prevent potential graft failure in children. PMID:7920320

  19. Radiation-induced lung fibrosis after treatment of small cell carcinoma of the lung with very high-dose cyclophosphamide

    SciTech Connect

    Trask, C.W.; Joannides, T.; Harper, P.G.; Tobias, J.S.; Spiro, S.G.; Geddes, D.M.; Souhami, R.L.; Beverly, P.C.

    1985-01-01

    Twenty-five previously untreated patients with small cell carcinoma of the lung were treated with cyclophosphamide 160 to 200 mg/kg (with autologous bone marrow support) followed by radiotherapy (4000 cGy) to the primary site and mediastinum. No other treatment was given until relapse occurred. Nineteen patients were assessable at least 4 months after radiotherapy; of these, 15 (79%) developed radiologic evidence of fibrosis, which was symptomatic in 14 (74%). The time of onset of fibrosis was related to the volume of lung irradiated. A retrospective analysis was made of 20 consecutive patients treated with multiple-drug chemotherapy and an identical radiotherapy regimen as part of a randomized trial. Radiologic and symptomatic fibrosis was one half as frequent (35%) as in the high-dose cyclophosphamide group. Very high-dose cyclophosphamide appears to sensitize the lung to radiotherapy and promotes the production of fibrosis.

  20. Lymphoid reconstitution after transplantation of congenic hematopoietic cells in busulfan-treated mice.

    PubMed

    Yeager, A M; Shinn, C; Pardoll, D M

    1991-12-15

    The effects of pretransplant conditioning with high-dose busulfan, a myeloablative but nonimmunosuppressive alkylating agent, on reconstitution of lymphoid tissues by donor cells after bone marrow transplantation (BMT) has not been extensively examined. We used flow cytometric analyses to study the kinetics and extent of lymphocyte repopulation in C57BL/6 mice (immunophenotype Ly-5.2) given graded doses of busulfan (10 to 100 mg/kg) or total body irradiation (TBI; 900 rad) and hematopoietic cell transplantation (HCT; transplantation of bone marrow and spleen cells) from congenic Ly-5.1 donors. Mice transplanted after 10 mg/kg of busulfan had slow and incomplete lymphoid engraftment; only 6% to 11% of lymphocytes in the peripheral blood, lymph nodes, and spleen were positive for Ly-5.1 at 30 days after transplant, slightly increased to 13% to 20% at 60 days, and stabilized at 40% to 46% by 180 days after HCT. Higher doses of busulfan (20 to 100 mg/kg) provided dose-dependent congenic lymphoid reconstitution. Thirty days after HCT, the range of Ly-5.1 cells in blood, lymph nodes, and spleen of Ly-5.2 recipient mice was 43% to 54% after 20 mg/kg of busulfan, 66% to 71% after 50 to 80 mg/kg, and 77% to 85% after 100 mg/kg. Sixty days after transplant, lymphoid chimerism increased to 57% to 68% in 20 mg/kg recipients, 72% to 79% after 35 mg/kg, and 75% to 90% in animals given 50 mg/kg or greater, as seen in radiation chimeras. Despite slower early reconstitution after lower doses of busulfan, donor lymphocytes exceeded 90% to 95% by 90 to 120 days after HCT in all mice given at least 20 mg/kg. Even though busulfan lacks directly immunosuppressive properties, virtually complete sustained lymphoid reconstitution by transplanted congenic donor stem cells occurs after its administration. These observations suggest that pretreatment with busulfan may be effective in gene therapy strategies that involve infusion of autologous marrow cells into which functional genes have been

  1. [Busulfan versus busulfan-interferon as maintenance therapy in chronic myeloid leukemia].

    PubMed

    López Hernández, M A; Flores-Chapa, J D; Trueba Christy, E; Borbolla Escoboza, J R; Carrillo Rosales, T

    1996-01-01

    We studied 30 patients in order to evaluate the therapeutic efficacy and toxicity of alfa interferon associated with busulfan as maintenance treatment in de novo chronic granulocytic leukemia. Patients received 0.2 mg/kg of busulfan and reached complete hematological remission (CHR). Patients were then randomized in two groups: one to receive busulfan to be administered when the leukocyte count was above 15 x 10(9)/L, and another to receive subcutaneously 5 million IU of alpha-interferon three times per week (plus busulfan if the leukocyte count went above 15 x 10(9)/L). The duration of CHR was longer in the alfa-interferon group: 31 vs 16 months (p = 0.03) but no cytogenetic remissions were observed. Alfa interferon was well tolerated: no patient was excluded from the study due to toxicity. PMID:8966391

  2. Prospective evaluation of concurrent paclitaxel and radiation therapy after adjuvant doxorubicin and cyclophosphamide chemotherapy for Stage II or III breast cancer

    SciTech Connect

    Burstein, Harold J. . E-mail: hburstein@partners.org; Bellon, Jennifer R.; Galper, Sharon; Lu, H.-M.; Kuter, Irene; Wong, Julia; Gelman, Rebecca; Bunnell, Craig A.; Parker, Leroy M.; Garber, Judy E.; Winer, Eric P.; Harris, Jay R.; Powell, Simon N.

    2006-02-01

    Purpose: To evaluate the safety and feasibility of concurrent radiation therapy and paclitaxel-based adjuvant chemotherapy, given either weekly or every 3 weeks, after adjuvant doxorubicin and cyclophosphamide (AC). Methods and Materials: After definitive breast surgery and AC chemotherapy, 40 patients with operable Stage II or III breast cancer received protocol-based treatment with concurrent paclitaxel and radiation therapy. Paclitaxel was evaluated on 2 schedules, with treatment given either weekly x 12 weeks (60 mg/m{sup 2}), or every 3 weeks x 4 cycles (135-175 mg/m{sup 2}). Radiation fields and schedules were determined by the patient's surgery and pathology. The tolerability of concurrent therapy was evaluated in cohorts of 8 patients as a phase I study. Results: Weekly paclitaxel treatment at 60 mg/m{sup 2} per week with concurrent radiation led to dose-limiting toxicity in 4 of 16 patients (25%), including 3 who developed pneumonitis (either Grade 2 [1 patient] or Grade 3 [2 patients]) requiring steroids. Efforts to eliminate this toxicity in combination with weekly paclitaxel through treatment scheduling and CT-based radiotherapy simulation were not successful. By contrast, dose-limiting toxicity was not encountered among patients receiving concurrent radiation with paclitaxel given every 3 weeks at 135-175 mg/m{sup 2}. However, Grade 2 radiation pneumonitis not requiring steroid therapy was seen in 2 of 24 patients (8%) treated in such a fashion. Excessive radiation dermatitis was not observed with either paclitaxel schedule. Conclusions: Concurrent treatment with weekly paclitaxel and radiation therapy is not feasible after adjuvant AC chemotherapy for early-stage breast cancer. Concurrent treatment using a less frequent paclitaxel dosing schedule may be possible, but caution is warranted in light of the apparent possibility of pulmonary injury.

  3. Ketobemidone may alter busulfan pharmacokinetics during high-dose therapy.

    PubMed

    Hassan, M; Svensson, J O; Nilsson, C; Hentschke, P; Al-Shurbaji, A; Aschan, J; Ljungman, P; Ringdén, O

    2000-08-01

    The authors report a possible interaction between ketobemidone and busulfan during myeloablative treatment of a patient with acute myeloid leukemia. At the time of admission, the patient was receiving ketobemidone 1,000 mg/d as analgesic for a rectal fissure. The patient started conditioning prior to bone marrow transplantation with busulfan (1 mg/kg x 4 for 4 days). High busulfan plasma concentrations were observed after the first dose and the next doses were reduced to 0.7 mg/kg. The kinetics of both drugs revealed that an increase in ketobemidone concentration was followed by an increase in busulfan levels. Substituting ketobemidone with morphine resulted in a decrease in busulfan concentration despite increasing the dose once more to 1 mg/kg. PMID:10942175

  4. Pharmacometabonomic Prediction of Busulfan Clearance in Hematopoetic Cell Transplant Recipients.

    PubMed

    Navarro, Sandi L; Randolph, Timothy W; Shireman, Laura M; Raftery, Daniel; McCune, Jeannine S

    2016-08-01

    Intravenous (IV) busulfan doses are often personalized to a concentration at steady state (Css) using the patient's clearance, which is estimated with therapeutic drug monitoring. We sought to identify biomarkers of IV busulfan clearance using a targeted pharmacometabonomics approach. A total of 200 metabolites were quantitated in 106 plasma samples, each obtained before IV busulfan administration in hematopoietic cell transplant (HCT) recipients. Both univariate linear regression with false discovery rate (FDR) and pathway enrichment analyses using the Global test were performed. In the univariate analysis, glycine, N-acetylglycine, 2-hydroxyisovaleric acid, creatine, serine, and tyrosine were statistically significantly associated with IV busulfan clearance at P < 0.05, with the first three satisfying the FDR of q < 0.1. Using pathway enrichment analysis, the glycine, serine, and threonine metabolism pathway was statistically significantly associated with IV busulfan clearance at P < 0.05 and q < 0.1, and a pathway impact >0.1. Glycine is a component of glutathione, which is conjugated with busulfan via glutathione transferase enzymes. These results demonstrate the potential utility of pharmacometabonomics to inform IV busulfan dosing. Future studies are required to validate these findings. PMID:27350098

  5. Melatonin and Testicular Damage in Busulfan Treated Mice

    PubMed Central

    Mirhoseini, Mehri; Saki, Ghasem; Hemadi, Masoud; Khodadadi, Ali; Mohammadi Asl, Javad

    2014-01-01

    Background: Advancement in the treatment of various types of cancer has led to greater patient survival. These treatments essentially have toxic effects on different kinds of cells, such as germ cells. Infertility as one of the side effects of cancer treatment has changed the quality of life of young cancer survivors dramatically. Melatonin is an antioxidant with receptors in the reproductive systems. Objectives: We supposed that melatonin, as an antioxidant, may protect testis against the toxic effects of the drugs. Materials and Methods: In this experimental study, three groups with seven mice each, were allocated. The control group received normal saline for two months, and the busulfan group received a single dose of 40 mg/kg busulfan intra-peritoneally, and the melatonin group received 20 mg/kg melatonin daily for two months, 45 days after a single dose of busulfan. Next, after decapitation and removal of the testis, tissues were fixed in Bouin's solution and stained by H&E and TUNEL. The sections were evaluated, assessing morphology and spermatogenesis. Results: In this research, a significant reduction in Johnson’s criteria in the busulfan group (Mean rank = 15.50) was found versus the control group (Mean rank = 45.50), P < 0.001 and in the melatonin group (Mean rank = 45.50) compared to the busulfan group (Mean rank = 15.50), P < 0.001. There was a significant difference between the melatonin and control groups, P < 0.05. In addition, a significant decrease in seminiferous tubule diameter was observed in the busulfan group (763.2 ± 104.41) versus the control group (855.4 ± 52.35), P < 0.01 and melatonin group (834.2 ± 87.26), P < 0.05. Testicular epithelium height was significantly decreased in the busulfan group (Mean rank = 14.60) compared to the control group (Mean rank = 26.40), P < 0.01 and in the busulfan group (Mean rank = 14.95) in comparison with the melatonin group (Mean rank = 26.05), P < 0.01. Also melatonin group (Mean rank = 25.42) showed

  6. [Busulfan and cycosporin in bone graft children].

    PubMed

    Bertolle, V; Martin, P; Bleyzac, N; Aulagner, G

    2004-05-01

    Most drugs exhibit both inter- and intra-individual pharmacokinetic and pharmacodynamic variability. This variability explains the different responses observed in patients exposed to standard doses and must be taken into consideration when the therapeutic window is narrow. Population pharmacokinetics provides mean (or median) values of pharmacokinetic parameters as well as the distribution pattern and the statistical relationship with covariables in a group of individuals presenting common characteristics. Among the different methods developed for population pharmacokinetics, the data pool method, as well as the two-step and one-step methods (NONMEM and NPEM) are attractive. Population models can then be developed using bayesian logistics to obtain an estimation of the pharmacokinetic parameters of a given patient and predict the most adapted dose in light of the therapeutic target (residual serum concentration, mean concentration.). Busulfan is an alkylizing agent used instead of radiotherapy for pre-graft preparation before bone marrow grafts in children. This compound requires dose monitoring because of its narrow therapeutic window: under-dosing raises the risk of graft rejection; inversely over-dosing can cause potentially fatal complications such as occlusive venous disease. Interindividual variability is characteristic of busulfan kinetics. Several factors can explain part of this variability: age, underlying disease, changes in liver function, drug bioavailability, chronobiology. The short treatments used (most protocols have 16 doses given in four days) require rapid monitoring to propose effective adjustments. In this context, use of bayesian logistics to estimate the patient's pharmokinetic parameters is very useful for correct dosing. This type of monitoring could also be used for other compounds such as cyclosporine, with a narrow therapeutic window. PMID:15243350

  7. Pharmacogenetics of intravenous and oral busulfan in hematopoietic cell transplant recipients.

    PubMed

    Abbasi, Nissa; Vadnais, Barbara; Knutson, Jennifer A; Blough, David K; Kelly, Edward J; O'Donnell, Paul V; Deeg, H Joachim; Pawlikowski, Matthew A; Ho, Rodney J-Y; McCune, Jeannine S

    2011-10-01

    Kinetics-based dose targeting is often conducted in hematopoietic cell transplant (HCT) patients conditioned with intravenous (IV) or oral busulfan to lower rates of rejection, nonrelapse mortality, and relapse. Using the candidate gene approach, the authors evaluated whether busulfan clearance was associated with polymorphisms in the genes regulating the predominant metabolizing enzymes involved in busulfan conjugation, specifically glutathione S-transferase (GST) isoenzymes A1 (GSTA1) and M1 (GSTM1). Busulfan clearance was estimated after the morning dose on days 1, 2, and 3; each patient's average clearance was used for analyses. The average (± standard deviation) busulfan clearance was 3.2 ± 0.56 mL/min/kg in the separate population of 95 patients who received oral busulfan and 103 ± 24 ml/min/m(2) in the 57 patients who received IV busulfan. Oral busulfan clearance was associated with GSTA1 (P = .008) but not GSTM1 (P = .57) genotypes. However, among the GSTA1 haplotypes (ie, *A*A, *A*B, *B*B), there was significant overlap in the observed oral busulfan clearance and similar rates of achieving the target busulfan exposure. Clearance of IV busulfan was not associated with GSTA1 (P = .21) or GSTM1 (P = .99). These data suggest that personalizing either IV or oral busulfan dosing cannot be simplified on the basis of GSTA1 or GSTM1 genotype. PMID:21135089

  8. Pharmacokinetic and metabolic studies of busulfan in rat plasma and brain.

    PubMed

    Hassan, M; Ehrsson, H; Wallin, I; Eksborg, S

    1988-01-01

    Busulfan kinetics were studied in the rat plasma and brain after an I.P. dose of 14C-busulfan or busulfan (15 mg/kg). The distribution of busulfan to the brain was rapid and the ratio brain/plasma concentration was 0.74 during the time-course of busulfan. The elimination half-lives in plasma and brain were 3h for intact busulfan and 8h for the 14C-radioactivity. The radioactivity remaining in plasma and brain after 24h was mostly busulfan metabolites e.g. sulfolane, 3-hydroxysulfolane and tetrahydrothiophene-1-oxide as identified by gas chromatography-mass spectrometry. The protein binding to rat plasma was low (9.2 +/- 4.4%). PMID:3243326

  9. On the biological activity of drug molecules: Busulfan and nabumetone

    NASA Astrophysics Data System (ADS)

    Novak, Igor; Kovač, Branka

    2010-10-01

    The electronic structures of drug molecules busulfan (BSU) and nabumetone (NAB) have been investigated by HeI and HeII UV photoelectron spectroscopy (UPS), quantum chemical calculations and virtual docking studies. Their biological activities are discussed in the framework of their electronic and molecular structures, reactivity and drug-enzyme binding.

  10. Pharmacokinetics of high-dose busulfan in children.

    PubMed

    Vassal, G; Gouyette, A; Hartmann, O; Pico, J L; Lemerle, J

    1989-01-01

    The pharmacokinetics of high-dose busulfan given orally at 1 mg/kg every 6 h over 4 days (total dose, 16 mg/kg) in combined chemotherapy followed by autologous bone marrow transplantation was studied in 12 children with a mean age of 7 years (range, 4-14 years). Busulfan levels in biological fluids were measured by a gas chromatographic assay with mass fragmentographic detection, using a deuterated analogue as the internal standard. In a high-dose regimen, busulfan followed one-compartment model kinetics with zero-order absorption. A mean maximal concentration of 803 +/- 228 ng/ml was achieved at 92-255 min after dosing. The mean elimination half-life was 2.33 h, and the mean total clearance was 119 +/- 54 ml/min per m2, with an apparent distribution volume of 27.10 +/- 11.50 l/m2. A mean trough level of 370 ng/ml was found throughout the 4 days of the chemotherapy course. There were no significant variations in pharmacokinetic parameters measured after the first and last doses. Busulfan was monitored in the CSF of nine children at 3.25-7 h after the last dose and was detected in all patients, with a mean CSF-to-plasma concentration ratio of 0.95 (range, 0.5-1.4). PMID:2791192

  11. Role of glutathione and glutathione S-transferases in the metabolism of busulfan

    SciTech Connect

    Marchand, D.H.

    1987-01-01

    Busulfan (1,4-dimethanesulfonate butanediol) is a bifunctional alkylating agent used in the treatment of chronic myelogenous leukemia. The major urinary metabolite of busulfan in mammals is 3-hydroxytetrahydrothiophene-1,1-dioxide (3-HOTHT). Previous metabolic studies with /sup 35/S-busulfan indicated that the sulfur in 3-HOTHT results from the reaction of busulfan with endogenous thiols. These studies also found that mixing L-cysteine with busulfan at pH 8.0 produced a tetrahydrothiophenium-cysteine conjugate (THT-cys). Treatment of THT-cys with sodium hydroxide produced tetrahydrothiophene (THT). Administration of THT-cyc or THT to rats resulted in the appearance of 3-HOTHT in rat urine. Glutathione (GSH) is the major non-protein thiol in cells. As part of the present studies, the reaction between GSH and busulfan was examined.

  12. Busulfan conjugation by glutathione S-transferases alpha, mu, and pi.

    PubMed

    Czerwinski, M; Gibbs, J P; Slattery, J T

    1996-09-01

    Busulfan is eliminated by glutathione S-transferase (GST)-catalyzed conjugation with glutathione (GSH). We have characterized the busulfan-conjugating activity of purified human liver GSTA1-1, GSTA1-2, GSTA2-2, GSTM1-1, and placental GSTP1-1. Isoforms were purified from cytosol by GSH-affinity chromatography and chromatofocusing. In addition, the busulfan-conjugating activity of cDNA-expressed GTH1 and GTH2, corresponding to GSTA1-1 and GSTA2-2, were characterized. The major product of busulfan conjugation, a thiophenium ion (THT+), was assayed by GC/MS after conversion to tetrahydrothiophene (THT). THT+ formation rate increased linearly with busulfan concentration up to its solubility limit for all GST isoforms. Because Vmax and KM could not be determined separately, the slope of the velocity vs. substrate concentration plot, Vmax/KM was used to compare isoform activities. Vmax/KM for GSTA1-1 was 7.95 microliters/min/mg protein, the highest busulfan-conjugating activity of all human liver and placenta isoforms evaluated. GSTM1-1 and GSTP1-1, respectively, had 46% and 18% of the activity of GSTA1-1. Since the polymorphic mu-class GST catalyzed busulfan conjugation, we examined busulfan clearance in 50 patients undergoing high-dose busulfan before bone marrow transplantation. Busulfan clearance was normally distributed, suggesting that GSTM1-1 does not contribute significantly to the elimination of busulfan from the body. We conclude that GSTA1-1 is the major isoform catalyzing busulfan conjugation, whereas GSTM1-1 and GSTP1-1 may be important in the protection of specific cells. PMID:8886613

  13. Busulfan Triggers Intrinsic Mitochondrial-Dependent Platelet Apoptosis Independent of Platelet Activation.

    PubMed

    Qiao, Jianlin; Wu, Yulu; Liu, Yun; Li, Xiaoqian; Wu, Xiaoqing; Liu, Na; Zhu, Feng; Qi, Kunming; Cheng, Hai; Li, Depeng; Li, Hongchun; Li, Zhenyu; Zeng, Lingyu; Ma, Ping; Xu, Kailin

    2016-09-01

    As a nonspecific alkylating antineoplastic agent, busulfan has been widely used in the treatment of patients with chronic myeloid leukemia. In vitro and in vivo studies demonstrated busulfan-induced cell apoptosis. Whether busulfan triggers platelet apoptosis remains unclear. This study aimed to evaluate the role of busulfan in platelet apoptosis. Isolated human platelets were incubated with busulfan followed by analysis of platelet apoptosis by flow cytometry or western blot, including mitochondrial depolarization, expression of Bcl-2, and Bax and caspase 3 activation. Meanwhile, platelet activation, expression of glycoprotein Ibα (GPIbα), glycoprotein VI (GPVI), and IIb3 and platelet aggregation in response to collagen and adenosine diphosphate (ADP) were measured. Additionally, busulfan was injected into mice with or without administration of caspase inhibitor QVD-Oph to investigate its effect on platelet lifespan. Our results showed that busulfan-treated platelets displayed increased mitochondrial membrane depolarization, decreased expression of Bcl-2, increased expression of Bax and caspase 3 activation in dose-dependent manner, which were inhibited by QVD-Oph. Platelet activation was not observed in busulfan-treated platelets as showed by no increased P-selectin expression and PAC-1 binding. However, busulfan reduced collagen- or ADP-induced platelet aggregation without affecting expression of GPIbα, GPVI, and IIb3. Furthermore, busulfan reduced circulating platelet lifespan which was ameliorated by QVD-Oph in mice. In conclusion, busulfan triggers mitochondrial-dependent platelet apoptosis and reduces platelet lifespan in mice. These data suggest targeting caspase activation might be beneficial in the prophylaxis of platelet apoptosis-associated thrombocytopenia after administration of busulfan. PMID:27292166

  14. Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible related donors.

    PubMed

    Maschan, A A; Trakhtman, P E; Balashov, D N; Shipicina, I P; Skorobogatova, E V; Skvortsova, Y V; Dyshlevaja, Z M; Samochatova, E V; Rumiantsev, A G

    2004-08-01

    Allogeneic hematopoietic stem cell transplantation (SCT) from unaffected donors remains the only modality for the correction of hematological abnormalities in Fanconi anemia (FA) patients. We performed four HLA-matched related donor SCT using a novel irradiation and cyclophosphamide-free conditioning regimen. The protocol included fludarabine 150 mg/m(2), busulfan 4 mg/kg, and antithymocyte globulin 90 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A, MTX, and daclizumab. The engraftment and occurrence of full stable donor hemopoiesis was rapid in all cases with minimal short-term toxic complications. There were no infections or febrile episodes during the inpatient phase. Three patients developed acute GVHD grade I-II involving gut and skin and one patient progressed to extensive chronic GVHD. The preparative conditioning regimen is safe and associated with low organ toxicity and effective immunosupression for the stable engraftment in FA patients undergoing SCT with matched related donors. PMID:15195080

  15. Intravenous Busulfan-Based Myeloablative Conditioning Regimens Prior to Hematopoietic Cell Transplantation for Hematologic Malignancies.

    PubMed

    Pasquini, Marcelo C; Le-Rademacher, Jennifer; Zhu, Xiaochun; Artz, Andrew; DiPersio, John; Fernandez, Hugo F; Mineishi, Shin; Kamishohara, Masaru; Mehta, Jayesh; Nakamura, Yuki; Ratanatharathorn, Voravit; Sobecks, Ronald; Burkart, Jeanne; Bredeson, Christopher

    2016-08-01

    Busulfan (Bu)-containing regimens are commonly used in myeloablative conditioning regimens before allogeneic hematopoietic cell transplantation (HCT). Yet, there is considerable variability on how Bu is administered related to frequency (4 times a day [Q6] or daily [Q24]) and combinations with other chemotherapeutic agents (cyclophosphamide [Cy] or fludarabine [Flu]). We performed a prospective cohort study of recipients of Bu-based conditioning according to contemporary practices to compare different approaches (BuCy Q6, n = 495; BuFlu Q24, n = 331; BuCy Q24, n = 96; BuFlu Q6, n = 91) in patients with myeloid malignancies between 2009 and 2011. BuFlu Q24 recipients were more likely to be older and tended to have worse performance status and a higher comorbid burden. The cumulative incidences of hepatic veno-occlusive disease (P = .40), idiopathic pneumonia (P = .50), and seizures (P = .50) did not differ across groups. One-year HCT-related mortality ranged from 12% to 16% (P = .80), 3-year relapse incidence ranged from 32% to 36% (P = .80), and 3-year overall survival ranged from 51% to 58% (P = .20) across groups. This study demonstrates that HCT conditioning regimens using i.v. Bu Q6 or Q24 alone or in combination with Cy or Flu have similar outcomes in the myeloablative setting for treatment of myeloid malignancies. PMID:27154848

  16. Adjuvant treatment of node-positive breast cancer with adriamycin-cyclophosphamide with or without radiation therapy: interim results of an ongoing clinical trial.

    PubMed

    Jones, S E; Salmon, S E; Allen, H; Giordano, G F; Davis, S; Chase, E; Moon, T E; Heusinkveld, R S

    1982-01-01

    During 1974-1980, 138 women with node-positive stage II breast cancer were treated with either eight courses of adriamycin-cyclophosphamide (AC) chemotherapy (82 patients) or AC chemotherapy plus comprehensive regional radiotherapy (56 patients). The overall relapse-free survival of the treated patients was significantly superior (P less than 0.001) to a comparable group of women who underwent surgery alone. This effect of adjuvant therapy was clearly manifest in all groups of patients irrespective of nodal involvement or menopausal status. To date, relapse-free survival for patients receiving AC compared to AC plus radiotherapy is not different (P = 0.7). In summary, wer have demonstrated that a brief 6-month course of adjuvant chemotherapy with AC can significantly reduce the recurrence rate in women with stage II breast cancer. PMID:7036279

  17. Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning.

    PubMed

    Zao, Jamie H; Schechter, Tal; Liu, Wenchao Jessica; Gerges, Sandra; Gassas, Adam; Egeler, R Maarten; Grunebaum, Eyal; Dupuis, L Lee

    2015-08-01

    Achievement of a busulfan area-under-the-concentration versus time curve (AUC) of 900 to 1500 μM·min is associated with improved hematopoietic stem cell transplant (HSCT) outcomes. Multiple pediatric busulfan dosing guidelines aim to achieve this target. The authors' objective was to describe the AUCs achieved after simulated dosing using available pediatric i.v. busulfan dosing guidelines. The health records of children who received i.v. busulfan for HSCT conditioning at The Hospital for Sick Children were reviewed. Busulfan AUCs were calculated for each patient based on plasma busulfan concentrations using either a 1-compartment model or a validated limited-sampling strategy. Published pediatric busulfan dosing guidelines were identified. Initial busulfan doses were determined for all patients using each dosing guideline and total body weight (TBW). For overweight patients (TBW-to-ideal body weight [IBW] ≥ 1.25), initial busulfan doses were also determined using IBW and adjusted IBW (IBWadj). The resulting AUCs were simulated. The proportion of subjects (TBW/IBW < 1.25, TBW/IBW ≥ 1.25, and infants) with an AUC within target (900 to 1500 μM·min) after dosing simulation with each guideline was compared. One hundred eleven children (mean age, 6.2 years [SD, ±5.2]) who received i.v. busulfan were included. When dosing with each of the 12 i.v. busulfan dosing guidelines identified was simulated using TBW in 97 non-overweight patients, the proportion of patients with an AUC within the target range varied from 51% to 74% and from 45% to 64% in infants. Use of IBW or IBWadj to calculate initial busulfan doses in overweight children improved the performance of most guidelines. Current busulfan dosing guidelines vary in their ability to achieve AUCs within the target range. For children who are not overweight, we recommend 1 of 3 high-performing guidelines that allow individualization of the target busulfan AUC. Use of either IBW or IBWadj in overweight children

  18. Pharmacogenetic aspects of drug metabolizing enzymes in busulfan based conditioning prior to allogenic hematopoietic stem cell transplantation in children.

    PubMed

    Huezo-Diaz, Patricia; Uppugunduri, Chakradhara Rao S; Tyagi, Anuj Kumar; Krajinovic, Maja; Ansari, Marc

    2014-03-01

    Allogenic hematopoietic stem cell transplantation (HSCT) is a well established but complex treatment option for malignant and non-malignant disorders in pediatric patients. Most commonly used myeloablative and non-myeloablative conditioning regimens in children comprise alkylating agents, such as busulfan (BU) and cyclophosphamide. Inter-individual variability in the pharmacokinetics of BU can result in altered conditioning of the patient and therefore lead to relapse or rejection due to under exposures, or occurrence of toxicities due to over exposures. With the introduction of the intravenous formulation of BU, this variability has been reduced but still cannot be fully predicted. Inter and intra-individual variability of BU kinetics is more common in children compared to adults and toxicity of BU based regimens is still a concern. It has been hypothesized that some of this variability in BU pharmacokinetics and treatment outcomes, especially the toxicity, might be predicted by genetic variants of enzymes involved in the metabolism of BU. This review intends to summarize the studies performed to date on the pharmacokinetics and pharmacogenetics of BU based conditioning, specifically in relation to children. PMID:24524663

  19. Effects of Korean Red Ginseng extract on busulfan-induced dysfunction of the male reproductive system

    PubMed Central

    Jung, Seok-Won; Kim, Hyeon-Joong; Lee, Byung-Hwan; Choi, Sun-Hye; Kim, Hyun-Sook; Choi, Yang-Kyu; Kim, Joon Yong; Kim, Eun-Soo; Hwang, Sung-Hee; Lim, Kwang Yong; Kim, Hyoung-Chun; Jang, Minhee; Park, Seong Kyu; Cho, Ik-Hyun; Nah, Seung-Yeol

    2015-01-01

    Background Anticancer agents induce a variety of adverse effects when administered to cancer patients. Busulfan is a known antileukemia agent. When administered for treatment of leukemia in young patients, busulfan could cause damage to the male reproductive system as one of its adverse effects, resulting in sterility. Methods We investigated the effects of Korean Red Ginseng extract (KRGE) on busulfan-induced damage and/or dysfunction of the male reproductive system. Results We found that administration of busulfan to mice: decreased testis weight; caused testicular histological damage; reduced the total number of sperm, sperm motility, serum testosterone concentration; and eventually, litter size. Preadministration of KRGE partially attenuated various busulfan-induced damages to the male reproductive system. These results indicate that KRGE has a protective effect against busulfan-induced damage to the male reproduction system. Conclusion The present study shows a possibility that KRGE could be applied as a useful agent to prevent or protect the male reproductive system from the adverse side effects induced by administration of anticancer agents such as busulfan. PMID:26199556

  20. Improved assay for determination of busulfan by liquid chromatography using postcolumn photolysis.

    PubMed

    Jenke, Andreas; Renner, Ulf; Schuler, Ulrich S; Wauer, Sylvia; Leopold, Traugott; Schleyer, Eberhard; Ehninger, Gerhard

    2004-06-01

    A highly sensitive and time-reduced HPLC assay for the quantitative analysis of busulfan in plasma and aqueous samples is described. The assay is based on a precolumn derivatization of busulfan to 1,4-diiodobutane and UV-detection of iodide ions generated by a postcolumn photochemical dissociation of the derivative. The extraction and derivatization were carried out in a one-pot reaction without any solid phase extraction and is therefore suitable for high throughput analysis. Quantification was performed by using 1,5-pentanediol-bis-(methanesulfonate), a homologue of busulfan, as an internal standard. Linearity was demonstrated for concentrations from 50 to 10,000ng/ml. The limit of detection was found at 10ng/ml. Precision is indicated by an intra-day variety of 2.81% and by an inter-day variety of 6.61% for aqueous samples, 2.93 and 5.76% for plasma samples, respectively. The recovery of busulfan in plasma was more than 95%. No coelution with metabolites of busulfan or other drugs used in cancer therapy was found. The method was generated for measurements of busulfan in aqueous or plasma samples and applied in therapeutic drug monitoring of busulfan. PMID:15113551

  1. Variation in Prescribing Patterns and Therapeutic Drug Monitoring of Intravenous Busulfan in Pediatric Hematopoietic Cell Transplant Recipients

    PubMed Central

    McCune, Jeannine S.; Baker, K. Scott; Blough, David K.; Gamis, Alan; Bemer, Meagan J.; Kelton-Rehkopf, Megan C.; Winter, Laura; Barrett, Jeffrey S.

    2016-01-01

    Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors’ group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children. PMID:23444282

  2. Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients.

    PubMed

    McCune, Jeannine S; Baker, K Scott; Blough, David K; Gamis, Alan; Bemer, Meagan J; Kelton-Rehkopf, Megan C; Winter, Laura; Barrett, Jeffrey S

    2013-03-01

    Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors- group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children. PMID:23444282

  3. Determination of busulfan in plasma by GC-MS with selected-ion monitoring.

    PubMed

    Ehrsson, H; Hassan, M

    1983-10-01

    A GC-MS technique with selected-ion monitoring is described for the determination of busulfan in plasma. Busulfan is extracted from plasma with methylene chloride and converted to 1,4-diiodobutane. Analysis by GC-MS with selected-ion monitoring (m/z 183) gave a relative standard deviation of +/- 4.3% (n = 5) at the 10-ng/ml level. PMID:6644573

  4. Comparison of human liver and small intestinal glutathione S-transferase-catalyzed busulfan conjugation in vitro.

    PubMed

    Gibbs, J P; Yang, J S; Slattery, J T

    1998-01-01

    The apparent oral clearance of busulfan has been observed to vary as much as 10-fold in the population of children and adults receiving high-dose busulfan. The only identified elimination pathway for busulfan involves glutathione conjugation. The reaction is predominantly catalyzed by glutathione S-transferase (GST) A1-1, which is present in both liver and intestine. The purpose of this study was to compare busulfan Vmax/Km in cytosol prepared from adult human liver and small intestine. Tetrahydrothiophenium ion formation rate per milligram of cytosolic protein was constant along the length (assessed in 30-cm segments) of three individual small intestines. A 30-cm-long intestinal segment 90-180 cm from the pylorus was chosen to be representative of intestinal cytosolic busulfan conjugating activity. Busulfan Vmax/Km (mean +/- SD) in cytosol prepared from 23 livers and 12 small intestines was 0.166 +/- 0.066 and 0.176 +/- 0.085 microl/min/mg cytosolic protein, respectively, in incubations with 5 microM busulfan, 1 mM glutathione, and 2 mg of cytosolic protein. The relative content of GSTalpha (A1-1, A1-2, and A2-2) was compared for human liver and intestinal cytosol using Western blot. The levels of GSTalpha in liver and intestinal cytosol were 1.12 +/- 0.56 and 1.36 +/- 0.32 integrated optimal density units/5 microg cytosolic protein, respectively. Busulfan conjugation in vitro was comparable per milligram of cytosolic protein in liver and intestinal cytosol. PMID:9443852

  5. Busulfan administration produces sublethal effects on somatic tissues and inhibits gametogenesis in Senegalese sole juveniles.

    PubMed

    Pacchiarini, T; Olague, E; Sarasquete, C; Cabrita, E

    2014-05-01

    Busulfan, a cytotoxic alkylating agent used for treatment of chronic myeloid leukemia has effects in mammalian germ cells. In fish species, the use of this compound is of special interest in intra and interspecies germ cell transplants. To determine the effects of busulfan in fish a previous range finding experiment was designed. Survival and growth rate of 150-days after hatching (150DAH) Senegalese sole (Solea senegalensis) juveniles was determined. In a second experiment, the effects of a sublethal busulfan dose in fish germ cell depletion and in somatic tissues were analysed. Sublethal effects of several busulfan treatments (B10-10 days after injection, B20-20 days after injection, B20÷-20 days after injection with double injection) were determined in somatic and gonadal tissues. Alterations were registered through histopathological techniques, TUNEL (cell apoptosis) and quantified at molecular level (Q-PCR analyses) using the vasa mRNAs (Ssvasa1-2 and Ssvasa3-4 mRNAs) as molecular markers for germinal cells in Senegalese sole juveniles. Several sublethal effects were observed with 40 mg kg⁻¹ busulfan, a non-lethal dose, such as: pyknosis in liver, increase of melanomacrophage centres and blood stagnation in spleen and interruption of gonadal development. Females were more affected by busulfan treatments than males in terms of germ cell disruption, since a significant decrease in the expression of both Ssvasa1-2 and Ssvasa3-4 markers was found in the gonad of treated females rather than males. At 10 days post-treatment (B10), females already presented a decrease in germ cell proliferation, as confirmed by Q-PCR. Ssvasa expression proved to be a reliable tool for the direct evaluation of the effects of busulfan on Senegalese sole gonadal development, proving that busulfan can be a suitable treatment for causing transient sterility in recipient gonads for germ cell transplantation. PMID:24371034

  6. Testicular Busulfan Injection in Mice to Prepare Recipients for Spermatogonial Stem Cell Transplantation Is Safe and Non-Toxic

    PubMed Central

    Qin, YuSheng; Liu, Ling; He, YaNan; Wang, Chen; Liang, MingYuan; Chen, XiaoLi; Hao, HaiSheng; Qin, Tong; Zhao, XueMing; Wang, Dong

    2016-01-01

    Current methods of administering busulfan to remove the endogenous germ cells cause hematopoietic toxicity, require special instruments and a narrow transplantation time. We use a direct testicular injection of busulfan method for preparing recipients for SSC transplantation. Male ICR mice (recipients) were divided into four groups, and two experimental groups were treated with a bilateral testicular injection of 4 or 6 mg/kg/side busulfan (n = 60 per concentration group). Mice received an intraperitoneal injection (i.p.) of 40 mg/kg busulfan (n = 60, positive control) and bilateral testicular injections of 50% DMSO (n = 60, negative control). Donor SSCs from RFP-transgenic C57BL/6J mice were introduced into the seminiferous tubules of each recipient testis via efferent duct injection on day 16–17 after busulfan treatment. Recipient mice mated with mature female ICR mice and the number of progeny was recorded. The index detected at day 14, 21, 28, 35 and 70 after busulfan treatment. Blood analysis shows that the toxicity of busulfan treated groups was much lower than i.p. injection groups. Fertility was restored in mice treated with busulfan and donor-derived offspring were obtained after SSC transplantation. Our study indicated that intratesticular injection busulfan for the preparation of recipients in mice is safe and feasible. PMID:26871566

  7. Pro: Cyclophosphamide in lupus nephritis.

    PubMed

    Kallenberg, Cees G M

    2016-07-01

    Based on efficacy and toxicity considerations, both low-dose pulse cyclophosphamide as part of the Euro-Lupus Nephritis protocol and mycophenolate mofetil (MMF) with corticosteroids may be considered for induction of remission in patients with proliferative lupus nephritis. The long-term follow-up data available for low-dose pulse cyclophosphamide, the fact that compliance is guaranteed with this regimen and economic issues all favour the Euro-Lupus regimen in this author's opinion. For maintenance treatment, either azathioprine (AZA) or MMF may be used; AZA is preferred in case pregnancy is planned, while MMF is preferred when the disease relapses during use of AZA and, possibly, after successful induction of remission with MMF. PMID:27190359

  8. Cyclophosphamide and Busulfan Followed by Donor Stem Cell Transplant in Treating Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2014-04-03

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic Syndrome With Isolated Del(5q); Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  9. The Myeloablative Drug Busulfan Converts Cysteine to Dehydroalanine and Lanthionine in Redoxins.

    PubMed

    Scian, Michele; Guttman, Miklos; Bouldin, Samantha D; Outten, Caryn E; Atkins, William M

    2016-08-23

    The myeloablative agent busulfan (1,4-butanediol dimethanesulfonate) is an old drug that is used routinely to eliminate cancerous bone marrow prior to hematopoietic stem cell transplant. The myeloablative activity and systemic toxicity of busulfan have been ascribed to its ability to cross-link DNA. In contrast, here we demonstrate that incubation of busulfan with the thiol redox proteins glutaredoxin or thioredoxin at pH 7.4 and 37 °C results in the formation of putative S-tetrahydrothiophenium adducts at their catalytic Cys residues, followed by β-elimination to yield dehydroalanine. Both proteins contain a second Cys, in their catalytic C-X-X-C motif, which reacts with the dehydroalanine, the initial Cys adduct with busulfan, or the S-tetrahydrothiophenium, to form novel intramolecular cross-links. The reactivity of the dehydroalanine (DHA) formed is further demonstrated by adduction with glutathione to yield a lanthionine and by a novel reaction with the reducing agent tris(2-carboxyethyl)phosphine (TCEP), which yields a phosphine adduct via Michael addition to the DHA. Formation of a second quaternary organophosphonium salt via nucleophilic substitution with TCEP on the initial busulfan-protein adduct or on the THT(+)-Redoxin species is also observed. These results reveal a rich potential for reactions of busulfan with proteins in vitro, and likely in vivo. It is striking that several of the chemically altered protein products retain none of the atoms of busulfan, in contrast to typical drug-protein adducts or traditional protein modification reagents. In particular, the ability of a clinically used drug to convert Cys to dehydrolanine in intact proteins, and its subsequent reaction with biological thiols, is unprecedented. PMID:27490699

  10. Compensatory proliferation of endogenous chicken primordial germ cells after elimination by busulfan treatment

    PubMed Central

    2013-01-01

    Introduction Primordial germ cells (PGCs) are the major population of cells in the developing bilateral embryonic gonads. Little is known about the cellular responses of PGCs after treatment with toxic chemicals such as busulfan during embryo development. In this study, we investigated the elimination, restorative ability, and cell cycle status of endogenous chicken PGCs after busulfan treatment. Methods Busulfan was emulsified in sesame oil by a dispersion-emulsifying system and injected into the chick blastoderm (embryonic stage X). Subsequently, we conducted flow cytometry analysis to evaluate changes in the PGC population and cell cycle status, and immunohistochemistry to examine the germ cell proliferation. Results Results of flow cytometry and immunohistochemistry analyses after busulfan treatment showed that the proportion of male PGCs at embryonic day 9 and female PGCs at embryonic day 7 were increased by approximately 60% when compared with embryonic day 5.5. This result suggests the existence of a compensatory mechanism in PGCs in response to the cytotoxic effects of busulfan. Results of cell cycling analysis showed that the germ cells in the G0/G1 phase were significantly decreased, while S/G2/M-phase germ cells were significantly increased in the treatment group compared with the untreated control group in both 9-day-old male and female embryos. In addition, in the proliferation analysis with 5-ethynyl-2′-deoxyuridine (EdU) incorporation, we found that the proportion of EdU-positive cells among VASA homolog-positive cells in the 9-day embryonic gonads of the busulfan-treated group was significantly higher than in the control group. Conclusions We conclude that PGCs enter a restoration pathway by promoting their cell cycle after experiencing a cytotoxic effect. PMID:24405696

  11. LC-MS/MS method development for quantification of busulfan in human plasma and its application in pharmacokinetic study.

    PubMed

    Nadella, Taraka Ramarao; Suryadevara, Vidyadhara; Lankapalli, Sasidhar Reddyvallam; Mandava, Venkata Basaveswara Rao; Bandarupalli, Deepti

    2016-02-20

    A simple, rapid, specific and precise liquid chromatography-tandem mass spectrophotometric (LC-MS/MS) method was developed and validated for quantification of busulfan, in human plasma. busulfan d8 was used as internal standard, added to plasma sample prior to extraction using acetonitrile as a precipitating agent. Chromatographic separation was achieved on phenomenex kinetex C18 column (50mm×2.1mm, 2.6μm) with acteonitrile: 10mM ammonium formate buffer (80:20v/v) as an isocratic mobile phase with a flow rate of 0.5mLmin(-1). Quantitation was performed by transition of 264.1→151.1 (m/z) for busulfan and 272.1→159.1 (m/z) for busulfan d8. The lower limit of quantitation was 0.2ngmL(-1) with a 100μL plasma sample. The concentrations of nine working standards showed linearity between 0.2 and 100ngmL(-1) (r(2)≥0.9986). Chromatographic separation was achieved within 2.0min. The average extraction recoveries of 3quality control concentrations were 92.52% for busulfan and 90.75% for busulfan d8. The coefficient of variation was ≤15% for intra- and inter-batch assays. The developed method was successfully applied for the determination of Busulfan pharmacokinetics after oral administration. PMID:26736033

  12. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation.

    PubMed

    Mielcarek, Marco; Furlong, Terry; O'Donnell, Paul V; Storer, Barry E; McCune, Jeannine S; Storb, Rainer; Carpenter, Paul A; Flowers, Mary E D; Appelbaum, Frederick R; Martin, Paul J

    2016-03-17

    The cumulative incidence of National Institutes of Health (NIH)-defined chronic graft-versus-host disease (GVHD) requiring systemic treatment is ∼35% at 1 year after transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized blood cells from HLA-matched related or unrelated donors. We hypothesized that high-dose cyclophosphamide given after G-CSF-mobilized blood cell transplantation would reduce the cumulative 1-year incidence of chronic GVHD to 15% or less. Forty-three patients with high-risk hematologic malignancies (median age, 43 years) were enrolled between December 2011 and September 2013. Twelve (28%) received grafts from related donors, and 31 (72%) received grafts from unrelated donors. Pretransplant conditioning consisted of fludarabine and targeted busulfan (n = 25) or total body irradiation (≥12 Gy; n = 18). Cyclophosphamide was given at 50 mg/kg per day on days 3 and 4 after transplantation, followed by cyclosporine starting on day 5. The cumulative 1-year incidence of NIH-defined chronic GVHD was 16% (95% confidence interval, 5-28%). The cumulative incidence estimates of grades 2-4 and 3-4 acute GVHD were 77% and 0%, respectively. At 2 years, the cumulative incidence estimates of nonrelapse mortality and recurrent malignancy were 14% and 17%, respectively, and overall survival was projected at 70%. Of the 42 patients followed for ≥1 year, 21 (50%) were relapse-free and alive without systemic immunosuppression at 1 year after transplantation. Thus, myeloablative pretransplant conditioning can be safely combined with high-dose cyclophosphamide after transplantation, and the risk of chronic GVHD associated with HLA-matched mobilized blood cell grafts can be substantially reduced. This trial was registered at www.clinicaltrials.gov as #NCT01427881. PMID:26764356

  13. Intermittent cyclophosphamide treatment of autoimmune thrombocytopenia

    PubMed Central

    Weinerman, Brian; Maxwell, Ian; Hryniuk, William

    1974-01-01

    Cyclophosphamide was given intermittently rather than daily to 14 patients with autoimmune thrombocytopenic purpura. Eight patients responded and six did not. In those who responded the rise in platelet count was rapid, and in all patients the lack of toxicity was striking. Intermittent cyclophosphamide seems effective in some cases of autoimmune thrombocytopenia and is safe, at least in the short term. Controlled trials would be required to prove that intermittent is better than daily administration. PMID:4473260

  14. Moderator's view: Cyclophosphamide in lupus nephritis.

    PubMed

    Tesar, Vladimir

    2016-07-01

    Mycophenolate mofetil was recently accepted as the effective induction treatment of lupus nephritis, with the potential to replace cyclophosphamide or at least expand our therapeutic armamentarium in patients with this lifelong disease often requiring repeated induction treatment of its relapses. Compared with cyclophosphamide, mycophenolate may be more effective in black patients, and the risk of gonadotoxicity may be significantly lower in mycophenolate-treated subjects. However, experience with mycophenolate in severe lupus nephritis is still limited and we also have insufficient data on the long-term outcome of mycophenolate-treated patients. Treatment with mycophenolate is more expensive than with cyclophosphamide, which may limit its use, especially in low- and middle-income countries. The efficacy of mycophenolate mofetil may be more dependent on the patient's compliance compared with intravenous cyclophosphamide pulses. Low-dose cyclophosphamide remains an effective and relatively safe induction treatment of active lupus nephritis, but to decrease its cumulative toxicity, repeated exposure to cyclophosphamide in relapsing patients should be (if possible) avoided. PMID:27190357

  15. Low dose busulfan facilitates chimerism and tolerance in a murine model.

    PubMed

    Anam, Khairul; Black, Alfred T; Hale, Douglas A

    2006-01-01

    T cell depletion, sirolimus and "mega" dose donor specific bone marrow (DSBM) infusion promotes stable multilineage chimerism and indefinite survival of skin allografts in completely mismatched mice. The purpose of this study is to determine whether the addition of low dose busulfan can reduce the amount of DSBM required while preserving efficacy. C57BL/6 recipients of BALB/c skin allografts were treated with alphaCD4 and alphaCD8 monoclonal antibodies, DSBM, sirolimus and various doses of busulfan. The kinetics and phenotype of chimerism and the presence of clonal deletion of alloreactive T-cells were defined using flow cytometry. In vitro reactivity was determined using mixed lymphocyte culture. Second skin grafts confirmed the presence of tolerance. All doses of busulfan resulted in engraftment when combined with this regimen using a reduced dose of donor marrow. The level, kinetics and character of chimerism observed were dose related. Chimerism was associated with indefinite allograft acceptance (>200 days). Tolerance was documented both in vitro/in vivo and was associated with clonal deletion. Addition of a single low dose of busulfan to an established tolerance protocol reduced the required DSBM dose by over 80% while still promoting comparable levels of donor chimerism and donor-specific tolerance. PMID:16431286

  16. A Pilot Pharmacologic Biomarker Study of Busulfan and Fludarabine in Hematopoietic Cell Transplant Recipients

    PubMed Central

    McCune, Jeannine S.; Woodahl, Erica L.; Furlong, Terry; Storer, Barry; Wang, Joanne; Heimfeld, Shelly; Deeg, H. Joachim; O'Donnell, Paul V.

    2012-01-01

    Purpose Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin®) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/Tbusulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients. Methods We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan, specifically busulfan concentration at steady state (Css), and fludarabine, specifically F-ara-A area under the curve (AUC) and fludarabine triphosphate (F-ara-ATP) intracellular accumulation and concentration in separate CD4+ and CD8+ T-lymphocyte populations. Results Acute and chronic graft versus host disease (GvHD) occurred in 11 patients and one patient, respectively. Four patients died before day +100 of non-relapse causes, which met the protocol stopping guidelines. The cumulative incidence of relapse was 25% at three year post-HCT. Interpatient variability in the busulfan- and fludarabine-relevant pharmacologic biomarkers was 2.1- to 2.7-fold. F-ara-A AUC and accumulated F-ara-ATP in CD8+ cells had the highest hazard ratio for non-relapse mortality and overall survival, respectively. However, neither achieved statistical significance. Conclusions The low rates of GvHD, particularly in its chronic form, were encouraging and further biomarker studies are warranted to optimize the fludarabine/Tbusulfan/rATG conditioning regimen. PMID:21909959

  17. Synthesis and biological effects of new hybrid compounds composed of benzylguanidines and the alkylating group of busulfan on neuroblastoma cells.

    PubMed

    Hampel, Thomas; Bruns, Marietta; Bayer, Melanie; Handgretinger, Rupert; Bruchelt, Gernot; Brückner, Reinhard

    2014-06-15

    (131)Iodine-labelled (meta-iodobenzyl)guanidine ([(131)I]-mIBG) and busulfan [butane-1,4-diylbis(methanesulfonate)] are well-established pharmaceuticals in neuroblastoma therapy. We report the design, synthesis, and testing of hybrid molecules-mBBG and pBBG-which combine key structural features of (meta-iodobenzyl)guanidine and busulfan: they contain a benzylguanidine moiety for accumulating in neuroblastoma cells via the noradrenaline transporter and, in the meta- or para-position, respectively, one of the two identical alkylating motives of busulfan for killing cells. Uptake and toxicity of hybrids mBBG and pBBG in human neuroblastoma cells compared favorably to their ancestors [(131)I]-mIBG and busulfan. PMID:24814532

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

    SciTech Connect

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

    1987-05-01

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

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

    SciTech Connect

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

    1987-05-01

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

  20. Busulfan in infants to adult hematopoietic cell transplant recipients: A population pharmacokinetic model for initial and Bayesian dose personalization

    PubMed Central

    McCune, Jeannine S.; Bemer, Meagan J.; Barrett, Jeffrey S.; Baker, K. Scott; Gamis, Alan S.; Holford, Nicholas H.G.

    2014-01-01

    Purpose Personalizing intravenous (IV) busulfan doses to a target plasma concentration at steady state (Css) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict IV busulfan doses over a wide age spectrum (0.1 – 66 years) that accounts for differences in age and body size. Experimental design A population pharmacokinetic model based on normal fat mass and maturation based on post-menstrual age was built from 12,380 busulfan concentration-time points obtained after IV busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target Css with this model were compared with pediatric-only models. Results A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62kg normal fat mass (equivalent to 70kg total body weight). Busulfan clearance, scaled to body size – specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years post-natal age. With a target Css of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared to dosing recommended by the Food and Drug Administration (57%) or the European Medicines Agency (70%). Conclusion This is the first population pharmacokinetic model developed to predict initial IV busulfan doses and personalize to a target Css over a wide age spectrum, ranging from infants to adults. PMID:24218510

  1. Busulfan Conditioning Enhances Engraftment of Hematopoietic Donor-derived Cells in the Brain Compared With Irradiation

    PubMed Central

    Wilkinson, Fiona L; Sergijenko, Ana; Langford-Smith, Kia J; Malinowska, Marcela; Wynn, Rob F; Bigger, Brian W

    2013-01-01

    Hematopoietic stem cell gene therapy for neurological disorders relies on transmigration of donor-derived monocytes to the brain, where they can engraft as microglia and deliver therapeutic proteins. Many mouse studies use whole-body irradiation to investigate brain transmigration pathways, but chemotherapy is generally used clinically. The current evidence for transmigration to the brain after chemotherapy is conflicting. We compared hematopoietic donor cell brain engraftment after bone marrow (BM) transplants in busulfan- or irradiation-conditioned mice. Significantly more donor-derived microglial cells engrafted posttransplant in busulfan-conditioned brain compared with the irradiated, in both the short and long term. Although total Iba-1+ microglial content was increased in irradiated brain in the short term, it was similar between groups over long-term engraftment. MCP-1, a key regulator of monocyte transmigration, showed long-term elevation in busulfan-conditioned brain, whereas irradiated brains showed long-term elevation of the proinflammatory chemokine interleukin 1α (IL-1α), with increased in situ proliferation of resident microglia, and significant increases in the relative number of amoeboid activated microglia in the brain. This has implications for the choice of conditioning regimen to promote hematopoietic cell brain engraftment and the relevance of irradiation in mouse models of transplantation. PMID:23423338

  2. EVALUATION OF THE POTENTIAL CARCINOGENICITY OF CYCLOPHOSPHAMIDE

    EPA Science Inventory

    Cyclophosphamide is a probable human carcinogen, classified as weight-of-evidence Group B1 under the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a).Evidence on potential carcinogenicity from animal studies is "Sufficient," and the evidence from human studies is "...

  3. Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration-time curve in pediatric hematopoietic stem cell transplant recipients.

    PubMed

    Watanabe, Erika; Nishikawa, Takuro; Ikawa, Kazuro; Yamaguchi, Hiroki; Abematsu, Takanari; Nakagawa, Shunsuke; Kurauchi, Koichiro; Kodama, Yuichi; Tanabe, Takayuki; Shinkoda, Yuichi; Matsumoto, Kazuaki; Okamoto, Yasuhiro; Takeda, Yasuo; Kawano, Yoshifumi

    2015-11-01

    Optimizing systemic busulfan exposure, the area under the concentration-time curve (AUC), improves the outcomes for hematopoietic stem cell transplantation (HSCT). The AUC is conventionally calculated using six plasma concentrations (AUC(0-∞)) drawn after the first of 16 intravenous busulfan doses given as a 2-h infusion every 6 h. The aim of the present study was to develop limited sampling strategies using three or fewer busulfan concentrations to reliably calculate AUC(0-∞) in patients undergoing HSCT. We investigated the pharmacokinetics of busulfan 46 times in 29 pediatric patients receiving intravenous busulfan. Limited sampling strategies using one, two, or three plasma busulfan concentrations were developed by multiple linear regression that showed excellent agreement with AUC(0-∞). In single-point sampling strategies, the AUC(0-∞) predicted based on C(6) (trough level: busulfan plasma concentration 6 h after the start of the infusion) was significantly correlated with, and not statistically different from, actual values as follows: AUC(0-∞) = 2556.5 C6 + 320.9 (r(2) = 0.929, P < 0.0001, mean bias 0.282 %, precision 7.91 %). In contrast, the predicted AUCs derived from the other sampling single points did not meet the criteria. The trough level well correlated with actual AUC(0-∞), suggesting that this time-point is acceptable for busulfan monitoring. PMID:26243625

  4. Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation.

    PubMed

    Perkins, Janelle B; Kim, Jongphil; Anasetti, Claudio; Fernandez, Hugo F; Perez, Lia E; Ayala, Ernesto; Kharfan-Dabaja, Mohamed A; Tomblyn, Marcie R; Sullivan, Daniel M; Pidala, Joseph A; Field, Teresa L

    2012-07-01

    Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 μM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ≥70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 μM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 μM-min (level 2) and 220 mg/m(2)/day for AUC 9,000 μM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 μM-min × 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 μM-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse. PMID:22198540

  5. Near infrared spectroscopy and process analytical technology to master the process of busulfan paediatric capsules in a university hospital.

    PubMed

    Paris, I; Janoly-Dumenil, A; Paci, A; Mercier, L; Bourget, P; Brion, F; Chaminade, P; Rieutord, A

    2006-06-16

    The prescription of unlicensed oral medicines in paediatrics leads the hospital pharmacists to compound hard capsules, such as busulfan, an alkylating agent prescribed in preparative regimens for bone marrow transplantation. In this study, we have investigated how the general principle of process analytical technology (PAT) can be implemented at the small size of our hospital pharmacy manufacturing unit. Near infrared spectroscopy (NIRS) was calibrated for raw material identification, blend uniformity analysis and final content uniformity of busulfan hard capsules of 11 different strengths. Measurements were performed on capsules from 2 to 40 mg (n=440). After optimisation, accuracy and linearity of the NIRS quantitative method was demonstrated after comparison with a previously validated quantitative high performance thin layer chromatography (HPTLC) method. Such a comparison led to attractive NIRS precision: +/-0.7 to +/-1.0 mg for capsules from 2 to 40 mg, respectively. As NIRS is a rapid and non-destructive technique, the individual control of a whole batch of busulfan paediatric capsules intended to be administrated is possible. Actually, mastering the process of busulfan paediatric capsules with the NIRS integrated into the notion of PAT is a powerful analytical tool to assess the process quality and to perform content uniformity of at least 5mg busulfan-containing capsules. PMID:16621419

  6. Overexpression of glutathione S-transferase A1-1 in ECV 304 cells protects against busulfan mediated G2-arrest and induces tissue factor expression

    PubMed Central

    Ritter, Christoph A; Sperker, Bernhard; Grube, Markus; Dressel, Dana; Kunert-Keil, Christiane; Kroemer, Heyo K

    2002-01-01

    The antineoplastic drug busulfan is frequently used in preconditioning regimens for bone marrow transplantation. Pharmacokinetics vary tremendously between patients due to extensive metabolism in the liver via conjugation to glutathione catalysed by glutathione S-transferase (GST) A1-1. Since elevated busulfan plasma levels have been reported to be a risk factor for developing veno-occlusive disease (VOD), metabolism of busulfan may play a pivotal role in the induction of VOD. Therefore, we developed a cell model to investigate the influence of busulfan metabolism on its biological effects. GSTA1-1 cDNA was transfected into the cell line ECV 304 and protein expression was demonstrated by Western blotting. Enzymatic activity could be detected by formation of tetrahydrothiophene. Additionally, effects of busulfan treatment on cell cycle and expression of tissue factor have been investigated. A busulfan-induced G2-arrest was reduced in GSTA1-1-transfected cells, which consequently displayed a significantly higher activity of cdc2 kinase (24.1±1.5 AU mg−1 protein) after busulfan treatment compared to controls (14.7±2.3 AU mg−1 protein; P<0.01). Elevated basal expression of tissue factor in GSTA1-1-transfected ECV 304 cells could be 4 fold increased by busulfan treatment. These data demonstrate that ECV 304 cells transfected with GSTA1-1 provide a valuable tool to assess busulfan metabolism in vitro. Furthermore, overexpression of GSTA1-1 leads to a partial protection against cell cycle effects of busulfan and affects tissue factor expression. PMID:12429583

  7. Late Effects after Umbilical Cord Blood Transplantation in Very Young Children after Busulfan-Based, Myeloablative Conditioning.

    PubMed

    Allewelt, Heather; El-Khorazaty, Jill; Mendizabal, Adam; Taskindoust, Mahsa; Martin, Paul L; Prasad, Vinod; Page, Kristin; Sanders, Jean; Kurtzberg, Joanne

    2016-09-01

    Infants and young children who undergo allogeneic cord blood transplantation (CBT) are at increased risk for late effects because of exposure of developing organs to chemotherapy and radiation therapy typically used in transplant conditioning regimens. Busulfan (Bu)-based myeloablative regimens were developed to eliminate radiation exposure in these young children with the hope that late effects would be minimized. We now describe the late effects in 102 consecutive patients surviving a minimum of 5 years (median follow-up, 12.9 years) post-CBT. Patients were conditioned with high-dose chemotherapy using Bu-containing regimens. No patient received total body irradiation. The median age at transplant was 1 year (range, .1 to 2). Diagnoses included inherited metabolic diseases (59.8%), leukemia (17.6%), congenital immune deficiency (20.2%), bone marrow failure/myelodysplastic syndrome (3.9%), and hemoglobinopathy (2%). Among patients surviving 5 years, the overall survival rate at 10 years post-CBT was 93% (95% CI, 84.9 to 96.8). Virtually all patients (98%) experienced at least 1 significant late effect. Most (83.3%) experienced 2 or more late effects, and more than half of the patients (64.7%) experienced 3 or more late effects. The most commonly observed late effects included dental problems (92.2%), short stature (55.9%), cognitive deficits (53.6%), pulmonary dysfunction (18.6%), and abnormal pubertal development (27.9%). This is the first report of late effects of Bu-based conditioning in a cohort of very young patients at the time of transplant. These results will inform clinical care guidelines for long-term follow-up and add to the growing information regarding outcomes of hematopoietic stem cell transplantation. PMID:27264632

  8. Prospective validation of a novel dosing scheme for intravenous busulfan in adult patients undergoing hematopoietic stem cell transplantation

    PubMed Central

    Cho, Sang-Heon; Lee, Jung-Hee; Lim, Hyeong-Seok; Lee, Kyoo-Hyung; Kim, Dae-Young; Choe, Sangmin; Lee, Je-Hwan

    2016-01-01

    The objective of this study was to externally validate a new dosing scheme for busulfan. Thirty-seven adult patients who received busulfan as conditioning therapy for hematopoietic stem cell transplantation (HCT) participated in this prospective study. Patients were randomized to receive intravenous busulfan, either as the conventional dosage (3.2 mg/kg daily) or according to the new dosing scheme based on their actual body weight (ABW) (23×ABW0.5 mg daily) targeting an area under the concentration-time curve (AUC) of 5924 µM·min. Pharmacokinetic profiles were collected using a limited sampling strategy by randomly selecting 2 time points at 3.5, 5, 6, 7 or 22 hours after starting busulfan administration. Using an established population pharmacokinetic model with NONMEM software, busulfan concentrations at the available blood sampling times were predicted from dosage history and demographic data. The predicted and measured concentrations were compared by a visual predictive check (VPC). Maximum a posteriori Bayesian estimators were estimated to calculate the predicted AUC (AUCPRED). The accuracy and precision of the AUCPRED values were assessed by calculating the mean prediction error (MPE) and root mean squared prediction error (RMSE), and compared with the target AUC of 5924 µM·min. VPC showed that most data fell within the 95% prediction interval. MPE and RMSE of AUCPRED were -5.8% and 20.6%, respectively, in the conventional dosing group and −2.1% and 14.0%, respectively, in the new dosing scheme group. These fi ndings demonstrated the validity of a new dosing scheme for daily intravenous busulfan used as conditioning therapy for HCT. PMID:27162478

  9. Haploidentical Bone Marrow Transplantation With Clofarabine and Busulfan Conditioning for a Child With Multiple Recurrent Acute Lymphoblastic Leukemia.

    PubMed

    Aoki, Yuki; Miyawaki, Reiji; Imai, Kohsuke; Takagi, Masatoshi; Kajiwara, Michiko; Ishiwata, Yasuyoshi; Yasuhara, Masato; Morio, Tomohiro; Mizutani, Shuki; Tomizawa, Daisuke

    2016-01-01

    Outcome of children with acute lymphoblastic leukemia (ALL) has improved over the years, but not for those with multiple recurrences because of high therapy resistance and heavily pretreated history that potentially cause physical damages. We describe the case of an 11-year-old boy with a third relapse of ALL and a history of 2 allogeneic bone marrow transplantations. He was successfully treated with clofarabine combination chemotherapy and achieved a fourth remission at 16 months following haploidentical bone marrow transplantation with conditioning regimen of clofarabine and busulfan. Clofarabine/busulfan conditioning might be a preferable option for children with multiple recurrent ALL, and warrants further investigation. PMID:26523380

  10. OCTET-CY: a phase II study to investigate the efficacy of post-transplant cyclophosphamide as sole graft-versus-host prophylaxis after allogeneic peripheral blood stem cell transplantation

    PubMed Central

    Holtick, Udo; Chemnitz, Jens-Markus; Shimabukuro-Vornhagen, Alexander; Theurich, Sebastian; Chakupurakal, Geothy; Krause, Anke; Fiedler, Anne; Luznik, Leo; Hellmich, Martin; Wolf, Dominik; Hallek, Michael; von Bergwelt-Baildon, Michael; Scheid, Christof

    2016-01-01

    Objective Post-transplant cyclophosphamide is increasingly used as graft-versus-host disease (GvHD) prophylaxis in the setting of bone marrow transplantation. No data have been published on the use of single-agent GvHD prophylaxis with post-transplant cyclophosphamide in the setting of peripheral blood stem cell transplantation (PBSCT). Methods In a phase II trial, 11 patients with myeloma or lymphoma underwent conditioning with fludarabine and busulfan followed by T-replete PBSCT and application of 50 mg/kg/d of cyclophosphamide on day+3 and +4 without other concurrent immunosuppression (IS). Results Median time to leukocyte, neutrophil, and platelet engraftment was 18, 21, and 18 d. The incidence of grade II–IV and grade III–IV GvHD was 45% and 27%, with a non-relapse mortality (NRM) of 36% at one and 2 yr. After median follow-up of 927 d, overall and relapse-free survival was 64% and 34%. Three patients did not require any further systemic IS until day+100 and thereafter. Analysis of immune reconstitution demonstrated rapid T- and NK-cell recovery. B- and CD3+/CD161+NK/T-cell recovery was superior in patients not receiving additional IS. Conclusion Post-transplant cyclophosphamide as sole IS in PBSCT is feasible and allows rapid immune recovery. Increased rates of severe acute GvHD explain the observed NRM and may advise a temporary combination partner such as mTor-inhibitors in the PBSCT setting. PMID:25703164

  11. Protective effects of L-carnitine and homogenized testis tissue on the testis and sperm parameters of busulfan-induced infertile male rats

    PubMed Central

    Dehghani, Farzaneh; Hassanpour, Ashraf; Poost-pasand, Aghdas; Noorafshan, Ali; Karbalay-Doust, Saeid

    2013-01-01

    Background: Busulfan(Bus) is a chemotherapy drug that is widely used for cancer treatment. However, administration of busulfan may cause temporary or permanent sterility in male patients. Therefore, reduction of this side is necessary. Objective: evaluation of the protective effects of L-carnitine and testis homogenized tissue(THT) on sperm parameters and the testis structure after busulfan treatment. Materials and Methods: Twenty rats were divided four groups. Group I (Control) received a single dose of DMSO and 1mL of distilled water (I.P.). Group II (Bus) received a single of busulfan (10 mg/kg) plus 1 ml of the distilled water(I.P.). Group III (Bus+THT) received busulfan plus 1mL of THT daily by oral gavages. Group IV (Bus+L-car) received a single dose of busulfan plus 100 mg/kg/day L-carnitine(I.P.). after 48 dayst, the Stereological technique was used for the estimating volume and diameter of testis, seminiferous tubules and interstitial tissue, flagella length, germinal epithelium height and spermatoginic cell number. Semen analysis was used for the assessment of sperm parameters. Results: THT increased volume of testis (6.5%), seminiferous tubule and interstitial tissue volume (6.5%), 6.9% and 11.7% respectively), germinal epithelium height (13%), sperm count (7.5%), and decreased sperm with abnormal morphology (1%) in comparison with the L-carnitine in busulfan treated group. Conclusion: It seems the use of L-carnitine and THT decreases side effects of busulfan on the male reproductive system. However, in our study, THT is more effective than L-carnitine and leads to the recovery testis structure and sperm parameters after treatment with busulfan. This article extracted from M.Sc. thesis. (Ashraf Hassanpour) PMID:24639808

  12. Evaluation of existing limited sampling models for busulfan kinetics in children with beta thalassaemia major undergoing bone marrow transplantation.

    PubMed

    Balasubramanian, P; Chandy, M; Krishnamoorthy, R; Srivastava, A

    2001-11-01

    Busulfan pharmacokinetic parameters are useful in predicting the outcome of allogeneic bone marrow transplantation (BMT). Standard pharmacokinetic measurements require multiple blood samples. Various limited sampling models (LSM) have been proposed for reducing the sample number required for these measurements, essentially for patients with malignant disorders undergoing BMT. This study was undertaken to evaluate the existing LSM for busulfan pharmacokinetics to find out the most suitable method for patients with thalassaemia major undergoing BMT. Busulfan levels in plasma samples were analysed by HPLC. The AUC calculated by non-compartmental analysis using the program 'TOPFIT' was compared with previously published LSMs. Our seven sample pharmacokinetic data for AUC calculation was compared with the published LSMs. The three sample models suggested by Chattergoon et al and Schuler et al showed significant agreement with AUC TOPFIT (R(2) = 0.98 and 0.94, respectively) in our clinical context. Other models resulted in significant over or under representation of observed values (Vassal's model R(2) = 0.61; Chattergoon's two sample model R(2) = 0.84; four sample model R(2) = 0.83; Schuler's two sample model R(2) = 0.79). By these data the three sample LSM proposed by Chattergoon et al and Schuler et al are suitable for calculation of the AUC in patients with thalassaemia major undergoing BMT conditioned with oral busulfan. PMID:11781641

  13. Granulopoiesis in long-term culture by marrow from mice with busulfan-induced chronic latent aplasia.

    PubMed

    Boyd, R L; Caro, J; Halka, K G; Erslev, A J

    1986-09-01

    Mice given high-dose busulfan therapy develop a chronic latent marrow aplasia characterized by normal peripheral blood neutrophil numbers, hematocrits and marrow cellularity but reduced numbers of pluripotent hemopoietic stem cells (CFU-s) and granulocyte-monocyte progenitor cells (CFU-gm). To study the pathogenesis of this lesion, bone marrow was propagated in long-term marrow cultures (LTMC). Small amounts of normal marrow readily established and sustained long-term granulopoiesis in vitro. In contrast, inocula of marrow from busulfan-treated animals containing three to five times as many stem and progenitor cells failed to establish long-term granulopoiesis in vitro. These results suggest that high-dose busulfan therapy produces a qualitative defect in either the hemopoietic stem cells, the stromal-forming elements, or both, rendering them incapable of establishing long-term granulopoiesis in vitro. Furthermore, mixing experiments employing normal and busulfan-damaged marrow demonstrate that this qualitative defect is not due to the emergence of a suppressor cell population. LTMC can show types of marrow damage not detectable by other techniques currently available and represent a powerful tool for studying latent bone marrow failure. PMID:3772175

  14. Stereological study of the effect of ginger's alcoholic extract on the testis in busulfan-induced infertility in rats

    PubMed Central

    Bordbar, Hossein; Esmaeilpour, Tahereh; Dehghani, Farzaneh; Panjehshahin, Mohammad Reza

    2013-01-01

    Background: In traditional medicine zingiber officinale used to regulate female menstural cycle and treat male infertility. Recent studies have suggested the possible role of ginger extract in improving the testicular damage of busulfan. Objective: The aim of this study was to evaluate the effects of zingiber officinale on the sperm parameters, testosterone level and the volume of the testes and seminiferous tubules by stereological methods. Materials and Methods: Fifty rats were divided into four groups. All the rats were given a single intraperitoneally injection of 5mg/kg busulfan solution. The first group was kept as busulfan control, while the other groups were orally administrated ginger extract in graded doses of 50, 100 and 150mg/kg b.wt, for 48 consecutive days. At the end, all animals were anesthetized and their testes and vas deference were removed, fixed, embedded, and stained. The volume of testes and seminiferous tubules were estimated by cavalieri methods. Results: The result showed, that zingiber officinale increased the volumes of seminiferous tubule in 100mg/kg treated group compared to control group. Sperm count (706×105 and 682×105) and the level of testosterone (50.90 ng/mL and 54.10 ng/mL) enhanced in 100 mg/kg and 150 mg/kg treated groups compared to control group (p=0.00). Conclusion: It seems that zingiber officinale stimulate male reproductive system in induce busulfan infertility. PMID:24639780

  15. HLA Haplotype Mismatch Transplants and Posttransplant Cyclophosphamide

    PubMed Central

    Bacigalupo, Andrea; Sica, Simona

    2016-01-01

    The use of high dose posttransplant cyclophosphamide (PT-CY) introduced by the Baltimore group approximately 10 years ago has been rapidly adopted worldwide and is becoming a standard for patients undergoing unmanipulated haploidentical (HAPLO) transplants. PT-CY has been used following nonmyeloablative as well as myeloablative conditioning regimens, for bone marrow or peripheral blood grafts, for patients with malignant and nonmalignant disorders. Retrospective comparisons of HAPLO grafts with conventional sibling and unrelated donor grafts have been published and suggest comparable outcome. The current questions to be answered include the use of PT-CY for sibling and unrelated donors transplant, possibly in the context of prospective randomized trial. PMID:27143973

  16. Radiolabeled BC8 Antibody, Busulfan, Cyclophosphamide Followed by Donor Stem Cell Transplant in Treating Patients With Acute Myelogenous Leukemia in First Remission

    ClinicalTrials.gov

    2015-11-16

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)

  17. Cytoprotective and anti-apoptotic effects of Satureja khuzestanica essential oil against busulfan-mediated sperm damage and seminiferous tubules destruction in adult male mice.

    PubMed

    Nasimi, P; Vahdati, A; Tabandeh, M R; Khatamsaz, S

    2016-02-01

    We studied the protective effect of Satureja khuzestanica essential oil (SKEO) against damage caused by busulfan on testis in male mice. The NMRI mice (n = 40) were assigned to four groups including: G1: control, G2: treated with busulfan for 4 days (3.2 mg kg(-1)), G3: receive busulfan (4 days, 3.2 mg kg(-1)) and SKEO (28 days, 225 mg kg(-1)) at the same time, G4: pre-treated with SKEO (7 days, 225 mg kg(-1)) and subsequently cotreated with busulfan (4 days, 3.2 mg kg(-1)) and SKEO (28 days, 225 mg kg(-1)). The histological changes of testis were analysed using H&E staining. Sperm parameters, cytotoxic and apoptotic factors were also studied by computer-aided sperm analyzer, MTT and TUNEL assays respectively. Our results showed that SKEO pre-administration significantly improved all parameters of epididymal spermatozoa and decreased germinal epithelium destruction following busulfan chemotherapy. We also found lower MTT levels and TUNEL-positive cells in SKEO pre-treated groups. In conclusion, SKEO possesses beneficial effects on sperm parameters when taken before chemotherapy and continued during and after chemotherapy for a long time, than when used short-term coinciding with the chemotherapy. Our results support valuable data about the application of SKEO for protection against adverse effects of busulfan on male genital system in patients under chemotherapy. PMID:26011020

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

    NASA Astrophysics Data System (ADS)

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

    2008-02-01

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

  19. Low dose cyclophosphamide: Mechanisms of T cell modulation.

    PubMed

    Madondo, Mutsa Tatenda; Quinn, Michael; Plebanski, Magdalena

    2016-01-01

    Cyclophosphamide is considered one of the most successful chemotherapy drugs and is listed on the World Health Organisations List of Essential Medicines. Since its initial synthesis in 1958, it has been widely used to treat a range of cancers but its use has been declining due to the advent of platinum based and other chemotherapy agents. However, cyclophosphamide is still used either as a single agent or as adjuvant therapy to treat lymphomas, and breast and ovarian cancers at much lower doses. The efficacy of low dose cyclophosphamide is primarily due to its ability to promote anti-tumour immunity, by selectively depleting regulatory T cells and enhancing effector T cell function. Compared to effecter T cells, regulatory T cells have metabolic adaptations that make them more susceptible to cyclophosphamide-mediated cytotoxicity. In this review, we highlight the potential for improving the efficacy of low dose cyclophosphamide by combining insights on the mechanisms of cyclophosphamide-mediated cytotoxicity, and how these cytotoxic effects of cyclophosphamide influence T cell function, thereby contributing to anti-tumour immunity. PMID:26620820

  20. Effect of Paclitaxel on Antitumor Activity of Cyclophosphamide: Study on Two Transplanted Tumors in Mice.

    PubMed

    Kaledin, V I; Nikolin, V P; Popova, N A; Pyshnaya, I A; Bogdanova, L A; Morozkova, T S

    2015-11-01

    Antitumor effect of paclitaxel used as the monotherapy or in combination with cyclophosphamide was studied on CBA/LacSto mice with transplanted LS and RLS tumors characterized by high (LS) and low (RLS) sensitivity to cyclophosphamide. The therapeutic effects of cyclophosphamide and paclitaxel were summed in animals with drug-resistant RLS tumor, while combined use of these drugs in LS tumor highly sensitive to the apoptogenic effect of cyclophosphamide was no more effective than cyclophosphamide alone. PMID:26597686

  1. Population Pharmacokinetics of Busulfan in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplant: A Model-Based Dosing Algorithm for Personalized Therapy and Implementation into Routine Clinical Use

    PubMed Central

    Long-Boyle, Janel; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J.; Dvorak, Christopher C.

    2014-01-01

    Background Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared to conventional dosing. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration-at-steady-state, Css) and implement a simple, model-based tool for the initial dosing of busulfan in children undergoing HCT. Patients and Methods Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone HCT with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the non-linear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly, Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Results Modeling of busulfan time-concentration data indicates busulfan CL displays non-linearity in children, decreasing up to approximately 20% between the concentrations of 250–2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan CL were actual body weight and age. The percentage of individuals achieving a therapeutic Css was significantly higher in subjects receiving initial doses based on the population PK model (81%) versus historical controls dosed on conventional guidelines (52%) (p = 0.02). Conclusion When compared to the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults. PMID:25162216

  2. Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas.

    PubMed

    Nieto, Yago; Valdez, Benigno C; Thall, Peter F; Ahmed, Sairah; Jones, Roy B; Hosing, Chitra; Popat, Uday; Shpall, Elizabeth J; Qazilbash, Muzaffar; Gulbis, Alison; Anderlini, Paolo; Alousi, Amin; Shah, Nina; Bashir, Qaiser; Liu, Yan; Oki, Yasuhiro; Hagemeister, Frederick; Fanale, Michelle; Dabaja, Bouthaina; Pinnix, Chelsea; Champlin, Richard; Andersson, Borje S

    2015-11-01

    More active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days -8 to -3). Gemcitabine was infused continuously at 10 mg/m(2)/minute over 4.5 hours (days -8 and -3). Busulfan dosing targeted 4000 μM-minute/day (days -8 to -5). Melphalan was infused at 60 mg/m(2)/day (days -3 and -2). Patients with CD20(+) tumors received rituximab (375 mg/m(2), days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography-positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation. This trial was registered at ClinicalTrials.gov (NCI-2011-02891). PMID:26071868

  3. Busulfan depletes neutrophils and delays accelerated acute rejection of discordant xenografts in the guinea pig-to-rat model.

    PubMed

    Brauer, Robert B; Beck, Tino; Stehle, Ingo; Kremer, Marcus; Heidecke, Claus-Dieter

    2003-01-01

    Complement factor C6 plays a critical role in mediating hyperacute rejection of discordant xenografts. In order to explore the mechanism of discordant xenograft rejection, we investigated kinetics and phenotypes of the cellular infiltrate in xenografts in untreated and leukocyte-depleted recipients, in relation to graft survival. Guinea pig cardiac xenografts were heterotopically transplanted to totally C6-deficient PVG (C-) rats. Grafts were removed after 0, 6, 12, and 24 h ( n = 6). Histological evaluation was performed with hematoxylin and eosin (H & E) and immunoperoxidase staining. The agents fucoidin and busulfan were applied to delay xenograft rejection further. Within 6 h, minimal perivascular edema with isolated infiltrating CD11b/c- and ED1-positive cells were found. An intense infiltration of CD11b/c- and ED1-positive cells with interstitial hemorrhage was present after 24 h, though with little CD161 and CD3 cell infiltration. Inhibition of cell adhesion by fucoidin did not prolong xenograft survival (34 +/- 15 h, n = 4, P<0.47), but the depletion of granulocytes by injection of busulfan did prolong survival of the discordant xenografts, to 62 +/- 22 h ( n = 7, P < or = 0.0039). These results demonstrate a significant effect of specific depletion of granulocytes and macrophages by busulfan therapy on guinea pig cardiac xenograft survival in PVG (C-) rats, suggesting the participation of these infiltrating cells in the xenoreactive rejection process. PMID:12545340

  4. Phase I/II Trial of Dose-Escalated Busulfan Delivered by Prolonged Continuous Infusion in Allogeneic Transplant Patients.

    PubMed

    Shea, Thomas C; Walko, Christine; Chung, Yunro; Ivanova, Anastasia; Sheets, Julia; Rao, Kamakshi; Gabriel, Don; Comeau, Terry; Wood, William; Coghill, James; Armistead, Paul; Sarantopoulos, Stefanie; Serody, Jonathan

    2015-12-01

    Intensive chemotherapy or chemotherapy plus irradiation and allogeneic stem cell transplantation can be curative for patients with hematologic diseases. Reduced-intensity transplants can also achieve cure and result in less treatment-related mortality but higher relapse rates. Thus, optimizing the conditioning regimens used in allogeneic transplantation remains an important goal. We conducted a phase I/II trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a continuous infusion of busulfan over 90 hours in conjunction with fludarabine followed by allogeneic related or unrelated donor transplant. Fifty-four patients with advanced hematologic malignancies were enrolled on this study. The MTD was identified as a 24-hour area under the curve (AUC) of approximately 7095 μM/min, which represents a 43% increase over the standard total daily AUC dose of 4800 μM/min given by intermittent schedules. DLTs at doses over 8000 μM/min were identified by a desquamative skin rash and mucositis. No dose-related increase in hepatic, pulmonary, or other organ toxicities were seen, whereas efficacy appeared to be improved at higher dose levels. Continuous-infusion busulfan with intermittent fludarabine provides an alternative treatment strategy that is generally well tolerated and permits an increase in total busulfan dose with encouraging efficacy. (NCI study no. NCT00448357.). PMID:26210442

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

    PubMed

    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 < 0.05). Only catalase activities were decreased significantly in both groups (cyclophosphamide + MESNA and cyclophosphamide + CAPE, p < 0.05). Pretreatment with CAPE (p < 0.01) resulted in a significant decrease in nitric oxide levels when compared with the cyclophosphamide group. When we consider the studies that show the critical importance of increased nitric oxide levels in pathogenesis of cyclophosphamide-induced hemorrhagic cystitis, we suggest that it would be more beneficial to use MESNA with CAPE to prevent histological damage. PMID:26207616

  6. Busulfan Injection

    MedlinePlus

    ... cells) in combination with other medications to destroy bone marrow and cancer cells in preparation for a bone marrow transplant. ... in combination with other drugs to destroy the bone marrow and cancer cells in preparation for a bone marrow transplant ...

  7. Allogeneic Stem Cell Transplantation in Congenital Hemoglobinopathies Using a Tailored Busulfan-Based Conditioning Regimen: Single-Center Experience.

    PubMed

    Zaidman, Irina; Rowe, Jacob M; Khalil, Abdalla; Ben-Arush, Myriam; Elhasid, Ronit

    2016-06-01

    Hematopoietic stem cell transplantation (HSCT) is the only proven curative option for patients with hemoglobinopathies, both thalassemia and sickle cell anemia (SCA). A busulfan-based myeloablative conditioning regimen is the standard of care for HSCT in these patients, although increased treatment-related morbidity, including veno-occlusive disease (VOD), has been demonstrated. Thirty-eight pediatric patients, median age 8 years (range, 6 months to 22 years), suffering from hemoglobinopathy were treated at Rambam Medical Center in Haifa, Israel, between 1998 and 2011. Thirty-four patients had thalassemia major and 4 had SCA. The 38 patients underwent 40 HSCTs, 34 of which were first transplants and 6 second transplants. Most transplants (32/40) were from matched sibling donors. Sources of stem cells were peripheral blood in 30 transplants, bone marrow in 7 transplants, and cord blood in 3 transplants. All received different customized busulfan-based conditioning regimens tailored by pharmacokinetic analysis of busulfan levels. Primary engraftment occurred in 37 of 40 transplants. Neutrophil engraftment (>.5 × 10(9)/L) occurred at a median of 15.3 days post-transplantation (range, 10 to 45). Platelet transfusion independence (>20 × 10(9)/L) occurred at a median of 22.3 days (range, 11 to 60). The rate of 5-year overall survival for thalassemia patients after first transplantation was 90.5% ± 5.3%. The rate of 5-year thalassemia-free survival was 81.7% ± 6.8%. Cumulative incidence of acute graft-versus-host disease (GVHD) was 17.6%. Rate of grades III to IV GVHD was 8.8%. Cumulative incidence of chronic GVHD was 23.5%, with 11.8% incidence of extensive chronic GVHD. One patient developed VOD. Full donor chimerism occurred in 36.4% of patients with class 1 + 2 thalassemia, compared with 78.6% in class 3 thalassemia (P = .049). Overall survival above 90% in patients undergoing their first transplant was demonstrated using busulfan

  8. TERATOGENICITY OF CYCLOPHOSPHAMIDE IN A COUPLED MICROSOMAL ACTIVATING/EMBRYO CULTURE SYSTEM

    EPA Science Inventory

    Using the coupled microsomal activating/embryo culture system, in vitro experiments were performed to establish the role of metabolism in the embryo toxicity and teratogenicity of cyclophosphamide. Cyclophosphamide in the coupled microsomal activating/embryo culture system produc...

  9. Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy.

    PubMed

    Bhagwatwar, H P; Phadungpojna, S; Chow, D S; Andersson, B S

    1996-01-01

    The bifunctional alkylating agent busulfan (Bu) was solubilized in a cosolvent mixture of anhydrous dimethylacetamide (DMA), polyethylene glycol 400 (PEG400), and water at a ratio of 1:2:2 (v/v/v), to achieve a Bu concentration of 3 mg/ml, a preparation that would be suitable for parenteral administration in high-dose chemotherapy preceding bone marrow transplantation. The complete formulation was stable for more than 54 h at room temperature (RT, 22 degrees C). An accelerated stability study of Bu in anhydrous DMA or DMA/PEG400 (1:2) as stock solutions indicated shelf-lives of 191 and 180 days respectively, at RT, and 8.2 and 7.5 years, respectively, at 4 degrees C. Although the complete formulation with Bu was very hypertonic, hemolysis studies indicated that the formulation would be safe for intravenous (i.v.) administration, since it would be rapidly diluted to harmless tonicity levels in the blood. Cytotoxicity studies of the complete formulation in vitro proved that Bu retained its activity when dissolved in the complete vehicle. A preliminary pharmacokinetic study in a rodent model after the i.v. administration of Bu at a dose of 1 mg/kg body weight yielded high plasma concentrations of Bu for at least 5 h after injection. PMID:8599861

  10. Busulfan-melphalan in high-risk neuroblastoma: the 30-year experience of a single institution.

    PubMed

    Proust-Houdemont, S; Pasqualini, C; Blanchard, P; Dufour, C; Benhamou, E; Goma, G; Semeraro, M; Raquin, M-A; Hartmann, O; Valteau-Couanet, D

    2016-08-01

    High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980 to 2009, 215 patients aged >1 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year event-free survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy. PMID:27042850

  11. Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis

    PubMed Central

    Stone, John H.; Merkel, Peter A.; Spiera, Robert; Seo, Philip; Langford, Carol A.; Hoffman, Gary S.; Kallenberg, Cees G.M.; St. Clair, E. William; Turkiewicz, Anthony; Tchao, Nadia K.; Webber, Lisa; Ding, Linna; Sejismundo, Lourdes P.; Mieras, Kathleen; Weitzenkamp, David; Ikle, David; Seyfert-Margolis, Vicki; Mueller, Mark; Brunetta, Paul; Allen, Nancy B.; Fervenza, Fernando C.; Geetha, Duvuru; Keogh, Karina A.; Kissin, Eugene Y.; Monach, Paul A.; Peikert, Tobias; Stegeman, Coen; Ytterberg, Steven R.; Specks, Ulrich

    2011-01-01

    BACKGROUND Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; Clinical

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

    PubMed

    Schneider, Beatriz Ursinos Catelan; Meza, Alisson; Beatriz, Adilson; Pesarini, João Renato; Carvalho, Pamela Castilho de; Mauro, Mariana de Oliveira; Karaziack, Caroline Bilhar; Cunha-Laura, Andréa Luiza; Monreal, Antônio Carlos Duenhas; Matuo, Renata; Lima, Dênis Pires de; Oliveira, Rodrigo Juliano

    2016-01-01

    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. PMID:27303909

  13. CYCLOPHOSPHAMIDE TERATOGENESIS: EVIDENCE FOR COMPENSATORY RESPONSES TO INDUCED CELLULAR TOXICITY

    EPA Science Inventory

    Cyclophosphamide (CP) administered ip to pregnant mice on day 10 og gestation causes severe malformations at 20 mg/kg and is embryolethal at higher doses. n the present study, CP was administered at 1, 5, 10 or 20 mg/kg. mbryos were removed at 8 and 28 hrs post dosing for immedia...

  14. CYCLOPHOSPHAMIDE EFFECTS ON IMMUNE FUNCTION OF EUROPEAN STARLINGS

    EPA Science Inventory

    Cyclophosphamide (CY) is a widely used immunosuppressive and chemotherapeutic agent. t is a potent immunotoxicant that suppresses some aspects of immune function in most animals in which it has been researched. n this study, CY suppressed immunological endpoints measured in starl...

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

    PubMed Central

    Schneider, Beatriz Ursinos Catelan; Meza, Alisson; Beatriz, Adilson; Pesarini, João Renato; de Carvalho, Pamela Castilho; Mauro, Mariana de Oliveira; Karaziack, Caroline Bilhar; Cunha-Laura, Andréa Luiza; Monreal, Antônio Carlos Duenhas; Matuo, Renata; de Lima, Dênis Pires; Oliveira, Rodrigo Juliano

    2016-01-01

    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. PMID:27303909

  16. Romidepsin enhances the cytotoxicity of fludarabine, clofarabine and busulfan combination in malignant T-cells.

    PubMed

    Valdez, Benigno C; Brammer, Jonathan E; Li, Yang; Murray, David; Teo, Esmeralda C; Liu, Yan; Hosing, Chitra; Nieto, Yago; Champlin, Richard E; Andersson, Borje S

    2016-08-01

    Novel approaches to pre-transplant conditioning are needed to improve treatment of advanced T-cell malignancies. We investigated the synergism of fludarabine (Flu), clofarabine (Clo), busulfan (Bu), and romidepsin (Rom) in T-cell lines and patient-derived cell samples. [Flu+Clo+Bu+Rom] had combination indexes of 0.4-0.5 at ∼50% cytotoxicity in PEER and SUPT1 cells, suggesting synergism. Drug exposure resulted in histone modifications, DNA-damage response (DDR), increased reactive oxygen species (ROS), decreased glutathione (GSH) and mitochondrial membrane (MM) potential, and apoptosis. Similar activation of DDR and apoptosis was observed in patient samples. The PI3K-AKT-mTOR, NFκB, Raf-MEK-ERK, JAK-STAT and Wnt/β-catenin pro-survival pathways were inhibited by the 4-drug combination. The SAPK/JNK stress pathway was activated. A novel finding was the down-regulation of the drug transporter MRP1. We propose the following mechanisms of synergism: Flu, Clo and Rom induce histone modifications and chromatin remodeling, exposing DNA to Bu alkylation; the increased production of ROS, due to drug-mediated stress response and decreased GSH, damages the MM causing leakage of pro-apoptotic factors; down-regulation of MRP1 increases intracellular Bu concentration and exacerbates the DDR; and inhibition of multiple survival pathways. Our results provide the basis for a clinical trial to evaluate [Flu+Clo+Bu+Rom] as part of conditioning regimen for refractory T-cell malignancy patients undergoing stem cell transplantation. PMID:27294334

  17. Induction of Spermatogenesis by Bone Marrow-derived Mesenchymal Stem Cells in Busulfan-induced Azoospermia in Hamster

    PubMed Central

    Tamadon, Amin; Mehrabani, Davood; Rahmanifar, Farhad; Jahromi, Alireza Raayat; Panahi, Mohadeseh; Zare, Shahrokh; Khodabandeh, Zahra; Jahromi, Iman Razeghian; Tanideh, Nader; Dianatpour, Mehdi; Ramzi, Mani; Koohi-Hoseinabadi, Omid

    2015-01-01

    Background Bone marrow-derived mesenchymal stem cells (BM-MSCs) have potential of differentiation and they secrete anti-inflammatory cytokines and growth factors which make them appropriate for cell therapy. Aim of the Work Were to evaluate the healing effect of BM-MSCs transplantation on germinal cells of busulfan-induced azoospermic hamsters. Material and Methods In the present experimental case control study, BM-MSCs were isolated from bone marrow of donor albino hamsters. Five mature male recipient hamsters received two doses of 10 mg/kg of busulfan with 21 days interval to stop endogenous spermatogenesis. After induction of azoospermia, right testis of hamsters was injected with 106 BM-MSCs via efferent duct and the left one remained as azoospermia control testis. Five normal mature hamsters were selected as normal intact control. After 35 days, testes and epididymis of three groups were removed for histological evaluation. Results Histomorphological analyses of BM-MSCs treated testes and epididymis showed the epithelial tissue of seminiferous tubules had normal morphology and spermatozoa were present in epididymis tubes. Spermatogenesis was observed in most cell-treated seminiferous tubules. The untreated seminiferous tubules were empty. Conclusion Transplanted BM-MSCs could successfully induce spermatogenesis in seminiferous tubules of azoospermic hamster. Therefore, BM-MSCs can be an attractive candidate in cell transplantation of azoospermia. PMID:26634062

  18. HLA haploidentical peripheral blood stem cell transplantation using reduced dose of posttransplantation cyclophosphamide for poor-prognosis or refractory leukemia and myelodysplastic syndrome.

    PubMed

    Nakamae, Hirohisa; Koh, Hideo; Katayama, Takako; Nishimoto, Mitsutaka; Hayashi, Yoshiki; Nakashima, Yasuhiro; Nakane, Takahiko; Nakamae, Mika; Hirose, Asao; Hino, Masayuki

    2015-11-01

    Nonmyeloablative, human leukocyte antigen (HLA) haploidentical, T-cell-replete bone marrow transplantation followed by high-dose posttransplantation cyclophosphamide (PT/Cy) has recently been developed. This transplantation milieu has resulted in favorable outcomes with low transplantation-related mortality, owing to a low incidence of graft-versus-host disease (GVHD), without increased infectious complications. However, the high relapse rate remains a major concern. We therefore performed a prospective pilot study of HLA haploidentical peripheral blood stem cell transplantation (PBSCT) with intensified conditioning, followed by two lower doses of PT/Cy. A total of 20 patients with refractory or poor-prognosis myelodysplastic syndrome (MDS) and leukemia were enrolled in the study. A trend toward a lower incidence of grade III-IV acute GVHD at day 100 in the group receiving 25 mg/kg × 2 doses of PT/Cy, compared with the group receiving 25 mg/kg of PT/Cy (9.1% vs. 33%, p = 0.20), was noted. However, the cumulative incidence of chronic GVHD was low, at 10% irrespective of PT/Cy dose. The number of infused CD34(+) cells significantly correlated with the grade of acute GVHD (p = 0.004). In addition, the occurrence of BK virus hemorrhagic cystitis was significantly more common in the double-dose PT/Cy group (25% vs. 0%, p = 0.043), especially when combined with busulfan. The probability of overall survival at 1 year in the double-dose group tended to be better compared with that in the single-dose group (64% vs. 44%, respectively; p = 0.20). In conclusion, HLA haploidentical, T-cell-replete PBSCT with 25 mg/kg × 2 doses of PT/Cy might be a feasible option for treating high-risk leukemia and MDS. PMID:26284307

  19. Effect of nephrotoxic drugs on the development of radiation nephropathy after bone marrow transplantation

    SciTech Connect

    Lawton, C.A.; Fish, B.L.; Moulder, J.E. )

    1994-03-01

    Chronic renal failure is a significant cause of late morbidity in bone marrow transplant patients whose conditioning regimen includes total body irradiation (TBI). Radiation is a major cause of this syndrome (bone marrow transplant nephropathy), but it may not be the only cause. These studies use a rat syngeneic bone marrow transplant model to determine whether nephrotoxic agents used in conjunction with bone marrow transplantation (BMT) could be enhancing or accelerating the development of radiation nephropathy. Rats received 11-17 Gy TBI in six fractions over 3 days followed by syngeneic bone marrow transplant. In conjunction with the bone marrow transplants, animals received either no drugs, cyclosporine, amphotericin, gentamicin, or busulfan. Drugs were given in schedules analogous to their use in clinical bone marrow transplantation. Drug doses were chosen so that the drug regimen alone caused detectable acute nephrotoxicity. Animals were followed for 6 months with periodic renal function tests. Gentamicin had no apparent interactions with TBI. Amphotericin increased the incidence of engraftment failure, but did not enhance radiation nephropathy. Cyclosporin with TBI caused late morbidity that appeared to be due to neurological problems, but did not enhance radiation nephropathy. Busulfan resulted in a significant enhancement of radiation nephropathy. Of the nephrotoxins used in conjunction with bone marrow transplantation only radiation and busulfan were found to be risk factors for bone marrow transplant nephropathy. 34 refs., 4 figs., 2 tabs.

  20. Successful treatment of idiopathic pulmonary capillaritis with intravenous cyclophosphamide.

    PubMed

    Flanagan, Frances; Glackin, Louisa; Slattery, Dubhfeasa M

    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. PMID:22573417

  1. Effect of cyclophosphamide on the response of chickens to a virulent strain of Marek's disease virus.

    PubMed Central

    Kermani-Arab, V; Moll, T; Cho, B R; Davis, W C; Lu, Y S

    1975-01-01

    The effect of cyclophosphamide on the pathogenesis of Marek's disease was examined in a line of chickens which is relatively resistant to Marek's disease. The injection of cyclophosphamide into newly hatched chickens delayed and reduced viremia and also reduced the development of Marek's disease lesions until 2 weeks after exposure to Marek's disease virus. The data indicate that a population of T cells susceptible to infection with virus and possibly viral transformation is affected by cyclophosphamide. PMID:172451

  2. Concurrent activation of granulocytes and osteoclasts in busulfan-suppressed bone marrow in response to transplantation of a mammary carcinoma in mice.

    PubMed

    McCracken, C H; Lottsfeldt, J L; Lee, M Y

    1988-05-01

    Transplantation of CE mammary adenocarcinoma (CE maca) into normal mice produces both neutrophilia and hypercalcemia due to osteoclastic bone resorption. In order to explore the physiology of osteoclast formation in vivo, the time course of neutrophilia and osteoclast development was examined in mice that had been pretreated with busulfan prior to the CE maca implantation. Busulfan-treated tumor-bearing mice (BUTUM), busulfan-treated control mice (BUCON), tumor-bearing mice with no busulfan (TUM), and normal controls (CON) were sacrificed on days 4, 7, 11, 14, and 17 after tumor implantation. Leukocyte counts, serum calcium levels, marrow cellularity, and marrow colony-forming units (CFU) were determined. Osteoclasts were quantified histologically by the osteoclast: endosteum ratio (OER). BUCON bone marrow was hypoplastic with CFU remaining significantly lower than that of controls over the course of the experiment. In contrast, BUTUM marrow CFU increased dramatically with the growth of the tumor. The most predominant increase was observed in neutrophilic CFU. Development of hypercalcemia closely paralleled neutrophilia in both TUM and BUTUM mice, although these changes were significantly delayed in the BUTUM group. The neutrophil count and serum calcium levels remained within normal control levels for BUCON mice. The OER correlated with serum calcium, and it closely paralleled the neutrophil count in TUM and BUTUM mice. These results clearly indicated the stimulation of bone marrow neutrophilic granulocyte progenitors and osteoclasts by the CE maca, indicating that the bone marrow is the primary target of this tumor. There may be a closely related mechanism in osteoclast and granulocyte stimulation by one or more CE maca factors. PMID:3360066

  3. Subacute hepatic necrosis mimicking veno-occlusive disease in a patient with HFE H63D homozygosity after allogeneic hematopoietic cell transplantation with busulfan conditioning.

    PubMed

    Chen, Sylvia; Osborn, James Dane; Chen, Xinjian; Boyer, Michael W; McDonald, George B; Hildebrandt, Gerhard Carl

    2015-12-01

    Busulfan is a commonly used chemotherapeutic agent in myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). It has been associated with sinusoidal-obstructive syndrome(SOS) as a life-threatening complication of myeloablative allo-HCT, yet it has not been found to cause severe hepatocellular injury, even in cases of significant accidental overdose.We report the case of a 31-year-old male with a history of high-risk myelodysplastic syndrome transitioning to acute myeloid leukemia, who in complete remission underwent allo-HCT using myeloablative busulfan–fludarabine conditioning, and who developed hepatic failure. While he met clinical criteria for SOS and was treated with defibrotide,liver biopsy demonstrated severe subacute hepatic necrosis and lacked characteristics of SOS. Further evaluation revealed that the patient was homozygous for the HFE H63D gene mutation, associated with hereditary hemochromatosis.Both Busulfan and iron overload related to HFE H63D homozygosity can cause oxidative stress resulting in cellular injury, and the cumulative effects of these risk factors are possibly responsible for the severe hepatocellular injury in this case, making our patient the first-known case of subacute hepatic necrosis related to busulfan administration. PMID:26497867

  4. Apricot Kernel Oil Ameliorates Cyclophosphamide-Associated Immunosuppression in Rats.

    PubMed

    Tian, Honglei; Yan, Haiyan; Tan, Siwei; Zhan, Ping; Mao, Xiaoying; Wang, Peng; Wang, Zhouping

    2016-08-01

    The effects of dietary apricot kernel oil (AKO), which contains high levels of oleic and linoleic acids and lower levels of α-tocopherol, were evaluated in a rat model of cyclophosphamide-induced immunosuppression. Rats had intraperitoneal injection with cyclophosphamide to induce immunosuppression and were then infused with AKO or normal saline (NS) for 4 weeks. Enzyme-linked immunosorbent assays were used to detect antimicrobial factors in lymphocytes and anti-inflammatory factors in hepatocytes. Hematoxylin & eosin staining was conducted prior to histopathological analysis of the spleen, liver, and thymus. Significant differences were observed between the immune functions of the healthy control group, the normal saline group, and the AKO group. Compared to the normal saline-treated group, lymphocytes isolated from rats administered AKO showed significant improvement in immunoglobulin (Ig)A, IgM, IgG, interleukin (IL)-2, IL-12, and tumor necrosis factor-α (TNF-α) levels (p < 0.01). Liver tissue levels of malondialdehyde and activities of superoxide dismutase and glutathione peroxidase indicated reduced oxidative stress in rats treated with AKO (p < 0.01). Dietary AKO positively affected rat growth and inhibited cyclophosphamide-associated organ degeneration. These results suggested that AKO may enhance the immune system in vivo. These effects may reflect the activities of intermediate oleic and linoleic acid metabolites, which play a vital role in the immune system, and the α-tocopherol in AKO may further enhance this phenomenon. Thus, the use of AKO as a nutritional supplement can be proposed to ameliorate chemotherapy-associated immunosuppression. PMID:27262314

  5. [The use of hydroxamic acids and sodium nitrate to enhance the antitumor effect of cyclophosphamide].

    PubMed

    Bogatyrenko, T N; Kuropteva, Z V; Sashenkova, T E; Baĭder, L M; Konovalova, N P

    2013-01-01

    It has been showed that the introduction of nitrocompounds (as nitic oxide donors) in to the compositions of cyclophosphamide and hydroxamic acids for curing animals having leukemia P-388 increased duration of life by 290%. Thereby 40% of animals have recovered. The therapeutic dose cyclophosphamide have been reduced by 6 times. PMID:23814833

  6. [Examination of Measures for Preventing Exposure in Nurses Who Handle Cyclophosphamide].

    PubMed

    Suzuki, Kaoru; Ono, Yuki; Suzuki, Yumi; Omori, Keiko; Matsuda, Mikiko; Sato, Hiroko; Omoto, Eijiro

    2015-12-01

    Health hazards due to long-term exposure to anticancer drugs have been reported among health care professionals. In Yamagata Prefectural Central Hospital, constant use of personal protective equipment(gloves and mask with face shield)is mandatory, but there is no clear description of the protective gown. To verify the exposure status of nurses while handling cyclophosphamide and the usefulness of a protective gown as a protective measure, urinary concentration of cyclophosphamide was measured for nurses who handled cyclophosphamide. No cyclophosphamide was detected in the urine samples collected from nurses who handled cyclophosphamide while wearing protective gowns or in the samples collected from nurses who handled cyclophosphamide without protective gowns. This finding suggests that gloves and a mask with a face shield are sufficient for preventing exposure to cyclophosphamide. However, considering that only experienced nurses were included as subjects in this study, we cannot conclude that a protective gown is unnecessary, because inexperienced nurses may be exposed to cyclophosphamide. Our study's findings may be one reference to examine measures for preventing exposure in nurses. PMID:26809304

  7. Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children's Oncology Group Study D9803

    PubMed Central

    Arndt, Carola A.S.; Stoner, Julie A.; Hawkins, Douglas S.; Rodeberg, David A.; Hayes-Jordan, Andrea A.; Paidas, Charles N.; Parham, David M.; Teot, Lisa A.; Wharam, Moody D.; Breneman, John C.; Donaldson, Sarah S.; Anderson, James R.; Meyer, William H.

    2009-01-01

    Purpose The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC). Patients and Methods Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided α level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC. Results A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups. Conclusion For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC. PMID:19770373

  8. Plasmapheresis and subsequent pulse cyclophosphamide versus pulse cyclophosphamide alone in severe lupus: design of the LPSG trial. Lupus Plasmapheresis Study Group (LPSG).

    PubMed

    Clark, W F; Dau, P C; Euler, H H; Guillevin, L; Hasford, J; Heer, A H; Jones, J V; Kashgarian, M; Knatterud, G; Lockwood, C M

    1991-01-01

    A group of clinics are collaborating in the Lupus Plasmapheresis Study Group (LPSG) to investigate whether repeated plasmapheresis prior to pulse cyclophosphamide improves the therapeutical results in severe systemic lupus erythematosus (SLE). The underlying rationale is the hypothesis that plasmapheresis 1) eliminates pathogenic autoantibodies and immune complexes and 2) induces compensatory lymphocyte activation via feedback mechanisms between circulating antibodies and their respective clones ("antibody rebound"). It should be possible to utilize this enhanced activity for increased clonal deletion if pulse cyclophosphamide is applied shortly after plasmapheresis. Accordingly, in a randomized study, the LPSG will be comparing the repeated application of pulse cyclophosphamide alone with a treatment involving repeated plasmapheresis prior to the cyclophosphamide pulses in severe SLE. A third arm of the study will be gathering experience with a more intensified procedure. This overview summarizes the most important details of the planned study. PMID:2045382

  9. Cytochrome P450 Oxidoreductase Influences CYP2B6 Activity in Cyclophosphamide Bioactivation

    PubMed Central

    El-Serafi, Ibrahim; Afsharian, Parvaneh; Moshfegh, Ali; Hassan, Moustapha; Terelius, Ylva

    2015-01-01

    Introduction Cyclophosphamide is commonly used as an important component in conditioning prior to hematopoietic stem cell transplantation, a curative treatment for several hematological diseases. Cyclophosphamide is a prodrug activated mainly by cytochrome P450 2B6 (CYP2B6) in the liver. A high degree of inter- and intra-individual variation in cyclophosphamide kinetics has been reported in several studies. Materials and Methods Hydroxylation of cyclophosphamide was investigated in vitro using three microsomal batches of CYP2B6*1 with different ratios of POR/CYP expression levels. Twenty patients undergoing hematopoietic stem cell transplantation were also included in the study. All patients received an i.v. infusion of cyclophosphamide (60 mg/kg/day, for two days) as a part of their conditioning. Blood samples were collected from each patient before cyclophosphamide infusion, 6 h after the first dose and before and 6 h after the second dose. POR gene expression was measured by mRNA analysis and the pharmacokinetics of cyclophosphamide and its active metabolite were determined. Results A strong correlation between the in vitro intrinsic clearance of cyclophosphamide and the POR/CYP ratio was found. The apparent Km for CYP2B6.1 was almost constant (3-4 mM), while the CLint values were proportional to the POR/CYP ratio (3-34 μL/min/nmol CYP). In patients, the average expression of the POR gene in blood was significantly (P <0.001) up-regulated after cyclophosphamide infusion, with high inter-individual variations and significant correlation with the concentration ratio of the active metabolite 4-hydroxy-cyclophosphamide/cyclophosphamide. Nine patients were carriers for POR*28; four patients had relatively high POR expression. Conclusions This investigation shows for the first time that POR besides CYP2B6 can influence cyclophosphamide metabolism. Our results indicate that not only CYPs are important, but also POR expression and/or activity may influence

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

    PubMed

    Elazzazy, Shereen; Mohamed, Asmaa Elhassan; Gulied, Amaal

    2014-01-01

    Cyclophosphamide is commonly used in the treatment of malignant diseases. Symptomatic severe hyponatremia induced by low-dose cyclophosphamide is very uncommon worldwide. We report a case of severe symptomatic hyponatremia that developed in a female breast cancer patient following the first cycle of chemotherapy containing low-dose cyclophosphamide. Her laboratory test showed serum Na of 112 mmol/L. Her hyponatremia was initially treated with sodium bicarbonate. She completely recovered without neurological deficits after slow correction of the serum Na concentration. Although hyponatremia is a rare toxicity it should always be considered during the usage of cyclophosphamide, even if the dosage is low, especially with concurrent use of other medications that impair water excretion, like chlorthalidone. This report describes the first reported case of cyclophosphamide-induced hyponatremia in Qatar. PMID:25336968

  11. Bleomycin, cyclophosphamide and radiotherapy in regionally advanced epidermoid carcinoma of the head and neck

    SciTech Connect

    Seagren, S.L.; Byfield, J.E.; Davidson, T.M.; Sharp, T.R.

    1982-01-01

    Twenty-four patients with squamous carcinoma of the head and neck and advanced regional (N/sub 2-3) disease were treated. The regimen consisted of 3 cycles, each of 28 days. Cyclophosphamide (1 gm/ M/sup 2/ I.V.) was given on day 1, bleomycin (15 u I.M.) on days 2, 4, 9 and 11, and ionizing radiation (/sup 60/Co, 180 rad/fraction) days 1-5, and 8-12. No therapy was given on days 13-28. After three cycles of therapy, 13 patients had a complete response; following further therapy (surgery, interstitial or external beam radiation), 16 patients were free of disease. However, remissions were not durable and 11/16 patients recurred loco-regionally with a median time to recurrence of 5 months; most (7/11) also developed distant metatases. These patients have biologically aggressive disease and may have a worse prognosis than patients who are Stage IV based on a T/sub 4/ primary lesion only.

  12. Bleomycin, cyclophosphamide and radiotherapy in regionally advanced epidermoid carcinoma of the head and neck

    SciTech Connect

    Seagren, S.L.; Byfield, J.E.; Davidson, T.M.; Sharp, T.R.

    1982-01-01

    Twenty four patients with squamous carcinoma of the head and neck and advanced regional (N/sub 2//sub -//sub 3/) disease were treated. The regimen consisted of 3 cycles, each of 28 days. Cyclophosphamide (I gm/m/sup 2/ I.V.) were given on day 1, bleomycin (15 ..mu.. I.M.) on days 2, 4, 9 and 11, and ionizing radiation (/sup 60/Co, 180 rad/fraction) days 1-5, and 8-12. No therapy was given on days 13-28. After three cycles of therapy, 13 patients had a complete response; following further therapy (surgery, interstitial or extenal beam radiation), 16 patients were free of disease. However, remissions were not durable and 11/16 patients recurred loco-regionally with a median time to recurrence of 5 months; most (7/11) also developed distant metastases. These patients have biologically aggressive disease and may have a worse prognosis than patients who are Stage IV based on a T/sub 4/ primary lesion only.

  13. Design and Testing of an EHR-Integrated, Busulfan Pharmacokinetic Decision Support Tool for the Point-of-Care Clinician

    PubMed Central

    Abdel-Rahman, Susan M.; Breitkreutz, Matthew L.; Bi, Charlie; Matzuka, Brett J.; Dalal, Jignesh; Casey, K. Leigh; Garg, Uttam; Winkle, Sara; Leeder, J. Steven; Breedlove, JeanAnn; Rivera, Brian

    2016-01-01

    Background: Busulfan demonstrates a narrow therapeutic index for which clinicians routinely employ therapeutic drug monitoring (TDM). However, operationalizing TDM can be fraught with inefficiency. We developed and tested software encoding a clinical decision support tool (DST) that is embedded into our electronic health record (EHR) and designed to streamline the TDM process for our oncology partners. Methods: Our development strategy was modeled based on the features associated with successful DSTs. An initial Requirements Analysis was performed to characterize tasks, information flow, user needs, and system requirements to enable push/pull from the EHR. Back-end development was coded based on the algorithm used when manually performing busulfan TDM. The code was independently validated in MATLAB using 10,000 simulated patient profiles. A 296-item heuristic checklist was used to guide design of the front-end user interface. Content experts and end-users (n = 28) were recruited to participate in traditional usability testing under an IRB approved protocol. Results: Decision support software was developed to systematically walk the point-of-care clinician through the TDM process. The system is accessed through the EHR which transparently imports all of the requisite patient data. Data are visually inspected and then curve fit using a model-dependent approach. Quantitative goodness-of-fit are converted to single tachometer where “green” alerts the user that the model is strong, “yellow” signals caution and “red” indicates that there may be a problem with the fitting. Override features are embedded to permit application of a model-independent approach where appropriate. Simulations are performed to target a desired exposure or dose as entered by the clinician and the DST pushes the user approved recommendation back into the EHR. Usability testers were highly satisfied with our DST and quickly became proficient with the software. Conclusions: With early

  14. Concurrent Cyclophosphamide, Methotrexate, and 5-Fluorouracil Chemotherapy and Radiotherapy for Early Breast Carcinoma

    SciTech Connect

    Livi, Lorenzo Saieva, Calogero; Borghesi, Simona; Paoletti, Lisa; Meattini, Icro; Rampini, Andrea; Petrucci, Alessia; Scoccianti, Silvia; Paiar, Fabiola; Cataliotti, Luigi; Leonulli, Barbara Grilli; Bianchi, Simonetta; Biti, Gian Paolo

    2008-07-01

    Purpose: The optimal sequencing of adjuvant chemotherapy (CT) and radiation therapy (RT) in patients with early-stage breast cancer remains unclear. Patients and Methods: We retrospectively compared 485 patients treated with conservative breast surgery and postoperative whole-breast RT and six courses of CMF (cyclophosphamide 600 mg/m{sup 2}, methotrexate 40 mg/m{sup 2}, and 5-fluorouracil 600 mg/m{sup 2}) with 300 patients who received postoperative CMF only and with 509 patients treated with postoperative whole-breast RT only. The mean radiation dose delivered was 50 Gy (range, 46-52 Gy) with standard fractionation. The boost dose was 6-16 Gy according to resection margins and at the discretion of the radiation oncologist. Acute and late RT toxicity were scored using respectively the Radiation Therapy Oncology Group and the Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scale. Results: A slightly higher Grade 2 acute skin toxicity was recorded in the concurrent group (21.2% vs. 11.2% of the RT only group, p < 0.0001). RT was interrupted more frequently in the CMF/RT group respective to the RT group (8.5% vs. 4.1%; p = 0.006). There was no difference in late toxicity between the two groups. All patients in the concurrent group successfully received the planned dose of RT and CT. Local recurrence rate was 7.6% in CT/RT group and 9.8% in RT group; this difference was not statistically significant at univariate analysis (log-rank test p = 0.98). However, at multivariate analysis adjusted also for pathological tumor, pathological nodes, and age, the CT/RT group showed a statistically lower rate of local recurrence (p = 0.04). Conclusions: Whole-breast RT and concurrent CMF are a safe adjuvant treatment in terms of toxicity.

  15. Immunotoxic effects of cyclophosphamide and cyclosporine in the dog.

    PubMed

    Legrand, Jean-Jacques; Bouchez, Caroline; Mimouni, Cécile; N'Guyen, Armelle; Bouchard, Johanne; Ameller, Thibault; Descotes, Jacques

    2013-01-01

    Limited non-clinical immunotoxicity data are available in the dog, although this is a major non-rodent species in regulatory safety studies. The present study aimed to test whether widely accepted immunotoxicity endpoints including lymphocyte subset immunophenotyping, the anti-KLH TDAR assay, and histological examination of the main lymphoid organs were reliable to detect immunosuppression induced by cyclosporine and cyclophosphamide in dogs and could, therefore, be used for non-clinical immunotoxicity evaluation in this species. Male and female Beagle dogs were treated orally from Day 1 for 4 weeks with 25 mg/kg cyclosporine daily, or with 2 mg/kg cyclophosphamide on 4 consecutive days each week, or the same volume of drinking water daily. Blood samples were withdrawn pre-test and on Days 11, 18, and 23 to measure standard hematology parameters and analyze lymphocyte subsets. All animals received an intramuscular injection of 5 mg KLH on Day 11. Sandwich ELISA assays were used to quantify anti-KLH IgM and anti-KLH IgG levels in blood samples taken pre-test, on Days 18 and 23, and pre-test, on Days 23 and 28, respectively. At the end of the treatment period, all animals were submitted to histological examination of lymphoid organs, liver, and kidneys. No signs of marked toxicity were observed. No changes in lymphocyte subsets, but markedly decreased primary anti-KLH IgM and IgG responses, and a slightly-to-markedly increased cortex/medulla ratio in the thymus were observed in cyclosporine-treated dogs. Lower total WBC counts correlating with lower total and B-lymphocyte subset and decreased germinal center development in mesenteric lymph nodes, but no changes in primary anti-KLH IgM and IgG responses were observed in cyclophosphamide-treated dogs. These results demonstrate that widely accepted immunotoxicity endpoints can adequately detect the effects of known immunosuppressive drugs in the dog and support the conclusion that it is a relevant animal species

  16. Leukemia cell mobilization with G-CSF plus plerixafor during busulfan-fludarabine conditioning in allogeneic stem cell transplantation

    PubMed Central

    Thall, Peter F.; Zeng, Zhihong; Shpall, Elizabeth; Ciurea, Stefan; Kebriaei, Partow; Alousi, Amin; Popat, Uday; Anderlini, Paolo; Nieto, Yago; Parmar, Simrit; Qiao, Wei; Chen, Julianne; Rondon, Gabriela; McMullin, Becky; Wang, Rui-Yu; Lu, Hongbo; Schober, Wendy; Woodworth, Glenda; Gulbis, Alison; Cool, Rita; Andreeff, Michael; Champlin, Richard

    2015-01-01

    We hypothesized that during conditioning chemotherapy for allogeneic stem cell transplant (allo-SCT), disruption of stromal-leukemia interactions using granulocyte-colony stimulating factor (G-CSF) in combination with the CXCR4-specific inhibitor plerixafor, may promote release of leukemic cells from the niche and increase tumor elimination. In a phase 1/2 investigation, we treated 45 AML/MDS/CML patients (34 AML, 7 MDS, and 4 CML) with G-CSF (10 μg/kg daily for 6 days starting on day −9) plus plerixafor (doses of 0, 80, 160 or 240 μg/kg daily for 4 days starting on day −7) along with the busulfan-fludarabine (Bu-Flu) conditioning regimen. In the phase 1 part, we determined that G-CSF plus plerixafor is safe in this setting. We compared clinical effects and outcomes of AML/MDS study patients (n = 40) to 164 patients from a historical data set who received Bu-Flu alone prior to allo-SCT by stratifying on cytogenetics and disease status to correct for bias. Study patients had increased myeloid chimerism and lower rates of GvHD. There was no significant difference in relapse free survival or overall survival. The G-CSF plus plerixafor combination increased circulating white blood cells, CD34+ cells, and CXCR4+ cells, and preferentially mobilized FISH+ leukemic cells. ClinicalTrials.gov identifier is NCT00822770. PMID:25867648

  17. Long-term survival of intestinal allografts induced by costimulation blockade, busulfan and donor bone marrow infusion.

    PubMed

    Guo, Zhong; Wang, Jun; Dong, Ying; Adams, Andrew B; Shirasugi, Nozomu; Kim, Oliver; Hart, John; Newton-West, Marvin; Pearson, Thomas C; Larsen, Christian P; Newell, Kenneth A

    2003-09-01

    Tolerance-inducing strategies that infuse donor bone marrow cells in conjunction with costimulation blockade have not been applied to intestinal transplantation. Intestines from BALB/c mice were transplanted into C57BL/6 recipients treated with anti-CD40L mAb, CTLA4-Ig, donor bone marrow, and busulfan. The majority of mice transplanted after completion of this regimen developed hematopoietic macrochimerism, although the degree of chimerism varied widely between recipients, and experienced long-term allograft survival. T cells from these mice demonstrated donor-specific hyporesponsiveness in vitro. However, T cells from chimeric mice proliferated to donor alloantigen in vivo. Furthermore, chimeric mice bearing intestinal allografts were capable of rejecting subsequently placed donor-strain skin grafts. These data suggest that although long-term allograft survival occurs in the absence of acute or chronic rejection, recipient mice are not completely unresponsive to donor alloantigens. When intestinal transplantation was performed at the time of initial bone marrow infusion (initiation of the chimerism protocol), most recipients failed to develop chimerism and promptly rejected the intestinal allograft. Although this is the most effective protocol that we have tested using this stringent model of transplantation, our observations suggest that modifications will be necessary before it can be reliably applied to the transplantation of highly immunogeneic organs like the intestine. PMID:12919088

  18. Cladribine, gemcitabine, busulfan, and SAHA combination as a potential pretransplant conditioning regimen for lymphomas: A preclinical study.

    PubMed

    Ji, Jie; Valdez, Benigno C; Li, Yang; Liu, Yan; Teo, Esmeralda C; Nieto, Yago; Champlin, Richard E; Andersson, Borje S

    2016-06-01

    Hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with refractory lymphomas. Nucleoside analogs (NAs) and DNA alkylating agents are efficacious in treating hematologic malignancies. To design an efficacious and more economical pretransplant regimen for lymphoma patients, we analyzed the cytotoxicity of cladribine (Clad), gemcitabine (Gem), busulfan (Bu), and suberoylanilide hydroxamic acid (SAHA) in lymphoma cell lines. J45.01 and U937 lymphoma cell lines were exposed to drugs, alone or in combination, for 48 hours and analyzed with the MTT and annexin V assays, Western blotting, and flow cytometry. On the basis of the IC5-10 values of the drugs, the Clad+Gem+Bu combination inhibited the proliferation of both cell lines to ∼55%-60%. Addition of SAHA to this combination decreased proliferation further to ∼30%. Exposure to the Clad+Gem+Bu+SAHA combination activated the DNA damage response and ATM-CHK2 pathway; modified histones; decreased mitochondrial membrane potential, which caused leakage of apoptosis-inducing factors; and activated apoptosis. Pretreatment of cells with the pan-caspase inhibitor Z-VAD-FMK blocked the phosphorylation of histone 2AX and cleavage of PARP-1 and caspases. The Clad+Gem+Bu+SAHA combination provides synergistic cytotoxicity in lymphoma cell lines. Our results may be a basis for using this combination as a pretransplant conditioning regimen in a clinical trial for lymphoma patients undergoing hematopoietic stem cell transplantation, replacing the more expensive nucleoside analog clofarabine. PMID:26976752

  19. Salt-bridge-supported bilayer lipid membrane biosensor for determination of anticancer drug cyclophosphamide

    NASA Astrophysics Data System (ADS)

    Zhang, Yanli; Wang, Tao; Zhang, Chunxu; Shen, Hanxi; Chao, Fuhuan

    2001-09-01

    A novel biosensor for assaying anticancer drug cyclophosphamide was constructed with salt-bridge supported bilayer lipid membrane modified with tetraphenylborate- cyclophosphamide complex. The modification was achieved by the introduction of the complex into the membrane forming solution. The biosensor show a linear response to the drug over the concentration range 8.96 X 10-6 mol L-1. The effects of coexistent substances and pH on assay were evaluated. The results show that the distinguish merits of this kind of biosensor is the excellently biological compatibility and no need of mediator for ions exchange. It also shows good selectivity and sensitivity for cyclophosphamide assay.

  20. Schnitzler's syndrome treated successfully with intravenous pulse cyclophosphamide.

    PubMed

    Peterlana, D; Puccetti, A; Tinazzi, E; Simeoni, S; Lunardi, C

    2005-01-01

    Schnitzler's syndrome is a rare clinical condition characterized by chronic urticaria, intermittent fever, bone pain, arthralgia or arthritis, and monoclonal immunoglobulin M (IgM) gammopathy. Here we describe the case of a 48-year-old Italian female with a long history of arthralgia, leucocytosis, spiking fever, and chronic urticaria with severe pruritus. The IgM-kappa monoclonal component in the serum and bone densification on conventional X-ray with hyperfixation on bone technetium scanning at the distal part of the femurs and at the proximal part of the tibias were detected 4 years after the onset of the symptoms. After many ineffective treatments, the use of pulse cyclophosphamide (CPX) resulted in complete remission of the disease that is still lasting after a 2-year follow-up. PMID:16195169

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

    PubMed

    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. PMID:6740189

  2. High-Dose Busulfan and High-Dose Cyclophosphamide Followed By Donor Bone Marrow Transplant in Treating Patients With Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, or Recurrent Hodgkin or Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2010-08-05

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With T(15;17)(q22;q12); Adult Acute Myeloid Leukemia With T(16;16)(p13;q22); Adult Acute Myeloid Leukemia With T(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Burkitt Lymphoma; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myeloid Leukemia in Remission; Childhood Acute Myelomonocytic Leukemia (M4); Childhood Acute Promyelocytic Leukemia (M3); Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; De Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-Cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  3. Fetal Cyclophosphamide Exposure Induces Testicular Cancer and Reduced Spermatogenesis and Ovarian Follicle Numbers in Mice

    PubMed Central

    Comish, Paul B.; Drumond, Ana Luiza; Kinnell, Hazel L.; Anderson, Richard A.; Matin, Angabin; Meistrich, Marvin L.; Shetty, Gunapala

    2014-01-01

    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. PMID:24691397

  4. Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

    PubMed

    Comish, Paul B; Drumond, Ana Luiza; Kinnell, Hazel L; Anderson, Richard A; Matin, Angabin; Meistrich, Marvin L; Shetty, Gunapala

    2014-01-01

    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. PMID:24691397

  5. Long-term outcome of adjuvant chemotherapy cyclophosphamide, mitoxantrone, and fluorouracil in women with breast cancer.

    PubMed

    Kumpulainen, Eero J; Hirvikoski, Pasi P; Johansson, Risto T

    2008-01-01

    The aim of the study is to report the long-term outcome and secondary tumours of early breast cancer patients of adjuvant CNF (cyclophosphamide, mitoxantrone, and 5-fluorouracil) chemotherapy. One hundred and ninety four patients, 185 primary early breast cancer and nine locoregionally recurrent breast cancer patients, were entered onto the trial between May 1986 and November 1993. The therapies included surgery, radiation therapy, adjuvant CNF chemotherapy, and tamoxifen according to hormonal status. Some of patients were treated twice with CMF (methotrexate). The median follow-up time was 12.9 years. Eighty nine (48%) primary breast cancers relapsed, and six locoregional breast cancers relapsed. After 5-10 years the relapse incidence decreased notably. Eighty three patients died of breast cancer, and nine of other causes. Two cases of leukemia, six cases of skin cancer, two cases of Hodgkin's disease, two cases of meningioma, and two cases of endometrial cancer were observed. This article confirms the feasibility of adjuvant CNF for early breast cancer patients. Questions of possible causability of secondary cancer have yet to be explored. PMID:18097780

  6. 78 FR 47321 - Determination That CYTOXAN (Cyclophosphamide) for Injection Was Not Withdrawn From Sale for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-05

    ...The Food and Drug Administration (FDA) has determined that CYTOXAN (cyclophosphamide) for Injection (lyophilized formulations), 100 milligrams (mg)/vial, 200 mg/vial, 500 mg/vial, 1 gram (g)/vial, and 2 g/vial, and CYTOXAN (cyclophosphamide) for Injection (non- lyophilized formulations), 100 mg/vial and 200 mg/vial, were not withdrawn from sale for reasons of safety or effectiveness. This......

  7. Modulatory effects of ixora coccinea flower on cyclophosphamide-induced toxicity in mice.

    PubMed

    Latha, P G; Panikkar, K R

    1999-09-01

    The active fraction of Ixora coccinea flowers showed chemoprotective effects on cyclophosphamide - induced toxicity by increasing the life span of treated mice, preventing body weight loss and maintaining near normal leucocyte and haemoglobin levels compared with cyclophosphamide treated controls. Decreased serum glutamate pyruvate transaminase (SGPT) and serum alkaline phosphatase (SAKP) levels in the Ixora coccinea treated groups indicated protection against hepatic toxicity. The active fraction was identified by phytochemical methods as the triterpenoid, ursolic acid. PMID:10479765

  8. Effects of carnosine on cyclophosphamide-induced hematopoietic suppression in mice.

    PubMed

    Xu, Meng; He, Rong-Rong; Zhai, Yu-Jia; Abe, Keiichi; Kurihara, Hiroshi

    2014-01-01

    Cyclophosphamide is one of the most widely used chemotherapeutic agents in treating cancers. Chemotherapy drug-induced oxidative stress produces side effects. The severity of myelosuppression increases with a high dose of cyclophosphamide. Chicken soup or chicken essence, a traditional Chinese aliment, is a popular health supplement for patients with cancers or other diseases in Asia. As a major functional component of chicken meat extract, carnosine (beta-alanyl-L-histidine), a dipeptide of the amino acids beta-alanine and histidine, has been shown to have strong antioxidant activities. In the present study, we investigated the effects of carnosine on hematopoietic suppression in mice treated with cyclophosphamide. As expected, we found that cyclophosphamide administration (with a single dose of 150 mg/kg) induced a rapid (within 24 hours) and severe hematopoietic suppression in mice. We further showed that carnosine administration (100 mg/kg/day or 200 mg/kg/day for continuous seven days) could substantially improve suppressed hematopoietic functions and accelerate the recovery of leukocyte counts, bone marrow spontaneous proliferation, colony stimulating activity (CSA) in serum, and production of endogenous cytokines such as interleukin-3 (IL-3) and stem cell factor (SCF). These results indicate that carnosine has the potential to promote the recovery from hematopoietic suppression induced by cyclophosphamide. Our data suggest that carnosine holds a potential in clinical application to minimize the side effects induced by chemotherapeutic agents such as cyclophosphamide and thus will substantially improve the overall anti-tumor effects of the standard chemotherapies. PMID:24467540

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

    PubMed

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

    2016-04-01

    The hepatoprotective activity of Marrubium vulgare against cyclophosphamide toxicity in Wistar rats was evaluated. Adult male rats were divided into 4 groups of 6 each: a control group, a group injected with cyclophosphamide (150 mg·kg(-1)) for 3 days, a group orally given a M. vulgare aqueous extract ((500 mg of dry leaves)·kg(-1)·day(-1)) for 30 days then treated with cyclophosphamide, and a group receiving only M. vulgare for 30 days. After 33 days of treatment, activities of alanine amino transferase (ALAT), aspartate amino transferase (ASAT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) were determined in serum. Moreover, lipid peroxidation level and superoxide dismutase (SOD) activities, catalase (CAT) and glutathione peroxidase (GPx) were measured in liver. Alterations of these hepatic biomarkers and increased lipid peroxidation confirmed cyclophosphamide-induced liver toxicity. Cyclophosphamide also decreased the enzymatic defense system against oxidative stress. However, when this drug was administered in rats given M. vulgare extract, all the biological parameters underwent much less alteration. Administration of M. vulgare extract was found to be beneficial by attenuating cyclophosphamide-induced liver damage. The protective effect of the plant is mainly attributed to its antioxidant properties and the existence of phenolic acids and flavonoids, as highlighted by HPLC-based analysis. PMID:26886858

  10. Submyeloablative conditioning with busulfan permits bone marrow-derived cell accumulation in a murine model of Alzheimer's disease.

    PubMed

    Barr, Christine M; Manning, John; Lewis, Coral Ann B; Rossi, Fabio M V; Krieger, Charles

    2015-02-19

    Previous work has suggested that bone marrow (BM)-derived cells (BMDCs) accumulate within the CNS and could potentially associate with β-amyloid plaques in Alzheimer's disease (AD). To explore the accumulation of BMDCs in murine AD, we transplanted green fluorescent protein (GFP)-labeled BM cells into triple transgenic (3×Tg) and wild-type (wt) mice using non-irradiative myelosuppresive conditioning with busulfan (BU). We find that BU (80mg/kg) is sufficient to obtain adequate chimerism (>85%) in wt mice. In order to obtain appreciable non-irradiative chimerism in the 3×Tg mice (>80%), anti-asialo ganglio-N-tetraosylceramide (α-ASGM-1) antibody was also used to reduce natural killer cell function and thereby abrogate the hybrid resistance of the 3×Tg mouse strain. Using BU conditioning and α-ASGM-1 together, we observed sustained BM chimerism and BMDC accumulation within the CNS of the 3×Tg and wt mice. In cortex and hippocampus, BMDC accumulation was perivascular in distribution and similar between 3×Tg and wt mice, with no clear association between BMDCs and AD plaques. We conclude that non-irradiative BM chimerism can be achieved with BU in 3×Tg mice, but requires α-ASGM-1 (or similar appropriate NK-cell depletion). Use of this chimerism protocol permits BMDCs accumulation in the CNS of mixed strain recipient mice although BMDCs appear to be largely perivascular within cortex and hippocampus. PMID:25582787

  11. Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation.

    PubMed

    Chunduri, S; Dobogai, L C; Peace, D; Saunthararajah, Y; Chen, H Y; Mahmud, N; Quigley, J; Hoffman, R; Jessop, E; Beri, R; Rondelli, D

    2006-10-01

    Fludarabine was utilized in the conditioning regimen of 30 adult patients undergoing an allogeneic hematopoietic stem cell transplant. In 18 patients it was combined with full-dose busulfan (FluBu) as a myeloablative regimen and in 12 cases with melphalan (FluMel) as a reduced intensity conditioning (RIC) regimen. Patients in the FluBu group were younger than in the FluMel group (P=0.03). Of 30 patients, 24 received peripheral blood stem cells (PBSC) whereas six patients in the FluBu group received bone marrow cells. The hematological toxicity of each regimen was evaluated by analyzing the kinetics of the neutropenia induced by preparative regimens and the time to recovery of the absolute neutrophils count (ANC) and platelets post transplantation. In PBSC transplants, the median day of severe neutropenia (<500 ANC/microl) occurred on day +6 after the FluBu regimen and on day +3 after FluMel (P=ns), whereas both groups had a duration of severe neutropenia of 9 days and a comparable time for ANC and platelet engraftment. Extra-hematological toxicities were also comparable in the two groups. These findings suggest that the hematological and extra-hematological toxicities induced by fludarabine/full-dose i.v. busulfan are similar to those induced by a standard RIC regimen such as fludarabine/melphalan. PMID:16980995

  12. Fludarabine and busulfan as a reduced-toxicity myeloablative conditioning regimen in allogeneic hematopoietic stem cell transplantation for acute leukemia patients

    PubMed Central

    DAI, ZHIMING; LIU, JIE; ZHANG, WANG-GANG; CAO, XINGMEI; ZHANG, YANG; DAI, ZHIJUN

    2016-01-01

    The optimal conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute leukemia remains undefined. We evaluated the outcomes in 30 patients with acute leukemia who underwent allo-HSCT from human leukocyte antigen-matched donors after conditioning with busulfan and fludarabine (BuFlu). The regimen comprised injection of busulfan 3.2 mg/kg daily on 4 consecutive days and fludarabine 30 mg/m2 daily for 4 doses. All 30 patients achieved hematopoiesis reconstitution with full donor chimerism confirmed by short tandem repeat DNA analysis. The most common regimen-related toxicity was mucositis (86.7%), followed by cytomegalovirus infection (80%). Serious regimen-related toxicities were rare. Acute graft vs. host disease (aGVHD) was detected in 46.7% of the patients; 33.4% had grade I–II aGVHD and 13.3% had grade III–IV aGVHD. Chronic GVHD (cGVHD) was noted in 20% of the patients. The overall survival and disease-free survival rates were 66.7 and 53%, respectively, with a median follow-up of 25 months for surviving patients. Therefore, BuFlu was an effective conditioning regimen with a low rate of transplant-related adverse effects and increased antileukemic effects in patients with acute leukemia undergoing allo-HSCT. PMID:27073687

  13. The histone deacetylase inhibitor SAHA sensitizes acute myeloid leukemia cells to a combination of nucleoside analogs and the DNA-alkylating agent busulfan.

    PubMed

    Song, Guiyun; Valdez, Benigno C; Li, Yang; Dominguez, Jose R; Corn, Paul; Champlin, Richard E; Andersson, Borje S

    2014-07-01

    Fludarabine (Flu), clofarabine (Clo) and busulfan (Bu) are used in allogeneic hematopoietic stem cell transplant (allo-HSCT). We reported that combining [Flu + Clo + Bu] had a synergistic cytotoxicity in AML cells. We hypothesized that combining [Flu + Clo + Bu] with the histone deacetylase inhibitor SAHA will further enhance cytotoxicity. We exposed the acute myeloid leukemia (AML) cell lines KBM3/Bu250(6) and OCI-AML3 to Flu, Clo, Bu and SAHA alone and in various combinations. [Flu + Clo + Bu + SAHA] resulted in synergistic cytotoxicity, which can be attributed to (1) activated DNA-damage response and cell cycle checkpoint activation through the ATM-CHK2-P53 (or P73) pathway or ATM-CHK2-cdc25-cdc2 pathway, (2) histone modifications and (3) activated apoptosis pathway. The [Flu + Clo + Bu + SAHA] combination causes mitochondrial outer membrane permeabilization, leakage of cytochrome c and Smac/Diablo into the cytosol with caspase activation, and release of apoptosis-inducing factor (AIF) into the nucleus resulting in nuclear fragmentation and cell death. These results provide a mechanistic basis for using SAHA in future clinical trials with double nucleoside analog-busulfan combinations in pretransplant conditioning therapy. PMID:24144307

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

    PubMed Central

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

    2014-01-01

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

  15. Processed Aloe vera Gel Ameliorates Cyclophosphamide-Induced Immunotoxicity

    PubMed Central

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

    2014-01-01

    The effects of processed Aloe vera gel (PAG) on cyclophosphamide (CP)-induced immunotoxicity were examined in mice. Intraperitoneal injection of CP significantly reduced the total number of lymphocytes and erythrocytes in the blood. Oral administration of PAG quickly restored CP-induced lymphopenia and erythropenia in a dose-dependent manner. The reversal of CP-induced hematotoxicity by PAG was mediated by the functional preservation of Peyer’s patch cells. Peyer’s patch cells isolated from 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. PMID:25347273

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

    PubMed

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

    2003-03-01

    Beta-ionone (BI) is a degraded (C 13) sesquiterpene found in plant essential oils. It has been used in the synthesis of perfume chemicals and vitamin A. Recently, it was reported that BI is a rather potent in vitro inhibitor of CYP2B1-catalysed reactions in rat liver microsomes. The present study was performed to investigate whether inhibition of CYP2B1 reactions by BI could lead to an attenuation of cyclophosphamide (CP)-induced embryotoxicity in the rat. In a preliminary experiment, a dose-dependent prolongation of pentobarbital sleeping time in male and female Wistar rats suggested that BI inhibits CYP2B1 in vivo as well. In a second experiment, rats were treated by gavage with BI (0, 250, 500, 750 or 1000 mg/kg body wt) 45 min prior to a subcutaneous injection of either CP (7.5 mg/kg body wt) or its vehicle (saline) on day 11 of pregnancy. BI alone, at the highest dose tested, caused a high proportion of resorptions. Lower doses of BI, however, clearly attenuated CP-induced embryolethality and teratogenicity. These results seem to support the view that, as far as rats are concerned, CYP2B1 plays an important role in the conversion of CP into its embryolethal and teratogenic metabolites. PMID:12565197

  17. Doxycycline potentiates antitumor effect of cyclophosphamide in mice

    SciTech Connect

    Chhipa, Rishi Raj; Singh, Sandeep; Surve, Sachin V.; Vijayakumar, Maleppillil Vavachan; Bhat, Manoj Kumar . E-mail: manojkbhat@nccs.res.in

    2005-02-01

    Cyclophosphamide (CPA) is a widely used chemotherapeutic drug in neoplasias. It is a DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining well-tolerated antibiotic doxycycline (DOX) with CPA and understanding the mechanism of cell killing. Interestingly, we found that DOX significantly enhances the tumor regression activity of CPA on xenograft mice model bearing MCF-7 cells. DOX also potentiates MCF-7 cell killing by CPA in vitro. In presence of DOX (3 {mu}g/ml), the IC{sub 50} value of CPA decreased significantly from 10 to 2.5 mM. Additional analyses indicate that the tumor suppressor p53 and p53-regulated proapoptotic Bax were upregulated in vivo and in vitro following CPA treatment in combination with DOX, suggesting that upregulation of p53 may contribute to the enhancement of antitumor effect of CPA by DOX. Furthermore, downregulation of antiapoptotic Bcl-2 was observed in animals treated with CPA and CPA plus DOX when compared to untreated or DOX-treated groups. Our results raise the possibility that this combination chemotherapeutic regimen may lead to additional improvements in treatment of breast cancer.

  18. Effect of cyclophosphamide and electromagnetic fields on mouse bone marrow

    SciTech Connect

    Cadossi, R.; Zucchini, P.; Emilia, G.; Torelli, G. )

    1990-02-26

    The authors have previously shown that the exposure to low frequency pulsing electromagnetic fields (PEMF) of mice X-ray irradiated resulted in an increased damage to the bone marrow. The series of experiments here reported were designed to investigate the effect of PEMF exposure after intraperitoneum injection of 200mg/kg of cyclophosphamide (CY). Control mice were CY injected only; experimental mice were CY injected and then exposed to PEMF. Exposure to PEMF (24 hours/day) increased the rate of decline of white blood cells in peripheral blood. Spleen weight was statistically higher among control mice than among mice exposed to PEMF at day 6, 8 and 10 after CY injection. Spleen autoradiography proved to be higher among PEMF exposed mice than among controls at day 8 and 9 after CY injection. The grafting efficiency of the bone marrow obtained from control mice was higher than the grafting efficiency of the bone marrow recovered from mice exposed to PEMF. All these data indicate that the exposure to PEMF increases the cytotoxic effect of CY.

  19. Isophosphoramide mustard, a metabolite of ifosfamide with activity against murine tumours comparable to cyclophosphamide.

    PubMed Central

    Struck, R. F.; Dykes, D. J.; Corbett, T. H.; Suling, W. J.; Trader, M. W.

    1983-01-01

    Isophosphoramide mustard was synthesized and was found to demonstrate activity essentially comparable to cyclophosphamide and ifosfamide against L1210 and P388 leukaemia. Lewis lung carcinoma, mammary adenocarcinoma 16/C, ovarian sarcoma M5076, and colon tumour 6A, in mice and Yoshida ascitic sarcoma in rats. At doses less than, or equivalent to, the LD10, isophosphoramide mustard retained high activity against cyclophosphamide-resistant L1210 and P388 leukaemias, but was less active against intracerebrally-implanted P388 leukaemia while cyclophosphamide produced a 4 log10 tumour cell reduction. It was also less active (one log10 lower cell kill) than cyclophosphamide against the B16 melonoma. Metabolism studies on ifosfamide in mice identified isophosphoramide mustard in blood. In addition, unchanged drug, carboxyifosfamide, 4-ketoifosfamide, dechloroethyl cyclophosphamide, dechloroethylifosfamide, and alcoifosfamide were identified. The latter 4 metabolites were also identified in urine from an ifosfamide-treated dog. In a simulated in vitro pharmacokinetic experiment against L1210 leukaemia in which drugs were incubated at various concentrations for various times, both 4-hydroxycyclophosphamide and isophosphoramide mustard exhibited significant cytoxicity at concentration times time values of 100-1000 micrograms X min ml-1, while acrolein was significantly cytotoxic at 10 micrograms X min ml-1. Treatment of mice with drug followed by L1210 cells demonstrated a shorter duration of effective levels of cytotoxic activity for isophosphoramide mustard and phosphoramide mustard in comparison with cyclophosphamide and ifosfamide. Isophosphoramide mustard and 2-chloroethylamine, a potential hydrolysis product of isophosphoramide mustard and carboxyifosfamide, were less mutagenic in the standard Ames test than the 2 corresponding metabolites of cyclophosphamide [phosphoramide mustard and bis(2-chloroethyl)amine]. PMID:6821629

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

    SciTech Connect

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

    1983-09-01

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

  1. Campomanesia adamantium extract induces DNA damage, apoptosis, and affects cyclophosphamide metabolism.

    PubMed

    Martello, M D; David, N; Matuo, R; Carvalho, P C; Navarro, S D; Monreal, A C D; Cunha-Laura, A L; Cardoso, C A L; Kassuya, C A L; Oliveira, R J

    2016-01-01

    Campomanesia adamantium (Cambess.) O. Berg. is originally from Brazil. Its leaves and fruits have medicinal properties such as anti-inflammatory, antidiarrheal and antiseptic properties. However, the mutagenic potential of this species has been reported in few studies. This study describes the mutagenic/antimutagenic, splenic phagocytic, and apoptotic activities of C. adamantium hydroethanolic extract with or without cyclophosphamide in Swiss mice. The animals orally received the hydroethanolic extract at doses of 30, 100, or 300 mg/kg with or without 100 mg/kg cyclophosphamide. Mutagenesis was evaluated by performing the micronucleus assay after treatment for 24, 48, and 72 h, while splenic phagocytic and apoptotic effects were investigated after 72 h. Short-term exposure of 30 and 100 mg/kg extract induced mild clastogenic/aneugenic effects and increased splenic phagocytosis and apoptosis in the liver, spleen, and kidneys. When the extract was administered in combination with cyclophosphamide, micronucleus frequency and apoptosis reduced. Extract components might affect cyclophosphamide metabolism, which possibly leads to increased clearance of this chemotherapeutic agent. C. adamantium showed mutagenic activity and it may decrease the effectiveness of drugs with metabolic pathways similar to those associated with cyclophosphamide. Thus, caution should be exercised while consuming these extracts, especially when received in combination with other drugs. PMID:27173259

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

    PubMed

    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

    2016-01-01

    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. PMID:27173316

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

    PubMed

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

    2014-02-01

    Bladder inflammation (cystitis) underlies numerous bladder pathologies and is elicited by a plethora of agents such as urinary tract infections, bladder outlet obstruction, chemotherapies, and catheters. Pattern recognition receptors [Toll-like receptors (TLRs) and Nod-like receptors (NLRs)] that recognize pathogen- and/or damage-associated molecular patterns (PAMPs and/or DAMPs, respectively) are key components of the innate immune system that coordinates the production (TLRs) and maturation (NLRs) of proinflammatory IL-1β. Despite multiple studies of TLRs in the bladder, none have investigated NLRs beyond one small survey. We now demonstrate that NLRP3 and NLRC4, and their binding partners apoptosis-associated speck-like protein containing a COOH-terminal caspase recruitment domain (ASC) and NLR family apoptosis inhibitory protein (NAIP), are expressed in the bladder and localized predominantly to the urothelia. Activated NLRs form inflammasomes that activate caspase-1. Placement of a NLRP3- or NLRC4-activating PAMP or NLRP3-activating DAMPs into the lumen of the bladder stimulated caspase-1 activity. To investigate inflammasomes in vivo, we induced cystitis with cyclophosphamide (CP, 150 mg/kg ip) in the presence or absence of the inflammasome inhibitor glyburide. Glyburide completely blocked CP-induced activation of caspase-1 and the production of IL-1β at 4 h. At 24 h, glyburide reduced two markers of inflammation by 30-50% and reversed much of the inflammatory morphology. Furthermore, glyburide reversed changes in bladder physiology (cystometry) induced by CP. In conclusion, NLRs/inflammasomes are present in the bladder urothelia and respond to DAMPs and PAMPs, whereas NLRP3 inhibition blocks bladder dysfunction in the CP model. The coordinated response of NLRs and TLRs in the urothelia represents a first-line innate defense that may provide an important target for pharmacological intervention. PMID:24285499

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

    PubMed

    Mok, Chi Chiu

    2016-07-01

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

  5. Rutin Ameliorates Cyclophosphamide-induced Reproductive Toxicity in Male Rats

    PubMed Central

    Abarikwu, S. O.; Otuechere, C. A.; Ekor, M.; Monwuba, K.; Osobu, D.

    2012-01-01

    Cyclophosphamide (CYC) as an anticancer alkylating agent has been known as a male reproductive toxicant. This study was aimed to evaluate the protective effect of rutin (RUT) on CYC-induced reproductive toxicity. Sexually mature Wistar rats (weighing 199 ± 10 g with five animals in each group) were given CYC (15 mg/kg) and/or RUT (30 mg/kg) twice a week via gavage for 4 weeks. The sperm counts, sperm motility, sperm morphology, daily sperm production (DSP), testicular, and epididymal antioxidant systems: superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and testicular steroidogenic enzymes (3β-hydroxysteroid dehydrogenase and 17β-HSD and spermatogenesis marker enzymes (lactate dehydrogenase (LDH), sorbitol dehydrogenase (SDH), alkaline phosphatase (ALP), acid phosphatase (ACP) in the testes, epididymis and seminal vesicles were investigated at the end of the fourth week. By the end of the fourth week, RUT prevented lower sperm counts, sperm motility, DSP, and higher abnormal sperm numbers induced by CYC. In testes, RUT decreased SOD, LDH, and SDH and increased CAT, 3β-HSD, 17β-HSD, ALP, and ACP induced by CYC. In epididymis, RUT increased SOD, CAT, GSH, GSH-Px, GR, GST SDH, ALP and ACP and decreased MDA and LDH induced by CYC. In seminal vesicles, marker enzymes were unchanged in rats given CYC alone or in combination with RUT. It appears that RUT ameliorates CYC reproductive toxicity at the investigated dose. PMID:22778522

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

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

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

  7. Acute Cyclophosphamide Hemorrhagic Myopericarditis: Dilemma Case Report, Literature Review and Proposed Diagnostic Criteria

    PubMed Central

    2015-01-01

    Cyclophosphamide is a potent DNA alkylating agent used in chemotherapy and immunosuppression. Although an old agent, its use in the present day has expanded for cases of refractory autoimmune disease. In this report, a case of haemorrhagic myopericarditis resulting from high-dose cyclophosphamide for chronic inflammatory demyelinating polyneuropathy is presented. The patient had no predisposing cardiovascular risk factors and a structurally normal heart on previous echocardiogram. Following administration of high-dose cyclophosphamide, the patient developed acute congestive heart failure. Serial echocardiography demonstrated pericardial effusion, myocardial thickening, and progressive right ventricular dysfunction. Histopathology on autopsy revealed acute myocardial necrosis, intra-myocardial extravasation of blood, fibrin, and fibrin-platelet microthrombi compatible with the diagnosis of haemorrhagic myopericarditis. The ante-mortem diagnostic dilemma is described to emphasize the need for pattern recognition and clinical criteria for diagnosis. Subsequent comprehensive literature review was performed to identify features that will facilitate earlier diagnosis of haemorrhagic myopericarditis by healthcare providers. PMID:26674419

  8. Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration

    PubMed Central

    Juma, F. D.; Rogers, H. J.; Trounce, J. R.

    1979-01-01

    1 Plasma cyclophosphamide levels were estimated by gas-chromatography in seven patients following intravenous and oral cyclophosphamide administration. Plasma alkylating activity was determined by the nitrobenzyl pyridine (NBP) reaction. 2 The plasma T½ after intravenous administration ranged from 5.97 to 12.37 h but after oral administration was shorter, 1.32-6.8 h. The mean total body clearance was 66.6 ml kg-1 h-1 after intravenous dosing and 93.1 ml kg-1 h-1 following oral dosing. Vdβ was 0.71 (0.10 s.d.) 1 kg-1 suggesting that cyclophosphamide is distributed largely in body water. 3 The mean hepatic extraction ratio was 0.25, indicating a modest first pass metabolism. The metabolic clearance was 3.72 1 kg-1 and the intrinsic hepatic clearance 5.17 1 kg-1. 4 The mean renal clearance was 4.8 ml kg-1 h-1 with 6.5% of the administered dose excreted unchanged in the urine suggesting tubular reabsorption of cyclophosphamide. 5 The mean T½ of plasma alkylating activity was 8.82 h, there being no significant difference following oral and intravenous administration. On average, 3.5 times the alkylating activity was produced by an oral dose of cyclophosphamide as compared to an intravenous dose. It is possible that this may reflect production of a different pattern of alkylating metabolites following cyclophosphamide administration by different routes. The clinical significance of these observations is unknown. PMID:497087

  9. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.

    PubMed

    Zavada, J; Pesickova, Ss; Rysava, R; Olejarova, M; Horák, P; Hrncír, Z; Rychlík, I; Havrda, M; Vítova, J; Lukác, J; Rovensky, J; Tegzova, D; Böhmova, J; Zadrazil, J; Hána, J; Dostál, C; Tesar, V

    2010-10-01

    Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.(ClinicalTrials.gov identifier: NCT00976300) PMID:20605876

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

    PubMed Central

    Li, Dong; He, Song

    2015-01-01

    Lung cancer is the leading cause of cancer-related mortality. This study was undertaken to investigate the efficacy and safety of adding regulatory T cell inhibitor cyclophosphamide to pemetrexed therapy for the second-line treatment of NSCLC with wild-type epidermal growth factor receptor (EGFR). A total of 70 patients were screened between March 2011 and December 2013, out of which 62 patients were enrolled in the study. Patients were randomized to receive 500 mg/m2 pemetrexed in combination with 20 mg/kg cyclophosphamide in a 21 day cycle (n=30) or 500 mg/m2 pemetrexed (n=32), and followed up for 30 months. Disease progression was observed in 23 patients in the pemetrexed plus cyclophosphamide arm and 27 patients in the pemetrexed monotherapy arm. Median progression-free survival was 3.6 months (95% confidence interval [CI], 1.3 to 5.9 months) in the pemetrexed plus cyclophosphamide arm and 2.2 months (95% CI, 1.3 to 3.1 months) in the pemetrexed monotherapy arm. The 6-month PFS rates were 22% (95% CI, 10 to 34) and 14.5% (95% CI, 6 to 23) in the pemetrexed plus cyclophosphamide arm and pemetrexed monotherapy arm, respectively. Median overall survival was 9.8 months for the pemetrexed combination therapy arm and 8.8 months for the pemetrexed arm, and the 1-year survival rates were 46% and 33%, respectively. The present study showed that pemetrexed in combination with low-dose cyclophosphamide may be a better treatment approach than pemetrexed monotherapy when considering second-line treatment for wild-type EGFR NSCLC. PMID:26823793

  11. Steroid-resistant nephrotic syndrome: the influence of race on cyclophosphamide sensitivity.

    PubMed

    Bhimma, Rajendra; Adhikari, Miriam; Asharam, Kareshma

    2006-12-01

    Steroid-resistant (SR) forms of nephrotic syndrome (NS) have a poorer outcome in blacks compared to other racial groups. In this study, 223 children with SRNS, aged 1-16 years old, were analysed retrospectively for the period 1976-2004. Treatment schedules included oral cyclophosphamide (2-3 mg/kg) with prednisone 0.5-1 mg/kg (maximum 60 mg) only (n=90); prednisone on alternate days with methylprednisolone (30 mg/kg, maximum 1 g) and oral cyclophosphamide (n=117); oral prednisone on alternate days, three doses of intravenous methylprednisolone on alternate days and monthly doses of intravenous cyclophosphamide (500-750 mg m(-2) dose(-1)x7 doses monthly) (n=10); or cyclosporine 5 mg kg(-1) day(-1) adjusted to a trough level of 150-200 mg/ml (n=6). We compared the clinical and biochemical characteristics and outcome using different forms of therapies. A total of 183 (82.1%) underwent biopsy; 84 (45.9%) were Indian and 99 (54.1%) were black. Sixty-six (36.1%) had minimal change NS, 66 (36.1%) had focal segmental glomerulosclerosis (FSGS), 15 (8.2%) had a proliferative form of NS, and 36 (19.7%) had other forms of NS. Of the 84 Indian children biopsied, 58 (69.0%) were in complete remission, including 29 of 40 (72.5%) treated with oral cyclophosphamide and prednisone only. Of the 99 black children who were biopsied, 20 (20.2%) achieved complete remission; none of those treated with oral cyclophosphamide and prednisone only achieved complete remission. Of the 40 Indian children who were not biopsied who received only oral prednisone and cyclophosphamide, 32 (80%) achieved complete remission. This study shows Indian children with SRNS respond better to treatment than black children (69.0 vs. 20.2%). Since 80% of Indian children with SRNS responded to a trial of oral cyclophosphamide and prednisone, we propose the use of oral cyclophosphamide therapy in non-black children before embarking on renal biopsy. PMID:16967286

  12. Radiation

    NASA Video Gallery

    Outside the protective cocoon of Earth's atmosphere, the universe is full of harmful radiation. Astronauts who live and work in space are exposed not only to ultraviolet rays but also to space radi...

  13. Results from a clofarabine-busulfan-containing, reduced-toxicity conditioning regimen prior to allogeneic stem cell transplantation: the phase 2 prospective CLORIC trial.

    PubMed

    Chevallier, Patrice; Labopin, Myriam; Socié, Gérard; Tabrizi, Reza; Furst, Sabine; Lioure, Bruno; Guillaume, Thierry; Delaunay, Jacques; de La Tour, Régis Peffault; Vigouroux, Stéphane; El-Cheikh, Jean; Blaise, Didier; Michallet, Mauricette; Bilger, Karin; Milpied, Noel; Moreau, Philippe; Mohty, Mohamad

    2014-09-01

    We prospectively evaluated the safety and efficacy of a clofarabine, intravenous busulfan and antithymocyte globulin-based reduced-toxicity conditioning (CloB2A2) regimen before allogeneic stem cell transplantation. Thirty high-risk patients (median age: 59 years; acute myeloid leukemia n=11, acute lymphoblastic leukemia n=13; myelodysplastic syndrome n=5, bi-phenotypic leukemia n=1) were included in this phase 2 study. At time of their transplant, 20 and seven patients were in first and second complete remission, respectively, while three patients with myelodysplastic syndrome were responding to chemotherapy or who had not been previously treated. The CloB2A2 regimen consisted of clofarabine 30 mg/m(2)/day for 4 days, busulfan 3.2 mg/kg/day for 2 days and antithymocyte globulin 2.5 mg/kg/day for 2 days. The median follow-up was 23 months. Engraftment occurred in all patients. The 1-year overall survival, leukemia-free survival, relapse incidence and non-relapse mortality rates were 63±9%, 57±9%, 40±9%, and 3.3±3%, respectively. Comparing patients with acute myeloid leukemia/myelodysplastic syndrome versus those with acute lymphoblastic leukemia/bi-phenotypic leukemia, the 1-year overall and leukemia-free survival rates were 75±10% versus 50±13%, respectively (P=0.07) and 69±12% versus 43±13%, respectively (P=0.08), while the 1-year relapse incidence was 25±11% versus 57±14%, respectively (P=0.05). The CloB2A2 regimen prior to allogeneic stem cell transplantation is feasible, allowing for full engraftment and low toxicity. Disease control appears to be satisfactory, especially in patients with acute myeloid leukemia/myelodysplastic syndrome. The trial was registered at www.clinicaltrials.gov no. NCT00863148. PMID:24951467

  14. Prospective phase II trial to evaluate the complications and kinetics of chimerism induction following allogeneic hematopoietic stem cell transplantation with fludarabine and busulfan.

    PubMed

    Saito, Akiko M; Kami, Masahiro; Mori, Shin-Ichiro; Kanda, Yoshinobu; Suzuki, Ritsuro; Mineishi, Shin; Takami, Akiyoshi; Taniguchi, Shuichi; Takemoto, Yoshinobu; Hara, Masamichi; Yamaguchi, Masaki; Hino, Masayuki; Yoshida, Takashi; Kim, Sung-Won; Hori, Akiko; Ohashi, Yasuo; Takaue, Yoichi

    2007-10-01

    This prospective trial assessed the safety and efficacy of allogeneic hematopoietic stem cell transplantation from a HLA-matched donor with a reduced-intensity regimen (RIST) consisting of iv fludarabine 30 mg/m(2) for 6 days and oral busulfan 4 mg/kg/day for 2 days in patients older than 50 years with hematological malignancies. Cyclosporine alone or cyclosporine with short-term methotrexate was randomized for graft-versus-host disease prophylaxis. After 30 patients had been enrolled, an interim analysis was performed, and this report focuses on a precise evaluation of the toxicity profile and chimerism kinetics. Sustained engraftment in all patients, no severe regimen-related toxicity (RRT) within 20 days, and no transplant-related mortality through Day 100 were observed. T-cell (CD3+) full-donor (over 90%) chimerism was observed in 22 of the 30 patients, while the remaining eight had mixed-donor chimerism over 77% on Day 90. Thereafter, five subsequently converted to full-donor chimerism without donor lymphocyte infusion by day 120 (n = 4) or Day 180 (n = 1). Two showed persistent mixed chimerism without relapse through Day 180. Grade III-IV acute graft-versus-host disease and extensive chronic graft-versus-host disease occurred in 10% and 73%, respectively. With a median follow-up of 1.5 years, overall survival and disease-free survival at 1 year was 83% and 62%, respectively. Seven patients hematologically relapsed overall, and five of them had myelodysplastic syndrome with poor prognostic factors. In older patients, RIST with fludarabine and busulfan was associated with acceptable toxicities and a satisfactory antileukemia effect, regardless of the early chimerism status. PMID:17570513

  15. Does anti-thymocyte globulin have a place in busulfan/fludarabine conditioning for matched related donor hematopoietic stem cell transplantation?

    PubMed Central

    Ji, Young Sok; Lee, Min Sung; Min, Chang Wook; Park, Seong Kyu; Kim, Se Hyung; Yun, Jina; Kim, Hyun Jung; Kim, Kyoung Ha; Kim, Chan Kyu; Lee, Kyu-Taek; Won, Jong-Ho; Hong, Dae Sik

    2016-01-01

    Background/Aims: There is controversy about the prophylactic effect of anti-thymocyte globulin (ATG) on graft versus host disease (GVHD) in the setting of matched related-donor hematopoietic stem cell transplantation (HSCT). This study assessed the inf luences of ATG on the incidences of acute and chronic GVHD and other clinical outcomes in matched related-donor HSCT. Methods: Sixty-one patients received allogeneic HSCT from human leukocyte antigen-matched, related donors. Patients received busulfan/fludarabine conditioning regimens and standard GVHD prophylaxis with or without additional ATG. Results: There was no significant difference in the cumulative incidences of overall acute GVHD, grade II to IV acute GVHD at day 100, and chronic GVHD during the follow-up period between the ATG and non-ATG groups. Three-year overall survival rates were very similar, but three year disease-free survival of the non-ATG group was higher than that of the ATG group (56.2% for ATG vs. 63.1% for non-ATG, p = 0.597). Relapse rate at 3 years in the ATG group was slightly higher than that of the non-ATG group (37.5% vs. 20%, p = 0.29). Non-relapse mortality rate at 3 years was lower in the ATG group (6.25% vs. 15.6%, p = 0.668). Conclusions: Although the addition of ATG doesn’t guarantee a reduction in the incidences of acute and chronic GVHD, pre-transplantation ATG may result in lower non-relapse mortality in the context of matched related-donor HSCT with a busulfan/fludarabine conditioning regimen. However, caution is needed when using ATG because of a possibility to increase relapse rate. PMID:27017944

  16. Fludarabine-Busulfan Reduced-Intensity Conditioning in Comparison with Fludarabine-Melphalan Is Associated with Increased Relapse Risk In Spite of Pharmacokinetic Dosing.

    PubMed

    Damlaj, Moussab; Alkhateeb, Hassan B; Hefazi, Mehrdad; Partain, Daniel K; Hashmi, Shahrukh; Gastineau, Dennis A; Al-Kali, Aref; Wolf, Robert C; Gangat, Naseema; Litzow, Mark R; Hogan, William J; Patnaik, Mrinal M

    2016-08-01

    Fludarabine with busulfan (FB) and fludarabine with melphalan (FM) are commonly used reduced-intensity conditioning (RIC) regimens. Pharmacokinetic dosing of busulfan (Bu) is frequently done for myeloablative conditioning, but evidence for its use is limited in RIC transplants. We compared transplant outcomes of FB versus FM using i.v. Bu targeted to the area under the curve (AUC). A total of 134 RIC transplants (47 FB and 87 FM) for acute myelogenous leukemia and myelodysplastic syndrome were identified, and median follow-up of the cohort was 40 months (range, 0 to 63.3). A significantly higher 2-year cumulative incidence of relapse (CIR) was associated with FB versus FM at 35.6% versus 17.3%, respectively (P = .0058). Furthermore, 2-year progression-free survival rates were higher for FM versus FB at 60.5% versus 48.7%, respectively (P = .04). However, 2-year rates of nonrelapse mortality (NRM) and overall survival (OS) were similar. The need for dose adjustment based on AUC did not alter relapse risk or NRM. Patients with Karnofsky performance status ≥ 90 who received FM had a 2-year OS rate of 74.8% versus 48.3% for FB (P = .03). FB use remained prognostic for relapse in multivariable analysis (hazard ratio, 2.75; 95% confidence interval, 1.28 to 5.89; P = .0097). In summary, in spite of AUC-directed dosing, FB compared with FM was associated with a significantly higher CIR. PMID:27164061

  17. Clofarabine ± fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS.

    PubMed

    Andersson, Borje S; Valdez, Benigno C; de Lima, Marcos; Wang, Xuemei; Thall, Peter F; Worth, Laura L; Popat, Uday; Madden, Timothy; Hosing, Chitra; Alousi, Amin; Rondon, Gabriela; Kebriaei, Partow; Shpall, Elizabeth J; Jones, Roy B; Champlin, Richard E

    2011-06-01

    Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen's antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT). Patients were adaptively randomized as follows: Arm I-Clo:Flu 10:30 mg/m(2), Arm II-20:20 mg/m(2), Arm III-30:10 mg/m(2), and Arm IV-single-agent Clo at 40 mg/m(2). The nucleoside analog(s) were/was infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 6000 μMol-min ± 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females, with a median age of 45 years (range: 6-59). Nine patients had chronic myeloid leukemia (CML) (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first chronic phase [CP]: 4). Forty-two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second complete remission (CR), and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methorexate (MTX), and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit

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

    PubMed

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

    2015-05-01

    Previous investigation demonstrated that oral administration of ginseng stem-leaf saponins in chickens could enhance the immune response. The present study was designed to evaluate the effects of ginseng stem-leaf saponins on oxidative stress induced by cyclophosphamide in chickens. One hundred and twenty chickens were randomly divided into 5 groups. Groups 1 to 4 received intramuscular injection of cyclophosphamide to induce oxidative stress while group 5 was injected with saline solution and served as control. Following administration of cyclophosphamide, groups 1 to 3 were orally administered ginseng stem-leaf saponins at 2.5, 5, and 10 mg/kg BW in drinking water for 7 d, respectively. After that, the spleen, thymus, bursa, and serum were collected to measure the indices of the organs and oxidative parameters. The results showed that ginseng stem-leaf saponins significantly inhibited cyclophosphamide-induced oxidative stress by increasing the organ indices, total antioxidant capacity, and the levels of glutathione, ascorbic acid, and α-tocopherol, while elevating the activity of total superoxide dismutase, catalase, and glutathione peroxidase, as well as decreasing the protein carbonyl content and malondialdehyde. Therefore, ginseng stem-leaf saponins could be a promising agent against oxidative stress in the poultry industry. PMID:25713395

  19. EVALUATION OF THE IMMUNOTOXIC POTENTIAL OF CHLORDECONE WITH COMPARISON TO CYCLOPHOSPHAMIDE

    EPA Science Inventory

    The immunotoxic potential of chlordecone was evaluated in male Fischer 344 rats following 10 days of dosing by oral gavage. These results were compared with a comparable dosing regimen with the known immunosuppressive drug cyclophosphamide. Significant changes in the immune param...

  20. Phase II trial of cyclophosphamide, leucovorin, 5-fluorouracil 24-hour infusion and tamoxifen in pancreatic cancer.

    PubMed

    Eckel, F; Lersch, C; Lippl, F; Assmann, G; Schulte-Frohlinde, E

    2000-09-01

    Leucovorin modulates the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. 24-hour infusion of 5-FU has been shown to enhance antitumor activity in colorectal cancer compared to bolus infusion. According to experimental data cyclophosphamide and tamoxifen may enhance the effectiveness of leucovorin and 5-FU. A phase II trial was initiated to evaluate the effect of a combination of low-dose cyclophosphamide (C), leucovorin (L), 5-FU (F) and tamoxifen (T) (CLFT) in advanced pancreatic cancer. Fifty patients were treated monthly with 300 mg/m2 cyclophosphamide and weekly with 500 mg/m2 leucovorin followed by a 24-hour infusion of 2000 mg/m2 5-FU and tamoxifen 20 mg bid. Three patients had a partial response (6%), two a minor response (4%) and 32 (64%) no change of disease. The median survival time was 8.5 months for all patients, the median time to progression of disease was 4.6 months and the 1-year survival rate was 28%. CLFT was fairly well tolerated. These data suggest that biochemical modulation of 24-hour infusional 5-FU with leucovorin together with cyclophosphamide and tamoxifen has some positive effects in the treatment of pancreatic cancer. PMID:11144522

  1. Cardioprotective effect of Saraca indica against cyclophosphamide induced cardiotoxicity in rats: A biochemical, electrocardiographic and histopathological study

    PubMed Central

    Viswanatha Swamy, A. H. M.; Patel, U. M.; Koti, B. C.; Gadad, P. C.; Patel, N. L.; Thippeswamy, A. H. M.

    2013-01-01

    Objectives: Cardioprotective activity of alcoholic extract of Saraca indica (SI) bark was investigated against cyclophosphamide induced cardiotoxicity. Materials and Methods: Cardiotoxicity was induced in Wistar rats by administering cyclophosphamide (200 mg/kg, i.p.) single injection on first day of experimental period. Saraca indica (200 and 400 mg/kg, p.o.) was administered immediately after administration of cyclophosphamide on first day and daily for 10 days. The general observations and mortality were measured. Results: Cyclophosphamide administration significantly (p < 0.05) increased lipid peroxidation (LPO) and decreased the levels of antioxidant markers such as reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). Cyclophosphamide elevated the levels of biomarker enzymes like creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB), lactate dehydrogenase (LDH), aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). Further, the cyclophosphamide treated rats showed changes in electrocardiogram (ECG) along with increased levels of cholesterol and triglycerides. Treatment with Saraca indica significantly (p < 0.05) reversed the status of cardiac biomarkers, ECG, oxidative enzymes and lipid profile in cyclophosphamide induced cardiotoxicity. Potential cardioprotective effect of Saraca indica was supported by histopathological examination that reduced severity of cellular damage of the myocardium. Conclusion: The biochemical, ECG and histopathology reports support the cardioprotective effect of Saraca indica which could be attributed to antioxidant activity. PMID:23543849

  2. Telocytes as potential targets in a cyclophosphamide-induced animal model of premature ovarian failure.

    PubMed

    Liu, Te; Wang, Suwei; Li, Qiong; Huang, Yongyi; Chen, Chuan; Zheng, Jin

    2016-09-01

    Premature ovarian failure (POF) refers to the presence of ovarian atrophic permanent amenorrhea in women under the age of 40. The pathogenesis of POF remains to be fully elucidated. Telocytes are a group of specialized cells with a small cell volume and very long cytoplasmic prolongations with dichotomous branching. Previous studies have indicated that telocytes function to support the trachea and serve as stem cell niches. Although it has been confirmed that telocytes are present in numerous organs in mammals, it remains to be determined whether they are present in ovarian tissues and whether they are involved in the development of POF. The present study used a cyclophosphamide-induced mouse model of POF. Hematoxylin and eosin staining and an enzyme‑linked immunosorbent assay revealed that cyclophosphamide induced edema and apoptosis of ovarian stromal and granulosa cells and increased atretic follicles. In addition, cyclophosphamide induced abnormal peripheral blood FSH and E2 levels in mice. Transmission electron microscopy revealed a small number of telocyte‑like cell structures in the ovarian stroma of wild‑type mice. In addition, flow cytometry and immunohistochemical staining results suggested that the number of cluster of differentiation (CD)34/platelet‑derived growth factor receptor (PDGFR)α, CD34/PDGFRβ and CD34/vimentin double‑positive cells in the ovaries of POF mice was significantly decreased compared with wild‑type mice. In conclusion, mouse ovarian tissues appear to contain telocytes, and cyclophosphamide treatment significantly reduced the number of ovarian telocytes. Therefore, telocytes may serve as a potential novel marker of POF induced by cyclophosphamide. PMID:27485835

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

    PubMed

    Murakami-Nakayama, Masahiro; Tsubota, Maho; Hiruma, Saki; Sekiguchi, Fumiko; Matsuyama, Kenji; Kimura, Takeshi; Moriyama, Masahiro; Kawabata, Atsufumi

    2015-02-01

    Cav3.2 T-type Ca(2+) 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. PMID:25727961

  4. Human metabolites and transformation products of cyclophosphamide and ifosfamide: analysis, occurrence and formation during abiotic treatments.

    PubMed

    Česen, Marjeta; Kosjek, Tina; Busetti, Francesco; Kompare, Boris; Heath, Ester

    2016-06-01

    This study describes a gas chromatography-mass spectrometry analytical method for the analysis of cytostatic cyclophosphamide (CP), ifosfamide (IF) and their selected metabolites/transformation products (TPs): carboxy-cyclophosphamide (carboxy-CP), keto-cyclophosphamide (keto-CP) and 3-dechloroethyl-ifosfamide/N-dechloroethyl-cyclophosphamide (N-decl-CP) in wastewater (WW). Keto-cyclophosphamide, CP and IF were extracted with Oasis HLB and N-decl-CP and carboxy-CP with Isolute ENV+ cartridges. Analyte derivatization was performed by silylation (metabolites/TPs) and acetylation (CP and IF). The recoveries and LOQs of the developed method were 58, 87 and 103 % and 77.7, 43.7 and 6.7 ng L(-1) for carboxy-CP, keto-CP and N-decl-CP, respectively. After validation, the analytical method was applied to hospital WW and influent and effluent samples of a receiving WW treatment plant. In hospital WW, levels up to 2690, 47.0, 13,200, 2100 and 178 ng L(-1) were detected for CP, IF, carboxy-CP, N-decl-CP and keto-CP, respectively, while in influent and effluent samples concentrations were below LOQs. The formation of TPs during abiotic treatments was also studied. Liquid chromatography-high-resolution mass spectrometry was used to identify CP and IF TPs in ultrapure water, treated with UV and UV/H2O2. UV treatment produced four CP TPs and four IF TPs, while UV/H2O2 resulted in five CPs and four IF TPs. Besides already known TPs, three novel TPs (CP-TP138a, imino-ifosfamide and IF-TP138) have been tentatively identified. In hospital WW treated by UV/O3/H2O2, none of the target metabolites/TPs resulted above LOQs. PMID:26920534

  5. Telocytes as potential targets in a cyclophosphamide-induced animal model of premature ovarian failure

    PubMed Central

    Liu, Te; Wang, Suwei; Li, Qiong; Huang, Yongyi; Chen, Chuan; Zheng, Jin

    2016-01-01

    Premature ovarian failure (POF) refers to the presence of ovarian atrophic permanent amenorrhea in women under the age of 40. The pathogenesis of POF remains to be fully elucidated. Telocytes are a group of specialized cells with a small cell volume and very long cytoplasmic prolongations with dichotomous branching. Previous studies have indicated that telocytes function to support the trachea and serve as stem cell niches. Although it has been confirmed that telocytes are present in numerous organs in mammals, it remains to be determined whether they are present in ovarian tissues and whether they are involved in the development of POF. The present study used a cyclophosphamide-induced mouse model of POF. Hematoxylin and eosin staining and an enzyme-linked immunosorbent assay revealed that cyclophosphamide induced edema and apoptosis of ovarian stromal and granulosa cells and increased atretic follicles. In addition, cyclophosphamide induced abnormal peripheral blood FSH and E2 levels in mice. Transmission electron microscopy revealed a small number of telocyte-like cell structures in the ovarian stroma of wild-type mice. In addition, flow cytometry and immunohistochemical staining results suggested that the number of cluster of differentiation (CD)34/platelet-derived growth factor receptor (PDGFR)α, CD34/PDGFRβ and CD34/vimentin double-positive cells in the ovaries of POF mice was significantly decreased compared with wild-type mice. In conclusion, mouse ovarian tissues appear to contain telocytes, and cyclophosphamide treatment significantly reduced the number of ovarian telocytes. Therefore, telocytes may serve as a potential novel marker of POF induced by cyclophosphamide. PMID:27485835

  6. Environmental Contamination with Cyclophosphamide, Ifosfamide, and Methotrexate: A Study of 51 Canadian Centres

    PubMed Central

    Janes, Alexia; Tanguay, Cynthia; Caron, Nicolas J; Bussières, Jean-François

    2015-01-01

    Background: Occupational exposure to hazardous drugs may lead to adverse reproductive effects. There is no safe exposure limit for health care professionals. Objectives: To monitor levels of cyclophosphamide, ifosfamide, and methotrexate contamination in oncology pharmacy and patient care areas in Canadian health care institutions. Methods: The study was conducted in 2014. Hospitals with at least 50 acute care beds were invited to participate. At each participating centre, 12 standardized sites (6 in pharmacy areas and 6 in patient care areas) were sampled. The samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography tandem mass spectrometry technology. The limits of detection were 0.36 pg/cm2 for cyclophosphamide, 0.95 pg/cm2 for ifosfamide, and 0.97 pg/cm2 for methotrexate. Descriptive statistical analyses were performed to determine the median, 75th percentile, and maximum levels. Results: Fifty-one hospitals participated in this descriptive study, and a total of 584 samples were quantified. Overall, 294 (50%) of the samples were positive for cyclophosphamide, 125 (21%) for ifosfamide, and 54 (9%) for methotrexate. The most frequently contaminated sampling sites in pharmacy areas were the front grille inside the hood and the floor in front of the hood and, in patient care areas, the armrest and outpatient clinic counter. The 75th percentiles for surface concentration were 10.8 pg/cm2 for cyclophosphamide, 1.59 pg/cm2 for ifosfamide, and below the limit of detection for methotrexate. Conclusions: Relative to 3 other multicentre studies conducted in Quebec over the past few years, the proportion of positive samples remained constant. Nonetheless, the 75th percentile surface concentration of antineoplastic drugs has been decreasing and seems to have reached a plateau. Local (country-specific or region-specific) and attainable goals for surface contamination with hazardous drugs should be set

  7. Cyclophosphamide-Induced Morphological Changes in Dental Root Development of ICR Mice

    PubMed Central

    Kawakami, Tomomi; Nakamura, Yuko; Karibe, Hiroyuki

    2015-01-01

    Background Survivors of childhood cancer are at risk of late dental development. Cyclophosphamide is one of the most commonly used chemotherapeutic agents against cancer in children. The aim of this study was to investigate the effects of cyclophosphamide on root formation in the molars of growing mice and to assess the morphological changes in these roots using three-dimensional structural images. Methods We treated 16 12-day-old ICR mice with cyclophosphamide (100 mg/kg, i.p.) and 16 control mice with saline. At 16, 20, 24, and 27 days of age, the mandibular left first molars were scanned using soft micro-computed tomography. After scanning, the structural indices were calculated using a three-dimensional image analysis system, and the images were subjected to three-dimensional reconstruction. The length and apical foramen area of all distal roots were assessed. Histological changes in the apical region were then assessed via hematoxylin and eosin staining. Results The mandibular molars of all experimental mice showed evidence of cytotoxic injury, which appeared in the form of anomalous root shapes. Although all roots developed further after cyclophosphamide injection, the three-dimensional structural images showed that the roots in the experimental group tended to develop more slowly and were shorter than those in the control group. At 27 days of age, the mean root length was shorter in the experimental group than in the control group. Conversely, the apical foramen of the roots in the experimental group tended to close faster than that of roots in the control group. In addition, hematoxylin and eosin staining of the distal roots in the experimental group showed increased dentin thickness in the apical region. Conclusion Our results suggest that cyclophosphamide can result in short root lengths and early apical foramen closure, eventually leading to V-shaped or thin roots. PMID:26186337

  8. Effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis in rats.

    PubMed

    Cannon, G W; McCall, S; Cole, B C; Radov, L A; Ward, J R; Griffiths, M M

    1993-03-01

    The prophylactic and therapeutic effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis (CIA) were evaluated in DA rats. Prophylactic treatment with cyclosporin A and cyclophosphamide suppressed the arthritis incidence, clinical inflammation, destructive bone changes, and development of anti-collagen antibody in DA rats subsequently injected with porcine type-II collagen. Therapeutic treatment with cyclosporin A and cyclophosphamide had a definite suppression on established CIA when started 21 days after the initial collagen injection, but the suppression was less marked than that of prophylactic treatment. Gold had no impact on CIA in DA rats when administered either prophylactically or therapeutically. PMID:8213350

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

    PubMed Central

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

    2016-01-01

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

  10. Combined thin-layer chromatography-photography-densitometry for the quantitation of cyclophosphamide and its four principal urinary metabolites.

    PubMed

    Hadidi, A H; Idle, J R

    1988-05-13

    A novel method for the quantitative determination of the anti-cancer drug cyclophosphamide and its principal urinary metabolites 4-oxocyclophosphamide, carboxyphosphamide, phosphoramide mustard and bis(2-chloroethyl)amine has been devised. The assay combines adsorption of drug-related material onto Amberlite XAD-2 and thin-layer chromatography with spot visualization using 4-(4-nitrobenzyl)pyridine, rapid photography and densitometry. The intra-assay coefficient of variation for each compound was less than 6%. The limit of detection of the assay was 1 microgram ml-1 for cyclophosphamide, phosphoramide mustard and bis(2-chloroethyl)amine and 0.5 microgram ml-1 for 4-oxocyclophosphamide and carboxyphosphamide. The method was validated for cyclophosphamide and 4-oxocyclophosphamide using gas chromatography. It is concluded that the method provides the first means of determining the full metabolic spectrum for cyclophosphamide in patients without recourse to the administration of radioisotopically labelled drug. PMID:3410892

  11. EFFECTS OF IMMUNOSUPPRESSION WITH CYCLOPHOSPHAMIDE ON ACUTE MURINE CYTOMEGALOVIRUS INFECTION AND VIRUS-AUGMENTED NATURAL KILLER CELL ACTIVITY

    EPA Science Inventory

    The effects of cyclophosphamide (CY) treatment on acute murine cytomegalovirus (MCMV) infection were studied to explore the potential usefulness of MCMV as a means of detecting immune dysfunction and to identify host defense mechanisms important for protection against MCMV.

  12. Impact of T cell chimerism on clinical outcome in 117 patients who underwent allogeneic stem cell transplantation with a busulfan-containing reduced-intensity conditioning regimen.

    PubMed

    Saito, Bungo; Fukuda, Takahiro; Yokoyama, Hiroki; Kurosawa, Saiko; Takahashi, Toshihiro; Fuji, Shigeo; Takahashi, Noriko; Tajima, Kinuko; Kim, Sung-Won; Mori, Shin-Ichiro; Tanosaki, Ryuji; Takaue, Yoichi; Heike, Yuji

    2008-10-01

    Within the concept of reduced-intensity stem cell transplantation (RIST) there is a wide range of different regimens used, and little information is available on the clinical impact of chimerism status in patients conditioned with a busulfan-containing regimen. Therefore, we retrospectively reviewed lineage-specific chimerism and the subsequent clinical outcome in 117 patients (median age, 55 years; range: 29-68) who underwent busulfan-containing RIST. The conditioning regimen consisted of busulfan (oral 8 mg/kg or i.v. 6.4 mg/kg) and fludarabine (180 mg/m(2), n = 64) or cladribine (0.66 mg/kg, n = 53), with or without 2-4 Gy total-body irridiation (TBI) (n = 26) or antihuman T-lymphocyte immunoglobulin (ATG; 5-10 mg/kg; n = 31). Chimerism was evaluated with peripheral blood samples taken on days 30, 60, and 90 after transplantation by polymerase chain reaction (PCR)-based amplification of polymorphic short tandem repeat regions. The median follow-up of surviving patients was 1039 days (153-2535). The percent donor-chimerism was significantly higher in granulocyte than T cell fraction throughout the entire course, and the median (mean) values were, respectively, 100% (96%) versus 95% (83%), 100% (98%) versus 100% (89%), and 100% (98%) versus 100% (91%) at days 30, 60, and 90 after RIST. In a multivariate analysis, having received <2 types of chemotherapy regimens before RIST was the only factor that was significantly associated with low donor T cell chimerism (<60%) at day 30 (hazard ratio [HR]: 6.1; 95% confidence interval [CI], 2.1-18.4; P < .01). The median percentage of donor T cell chimerism at day 30 was 9% (0%-63%) in 5 patients who experienced graft failure, which was significantly lower than that (97%; 15%-100%) in the rest of the patients (P < .01). No correlation was found between the kinetics of T cell chimerism and the occurrence of acute or chronic GVHD (aGVHD, cGVHD). The stem cell source and the addition of TBI or ATG were not associated with the

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

    PubMed Central

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

    2016-01-01

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

  14. Cyclophosphamide-Mediated Tumor Priming for Enhanced Delivery and Antitumor Activity of HER2-Targeted Liposomal Doxorubicin (MM-302).

    PubMed

    Geretti, Elena; Leonard, Shannon Curtis; Dumont, Nancy; Lee, Helen; Zheng, Jinzi; De Souza, Raquel; Gaddy, Daniel F; Espelin, Christopher W; Jaffray, David A; Moyo, Victor; Nielsen, Ulrik B; Wickham, Thomas J; Hendriks, Bart S

    2015-09-01

    Given the bulky nature of nanotherapeutics relative to small molecules, it is hypothesized that effective tumor delivery and penetration are critical barriers to their clinical activity. HER2-targeted PEGylated liposomal doxorubicin (MM-302, HER2-tPLD) is an antibody-liposomal drug conjugate designed to deliver doxorubicin to HER2-overexpressing cancer cells while limiting uptake into nontarget cells. In this work, we demonstrate that the administration and appropriate dose sequencing of cyclophosphamide can improve subsequent MM-302 delivery and enhance antitumor activity in preclinical models without negatively affecting nontarget tissues, such as the heart and skin. We demonstrate that this effect is critically dependent on the timing of cyclophosphamide administration. Furthermore, the effect was found to be unique to cyclophosphamide and related analogues, and not shared by other agents, such as taxanes or eribulin, under the conditions examined. Analysis of the cyclophosphamide-treated tumors suggests that the mechanism for improved MM-302 delivery involves the induction of tumor cell apoptosis, reduction of overall tumor cell density, substantial lowering of interstitial fluid pressure, and increasing vascular perfusion. The novel dosing strategy for cyclophosphamide described herein is readily translatable to standard clinical regimens, represents a potentially significant advance in addressing the drug delivery challenge, and may have broad applicability for nanomedicines. This work formed the basis for clinical evaluation of cyclophosphamide for improving liposome deposition as part of an ongoing phase I clinical trial of MM-302 in HER2-positive metastatic breast cancer. PMID:26162690

  15. Successful treatment of refractory peripheral T-cell lymphoma with a combination of fludarabine and cyclophosphamide.

    PubMed

    Yamaguchi, Masaki; Kotani, Takeharu; Nakamura, Yoshihisa; Ueda, Mikio

    2006-06-01

    We report a case of refractory peripheral T-cell lymphoma (PTCL) successfully treated with a combination of fludarabine and cyclophosphamide (FLU/CY). A 68-year-old man with concurrent PTCL and diffuse large B-cell lymphoma was treated effectively with 3-course CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy, but PTCL relapse occurred and was resistant to ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) therapy. FLU/CY therapy led to complete remission, which was maintained for almost 14 months after a single course. We concluded that a FLU/CY regimen may be useful for attaining long-term remission in patients with refractory relapsed PTCL and should therefore be considered a valuable treatment choice. PMID:16787878

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

    PubMed

    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. PMID:21117458

  17. Chronodependent effect of interleukin-2 on mouse spleen cells in the model of cyclophosphamide immunosuppression.

    PubMed

    Shurlygina, A V; Mel'nikova, E V; Trufakin, V A

    2015-02-01

    We studied the chronodependent effect of IL-2 in the experimental model of immunodeficiency, cyclophosphamide-induced immunosuppression in mice. IL-2 in a dose of 100 U/ mouse was administered at 10.00 and 16.00 for 3 days after injection of cyclophosphamide. In contrast to the morning treatment with the cytokine, evening administration produced antiapoptotic effect on splenocytes and stimulated proliferation to a greater extent. This was accompanied by an increase in the number of CD4(+), CD25(+) and CD4(+)25(+) cells in the spleen to a level of intact mice. More pronounced effect of the evening mode of IL-2 administration on the proliferation and subpopulation composition of mouse spleen cells in the studied model can be associated with high blood level of CD25(+) cells at this time of the day. PMID:25708328

  18. Irradiation- and cyclophosphamide-induced alterations in Syrian hamster T-cell population activity

    SciTech Connect

    Bagasra, O.; Tabor, D.

    1986-02-01

    The treatment of hamsters with either irradiation (IR) or cyclophosphamide (CYP) markedly alters select aspects of their cellular immune functions in a dose-related manner. One mechanism that may be responsible for this activity appears to be the dimunition of a T-lymphocyte subpopulation that exerts suppressive influence upon the B-lymphocyte reactivity toward antigens. This study shows that in the hamster, immune susceptibility is affected by the magnitude and orientation of these agents (ie, IR, CYP) as they temporally relate to immunization and/or challenge with the antigen. Moreover, there is evidence that T-independent as well as T-dependent responses are affected by these treatments. Therefore, cyclophosphamide and irradiation modalities can be employed to modify the cellular immune responses in the hamster.

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

    PubMed Central

    Anwer, Faiz; Yun, Seongseok; Nair, Anju; Ahmad, Yusuf; Krishnadashan, Ravitharan; Deeg, H. Joachim

    2015-01-01

    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. PMID:26180646

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

    PubMed

    Anwer, Faiz; Yun, Seongseok; Nair, Anju; Ahmad, Yusuf; Krishnadashan, Ravitharan; Deeg, H Joachim

    2015-01-01

    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. PMID:26180646

  1. Exclusion of an interactive effect of combined x-irradiation and activated cyclophosphamide in tissue culture

    SciTech Connect

    Byfield, J.E.; Lynch, M.; Kulhanian, F.

    1986-08-01

    The effect of Cyclophosphamide (CY) on the X ray survival of clonogenic tumor cells has been studied in vitro. Two activated derivatives of the drug, Peroxycyclophosphamide and Hydroperoxycyclophosphamide, were employed. Two cell lines, repair-competent human HeLa cells and the repair-deficient rat REQ line, were investigated. Neither form of CY had any effect on the X ray survival curve of either cell line, indicating that any interaction anticipated in vivo could be expected to be additive.

  2. Oxidation kinetics of cyclophosphamide and methotrexate by ozone in drinking water.

    PubMed

    Garcia-Ac, Araceli; Broséus, Romain; Vincent, Simon; Barbeau, Benoit; Prévost, Michèle; Sauvé, Sébastien

    2010-05-01

    This study investigates the aqueous degradation by ozone of two target cytostatic drugs, cyclophosphamide and methotrexate. A column switching technique for on-line solid phase extraction (SPE) coupled to electro-spray ionization-tandem mass spectrometry (LC-ESI-MS/MS) was used for the simultaneous detection of the trace contaminants. The second-order kinetic rate constants for the reaction of cyclophosphamide with molecular ozone and hydroxyl radicals were determined in bench-scale experiments at pH 8.10. The molecular ozone oxidation kinetics was studied in buffered ultrapure water and compared to the oxidation kinetics in natural water from a municipal drinking water treatment plant in the province of Quebec (Canada). For cyclophosphamide, the degradation rate constant with molecular ozone in ultrapure water was low (k(O3)=3.3+/-0.2M(-1)s(-1)) and the extent of oxidation was linearly correlated to the ozone exposure. The impact of water quality matrix on oxidation efficacy was not significant during direct ozone reaction (k(O3) =2.9+/-0.3M(-1)s(-1)). The rate constant with hydroxyl radicals was higher at 2.0 x 10(9) M(-1)s(-1). Methotrexate reacted quickly with molecular ozone at dosages typically applied in drinking water treatment (k(O3)>3.6 x 10(3)M(-1)s(-1)). Overall, the results confirmed that organic compounds reactivity with ozone was dependent of their chemical structure. Ozone was very effective against methotrexate but high oxidant concentration x contact time (CT) values were required to completely remove cyclophosphamide from drinking water. Further studies should be conducted in order to identify the ozonation by-products and explore the impact of ozone on their degradation and toxicity. PMID:20403630

  3. Design, synthesis, and evaluation of new cyclophosphamide-based anticancer prodrugs

    SciTech Connect

    Moon, Ki-Young.

    1993-01-01

    Cyclophosphamide (CP,1) is a prodrug that is activated by hepatic microsomal mixed-function oxidase (MFO) catalyzed C[sub 4]-hydroxylation. The resulting 4-hydroxycyclophosphamide (4-OH-CP) undergoes ring opening to aldophosphamide (Aldo), followed by generation of cytotoxic phosphoramide mustard (PDA,2) and acrolein by [beta]-elimination. The cytotoxic activity of CP is attributed to the aziridinium ion species derived from PDA that cross-links interstrand DNA. The aim of this research is to design, synthesize, and evaluate new cyclophosphamide-based alkylating agents to achieve improved therapeutic efficacy against neoplastic cells. Benzyl phosphoramide mustard (Benzyl PDA,4), 2.4-difluorobenzyl phosphoramide mustard (2,4-Difluorobenzyl PDA,5) and methyl phosphoramide mustard (Methyl PDA,6) were examined as lipophilic, chemically stable prodrugs of PDA (2). These phosphorodiamidic esters were designed to undergo biotransformation by hepatic microsomal enzymes to produce 2 without generation of acrolein and to be active against CP-resistant tumor cells. Several N-methyl-4-(alkylthio)cyclophosphamide derivatives were synthesized and examined as chemically stable, biooxidative prodrugs of 4-OH-CP, the activated species of CP. All of the prodrugs underwent N-demethylation in a time-dependent manner when incubated with rat hepatic microsomes, which resulted in formation of formaldehyde as well as alkylating species. Among the prodrugs, N-methyl-4-(diethyldithiocarbamoyl)cyclophosphamide (N-CH[sub 3]-4-DDTC-CP,15) showed exceptional in vitro cytotoxicity against 3T3 cells as well as against a panel of human tumor cell lines, with a particular sensitivity to leukemia and small cell lung cancer cell lines. Preliminary in vivo antitumor evaluation against L1210 leukemia in mice showed that all of the prodrugs were active.

  4. Lesson of the month: selective use of cyclophosphamide in pregnancy for severe autoimmune respiratory disease.

    PubMed

    Nelson-Piercy, Catherine; Agarwal, Sangita; Lams, Boris

    2016-07-01

    We present the cases of two pregnant women who developed severe respiratory compromise in mid pregnancy, one due to rapidly progressive interstitial lung disease associated with mixed connective tissue disease and one secondary to diffuse alveolar haemorrhage due to antiglomerular basement membrane disease. Both were treated with high-dose steroids followed by pulsed intravenous cyclophosphamide. Both women went onto have live births although one baby was growth restricted and preterm. Neither baby had any evidence of congenital abnormalities. PMID:27033023

  5. Low-dose cyclophosphamide effectively mobilizes peripheral blood stem cells in patients with autoimmune disease.

    PubMed

    Blank, Norbert; Lisenko, Katharina; Pavel, Petra; Bruckner, Thomas; Ho, Anthony D; Wuchter, Patrick

    2016-07-01

    For patients with severe and refractory autoimmune diseases, high-dose chemotherapy and autologous hematopoietic stem cell transplantation has been established as a considerable therapeutic option in recent years. In this retrospective single-center analysis, we assessed the feasibility and efficacy of peripheral blood stem cells (PBSC) mobilization and collection in 35 patients with refractory autoimmune disease (AID). The mobilization data of 15 patients with systemic sclerosis (SSc), 11 patients with multiple sclerosis (MS), and 9 patients with other AID were analyzed. Stem cell mobilization with cyclophosphamide chemotherapy 2 × 2 g/m(2) (n = 16) or 1 × 2 g/m(2) (n = 17) and G-CSF followed by PBSC collection was performed between 1999 and 2015. Leukapheresis was performed in 16 inpatients and 19 outpatients. All patients reached their collection goal and no collection failures were observed. The median PBSC collection result was 12.2 (SSc), 8.0 (MS), and 8.2 (other AID) × 10(6) CD34+ cells/kg, respectively. Twenty-five of 35 (71%) patients achieved a sufficient collection with one leukapheresis session, while 6 patients (17%) required two and 4 patients (11%) required three or more leukapheresis sessions. No correlation of the collected PBSC number was observed regarding age, body weight, diagnosis, disease duration, skin sclerosis, or previous cyclophosphamide. Mobilization chemotherapy with cyclophosphamide 2 × 2 g/m(2) and 1 × 2 g/m(2) delivered comparable mobilization results with leukapheresis on day 13 or 14. In summary, we demonstrate that PBSC collection is safe and feasible in patients with AID. Mobilization chemotherapy with cyclophosphamide 1 × 2 g/m(2) and 2 × 2 g/m(2) is equally effective in those patients. PMID:26381040

  6. Cyclophosphamide-induced apoptosis in COV434 human granulosa cells involves oxidative stress and glutathione depletion.

    PubMed

    Tsai-Turton, Miyun; Luong, Brian T; Tan, Youming; Luderer, Ulrike

    2007-07-01

    The anticancer drug cyclophosphamide induces granulosa cell apoptosis and is detoxified by glutathione (GSH) conjugation. We previously showed that both cyclophosphamide treatment and GSH depletion induced granulosa cell apoptosis in rats, but the role of GSH in apoptosis in human ovarian cells has not been studied. Using the COV434 human granulosa cell line, we tested the hypotheses that (1) GSH depletion or treatment with 4-hydroperoxycyclophosphamide (4HC), a preactivated form of cyclophosphamide, induces apoptosis, (2) GSH depletion potentiates 4HC-induced apoptosis, and (3) 4HC-induced apoptosis is mediated by GSH depletion and oxidative stress. Cells were treated with buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, with or without follicle stimulating hormone (FSH) or serum. A significant increase in the number of apoptotic cells, assessed by terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick-end labeling (TUNEL) and Hoechst 33342 staining, occurred with BSO treatment. Treatment with 4HC dose-dependently induced apoptosis by TUNEL, Hoechst staining, and caspase 3 activation. Treatment with 4HC caused an increase in reactive oxygen species generation, measured by dichlorofluorescein fluorescence, oxidative DNA damage, measured by 8-hydroxyguanosine immunostaining, and an oxidation of the redox potential for the oxidized glutathione/reduced glutathione couple. Total intracellular GSH declined after 4HC treatment, preceding the onset of cell death. Treatment with antioxidants inhibited 4HC-induced apoptosis. Combined treatment with BSO and 4HC caused greater induction of apoptosis than either treatment alone. These findings are consistent with roles for oxidative stress and GSH depletion in mediating the induction of apoptosis in COV434 cells by cyclophosphamide. PMID:17434952

  7. Pharmacodynamic Interaction of Green Tea Extract with Hydrochlorothiazide against Cyclophosphamide-Induced Myocardial Damage

    PubMed Central

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

    2014-01-01

    Objective: Treatment of ischemic hypertensive patients with hydrochlorothiazide can precipitate cardiac arrhythmias. Green tea by virtue of its antioxidant potential is responsible for cardio-protective activity. The present study was undertaken to evaluate the pharmacodynamic interaction of green tea extract with hydrochlorothiazide against cyclophosphamide-induced myocardial toxicity. Materials and Methods: Rats were treated with high (500 mg/kg, p.o.) and low (100 mg/kg, p.o.) dose of green tea extract in alone and interactive groups for 10 days. Standard, high, and low dose of interactive groups received hydrochlorothiazide (10 mg/kg, p.o.) for last 7 days. Apart from normal control, all other groups were subjected to cyclophosphamide (200 mg/kg, i.p.) toxicity on day first and the effects of different treatments were evaluated by changes in electrocardiographic parameters, serum biomarkers, and tissue antioxidant levels. Apart from that, lipid profile and histological studies were also carried out. Results: Compared to cyclophosphamide control group, both high and low dose of green tea exhibited significant decrease in serum biomarkers and increase in tissue antioxidant levels. Green tea treatment was also responsible for significant improvement in echocardiography (ECG) parameter, lipid profile, and histological score. Incorporation of high and low dose of green tea with hydrochlorothiazide-exhibited significant protection compared to hydrochlorothiazide-alone-treated group. Conclusion: The present findings clearly suggested that green tea extract dose dependently reduces cyclophosphamide-induced myocardial toxicity. Green tea when combined with hydrochlorothiazide can reduce the associated side effects and exhibits myocardial protection. PMID:25253931

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

    PubMed Central

    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

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

    PubMed

    Chen, Xin; Yang, Yuan; Zhou, Qiong; Weiss, Jonathan M; Howard, Olamae Zack; McPherson, John M; Wakefield, Lalage M; Oppenheim, Joost J

    2014-01-01

    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. PMID:24416401

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

    NASA Astrophysics Data System (ADS)

    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.

  11. Curcumin Enhanced Busulfan-Induced Apoptosis through Downregulating the Expression of Survivin in Leukemia Stem-Like KG1a Cells.

    PubMed

    Weng, Guangyang; Zeng, Yingjian; Huang, Jingya; Fan, Jiaxin; Guo, Kunyuan

    2015-01-01

    Leukemia relapse and nonrecurrence mortality (NRM) due to leukemia stem cells (LSCs) represent major problems following hematopoietic stem cell transplantation (HSCT). To eliminate LSCs, the sensitivity of LSCs to chemotherapeutic agents used in conditioning regimens should be enhanced. Curcumin (CUR) has received considerable attention as a result of its anticancer activity in leukemia and solid tumors. In this study, we investigated the cytotoxic effects and underlying mechanisms in leukemia stem-like KG1a cells exposed to busulfan (BUS) and CUR, either alone or in combination. KG1a cells exhibiting BUS-resistance demonstrated by MTT and annexin V/propidium iodide (PI) assays, compared with HL-60 cells. CUR induced cell growth inhibition and apoptosis in KG1a cells. Apoptosis of KG1a cells was significantly enhanced by treatment with CUR+BUS, compared with either agent alone. CUR synergistically enhanced the cytotoxic effect of BUS. Seven apoptosis-related proteins were modulated in CUR- and CUR+BUS-treated cells analyzed by proteins array analysis. Importantly, the antiapoptosis protein survivin was significantly downregulated, especially in combination group. Suppression of survivin with specific inhibitor YM155 significantly increased the susceptibility of KG1a cells to BUS. These results demonstrated that CUR could increase the sensitivity of leukemia stem-like KG1a cells to BUS by downregulating the expression of survivin. PMID:26557682

  12. Curcumin Enhanced Busulfan-Induced Apoptosis through Downregulating the Expression of Survivin in Leukemia Stem-Like KG1a Cells

    PubMed Central

    Weng, Guangyang; Zeng, Yingjian; Huang, Jingya; Fan, Jiaxin; Guo, Kunyuan

    2015-01-01

    Leukemia relapse and nonrecurrence mortality (NRM) due to leukemia stem cells (LSCs) represent major problems following hematopoietic stem cell transplantation (HSCT). To eliminate LSCs, the sensitivity of LSCs to chemotherapeutic agents used in conditioning regimens should be enhanced. Curcumin (CUR) has received considerable attention as a result of its anticancer activity in leukemia and solid tumors. In this study, we investigated the cytotoxic effects and underlying mechanisms in leukemia stem-like KG1a cells exposed to busulfan (BUS) and CUR, either alone or in combination. KG1a cells exhibiting BUS-resistance demonstrated by MTT and annexin V/propidium iodide (PI) assays, compared with HL-60 cells. CUR induced cell growth inhibition and apoptosis in KG1a cells. Apoptosis of KG1a cells was significantly enhanced by treatment with CUR+BUS, compared with either agent alone. CUR synergistically enhanced the cytotoxic effect of BUS. Seven apoptosis-related proteins were modulated in CUR- and CUR+BUS-treated cells analyzed by proteins array analysis. Importantly, the antiapoptosis protein survivin was significantly downregulated, especially in combination group. Suppression of survivin with specific inhibitor YM155 significantly increased the susceptibility of KG1a cells to BUS. These results demonstrated that CUR could increase the sensitivity of leukemia stem-like KG1a cells to BUS by downregulating the expression of survivin. PMID:26557682

  13. Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients.

    PubMed

    Ansari, M; Huezo-Diaz, P; Rezgui, M A; Marktel, S; Duval, M; Bittencourt, H; Cappelli, B; Krajinovic, M

    2016-03-01

    Hematopoietic stem-cell transplantation (HSCT) is currently the only curative therapeutic option for the treatment of thalassemia. In spite of the high cure rate, HSCT can lead to life-threatening adverse events in some patients. Busulfan (Bu) is a key component of the conditioning regimen prior to HSCT. Inter-individual differences in Bu pharmacokinetics (PK) are hypothesized to influence Bu efficacy and toxicity. Since Bu is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship of GSTA1 and GSTM1 genotypes with first-dose PK and HSCT outcomes in 44 children with thalassemia intermedia and thalassemia major. All children received a myeloablative conditioning regimen with IV Bu. Association analysis revealed a relationship between GSTA169C>T (or haplotype *A/*B) and first Bu dose PK that was dependent on sex and Pesaro risk classification (PRC). Among female patients and patients with PRC I-II, homozygous individuals for the GSTA1T-69 allele defining haplotype *B, had higher Bu exposure and lower clearance (P⩽0.01). Association with HSCT outcomes showed that patients with the GSTM1 null genotypes had higher occurrence of regimen-related toxicity (P=0.01). These results suggest that GST genotypes could be useful to tailor the first Bu dose accordingly to improve HSCT outcome. PMID:26691424

  14. Tandem high-dose chemotherapy with thiotepa and busulfan-melphalan and autologous stem cell transplantation in very high-risk neuroblastoma patients.

    PubMed

    Pasqualini, C; Dufour, C; Goma, G; Raquin, M-A; Lapierre, V; Valteau-Couanet, D

    2016-02-01

    High-risk neuroblastoma is characterised by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). We report the results of an intensified high-dose chemotherapy (HDC) strategy to improve the prognosis of VHR patients. This strategy was based on tandem HDC with thiotepa and busulfan-melphalan (Bu-Mel) followed by autologous stem cell transplantation (ASCT). All data were prospectively recorded in the Gustave Roussy Paediatric ASCT database. From April 2004 to August 2011, 26 patients were eligible for tandem HDC. The median age at diagnosis was 4.4 years (1-15.9). All patients had metastatic disease. MYCN was amplified in 5/26 tumours. Despite the cumulative toxicity of alkylating agents, the toxicity of the intensified HDC strategy was manageable. Thiotepa-related toxicity was mainly digestive, whereas sinusoidal obstruction syndrome was the main toxicity observed after Bu-Mel. The 3-year event-free survival of this cohort was 37.3% (21.3-56.7). This strategy will be compared with combined (131)I-mIBG/Bu-Mel in the upcoming SIOPEN VHR Neuroblastoma Protocol. PMID:26524264

  15. Correlation of somatic mutations with outcome after FLAMSA-busulfan sequential conditioning and allogeneic stem cell transplantation in patients with myelodysplastic syndromes.

    PubMed

    Christopeit, Maximilian; Badbaran, Anita; Alawi, Malik; Zabelina, Tatjana; Zeck, Gaby; Wolschke, Christine; Ayuk, Francis; Kröger, Nicolaus

    2016-09-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for myelodysplastic syndromes (MDS). Little is known about the prognostic impact of mutations, for example, in TP53 specifically after allo-HSCT. We here describe the prognostic impact of mutations in a panel of 19 genes analyzed by amplicon-based next-generation-sequencing in a uniformly treated patient cohort. Sixty-two patients with a median age of 61 yr suffered from MDS with 0-20% bone marrow blasts. International Prognostic Score was intermediate 1 (15%) and higher (79%). Conditioning uniformly was performed using a sequential approach in which FLAMSA chemotherapy was followed by Busulfan-based conditioning. Patients mostly were transplanted from an unrelated donor (77%), and 36% of patients received a graft from a mismatched donor. Median number of mutations was 2 (range 0-6). RUNX1, GATA2, TET2, and CEBPA were the genes most frequently found mutated. TP53, a factor previously reported to confer adverse prognostic impact after allogeneic stem cell transplantation, was mutated in samples from eight patients, one of which showed a silent mutation. With an estimated 5-yr overall/disease-free survival of 48 ± 7%/41 ± 7%, none of the mutations analyzed showed a prognostic impact in this analysis of the largest uniformly treated cohort thus far. This especially holds true for patients with a mutation in TP53. PMID:26680262

  16. Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients

    PubMed Central

    Ansari, M; Huezo-Diaz, P; Rezgui, M A; Marktel, S; Duval, M; Bittencourt, H; Cappelli, B; Krajinovic, M

    2016-01-01

    Hematopoietic stem-cell transplantation (HSCT) is currently the only curative therapeutic option for the treatment of thalassemia. In spite of the high cure rate, HSCT can lead to life-threatening adverse events in some patients. Busulfan (Bu) is a key component of the conditioning regimen prior to HSCT. Inter-individual differences in Bu pharmacokinetics (PK) are hypothesized to influence Bu efficacy and toxicity. Since Bu is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship of GSTA1 and GSTM1 genotypes with first-dose PK and HSCT outcomes in 44 children with thalassemia intermedia and thalassemia major. All children received a myeloablative conditioning regimen with IV Bu. Association analysis revealed a relationship between GSTA169C>T (or haplotype *A/*B) and first Bu dose PK that was dependent on sex and Pesaro risk classification (PRC). Among female patients and patients with PRC I–II, homozygous individuals for the GSTA1T−69 allele defining haplotype *B, had higher Bu exposure and lower clearance (P⩽0.01). Association with HSCT outcomes showed that patients with the GSTM1 null genotypes had higher occurrence of regimen-related toxicity (P=0.01). These results suggest that GST genotypes could be useful to tailor the first Bu dose accordingly to improve HSCT outcome. PMID:26691424

  17. Cisplatin-MECY (methotrexate-leucovorin rescue plus cyclophosphamide) versus cisplatin-CHAD (cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin) as initial chemotherapy in stage III-IV ovarian adenocarcinoma.

    PubMed

    Barlow, J J; Lele, S B

    1984-12-01

    Thirty-three patients with advanced-stage ovarian adenocarcinomas, with no prior chemotherapy, were treated with weekly cisplatin (DDP) for four courses followed by five monthly courses of one of two randomly assigned multidrug combinations. These combinations were high-dose methotrexate-leucovorin plus cyclophosphamide (MECY) or cyclophosphamide, hexamethylmelamine, doxorubicin, and DDP (CHAD). Patients with no clinically measurable disease after 6 months of therapy were evaluated by laparoscopy. In the absence of disease progression at the time of the laparoscopy the study design called for a repeat cycle of four weekly DDP courses and another five monthly courses of the assigned multidrug combination. All patients with no evidence of disease after 1 year of treatment had a second-look laparoscopy which, if negative, was followed by a second-look laparotomy. This report includes all of the consecutively entered patients observed for a minimum of 1 year or to death. DDP-MECY and DDP-CHAD were similarly active for overall response rates and complete response rates according to laparoscopic criteria. However, DDP-MECY had a statistically significantly lower relapse rate (P less than 0.02) and a statistically significantly higher negative second-look laparotomy rate than did DDP-CHAD. Using all entered patients, with no exclusions from analysis, eight of 17 patients (47%) treated with DDP-MECY had negative second-looks after 1 year of treatment. This compares with one of 16 (6%) negative second-looks in patients treated with DDP-CHAD (P less than 0.02). The high negative second-look rate with DDP-MECY is exciting. Positive cytologic washings at the 6-month laparoscopic evaluation were highly predictive that residual disease would be found at the 1-year second-look surgery. Only one patient with positive peritoneal cytology after 6 months of treatment was found to have a negative second-look after 1 year of therapy. PMID:6439408

  18. Inhibitors of melanogenesis increase toxicity of cyclophosphamide and lymphocytes against melanoma cells.

    PubMed

    Slominski, Andrzej; Zbytek, Blazej; Slominski, Radomir

    2009-03-15

    High mortality rate for metastatic melanoma is related to its resistant to the current methods of therapy. Melanogenesis is a metabolic pathway characteristic for normal and malignant melanocytes that can affect the behavior of melanoma cells or its surrounding environment. Human melanoma cells in which production of melanin pigment is dependent on tyrosine levels in medium were used for experiments. Peripheral blood mononuclear cells were derived from the buffy coats purchased from Lifeblood Biological Services. Cell pigmentation was evaluated macroscopically, and tyrosinase activity was measured spectrophotometrically. Cell proliferation and viability were measured using lactate dehydrogenase release MTT, [(3)H]-thymidine incorporation and DNA content analyses, and gene expression was measured by real time RT-PCR. Pigmented melanoma cells were significantly less sensitive to cyclophosphamide and to killing action of IL-2-activated peripheral blood lymphocytes. The inhibition of melanogenesis by either blocking tyrosinase catalytic site or chelating copper ions sensitized melanoma cells towards cytotoxic action of cyclophosphamide, and amplified immunotoxic activities of IL-2 activated lymphocytes. Exogenous L-DOPA inhibited lymphocyte proliferation producing the cell cycle arrest in G1/0 and dramatically inhibited the production of IL-1beta, TNF-alpha, IL-6 and IL-10. Thus, the active melanogenesis could not only impair the cytotoxic action of cyclophosphamid but also has potent immunosuppressive properties. This resistance to a chemotherapeutic agent or immunotoxic activity of lymphocytes could be reverted by the action of tyrosinase inhibitors. Thus, the inhibition of melanogenesis might represent a valid therapeutic target for the management of advanced melanotic melanomas. PMID:19085934

  19. Natural cell-mediated cytotoxicity against Candida albicans induced by cyclophosphamide: nature of the in vitro cytotoxic effector.

    PubMed Central

    Baccarini, M; Bistoni, F; Puccetti, P; Garaci, E

    1983-01-01

    We have recently reported the in vivo modulation of resistance to experimental Candida albicans infection by cyclophosphamide (150 mg/kg intraperitoneally) in mice and have shown that increased resistance to the microbial challenge occurs 12 to 21 days after treatment with the drug (Bistoni et al., Infect. Immun. 40: 46-55, 1983). The event is accompanied by the appearance of a highly candidacidal cell population in the spleen and the activation of a subpopulation of natural cytotoxic effectors reactive in vitro against YAC-1 tumor cells. We now provide evidence that these anti-YAC-1 cytotoxic effectors are clearly distinct from the cyclophosphamide-induced candidacidal effectors, which seem to belong to a macrophage-monocyte lineage. The enhanced cytotoxic activity induced by cyclophosphamide was not restricted to C. albicans but was also exerted against a panel of Candida strains. PMID:6352489

  20. The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up.

    PubMed Central

    Baltus, J A; Boersma, J W; Hartman, A P; Vandenbroucke, J P

    1983-01-01

    In a retrospective follow-up we compared the incidence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide with that in another group of patients with rheumatoid arthritis and also with the incidence of malignancies in the general population. Among 81 patients treated with cyclophosphamide in the past decade 15 malignancies occurred. This was 4.1 times the expected number obtained from a closely matched control group of patients with rheumatoid arthritis not treated with cytotoxic drugs (95% confidence interval 1.5 to 19.0), and 3.7 times the expected number calculated from general population rates (95% confidence interval 2.1 to 5.9). The increase in haematological and lymphoreticular malignancies was specially notable. The data also indicate that the development of malignancies after the start of cyclophosphamide therapy necessitates a certain induction time and that it is to some extent dose-dependent. PMID:6882031

  1. A randomized trial of plasmapheresis and subsequent pulse cyclophosphamide in severe lupus: design of the LPSG trial.

    PubMed

    Euler, H H; Schroeder, J O; Zeuner, R A; Teske, E

    1991-10-01

    A group of clinics cooperating as the Lupus Plasmapheresis Study Group (LPSG) is starting an international multicenter study of the treatment of severe systemic lupus erythematosus. The primary goal of this randomized and prospective trial is to establish whether treatment with plasmapheresis and subsequent pulse cyclophosphamide improves the outcome compared to treatment with pulse cyclophosphamide alone. The underlying rationale assumes that plasmapheresis: a) eliminates pathogenic autoantibodies and immune complexes and b) induces a compensatory activation of pathogenic lymphocyte clones through a feed-back between circulating antibodies and their respective antibody-producing clones. Synchronization of plasmapheresis with subsequent pulse cyclophosphamide should enhance the deletion of pathogenic clones during the period of greatest vulnerability. This overview reviews the first results of treatment approaches based on this concept and summarizes the design of the LPSG trial. PMID:1748532

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

    PubMed Central

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

    2016-01-01

    Propolis is a mixture having hundreds of polyphenols including caffeic acid phenethyl ester (CAPE). They have been using in several medical conditions/diseases in both in vitro and in vivo experimental setup. Cyclophosphamide (CP) has been used to treat a broad of malignancies including Hodgkin’s and non-Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, Ewing’s sarcoma, breast cancer, testicular cancer, etc. It may cause several side effects after treatment. In this mini review, the protective effects of propolis and CAPE were compared each other in terms of effectiveness against CP-induced injuries. PMID:27069732

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

    PubMed

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

    2016-01-01

    Propolis is a mixture having hundreds of polyphenols including caffeic acid phenethyl ester (CAPE). They have been using in several medical conditions/diseases in both in vitro and in vivo experimental setup. Cyclophosphamide (CP) has been used to treat a broad of malignancies including Hodgkin's and non-Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, Ewing's sarcoma, breast cancer, testicular cancer, etc. It may cause several side effects after treatment. In this mini review, the protective effects of propolis and CAPE were compared each other in terms of effectiveness against CP-induced injuries. PMID:27069732

  4. 4-Aminoantipyrine reduces toxic and genotoxic effects of doxorubicin, cisplatin, and cyclophosphamide in male mice.

    PubMed

    Berno, Claudia Rodrigues; Rós, Barbara de Toledo; da Silveira, Ingridhy Ostaciana Maia Freitas; Coelho, Henrique Rodrigues; Antoniolli, Andréia Conceição Milan Brochado; Beatriz, Adilson; de Lima, Dênis Pires; Monreal, Antônio Carlos Duenhas; Sousa, Fabricio Garmus; da Silva Gomes, Roberto; Oliveira, Rodrigo Juliano

    2016-07-01

    The analgesic drug dipyrone is used to treat side effects (including pain and fever) of cancer chemotherapeutic agents. Dipyrone is metabolized to 4-aminoantipyrine (4-AA), a PGE2-dependent blocker and inhibitor of cyclooxygenase (COX). We evaluated the genotoxic, mutagenic, apoptotic, and immunomodulatory activities of 4-AA in vivo and the effects of its combination with the antineoplastic drugs doxorubicin, cisplatin, and cyclophosphamide. 4-AA did not cause genotoxic/mutagenic damage, splenic phagocytosis, or leukocyte alterations. However, when combined with the antineoplastic agents, 4-AA decreased their genotoxic, mutagenic, apoptotic, and phagocytic effects. These results suggest that 4-AA might interfere with DNA damage-mediated chemotherapy. PMID:27402479

  5. Ecotoxicity and genotoxicity of cyclophosphamide, ifosfamide, their metabolites/transformation products and their mixtures.

    PubMed

    Česen, Marjeta; Eleršek, Tina; Novak, Matjaž; Žegura, Bojana; Kosjek, Tina; Filipič, Metka; Heath, Ester

    2016-03-01

    Cyclophosphamide (CP) and ifosfamide (IF) are commonly used cytostatic drugs that repress cell division by interaction with DNA. The present study investigates the ecotoxicity and genotoxicity of CP, IF, their human metabolites/transformation products (TPs) carboxy-cyclophosphamide (CPCOOH), keto-cyclophosphamide (ketoCP) and N-dechloroethyl-cyclophosphamide (NdCP) as individual compounds and as mixture. The two parent compounds (CP and IF), at concentrations up to 320 mg L(-1), were non-toxic towards the alga Pseudokirchneriella subcapitata and cyanobacterium Synecococcus leopoliensis. Further ecotoxicity studies of metabolites/TPs and a mixture of parent compounds and metabolites/TPs performed in cyanobacteria S. leopoliensis, showed that only CPCOOH (EC50 = 17.1 mg L(-1)) was toxic. The measured toxicity (EC50 = 11.5 mg L(-1)) of the mixture was lower from the toxicity predicted by concentration addition model (EC50 = 21.1 mg L(-1)) indicating potentiating effects of the CPCOOH toxicity. The SOS/umuC assay with Salmonella typhimurium revealed genotoxic activity of CP, CPCOOH and the mixture in the presence of S9 metabolic activation. Only CPCOOH was genotoxic also in the absence of metabolic activation indicating that this compound is a direct acting genotoxin. This finding is of particular importance as in the environment such compounds can directly affect DNA of non-target organisms and also explains toxicity of CPCOOH against cyanobacteria S. leopoliensis. The degradation study with UV irradiation of samples containing CP and IF showed efficient degradation of both compounds and remained non-toxic towards S. leopoliensis, suggesting that no stable TPs with adverse effects were formed. To our knowledge, this is the first study describing the ecotoxicity and genotoxicity of the commonly used cytostatics CP and IF, their known metabolites/TPs and their mixture. The results indicate the importance of toxicological evaluation and monitoring of

  6. A feasibility study of accelerated polychemotherapy with cisplatin, epidoxorubicin and cyclophosphamide (PEC) in advanced ovarian cancer.

    PubMed Central

    Pronzato, P.; Bertelli, G.; Vigani, A.; Vaira, F.

    1996-01-01

    We have evaluated the feasibility of an increase in dose intensity of the cisplatin, epidoxorubicin and cyclophosphamide (PEC) regimen, with granulocyte colony-stimulating factor (G-CSF) support, in 22 patients with advanced ovarian cancer. Twenty-one patients (95.4%) received six cycles of treatment: of these, 13 (61.9%) were also able to repeat cycles every 14 days as planned. Marrow toxicity was similar to that observed during conventional treatments. No severe mucositis or thrombocytopenia was observed. A clinical complete response was observed in 9 out of 16 evaluable patients (56.2%). PMID:8645591

  7. Cyclophosphamide in systemic sclerosis: still in search of a 'real life' scenario

    PubMed Central

    Miniati, Irene; Valentini, Gabriele; Cerinic, Marco Matucci

    2009-01-01

    In systemic sclerosis (SSc), there is no proven treatment to prevent disease progression. In a recent meta-analysis of three randomised controlled trials (RCTs) and six open prospective studies on cyclophosphamide (CYC), no significant changes in lung function were observed. However, CYC is associated with an improvement of Mahler's dyspnea index, short form-36 (physical and mental domains), and health-related quality of life, contributing to the amelioration of patients' functional status. Further RCTs on early SSc are needed to assess the real efficacy of CYC in inducing remission and increasing survival. PMID:19226435

  8. Apoptosis and proliferation (PCNA labelling) in CML--a comparative immunohistological study on bone marrow biopsies following interferon and busulfan therapy.

    PubMed

    Thiele, J; Zirbes, T K; Lorenzen, J; Kvasnicka, H M; Dresbach, S; Manich, B; Leder, L D; Niederle, N; Diehl, V; Fischer, R

    1997-03-01

    A comparative morphometric analysis was performed on smears and trephine biopsies of normal bone marrow and in chronic myelogenous leukaemia (CML) to assess the effects of therapy on apoptosis and cell proliferation. The in situ end-labelling (ISEL) technique was used for the demonstration of programmed cell death, in combination with the monoclonal antibody PG-M1 to identify macrophages. Cell proliferation was evaluated by employing the monoclonal antibody PC10 directed against proliferating cell nuclear antigen (PCNA). In CML (48 patients), significantly higher rates of apoptosis were observed than in normal bone marrow (smears, frozen sections, and paraffin-embedded samples) of 15 patients. In contrast, the PCNA labelling index of CML was not different from controls. In bone marrow tissue derived from CML patients, about 36 per cent of apoptotic bodies were ingested with CD68-positive macrophages. Study of the histotopographical distribution of labelled cells revealed that in CML, in contrast to the normal bone marrow, programmed cell death and PCNA activity were concentrated along the paratrabecular generation zone. In 28 patients with CML treated with interferon (IFN), sequential trephine biopsies displayed a significant enhancement of apoptosis which was associated with a decrease in PCNA reactivity. In contrast to this finding, no such alterations could be observed in 24 patients who received busulfan (BU) monotherapy. This study furthers the understanding of cell kinetics in CML. IFN therapy induces apoptosis and suppresses cell proliferation. The rate of programmed cell death prior to therapy and the extent of IFN-triggered apoptosis exert a significant predictive impact on survival. In this study, ISEL-positive (apoptotic) cells and bodies do not correspond to unscheduled cell repair as detected by PCNA immunoreactivity. PMID:9155719

  9. Busulfan, Melphalan, and Bortezomib versus High-Dose Melphalan as a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.

    PubMed

    Rodriguez, Tulio E; Hari, Parameswaran; Stiff, Patrick J; Smith, Scott E; Sterrenberg, Danielle; Vesole, David H

    2016-08-01

    High-dose melphalan 200 mg/m(2) (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m(2) (MEL 140) and VEL 1.6 mg/m(2) were administered i.v. on days -2 and -1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P = .89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials. PMID:27164062

  10. Comparison of the cytotoxicity of cladribine and clofarabine when combined with fludarabine and busulfan in AML cells: Enhancement of cytotoxicity with epigenetic modulators.

    PubMed

    Valdez, Benigno C; Li, Yang; Murray, David; Ji, Jie; Liu, Yan; Popat, Uday; Champlin, Richard E; Andersson, Borje S

    2015-06-01

    Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) combinations are efficacious in hematopoietic stem cell transplantation for myeloid leukemia. We sought to determine whether the more affordable drug cladribine (Clad) can provide a viable alternative to Clo, with or without panobinostat (Pano) and 5-aza-2'-deoxycytidine (DAC). Both Clad+Flu+Bu and Clo+Flu+Bu combinations showed synergistic cytotoxicity in KBM3/Bu250(6), HL60, and OCI-AML3 cell lines. Cell exposure to these drug combinations resulted in 60%-80% inhibition of proliferation; activation of the ATM pathway; increase in histone modifications; decrease in HDAC3, HDAC4, HDAC5 and SirT7 proteins; decrease in mitochondrial membrane potential; activation of apoptosis and stress signaling pathways; and downregulation of the AKT pathway. These drug combinations activated DNA-damage response and apoptosis in primary cell samples from AML patients. At lower concentrations of Clad/Clo, Flu, and Bu, inclusion of Pano and DAC enhanced cell killing, increased histone modifications and DNA demethylation, and increased the levels of P16/INK4a, P15/INK4b and P21/Waf1/Cip1 proteins. The observed DNA demethylating activity of Clad and Clo may complement DAC activity; increase demethylation of the gene promoters for SFRP1, DKK3, and WIF1; and cause degradation of β-catenin in cells exposed to Clad/Clo+Flu+Bu+DAC+Pano. The overlapping activities of Clad/Clo+Flu+Bu, Pano, and DAC in DNA-damage formation and repair, histone modifications, DNA demethylation, and apoptosis may underlie their synergism. Our results provide a basis for supplanting Clo with Clad and for including epigenetic modifiers in the pre-hematopoietic stem cell transplantation conditioning regimen for myeloid leukemia patients. PMID:25704054

  11. Toxicities of busulfan/melphalan versus carboplatin/etoposide/melphalan for high-dose chemotherapy with stem cell rescue for high-risk neuroblastoma.

    PubMed

    Desai, A V; Heneghan, M B; Li, Y; Bunin, N J; Grupp, S A; Bagatell, R; Seif, A E

    2016-09-01

    The optimal autologous stem cell rescue (HDC-SCR) regimen for children with high-risk neuroblastoma (HR-NBL) is not defined. Carboplatin/etoposide/melphalan (CEM) is the current US standard; however, European data suggest busulfan/melphalan (Bu/Mel) may have less toxicity. Published data regarding toxicities associated with CEM and Bu/Mel are limited. We conducted a single-institution retrospective cohort study of children with HR-NBL who received CEM or Bu/Mel preparative regimens. Toxicity data were analyzed using χ(2) or Fisher's exact, Wilcoxon two-sample or log-rank tests. Sinusoidal obstruction syndrome (SOS) was observed in 7/44 CEM (15.9%) and 5/21 (24%) Bu/Mel patients (P=0.50). Median time to SOS was longer following Bu/Mel than CEM (20 versus 9 days, P=0.02). Pulmonary hypertension (PHTN) was observed in ~20% of children after Bu/Mel and none after CEM (P=0.01). CEM patients had more nephrotoxicity (P=0.001), packed red blood cell (P=0.02) and platelet transfusions (P=0.008), and days on maximum pain support (P=0.0007). Time to engraftment, length of stay, documented infection rates and HDC-SCR-related mortality were similar. Nephrotoxicity and resource utilization associated with cytopenias and mucositis were greater after CEM. Pulmonary toxicities were more severe after Bu/Mel, and increased vigilance for PHTN may be warranted, particularly in children with hypoxemia out of proportion to respiratory distress. PMID:27159174

  12. Human CD4+CD25+ Regulatory T Cells Are Sensitive to Low Dose Cyclophosphamide: Implications for the Immune Response

    PubMed Central

    Becker, Huong; van Gool, Stefaan; Bacher, Nicole; Steinbrink, Kerstin; Kaina, Bernd

    2013-01-01

    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. PMID:24376696

  13. Treosulfan, cyclophosphamide and antithymocyte globulin for allogeneic hematopoietic cell transplantation in acquired severe aplastic anemia.

    PubMed

    Giebel, Sebastian; Wojnar, Jerzy; Krawczyk-Kulis, Malgorzata; Markiewicz, Miroslaw; Wylezoł, Iwona; Seweryn, Marek; Holowiecka-Goral, Aleksandra; Holowiecki, Jerzy

    2006-01-01

    To reduce the risk of graft rejection after allogeneic hematopoietic cell transplantation (alloHCT) for patients with acquired severe aplastic anemia (SAA), we introduced an intensified preparative regimen consisting of treosulfan 10 g/m2/d on days -7, -6, cyclophosphamide 40 mg/kg/d on days -5, -4, -3, -2 and anti-thymocyte globulin 2 mg/kg/d on days -3, -2, -1. Six patients with the history of multiple transfusions were treated with alloHCT from either HLA-identical sibling (n=3) or an unrelated volunteer (n=3). Each, bone marrow and peripheral blood was used as a source of stem cells in three cases. All patients engrafted and achieved complete donor chimerism. None of the patients experienced severe organ toxicity. No severe acute graft-versus-host-disease (GVHD) was observed; two patients experienced extensive chronic GVHD. At the median follow-up of 14.5 (13-27) months all patients remained alive and disease-free. Our observation indicates that treosulfan + cyclophosphamide + antithymocyte globulin conditioning is well-tolerated and allows stable engraftment in acquired SAA. PMID:17494286

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

    PubMed Central

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

    2011-01-01

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

  15. Aldehyde Dehydrogenase Expression Drives Human Regulatory T Cell Resistance to Posttransplantation Cyclophosphamide

    PubMed Central

    Kanakry, Christopher G.; Ganguly, Sudipto; Zahurak, Marianna; Bolaños-Meade, Javier; Thoburn, Christopher; Perkins, Brandy; Fuchs, Ephraim J.; Jones, Richard J.; Hess, Allan D.; Luznik, Leo

    2014-01-01

    High-dose, posttransplantation cyclophosphamide (PTCy) is an effective strategy for preventing graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT). However, the mechanisms by which PTCy modulates alloimmune responses are not well understood. We studied early T cell reconstitution in patients undergoing alloBMT with PTCy and the effects of mafosfamide, a cyclophosphamide (Cy) analog, on CD4+ T cells in allogeneic mixed lymphocyte reactions (MLRs) in vitro. Patients exhibited reductions in naïve, potentially alloreactive conventional CD4+ T cells with relative preservation of memory CD4+Foxp3+ T cells. In particular, CD4+CD45RA−Foxp3+hi effector regulatory T cells (Tregs) recovered rapidly after alloBMT and, unexpectedly, were present at higher levels in patients with GVHD. CD4+Foxp3+ T cells from patients and from allogeneic MLRs expressed relatively high levels of aldehyde dehydrogenase (ALDH), the major in vivo mechanism of Cy resistance. Treatment of MLR cultures with the ALDH inhibitor diethylaminobenzaldehyde reduced the activation and proliferation of CD4+ T cells and sensitized Tregs to mafosfamide. Finally, removing Tregs from peripheral blood lymphocyte grafts obviated PTCy's GVHD-protective effect in a xenogeneic transplant model. Together, these findings suggest that Treg resistance to Cy through expression of ALDH may contribute to the clinical activity of PTCy in preventing GVHD. PMID:24225944

  16. Hematological and clinical responses to combined mitoxantrone and cyclophosphamide administration to normal cats.

    PubMed Central

    Henry, C J; Brewer, W G; Royer, N S

    1994-01-01

    The purpose of this study was to examine the feasibility of a combination chemotherapy protocol ("CYCLONE") in cats, utilizing mitoxantrone and cyclophosphamide. Three normal adult cats were administered mitoxantrone (6.5 mg/m2 intravenously) and cyclophosphamide (100 mg/m2 intravenously) every 21 days for a total of three doses. Individual white blood cell count nadirs (range, 2.0-9.5 x 10(9)/L) and neutrophil count nadirs (range, 0.3 to 5.0 x 10(9)/L) occurred between days 2 and 10 after each dose of chemotherapy. Mean white blood cell count nadirs (range of mean, 5.5 to 8.4 x 10(9)/L) occurred between days 6 and 8, as did the mean neutrophil count nadir (range of mean, 1.7-4.0 x 10(9)/L). Side effects were limited to transient appetite suppression in one cat and loose stools in two cats. Myelosuppression and gastrointestinal side effects were comparable to those observed with single-agent mitoxantrone protocols. Further investigation of this protocol is warranted. PMID:7866961

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

    PubMed

    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

  18. Tamoxifen prevents apoptosis and follicle loss from cyclophosphamide in cultured rat ovaries.

    PubMed

    Piasecka-Srader, Joanna; Blanco, Fernando F; Delman, Devora H; Dixon, Dan A; Geiser, James L; Ciereszko, Renata E; Petroff, Brian K

    2015-05-01

    Recent studies documented that the selective estrogen receptor modulator tamoxifen prevents follicle loss and promotes fertility following in vivo exposure of rodents to irradiation or ovotoxic cancer drugs, cyclophosphamide and doxorubicin. In an effort to characterize the ovarian-sparing mechanisms of tamoxifen in preantral follicle classes, cultured neonatal rat ovaries (Day 4, Sprague Dawley) were treated for 1-7 days with active metabolites of cyclophosphamide (i.e., 4-hydroxycyclophosphamide; CTX) (0, 1, and 10 μM) and tamoxifen (i.e., 4-hydroxytamoxifen; TAM) (0 and 10 μM) in vitro, and both apoptosis and follicle numbers were measured. CTX caused marked follicular apoptosis and follicular loss. TAM treatment decreased follicular loss and apoptosis from CTX in vitro. TAM alone had no effect on these parameters. IGF-1 and IGF-1 receptor were assessed in ovarian tissue showing no impact of TAM or CTX on these endpoints. Targeted mRNA analysis during follicular rescue by TAM revealed decreased expression of multiple genes related to inflammation, including mediators of lipoxygenase and prostaglandin production and signaling (Alox5, Pla2g1b, Ptgfr), cytokine binding (Il1r1, Il2rg ), apoptosis (Tnfrsf1a), second messenger signaling (Mapk1, Mapk14, Plcg1), as well as tissue remodeling and vasodilation (Bdkrb2, Klk15). The results suggest that TAM protects the ovary from CTX-mediated toxicity through direct ovarian actions that oppose follicular loss. PMID:25833159

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

    PubMed Central

    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

  20. Effect of Butea monosperma leaf extracts on cyclophosphamide induced clastogenicity and oxidative stress in mice

    PubMed Central

    Singh, Amarjeet; Kaur, Mohanjit; Choudhary, Adarsh; Kumar, Bimlesh

    2015-01-01

    Background: Butea monosperma is a medium sized deciduous tree of family Fabaceae. It is widely used by rural people in India to cure many disorders. It possesses antioxidant and anticancer activity which is a prerequisite for anticlastogenic activity. Objective: To evaluate the effect of Butea monosperma leaf extracts on cyclophosphamide induced clastogenicity and oxidative stress in mice. Materials and Methods: The present study assessed the role of aqueous and ethanolic leaf extracts of B. monosperma (AQEBM and ETEBM) on cyclophosphamide (CP) induced oxidative stress and DNA damage in mice using micronucleus assay for anticlastogenic activity and biochemical estimation of malondialdehyde (MDA) and glutathione (GSH) for antioxidant activity. The frequency of the micronucleated erythrocytes and mitotic index was studied in peripheral blood and bone marrow after 24 and 48 h of clastogenic exposure. Results: CP treatment led to a significant (P < 0.001) increase in the frequency of micronuclei and decrease in the mitotic index (MI) in bone marrow and peripheral blood cells. Moreover, CP also significantly increased the lipid peroxidation as evidenced by an increase in the MDA content and decreased the antioxidant enzyme (GSH) in mice liver. Pretreatment with AQEBM and ETEBM reduced the frequency of micronuclei and increased the MI in the bone marrow and peripheral blood cells and also restored the MDA and GSH levels in mice liver. Conclusion: The AQEBM and ETEBM do contain compounds capable of inhibiting the CP induced oxidative stress and subsequent DNA damage in both the peripheral blood and bone marrow cells in mice. PMID:25598640

  1. The Hepatoprotective Effect of Haoqin Qingdan Decoction against Liver Injury Induced by a Chemotherapeutic Drug Cyclophosphamide

    PubMed Central

    Li, Xiaojiang; Li, Baole; Jia, Yingjie

    2015-01-01

    Haoqin Qingdan decoction (HQQD), a modern Chinese formula, has been widely used in Eastern Asia. Our study focuses on the hepatoprotective effect of HQQD against cyclophosphamide-induced hepatotoxicity. S180, a kind of ascites tumor cells, was used to establish S180-bearing mice, followed by the injection of cyclophosphamide (CP, 80 mg/kg) every other day for 5 times. HQQD was used intragastrically at the dose of 80 g/kg, 40 g/kg, and 20 g/kg twice a day for 12 days. HL-7702 hepatic cell line was incubated with HQQD-medicated serum. Then we detected the effects of HQQD on (i) tumor suppression; (ii) morphological examination; (iii) SOD, MDA, GSH, ALT, and AST; (iv) cleaved caspase-3 expression and (v) cellular viability. CP caused dramatic elevations of AST, ALT, and MDA, while HQQD notably attenuated these elevations. SOD and GSH were notably increased, which were efficiently attenuated by HQQD. CP injection significantly increased apoptosis by increasing cleaved caspase-3 expression, which was obviously inhibited by HQQD, accompanied by the improvement of cells viability. Histopathological examinations supported the above findings. Therefore, HQQD may protect liver tissue through attenuating oxidative stress and the caspase-3-dependent intrinsic apoptosis induced by CP, which suggests the potentially therapeutic effect of HQQD in the use of alkylating agent for cancer chemotherapy. PMID:26101538

  2. Continuous cyclophosphamide, doxorubicin, vincristine, and prednisolone. A new, innovative protocol for diffuse aggressive lymphomas

    SciTech Connect

    Banavali, S.D.; Advani, S.H.; Gopal, R.; Agarwala, S.; Dinshaw, K.A.; Saikia, T.K.; Pai, S.K.; Kurkure, P.; Nair, C.N.; Gonsalves, M. )

    1990-04-15

    One hundred eight patients with aggressive non-Hodgkin's lymphoma (high and intermediate grade) were treated with a new protocol: continuous cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). They were evaluated for long-term survival and pretreatment characteristics predictive of response and survival. Continuous CHOP protocol consists of initial 8 weeks of intensive chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone, followed by local/cranial radiotherapy and maintenance therapy. Complete remission (CR) was achieved in 84 of 108 (78%) patients; seven (6%) had a moderate response and 17 (16%) had a poor response. A statistically significant difference in CR rate was found only in patients with different stages. Seventeen of 84 (20%) complete responders have had a relapse of the disease. The median survival has not been reached. Results show an actuarial disease-free survival (DFS) of 77% for the 84 patients who had a complete response. The overall survival for all patients was 53% at 5 years of follow-up. The difference in DFS at the end of 5 years between different stages, main histologic subgroups, and age groups was not statistically significant. The toxicity observed was acceptable. Thus continuous CHOP appears to be an effective protocol for the treatment of intermediate-grade and high-grade lymphomas.

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

    PubMed

    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. PMID:2234455

  4. Combination of cyclophosphamide and interferon-β halts progression in patients with rapidly transitional multiple sclerosis

    PubMed Central

    Patti, F; Cataldi, M; Nicoletti, F; Reggio, E; Nicoletti, A; Reggio, A

    2001-01-01

    The effects of combined treatment with cyclophosphamide (CTX) and interferon-β (IFN-β) are described in selected patients with "rapidly transitional" multiple sclerosis. This form of multiple sclerosis is extremely active with very frequent and severe attacks which produce a dramatic increase on the expanded disability status scale (EDSS). Ten patients with rapidly transitional multiple sclerosis were previously treated with interferon-β, but none benefited by this treatment. Monthly treatment with intravenous CTX, from 500 mg/m2 to 1500 mg/m2 to obtain a chronic lymphocytopenia (600/mm3 to 900/mm3) produced a marked and significant reduction in the number of relapses (p<0.0001), disability previously accumulated (p<0.0001), and a reduction of T2 MRI burden of lesion. This particular group of patients benefited by combining cyclophosphamide and IFN-β. The possibility is considered of carrying out further studies to test the efficacy of the association between the two drugs for patients who are not responsive to IFN-β or other active disease modifying therapies.

 PMID:11511721

  5. Ultrastructural studies of the myocardium of rats on low-magnesium diet treated with cyclophosphamide.

    PubMed

    Wutzen, J

    1991-01-01

    Cyclophosphamide administration in 20 mg/kg doses intraperitoneally at intervals of 6 days for 6 weeks produced the appearance of slight focal changes in myocardial fibres from the third week on, with dilatation of T-tubules and smooth endoplasmic reticulum channels with electron-dense deposits in them, with the appearance of numerous fat droplets in myocardial fibres, slight mitochondrial changes, with swelling and the appearance of giant or bizarre shaped mitochondria with electron-dense granules and lamellae in them, with numerous lysosomes and some increase in the number of autophagosomes, focal widening of intercalated discs, lysis of myofilaments and myofibrils, cytoplasm swelling, focal necrosis of some myocardial fibres in the 6th week of the experiment, marked swelling of vascular endothelial cells, and a very great rise in the number of collagen fibres. Simultaneous administration of low-magnesium diet and cyclophosphamide caused a greater intensity and an earlier appearance from the 2nd week on, of the disseminated degenerative and necrotic changes in myocardial fibres. PMID:1842235

  6. Tamoxifen Prevents Apoptosis and Follicle Loss from Cyclophosphamide in Cultured Rat Ovaries1

    PubMed Central

    Piasecka-Srader, Joanna; Blanco, Fernando F.; Delman, Devora H.; Dixon, Dan A.; Geiser, James L.; Ciereszko, Renata E.; Petroff, Brian K.

    2015-01-01

    Recent studies documented that the selective estrogen receptor modulator tamoxifen prevents follicle loss and promotes fertility following in vivo exposure of rodents to irradiation or ovotoxic cancer drugs, cyclophosphamide and doxorubicin. In an effort to characterize the ovarian-sparing mechanisms of tamoxifen in preantral follicle classes, cultured neonatal rat ovaries (Day 4, Sprague Dawley) were treated for 1–7 days with active metabolites of cyclophosphamide (i.e., 4-hydroxycyclophosphamide; CTX) (0, 1, and 10 μM) and tamoxifen (i.e., 4-hydroxytamoxifen; TAM) (0 and 10 μM) in vitro, and both apoptosis and follicle numbers were measured. CTX caused marked follicular apoptosis and follicular loss. TAM treatment decreased follicular loss and apoptosis from CTX in vitro. TAM alone had no effect on these parameters. IGF-1 and IGF-1 receptor were assessed in ovarian tissue showing no impact of TAM or CTX on these endpoints. Targeted mRNA analysis during follicular rescue by TAM revealed decreased expression of multiple genes related to inflammation, including mediators of lipoxygenase and prostaglandin production and signaling (Alox5, Pla2g1b, Ptgfr), cytokine binding (Il1r1, Il2rg ), apoptosis (Tnfrsf1a), second messenger signaling (Mapk1, Mapk14, Plcg1), as well as tissue remodeling and vasodilation (Bdkrb2, Klk15). The results suggest that TAM protects the ovary from CTX-mediated toxicity through direct ovarian actions that oppose follicular loss. PMID:25833159

  7. Busulfan, Etoposide, and Intensity-Modulated Radiation Therapy Followed By Donor Stem Cell Transplant in Treating Patients With Advanced Myeloid Cancer

    ClinicalTrials.gov

    2016-04-08

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts

  8. Complete Response and Fatigue Improvement With the Combined Use of Cyclophosphamide and Quercetin in a Patient With Metastatic Bladder Cancer

    PubMed Central

    Di Lorenzo, Giuseppe; Pagliuca, Martina; Perillo, Teresa; Zarrella, Aquilino; Verde, Antonio; De Placido, Sabino; Buonerba, Carlo

    2016-01-01

    Abstract Bladder cancer is a major cause of cancer-related mortality, with an estimated 74,000 new cases and 16,000 deaths in the United States in 2015. In patients with metastatic disease, vinflunine and taxanes are the most widely used chemotherapy agents in the second-line setting after failure of platinum-based treatment. Cyclophosphamide has been used in combination with paclitaxel in urothelial carcinoma of the bladder, but there are no data about the effectiveness of cyclophosphamide administered as a single agent. We here describe the first case of an advanced bladder cancer patient suffering from grade 2 fatigue. He benefited from administration of third-line single-agent metronomic oral cyclophosphamide plus oral doses of quercetin. A complete, prolonged radiologic response according to the RECIST criteria 1.1 was achieved with minimal toxicity and an improvement in fatigue. Further studies are required to assess the potential benefits associated with the combined use of cyclophosphamide plus quercetin in advanced bladder cancer patients. PMID:26844468

  9. Evaluation of surface contamination with cyclophosphamide following simulated hazardous drug preparation activities using two closed-system products

    PubMed Central

    Zock, Matthew D; Soefje, Scott; Rickabaugh, Keith

    2011-01-01

    Purpose. A preliminary investigation was conducted to evaluate and compare the effectiveness of two closed-system products in preventing contamination of typical pharmacy workplace surfaces with cyclophosphamide during simulated hazardous drug preparation activities in a controlled laboratory setting. Methods. Two separate trials simulating hazardous drug compounding using cyclophosphamide were performed with two different closed-system products. Prior to each trial, work area surfaces of the biological safety cabinet (BSC) workbench, the BSC airfoil and front grill, and the floor below the BSC were cleaned, and wipe samples were collected and analyzed to determine, if present, levels of cyclophosphamide. Following each trial, wipe samples were collected from the work area surfaces to determine the hazardous drug containment effectiveness of each closed-system product. Results. Cyclophosphamide was not detected on work area surfaces prior to each trial. Low levels were detected on the BSC workbench surface following both trials. Discussion. Based on the limited number of samples obtained during this preliminary study and the determination of the presence of the chemical of interest on the drug vials, no statistical evaluation was performed to compare the relative effectiveness of the two systems tested. Work practices and procedures regarding product operation may affect hazardous drug containment and worker safety. Further study and statistical analyses are needed. PMID:20584743

  10. SYNAPTONEMAL COMPLEX DAMAGE IN RELATION TO MEIOTIC CHROMOSOME ABERRATIONS AFTER EXPOSURE OF MALE MICE TO CYCLOPHOSPHAMIDE (JOURNAL VERSION)

    EPA Science Inventory

    Cyclophosphamide (CP) has been reported to cause structural and numerical chromosome aberrations in mouse spermatocyte metaphase chromosomes. Further, it was concluded to be one of the few chemicals for which there appears to be reliable data suggesting that it can induce germ ce...

  11. Moderate-dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution.

    PubMed

    Scheinberg, Phillip; Townsley, Danielle; Dumitriu, Bogdan; Scheinberg, Priscila; Weinstein, Barbara; Daphtary, Maithili; Rios, Olga; Wu, Colin O; Young, Neal S

    2014-10-30

    First-line therapy of severe aplastic anemia (SAA) with high-dose cyclophosphamide causes toxicity and increased short-term mortality. We investigated cyclophosphamide at a lower, more moderate dose in combination with aggressive supportive care to determine whether severe infections might be avoided and hematologic outcomes defined for this regimen. From 2010 to 2012, 22 patients received cyclophosphamide at 120 mg/kg plus cyclosporine and antibacterial, antiviral, and antifungal prophylaxis. Toxicity was considerable, mainly due to prolonged absolute neutropenia, which occurred regardless of pretherapy blood counts, and persisted an average of 2 months. Granulocyte transfusions for uncontrolled infection were required in 5 patients, confirmed fungal infections were documented in 6, and 9 patients died. Nine patients (41%) responded at 6 months. After a median follow-up of 2.2 years, relapse occurred in 2 patients, and cytogenetic abnormalities (including monosomy 7) were observed in 4 patients. Although cyclophosphamide has activity in SAA, its toxicity is not justified when far less dangerous alternatives are available. This trial was registered at www.clinicaltrials.gov as #NCT01193283. PMID:25185712

  12. KINETICS OF IN VIVO SISTER CHROMATID EXCHANGE INDUCTION IN MOUSE BONE MARROW CELLS BY ALKYLATING AGENTS: CYCLOPHOSPHAMIDE

    EPA Science Inventory

    Administration of cyclophosphamide (5, 10, 20 and 25 mg/kg body weight) to male CD-1 mice 2 hours after subcutaneous implantation of a 5-bromo-2'-deoxyuridine (BrdU) pellet (55 mg) resulted in a dose-dependent increase in sister chromatid exchanges (SCE) in bone marrow cells. Tre...

  13. HOST RESISTANCE TO TRICHINELLA SPIRALIS INFECTION IN MICE AND RATS: SPECIES-DEPENDENT EFFECTS OF CYCLOPHOSPHAMIDE EXPOSURE

    EPA Science Inventory

    Host resistance to Trichinella spiralis infection was compared in rats (F344) and mice (C57BL/6J) following various cyclophosphamide (CY) treatment schedules. Dozes of CY given to mice were adjusted by body surface area to be comparable to rat doses. dult parasite elimination was...

  14. Cyclophosphamide induced generation of giant hypersegmented granulocytes in rat bone marrow: cell cycle distribution and silver nucleolar staining.

    PubMed

    Kotelnikov, V M; Pogorelov, V M; Berger, J; Kozinets, G I

    1988-01-01

    Daily injection of cyclophosphamide (20 mg/kg body weight) for 7 days resulted in accumulation of 50% of rat bone marrow granulocytes in G2. Tetraploid neutrophils were hypersegmented (7.25 +/- 0.33) in comparison with diploid ones (3.92 +/- 0.33). After 14 days of cyclophosphamide treatment tetraploid hypersegmented neutrophils could be found in peripheral blood. Diploid neutrophils in these animals were also hypersegmented (4.78 +/- 0.14 versus 3.15 +/- 0.02 in control, p less than 0.001). Nucleolar ribosomal gene activities, evaluated by morphometry of silver nucleolar grains, decreased on bone marrow granulocytes in the course of differentiation in control rats. After cyclophosphamide treatment mature granulocytes contained more silver grains than in controls which may be explained by conservation of silver binding sites of nucleoli from the stages of promyelocytes and myelocytes. These results suggest two mechanisms of hypersegmented neutrophil, generation in cyclophosphamide treated rats: the first, via maturation of myelocytes arrested in G2, and second, a direct one, without tetraploid granulocyte involvement. PMID:2465255

  15. Is anti-mullerian hormone a marker of acute cyclophosphamide-induced ovarian follicular destruction in mice pretreated with cetrorelix?

    PubMed Central

    Browne, Hyacinth N.; Moon, Kimberly S.; Mumford, Sunni L.; Schisterman, Enrique F.; DeCherney, Alan H.; Segars, James H.; Armstrong, Alicia Y.

    2011-01-01

    Objective To define whether anti-mullerian hormone may be a marker of acute cyclophosphamide-induced germ cell destruction in mice pretreated with the GnRH antagonist, cetrorelix. Design Controlled, experimental study. Setting Research laboratory in a federal research facility. Animals Balb/c female mice (6 weeks old). Interventions Mice were treated with GnRH antagonist (cetrorelix) or saline for 15 days followed by 75 mg/kg or 100 mg/kg of cyclophosphamide or saline control on day 9. Main Outcome Measure(s) Number of primordial follicles (PMF), DNA damage, AMH protein expression, and AMH serum levels. Results Ovaries in mice pre-treated with cetrorelix had significantly more PMF and reduced DNA damage compared to those exposed to cyclophosphamide alone. Immunohistochemical staining for AMH expression and serum AMH levels did not differ significantly between treatment groups. Conclusions Cetrorelix protected primordial follicles and reduced DNA damage in follicles of mice treated with cyclophosphamide, but AMH levels in tissue and serum did not correlate with germ cell destruction. Further research is needed to determine the mechanism responsible for the protective effects on PMF counts observed with cetrorelix. PMID:21550044

  16. Development and validation of a test dose strategy for once-daily i.v. busulfan: importance of fixed infusion rate dosing.

    PubMed

    Kangarloo, S Bill; Naveed, Farrukh; Ng, Ella S M; Chaudhry, M Ahsan; Wu, Judy; Bahlis, Nizar J; Brown, Christopher B; Daly, Andrew; Duggan, Peter; Geddes, Michelle; Quinlan, Diana; Savoie, Mary Lynn; Shafey, Mona; Stewart, Douglas A; Storek, Jan; Yang, Maggie; Zacarias, Nancy; Yue, Ping; Magliocco, Anthony M; Russell, James A

    2012-02-01

    Intravenous (i.v.) busulfan (Bu) administered once daily in myeloablative transplant regimens is convenient, effective, and relatively well tolerated. Therapeutic drug monitoring is recommended as nonrelapse mortality increases when daily exposure, as determined by the area under the plasma concentration versus time curve (AUC), exceeds 6000 μM·min. We describe sequential studies to achieve accurate prediction of treatment doses of Bu based on the kinetics of a smaller test dose. A total of 335 patients with hematologic malignancies were given daily i.v. Bu 3.2 mg/kg × 4 and fludarabine 50 mg/m(2) × 5. Pharmacokinetic monitoring was conducted for both the test dose and first treatment dose of Bu (day -5). Three different test dose schedules were evaluated: 12 mg Bu administered over 20 minutes, 0.8 mg/kg over 3 hours, and 0.8 mg/kg infused at 80 mg/h. The 3.2 mg/kg treatment doses were infused over a fixed time of 3 hours for the first 2 test dose trials and at a fixed rate of 80 mg/h for the final protocol. All test dose infusions were on day -7. In the first 2 schedules, Bu administered over a fixed time had significantly higher clearance for the test dose compared with the treatment dose. However, when both the test and the treatment doses were administered at the same infusion rate, clearance of the drug between the 2 dosing days was equivalent. Predicted day -5 AUC (AUC(-5)) showed a high linear correlation (r(2) = 0.74) to the actual AUC(-5). The error of these predictions was <20% in 98% of patients and <10% in 80%. In 24 individuals, the test dose predicted an AUC >5500 μM·min; therefore, the first Bu treatment dose was reduced to a desired target AUC. All adjusted doses fell within 20% of the targeted exposure. We conclude that a test dose strategy for therapeutic drug monitoring of daily i.v. Bu is accurate if the test and treatment doses are infused at the same rate. This approach allows targeting of therapeutic doses of Bu to desired levels and

  17. Synergistic cytotoxicity of sorafenib with busulfan and nucleoside analogs in human FMS-like tyrosine kinase 3 internal tandem duplications-positive acute myeloid leukemia cells.

    PubMed

    Song, Guiyun; Valdez, Benigno C; Li, Yang; Liu, Yan; Champlin, Richard E; Andersson, Borje S

    2014-11-01

    Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) are used in pretransplantation conditioning therapy for patients with myeloid leukemia. To further improve their efficacy in FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)-positive acute myeloid leukemia (AML), we investigated their synergism with sorafenib (Sor). Exposure of FLT3-ITD-positive MV-4-11 and MOLM 13 cells to Bu+Clo+Flu+Sor resulted in synergistic cytotoxicity; no such synergism was observed in the FLT3-wild type THP-1 and KBM3/Bu250(6) cell lines. The drug synergism in MV-4-11 cells could be attributed to activation of DNA damage response, histone 3 modifications, inhibition of prosurvival kinases, and activation of apoptosis. Further, the phosphorylation of kinases, including FLT3, MAPK kinase (MEK), and AKT, was inhibited. The FLT3-ITD substrate STAT5 and its target gene PIM 2 product decreased when cells were exposed to Sor alone, Bu+Clo+Flu, and Bu+Clo+Flu+Sor. The level of the proapoptotic protein p53 upregulated modulator of apoptosis (PUMA) increased, whereas the level of prosurvival protein MCL-1 decreased when cells were exposed to Bu+Clo+Flu+Sor. The interactions of PUMA with MCL-1 and/or BCL-2 were enhanced when cells were exposed to Bu+Clo+Flu or Bu+Clo+Flu+Sor. The changes in the level of these proteins, which are involved in mitochondrial control of apoptosis, correlate with changes in mitochondrial membrane potential. Bu+Clo+Flu+Sor decreased mitochondrial membrane potential by 60% and caused leakage of cytochrome c, second mitochondria-derived activator of caspases (SMAC)/direct IAP Binding protein with low pI (DIABLO), and AIF from the mitochondria to the cytoplasm, caspase activation, and cell death, suggesting the activation of apoptosis. Analogous, synergistic cytotoxicity in response to Bu, Clo, Flu, and Sor was observed in mononuclear cells isolated from FLT3-ITD-positive AML patients. Although our previous studies were aimed at standardizing the

  18. Pulse infusion interleukin-2 with famotidine and cyclophosphamide has activity in previously treated metastatic melanoma.

    PubMed

    Quan, Walter; Knupp, Charles; Quan, Francine; Walker, Paul

    2010-04-01

    There is no established systemic therapy for patients with stage IV melanoma refractory to prior systemic treatment. Interleukin-2 (IL-2) is capable of inducing T-lymphocyte cytotoxicity against melanoma in vitro and in vivo. Famotidine may enhance the activity of T-cells further by allowing for increased IL-2 internalization by the IL-2 receptor on lymphocytes. Cyclophosphamide may decrease the immunosuppressive effects of regulatory T-cells. Daily short intravenous (i.v.) infusions (pulses) of IL-2 were used to treat 14 patients with metastatic melanoma, all of whom had experienced disease progression despite prior systemic therapy. The patients received 21.6 million IU/m(2) of pulse IL-2 i.v. for 15-30 minutes, preceded by 20 mg of famotidine i.v. (13) patients received 350 mg/m(2) of cyclophosphamide i.v. on day 1 (1 patient did not). Eight (8) patients were treated in an oncology inpatient unit while, most recently, 6 patients have received therapy on an outpatient basis. The cycles were repeated every 3 weeks until disease progression occurred. The patients included 10 males with a median age of 56 (range 31-87) with an Eastern Cooperative Oncology Group performance status of -1 (range 0 - -1). Common metastatice sites included lymph nodes (13), lungs (8), liver (4), and subcutaneous (4). Prior systemic therapy included IL-2 (11), interferon (7), and chemotherapy (7). The median number of cycles the patients underwent was 3 with a range of 1-7. The most common toxic reactions were fever, rigors, nausea/emesis, hypomagnesemia, and hypophosphatemia. One complete response and four partial responses were observed (response rate, 36%; 95% confidence interval: 14%-64%). Responses occurred in the lungs, liver, lymph nodes, and subcutaneous sites. The median response duration was 3.4 months, with a median survival of 8.3 months for the entire group. Six (6) patients remain alive with a median survival of 10.3 months. Pulse IL-2 with famotidine and cyclophosphamide

  19. Metabolism and binding of cyclophosphamide and its metabolite acrolein to rat hepatic microsomal cytochrome P-450

    SciTech Connect

    Marinello, A.J.; Bansal, S.K.; Paul, B.; Koser, P.L.; Love, J.; Struck, R.F.; Gurtoo, H.L.

    1984-10-01

    The hepatic cytochrome P-450-mediated metabolism and metabolic activation of (chloroethyl-3H)cyclophosphamide (( chloroethyl-3H)CP) and (4-14C)cyclophosphamide (( 4-14C)CP) were investigated in vitro in the reconstituted system containing cytochrome P-450 isolated from phenobarbital-treated rats. In addition, hepatic microsomal binding and the hepatic microsome-mediated metabolism of (14C)acrolein, a metabolite of (4-14C)CP, were also investigated. The metabolism of (chloroethyl-3H)CP and (4-14C)CP to polar metabolites was found to depend on the presence of NADPH and showed concentration dependence with respect to cytochrome P-450 and NADPH:cytochrome P-450 reductase. Km and Vmax values were essentially similar. The patterns of inhibition by microsomal mixed-function oxidase inhibitors, anti-cytochrome P-450 antibody, and heat denaturation of the cytochrome P-450 were essentially similar, with subtle differences between (4-14C)CP and (chloroethyl-3H)CP metabolism. The in vitro metabolic activation of CP in the reconstituted system demonstrated predominant binding of (chloroethyl-3H)CP to nucleic acids and almost exclusive binding of (4-14C)CP to proteins. Gel electrophoresis-fluorography of the proteins in the reconstituted system treated with (4-14C)CP demonstrated localization of the 14C label in the cytochrome P-450 region. To examine this association further, hepatic microsomes were modified with (14C)acrolein in the presence and the absence of NADPH. The results confirmed covalent association between (14C)acrolein and cytochrome P-450 in the microsomes and also demonstrated further metabolism of (14C)acrolein, apparently to an epoxide, which is capable of binding covalently to proteins. The results of these investigations not only confirm the significance of primary metabolism but also emphasize the potential role of the secondary metabolism of cyclophosphamide in some of its toxic manifestations.

  20. Nuclear aberrations in hair follicle cells of patients receiving cyclophosphamide. A possible in vivo assay for human exposure to genotoxic agents.

    PubMed

    Goldberg, M T; Tackaberry, L E; Hardy, M H; Noseworthy, J H

    1990-01-01

    The toxic effect of cyclophosphamide on the proliferative cell population of hair follicles plucked from the human scalp was examined by the in vivo nuclear aberration assay. Patients participating in an independent clinical trial received oral low dose cyclophosphamide, intravenous high dose cyclophosphamide or oral placebo treatment. The percent of cells with nuclear aberrations (indicating apoptosis, a special form of cell death) and the percent of mitotic cells, in the hair matrix, were calculated for each patient before treatment and at several time points following cyclophosphamide or placebo treatment. The mean percentages of nuclear aberrations in both the treated Low dose and High dose cyclophosphamide patients were significantly higher than those for the pre-treatment and Placebo patients. The nuclear aberrations in hair follicle cells increased from pre-treatment (and Placebo) to treated Low dose and finally to treated High dose patients. The average percentage for pre-treatment samples from all patients was 0.06 +/- 0.03 SE. For 1 week and 1 month samples from Low dose patients it was 0.35 +/- 0.08 SE, and for combined 2,3 and 4 day samples from High dose patients it was 1.08 +/- 0.12 SE. Cyclophosphamide also had a significant effect on mitosis. A decrease in mitotic activity was observed at 1 month following the initial low dose cyclophosphamide treatment and at 24 +/- 2 h following each of the first two high dose cyclophosphamide treatments. The observed increase in nuclear aberrations following low dose as well as high dose cyclophosphamide suggests that it is feasible to use the nuclear aberration assay for in vivo human genotoxicity testing, using proliferating hair follicle cells. PMID:2190540

  1. Antihepatotoxic efficacy of Mangifera indica L. polysaccharides against cyclophosphamide in rats.

    PubMed

    Fahmy, Sohair R; Amien, Ahmed I; Abd-Elgleel, Fathi M; Elaskalany, Sara M

    2016-01-25

    The present study aims to evaluate the possible protective role of polysaccharides extracted from the Egyptian mango Mangifera indica L. (MPS) and/or silymarine against cyclophosphamide (CP) toxicity in male albino rats. The MPS and/or silymarin significantly decreased the activities of serum ASAT and ALAT. However, MPS (1000 mg/kg) normalized their activities towards the normal levels recording 28.75 and 78.75 U/ml respectively. The recorded data also showed the antioxidant effect of MPS by decreasing the level of malondialdehyde (MDA) and increasing the level of reduced glutathione (GSH) as well as normalized the activities of the antioxidant enzyme GST and SOD. Histopathological examinations also confirmed the protective efficacy of MPS against liver toxicity of CP. In conclusion, the recorded results of the present study support the protective role of MPS and/or silymarin against CP-induced hepatic damage. PMID:26615121

  2. Virgin coconut oil supplementation ameliorates cyclophosphamide-induced systemic toxicity in mice.

    PubMed

    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. PMID:25805601

  3. Lights and Shadows of Cyclophosphamide in the Treatment of Multiple Sclerosis

    PubMed Central

    Patti, Francesco; Lo Fermo, Salvatore

    2011-01-01

    Cyclophosphamide (cy) is an alkylating agent used to treat malignancies and immune-mediated inflammatory nonmalignant processes. It has been used as a treatment in cases of worsening multiple sclerosis (MS). Cy is currently used for patients whose disease is not controlled by beta-interferon or glatiramer acetate as well as those with rapidly worsening MS. The most commonly used regimens involve outpatient IV pulse therapy given with or without corticosteroids every 4 to 8 weeks. Side effects include nausea, headache, alopecia, pain, male and women infertility, bladder toxicity, and risk of malignancy. Previous studies suggest that cy is effective in patients in the earlier stages of disease, where inflammation predominates over degenerative processes. Given that early inflammatory events appear to correlate with later disability, a major question is whether strong anti-inflammatory drugs, such as cy, will have an impact on later degenerative changes if given early in the disease to halt inflammation. PMID:21547093

  4. Tumor xenotransplantation in Wistar rats after treatment with cyclophosphamide and total lymphoid irradiation. [X-ray

    SciTech Connect

    Hoogenhout, J.; Kazem, I.; Jerusalem, C.R.; Bakkeren, J.A.J.; de Jong, J.; Kal, H.B.; van Munster, P.J.J.

    1982-10-01

    Three-month-old male Wistar rats were treated with cyclophosphamide and total lymphoid irradiation, and C22LR mouse osteosarcoma was transplanted into the rats. The effects of immunosuppression were monitored by lymphocyte counts, serum IgG determinations, phytohemagglutinin (PHA) and concanavalin A (Con A) responses, measurement of the proportion of B cells, and histopathological studies of the lymphoid organs. At eight days after treatment, the lymphocyte counts, IgG levels, and PHA and Con A values were decreased. Mitotic activity started in the depleted B and T cell areas of the peripheral lymphatic organs two weeks after treatment. There was a 94% graft take of the osteosarcoma. It was determined that the optimum time for tumor xenograft transplantation is 4 days after treatment. The duration of growth was 11 days, and this was followed by regression up to day 21.

  5. Tumor xenotransplantation in Wistar rats after treatment with cyclophosphamide and total lymphoid irradiation

    SciTech Connect

    Hoogenhout, J.; Kazem, I.; Jerusalem, C.R.; Bakkeren, J.A.; de Jong, J.; Kal, H.B.; van Munster, P.J.

    1982-10-01

    Three-month-old male Wistar rats were treated with cyclophosphamide and total lymphoid irradiation, and C22LR mouse osteosarcoma was transplanted into the rats. The effects of immunosuppression were monitored by lymphocyte counts, serum IgG determinations, phytohemagglutinin (PHA) and concanavalin A (Con A) responses, measurement of the proportion of B cells, and histopathological studies of the lymphoid organs. At eight days after treatment, the lymphocyte counts, IgG levels, and PHA and Con A values were decreased. Mitotic activity started in the depleted B and T cell areas of the peripheral lymphatic organs two weeks after treatment. There was a 94% graft take of the osteosarcoma. It was determined that the optimum time for tumor xenograft transplantation is 4 days after treatment. The duration of growth was 11 days, and this was followed by regression up to day 21.

  6. [Immunomodulative effects of Chinese herbs in mice treated with anti-tumor agent cyclophosphamide].

    PubMed

    Jin, R; Wan, L L; Mitsuishi, T; Kodama, K; Kurashige, S

    1994-07-01

    Extracts of Chinese herbs were administered with antitumor agent, cyclophosphamide (CY), and their effects on macrophages and lymphocytes were studied. Number of peritoneal macrophages significantly decreased and their chemotactic activity was suppressed by treatment with CY. Blastogenic responsiveness to Concanavalin A and NK cell activity of spleen lymphocytes were suppressed significantly in CY-treated mice. Extracts of Lithospermi radix, Astragali radix and Glycyrrhizae radix showed protective effects on immunosuppressive mice. The number of macrophages, chemotactic activity of macrophages and blastogenic response of lymphocytes were recovered to the same or more than that of normal levels. An extract of Ginseng radix showed protective effects on the number and functions of macrophages by treatment with CY but did not show any effects on the lymphocytic blastogenesis. On the contrary it showed a strong inhibitory effect on the NK cell activity. These results suggest that Chinese herbs could modulate cellular immune response, especially in the activation of macrophages and splenic lymphocytes. PMID:7932098

  7. Adjuvant chemotherapy of axillary node-negative carcinoma of the breast using doxorubicin and cyclophosphamide.

    PubMed

    Brooks, R J; Jones, S E; Salmon, S E; Chase, E M; Davis, S L; Moon, T E; Giordano, G F; Ketchel, S J; Jackson, R A

    1986-01-01

    One hundred fifty-six women with axillary node-negative breast cancer and primary tumors less than or equal to 5 cm in diameter (T1N0 or T2N0) were treated with a brief course of postoperative adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide. Treatment was well tolerated and toxicity was minimal. With a median follow-up time of 58 months, there has been 1 relapse among 58 patients with T1 primary lesions and 15 relapses among 98 patients with T2 primary tumors. When compared with a matched historical control group receiving surgery alone, significant improvement was apparent in disease-free survival among the patients who received adjuvant chemotherapy. Prospective controlled trials are needed if we are to confirm this favorable experience with adjuvant chemotherapy in the treatment of women with node-negative breast cancer. PMID:3534586

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

    PubMed

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

    2004-01-01

    The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial. PMID:15299189

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

    PubMed

    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. PMID:26786992

  10. Chemotherapeutic (cyclophosphamide) effects on rat breast tumor hemodynamics monitored by multi-channel NIRS

    NASA Astrophysics Data System (ADS)

    Kim, Jae G.; Zhao, Dawen; Mason, Ralph P.; Liu, Hanli

    2005-04-01

    We previously suggested that the two time constants quantified from the increase of tumor oxyhemoglobin concentration, ▵ [HbO2], during hyperoxic gas intervention are associated with two blood flow/perfusion rates in well perfused and poorly perfused regions of tumors. In this study, our hypothesis is that when cancer therapy is applied to a tumor, changes in blood perfusion will occur and be detected by the NIRS. For experiments, systemic chemotherapy, cyclophosphamide (CTX), was applied to two groups of rats bearing syngeneic 13762NF mammary adenocarcinomas: one group received a single high dose i. p. (200 mg/kg CTX) and the other group continuous low doses (20 mg/kg CTX i. p. for 10 days). Time courses of changes in tumor ▵ [HbO2] were measured at four different locations on the breast tumors non-invasively with an inhaled gas sequence of air-oxygen-air before and after CTX administration. Both rat body weight and tumor volume decreased after administration of high dose CTX, but continuous low doses showed decrease of tumor volume only. Baselines (without any therapy) intra- and inter-tumor heterogeneity of vascular oxygenation during oxygen inhalation were similar to our previous observations. After CTX treatment, significant changes in vascular hemodynamic response to oxygen inhalation were observed from both groups. By fitting the increase of ▵ [HbO2] during oxygen inhalation, we have obtained changes of vascular structure ratio and also of perfusion rate ratio before and after chemotherapy. The preliminary results suggest that cyclophosphamide has greatest effect on the well perfused tumor vasculature. Overall, our study supports our earlier hypothesis, proving that the effects of chemotherapy in tumor may be monitored non-invasively by using NIRS to detect changes of hemodynamics induced with respiratory challenges.

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

    SciTech Connect

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

    1982-12-01

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

  12. Determination of tetrahydrothiophene formation as a probe of in vitro busulfan metabolism by human glutathione S-transferase A1-1: use of a highly sensitive gas chromatographic-mass spectrometric method.

    PubMed

    Ritter, C A; Bohnenstengel, F; Hofmann, U; Kroemer, H K; Sperker, B

    1999-06-25

    A method for the sensitive determination of tetrahydrothiophene (THT) in cytosolic incubation mixtures was developed. Busulfan conjugation with glutathione was predominantly catalysed by glutathione S-transferase A1-1 (GST A1-1) and THT was released from the primary metabolite by alkalization. After liquid-liquid extraction using n-pentane separation and quantification of the product was performed by gas chromatography with a mass-selective detector. The method showed good sensitivity, accuracy and reproducibility with a detection limit of 2 ng ml(-1) and a limit of quantification of 5 ng ml(-1). The suitability of the method is shown for enzyme kinetic studies in human liver cytosol as well as for determination of GST A1-1 activity. PMID:10437668

  13. Phase II Trial of Reduced-Intensity Busulfan/Clofarabine Conditioning with Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Acute Myeloid Leukemia, Myelodysplastic Syndromes, and Acute Lymphoid Leukemia.

    PubMed

    El-Jawahri, Areej; Li, Shuli; Ballen, Karen K; Cutler, Corey; Dey, Bimalangshu R; Driscoll, Jessica; Hunnewell, Chrisa; Ho, Vincent T; McAfee, Steven L; Poliquin, Cathleen; Saylor, Meredith; Soiffer, Robert J; Spitzer, Thomas R; Alyea, Edwin; Chen, Yi-Bin

    2016-01-01

    Clofarabine has potent antileukemia activity and its inclusion in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) for acute leukemia could potentially improve outcomes. We conducted a phase II study of busulfan (.8 mg/kg i.v. twice daily on days -5, -4, -3, and -2) with clofarabine (40 mg/m(2) i.v. daily on days -5, -4, -3, and -2) conditioning before allogeneic 8/8 HLA-matched related or unrelated HSCT. The primary endpoint was donor neutrophil engraftment by day +40. Secondary endpoints included nonrelapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD), progression-free survival (PFS), and overall survival (OS). Thirty-four patients (acute myeloid leukemia [AML], n = 25; myelodysplastic syndromes, n = 5; and acute lymphoid leukemia, n = 4) were enrolled. Day 40+ engraftment with donor chimerism was achieved in 33 of 34 patients with 1 patient dying before count recovery. Day 100 and 1-year NRM were 5.9% (95% confidence interval [CI], 1.0 to 17.4) and 24% (95% CI, 11 to 39), respectively. The 2-year relapse rate was 26% (95% CI, 13 to 42). Cumulative incidences of acute and chronic GVHD were 21% and 44%, respectively. The 2-year PFS was 50% (95% CI, 32 to 65) and OS was 56% (95% CI, 38 to 71). For patients with AML in first complete remission, 2-year PFS and OS were both 82% (95% CI, 55 to 94). RIC with busulfan and clofarabine leads to successful engraftment with acceptable rates of NRM and GVHD. PMID:26260679

  14. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes.

    PubMed

    Russell, J A; Tran, H T; Quinlan, D; Chaudhry, A; Duggan, P; Brown, C; Stewart, D; Ruether, J D; Morris, D; Glick, S; Gyonyor, E; Andersson, B S

    2002-01-01

    The availability of an i.v. form of busulfan (Bu) has prompted investigation of administration schedules other than the 4-times-daily dosage commonly used with oral Bu. We have studied an allogeneic stem cell transplantation (SCT) preparative regimen comprising fludarabine (FLU) 50 mg/m2 on days -6 to -2 plus i.v. Bu 3.2 mg/kg daily in a 3-hour infusion on days -5 to -2. The regimen was given to 70 patients aged 15 to 64 years (median, 41 years) with hematologic malignancy. Thirty-six patients (51%) had high-risk malignancy, 28 (40%) had unrelated or genotypically mismatched related donors (alternate donors [AD]) and 29 (41%) received bone marrow rather than blood as stem cell source. Acute GVHD prevention comprised antithymocyte globulin 4.5 mg/kg over 3 days pretransplantation, cyclosporin A, and short-course methotrexate with folinic acid. Hepatic toxicity was transient and there was no clinically diagnosed veno-occlusive disease. Grade II stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 patients (13%). One patient with subtherapeutic phenytoin levels had a convulsion 8 hours after the third i.v. Bu dose, but no other neurotoxicity was apparent. Incidence of acute GVHD grades II to IV was 8% and incidence of grade III-IV was 3%, with no deaths from this cause. Actuarial incidence of chronic GVHD at 2 years is 38%. There were 2 cases of graft failure in unrelated donor BMT recipients, 1 of which was reversed by asecond transplantation. With a median follow-up of 16 months (range, 6-27 months), transplantation-related mortality at 100 days and 2 years was 2% and 5% for matched related donor (MRD) SCT and 8% and 19% for AD SCT, respectively (P = not significant). Relapse rates were 21% for 34 patients with acute myeloid leukemia (AML) in complete remission or chronic myeloid leukemia in chronic phase (low-risk), 66% for 19 patients with high-risk AML, and 18% for 17 patients with other active malignancy. Projected disease-free and overall

  15. [On certain embryopathies induced by teratogenic agents (author's transl].

    PubMed

    Majewski, F

    1977-06-01

    In a survey of the literature the teratogenic effects of radiation and some drugs are discussed. Teratogenicity is proved for thalidomide, aminopterin, busulfan, cyclophosphamide, chlorambucil, mercaptopurin and diphenylhydantoin, trimethadione and warfarin. After the thalidomide-tragedy drug-induced malformations of the embryo are extremely rare, whereas malformations due to alcohol are rather frequent. Own experiences with more than 70 patients with alcoholembryopathy are reported. Nicotin seems not to be teratogenic, but due to nicotin the perinatal mortality is elevated. The questionable teratogenic effects of Heroin and LSD are discussed. PMID:329123

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

    PubMed

    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. PMID:21227669

  17. Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice

    SciTech Connect

    Conklin, Daniel J.; Haberzettl, Petra; Jagatheesan, Ganapathy; Baba, Shahid; Merchant, Michael L.; Prough, Russell A.; Williams, Jessica D.; Prabhu, Sumanth D.; Bhatnagar, Aruni

    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

  18. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease

    PubMed Central

    Fuchs, Ephraim J.; Luznik, Leo; Lanzkron, Sophie M.; Gamper, Christopher J.; Jones, Richard J.; Brodsky, Robert A.

    2012-01-01

    Allogeneic marrow transplantation can cure sickle cell disease; however, HLA-matched donors are difficult to find, and the toxicities of myeloablative conditioning are prohibitive for most adults with this disease. We developed a nonmyeloablative bone marrow transplantation platform using related, including HLA-haploidentical, donors for patients with sickle cell disease. The regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, and graft-versus-host disease prophylaxis with posttransplantation high-dose cyclophosphamide, mycophenolate mofetil, and tacrolimus or sirolimus. After screening 19 patients, we transplanted 17, 14 from HLA-haploidentical and 3 from HLA-matched related donors. Eleven patients engrafted durably. With a median follow-up of 711 days (minimal follow up 224 days), 10 patients are asymptomatic, and 6 patients are off immunosupression. Only 1 patient developed skin-only acute graft-versus-host disease that resolved without any therapy; no mortality was seen. Nonmyeloablative conditioning with posttransplantation high-dose cyclophosphamide expands the donor pool, making marrow transplantation feasible for most patients with sickle cell disease, and is associated with a low risk of complications, even with haploidentical related donors. Graft failure, 43% in haploidentical pairs, remains a major obstacle but may be acceptable in a fraction of patients if the majority can be cured without serious toxicities. PMID:22955919

  19. Protective effects of cyclophosphamide, cyclosporin A and FK506 against antigen-induced lung eosinophilia in guinea-pigs.

    PubMed Central

    Norris, A A; Jackson, D M; Eady, R P

    1992-01-01

    A close association has been recognized between activated T cells and eosinophils in asthma, albeit circumstantial. The present study attempted to investigate this relationship in an animal model of lung eosinophilia using the new generation of T cell-selective immunosuppressants, cyclosporin A and FK506, compared with the myelotoxic immunosuppressive agent cyclophosphamide. Antigen challenge of ovalbumin-sensitized guinea-pigs resulted in a lung eosinophilia which was assessed by bronchoalveolar lavage. All three agents caused a marked suppression of lung eosinophilia at 24 h post-challenge when the compounds were administered at the time of sensitization but not when administered for 3 days before lavage. However, the lung eosinophilia at 72 h post-challenge was reduced significantly by FK506 and by cyclophosphamide, but not by cyclosporin A, when the drugs were administered for 3 days, before lavage. These results strongly suggest the involvement of T cells in antigen-induced late phase (72 h) eosinophilia in guinea-pigs but not at 24 h. The effects of cyclophosphamide were always associated with a reduction in circulating white cell counts, whereas cyclosporin A and FK506 showed no myelotoxic properties. These results suggest the potential therapeutic use of selective, non-cytotoxic immunosuppressive agents in asthma. PMID:1381297

  20. [The flavonoids effect against vinblastine, cyclophosphamide and paracetamol toxicity by inhibition of lipid-peroxydation and increasing liver glutathione concentration].

    PubMed

    Lahouel, M; Boulkour, S; Segueni, N; Fillastre, J P

    2004-07-01

    The paracetamol and cyclophosphamid are metabolized in the liver by the cytochrome P450. The formed reactive intermediates are responsible of a hepatocyte depletion of the glutathion and a lipoperoxydation. the vinblastine is also a chemotherapeutic agent hepatotoxic and hematotoxic. Otherwise, flavonoïds are polyphenols substances of plant origin having some biological and anti-oxydative properties. However no information is available on their effects on glutathion and glutathion-s-transferases. In our research, we valued the effect of oral administration of flavonoids (diosmine and quercetine) under shape of propolis extract to 60 mg/kg daily during 14 days, on hematological and hepatic toxicity of a single dose of cyclophosphamide 80 mg/kg by intravenous way, vinblastine 2 mg/kg by intravenous way and the hepatic toxicity of the paracetamol managed by oral way to 200 mg/kg corresponding to 2/3 the DL50 at the rat female albinos wistar. We did a blood numeration, an assessment of serum activities of transaminases and alkali phosphatases as well as quantification of the glutathion and the malondialdehyde (MDA) in liver homogenats of rats treated. Analyses are done at regular intervals; 1, 3, 7 and 14 days after the administration of drugs. In the group of rats treated by the cyclophosphamid paracetamol alone we observed since the 1st day, an increase of lipid peroxide (MDA) of 120% and a downfall of hepatic glutathion including the group receiving the vinblastine (until 210% of reduction). In the same way a severe leucopenia and a thrombopenia (70% of reduction) are observed between the 3rd and the 14th day at rats treated by the chemotherapeutic agents alone (cyclophosphamide and vinblastine). The combination of flavonoids with drugs have clearly reduced the effect of drugs toxicity. Indeed, the aplasic observed with the vinblastine, as well as the leucopenia and thrombopenia of the cyclophosphamide are corrected entirely. In the same way, we noted a restoration

  1. Cytoreduction of lymphoid malignancies and mobilization of blood hematopoietic progenitor cells with high doses of cyclophosphamide and etoposide plus filgrastim.

    PubMed

    Damon, Lloyd; Rugo, Hope; Tolaney, Sara; Navarro, Willis; Martin, Thomas; Ries, Curt; Case, Delvyn; Ault, Kenneth; Linker, Charles

    2006-03-01

    We evaluated the efficiency of high doses of cyclophosphamide (6 g/m2) and etoposide (2 g/m2) plus filgrastim (granulocyte colony-stimulating factor; G-CSF) to mobilize autologous hematopoietic progenitor cells in patients with non-Hodgkin lymphoma, multiple myeloma, and Waldenström macroglobulinemia. We also evaluated the safety of this regimen and the engraftment kinetics after myeloablative chemotherapy. Seventy-nine patients with high-risk or relapsed/primary refractory non-Hodgkin lymphoma, multiple myeloma, or Waldenström macroglobulinemia were treated. The mobilizing regimen was as follows: cyclophosphamide 600 mg/m2 twice daily for 10 doses, etoposide 200 mg/m2 twice daily for 10 doses (continuous; n=57) or 2 g/m2 over 10 hours on day 5 of etoposide (bolus; n=22), and G-CSF 5 microg/kg/d beginning day 14. Fifty-nine percent of patients achieved the primary end point (a CD34 cell dose of 5 million per kilogram with a single leukapheresis). More bolus etoposide patients achieved the primary end point (86%) compared with continuous etoposide patients (47%; P<.0001). The CD34 cell dose collected was greater in bolus etoposide patients (44 million per kilogram) than in continuous etoposide patients (10.9 million per kilogram; P<.0001). Patients took 3 weeks to recover >500/microL neutrophils and >20000/microL platelets after cyclophosphamide and etoposide. The overall response rate was 69% for non-Hodgkin lymphoma patients and 71% for multiple myeloma/Waldenström macroglobulinemia patients. The treatment-related mortality was 2.5%. Sixteen percent of surviving patients experienced grade>or=3 nonhematologic toxicity. Patients receiving bolus etoposide had significantly less grade>or=2 oral mucositis, less use of total parenteral nutrition, and less need for red blood cell and platelet transfusions. Sixty-four patients (81%) underwent autologous hematopoietic progenitor cell transplantation, with prompt engraftment. Four patients (5%) did not undergo autologous

  2. Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience.

    PubMed

    Berruti, A; Borasio, P; Gerbino, A; Gorzegno, G; Moschini, T; Tampellini, M; Ardissone, F; Brizzi, M P; Dolcetti, A; Dogliotti, L

    1999-11-01

    From 1990 to 1997, 16 consecutive patients with stage III and IVa invasive thymoma were treated in a single institution with primary chemotherapy consisting in adriamycin (40 mg m(-2)), cisplatin (50 mg m(-2)) administered intravenously on day 1, vincristine (0.6 mg m(-2)) on day 2 and cyclophosphamide (700 mg m(-2)) on day 4 (ADOC). The courses were repeated every 3 weeks. The aim was to evaluate the impact of this cytotoxic regimen with respect to response rate, per cent of patients radically resected, time to progression and overall survival. Two complete responses (one clinical and one pathological) and 11 partial responses were observed (overall response rate 81.2%); two patients had stable disease and one progressed. Toxicity was mild as only two patients developed grade III/IV neutropenia and one patient grade III nausea/vomiting. Nine patients were radically resected (five out of ten with stage III, and four out of six with stage IVa). Median time to progression and overall survival was 33.2 and 47.5 months respectively. Three patients were alive and disease free after more than 5 years. The ADOC scheme is highly active and manageable in the treatment of locally advanced thymoma. As a preoperative approach it should be offered to patients not amenable to surgery or to those surgically resectable but with a great deal of morbidity. PMID:10555755

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

    PubMed Central

    Gonzalez, Eric J.; Peterson, Abbey; Malley, Susan; Daniel, Mitchel; Lambert, Daniel; Kosofsky, Michael; Vizzard, Margaret A.

    2015-01-01

    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. PMID:25973443

  4. Protective effects of pine bark extract on developmental toxicity of cyclophosphamide in rats.

    PubMed

    Kim, Sung-Hwan; Lee, In-Chul; Lim, Jeong-Hyeon; Moon, Changjong; Bae, Chun-Sik; Kim, Sung-Ho; Shin, Dong-Ho; Park, Seung-Chun; Kim, Hyoung-Chin; Kim, Jong-Choon

    2012-02-01

    This study investigated the protective effects of pine bark extract (Pycnogenol®, PYC) against cyclophosphamide (CP)-induced developmental toxicity in rats. A total of 44 mated females were randomly assigned to the following four experimental groups: (1) vehicle control, (2) CP, (3) CP&PYC, or (4) PYC. All dams were subjected to a Caesarean section on day 20 of gestation, and fetuses were examined for morphological abnormalities. Oxidative stress analysis was performed on maternal hepatic tissues. CP treatment caused decreased fetal and placental weights and increased embryonic resorptions and fetal malformations. In addition, an increased malondialdehyde (MDA) concentration and decreased reduced glutathione (GSH) content and catalase activity were observed in the hepatic tissues. On the contrary, PYC treatment during pregnancy significantly ameliorated the CP-induced embryo-fetal developmental toxicity in rats. Moreover, MDA and GSH concentrations and catalase activity in hepatic tissues were not affected when PYC was administered in conjunction with CP. These results suggest that repeated administration of PYC has beneficial effects against CP-induced embryo-fetal developmental toxicity in rats, and that the protective effects of PYC may be due to both inhibition of lipid peroxidation and increased antioxidant activity. PMID:22036974

  5. Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid

    PubMed Central

    Zhu, He; Long, Min-Hui; Wu, Jie; Wang, Meng-Meng; Li, Xiu-Yang; Shen, Hong; Xu, Jin-Di; Zhou, Li; Fang, Zhi-Jun; Luo, Yi; Li, Song-Lin

    2015-01-01

    Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes’ activities and GSH’s level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co-administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver. PMID:26625948

  6. The dose of cyclophosphamide for treating paraquat-induced rat lung injury

    PubMed Central

    Choi, Jae-Sung; Jou, Sung-Shick; Oh, Mee-Hye; Kim, Young-Hee; Park, Min-Ju; Song, Ho-Yeon; Hong, Sae-Yong

    2013-01-01

    Background/Aims Cyclophosphamide (CP) is a promising treatment for severe cases of paraquat (PQ) poisoning. We investigated the effective dose of CP for mitigating PQ-induced lung injury. Methods Adult male Sprague-Dawley rats were allocated into five groups: control, PQ (35 mg/kg, intraperitoneal injection), and PQ + CP (1.5, 15, or 30 mg/kg). The dimensions of lung lesions were determined using X-ray microtomography (micro-CT), and histological changes and cytokine levels were recorded. Results The micro-CT results showed that 15 mg/kg CP was more effective than 1.5 mg/kg CP for treating PQ-induced lung injury. At a dose of 1.5 mg/kg, CP alleviated the histological evidence of inflammation and altered superoxide dismutase activity. Using 15 mg/kg CP reduced the elevated catalase activity and serum transforming growth factor (TGF)-β1 level. Conclusions A CP dose of > 15 mg/kg is effective for reducing the severity of PQ-induced lung injury as determined by histological and micro-CT tissue examination, possibly by modulating antioxidant enzyme and TGF-β1 levels. PMID:23864800

  7. Alternative donor hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for nonmalignant disorders

    PubMed Central

    Klein, Orly R.; Chen, Allen R.; Gamper, Christopher; Loeb, David; Zambidis, Elias; Llosa, Nicolas; Huo, Jeffrey; Dezern, Amy E.; Steppan, Diana; Robey, Nancy; Holuba, Mary Jo; Cooke, Kenneth R.; Symons, Heather J.

    2016-01-01

    Allogeneic (allo-) hematopoietic stem cell transplant (HSCT) is curative for many nonmalignant pediatric disorders, including hemoglobinopathies, bone marrow failure syndromes, and immunodeficiencies. There is great success using HLA-matched related donors for these patients; however, the use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplant-related mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) for GVHD prophylaxis has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable to that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant pediatric disorders other than hemoglobinopathies using alternative donors and PT/Cy. We transplanted eleven pediatric patients with life-threatening nonmalignant conditions using reduced intensity conditioning (RIC), alternative donors, and PT/Cy alone or in combination with tacrolimus and mycophenolate mofetil. We observed limited GVHD, no TRM, and successful engraftment sufficient to eliminate manifestations of disease in all patients. Allo-HSCT using alternative donors and PT/Cy shows promise for curing nonmalignant disorders; development of prospective clinical trials to confirm these observations is warranted. PMID:26860634

  8. Successful treatment of cerebral large vessel vasculitis in systemic lupus erythematosus with intravenous pulse cyclophosphamide.

    PubMed

    Kato, R; Sumitomo, S; Kawahata, K; Fujio, K; Yamamoto, K

    2015-07-01

    A 39-year-old woman with a six-year history of systemic lupus erythematosus (SLE) was admitted because of a prolonged high fever, discoid rash, and multiple lymphadenopathies. She also developed pericarditis, and was treated with intravenous methylprednisolone pulse therapy followed by prednisolone 50 mg daily and cyclosporine 100 mg daily. Meanwhile, she had a progressive headache, and a brain MRI revealed right pons infarction, although she did not have any abnormal neurological findings. An MRA revealed obvious irregular narrowing in the basilar, right vertebral and right posterior cerebral artery. There was no evidence of antiphospholipid syndrome. We concluded that the cause of the asymptomatic brain infarction was cerebral large vessel vasculitis associated with neuropsychiatric SLE. Intravenous cyclophosphamide pulse therapy was started, and two months later, we confirmed that the irregular arterial narrowing had markedly ameliorated.Cerebral large vessel vasculitis in neuropsychiatric SLE is very rare, and a marked amelioration has not been reported to date. Here, we present a rare case of cerebral large vessel vasculitis treated successfully with a clear visual presentation. PMID:25661835

  9. Combination of cyclophosphamide, rituximab, and intratumoral CpG oligodeoxynucleotide successfully eradicates established B cell lymphoma.

    PubMed

    Betting, David J; Hurvitz, Sara A; Steward, Kristopher K; Yamada, Reiko E; Kafi, Kamran; van Rooijen, Nico; Timmerman, John M

    2012-09-01

    Rituximab plus chemotherapy is standard therapy for patients with non-Hodgkin B cell lymphoma, but often complete response or cure is not achieved. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) can improve antibody-dependent cellular cytotoxicity and adaptive antitumor immune responses. Using a syngeneic murine B cell lymphoma expressing human CD20 (38C13-huCD20), we previously demonstrated that rituximab plus intratumoral CpG, but not systemic CpG, could eradicate up to half of 7-day established 38C13-huCD20 tumors. However, larger 10-day established tumors could not be cured with this regimen. We thus hypothesized that cytoreduction with cyclophosphamide (Cy) before immunotherapy might permit eradication of these more advanced tumor burdens. Pretreatment with Cy resulted in tumor eradication from 83% of animals treated with rituximab/CpG, whereas Cy/CpG or Cy/rituximab treatments only cured 30% or 17%, respectively (P<0.005). Tumor eradication depended on natural killer cells, but not T cells, macrophages, or complement. Only mice treated with Cy/rituximab/CpG partially resisted rechallenge with tumor cells. Foxp3 Treg and CD11bGr1 myeloid suppressor cells persisted within lymphoid organs after therapy, possibly influencing the ability to establish adaptive tumor immunity. In conclusion, cytoreduction with Cy permitted the cure of large, established lymphomas not otherwise responsive to rituximab plus intratumoral CpG immunotherapy. PMID:22892450

  10. Preventive effects of cedrol against alopecia in cyclophosphamide-treated mice.

    PubMed

    Chen, Shan-Shan; Zhang, Yan; Lu, Qiu-Li; Lin, Zhe; Zhao, Yuqing

    2016-09-01

    Although numerous hypotheses have been proposed to prevent chemotherapy-induced alopecia (CIA), effective pharmaceuticals have yet to be developed. In our study, the back hairs of C57BL/6 mice were factitiously removed. These mice were then treated with cedrol or minoxidil daily. Mice with early-stage anagen VI hair follicles were treated with cyclophosphamide (CYP, 125mg/kg) to induce alopecia. The CYP-damaged hair follicles were observed and quantified by using a digital photomicrograph. The results demonstrated that the minoxidil-treated mice suffered from complete alopecia similar to the model 6days after CYP administration. Simultaneously, the cedrol-treated (200mg/kg) mice manifested mild alopecia with 40% suppression. Histological observation revealed that anagen hair follicles of the cedrol-pretreated mice (82.5%) likely provided from damage compared with the sparse and dystrophic hair follicles of the model mice (37.0%). Therefore, the use of topical cedrol can prevent hair follicle dystrophy and provide local protection against CIA. PMID:27522546

  11. Soy-Based Multiple Amino Acid Oral Supplementation Increases the Anti-Sarcoma Effect of Cyclophosphamide

    PubMed Central

    Yao, Chien-An; Chen, Chin-Chu; Wang, Nai-Phog; Chien, Chiang-Ting

    2016-01-01

    The use of a mixture of amino acids caused a selective apoptosis induction against a variety of tumor cell lines, reduced the adverse effects of anti-cancer drugs and increased the sensitivity of tumor cells to chemotherapeutic agents. We evaluated the effects and underlying mechanisms of soy-derived multiple amino acids’ oral supplementation on the therapeutic efficacy of low-dose cyclophosphamide (CTX) and on tumor growth, apoptosis, and autophagy in severe combined immunodeficiency (SCID) mice that were injected with sarcoma-180 (S-180) cells. 3-methyladenine or siRNA knockdown of Atg5 was used to evaluate its effect on sarcoma growth. A comparison of mice with implanted sarcoma cells, CTX, and oral saline and mice with implanted sarcoma cells, CTX, and an oral soy-derived multiple amino acid supplement indicated that the soy-derived multiple amino acid supplement significantly decreased overall sarcoma growth, increased the Bax/Bcl-2 ratio, caspase 3 expression, and apoptosis, and depressed LC3 II-mediated autophagy. Treatment with 3-methyladenine or Atg5 siRNA elicited similar responses as CTX plus soy-derived multiple amino acid in downregulating autophagy and upregulating apoptosis. A low dose of CTX combined with an oral soy-derived multiple amino acid supplement had a potent anti-tumor effect mediated through downregulation of autophagy and upregulation of apoptosis. PMID:27043621

  12. Importance of pharmacokinetic studies on cyclophosphamide (NSC-26271) in understanding its cytotoxic effect.

    PubMed

    Donelli, M G; Bartosek, I; Guaitani, A; Martini, A; Colombo, T; Pacciarini, M A; Modica, R

    1976-04-01

    Pharmacokinetic studies on cyclophosphamide (CP) and its alkylating metabolites produced by hepatic biotransformation have been performed in vivo in animals and in vitro in the perfused liver. CP levels were determined by a gas-chromatographic method combined with mass-spectrometry, and production of alkylating metabolites was assayed by the 4-(4-nitrobenzyl)pyridine reaction for alkylating compounds. Differenes in serum drug levels between normal rats and rats bearing Walker 256 carcinosarcoma were observed in vivo and were confirmed by the liver-perfusion technique. Pharmacokinetic parameters and enzyme kinetic data both in normal and in tumor-bearing animals will be presented. The disappearance of CP and the corresponding formation of CP metabolites was significantly modified when (a) CP was given after previous treatment with a compound which alters its biotransformation (ie, phenobarbital, an inducer of microsomal metabolism), (b) CP was given after previous treatment with CP (which inhibits microsomal metablism), or (c) CP was given with competitive substrates of aldehyde oxidase or dehydrogenase (glyceraldehyde, chloral hydrate, and disulfiram). Results obtained in animals or in the perfused liver will be discussed. The significance of this modified CP metabolism in influencing its cytotoxic effect will be discussed and correlations between drug levels and activity will be presented. PMID:1277213

  13. Human Umbilical Cord Mesenchymal Stem Cells Therapy in Cyclophosphamide-Induced Premature Ovarian Failure Rat Model

    PubMed Central

    Song, Dan; Zhong, Yun; Qian, Chunfeng; Zou, Qinyan; Ou, Jian; Shi, Yichao; Gao, Liang; Wang, Gaigai; Liu, Zhenxing; Li, Haibo; Ding, Hailei; Wu, Huihua; Wang, Fuxin; Wang, Jing

    2016-01-01

    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. PMID:27047962

  14. Activity of lung neutrophils and matrix metalloproteinases in cyclophosphamide-treated mice with experimental sepsis

    PubMed Central

    Hirsh, Mark; Carmel, Julie; Kaplan, Viktoria; Livne, Erella; Krausz, Michael M

    2004-01-01

    Sepsis in patients receiving chemotherapy may result in acute respiratory distress syndrome, despite decreased number of blood neutrophils [polymorphonuclear neutrophils (PMNs)]. In the present study, we investigated the correlation of cyclophosphamide (CY)-induced neutropenia with the destructive potential of lung PMN in respect to formation of septic acute lung injury (ALI). Mice were treated with 250 mg/kg of CY or saline (control) and subjected to cecal ligation and puncture (CLP) or sham operation. ALI was verified by histological examination. Lung PMNs and matrix metalloproteinases (MMPs) were assessed by flow cytometry and gelatin zymography. CLP in CY-treated mice induced a typical lung injury. Despite profound neutropenia, CY treatment did not attenuate CLP-induced ALI. This might relate to only a partial suppression of PMN: CY has significantly reduced PMN influx into the lungs (P = 0.008) and suppressed their oxidative metabolism, but had no suppressive effect on degranulation (P = 0.227) and even induced MMP-9 activity (P = 0.0003). In CY-untreated animals, peak of CLP-induced ALI coincided with massive PMN influx (P = 0.013), their maximal degranulation (P = 0.014) and activation of lung MMP-9 (P = 0.002). These findings may indicate an important role of the residual lung PMN and activation of MMP-9 in septic lung injury during CY chemotherapy. PMID:15255968

  15. Blueberry anthocyanins-enriched extracts attenuate the cyclophosphamide-induced lung toxicity.

    PubMed

    Tan, Dehong; Liu, Yunen; Shi, Lin; Li, Bin; Liu, Ling; Bai, Bing; Meng, Xianjun; Hou, Mingxiao; Liu, Xiaoxu; Sheng, Lei; Luo, Xinyue

    2014-10-16

    The influence of blueberry anthocyanins-enriched extracts (BAE) on cyclophosphamide (CTX)-induced lung damage was investigated. BAE (20 and 80mg/kg/d) were orally dosed to rats 7d both before and after CTX administration (100mg/kg, intraperitoneal injection, single dose). The results showed CTX treatment induced obvious pathological pulmonary injury with raised injury score and lung/body weight ratio. In CTX group, the activity of lysosomal proteases, lung permeability and the number of neutrophil infiltrates all elevated. On the other hand, claudin-4 and zonula occluden-1 protein levels decreased. And also changes of oxidative stress and inflammatory cytokines parameters together with nuclear factor-κB activation were shown. Improvement of all above-mentioned physiological and biochemical parameters was exhibited in BAE groups, with a dose-dependent manner. In conclusion, BAE attenuate the CTX-induced lung toxicity, antioxidant and anti-inflammatory characteristics are involved in the protective mechanism of BAE. PMID:25451569

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

    PubMed

    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. PMID:26133371

  17. Effect of epimedium polysaccharide-propolis flavone immunopotentiator on immunosuppression induced by cyclophosphamide in chickens.

    PubMed

    Fan, Yunpeng; Lu, Yu; Wang, Deyun; Liu, Jiaguo; Song, Xiaoping; Zhang, Weimin; Zhao, Xiaojuan; Nguyen, The Luong; Hu, Yuanliang

    2013-01-01

    Two hundred and fifty 11-day-old chickens were randomly assigned into 5 groups and except normal control group injected with cyclophosphamide once a day for 3 successive days. At day-14-old, all chickens were vaccinated with Newcastle disease vaccine. At the same time of the first vaccination, the chickens in three experimental groups were injected respectively with epimedium polysaccharide-propolis flavone immunopotentiator (EPI) at three dosages, once a day for 3 successive days. On days 7, 14, 21 and 28 after the first vaccination, the serum antibody titer and IgG, IgM, IFN-γ and IL-6 concentrations, peripheral lymphocyte proliferation, including immune organ index on day 28, were measured. The results demonstrated that EPI at high and medium doses could significantly enhance antibody titer and IgG, IgM, IFN-γ and IL-6 concentrations, promote lymphocyte proliferation and enlarge immune organ index as compared with model control group. This indicated that EPI could effectively resist the immunosuppression. PMID:23435348

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

    PubMed Central

    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. PMID:26133371

  19. Follicle Loss and Apoptosis in Cyclophosphamide-Treated Mice: What’s the Matter?

    PubMed Central

    Chen, Xiu-Ying; Xia, He-Xia; Guan, Hai-Yun; Li, Bin; Zhang, Wei

    2016-01-01

    With increasing numbers of young female cancer survivors following chemotherapy, chemotherapy-induced fertility loss must be considered. Menstrual disorder and infertility are of particular concern in female cancer patients. We showed that treatment with the alkylating agent cyclophosphamide (CTX) could cause severe primordial follicle loss and growing follicle apoptosis, resulting in loss of ovarian reserve. SPF C57BL/6 female mice were treated with a single dose of 120 mg/kg of CTX or saline as a control, and both sides of ovaries were collected three or seven days after injection. Following CTX treatment, the ovaries were mostly composed of collapsed oocytes and presented marked cortical fibrosis and a reduced number of follicles, especially primordial follicles. The loss of primordial follicles was confirmed by primordial follicle counting, immunohistochemistry and Western blot detection of DDx4/MVH. Follicle apoptosis was tested by a TUNEL assay and the number of TUNEL-positive follicle cells increased, as expected, in CTX-treated mice. Furthermore, expression of APAF-1 and cleaved caspase-3 was also increased after CTX treatment. Analysis of the PI3K/Akt/mTOR signaling pathway showed that CTX increased phosphorylation of Akt, mTOR and downstream proteins without affecting total levels. These results demonstrated that the CTX treatment led to the hyperactivation of the PI3K/Akt/mTOR signaling pathway in ovaries which may be related to primordial follicle loss and growing follicle apoptosis. PMID:27248997

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

    PubMed Central

    Bakhtiary, Zahra; Shahrooz, Rasoul; Ahmadi, Abbas; Soltanalinejad, Farhad

    2016-01-01

    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. PMID:27123204

  1. Honey bee is a potential antioxidant against cyclophosphamide-induced genotoxicity in albino male mice.

    PubMed

    Zoheir, Khairy Mohamed Abdallah; Harisa, Gamaleldin Ibrahim; Abo-Salem, Osama Mohamed; Ahmad, Sheikh Fayaz

    2015-05-01

    The protective effects of honey bee (HB) and pollen grains against cyclophosphamide (CPM) -induced cytotoxic and genotoxic effects in mice were investigated. This was achieved through study the effects of CPM and HB on oxidative status, chromosomal aberrations and gene expression of the tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin-1β (IL1β), interleukin 17A (IL-17A) and interferon-gamma (IFN-γ) in mice. In addition, the levels of reduced glutathione (GSH) and malondialdehyde were determined. The results of this study revealed that CPM decrease in GSH level and increase in malondialdehyde (MDA) level in the liver and kidney tissues. Moreover, CPM induced sperm abnormality, chromosomal aberrations and down regulated the expression of the studied cytokine genes. HB treatment in association with CPM ameliorates GSH, MDA, chromosomal aberrations and regulated the expression of IL-1-β, IL-17A, IL-6, TNF-α and IFN-γ. Thus, HB inhibits the cytotoxic and genotoxic risks associated with CPM treatment in mice. PMID:26004732

  2. Alternative-Donor Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide for Nonmalignant Disorders.

    PubMed

    Klein, Orly R; Chen, Allen R; Gamper, Christopher; Loeb, David; Zambidis, Elias; Llosa, Nicolas; Huo, Jeffrey; Dezern, Amy E; Steppan, Diana; Robey, Nancy; Holuba, Mary Jo; Cooke, Kenneth R; Symons, Heather J

    2016-05-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many nonmalignant pediatric disorders, including hemoglobinopathies, bone marrow failure syndromes, and immunodeficiencies. There is great success using HLA-matched related donors for these patients; however, the use of alternative donors has been associated with increased graft failure, graft-versus-host disease (GVHD), and transplant-related mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) for GVHD prophylaxis has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable with that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant pediatric disorders other than hemoglobinopathies using alternative donors and PT/Cy. We transplanted 11 pediatric patients with life-threatening nonmalignant conditions using reduced-intensity conditioning, alternative donors, and PT/Cy alone or in combination with tacrolimus and mycophenolate mofetil. We observed limited GVHD, no TRM, and successful engraftment sufficient to eliminate manifestations of disease in all patients. Allogeneic HSCT using alternative donors and PT/Cy shows promise for curing nonmalignant disorders; development of prospective clinical trials to confirm these observations is warranted. PMID:26860634

  3. Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid.

    PubMed

    Zhu, He; Long, Min-Hui; Wu, Jie; Wang, Meng-Meng; Li, Xiu-Yang; Shen, Hong; Xu, Jin-Di; Zhou, Li; Fang, Zhi-Jun; Luo, Yi; Li, Song-Lin

    2015-01-01

    Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes' activities and GSH's level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co-administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver. PMID:26625948

  4. Immuno-enhancement effects of Lycium ruthenicum Murr. polysaccharide on cyclophosphamide-induced immunosuppression in mice

    PubMed Central

    Gong, Yuan; Wu, Jin; Li, Shi-Tong

    2015-01-01

    Lycium ruthenicum Murr. is commonly used in traditional Tibetan medicine, and the fruits of Lycium ruthenicum Murr. contain an immunologically active pectin which improves immune function against chronic diseases. The present study was performed to evaluate the immunomodulatory effects of Lycium ruthenicum Murr. polysaccharide 3 (LRGP3) in cyclophosphamide (Cy)-induced immunosuppressed mice. Mice were injected intraperitoneally once daily with low-dose (25 mg/kg), intermediate-dose (50 mg/kg), high-dose (100 mg/kg) of LRGP3 for 10 consecutive days, respectively. Compared with Cy group, LRGP3 accelerated recovery of spleen and thymus indices, enhanced T cell and B cell proliferation responses, as well as peritoneal macrophage phagocytosis. In addition, LRGP3 treatment restored the levels of interleukin-2 (IL-2), IL-6 and tumor necrosis factor-α (TNF-α) in the serum of Cy-treated mice. These results indicate that LRGP3 plays an important role in the protection against immunosuppression in Cy-treated mice and could be a potential immunomodulatory agent. PMID:26884983

  5. Comparison of Doctors' and Breast Cancer Patients' Perceptions of Docetaxel, Epirubicin, and Cyclophosphamide (TEC) Toxicity.

    PubMed

    Bayo, Juan; Prieto, Blanca; Rivera, Francisco

    2016-05-01

    In Spain, around 26,000 cases of breast cancer are diagnosed each year, representing nearly 30% of all cancers in women. The aim this study was to compare the perceptions of nonhematologic toxicities after administration of a docetaxel, epirubicin, and cyclophosphamide (TEC) regimen between breast cancer patients and oncologists. Furthermore, the relationship between such adverse events and quality of life (QOL) was evaluated. Cross-sectional study carried out among 92 breast cancer patients who received TEC as neoadjuvant or adjuvant treatment. The main nonhematologic toxicities experienced by breast cancer patients treated with the TEC regimen were asthenia, nausea, dysgeusia, arthralgia, headache, and myalgia. Patients were less likely to be affected by vomiting and peripheral neuropathy. Oncologists seemed to show greater interest in toxicities, such as asthenia, nausea, and diarrhea. Vomiting was the toxicity with the most substantial degree of agreement between oncologist and patient. Toxicities with greater disagreement were dysgeusia, arthralgia, myalgia, asthenia, and headache. Asthenia, dysgeusia, loss of appetite, skin allergies, peripheral edema, abdominal pain, and myalgia were found to significantly affect the QOL. Tolerability and QOL were more favorable in patients treated with pegfilgrastim compared with filgrastim. Oncologists tend to underestimate toxicities experienced by breast cancer patients treated with the TEC regimen. The establishment of a protocol to record these toxicities may reduce that problem. PMID:26864346

  6. Hemophagocytic syndrome following haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide.

    PubMed

    Jaiswal, Sarita Rani; Chakrabarti, Aditi; Chatterjee, Sumita; Bhargava, Sneh; Ray, Kunal; Chakrabarti, Suparno

    2016-02-01

    Hemophagocytic syndrome (HPS) is a rare but serious complication after allogeneic transplantation which has been reported to be particularly high after unrelated cord blood transplantation. We report on the incidence, risk factors and outcome of HPS in 51 patients (age 2-64 years) after haploidentical peripheral blood stem cell (PBSC) transplantation with post-transplantation cyclophosphamide (PTCY). The incidence of HPS was 12.2 %, occurring at a median of 18 days. The non-relapse mortality in patients with HPS was 83.3 % compared to 11.6 % in patients without HPS. Complete donor chimerism was documented in all patients with HPS. Definite infective etiology was identified in two patients only. The others were refractory to multiple lines of treatment and 3 patients underwent a second transplant. Even though the symptoms and biochemical markers of HPS showed prompt response in 2/3 patients undergoing a second allograft, they succumbed to infections before haematological recovery. The others succumbed to multi-organ failure or infections. Age < 10 years, transplantation for non-malignant disease and high CD34 content of the graft were identified as risk factors for HPS. Considering the fact that post-transplant HPS is usually a refractory and fatal condition, we discuss further attempts at deciphering the pathogenesis, developing modalities to prevent this complication and improve the outcome. PMID:26619832

  7. Cyclophosphamide, doxorubicin, and cisplatin in the treatment of non-small cell bronchogenic carcinoma.

    PubMed

    Evans, W K; Feld, R; DeBoer, G; Osoba, D; Curtis, J E; Baker, M A; Myers, R E; Quirt, I C; Pritchard, K I; Brown, T C; Kutas, G J; Blackstein, M E; Ottema, B; Millband, L

    1981-01-01

    One hundred and forty-three patients with unresectable non-small cell bronchogenic carcinoma were treated with combination chemotherapy consisting of cyclophosphamide, doxorubicin, and cisplatin (CAP). Objective responses were seen in 27.5% of 131 evaluable patients. Response rates for squamous cell carcinoma, adenocarcinoma, and large cell anaplastic carcinoma were 30.2% (13 of 43 patients), 28.0% (14 of 50), and 32.1% (nine of 28), respectively. The median survival time for responders with extensive disease was 33.0 weeks compared with 29.3 weeks for patients with stable disease and only 9.6 weeks for patients with disease progression. The survival advantage of patients responding to CAP relative to those who had disease progression during treatment is highly significant statistically (P = 0.0005). However, patients whose disease remained stable also had longer survival than those who had disease progression (P = 0.001), and their survival was not significantly different from that of responders (P = 0.19). The CAP chemotherapy regimen was generally well-tolerated, although acute gastrointestinal symptoms were common. Our results indicate that CAP chemotherapy can cause tumor regression in patients with non-small cell bronchogenic carcinoma and may extend the survival of responding patients. PMID:7028256

  8. Cadmium chloride strongly enhances cyclophosphamide-induced chromosome aberrations in mouse bone marrow cells

    SciTech Connect

    Pandurangarao, V.L.; Blazina, S.; Bherje, R.

    1997-10-01

    Earlier we reported that a single 5 mg cadmium chloride (CdCl{sub 2})/kg ip dose enhanced chromosome aberrations (ca) with 50 mg/kg cyclophosphamide (CP) in mouse bone marrow cells. In this report groups of 4 mice were injected ip with saline, 0.31, 0.62, 1.25, 2.5 or 5.0 mg/kg CdCl{sub 2}, followed by saline injections at 24 h. Other mice similarly uninjected at 0 h were injected with 50 mg/kg CP at 24 h. All the mice were injected ip with 4 mg colchicine/kg at 44 h. At 48 h the bone marrow cells were processed for chromosome spreads. After dissection, visual examination revealed obvious internal hemorrhaging of the testes at 1.25 CdCl{sub 2} mg/kg and higher doses. This effect was not further increased by CP treatment. The lowest ca enhancing dose of CdCl{sub 2} on CP was 0.625 mg/kg. Our hypothesis is that Cd replaces zinc presents in numerous DNA repair enzymes and proteins resulting in diminished repair. Subsequently, the excess of unrepaired DNA damage is seen as chromatid breaks, deletions, fragments and exchanges.

  9. Curculigo orchioides Gaertn Effectively Ameliorates the Uro- and Nephrotoxicities Induced by Cyclophosphamide Administration in Experimental Animals.

    PubMed

    Murali, Vishnu Priya; Kuttan, Girija

    2016-06-01

    Background Curculigo orchioides Gaertn is an ancient medicinal plant (Family: Amaryllidaceae), well known for its immunomodulatory and rejuvenating effects. Cyclophosphamide (CPA) is an alkylating agent widely used for treating a variety of human malignancies, but associated with different toxicities too. Our previous reports regarding the hemoprotective and hepatoprotective effects of the plant against CPA toxicities provide the background for the present study, which is designed to analyze the ameliorative effect of the methanolic extract of C orchioides on the urotoxicity and nephrotoxicity induced by CPA. Methods CPA was administered to male Swiss albino mice at a single dose of 1.5 mmol/kg body weight to induce urotoxicity after 5 days of prophylactic treatment with C orchioides extract (20 mg/kg body weight). Mesna (2-mercaptoethanesulfonate) was used as a control drug. Serum, tissue, and urine levels of kidney function markers and antioxidant levels were checked along with the serum cytokine levels. Results The plant extract was found to be effective in ameliorating the urotoxic and nephrotoxic side effects of CPA. Upregulation of serum interferon-γ and interleukin-2 levels were observed with C orchioides treatment, which was decreased by CPA administration. Besides these, serum tumor necrosis factor-α level was also downregulated by C orchioides treatment. Conclusion Curculigo orchioides was found to be effective against the CPA-induced bladder and renal toxicities by its antioxidant capability and also by regulating the pro-inflammatory cytokine levels. PMID:26424815

  10. Dietary L-arginine supplementation alleviates immunosuppression induced by cyclophosphamide in weaned pigs.

    PubMed

    Han, J; Liu, Y L; Fan, W; Chao, J; Hou, Y Q; Yin, Y L; Zhu, H L; Meng, G Q; Che, Z Q

    2009-10-01

    A study was conducted to investigate the effects of L-arginine (Arg) on performance and immune function in cyclophosphamide (CY) immunosuppressed weaned pigs. The weaned pigs were allotted randomly into one of three treatments, including: (1) non-challenged control; (2) CY-challenged group; and (3) CY + 0.5% Arg. On days 14 and 21 of the trial, pigs were injected with CY or sterile saline. Blood samples were obtained on days 21 and 28 of the trial for further analysis. On day 28, delayed-type hypersensitivity reaction was evaluated. Arg alleviated the decrease of average daily gain (P < 0.05) induced by CY challenge from days 21 to 28. Arg mitigated the CY-induced decrease of total white blood cell numbers (P < 0.05) on day 28 and improved the lymphocyte percentage on day 21 (P < 0.05). Arg increased the delayed-type hypersensitivity reaction (P < 0.05), and attenuated the decrease of bovine serum albumin antibody level caused by CY treatment (P < 0.05) on day 28. In addition, Arg elevated the levels of serum interleukin-2 and interferon-gamma (P < 0.05) on day 28, and mitigated the decrease of serum interferon-gamma level on day 21 (P < 0.05). These results indicate that Arg supplementation has beneficial effects in attenuating the immunosuppressive effects of CY challenge, therefore improving growth performance of young pigs. PMID:18821052

  11. Beneficial Effects of American Ginseng on Epididymal Sperm Analyses in Cyclophosphamide Treated Rats

    PubMed Central

    Akram, Hosseini; Ghaderi Pakdel, Firouz; Ahmadi, Abbas; Zare, Samad

    2012-01-01

    Objective: This study aims to evaluate the protective effects of American ginseng administered by gastric intubation on sperm vital quality in adult male rats treated with cyclophosphamide (CP). Materials and Methods: In this experimental study, 28 Adult male Wistar rats were assigned to four groups, seven rats in each. The animals allocated to control, CP treated, Ginseng treated and CP-Ginseng treated groups. Rats were treated with CP (6.1 mg/kg/day, i.p) for 6 weeks. American ginseng was used at a dose of 500 mg/kg/day during treatment. Sperm analysis (motion, count, morphology and viability) were evaluated at the end of the experiments. Sperm motion was assessed by Computer-Assisted Sperm Analysis (CASA). The data were analyzed using GB stat software. Probability values of p<0.05 and p<0.01 were considered significant. Results: The epididymal sperm counts in the groups that received CP showed significant decreases compared to the control group. Also dead and abnormal sperms significantly increased following CP treatment compared with control. The motility of caudal sperm was reduced significantly with CP treatment. Therefore, according to the results of this study, co-administration of CP and American ginseng can improve these parameters. Conclusion: American ginseng can prevent the cytotoxic effects of CP on sperm quality factors. PMID:23508327

  12. A case of PRES in an active lupus nephritis patient after treatment of corticosteroid and cyclophosphamide.

    PubMed

    Jabrane, M; Ait Lahcen, Z; Fadili, W; Laouad, I

    2015-05-01

    Posterior reversible encephalopathy syndrome (PRES) is primarily a radiological diagnosis. The syndrome is characterized by headache, altered mental status, seizures, and bilateral posterior white matter edema in a nonvascular distribution on neuroimaging with resolution of findings usually in 7-14 days (Casey et al. in AJNR Am J Neuroradiol 21:1199-1206, 2000). In most cases, computed tomography of the brain will show hypodense lesions in the parieto-occipital lobe. Although this syndrome is uncommon, prompt and accurate recognition allows early treatment, which has been shown to produce favorable outcomes. It is hypothesized that the dysfunction can be caused by a failure of autoregulation systemic hypertension or by the cytotoxic effects of vasculitides and immunosuppressive drugs. The present report is a possible second case of cyclophosphamide-induced PRES in a 16-year-old girl with systemic lupus erythematous and lupus nephritis. The initial suspected diagnosis was an ischemic stroke, but it was later changed, with resolution of symptoms after management of the underlying cause. PMID:25387825

  13. Protective effect of diallyl disulfide on cyclophosphamide-induced testicular toxicity in rats

    PubMed Central

    Kim, Sung-Hwan; Lee, In-Chul; Baek, Hyung-Seon; Moon, Changjong; Kim, Sung-Ho

    2013-01-01

    This study investigated the protective effects of diallyl disulfide (DADS) against cyclophosphamide (CP)-induced testicular toxicity in male rats. DADS was gavaged to rats once daily for 3 days at 100 mg/kg/day. One hour after the final DADS treatment, the rats were given a single intraperitoneal dose of 150 mg/kg CP. All rats were killed and necropsied on day 56 after CP treatment. Parameters of testicular toxicity included reproductive organ weight, testicular sperm head count, epididymal sperm motility and morphology, epididymal index, and histopathologic examinations. The CP treatment caused a decrease in body weight, testicular sperm head count, epididymal sperm motility, and epididymal index. The histopathological examination revealed various morphological alterations, characterized by degeneration of spermatogonia/spermatocytes, vacuolization, and decreased number of spermatids/spermatocytes in the testis, and cell debris and mild oligospermia in the ductus epididymis. In contrast, DADS pretreatment effectively attenuated the testicular toxicity caused by CP, including decreased sperm head count, epididymal sperm motility, and epididymal index and increased histopathological alterations in the testis and epididymis. These results indicate that DADS attenuates testicular toxicity induced by CP in rats. PMID:24396385

  14. Interleukin-5 is necessary for eosinophilia induced by cyclophosphamide in immunized mice.

    PubMed Central

    Mu, H H; Penny, R; Sewell, W A

    1993-01-01

    Interleukin-5 (IL-5) has an important role in the induction of eosinophilia, which is associated with parasitic infestations and with allergic conditions, and which can be induced in a number of experimental systems. One of these model systems involves the administration of cyclophosphamide (CY) to immunized animals. In order to assess the role of IL-5 in this model, eosinophilia was induced in vivo and cell suspensions of spleens or lymph nodes were stimulated in vitro. IL-5 protein secretion was detected by bioassay using an IL-5-dependent cell line (T88-m), and mRNA was assessed by reverse transcription and polymerase chain reaction (RT-PCR). The production of IL-5 protein and mRNA were greatly enhanced in the cells from mice given CY with ovalbumin (OVA), compared with mice given either agent alone. IL-5 protein and mRNA were increased both in spleen and in lymph node cells, and in response either to OVA or to polyclonal stimuli. Further evidence for the importance of IL-5 in this model of eosinophilia was provided by experiments with monoclonal antibodies (mAb) in vivo. A single injection of an IL-5-specific mAb at the time of immunization completely abolished the eosinophilia. By contrast, a monoclonal antibody to IL-4 had no effect. These experiments indicate that IL-5 is required for the eosinophilia induced by CY in immunized mice. Images Figure 3 PMID:8406572

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

    PubMed

    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. PMID:22393965

  16. Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide

    PubMed Central

    Kanakry, Christopher G.; Coffey, David G.; Towlerton, Andrea M.H.; Vulic, Ante; Storer, Barry E.; Chou, Jeffrey; Yeung, Cecilia C.S.; Gocke, Christopher D.; Robins, Harlan S.; O’Donnell, Paul V.; Luznik, Leo; Warren, Edus H.

    2016-01-01

    Posttransplantation cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD), but its immunologic impact is poorly understood. We assessed lymphocyte reconstitution via flow cytometry (n = 74) and antigen receptor sequencing (n = 35) in recipients of myeloablative, HLA-matched allogeneic BM transplantation using PTCy. Recovering T cells were primarily phenotypically effector memory with lower T cell receptor β (TRB) repertoire diversity than input donor repertoires. Recovering B cells were predominantly naive with immunoglobulin heavy chain locus (IGH) repertoire diversity similar to donors. Numerical T cell reconstitution and TRB diversity were strongly associated with recipient cytomegalovirus seropositivity. Global similarity between input donor and recipient posttransplant repertoires was uniformly low at 1–2 months after transplant but increased over the balance of the first posttransplant year. Blood TRB repertoires at ≥3 months after transplant were often dominated by clones present in the donor blood/marrow memory CD8+ compartment. Limited overlap was observed between the TRB repertoires of T cells infiltrating the skin or gastrointestinal tract versus the blood. Although public TRB sequences associated with herpesvirus- or alloantigen-specific CD8+ T cells were detected in some patients, posttransplant TRB and IGH repertoires were unique to each individual. These data define the immune dynamics occurring after PTCy and establish a benchmark against which immune recovery after other transplantation approaches can be compared. PMID:27213183

  17. Bronchial hyperreactivity occurs in steroid-treated guinea pigs depleted of leukocytes by cyclophosphamide

    SciTech Connect

    Murlas, C.; Roum, J.H.

    1985-05-01

    The effects of cyclophosphamide and cortisone acetate treatment on O/sub 3/-induced changes in airway mucosal morphology and bronchial reactivity were assessed in guinea pigs. Animals in groups of four were studied at 2 or 6 h after O/sub 3/ (3.0 ppm, 2 h) and in one control group. Reactivity was determined by measuring specific airway resistance during intravenous acetylcholine infusion in intact, unanesthetized, spontaneously breathing animals. After testing, tracheal tissue was obtained from all animals for light microscopic examination. Another group of 10 drug-treated and 10 normal animals were tested at 2 h, 6 h, 1 day, and 4 days after O/sub 3/. Drug treatment resulted in substantial decreases in both circulating and airway mucosal granulocytes. Two hours after O/sub 3/, a marked decrease in airway mucosal goblet cells as well as ciliated cell damage occurred in both normal and treated animals. However, only in normal animals did neutrophilic infiltration develop thereafter. Nonetheless, hyperreactivity postozone occurred and progressed similarly in both groups. Our results indicate that acute O/sub 3/-induced bronchial hyperreactivity at 2 h is associated with signs of airway mucosal injury but appears independent of granulocyte changes. Airway neutrophilic infiltration and eosinophil depletion seem to be consequences of mucosal injury from O/sub 3/ and not causes of the bronchial hyperreactivity that results.

  18. Effects of cyclophosphamide on immune system and gut microbiota in mice.

    PubMed

    Xu, Xiaofei; Zhang, Xuewu

    2015-02-01

    Cyclophosphamide (CP) is the most commonly used drug in autoimmune disease, cancer, blood and marrow transplantation. Recent data revealed that therapy efficacy of CP is gut microbiota-dependent. So, it is very important to understand how CP affects intestinal microbiota and immune function. In this study, the effects of CP on mice immuno-activity were firstly evaluated, then, the fecal microbiota from normal and CP-treated mice was compared, and the characteristic bacterial diversity and compositions were identified, using 454 pyrosequencing technology. The results showed that CP reduced the diversity and shifted the fecal microbiota composition. Specifically, CP treatment decreased the proportion of Bacteroidetes while increased the proportion of Firmictutes in the microbial community. Most importantly, specific microbiota signatures belonging to Bacteroides acidifaciens, Streptococcaceae and Alistipes were also identified, which would provide new insight into the efficacy and side effects in clinical usage of CP. This should be helpful for further demonstration of CP's action mechanism, development of personalized therapy strategies, and prediction of potential side effects related to various treatment regimens of CP. PMID:25553830

  19. Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamide-induced hemorrhagic cystitis in rats.

    PubMed

    Vieira, Milena Morais; Macêdo, Francisco Yuri B; Filho, José Nelson Belarmino; Costa, Ana Carolina L V; Cunha, Adriano N; Silveira, Edilberto R; Brito, Gerly Anne C; Ribeiro, Ronaldo A

    2004-02-01

    To compare the classical uroprotective efficacy of mesna (2-mercaptoethanesulfonic acid) with ternatin (flavonoid isolated from Egletes viscosa Less.) in cyclophosphamide (CYP) and ifosfamide (IFS) induced hemorrhagic cystitis (HC). Male Wistar rats received an intraperitoneal injection of saline, CYP or IFS and were treated with saline or mesna, 5 min before, 4 and 8 h after CYP or IFS administration. In other animals, 1, 2 or 3 doses of mesna were replaced with ternatin or 3 doses of mesna were replaced with dimethylsulphoxide (DMSO), ternatin diluent. In an additional group, the last 2 doses of mesna were replaced with saline. HC was evaluated 24 h after CYP or IFS administration. CYP or IFS treatment induced marked changes in macroscopic and microscopic evaluation and in bladder wet weight (BWW), and these alterations were significantly inhibited by treatment with 3 doses of mesna, as well as by the replacement of 1 or 2 doses of mesna with ternatin. The replacement of 2 doses of mesna with saline or all doses of mesna with ternatin or DMSO did not prevent HC. In conclusion, the replacement of 1 or 2 doses of mesna with ternatin efficiently blocked CYP- or IFS-induced HC, however mesna is necessary for initial uroprotection. PMID:15022166

  20. A polysaccharide from Strongylocentrotus nudus eggs protects against myelosuppression and immunosuppression in cyclophosphamide-treated mice.

    PubMed

    Wang, Hui; Wang, Mengyu; Chen, Jing; Tang, Ying; Dou, Jie; Yu, Jian; Xi, Tao; Zhou, Changlin

    2011-11-01

    To assess the chemoprotective properties of a polysaccharide from Strongylocentrotus nudus eggs (SEP), myelosuppressed and immunosuppressed mouse models were generated by administration of cyclophosphamide (Cy) and then treated with SEP. SEP (16 mg/kg/d) remarkably increased spleen and thymus indices, activated the proliferation of leukocytes and erythrocytes and platelets from peripheral blood, and exhibited co-mitogenic activity on ConA- or LPS-stimulated splenocytes in a dose-dependent manner. An increased percentage of CD34(+) cells in bone marrow of Cy-treated mice was also observed. Furthermore, SEP elevated CD4(+) T lymphocyte counts as well as the CD4/CD8 ratio dose-dependently, and it increased interleukin-2 (IL-2), IgA, IgM, and IgG levels in the sera of Cy-treated mice. Pre-incubation with TLR2 and TLR4 blocking antibodies inhibited splenocyte proliferation and its IL-2 secretion. Finally, SEP significantly induced Akt phosphorylation in splenocytes from Cy-treated mice, suggesting that chemoprotection by SEP was mediated through the PI3K/Akt signaling pathway. These findings indicate that SEP plays an important role in the protection against myelosuppression and immunosuppression in Cy-treated mice and could be a potential immunomodulatory agent. PMID:21723424

  1. Pulse cyclophosphamide therapy in the management of patients with macular serpiginous choroidopathy

    PubMed Central

    Venkatesh, Pradeep; Gogia, Varun; Gupta, Shikha; Tayade, Akshay; Shilpy, Neha; Shah, Bhavin M; Guleria, Randeep

    2015-01-01

    Purpose: To evaluate safety and efficacy of intravenous pulse cyclophosphamide (CyP) in acute macular serpiginous choroiditis (SC). Methods: Patients with acute macular SC with lesions threatening and/or involving fovea were enrolled. All patients received CyP (1 g/m2 ) for 3 days followed by high-dose oral steroids (1.5 mg/kg) tapered over 6 months and monitored for visual acuity, response to treatment and systemic side effects. Results: Eight patients (seven unilateral and one bilateral) with median age of 27 years (range: 13–40 years) were recruited. Mean visual acuity at presentation was 0.71 ± 0.35 logarithm of the minimum angle of resolution while postpulse visual acuity was 0.40 ± 0.32. Final mean visual acuity at 1-year was 0.31 ± 0.23 (P ≤ 0.05). Three eyes had recurrence and 3 patients developed transient hair loss with no other adverse effect. Conclusion: Intravenous CyP provides rapid resolution of lesion activity and thereby helps in maintaining good functional acuity. PMID:26044470

  2. Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer

    PubMed Central

    Kummar, Shivaani; Oza, Amit M.; Fleming, Gini F.; Sullivan, Daniel M.; Gandara, David R.; Naughton, Michael J.; Villalona-Calero, Miguel A.; Morgan, Robert J.; Szabo, Peter M.; Youn, Ahrim; Chen, Alice P.; Ji, Jiuping; Allen, Deborah E.; Lih, Chih-Jian; Mehaffey, Michele G.; Walsh, William D.; McGregor, Paul M.; Steinberg, Seth M.; Williams, Paul M.; Kinders, Robert J.; Conley, Barbara A.; Simon, Richard M.; Doroshow, James H.

    2015-01-01

    Purpose Veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase 1 trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase 2 trial to determine the response rate of veliparib in combination with cyclophosphamide compared to cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC). Methods Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression. Results Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit. Conclusion This is the first trial that evaluated single agent, low dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression free survival. PMID:25589624

  3. Cyclophosphamide and tucotuzumab (huKS-IL2) following first-line chemotherapy in responding patients with extensive-disease small-cell lung cancer.

    PubMed

    Gladkov, Oleg; Ramlau, Rodryg; Serwatowski, Piotr; Milanowski, Janusz; Tomeczko, Janusz; Komarnitsky, Philip B; Kramer, Daniel; Krzakowski, Maciej J

    2015-11-01

    The humanized KS-interleukin-2, tucotuzumab (huKS-IL2; EMD 273066), is an EpCAM-specific immunocytokine with reported immunologic activity in combination with cyclophosphamide. This Phase 2, randomized, open-label study compared tucotuzumab/cyclophosphamide, administered as maintenance, with best supportive care (BSC) in patients with extensive-disease small-cell lung cancer (ED-SCLC) who responded to first-line platinum-based chemotherapy with/without prophylactic cranial irradiation (PCI). Patients received cyclophosphamide (300 mg/m, Day 1 of every 3-week cycle), followed by tucotuzumab (1.5 mg/m, Days 2-4) until disease progression. The primary endpoint was 6-month progression-free survival (PFS); the secondary objectives included overall survival (OS), treatment response, and safety. The 6-month PFS rate was lower in the tucotuzumab/cyclophosphamide group (n=64) than in the BSC group (n=44): 6.4 versus 12.2% [hazard ratio (HR): 0.98; 80% confidence interval (CI): 0.74-1.31]. HRs for PFS, time to progression, and OS indicated a similar risk of disease progression and death in both groups and best overall responses were generally comparable. For patients with previous PCI (n=26), there was a nonsignificant trend toward prolonged median PFS (1.7 vs. 1.5 months; HR: 0.60; 80% CI: 0.33-1.11) and OS (21.5 vs. 14.3 months; HR: 0.58; 80% CI: 0.31-1.05) in the tucotuzumab/cyclophosphamide group. Adverse events were more frequent with tucotuzumab/cyclophosphamide (92.2%) than with BSC (47.7%). Tucotuzumab/cyclophosphamide was well tolerated in ED-SCLC patients, but did not show PFS or OS benefits compared with BSC. The observed trend toward prolonged PFS and OS in the subgroup of patients receiving previous PCI may support further confirmation in a larger population. PMID:26295868

  4. Correlation between in vivo and in vitro studies of modulation of resistance to experimental Candida albicans infection by cyclophosphamide in mice.

    PubMed Central

    Bistoni, F; Baccarini, M; Blasi, E; Marconi, P; Puccetti, P; Garaci, E

    1983-01-01

    Mice receiving a single injection of cyclophosphamide (150 mg/kg) 1 to 6 days before inoculation with viable Candida albicans showed an increased susceptibility to the challenge accompanied by a reduction in peripheral blood polymorphonuclear leukocytes and lymphocytes as well as in spleen cellularity. Several immunological in vitro functions also appeared to be dramatically depressed. Most of these hematological and functional parameters returned to control values by day 9 after cyclophosphamide administration, at a time when resistance to C. albicans infection appeared to be unchanged. However, when exposure to cyclophosphamide occurred 12 to 21 days before inoculation with the live yeast, enhanced resistance was observed with the majority of the animals surviving challenge. To gain some insight into the mechanisms underlying this late increase in resistance to C. albicans infection after cyclophosphamide administration, we analyzed a series of immunological functions, including the in vitro candidacidal activity of polymorphonuclear neutrophils and plastic-adherent and nonadherent spleen cells as well as the activity of natural killer cells and alloreactive T lymphocytes. The results show that a numerical rebound of blood polymorphonuclear neutrophils and the appearance of a highly candidacidal cell population in the spleen may be among the factors underlying the late increase in resistance to C. albicans after administration of cyclophosphamide. PMID:6339410

  5. Correlation between in vivo and in vitro studies of modulation of resistance to experimental Candida albicans infection by cyclophosphamide in mice.

    PubMed

    Bistoni, F; Baccarini, M; Blasi, E; Marconi, P; Puccetti, P; Garaci, E

    1983-04-01

    Mice receiving a single injection of cyclophosphamide (150 mg/kg) 1 to 6 days before inoculation with viable Candida albicans showed an increased susceptibility to the challenge accompanied by a reduction in peripheral blood polymorphonuclear leukocytes and lymphocytes as well as in spleen cellularity. Several immunological in vitro functions also appeared to be dramatically depressed. Most of these hematological and functional parameters returned to control values by day 9 after cyclophosphamide administration, at a time when resistance to C. albicans infection appeared to be unchanged. However, when exposure to cyclophosphamide occurred 12 to 21 days before inoculation with the live yeast, enhanced resistance was observed with the majority of the animals surviving challenge. To gain some insight into the mechanisms underlying this late increase in resistance to C. albicans infection after cyclophosphamide administration, we analyzed a series of immunological functions, including the in vitro candidacidal activity of polymorphonuclear neutrophils and plastic-adherent and nonadherent spleen cells as well as the activity of natural killer cells and alloreactive T lymphocytes. The results show that a numerical rebound of blood polymorphonuclear neutrophils and the appearance of a highly candidacidal cell population in the spleen may be among the factors underlying the late increase in resistance to C. albicans after administration of cyclophosphamide. PMID:6339410

  6. Role of the KATP channel in the protective effect of nicorandil on cyclophosphamide-induced lung and testicular toxicity in rats.

    PubMed

    Ahmed, Lamiaa A; El-Maraghy, Shohda A; Rizk, Sherine M

    2015-01-01

    This study is the first to investigate the role of the KATP channel in the possible protection mediated by nicorandil against cyclophosphamide-induced lung and testicular toxicity in rats. Animals received cyclophosphamide (150 mg/kg/day, i.p.) for 2 consecutive days and then were untreated for the following 5 days. Nicorandil (3 mg/kg/day, p.o.) was administered starting from the day of cyclophosphamide injection with or without glibenclamide (5 mg/kg/day, p.o.). Nicorandil administration significantly reduced the cyclophosphamide-induced deterioration of testicular function, as demonstrated by increases in the level of serum testosterone and the activities of the testicular 3β- hydroxysteroid, 17β-hydroxysteroid and sorbitol dehydrogenases. Furthermore, nicorandil significantly alleviated oxidative stress (as determined by lipid peroxides and reduced glutathione levels and total antioxidant capacity), as well as inflammatory markers (tumour necrosis factor-α and interleukin-1β), in bronchoalveolar lavage fluid and testicular tissue. Finally, the therapy decreased the levels of fibrogenic markers (transforming growth factor-β and hydroxyproline) and ameliorated the histological alterations (as assessed by lung fibrosis grading and testicular Johnsen scores). The co-administration of glibenclamide (a KATP channel blocker) blocked the protective effects of nicorandil. In conclusion, KATP channel activation plays an important role in the protective effect of nicorandil against cyclophosphamide-induced lung and testicular toxicity. PMID:26403947

  7. Role of the KATP channel in the protective effect of nicorandil on cyclophosphamide-induced lung and testicular toxicity in rats

    PubMed Central

    Ahmed, Lamiaa A.; EL-Maraghy, Shohda A.; Rizk, Sherine M.

    2015-01-01

    This study is the first to investigate the role of the KATP channel in the possible protection mediated by nicorandil against cyclophosphamide-induced lung and testicular toxicity in rats. Animals received cyclophosphamide (150 mg/kg/day, i.p.) for 2 consecutive days and then were untreated for the following 5 days. Nicorandil (3 mg/kg/day, p.o.) was administered starting from the day of cyclophosphamide injection with or without glibenclamide (5 mg/kg/day, p.o.). Nicorandil administration significantly reduced the cyclophosphamide-induced deterioration of testicular function, as demonstrated by increases in the level of serum testosterone and the activities of the testicular 3β- hydroxysteroid, 17β-hydroxysteroid and sorbitol dehydrogenases. Furthermore, nicorandil significantly alleviated oxidative stress (as determined by lipid peroxides and reduced glutathione levels and total antioxidant capacity), as well as inflammatory markers (tumour necrosis factor-α and interleukin-1β), in bronchoalveolar lavage fluid and testicular tissue. Finally, the therapy decreased the levels of fibrogenic markers (transforming growth factor-β and hydroxyproline) and ameliorated the histological alterations (as assessed by lung fibrosis grading and testicular Johnsen scores). The co-administration of glibenclamide (a KATP channel blocker) blocked the protective effects of nicorandil. In conclusion, KATP channel activation plays an important role in the protective effect of nicorandil against cyclophosphamide-induced lung and testicular toxicity. PMID:26403947

  8. Reduction in Surface Contamination With Cyclophosphamide in 30 US Hospital Pharmacies Following Implementation of a Closed-System Drug Transfer Device

    PubMed Central

    Sessink, Paul J.M.; Trahan, Jason; Coyne, Joseph W.

    2013-01-01

    Purpose: In a follow-up to a previous study, surface contamination with the antineoplastic drug cyclophosphamide was compared in 30 US hospital pharmacies from 2004 to 2010 following preparation with standard drug preparation techniques or the PhaSeal closed system drug transfer device (CSTD). Methods: Wipe samples were taken from biological safety cabinet (BSC) surfaces, BSC airfoils (the front leading edge of the BSC), floors in front of BSCs, and countertops in the pharmacy, and they were analyzed for contamination with cyclophosphamide. Contamination was reassessed after a minimum of 6 months following the implementation of the CSTD. Surface contamination (ng/cm2) was compared between the 2 techniques and between the previous and current test periods and evaluated with the Kruskal-Wallis test. Results: With the use of CSTD compared to the standard preparation techniques, a significant reduction in levels of contamination with cyclophosphamide was observed (P < .0001). Median values for surface contamination with cyclophosphamide were reduced by 86% compared to 95% in the previous study. Conclusions: The CSTD significantly reduced, but did not totally eliminate, surface contamination with cyclophosphamide. In addition to other protective measures, increased usage of CSTDs should be employed to help protect health care workers from exposure to hazardous drugs. PMID:24421463

  9. Single low-dose cyclophosphamide combined with interleukin-12 gene therapy is superior to a metronomic schedule in inducing immunity against colorectal carcinoma in mice

    PubMed Central

    Malvicini, Mariana; Alaniz, Laura; Bayo, Juan; Garcia, Mariana; Piccioni, Flavia; Fiore, Esteban; Atorrasagasti, Catalina; Aquino, Jorge B.; Matar, Pablo; Mazzolini, Guillermo

    2012-01-01

    The use of conventional cytotoxic agents at metronomic schedules, alone or in combination with targeted agents or immunotherapy, is being explored as a promising anticancer strategy. We previously reported a potent antitumor effect of a single low-dose cyclophosphamide and interleukin-12 (IL-12) gene therapy against advanced gastrointestinal carcinoma, in mice. Here, we assessed whether the delivery of IL-12 by gene therapy together with metronomic cyclophosphamide exerts antitumor effects in a murine model of colorectal carcinoma. This combination therapy was able, at least in part, to reverse immunosuppression, by decreasing the number of regulatory T cells (Tregs) as well as of splenic myeloid-derived suppressor cells (MDSCs). However, metronomic cyclophosphamide plus IL-12 gene therapy failed to increase the number of tumor-infiltrating T lymphocytes and, more importantly, to induce a specific antitumor immune response. With respect to this, cyclophosphamide at a single low dose displayed a superior anticancer profile than the same drug given at a metronomic schedule. Our results may have important implications in the design of new therapeutic strategies against colorectal carcinoma using cyclophosphamide in combination with immunotherapy. PMID:23170252

  10. Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children.

    PubMed

    Meraz, José Eugenio Vázquez; Arellano-Galindo, José; Avalos, Armando Martínez; Mendoza-García, Emma; Jiménez-Hernández, Elva

    2016-01-01

    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/m(2) 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 × 10(9)/L. The average number of MNC/kg body weight (BW)/aphaeresis was 0.4 × 10(8) (0.1-1.4), 2.25 × 10(8) (0.56-6.28), and 1.02 × 10(8) (0.34-2.5) whereas the average number of CD34+ cells/kg BW/aphaeresis was 0.18 × 10(6)/kg (0.09-0.34), 1.04 × 10(6) (0.19-9.3), and 0.59 × 10(6) (0.17-0.87) and the count of CFU/kg BW/aphaeresis was 1.11 × 10(5) (0.31-2.12), 1.16 × 10(5) (0.64-2.97), and 1.12 × 10(5) (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 × 10(3)/μL in terms of MNC and CD34+ cells and there was no toxicity of the chemotherapy. PMID:26880960

  11. Intravesical epinephrine preserves uroplakin II expression in urinary bladder from cyclophosphamide-induced rat cystitis.

    PubMed

    Kyung, Yoon Soo; Park, Heeyoon; Lee, Gilho

    2012-08-01

    We investigated the attenuated effect of intravesical epinephrine (EPI) on uroplakin II (UPII) expression in cyclophosphamide (CYP)-induced rat cystitis. Sixty-eight Sprague-Dawley female rats were divided into one negative control group (GI) and five intraperitoneally CYP (150 mg CYP/kg)-injected groups (GII-VI) consisting of a positive control group (GII), three groups (GIII-V) with retaining intravesically instillated ameliorating agents for 90 min by urethral ligation until sacrifice, and one group (GVI) with freely voiding after intravesical EPI instillation. The retention groups were further classified into null-treated- (GIII), EPI- (GIV), and vehicle group (GV). All rats were euthanized 24 h after CYP injection. The UPII and α1-adrenergic receptors (AR) levels were measured with real-time polymerase chain reaction (RT-PCR) method and the morphological changes were also evaluated. CYP induced severe cystitis and decreased vesical UPII mRNA level. The EPI-treated groups had showed attenuation effects against submucosal edema and hemorrhage, and preserved UPII expression. Concurrently, intravesical EPI resulted in a significant preservation of both subtypes of α1A- and α1B AR expressions, which was well correlated with the hemostatic pattern in the samples. The obstructed and null-treated group (GIII) revealed severe cystitis and maximally decreased UPII levels, and the diluting effect of vehicle (GV) on CYP toxicity was insignificant on UPII preservation. The UPII level of RT-PCR was well correlated with the UPII immunohistological expression and their morphological changes. Intravesical instillation of EPI preserves UPII expression and attenuates the toxic responses in the bladder in CYP-induced rat cystitis. PMID:22638760

  12. Cyclophosphamide as a potent inhibitor of tumor thioredoxin reductase in vivo

    SciTech Connect

    Wang Xufang; Zhang Jinsong . E-mail: zjszyzzc@mail.hf.ah.cn; Xu Tongwen

    2007-01-01

    Cyclophosphamide (CTX) is in the nitrogen mustard group of alkylating antineoplastic chemotherapeutic agents. It is one of the most frequently used antitumor agents for the treatment of a broad spectrum of human cancers. Thioredoxin reductase (TrxR) catalyze the NADPH-dependent reduction of thioredoxin and play an important role in multiple cellular events related to carcinogenesis including cell proliferation, apoptosis, and cell signaling. This enzyme represents a promising target for the development of cytostatic agents. The purpose of this study is to determine whether CTX could target TrxR in vivo. Lewis lung carcinoma and solid H22 hepatoma treated with 50-250 mg/kg CTX for 3 h lost TrxR activity in a dose-dependent fashion. Over 75% and 95% of TrxR activity was lost at the dose of 250 mg/kg. There was, however, a recovery of TrxR activity such that it attained normal levels by 120 h after a dose of 250 mg/kg. In addition, we found that CTX caused a preferential TrxR inhibition over other antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase. We also used ascites H22 cells to investigate cancer cells response after TrxR was inhibited by CTX in vivo since CTX is needed to be activated by liver cytochrome P450 enzymes. The time course and dose-dependent changes of cellular TrxR activity were similar with those in tumor tissue. CTX caused a dose-dependent cellular proliferation inhibition which was positively correlated with TrxR inhibition at 3 h. Furthermore, when 3 h CTX-treated cells with various TrxR backgrounds, harvested from ascites-bearing mice, were implanted into mice, the proliferations of these cells were again proportionally dependent on TrxR activity. The TrxR inhibition could thereby be considered as a crucial mechanism contributing to anticancer effect seen upon clinical use of CTX.

  13. Protective effects of ethyl pyruvate on sperm quality in cyclophosphamide treated mice

    PubMed Central

    Bakhtiary, Zahra; Shahrooz, Rasoul; Ahmadi, Abbas; Zarei, Leila

    2015-01-01

    Background: One of the affecting factors in disturbance process of spermatogenesis is chemotherapeutic-induced oxidative stress resulted from cyclophosphamide (CP) treatment which leads to diminished sperm quality via interference in spermatogenesis process. Objective: This study was conducted to investigate the effects of ethyl pyruvate (EP) in reducing the CP-induced side effects on reproductive system. Materials and Methods: 24 mature male mice were randomly divided into 3 equal groups and were undergone therapy for 35 days. Control group received normal saline (0.1 ml/day, IP). CP group were injected CP (15 mg/kg/week, IP) and CP+EP group received EP (40 mg/kg/day, IP) as well as CP. In the end of the treatment period, the mice were euthanized by cervical dislocation. Then, the epididymis was incubated with CO2 in a human tubal fluid medium (1 ml) for half an hour in order to float sperm. Then, the number, motility, viability (eosin-nigrosin staining), DNA breakage (acridine orange staining), nucleus maturity, and sperm morphology (aniline blue staining) were analyzed. Results: The average (15.87±1.28), motility (35.77±2.75), viability (40±3.03), nucleus maturity (36±2.79) and sperm morphology (61.75±0.85) were decreased significantly in CP group in comparison with control and EP groups, whereas EP caused significant increase of these parameters. Also, the percentage of DNA damage was increased significantly in CP group (41.75±3.75) in comparison with control (2±0.71) and EP groups (22.5±4.13). Conclusion: The results of this study revealed ameliorating effects of EP on sperm quality of CP treated animals. PMID:26221128

  14. Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children

    PubMed Central

    Meraz, José Eugenio Vázquez; Arellano-Galindo, José; Avalos, Armando Martínez; Mendoza-García, Emma; Jiménez-Hernández, Elva

    2016-01-01

    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. PMID:26880960

  15. Protective effect of Andrographis paniculata and andrographolide on cyclophosphamide-induced urothelial toxicity.

    PubMed

    Sheeja, K; Kuttan, Girija

    2006-09-01

    The protective effect of Andrograhis paniculata and andrographolide (ANDLE) against cyclophosphamide (CTX)-induced urothelial toxicity was investigated in this study. Pretreatment of Swiss albino mice with A paniculata extract (10 mg/dose/animal intraperitoneally [ip]) and ANDLE (500 microg/dose/animal ip) could significantly reduce CTX (1.5 nmol/kg body weight)-induced urothelial toxicity. Morphological and histopathological analysis of urinary bladder of CTX-treated mice showed severe inflammation and dark coloration, whereas A paniculata and ANDLE-treated mice showed almost normal bladder morphology. Elevation of urinary protein level (7.33 +/- 0.3 g/L) by CTX administration was reduced by A paniculata (3.78 +/- 0.4 g/L) and ANDLE treatment (4.19 +/- 0.1 g/L). Urinary urea N2 level, which was elevated after 48 hours of CTX administration (24.25 +/- 0.2 g/L) was found to be reduced by the treatment with A paniculata (14.19 +/- 0.5 g/L) and ANDLE (15.79 +/- 0.4 g/L). A decreased level of reduced glutahione (GSH) content in liver (2.81 +/- 0.1 nmol/mg protein) and bladder (1.20 +/- 0.2 nmol/mg protein) after CTX administration was also increased by the treatment with A paniculata (liver: 5.78 +/- 0.3 nmol/mg protein; bladder: 2.96 +/- 0.2 nmol/mg protein) and ANDLE (liver: 5.14 +/- 0.3 nmol/mg protein; bladder: 2.84 +/- 0.2 nmol/mg protein). Production of the proinflammatory cytokine, tumor necrosis factor-alpha, which was elevated during CTX administration, was found to be inhibited by A paniculata and ANDLE treatment. The lowered level of interleukin-2 and interferon-gamma during CTX treatment was elevated by the administration of A paniculata and ANDLE. PMID:16880430

  16. Exhaled NO predicts cyclophosphamide response in scleroderma-related lung disease.

    PubMed

    Tiev, Kiet Phong; Rivière, Sébastien; Hua-Huy, Thong; Cabane, Jean; Dinh-Xuan, Anh Tuan

    2014-08-31

    Cyclophosphamide (CYC) is not always effective in patients with scleroderma-related interstitial lung disease (SSc-ILD), hence the need for biomarkers able to predict beneficial responses to CYC therapy. We therefore assessed whether baseline alveolar concentration of nitric oxide (CANO) could predict the favourable response to CYC therapy in patients with SSc-ILD. Nineteen non-smoker patients with SSc-ILD, were enrolled and treated with 6 courses of CYC (0.75 g/m2/monthly) for lung function decline the year before inclusion, and followed-up for 2 years period. We assessed the proportion of favourable response to CYC, defined as improvement of forced vital capacity (FVC) or total pulmonary capacity (TLC) more than 10% between the inclusion and each following visit, according to the validated cut-off of CANO at 8.5 ppb identifying progressive SSc-ILD subset. At inclusion, 7 patients out of 19 had CANO >8.5 ppb. Clinical parameters were comparable between patients with high (>8.5 ppb) and low level of CANO (≤8.5 ppb). After CYC therapy, and during the follow-up, 9 out of 19 patients had favourable response to CYC therapy, 10 did not meet responder's criteria, from whom 4 patients died from respiratory failure. Six out of 7 patients with CANO >8.5 ppb at inclusion had favourable response to CYC therapy, while only 3 out of 12 patients with CANO ≤8.5 ppb responded favourably to CYC therapy (p=0.001). High level of CANO >8.5 ppb reflecting alveolar inflammation identify SSc patients with a greater chance to benefit from CYC treatment with a significant lung function improvement. PMID:24831352

  17. Protective effect of quercetin on skeletal and neural tube teratogenicity induced by cyclophosphamide in rat fetuses

    PubMed Central

    Khaksary Mahabady, Mahmood; Gholami, Mohammad Reza; Najafzadeh Varzi, Hossein; Zendedel, Abolfazl; Doostizadeh, Mona

    2016-01-01

    Cyclophosphamide (CP) is a drug commonly used to treat neoplastic disease and some autoimmune diseases. It is also a well-known and well-studied teratogen causing a variety of birth defects in fetuses of pregnant women treated with the drug. There are many reports that show the adverse effects of CP can be decreased by use of antioxidant drugs. It appears that, quercetin has antioxidant effect. The aim of this study was prevention or decrease of teratogenicity of CP in fetuses of rats by quercetin. This study was performed on 35 pregnant rats divided into six groups. Control group was received normal saline (5 mL kg-1, intraperitoneally) and 2-6 groups received a single dose of CP (15 mg kg-1), a single dose of quercetin (75 or 200 mg kg-1), CP plus quercetin (75 or 200 mg kg-1) intraperitoneally at 9th day of gestation, respectively. Fetuses were collected at 20th day of gestation and after determination of weight and crown rump length were stained by alizarin red – alcian blue method and skeletal system were examined by stereomicroscope. The results showed that the cleft palate, exencephaly, spina bifida and omphalocele incidence were 55.56%, 27.77%, 33.34% and 11.11%, in fetuses of rat that received only CP, respectively. However, it decreased to 16.00%, 16.00%, 16.00% and 8.00% by quercetin (75 mg kg-1) and so to 12.90%, 12.90%, 6.45% and 3.28% by quercetin (200 mg kg-1), respectively. On the basis of results, quercetin significantly can decrease teratogenicity induced by CP. PMID:27482358

  18. Glutathione S Transferases Polymorphisms Are Independent Prognostic Factors in Lupus Nephritis Treated with Cyclophosphamide

    PubMed Central

    Verstuyft, Céline; Costedoat-Chalumeau, Nathalie; Hummel, Aurélie; Le Guern, Véronique; Sacré, Karim; Meyer, Olivier; Daugas, Eric; Goujard, Cécile; Sultan, Audrey; Lobbedez, Thierry; Galicier, Lionel; Pourrat, Jacques; Le Hello, Claire; Godin, Michel; Morello, Rémy; Lambert, Marc; Hachulla, Eric; Vanhille, Philippe; Queffeulou, Guillaume; Potier, Jacky; Dion, Jean-Jacques; Bataille, Pierre; Chauveau, Dominique; Moulis, Guillaume; Farge-Bancel, Dominique; Duhaut, Pierre; Saint-Marcoux, Bernadette; Deroux, Alban; Manuzak, Jennifer; Francès, Camille; Aumaitre, Olivier; Bezanahary, Holy; Becquemont, Laurent; Bienvenu, Boris

    2016-01-01

    Objective 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). Methods 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. Results 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. Conclusion This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients. PMID:27002825

  19. Effect of low frequency low energy pulsing electromagnetic fields on mice injected with cyclophosphamide

    SciTech Connect

    Cadossi, R.; Zucchini, P.; Emilia, G.; Franceschi, C.; Cossarizza, A.; Santantonio, M.; Mandolini, G.; Torelli, G. )

    1991-03-01

    C3H mice have been used to investigate the effect of a combination of cyclophosphamide (CY) and electromagnetic fields (PEMF). Mice were injected i.p. with a single dose of 200 mg/kg body weight of CY and then exposed to PEMF 24 h per day. In an initial series of experiments immediately after CY injection mice were exposed to PEMF until sacrifice. WBC counts in the peripheral blood demonstrated a quicker decline in WBC at days 1 and 2 in mice exposed to PEMF. Groups of mice were sacrificed at days 1, 4, 6, 8, and 10 after CY injection. In mice exposed to PEMF the spleen weight was less than in controls at days 6, 8, and 10. Autoradiographic studies demonstrated that the labeling index of bone marrow smears did not significantly differ between controls and experimental mice exposed to PEMF, whereas the spleen labeling index proved to be higher among control mice versus mice exposed to PEMF at day 6, and higher among mice exposed to PEMF versus controls at day 8. In a second series of experiments mice were exposed to PEMF only over the 24 h following CY injection. We found that the spleens of mice exposed to PEMF weighed less than those of controls at days 6 and 8. The labeling index of bone marrow did evidence a slight decrease among mice exposed to PEMF at days 8 and 10 after CY injection versus control mice. The spleen labeling index proved to be lower in experimental mice exposed to PEMF than in controls at days 4, 6, and 8. Mice were then injected with CY, half were exposed to PEMF, and 24 h later bone marrow was recovered from both groups of animals. The same number of bone marrow cells was injected via the tail vein into recipient mice irradiated to 8.5 Gy.

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

    PubMed

    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. PMID

  1. Alternative donor transplants for patients with advanced hematologic malignancies, conditioned with thiotepa, cyclophosphamide and antithymocyte globulin.

    PubMed

    Lamparelli, T; van Lint, M T; Gualandi, F; Raiola, A M; Barbanti, M; Sacchi, N; Ficai, G; Ghinatti, C; Bregante, S; Berisso, G; Dominietto, A; Di Grazia, C; Bruno, B; Sessarego, M; Casarino, L; Verdiani, S; Bacigalupo, A

    2000-12-01

    Preparative regimens without total body irradiation (TBI) have been reported for alternative donor hemopoietic stem cell transplants (HSCT). Between 7 September 1994 and 7 June 1999 48 patients with advanced hematologic malignancies were conditioned with thiotepa (THIO) 15 mg/kg, cyclophosphamide (CY) 150 mg/kg and antithymocyte globulin (ATG). Donors were HLA mismatched family members (1-2 antigens) (FAM) (n = 24, median age 31 years) or HLA matched unrelated donors (UD) (n = 24, median age 34 years). GVHD prophylaxis was cyclosporine and methotrexate. Stem cell source was peripheral blood (n = 8) or bone marrow (n = 40). Hematologic recovery was seen in 42/46 (91%) evaluable patients and complete chimerism in 31/37 patients (85%). Acute GVHD grades III-IV were seen in 10/46 patients surviving 10 days (21%) and extensive chronic GVHD in 2/36 patients surviving 100 days (5%). Twenty-six patients died (54%), eight of recurrent disease (17%) and 18 of transplant-related complications (37%): main causes of TRM were GVHD (15%), infections (15%) and graft failure (4%). Twenty-two patients (46%) survive with a median follow-up of 877 days (287-1840). The actuarial 3-year survival is 49% for FAM and 42% for UD transplants. Results obtained with this regimen in unrelated grafts for advanced CML (n = 15) were not significantly different when compared to 21 concurrent UD grafts for advanced CML prepared with CY-TBI. In conclusion, the combination of THIO-CY-ATG allows engraftment of alternative donor hemopoietic stem cells. Results are similar when using unrelated matched donors or partially mismatched family donors, and not significantly different when compared to patients conditioned with CY-TBI. PMID:11223970

  2. Protective effect of quercetin on skeletal and neural tube teratogenicity induced by cyclophosphamide in rat fetuses.

    PubMed

    Khaksary Mahabady, Mahmood; Gholami, Mohammad Reza; Najafzadeh Varzi, Hossein; Zendedel, Abolfazl; Doostizadeh, Mona

    2016-01-01

    Cyclophosphamide (CP) is a drug commonly used to treat neoplastic disease and some autoimmune diseases. It is also a well-known and well-studied teratogen causing a variety of birth defects in fetuses of pregnant women treated with the drug. There are many reports that show the adverse effects of CP can be decreased by use of antioxidant drugs. It appears that, quercetin has antioxidant effect. The aim of this study was prevention or decrease of teratogenicity of CP in fetuses of rats by quercetin. This study was performed on 35 pregnant rats divided into six groups. Control group was received normal saline (5 mL kg(-1), intraperitoneally) and 2-6 groups received a single dose of CP (15 mg kg(-1)), a single dose of quercetin (75 or 200 mg kg(-1)), CP plus quercetin (75 or 200 mg kg(-1)) intraperitoneally at 9(th) day of gestation, respectively. Fetuses were collected at 20(th) day of gestation and after determination of weight and crown rump length were stained by alizarin red - alcian blue method and skeletal system were examined by stereomicroscope. The results showed that the cleft palate, exencephaly, spina bifida and omphalocele incidence were 55.56%, 27.77%, 33.34% and 11.11%, in fetuses of rat that received only CP, respectively. However, it decreased to 16.00%, 16.00%, 16.00% and 8.00% by quercetin (75 mg kg(-1)) and so to 12.90%, 12.90%, 6.45% and 3.28% by quercetin (200 mg kg(-1)), respectively. On the basis of results, quercetin significantly can decrease teratogenicity induced by CP. PMID:27482358

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

    PubMed Central

    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 (P<0.05). Western blot and real-time PCR results showed that L-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 (P<0.05). In addition, TUNEL-positive cells were also more numerous in the CP group; however, L-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

  4. Fertility, ovarian failure, and pregnancy outcome in SLE patients treated with intravenous cyclophosphamide in Saudi Arabia.

    PubMed

    Alarfaj, Abdurhman Saud; Khalil, Najma

    2014-12-01

    Intravenous cyclophosphamide (IV CYC) has been and still used for treatment of severe manifestations of systemic lupus erythematosus (SLE), a disease occurring predominantly in women. IV CYC has been shown to predispose patients to ovarian failure and adverse pregnancy outcomes. We studied the impact of prior IV CYC treatment on ovarian function and pregnancy in our SLE patients, in terms of amenorrhea, fertility, and pregnancy outcome over a 26-year period. The study included 535 women (319 married), out of which 188 received IV CYC and 347 did not. Sixty-one patients experienced amenorrhea; the rate of amenorrhea in IV CYC user group (28.2 %; n = 53) was significantly higher than that in non-IV CYC group (3.7 %; n = 8) (P < 0.05). The type of amenorrhea was assessed in 99 women receiving IV CYC. Thirty-four (34.3 %) of them developed amenorrhea which was transient in 21 (21.2 %) and sustained in 13 (13.1 %) women. The older age at the time of receiving IV CYC and its higher cumulative dose were found to be risk factors for amenorrhea. Among married women, 48 of 99 (48.5 %) in IV CYC group conceived 90 pregnancies and 128 of 220 (58.2 %) in non-IV CYC group conceived 293 pregnancies. The rates of abortions, fetal loss, and live births between the two groups were similar; however, women with prior IV CYC had significantly more preterm births. Prior IV CYC was no barrier to conception; pregnancy outcome was favorable but associated with amenorrhea and preterm deliveries. PMID:24894105

  5. Renal Shielding and Dosimetry for Patients With Severe Systemic Sclerosis Receiving Immunoablation With Total Body Irradiation in the Scleroderma: Cyclophosphamide or Transplantation Trial

    SciTech Connect

    Craciunescu, Oana I.; Steffey, Beverly A.; Kelsey, Chris R.; Larrier, Nicole A.; Paarz-Largay, Cathy J.; Prosnitz, Robert G.; Chao, Nelson; Chute, John; Gasparetto, Cristina; Horwitz, Mitchell; Long, Gwynn; Rizzieri, David; Sullivan, Keith M.

    2011-03-15

    Purpose: To describe renal shielding techniques and dosimetry in delivering total body irradiation (TBI) to patients with severe systemic sclerosis (SSc) enrolled in a hematopoietic stem cell transplant protocol. Methods and Materials: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) protocol uses a lymphoablative preparative regimen including 800 cGy TBI delivered in two 200-cGy fractions twice a day before CD34{sup +} selected autologous hematopoietic stem cell transplantation. Lung and kidney doses are limited to 200 cGy to protect organs damaged by SSc. Kidney block proximity to the spinal cord was investigated, and guidelines were developed for acceptable lumbar area TBI dosing. Information about kidney size and the organ shifts from supine to standing positions were recorded using diagnostic ultrasound (US). Minimum distance between the kidney blocks (dkB) and the lumbar spine region dose was recorded, and in vivo dosimetry was performed at several locations to determine the radiation doses delivered. Results: Eleven patients were treated at our center with an anteroposterior (AP)/posteroanterior (PA) TBI technique. A 10% to 20% dose inhomogeneity in the lumbar spine region was achieved with a minimum kidney block separation of 4 to 5 cm. The average lumbar spine dose was 179.6 {+-} 18.1 cGy, with an average dkB of 5.0 {+-} 1.0 cm. Kidney block shield design was accomplished using a combination of US and noncontrast computerized tomography (CT) or CT imaging alone. The renal US revealed a wide range of kidney displacement from upright to supine positions. Overall, the average in vivo dose for the kidney prescription point was 193.4 {+-} 5.1 cGy. Conclusions: The dose to the kidneys can be attenuated while maintaining a 10% to 20% dose inhomogeneity in the lumbar spine area. Kidneys were localized more accurately using both US and CT imaging. With this technique, renal function has been preserved, and the study continues to enroll patients.

  6. A retrospective analysis of treatment outcomes in patients with hepatitis C related systemic vasculitis receiving intravenous methylprednisolone and cyclophosphamide.

    PubMed

    Shahin, Amira A; El Desouky, Soha M; Zayed, Hania S

    2011-05-01

    The aim of this work is to describe the outcome of a series of patients with hepatitis C virus (HCV)-related vasculitis who were treated with corticosteroids and I.V. cyclophosphamide without receiving any antiviral therapy. The data of 16 patients with HCV infection and vasculitis were retrospectively analyzed for the treatment outcome in the present study. Eleven patients were females (68.8%) with a mean age of 49.6 ± 10.0 years. Nine patients (56.2%) had medium-sized vessel vasculitis (group A) and seven patients (43.8%) had small vessel vasculitis (group B). Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS 2003) and organ damage was assessed by the Vasculitis Damage Index (VDI). HCV infection was confirmed in all patients by the detection of antibodies to HCV in serum by ELISA and HCV RNA using qualitative PCR. Quantitative PCR was done using the branched DNA technique. None of our study patients had received antiviral therapy, but they all received I.V.-pulsed cyclophosphamide monthly for 6 months, then every 3 months for six times if needed, preceded by I.V. methylprednisolone. Twelve patients (75%) had undetectable viral load by the quantitative technique. The drop in mean BVAS recorded at different intervals was highly significant. Although there was a drop in the VDI mean between the first and second reading, it was not statistically significant. All patients responded to treatment. Seven patients (43.8%) had relapse. Two patients died (12.5%). One patient died from renal failure (group B) and another died from sepsis (group A). The treatment outcomes were not statistically significant between the two vasculitis groups. A subset of patients with HCV-related vasculitis and with low levels of viremia can be safely treated with corticosteroids and cyclophosphamide alone. Despite successful treatment, a significant proportion of patients relapse and some develop severe complications and death. PMID:20924628

  7. Myeloprotective activity of crude methanolic leaf extract of Cassia occidentalis in cyclophosphamide-induced bone marrow suppression in Wistar rats

    PubMed Central

    Neboh, Emeka E; Ufelle, Silas A

    2015-01-01

    Background: Myelosuppression is the most common dose-limiting side effect of chemotherapy. Cassia occidentalis plays a vital role in preventing health disorders, but its hematological effects have not been documented much. This study is designed to investigate the myeloprotective activity of the crude methanolic leaf extract of C. occidentalis in cyclophosphamide-induced bone marrow suppression. Materials and Methods: Twenty-eight Wistar rats aged two to three months, weighing 120-170 g were used for the study. The rats were divided into four groups of seven rats each, labeled A to D. Groups A and B were administered with 3 mg/kg of cyclophosphamide intraperitoneally daily for three days to induce bone marrow suppression, after which groups B and C were orally fed with 250 mg/kg body weight of the crude leaf extract once daily for 14 days. Group D served as control without receiving the extract. On Day 15, blood samples (3.0 ml) were collected from each rat through the retro-orbital plexus of the median canthus into K3-EDTA containers for hematological analysis using standard operative procedures. Data were analyzed with Pearson's correlation test and multivariate analysis of variance using Statistical Package for Social Sciences (SPSS) version 17 and results were expressed as mean ± SD. The level of significance was determined at 95% confidence level. Results: Myelosuppression was achieved in Group A rats. Group B rats showed a significant increase in hemoglobin (Hb), hematocrit (Hct), and total white blood cell count (TWBC) compared with Group A. The Group C rats revealed a significant increase (P < 0.05) in Hb, Hct and TWBC when compared with control. Conclusions: Crude methanolic leaf extract of C. occidentalis may possess myeloprotective properties when orally administered in cyclophosphamide-induced bone marrow suppression. PMID:25625111

  8. Effect of unintentional cyclophosphamide underdosing on diffuse large B-cell lymphoma response to chemotherapy: a retrospective review

    PubMed Central

    Al-Ahmadi, Majed; Lazo-Langner, Alejandro; Mangel, Joy; Phm, Ally Dhalla BSc; Liu, Kevin; Minuk, Leonard

    2016-01-01

    Background: Between March 2012 and March 2013, a miscommunication in labelling between the drug compounder supplier and cancer centre pharmacies resulted in accidental overdilution of cyclophosphamide and gemcitabine used by several cancer centres in Canada. At our centre, 177 hematology patients were affected, among whom the largest subset of patients was those with diffuse large B-cell lymphoma. In this study, we evaluated the effect of such underdosing on disease response. Methods: We conducted a retrospective cohort study involving all patients with diffuse large B-cell lymphoma who received at least 1 chemotherapy cycle containing diluted cyclophosphamide at our centre and compared them with a historical group of patients matched by stage and age. The primary outcome was event-free survival (a composite of disease progression or death). Secondary outcomes included complete remission and overall response rate. Groups were compared using unpaired Student t, χ2 or Fisher exact tests, as appropriate. Survival analysis was done using the Kaplan-Meier method. Results: Event-free survival was no different between groups (log-rank p = 0.99). At a median follow-up of 548 days, progression or death occurred in 21 of 77 patients in the case group (27.3%) and in 24 of 74 patients in the control group (32.4%) (p = 0.5). At the end of treatment, complete remission was achieved in 41 patients in the case group (53.2%) and 43 patients in the control group (57.3%) (p = 0.6), whereas overall response rate was 71.4% in the case group and 66.7% in the control group (p = 0.5). Interpretation: Compared with a historical control group, we found no differences in event-free survival or response rates among patients with diffuse large B-cell lymphoma who received 1 or more doses of accidentally diluted cyclophosphamide-containing chemotherapy.

  9. High-dose cyclophosphamide, carboplatin, and etoposide with autologous stem cell rescue in patients with breast cancer.

    PubMed

    deMagalhaes-Silverman, M; Rybka, W B; Lembersky, B; Bloom, E J; Lister, J; Pincus, S M; Voloshin, M; Wilson, J; Ball, E D

    1996-04-01

    This study was designed to establish the toxicity and response rates o observed with a combination of high-dose cyclophosphamide, carboplatin, and etoposide with stem cell rescue in patients with breast carcinoma. Eligibility criteria included metastatic or locally advanced breast carcinoma ; aged < or equal to 60 years; performance status Eastern Cooperative Oncology Group (ECOG) 0-1; and creatinine clearance > or equal to 65 ml/min. Chemotherapy consisted of cyclophosphamide 25 mg/kg i.v. X 4 days, etoposide 400 mg/m(2) i.v. X 4 days, and carboplatin 375 mg/m(2) X 4 days. Bone marrow or peripheral blood stem cells were reinfused 48 h after completion of chemotherapy. Seventeen patients were treated in this study. The major toxicity was gastrointestinal (grades I and II). Fevers associated with neutropenia were observed in all the patients, but no episodes of bacteremia were documented. Hematopoietic toxicities were acceptable. No toxic deaths were observed. Six patients had chemotherapy-sensitive disease at time of transplant, nine had refractory disease, and two were untested. A response rate of 62% with 18% complete response (CR) was achieved. Two patients are free of disease at +7 and +9 months after transplantation. The combination of high-dose cyclophosphamide, carboplatin, and etoposide is well tolerated with a response rate comparable to previously reported high-dose chemotherapy regimens. However, in a poor prognostic risk group, namely patients with chemoinsensitive disease, this therapeutic approach seems to be of no advantage over standard chemotherapy. PMID:8610643

  10. Non-Pegylated Liposomal Doxorubicin-Cyclophosphamide in Sequential Regimens with Taxanes as Neoadjuvant Chemotherapy in Breast Cancer Patients

    PubMed Central

    Vici, Patrizia; Pizzuti, Laura; Gamucci, Teresa; Sergi, Domenico; Conti, Francesca; Zampa, Germano; Del Medico, Pietro; De Vita, Roy; Pozzi, Marcello; Botti, Claudio; Di Filippo, Simona; Tomao, Federica; Sperduti, Isabella; Di Lauro, Luigi

    2014-01-01

    Purpose: Chemotherapy regimens containing anthracyclines and taxanes represent the landmark of neoadjuvant systemic therapy of breast cancer. In advanced breast cancer patients liposomal anthracyclines (LA) have shown similar efficacy and less cardiac toxicity when compared to conventional anthracyclines. We performed this retrospective analysis in order to evaluate the efficacy and tolerability of neoadjuvant regimens including LA outside of clinical trials in routine clinical practice. Methods: Fifty operable or locally advanced, HER2 negative, breast cancer patients were retrospectively identified in 5 Italian cancer centres. Nineteen patients had received 4 cycles of non-pegylated liposomal doxorubicin (NPLD) and cyclophosphamide, followed by 4 cycles of docetaxel, every 3 weeks. In 25 patients the reverse sequence was employed, and a third subgroup of 6 patients received 4 cycles of NPLD/cyclophosphamide every 3 weeks followed by 4 cycles of weekly carboplatin and paclitaxel. Results: We observed 10 pathological complete responses (pCR) (20.0%, 95%CI, 9% to 31%), and 35 (70%, 95%CI, 57.3% to 82.7%) partial responses (pPR), whereas no patients progressed onto therapy. In the small subset of triple negative tumors the pCR rate was 37.5%, and in tumors expressing ER and/or PgR it was 16.7%. A pCR rate of 26.5% was observed in tumors with high Ki-67, whereas in tumors with low Ki-67 only one (6.2%) pCR was observed (p=0.14). Treatments were well tolerated. The most common toxicities were myelosuppression and palmar-plantar erytrodysesthesia; 4 asymptomatic and transient LVEF decrease have been recorded, without any case of clinical cardiotoxicity. Conclusions: NPLD-cyclophosphamide and taxanes sequential regimens were proven effective and well tolerated in breast cancer patients with contra-indication to conventional anthracyclines undergoing neoadjuvant chemotherapy, even outside of clinical trials in everyday clinical practice. PMID:24847380

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

    PubMed

    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. PMID:24772624

  12. Assessment of temporal association of relapse of canine multicentric lymphoma with components of the CHOP protocol: Is cyclophosphamide the weakest link?

    PubMed

    Wang, Shang-Lin; Lee, Jih-Jong; Liao, Albert Taiching

    2016-07-01

    Combination chemotherapy, using cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone (CHOP), is the most commonly used treatment for canine lymphoma. Most affected dogs respond during the initial stages of chemotherapy, but many relapse. The aim of this study was to evaluate the relationship between the use of specific chemotherapy drugs and clinical relapse, using the modified Madison-Wisconsin, 25 week chemotherapy protocol. Forty-one of 68 dogs affected with multicentric lymphoma relapsed during the treatment period. Relapse occurred more frequently after the administration of cyclophosphamide (n = 24; P < 0.01), compared with vincristine (n = 9) or doxorubicin (n = 5). Therefore, the therapeutic outcome of traditional CHOP-based chemotherapy might be improved by replacing cyclophosphamide with other cytotoxic drugs. PMID:27240922

  13. Macrophage activation syndrome as the initial manifestation of severe juvenile onset systemic lupus erythematosus. Favorable response to cyclophosphamide.

    PubMed

    Torres Jiménez, Alfonso; Solís Vallejo, Eunice; Zeferino Cruz, Maritza; Céspedes Cruz, Adriana; Sánchez Jara, Berenice

    2014-01-01

    The macrophage activation syndrome is a rare but potentially fatal complication of patients with autoimmune rheumatic diseases. This is a clinicopathological entity characterized by activation of histiocytes with prominent hemophagocytosis in the bone marrow and other reticuloendothelial systems. In patients with lupus it may mimic an exacerbation of the disease or infection. We report the case of a 7-year-old girl in whom the diagnosis of lupus erythematosus and macrophage activation syndrome was simultaneously made with response to the use of cyclophosphamide. PMID:24035795

  14. Cyclophosphamide-induced enhancement of stem cell recovery from whole-body irradiation is radiation dose-dependent

    SciTech Connect

    Pantel, K.; Nakeff, A. )

    1989-08-01

    Although the enhancement of CFU-S recovery by CY pretreatment has been described for combinations of TBI greater than 4 Gy, no information exists as to whether such enhancement is operative at lower TBI doses (less than 3 Gy). B6D2F1 mice received intraperitoneal injections of CY (2 and 5 mg/mouse) at various time intervals prior to 2, 5 or 9 Gy TBI. The control group received the same dose of TBI without CY pretreatment. Six days after TBI, we determined the femoral content of CFU-S. Administration of 5 mg CY per mouse 3 days prior to 5 or 9 Gy TBI enhanced recovery of CFU-S with a substantial increase in CFU-S of 3- and 30-fold over control, respectively. In contrast, the administration of CY prior to 2 Gy TBI delayed recovery with CFU-S remaining at only 10 to 40% of control. This prolongation in CFU-S recovery was similar for CY doses of either 2 or 5 mg per mouse at all the time intervals tested (2, 3, 4 and 7 days prior to TBI). Our results demonstrate an enhancement of CFU-S recovery by pretreatment with CY for high doses of TBI that is reversed if the subsequent TBI dose is too low.

  15. Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia

    PubMed Central

    Bouvet, Emmanuelle; Borel, Cécile; Obéric, Lucie; Compaci, Gisèle; Cazin, Bruno; Michallet, Anne-Sophie; Laurent, Guy; Ysebaert, Loic

    2013-01-01

    Fludarabine-cyclophosphamide-rituximab is the most efficient first-line treatment for chronic lymphocytic leukemia patients. Many dose adjustments of the original MD Anderson Cancer Center regimen have been proposed. However, whether fludarabine-cyclophosphamide-rituximab relative dose intensity may have an impact on outcome has not yet been investigated. We retrospectively assessed relative dose intensity in 106 community-based patients included in our regional healthcare network from 2004-11, all receiving fludarabine-cyclophosphamide-rituximab as first-line treatment outside clinical trials. Dose reductions were observed in 51.4% of patients, mainly decided by the individual physician and not based on recommendations (52.7%), while there were fewer reports of toxicity or dose reduction because of impaired renal function. Progression-free survival was significantly reduced in patients who had a reduction in dose intensity of more than 20% in fludarabine-cyclophosphamide and/or rituximab. Multivariate analysis showed dose of rituximab had a significant impact on minimal residual disease and progression-free survival. Although prophylactic granulocyte-colony stimulating factor significantly reduced the rate of grade 3-4 neutropenia and febrile neutropenia, it had no impact on relative dose intensity and outcome. This study shows that, in routine clinical practice, there is low adherence to the original MD Anderson Cancer Center fludarabine-cyclophosphamide-rituximab schedule, and that the decision to modify dosage was mostly taken by the individual physician and was based on anticipated toxicity. This study shows that reduction of fludarabine-cyclophosphamide and, more importantly, of rituximab doses seriously interferes with progression-free survival. PMID:23065520

  16. The role of P2X7 purinergic receptors in inflammatory and nociceptive changes accompanying cyclophosphamide-induced haemorrhagic cystitis in mice

    PubMed Central

    Martins, JP; Silva, RBM; Coutinho-Silva, R; Takiya, CM; Battastini, AMO; Morrone, FB; Campos, MM

    2012-01-01

    BACKGROUND AND PURPOSE ATP is released in response to cellular damage, and P2X7 receptors have an essential role in the onset and maintenance of pathological changes. Haemorrhagic cystitis (HC) is a well-known adverse effect of therapy with cyclophosphamide used for the treatment of many solid tumours and autoimmune conditions. Here we have evaluated the role of P2X7 receptors in a model of HC induced by cyclophosphamide. EXPERIMENTAL APPROACH Effects of pharmacological antagonism or genetic deletion of P2X7 receptor on cyclophosphamide-induced HC in mice was assessed by nociceptive and inflammatory measures. In addition, the presence of immunoreactive P2X7 receptors was assessed by immunohistochemistry. KEY RESULTS Pretreatment with the selective P2X7 receptor antagonist A-438079 or genetic ablation of P2X7 receptors reduced nociceptive behaviour scores in the HC model. The same strategies decreased both oedema and haemorrhage indices, on macroscopic or histological evaluation. Treatment with A-438079 decreased the staining for c-Fos in the lumbar spinal cord and brain cortical areas. Treatment with A-438079 also prevented the increase of urinary bladder myeloperoxidase activity and macrophage migration induced by cyclophosphamide and reduced the tissue levels of IL-1β and TNF-α. Finally, P2X7 receptors were markedly up-regulated in the bladders of mice with cyclophosphamide-induced HC. CONCLUSIONS AND IMPLICATIONS P2X7 receptors were significantly involved in a model of HC induced by cyclophosphamide. Pharmacological inhibition of these receptors might represent a new therapeutic option for this pathological condition. PMID:21675966

  17. A randomised pilot Phase II study of doxorubicin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) given 2 weekly with pegfilgrastim (accelerated) vs 3 weekly (standard) for women with early breast cancer

    PubMed Central

    Jones, R L; Walsh, G; Ashley, S; Chua, S; Agarwal, R; O'Brien, M; Johnston, S; Smith, I E

    2009-01-01

    Accelerated (dose-dense) chemotherapy, in which the frequency of administration is increased without changing total dose or duration, may increase the efficacy of cancer chemotherapy. We performed a randomised Phase II study to assess the safety and relative toxicity of AC (doxorubicin; cyclophosphamide) vs E(epirubicin)C given by conventional or accelerated schedules as neoadjuvant or adjuvant chemotherapy for early breast cancer. Furthermore, the relative toxicity of doxorubicin and epirubicin remains uncertain. Patients were randomised to one of four arms; four courses of standard 3 weekly cyclophosphamide 600 mg m−2 in combination with doxorubicin 60 mg m−2 (AC) vs epirubicin 90 mg m−2 (EC) 3 weekly vs the same regimens administered every 2 weeks with pegfilgrastim (G-CSF). A total of 126 patients were treated, 42 with standard AC, 42 with accelerated AC, 19 with standard EC and 23 with accelerated EC. Significantly more grade 3/4 day one neutropenia was seen with standard (6/61, 10%) compared to accelerated (0/65,) regimens (P=0.01). A trend towards more neutropenic sepsis was seen in the combined standard and accelerated AC arms (12/84, 14%) compared to the combined EC arms (1/42, 2%), P=0.06. Falls in left ventricular ejection fraction were not increased with accelerated treatment. Accelerated AC and EC with pegfilgrastim are safe and feasible regimens in the treatment of early breast cancer with less neutropenia than conventional 3 weekly schedules. PMID:19165198

  18. Kinetics of destruction and regeneration of the haemopoietic system after administration of busulphan and cyclophosphamide followed by bone marrow transplantation. Peripheral blood parameters.

    PubMed

    Szczylik, C; Ratajczak, M Z; Urbanowska, E; Jedrzejczak, W W

    1989-01-01

    The kinetics of restoration of haemopoiesis was studied in 10 patients prepared for allogenic bone marrow transplantation with busulphan combined with cyclophosphamide. The morphology of peripheral blood after administration of these drugs and transplantation of allogenic bone marrow was similar to that reported elsewhere after irradiation, cyclophosphamide administration and bone marrow transplantation, the cell counts falling almost to zero within several days after the end of the pharmacological preparation, and later rising to normal values within the period from several weeks to several months after transplantation. PMID:2519630

  19. Stereoselective pharmacokinetics and metabolism of the enantiomers of cyclophosphamide. Preliminary results in humans and rabbits.

    PubMed

    Holm, K A; Kindberg, C G; Stobaugh, J F; Slavik, M; Riley, C M

    1990-04-15

    [R(+),S(-)]-Cyclophosphamide [(R,S)-CP] is an anticancer drug, containing a chiral phosphorous atom, which is prepared and used clinically as the racemic mixture. A new high-performance liquid chromatographic assay suitable for pharmacokinetic studies of CP enantiomers in plasma has been reported recently by this laboratory (Reid et al., Anal Chem 61: 441-446, 1989). Briefly, the assay involves ethyl acetate extraction of CP enantiomers from plasma followed by derivatization to diastereomers in a two-step process utilizing chloral and (+)-naproxen acid chloride. Chromatographic analysis was performed on a reversed phase (ODS) column with detection at 232 nm. In the present study, preliminary results on the applicability of this assay to pharmacokinetic studies are presented. Several rabbits were used to compare the influence of i.p., i.v., and oral routes of administration on the stereoselective disposition of (R,S)-CP. Following i.p. administration, S-CP was cleared faster than R-CP. Following oral administration, only R-CP was detectable in plasma, while i.v. administration resulted in minor or no stereoselective disposition. These results indicated that there was a marked stereoselective metabolism of the S-CP enantiomer, with the i.p. and oral routes producing the greatest differences due to first-pass metabolism. Incubation of rabbit-liver microsomes with (R,S)-CP demonstrated that the monooxygenase system can exhibit marked stereoselectivity in its metabolism of CP. The ratio of R-CP to S-CP in the incubation medium increased during the incubation period from 1:1 initially to 4.5:1 after 60 min. The results from the experiments with rabbits indicate that the first-pass metabolism of this drug is highly stereoselective; in contrast, cancer patients who had received (R,S)-CP as an i.v. infusion showed no stereoselectivity in the elimination of the enantiomers. Pharmacokinetic studies with cancer patients, receiving (R,S)-CP as an oral dose, are in progress in

  20. Etoposide, carboplatin, cyclophosphamide and vincristine in previously untreated patients with small-cell lung cancer.

    PubMed

    Bishop, J F; Kefford, R; Raghavan, D; Zalcberg, J; Stuart-Harris, R; Ball, D; Olver, I N; Friedlander, M; Bull, C; Yuen, K

    1990-01-01

    The efficacy and toxicity of 120 mg/m2 etoposide and 100 mg/m2 carboplatin given i.v. daily x 3 together with 750 mg/m2 cyclophosphamide and 1.4 mg/m2 vincristine given i.v. on day 1 (ECCO) in a regimen given every 28 days for 6 courses was assessed in 90 (40 limited stage, 50 extensive stage) previously untreated patients with small-cell lung cancer. Mediastinal irradiation using 50 Gy in 25 fractions was given to limited-stage patients without progression after 3 courses of chemotherapy. Cranial irradiation with 30 Gy in 10 fractions was given to all patients attaining a complete response (CR). Objective responses were seen in 83% [CR, 60%; partial response (PR), 23%] of patients with limited and 76% (CR, 22%; PR, 54%) of those with extensive disease. The median relapse-free survival for objective responders with limited disease was 13.4 months, with a median of 8.0 months for extensive-stage patients. The median relapse-free survival for patients achieving a CR was 13.4 months, with a median of 7.8 months for those undergoing a PR. The median survival was 13.3 months for patients with limited disease, with a median of 9.6 months for those with extensive disease. The median survival following a CR was 18.2 months, with a median survival of 9.9 months for those showing a PR. The combination was well tolerated, with either no nausea or nausea only (WHO grade 0 or 1) in 56% of patients and minimal mucositis, renal toxicity, neurotoxicity or ototoxicity. Neutropenia measuring less than 1.0 x 10(9) WBC/l (WHO grade 3 or 4) was seen in 74% of patients, with two deaths due to infection occurring during neutropenia. Thrombocytopenia of less than 50 x 10(9) platelets/l (WHO grade 3 or 4) occurred in 24% of patients. ECCO is a new, active, well-tolerated program for previously untreated patients with small-cell lung cancer. PMID:2155064

  1. Occurrence of cyclophosphamide and ifosfamide in aqueous environment and their removal by biological and abiotic wastewater treatment processes.

    PubMed

    Česen, Marjeta; Kosjek, Tina; Laimou-Geraniou, Maria; Kompare, Boris; Širok, Brane; Lambropolou, Dimitra; Heath, Ester

    2015-09-15

    Cytostatic drug residues in the aqueous environment are of concern due to their possible adverse effects on non-target organisms. Here we report the occurrence and removal efficiency of cyclophosphamide (CP) and ifosfamide (IF) by biological and abiotic treatments including advanced oxidation processes (AOPs). Cyclophosphamide was detected in hospital wastewaters (14-22,000 ng L(-1)), wastewater treatment plant influents (19-27 ng L(-1)) and effluent (17 ng L(-1)), whereas IF was detected only in hospital wastewaters (48-6800 ng L(-1)). The highest removal efficiency during biological treatment (attached growth biomass in a flow through bioreactor) was 59 ± 15% and 35 ± 9.3% for CP and IF, respectively. Also reported are the removal efficiencies of both compounds from wastewater using hydrodynamic cavitation (HC), ozonation (O3) and/or UV, either individually or in combination with hydrogen peroxide (H2O2). Hydrodynamic cavitation did not remove CP and IF to any significant degree. The highest removal efficiencies: 99 ± 0.71% for CP and 94 ± 2.4% for IF, were achieved using UV/O3/H2O2 at 5 g L(-1) for 120 min. When combined with biological treatment, removal efficiencies were >99% for both compounds. This is the first report of combined biological and AOP treatment of CP and IF from wastewater with a removal efficiency >99%. PMID:25981944

  2. Nonmyeloablative HLA-Haploidentical BMT with High-Dose Posttransplantation Cyclophosphamide: Effect of HLA Disparity on Outcome

    PubMed Central

    Kasamon, Yvette L.; Luznik, Leo; Leffell, Mary S.; Kowalski, Jeanne; Tsai, Hua-Ling; Bolanos-Meade, Javier; Morris, Lawrence E.; Crilley, Pamela A.; O’Donnell, Paul V.; Rossiter, Nancy; Huff, Carol Ann; Brodsky, Robert A.; Matsui, William H.; Swinnen, Lode J.; Borrello, Ivan; Powell, Jonathan D.; Ambinder, Richard F.; Jones, Richard J.; Fuchs, Ephraim J.

    2010-01-01

    Although some reports have found increasing HLA disparity between donor and recipient to be associated with fewer relapses after allogeneic blood or marrow transplantation (BMT), this potential benefit has been offset by more graft-versus-host disease (GVHD) and nonrelapse mortality. However, the type of GVHD prophylaxis could influence the balance between GVHD toxicity and relapse. We analyzed the impact of greater HLA disparity on outcomes of a specific platform for nonmyeloablative, HLA-haploidentical transplantation. A retrospective analysis was performed on 185 patients with hematologic malignancies enrolled on three similar trials of nonmyeloablative, related donor, haploidentical BMT incorporating high-dose posttransplantation cyclophosphamide for GVHD prophylaxis. No significant association was found between the number of HLA mismatches (HLA-A, -B, -Cw, and -DRB1 combined) and risk of acute grade II–IV GVHD (hazard ratio .89, P = .68 for 3–4 versus fewer antigen mismatches). More mismatching also had no detrimental effect on event-free survival (on multivariate analysis, hazard ratio .60, P = .03 for 3–4 versus fewer antigen mismatches; hazard ratio .55, P = .03 for 3–4 versus fewer allele mismatches). Thus, greater HLA disparity does not appear to worsen overall outcomes after nonmyeloablative haploidentical BMT with high-dose posttransplantation cyclophosphamide. PMID:19925877

  3. Maintenance therapy with interferon-alpha 2b, cyclophosphamide, and prednisone in aggressive diffuse large cell lymphoma.

    PubMed

    Avilés, Agustin; Neri, Natividad; Nambo, M Jesús; Castañeda, Claudia; Talavera, Alejandra; Huerta-Guzmán, Judith; Murillo, Edgar

    2004-04-01

    Maintenance therapy in patients with aggressive malignant lymphoma using biological modifiers remains uncertain. We conducted a controlled clinical trial to evaluate the efficacy and toxicity of interferon-alpha 2b, cyclophosphamide, and prednisone as maintenance therapy in patients with aggressive diffuse large B cell lymphomas in complete remission after aggressive chemotherapy. In an intent-to-treat analysis, 169 patients were eligible for this study; the end points were event-free survival (EFS) and overall survival (OS). With a median follow-up of 49.3 months, no statistical differences were observed and actuarial curves at 5 years showed that EFS was 71% (95% confidence interval [CI], 63-79%) for patients who received maintenance compared to 63% (95% CI, 59-71%) for patients in control group (p = 0.05). No statistical differences were observed in OS between maintenance arm: 84% (95% CI, 78-89%) and control group 83% (95% CI, 77-88%) in control group (p = 0.2). All patients received the maintenance therapy as planned and in time, thus dose intensity was considered 1.0 in all cases. Acute toxicity was mild, and no delay or suspension of treatment was necessary. Late toxicity was not evident until now. We conclude that use of maintenance therapy combining interferon-alpha 2b, cyclophosphamide, and prednisone is not useful in patients with aggressive lymphoma if they had been treated with aggressive combined chemotherapy. PMID:15186737

  4. Avocado fruit (Persea americana Mill) exhibits chemo-protective potentiality against cyclophosphamide induced genotoxicity in human lymphocyte culture.

    PubMed

    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. PMID:22070054

  5. High content analysis of an in vitro model for metabolic toxicity: results with the model toxicants 4-aminophenol and cyclophosphamide.

    PubMed

    Cole, Stephanie D; Madren-Whalley, Janna S; Li, Albert P; Dorsey, Russell; Salem, Harry

    2014-12-01

    In vitro models that accurately and rapidly assess hepatotoxicity and the effects of hepatic metabolism on nonliver cell types are needed by the U.S. Department of Defense and the pharmaceutical industry to screen compound libraries. Here, we report the first use of high content analysis on the Integrated Discrete Multiple Organ Co-Culture (IdMOC) system, a high-throughput method for such studies. We cultured 3T3-L1 cells in the presence and absence of primary human hepatocytes, and exposed the cultures to 4-aminophenol and cyclophosphamide, model toxicants that are respectively detoxified and activated by the liver. Following staining with calcein-AM, ethidium homodimer-1, and Hoechst 33342, high content analysis of the cultures revealed four cytotoxic endpoints: fluorescence intensities of calcein-AM and ethidium homodimer-1, nuclear area, and cell density. Using these endpoints, we observed that the cytotoxicity of 4-aminophenol in 3T3-L1 cells in co-culture was less than that observed for 3T3-L1 monocultures, consistent with the known detoxification of 4-aminophenol by hepatocytes. Conversely, cyclophosphamide cytotoxicity for 3T3-L1 cells was enhanced by co-culturing with hepatocytes, consistent with the known metabolic activation of this toxicant. The use of IdMOC plates combined with high content analysis is therefore a multi-endpoint, high-throughput capability for measuring the effects of metabolism on toxicity. PMID:25239051

  6. AMPK Suppresses Connexin43 Expression in the Bladder and Ameliorates Voiding Dysfunction in Cyclophosphamide-induced Mouse Cystitis

    PubMed Central

    Zhang, Xiling; Yao, Jian; Gao, Kun; Chi, Yuan; Mitsui, Takahiko; Ihara, Tatsuya; Sawada, Norifumi; Kamiyama, Manabu; Fan, Jianglin; Takeda, Masayuki

    2016-01-01

    Bladder voiding dysfunction is closely related to local oxidation, inflammation, and enhanced channel activities. Given that the AMP-activated protein kinase (AMPK) has anti-oxidative, anti-inflammatory and channel-inhibiting properties, we examined whether and how AMPK affected bladder activity. AMPK activation in rat bladder smooth muscle cells (BSMCs) using three different AMPK agonists resulted in a decrease in connexin43 (Cx43) expression and function, which was associated with reduced CREB phosphorylation, Cx43 promoter activity and mRNA expression, but not Cx43 degradation. Downregulation of CREB with siRNA increased Cx43 expression. A functional analysis revealed that AMPK weakened BSMC contraction and bladder capacity. AMPK also counteracted the IL-1β- and TNFα-induced increase in Cx43 in BSMCs. In vivo administration of the AMPK agonist AICAR attenuated cyclophosphamide-initiated bladder oxidation, inflammation, Cx43 expression and voiding dysfunction. Further analysis comparing the responses of the wild-type (Cx43+/+) and heterozygous (Cx43+/−) Cx43 mice to cyclophosphamide revealed that the Cx43+/− mice retained a relatively normal micturition pattern compared to the Cx43+/+ mice. Taken together, our results indicate that AMPK inhibits Cx43 in BSMCs and improves bladder activity under pathological conditions. We propose that strategies that target AMPK can be developed as novel therapeutic approaches for treating bladder dysfunction. PMID:26806558

  7. Combination of metronomic cyclophosphamide and dietary intervention inhibits neuroblastoma growth in a CD1-nu mouse model

    PubMed Central

    Morscher, Raphael Johannes; Aminzadeh-Gohari, Sepideh; Hauser-Kronberger, Cornelia; Feichtinger, René Günther; Sperl, Wolfgang; Kofler, Barbara

    2016-01-01

    Background MYCN-amplification in high-grade Neuroblastoma (NB) tumors correlates with increased vascularization and therapy resistance. This study combines an anti-angiogenic approach with targeting NB metabolism for treatment. Methods and Results Metronomic cyclophosphamide (MCP) monotherapy significantly inhibited NB growth and prolonged host survival. Growth inhibition was more pronounced in MYCN-amplified xenografts. Immunohistochemical evaluation of this subtype showed significant decrease in blood vessel density and intratumoral hemorrhage accompanied by blood vessel maturation and perivascular fibrosis. Up-regulation of VEGFA was not sufficient to compensate for the effects of the MCP regimen. Reduced Bcl-2 expression and increased caspase-3 cleavage were evident. In contrast non MYCN-amplified tumors developed resistance, which was accompanied by Bcl-2-up-regulation. Combining MCP with a ketogenic diet and/or calorie-restriction significantly enhanced the anti-tumor effect. Calorie-restricted ketogenic diet in combination with MCP resulted in tumor regression in all cases. Conclusions Our data show efficacy of combining an anti-angiogenic cyclophosphamide dosing regimen with dietary intervention in a preclinical NB model. These findings might open a new front in NB treatment. PMID:26959744

  8. Combined radiotherapy and chemotherapy with cyclophosphamide, adriamycin, methotrexate, procarbazine (camp) in 64 consecutive patients with epidermoid bronchogenic carcinoma, limited disease: a prospective study. [/sup 60/Co

    SciTech Connect

    Trovo, M.G.; Tirelli, U.; De Paloi, A., et. al.

    1982-06-01

    Sixty-four consecutive patients with inoperable epidermoid bronchogenic carcinoma (limited disease) were treated with radiotherapy to the primary and nodal areas and combination chemotherapy with cyclophosphamide, adriamycin, methotrexate and procarbazine. The overall response rate (CR + PR) to combined treatment was 62%. The median survival time was 12.7 months. The toxicity was acceptable and no treatment-related death occurred.

  9. Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma.

    PubMed

    Klein, Oliver; Davis, Ian D; McArthur, Grant A; Chen, Li; Haydon, Andrew; Parente, Phillip; Dimopoulos, Nektaria; Jackson, Heather; Xiao, Kun; Maraskovsky, Eugene; Hopkins, Wendie; Stan, Rodica; Chen, Weisan; Cebon, Jonathan

    2015-04-01

    Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4(+) T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents. PMID:25662405

  10. Cycles of Transient High-Dose Cyclophosphamide Administration and Oncolytic Adenovirus Vector Intratumoral Injection for Long Term Tumor Suppression in Syrian Hamsters

    PubMed Central

    Dhar, Debanjan; Toth, Karoly; Wold, William S.M.

    2014-01-01

    Immune responses against oncolytic adenovirus (Ad) vectors are thought to limit vector anti-tumor efficacy. In Syrian hamsters, which are immunocompetent and whose tumors and normal tissues are permissive for replication of Ad5-based oncolytic Ad vectors, treating with high-dose cyclophosphamide to suppress the immune system and exert chemotherapeutic effects enhances Ad vector anti-tumor efficacy. However, long term cyclophosphamide treatment and immunosuppression can lead to anemia and vector spread to normal tissues. Here we employed three cycles of transient high-dose cyclophosphamide administration plus intratumoral injection of the oncolytic Ad vector VRX-007 followed by withdrawal from cyclophosphamide. Each cycle lasted 4-6 weeks. This protocol allowed the hamsters to remain healthy so the study could be continued for ~100 days. The tumors were very well suppressed throughout the study. With immunocompetent hamsters, the vector retarded tumor growth initially, but after 3-4 weeks the tumors resumed rapid growth and further injections of vector were ineffective. Preimmunization of the hamsters with Ad5 prevented vector spillover from the tumor to the liver yet still allowed for effective long term anti-tumor efficacy. Our results suggest that a clinical protocol might be developed with cycles of transient chemotherapy plus intratumoral vector injection to achieve significant anti-tumor efficacy while minimizing the side effects of cytostatic treatment. PMID:24722357

  11. Comparative analysis of pathologic processes developing in mice housed in SPF vs non-SPF conditions and treated with cyclophosphamide and dsDNA preparation.

    PubMed

    Dolgova, Evgeniya V; Efremov, Yaroslav R; Taranov, Oleg S; Potter, Ekaterina A; Nikolin, Valeriy P; Popova, Nelly A; Omigov, Vladimir V; Chernykh, Elena R; Proskurina, Anastasia S; Bogachev, Sergey S

    2015-10-01

    In our earlier studies, we observed that when mice are treated with cyclophosphamide and fragmented exogenous dsDNA (18-30 h post cytostatic treatment), they develop a very characteristic set of symptoms and 80-90% of such animals succumb within 6-25 days. This was called "delayed death" phenomenon, and the gap between cyclophosphamide and DNA injections required for such phenotype to develop was termed "death window". We established that mice succumbed to multi-organ failure, which was caused by systemic inflammation and sepsis. These processes unfolded along with accidental involution of lymphoid organs, which resulted from the failure of CD34(+) hematopoietic stem cells to differentiate into lymphoid lineage progenitors. Here we compare SPF and non-SPF animals, and demonstrate that the major cause of systemic inflammation and sepsis observed upon such treatments is activation of an opportunistic infection. Mice of the same strain (CBA) housed under SPF conditions do not develop the characteristic symptoms, nor do they become moribund. Yet, regardless of the breeding conditions, upon synergistic action of cyclophosphamide and dsDNA, CD34(+) hematopoietic stem cells consistently fail to give rise to lymphoid lineage progenitors. We demonstrate that this differentiation defect is reversible and that population of lymphoid progenitors is restored by day 29 after cyclophosphamide injection. PMID:26293796

  12. Molecular imaging of therapy response with 18F-FLT and 18F-FDG following cyclophosphamide and mTOR inhibition

    PubMed Central

    Saint-Hubert, Marijke De; Brepoels, Lieselot; Devos, Ellen; Vermaelen, Peter; Groot, Tjibe De; Tousseyn, Thomas; Mortelmans, Luc; Mottaghy, Felix M

    2012-01-01

    Purpose Evaluation and comparison of 3’-[18F]-fluoro-3’-deoxy-L-thymidine (FLT) and 2-[18F]-fluoro-2-deoxyglucose (FDG)-PET to monitor early response following both cyclophosphamide and temsirolimus treatment in a mouse model of Burkitt lymphoma. Methods Daudi xenograft mice were treated with either cyclophosphamide or temsirolimus and imaged with FLT-PET and FDG-PET on appropriate days post therapy inititiation. Immunohistochemical (IHC) studies (H&E, TUNEL, CD20, PCNA and ki-67) and DNA flow cytometry studies were performed. Results FDG tumor uptake decreased immediately after cyclophosphamide treatment while FLT-PET showed only a late and less pronounced decrease. A fast induction of apoptosis was observed together with an early accumulation of cells in the S-phase of the cell cycle, suggesting DNA repair. Temsirolimus treatment reduced both FDG and FLT tumor uptake immediately after therapy and resulted in a fast induction of apoptosis and G0-G1 phase accumulation. Conclusion FLT response was less distinct than FDG response and may be controlled by DNA repair early after cyclophosphamide. Nevertheless, FLT-PET was able to reflect decreased proliferation following temsirolimus. PMID:23133806

  13. 1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes

    PubMed Central

    Casteels, K; Waer, M; Bouillon, R; Depovere, J; Valckx, D; Laureys, J; Mathieu, C

    1998-01-01

    The activated form of vitamin D, 1,25(OH)2D3, and its analogues can prevent type I diabetes in NOD mice. Protection is achieved without signs of systemic immunosuppression and is associated with a restoration of the defective immune regulator system of the NOD mice. The aim of the present study was to investigate whether this restoration of regulator cell function is the only mechanism in the prevention of diabetes by 1,25(OH)2D3. We tested therefore if 1,25(OH)2D3 could prevent cyclophosphamide-induced diabetes, since diabetes occurring after cyclophosphamide injection is believed to be due to an elimination of suppresser cells. NOD mice treated with 1,25(OH)2D3 (5 μg/kg every 2 days) from the time of weaning were clearly protected against diabetes induced by cyclophosphamide (200 mg/kg body wt at 70 days old) (2/12 (17%) versus 36/53 (68%) in control mice, P < 0.005). By co-transfer experiments it was demonstrated that cyclophosphamide had indeed eliminated the suppresser cells present in 1,25(OH)2D3-treated mice. Since cyclophosphamide injection did not break the protection offered by 1,25(OH)2D3, it was clear that diabetogenic effector cells were affected by 1,25(OH)2D3 treatment as well. This was confirmed by the finding that splenocytes from 1,25(OH)2D3-treated mice were less capable of transferring diabetes in young, irradiated NOD mice, and by the demonstration of lower Th1 cytokine levels in the pancreases of 1,25(OH)2D3-treated, cyclophosphamide-injected mice. This better elimination of effector cells in 1,25(OH)2D3-treated mice could be explained by a restoration of the sensitivity to cyclophosphamide-induced apoptosis in both thymocytes and splenocytes, in normally apoptosis-resistant NOD mice. Altogether, these data indicate that the protection against diabetes offered by 1,25(OH)2D3 may be independent of the presence of suppresser cells, and may involve increased apoptosis of Th1 autoimmune effector cells. PMID:9649179

  14. 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

    NASA Astrophysics Data System (ADS)

    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.

  15. Comparison of the effectiveness and toxicity of neoadjuvant chemotherapy regimens, capecitabine/epirubicin/cyclophosphamide vs 5-fluorouracil/epirubicin/cyclophosphamide, followed by adjuvant, capecitabine/docetaxel vs docetaxel, in patients with operable breast cancer

    PubMed Central

    Zhang, Minmin; Wei, Wei; Liu, Jianlun; Yang, Huawei; Jiang, Yi; Tang, Wei; Li, Qiuyun; Liao, Xiaoming

    2016-01-01

    The aim of this study was to compare the effectiveness and toxicity of neoadjuvant chemotherapy regimens, xeloda/epirubicin/cyclophosphamide (XEC) vs 5-fluorouracil/epirubicin/cyclophosphamide (FEC), followed by adjuvant chemotherapy regimens, capecitabine/taxotere (XT) vs taxotere (T), in axillary lymph node (LN)-positive early-stage breast cancer. In this randomized, Phase III trial, 137 patients with operable primary breast cancer (T2-0, N0-1) who were tested axillary LN positive through aspiration biopsy of axillary LNs were randomized (1:1) to four 3-weekly cycles of XEC or FEC. Patients underwent surgery within 4–6 weeks after the fourth cycle, followed by four adjuvant cycles of 3-weekly XT or T. The primary end point was tumor pathological complete response. Toxicity profiles were secondary objectives. In total, 131 patients had clinical and radiological evaluation of response and underwent surgery. Treatment with XEC led to an increased rate of pathological complete response in primary tumor (18% vs 6%, respectively, P=0.027) and objective remission rate (87% vs 73%, P=0.048) compared to FEC. Clinical complete response occurred in 20% and 7% for XEC and FEC, respectively. Compared to FEC, XEC was associated with more hand-foot syndrome (57% vs 11%, P<0.001) and 3/4 grade nausea/vomiting/diarrhea (30% vs 14%, P=0.034) but less phlebitis (3% vs 14%, P=0.035). XT and T adjuvant chemotherapy regimens were well tolerated: treatment-related 3/4 grade adverse events occurred in 28% and 17% of patients receiving XT and T, respectively. PMID:27354816

  16. Comparison of the effectiveness and toxicity of neoadjuvant chemotherapy regimens, capecitabine/epirubicin/cyclophosphamide vs 5-fluorouracil/epirubicin/cyclophosphamide, followed by adjuvant, capecitabine/docetaxel vs docetaxel, in patients with operable breast cancer.

    PubMed

    Zhang, Minmin; Wei, Wei; Liu, Jianlun; Yang, Huawei; Jiang, Yi; Tang, Wei; Li, Qiuyun; Liao, Xiaoming

    2016-01-01

    The aim of this study was to compare the effectiveness and toxicity of neoadjuvant chemotherapy regimens, xeloda/epirubicin/cyclophosphamide (XEC) vs 5-fluorouracil/epirubicin/cyclophosphamide (FEC), followed by adjuvant chemotherapy regimens, capecitabine/taxotere (XT) vs taxotere (T), in axillary lymph node (LN)-positive early-stage breast cancer. In this randomized, Phase III trial, 137 patients with operable primary breast cancer (T2-0, N0-1) who were tested axillary LN positive through aspiration biopsy of axillary LNs were randomized (1:1) to four 3-weekly cycles of XEC or FEC. Patients underwent surgery within 4-6 weeks after the fourth cycle, followed by four adjuvant cycles of 3-weekly XT or T. The primary end point was tumor pathological complete response. Toxicity profiles were secondary objectives. In total, 131 patients had clinical and radiological evaluation of response and underwent surgery. Treatment with XEC led to an increased rate of pathological complete response in primary tumor (18% vs 6%, respectively, P=0.027) and objective remission rate (87% vs 73%, P=0.048) compared to FEC. Clinical complete response occurred in 20% and 7% for XEC and FEC, respectively. Compared to FEC, XEC was associated with more hand-foot syndrome (57% vs 11%, P<0.001) and 3/4 grade nausea/vomiting/diarrhea (30% vs 14%, P=0.034) but less phlebitis (3% vs 14%, P=0.035). XT and T adjuvant chemotherapy regimens were well tolerated: treatment-related 3/4 grade adverse events occurred in 28% and 17% of patients receiving XT and T, respectively. PMID:27354816

  17. Dose response and factors related to interstitial pneumonitis after bone marrow transplant

    SciTech Connect

    Sampath, Sagus; Schultheiss, Timothy E. . E-mail: schultheiss@coh.org; Wong, Jeffrey

    2005-11-01

    Purpose: Total body irradiation (TBI) and chemotherapy are common components of conditioning regimens for bone marrow transplantation. Interstitial pneumonitis (IP) is a known regimen-related complication. Using published data of IP in a multivariate logistic regression, this study sought to identify the parameters in the bone marrow transplantation conditioning regimen that were significantly associated with IP and to establish a radiation dose-response function. Methods and Materials: A retrospective review was conducted of articles that reported IP incidence along with lung dose, fractionation, dose rate, and chemotherapy regimen. In the final analysis, 20 articles (n = 1090 patients), consisting of 26 distinct TBI/chemotherapy regimens, were included in the analysis. Multivariate logistic regression was performed to determine dosimetric and chemotherapeutic factors that influenced the incidence of IP. Results: A logistic model was generated from patients receiving daily fractions of radiation. In this model, lung dose, cyclophosphamide dose, and the addition of busulfan were significantly associated with IP. An incidence of 3%-4% with chemotherapy-only conditioning regimens is estimated from the models. The {alpha}/{beta} value of the linear-quadratic model was estimated to be 2.8 Gy. The dose eliciting a 50% incidence, D {sub 50}, for IP after 120 mg/kg of cyclophosphamide was 8.8 Gy; in the absence of chemotherapy, the estimated D {sub 50} is 10.6 Gy. No dose rate effect was observed. The use of busulfan as a substitute for radiation is equivalent to treating with 14.8 Gy in 4 fractions with 50% transmission blocks shielding the lung. The logistic regression failed to find a model that adequately fit the multiple-fraction-per-day data. Conclusions: Dose responses for both lung radiation dose and cyclophosphamide dose were identified. A conditioning regimen of 12 Gy TBI in 6 daily fractions induces an IP incidence of about 11% in the absence of lung shielding

  18. Poliovirus infection of cyclophosphamide-treated mice results in persistence and late paralysis: I. Clinical, pathologic, and immunologic studies.

    PubMed

    Jubelt, B; Meagher, J B

    1984-04-01

    An attenuated human poliovirus infection of cyclophosphamide (CY)-treated mice was developed as a model of persistent CNS enterovirus infections and as an investigation of the interaction of virus with motor neurons during persistence. Ten percent of mice inoculated intracerebrally with undiluted virus developed clinical disease by day 90, but of those treated with CY, 80% developed disease. At higher virus dilutions plus CY there was a marked increase in the incubation period. The latest onset of clinical disease occurred on day 146. Only paralyzed animals had pathologic changes in the spinal cord and virus antigen in anterior horn cells. Neutralizing antibodies were suppressed by CY, as were humoral and cellular immune responses to other antigens. PMID:6322051

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

    PubMed

    2016-05-01

    Near panic around secondary exposure of staff and family members to chemotherapy products is being seen again in spite of the implementation of products and procedures that have been shown to decrease the incidence in these populations. Many erroneous statements surrounding the extent of inadvertent chemotherapy exposure can be found in patient education sheets, in American Cancer Society publications, and, of course, on the Internet.
 Therefore, it was with a sense of relief at finally finding a voice of reason that I turned to "Secondary Exposure of Family Members to Cyclophosphamide After Chemotherapy of Outpatients With Cancer: A Pilot Study."
 However, I was sadly disappointed for the following reasons.
. PMID:27105187

  20. Effect of Drakshavaleha in cyclophosphamide induced weight loss and reduction in crown-rump length in developing mice embryo

    PubMed Central

    Kumar, Sunil; Singh, Gajendra; Reddy, K. R. C.

    2013-01-01

    Being an anti-mitotic and apoptosis inducing agent, Cyclophosphamide (CP) causes stunting in size and loss of body weight of the pups on intra-peritoneal injection (10 mg/kg) to pregnant mice on day 11 of gestation. Loss of body weight due to CP administration could be minimized by feeding Drakshavaleha (16 g/kg) orally to pregnant mice from day “0” to day “18” of their gestation. Recovery observed in terms of body weight of the pups was statistically significant (P < 0.001) in Drakshavaleha treated pups. Drakshavaleha also recovered the crown-rump length of the pups occurred due to CP administration. Growth retardation with decreased fetal weight was observed in all CP treated pups when compared with the controls. PMID:24250134

  1. Cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (COMLA) combination sequential chemotherapy for advanced diffuse histiocytic lymphoma

    SciTech Connect

    Sweet, D.L.; Golomb, H.M.; Ultmann, J.E.

    1980-06-01

    A program of combination sequential chemotherapy using cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (COMLA) was administered to 42 previously untreated patients with advanced diffuse histiocytic lymphoma. Twenty-three patients achieved a complete remission as determined by strict clinical restaging criteria. The observed median duration of survival for the complete responders is longer than 33 months. Eight patients achieved a partial response, with a median survival longer than 21 months. Eleven patients showed no response, with a median survival of 5 months. Toxicity was acceptable. None of the responders have shown central nervous system relapse. There was no difference in response rates between patients with stage III or IV lymphoma or between asymptomatic or symptomatic patients. The COMLA program produces a high rate of complete and durable remissions and should be considered as an initial form of management of patients with advanced diffuse histiocytic lymphoma.

  2. Acute effects of benzene and cyclophosphamide exposure on cellular and humoral immunity of cotton rats, Sigmodon hispidus

    SciTech Connect

    McMurry, S.T.; Lochmiller, R.L.; Vestey, M.R.; Qualls, C.W. Jr.; Elangbam, C.S. )

    1991-06-01

    Many environmental pollutants are potent immunotoxicants with the capability of altering host resistance to pathogens and compromising overall immunological integrity. Because environmental contaminants typically occur as a diverse group of compounds that are difficult to individually identify, their hazardous potential is often difficult to study in the laboratory. Consequently, development of wild mammalian species as bioindicators of environmental contamination may provide an alterative approach to assessing the hazardous potential of immunotoxicants for both human and wildlife populations. The cotton rat (Sigmodon hispidus) is an excellent prospect as an in situ bioindicator of environmental contamination of terrestrial ecosystems. Recently, the authors initiated studies in their laboratory to develop a sensitive method to evaluate environmental immunotoxicity hazards to wildlife and humans. The present study was designed to test the sensitivity of selected humoral and cell-mediated immune response assays in the cotton rat to acute benzene and cyclophosphamide exposure which are known immunotoxicants.

  3. Tumor lysis syndrome in a chronic lymphocytic leukemia patient with pleural effusion after oral fludarabine and cyclophosphamide therapy.

    PubMed

    Nakazawa, Hideyuki; Nishina, Sayaka; Mimura, Yuto; Kawakami, Toru; Senoo, Yasushi; Sakai, Kaoko; Nakazawa, Ko; Kitano, Kiyoshi

    2014-06-01

    Tumor lysis syndrome (TLS) is a rare complication of the treatment for chronic lymphocytic leukemia (CLL). Since the advent of new therapeutic agents with higher response rates, however, TLS has been observed with increasing frequency. An 84-year-old woman with a nine-year history of untreated CLL presented with exacerbating dyspnea due to pleural effusion. CLL cells without Richter transformation were observed in the pleural effusion at a high concentration, as well as in lymph nodes and bone marrow. After 5 days of oral fludarabine and cyclophosphamide (FC) therapy, the patient developed TLS, which necessitated rescue with hemodialysis. Although transient exacerbation of pleurisy occurred, the effusion cytology ameliorated, and she eventually achieved complete remission after additional two courses of FC and rituximab. Sequestration of fludarabine in the pleural effusion may be attributable to the development of TLS. PMID:24584911

  4. Total lymphoid irradiation and cyclophosphamide conditioning prior to bone marrow transplantation for patients with severe aplastic anemia

    SciTech Connect

    Ramsay, N.K.; Kim, T.H.; McGlave, P.; Goldman, A.; Nesbit, M.E. Jr.; Krivit, W.; Woods, W.G.; Kersey, J.H.

    1983-09-01

    A preparative regimen, consisting of total lymphoid irradiation and cyclophosphamide, was utilized in 40 patients with severe aplastic anemia undergoing allogeneic marrow transplantation. This regimen was successful in decreasing rejection in these previously transfused patients, as only one patient rejected the marrow graft. Twenty-nine of the 40 transplanted patients are surviving from 1.5 to 59 mo, with a median follow-up of 24 mo. The actuarial survival rate for these heavily transfused patients with aplastic anemia is 72% at 2 yr. This preparative regimen is extremely effective in decreasing rejection following transplantation for severe aplastic anemia. Future efforts in this area must be aimed at the elimination of graft-versus-host disease and control of fatal infections.

  5. High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Luznik, Leo

    2010-01-01

    Graft-versus-host disease, or GVHD, is a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of hematologic malignancies. Here, we describe a novel method for preventing GVHD after alloHSCT using high-dose, post-transplantation cyclophosphamide (Cy). Post-transplantation Cy promotes tolerance in alloreactive host and donor T cells, leading to suppression of both graft rejection and GVHD after alloHSCT. High-dose, post-transplantation Cy facilitates partially HLA-mismatched HSCT without severe GVHD and is effective as sole prophylaxis of GVHD after HLA-matched alloHSCT. By reducing the morbidity and mortality of alloHSCT, post-transplantation Cy may expand the applications of this therapy to the treatment of autoimmune diseases and non-malignant hematologic disorders such as sickle cell disease. PMID:20066512

  6. Esophageal complications from combined chemoradiotherapy (cyclophosphamide + adriamycin + cisplatin + XRT) in the treatment of non-small cell lung cancer

    SciTech Connect

    Umsawasdi, T.; Valdivieso, M.; Barkley, H.T. Jr.; Booser, D.J.; Chiuten, D.F.; Murphy, W.K.; Dhingra, H.M.; Dixon, C.L.; Farha, P.; Spitzer, G.

    1985-03-01

    Esophageal complications from combined chemoradiotherapy (CCRT) were analyzed in 55 patients with limited non-small cell lung cancer. CCRT consisted of chemotherapy (cyclophosphamide, doxorubicin (Adriamycin), and cisplatin: CAP) and chest irradiation (5000 rad in 25 fractions/5 weeks). Forty-five patients received two courses of CAP, followed by five weekly courses of low dose CAP and irradiation followed by maintenance courses of CAP (Group 1). Ten patients received concomitant CCRT from the onset of treatment (Group 2). Esophagitis occurred in 80% of all patients. Severe esophagitis occurred in 27% of patients of Group 1 and 40% of patients of Group 2. Esophageal stricture or fistula developed in 1 of 45 (2%) patients in Group 1, and 3 of 10 (30%) patients in Group 2. The duration between onset of chemotherapy either before or after R should be greater than one week.

  7. Amenorrhea in premenopausal women on the doxorubicin-and-cyclophosphamide-followed-by-docetaxel arm of NSABP B-30 trial

    PubMed Central

    Land, Stephanie R.; Ritter, Marcie W.; Costantino, Joseph P.; Cecchini, Reena S.; Mamounas, Eleftherios P.; Wolmark, Norman; Ganz, Patricia A.

    2016-01-01

    The NSABP B-30 trial addresses whether amenorrhea after adjuvant chemotherapy increases survival. Preliminary to the trial outcome analysis, we examined the incidence of amenorrhea and its relationship to symptoms and quality of life (QOL) in the standard-care arm of this adjuvant breast cancer trial. Premenopausal women treated on the doxorubicin-and-cyclophosphamide-followed-by-docetaxel arm were included. Questionnaires assessing menstrual history, QOL, and symptoms were administered at baseline, day 1 of cycle 4 (or 9 weeks from start of chemotherapy for those who stopped chemotherapy early), and at 6, 12, and 24 months. Seven hundred and eight patients were evaluable for the analysis, with median potential follow-up of 57.5 months. Of these, 321 patients also participated in the QOL substudy. Of the 708 patients, 83% reported ≥1 episode of amenorrhea for ≥6 months. The estimated rate of resumption of menses at 24 months was 45.3% for women<40 years, 10.9% for women 40–50, and 3.2% for women >50 years. Those treated with tamoxifen were more likely to become amenorrheic (p = 0.003). Menstrual status was not significantly associated with QOL or symptoms. Prolonged amenorrhea is associated with a regimen that contains doxorubicin, cyclophosphamide, and docetaxel, and is age dependent and impacted by tamoxifen use. Vasomotor symptoms are common in this patient population but are not associated with menstrual status. These results can be used to inform premenopausal women about the risk and time course of amenorrhea associated with this common adjuvant therapy regimen, along with the effects on symptoms and QOL. PMID:18302020

  8. Feasibility Trial of Partial Breast Irradiation With Concurrent Dose-Dense Doxorubicin and Cyclophosphamide in Early-Stage Breast Cancer

    PubMed Central

    Zellars, Richard C.; Stearns, Vered; Frassica, Deborah; Asrari, Fariba; Tsangaris, Theodore; Myers, Lee; DiPasquale, Shirley; Lange, Julie R.; Jacobs, Lisa K.; Emens, Leisha A.; Armstrong, Deborah K.; Fetting, John H.; Garrett-Mayer, Elizabeth; Davidson, Nancy E.; Wolff, Antonio C.

    2016-01-01

    Purpose Anthracyclines and concurrent whole-breast irradiation result in prohibitive cutaneous toxicity. We hypothesized that anthracycline-based chemotherapy and concurrent partial breast irradiation (PBI) is safe and conducted a single-arm feasibility trial testing this hypothesis with dose-dense doxorubicin and cyclophosphamide (ddAC). Patients and Methods Women with T1-2, N0-1 breast cancer with ≥ 3 mm lumpectomy margins received PBI (40.5 Gy, 15 daily 2.7-Gy fractions) concurrently with the first two of four cycles of ddAC (60 and 600 mg/m2 of doxorubicin and cyclophosphamide, respectively, every 14 days with colony-stimulating support). Primary end points were local and systemic toxicity. Additional systemic therapy was given at the physician's discretion. Results Twenty-seven patients enrolled between November 2004 and January 2007, but two patients did not receive protocol therapy (one found with additional local disease and one withdrew consent). Twenty-five women completed all planned PBI. Four (16%) of 25 did not complete all ddAC (febrile neutropenia [FN], n = 2; diverticulitis and neutropenia, n = 1; and social/economic reasons, n = 1). Four among the remaining 21 who completed all ddAC had a cycle delayed (FN, n = 1; acute respiratory illness, n = 1; foot blisters, n = 1; perianal dermatitis, n = 1). There was no grade 3 to 4 anemia or thrombocytopenia. Grade 3 nonhematologic toxicities (none grade 4) occurred in 28% (seven of 25) of patients (nausea/vomiting, n = 3; stomatitis, n = 2; contralateral breast abscess, n = 1; fatigue, n = 1; and cough/bronchospasms, n = 1). The observed rate of ≥ grade 2 skin toxicity was 0% (0 of 25; one-sided 95% CI, 0% to 11%). Conclusion PBI with concurrent ddAC is feasible, and local/systemic toxicity is acceptable. Larger studies are warranted to assess long-term locoregional control and late toxicities. PMID:19332718

  9. Cyclophosphamide in combination with glucocorticoids for severe neuropsychiatric systemic lupus erythematosus: a retrospective, observational two-centre study.

    PubMed

    Fanouriakis, A; Pamfil, C; Sidiropoulos, P; Damian, L; Flestea, A; Gusetu, G; Rednic, S; Bertsias, G; Boumpas, D T

    2016-05-01

    Cyclophosphamide (CYC) is used in severe neuropsychiatric systemic lupus erythematosus (NPSLE), but long-term data regarding its efficacy and safety are lacking. We identified NPSLE cases who received CYC from two centres during the period 1999-2013 and had regular follow-up. General and neuropsychiatric outcome at last follow-up visit were determined, and major complications were documented. CYC was administered in 50 neuropsychiatric events. Median age was 45.0 years and 46% of patients were positive for antiphospholipid antibodies. Most frequent indications were psychosis (11 cases), polyneuropathy (six cases), and cerebrovascular disease, seizure disorder and cranial neuropathy (five cases). CYC was mainly administered as monthly pulses (median number: 8.0 (range 3-26), median cumulative dose: 7.2 g (range 2.4-33.8)). Cases were followed for a median of 46.5 months (range 5-408). At last follow-up, partial or complete response of NPSLE was observed in 84% of events; 10% had stable disease, whereas the remaining 6% failed to improve or worsened and were rescued with rituximab. In events that responded to CYC, maintenance therapy consisted of azathioprine in 31 events (65.9%), bimonthly or quarterly pulses of intravenous CYC in nine (19.1%), and mycophenolate mofetil in five (10.6%). Relapses were observed in six events (12%) at median eight months after initial response. No malignancies were observed, yet there were three cases of severe infections. Amenorrhea was recorded in three patients, who had not received gonadal protection. In conclusion, cyclophosphamide was efficacious and led to sustained response of severe NPSLE in a cohort with long follow-up. PMID:26692040

  10. [Shengqifuzheng Injection promotes the recovery of B cells in gut-associated lymphoid tissues of mice treated with cyclophosphamide].

    PubMed

    Deng, Xiangliang; Huang, Rongrong; Wen, Ruyan; Luo, Xia; Zhou, Lian

    2016-08-01

    Objective To investigate the effect of Shengqifuzheng Injection (SQFZ) on the number recovery of B cells in gut-associated lymphoid tissues (GALTs) of mice receiving cyclophosphamide-based chemotherapy. Methods BALB/c mice were randomly divided into control group, cyclophosphamide (Cy) group and SQFZ group. Mice in Cy group and SQFZ group were injected intraperitoneally with Cy (100 mg/kg), while the control mice were injected with an equal volume of normal saline. Twenty-four hours later, mice in SQFZ group were administrated intragastricly with 1 mL SQFZ once daily for 10 consecutive days, and mice in the other groups were given the same volume of normal saline. Body mass of all the mice was measured every day. Mice were killed on day 10, and the indexes of spleen and thymus were measured. Cell cycles of bone marrow cells and the percentage of B cells in lymphocytes in mesenteric lymph node (MLN) and Peyer's patch (PP) were detected by flow cytometry. In vitro, after being treated with SQFZ, activity of lymphocytes was evaluzed by MTT assay; expression of CD86 on B cell surface was analyzed by flow cytometry; and B cell proliferation was tested by carboxyfluorescein succinimidyl ester (CFSE)-based lymphocyte proliferation assay. Results SQFZ alleviated the loss of body mass caused by Cy and promoted the recovery of thymus indexes, spleen indexes and B cell number in MLN and PP. But it did not alleviate the bone marrow suppression of mice in this condition. In vitro, SQFZ enhanced lymphocyte activity, and improved the activation and proliferation of B cells. Conclusion SQFZ could accelerate the recovery of B cells in GALTs of mice receiving chemotherapy and it might act by promoting B cell proliferation. PMID:27412939

  11. The leaching behavior of cyclophosphamide and ifosfamide from soil in the presence of co-contaminant--Mixture sorption approach.

    PubMed

    Mioduszewska, Katarzyna; Maszkowska, Joanna; Białk-Bielińska, Anna; Krüger, Oliver; Kalbe, Ute; Liberek, Beata; Łukaszewicz, Paulina; Stepnowski, Piotr

    2016-01-15

    Anticancer drugs (ACDs) exhibit high biological activity, they are cytotoxic, genotoxic, and are constantly released into the environment as a result of incomplete metabolism. Consequently they pose a serious threat to the environment and human health due to their carcinogenic, mutagenic and/or reproductive toxicity properties. Knowledge of their bioavailability, including their sorption to soils and their impact on the soil-groundwater pathway, is crucial for their risk assessment. Laboratory batch and column leaching tests are important tools for determining the release potential of contaminants from soil or waste material. Batch and column tests were carried out with soils differing in physicochemical properties, each spiked with cyclophosphamide (CK) or ifosfamide (IF). Moreover, due to the fact that environmental pollutants may occur as coexisting compounds in the soil the mobility evaluation for ACDs in the mixture with metoprolol (MET; β-blocker) as a co-contaminant was performed. In order to assess appropriateness, the batch and column tests were compared. The release depended on the properties of both the soil and the presence of co-contaminants. The faster release was observed for coarse-grained soil with the smallest organic matter content (MS soil: 90% decrease in concentration until liquid-to-solid ratio (L/S) of 0.3 L kg(-1) for all tests' layout) than for loamy sand (LS soil: 90% decrease in concentration until ratio L/S of 0.75 L kg(-1)). ACDs are highly mobile in soil systems. Furthermore, the decrease of mobility of ifosfamide was observed with the presence of a co-contaminant (metoprolol) in both of the soils (in MS soil a decrease of 29%; in LS soil a decrease of 26%). The mobility of cyclophosphamide does not depend on the presence of a contaminant for MS soil, but also exhibits a decrease of 21% in LS soil. PMID:26562339

  12. Dactinomycin potentiation of radiation pneumonitis: A forgotten interaction

    SciTech Connect

    Cohen, I.J.; Loven, D.; Schoenfeld, T.; Sandbank, J.; Kaplinsky, C.; Yaniv, Y.; Jaber, L.; Zaizov, R. )

    1991-04-01

    No mention of dactinomycin potentiation of pulmonary radiation was found in a review of the literature of the past 12 years. Before that, this complication was well described and investigators had calculated that dactinomycin increased the toxic effect of lung radiation by a factor of 1.3 and reduced the radiation tolerance of the lung by at least 20%. An example of such a toxic effect is described in the treatment of a 7-year-old girl with lung metastases from Ewing's sarcoma. The chemotherapy protocol followed contained cyclophosphamide, vincristine, dactinomycin, adriamycin, cisplatinum, VP16, and radiotherapy. The treatment was associated with fatal pulmonary fibrosis following the reintroduction of dactinomycin after radiotherapy. The authors experience suggests that there is clinical significance to this complication in sarcoma therapy when dactinomycin-containing protocols are used with radiation in the treatment of pulmonary metastases. 20 references.

  13. The results with the addition of metronomic cyclophosphamide to palliative radiotherapy for the treatment of non-small cell lung carcinoma

    PubMed Central

    Joshi, Subhash Chandra; Pandey, Kailash Chandra; Rastogi, Madhup; Sharma, Mukesh; Gupta, Manoj

    2015-01-01

    Background A considerable proportion of non-small cell lung carcinoma (NSCLC) patients are ineligible for radical therapies. Many are frail not to tolerate intravenous palliative chemotherapy either. These patients often receive palliative radiotherapy (RT), or supportive care alone. We intend to compare outcomes with palliative RT alone, versus palliative RT plus oral low dose metronomic cyclophosphamide. Methods Data was mined from 139 eligible NSCLC patient records. Comparisons were made between 65 patients treated from January 2011 to March 2013 with palliative RT (20-30 Gray in 5-10 fractions) alone, versus 74 patients treated from April 2013 to December 2014 with palliative RT plus oral metronomic cyclophosphamide (50 mg once daily from day of initiation of RT until at least the day of disease progression). Response was assessed after 1-month post-RT by computed tomography. Patients with complete or partial response were recorded as responders. For the determination of progression free survival (PFS), progression would be declared in case of increase in size of lesions, development of new lesions, or development of effusions. The proportions of responders were compared with the Fisher exact test, and the PFS curves were compared with the log-rank test. Results Differences in response rates were statistically insignificant. The PFS was significantly higher when metronomic chemotherapy was added to RT in comparison to treatment with RT alone (mean PFS 3.1 vs. 2.55 months; P=0.0501). Further histological sub-group analysis revealed that the enhanced outcomes with addition of metronomic cyclophosphamide to RT were limited to patients with adenocarcinoma histology (3.5 vs. 2.4 months; P=0.0053), while there was no benefit for those with squamous cell histology (2.6 vs. 2.6 months; P=1). At the dose of oral cyclophosphamide used, there was no recorded instance of any measurable hematological toxicity. Conclusions For pulmonary adenocarcinoma patients, the treatment

  14. A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma

    PubMed Central

    Nademanee, Auayporn; Forman, Stephen; Molina, Arturo; Fung, Henry; Smith, David; Dagis, Andy; Kwok, Cheuk; Yamauchi, Dave; Anderson, Anne-Line; Falk, Peter; Krishnan, Amrita; Kirschbaum, Mark; Kogut, Neil; Nakamura, Ryotaro; O'Donnell, Margaret; Parker, Pablo; Popplewell, Leslie; Pullarkat, Vinod; Rodriguez, Roberto; Sahebi, Firoozeh; Smith, Eileen; Snyder, David; Stein, Anthony; Spielberger, Ricardo; Zain, Jasmine; White, Christine; Raubitschek, Andrew

    2005-01-01

    We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2) followed by autologous stem cell transplantation (ASCT) in 31 patients with CD20+ non-Hodgkin lymphoma (NHL). Patients underwent dosimetry (day -21) with 5 mCi (185 MBq) 111In-ibritumomab tiuxetan following 250 mg/m2 rituximab, followed a week later by 90Y-ibritumomab tiuxetan to deliver a target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day -7 to estimate radiation dose and stem cells were reinfused when the radiation dose was estimated to be less than 5 cGy. The median 90Y-ibritumomab tiuxetan dose was 71.6 mCi (2649.2 MBq; range, 36.6-105 mCi; range, 1354.2-3885 MBq). Histology included follicular lymphoma (n = 12), diffuse large B-cell (n = 14), and mantle cell (n = 5). The median number of prior chemo-therapy treatments was 2. The treatment was well tolerated. The median times to reach an absolute neutrophil count greater than 500/μL and platelet count more than 20 000/μL were 10 days and 12 days, respectively. There were 2 deaths and 5 relapses. At a median follow-up of 22 months, the 2-year estimated overall survival and relapse-free survival rates are 92% and 78%, respectively. We conclude that high-dose 90Y-ibritumomab tiuxetan can be combined safely with high-dose etoposide and cyclophosphamide without an increase in transplant-related toxicity or delayed engraftment. (Blood. 2005;106:2896-2902) PMID:16002426

  15. Transient engraftment of syngeneic bone marrow after conditioning with high-dose cyclophosphamide and thoracoabdominal irradiation in a patient with aplastic anemia

    SciTech Connect

    Matsue, K.; Niki, T.; Shiobara, S.; Ueda, M.; Ohtake, S.; Mori, T.; Matsuda, T.; Harada, M. )

    1990-01-01

    We describe the clinical course of a 16 year old girl with aplastic anemia who was treated by syngeneic bone marrow transplantation. Engraftment was not obtained by simple infusion of bone marrow without immunosuppression. The patient received a high-dose cyclophosphamide and thoracoabdominal irradiation, followed by second marrow transplantation from the same donor. Incomplete but significant hematologic recovery was observed; however, marrow failure recurred 5 months after transplantation. Since donor and recipient pairs were genotypically identical, graft failure could not be attributed to immunological reactivity of recipient cells to donor non-HLA antigens. This case report implies that graft failure in some cases of aplastic anemia might be mediated by inhibitory cells resistant to cyclophosphamide and irradiation.

  16. In vitro inhibitory effects of palonosetron hydrochloride, bevacizumab and cyclophosphamide on purified paraoxonase-I (hPON1) from human serum.

    PubMed

    Türkeş, Cüneyt; Söyüt, Hakan; Beydemir, Şükrü

    2016-03-01

    In this study, we investigated the effects of the drugs, palonosetron hydrochloride, bevacizumab and cyclophosphamide, on human serum paraoxonase-I (hPON1) enzyme activity in in vitro conditions. The enzyme was purified ∼231-fold with 34.2% yield by using ammonium sulphate precipitation, DEAE-Sephadex A-50 ion-exchange chromatography and Sephadex G-200 gel-filtration chromatography from human serum. hPON1 exhibited a single protein band on the SDS polyacrylamide gel electrophoresis. The inhibition studies were performed on paraoxonase activity of palonosetron hydrochloride, bevacizumab and cyclophosphamide. Ki constants were found as 0.033±0.001, 0.054±0.003mM and 3.419±0.518mM, respectively. Compared to the inhibition rates of the drugs, palonosetron hydrochloride has the maximum inhibition rate. However, inhibition mechanisms of the drugs were determined as noncompetitive by Lineweaver-Burk curves. PMID:26915059

  17. Immune-mediated necrotising myopathy associated with antibodies to the signal recognition particle treated with a combination of rituximab and cyclophosphamide.

    PubMed

    Fernandes das Neves, Marisa; Caetano, Joana; Oliveira, Susana; Delgado Alves, José

    2015-01-01

    A 50-year-old man presented with dysphagia and proximal muscle weakness. He was diagnosed with immune-mediated necrotising myopathy associated with antibodies to the signal recognition particle. After an initial response following treatment with high-dose steroids, intravenous immunoglobulin and methotrexate, there was a relapse of the immune condition. The clinical deterioration occurred less than 2 months after disease onset. The refractoriness of this disease was characterised by an increase of the already severe muscle wasting that led to respiratory failure and progressive dysphagia, regardless of the immunosuppressant treatment. At this time the patient was referred to our department. He was restarted on intravenous pulses of methylprednisolone associated with intravenous cyclophosphamide, but with no effect. After 3 weeks, rituximab was started with a dramatic and progressive improvement. There were no complications associated with rituximab/cyclophosphamide treatment and the disease has been kept in remission, for the last 3 years. PMID:26240092

  18. Phase I and Clinical Pharmacology Study of Bevacizumab, Sorafenib, and Low-dose Cyclophosphamide in Children and Young Adults with Refractory/Recurrent Solid Tumors

    PubMed Central

    Navid, Fariba; Baker, Sharyn D.; McCarville, M. Beth; Stewart, Clinton F.; Billups, Catherine A.; Wu, Jianrong; Davidoff, Andrew M.; Spunt, Sheri L.; Furman, Wayne L.; McGregor, Lisa M.; Hu, Shuiying; Panetta, John C.; Turner, David; Fofana, Demba; Reddick, Wilburn E.; Leung, Wing; Santana, Victor M.

    2012-01-01

    Purpose To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors. Patients and Methods Sorafenib dose was escalated from 90 mg/m2 to 110 mg/m2 twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m2 daily. Once sorafenib’s MTD was established, bevacizumab dose was escalated. Each course was 21 days. PK and PD studies were performed during the first course. Results Nineteen patients (11 males; median age, 9.2 years) received a median of 4 courses (range, 1 to 23). DLTs during course 1 included grade 3 rash (2), increased lipase (1), anorexia (1), and thrombus (1). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (9), lymphopenia (9), and rashes (4). Five of 17 evaluable patients had partial tumor responses, and 5 had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m2. Median day 1 sorafenib apparent oral clearance was 44 and 39 ml/min/m2 at the 2 dose levels evaluated, and steady-state concentrations ranged from1.64 to 4.8 mg/L. Inhibition of serum VEGFR2 was inversely correlated with sorafenib steady-state concentrations (p=0.019). Conclusion The recommended phase II doses are sorafenib, 90 mg/m2 twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m2 once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation. PMID:23143218

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

    PubMed

    Oliveira, Rodrigo Juliano; Pesarini, João Renato; Sparça Salles, Maria José; Nakamura Kanno, Tatiane Yumi; Dos Santos Lourenço, Ana Carolina; da Silva Leite, Véssia; da Silva, Ariane Fernanda; Matiazi, Hevenilton José; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2014-03-01

    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. PMID:24688298

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

    PubMed Central

    Oliveira, Rodrigo Juliano; Pesarini, João Renato; Sparça Salles, Maria José; Nakamura Kanno, Tatiane Yumi; dos Santos Lourenço, Ana Carolina; da Silva Leite, Véssia; da Silva, Ariane Fernanda; Matiazi, Hevenilton José; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2014-01-01

    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. PMID:24688298

  1. Role of (18)F-FDG PET-CT in Monitoring the Cyclophosphamide Induced Pulmonary Toxicity in Patients with Breast Cancer - 2 Case Reports.

    PubMed

    Taywade, Sameer Kamalakar; Kumar, Rakesh; Bhethanabhotla, Sainath; Bal, Chandrasekhar

    2016-09-01

    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 (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in lungs on fluorodeoxyglucose positron emission tomography-computed tomography ((18)F-FDG PET-CT) has been elicited in literature in relation to lymphoma. However, limited data is available regarding the role of (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 (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 (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. PMID:27540432

  2. A cyclophosphamide-sensitive cell compartment is essential for homologous protection conferred by licensed vaccines for the control of avian pathogenic Escherichia coli in chickens.

    PubMed

    Sadeyen, Jean-Rémy; Kaiser, Pete; Stevens, Mark P; Dziva, Francis

    2015-07-17

    Avian pathogenic Escherichia coli (APEC) exert substantial economic costs on poultry producers worldwide. Vaccination is an attractive method of control, but the immunological basis of protection is poorly understood. Here, we examine the effect of intramuscular injection of cyclophosphamide or saline on homologous protection induced by licensed inactivated or live-attenuated APEC O78 vaccines in chickens. In saline-treated birds, both vaccines induced significant APEC-specific IgY and protection against homologous challenge, as evidenced by enumeration of tissue-associated bacteria and analysis of pathology. In cyclophosphamide-treated birds, B cells were severely depleted whereas percentages of circulating CD4- and CD8-positive T cells were normal as detected by flow cytometry. Further, such birds did not produce APEC-specific IgY and were as susceptible to challenge as age-matched unvaccinated controls. The data indicate that homologous protection conferred by licensed APEC vaccines strictly requires a cyclophosphamide-sensitive cell population that includes B cells. PMID:26087298

  3. Combination of poly-gamma-glutamate and cyclophosphamide enhanced antitumor efficacy against tumor growth and metastasis in a murine melanoma model.

    PubMed

    Kim, Doo-Jin; Kim, Eun-Jin; Lee, Tae-Young; Won, Ji-Na; Sung, Moon-Hee; Poo, Haryoung

    2013-09-28

    Conventional chemotherapeutic regimens often accompany severe side effects and fail to induce complete regression of chemoresistant or relapsing metastatic cancers. The need for establishing more efficacious anticancer strategies led to the development of a combined modality treatment of chemotherapy in conjunction with immunotherapy or radiotherapy. It has been reported that poly-gamma-glutamate (γ-PGA), a natural polymer composed of glutamic acids, increases antitumor activity by activating antigen-presenting cells and natural killer (NK) cells. Here, we investigated the antitumor effect of γ-PGA in combination with cyclophosphamide in a murine melanoma model. Whereas cyclophosphamide alone directly triggered apoptosis of tumor cells in vitro, γ-PGA did not show cytotoxicity in tumor cells. Instead, it activated macrophages, as reflected by the upregulation of surface activation markers and the secretion of proinflammatory factors, such as nitric oxide and tumor necrosis factor α. When the antitumor effects were examined in a mouse model, combined treatment with cyclophosphamide and γ-PGA markedly suppressed tumor growth and metastasis. Notably, γ-PGA treatment dramatically increased the NK cell population in lung tissues, coinciding with decreased metastasis and increased survival. These data collectively suggest that γ-PGA can act as an immunotherapeutic agent that exhibits a synergistic antitumor effect in combination with conventional chemotherapy. PMID:23867701

  4. Prognostic impact of immune status and hematopoietic recovery before and after fludarabine, IV busulfan, and antithymocyte globulins (FB2 regimen) reduced-intensity conditioning regimen (RIC) allogeneic stem cell transplantation (allo-SCT).

    PubMed

    Le Bourgeois, Amandine; Lestang, Elsa; Guillaume, Thierry; Delaunay, Jacques; Ayari, Sameh; Blin, Nicolas; Clavert, Aline; Tessoulin, Benoit; Dubruille, Viviane; Mahe, Beatrice; Roland, Virginie; Gastinne, Thomas; Le Gouill, Steven; Moreau, Philippe; Mohty, Mohamad; Planche, Lucie; Chevallier, Patrice

    2013-03-01

    This retrospective analysis aimed to assess hematopoietic and immune recovery in a cohort of 53 patients [males: n = 33; median age: 59 yr (range: 22-70)] who received a FB2 (fludarabine 120-150 mg/m² + IV busulfan 6.4 mg/kg + antithymocyte globulin thymoglobulin 5 mg/kg) reduced-intensity conditioning (RIC) allo-stem cells transplantations (SCT). With a median follow-up of 19 months (range: 2-53), the 2-yr overall survival, disease-free survival (DFS), relapse incidence, and non-relapse mortality were 63%, 59.5%, 35%, and 6%, respectively. In univariate analysis, the factors correlated with a significantly higher 2-yr OS and DFS were a higher total circulating lymphocytes count at transplant (>730/mm(3) ; OS: 81% vs. 43%, P = 0.02; DFS: 73% vs. 45.5%, P = 0.03) and a higher recovery of leukocytes (>5300/mm(3) ) (2-yr OS: 81% vs. 44%, P = 0.007; 2-yr DFS: 72% vs. 46%, P = 0.08), neutrophils (>3200/mm(3) ) (2-yr OS: 76% vs. 50%, P = 0.03; 2-yr DFS: 67% vs. 52.0%, P = 0.1), and monocytes (>590/mm(3) ; 2-yr OS: 80% vs. 45%, P = 0.004; 2-yr DFS: 76% vs. 42%, P = 0.01) at day +30 post-transplant. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm(3) ) and a higher monocytes count (>590/mm(3) ) at day +30 post-transplant. These results suggest that immune status and hematopoietic recovery before and after FB2 RIC allo-SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo-SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo-SCT. PMID:23301689

  5. Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

    PubMed Central

    Bazzola, L; Foroni, C; Andreis, D; Zanoni, V; R Cappelletti, M; Allevi, G; Aguggini, S; Strina, C; Milani, M; Venturini, S; Ferrozzi, F; Giardini, R; Bertoni, R; Turley, H; Gatter, K; Petronini, P G; Fox, S B; Harris, A L; Martinotti, M; Berruti, A; Bottini, A; Reynolds, A R; Generali, D

    2015-01-01

    Purpose: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). Methods: Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. Results: Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by 18FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively). Conclusions: The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is

  6. Phase I Clinical Trial of Valacyclovir and Standard of Care Cyclophosphamide in Children With Endemic Burkitt Lymphoma in Malawi

    PubMed Central

    Olson, Dan; Gulley, Margaret L.; Tang, Weihua; Wokocha, Clifford; Mechanic, Oren; Hosseinipour, Mina; Gold, Stuart H.; Nguluwe, Nelson; Mwansambo, Charles; Shores, Carol

    2013-01-01

    Treatment options for Epstein-Barr virus (EBV)-associated Burkitt lymphoma in Africa are limited because of chemotherapy-associated toxicity. Since other EBV-associated diseases respond to antiviral agents, we investigated adding an antiviral agent, valacyclovir, to the current chemotherapy regimen in Malawi. In this phase I safety study, we showed that cyclophosphamide combined with valacyclovir was safe. Phase II efficacy trials should now be undertaken. Background Nucleoside analogues, including acyclovir, ganciclovir, and their precursors, have shown some efficacy against several Epstein-Barr virus (EBV)-associated diseases, including active EBV infection and posttransplantation lymphoproliferative disorder (PTLD). They have also been proposed as a possible treatment for EBV-associated malignancies, including endemic Burkitt lymphoma. The safety of nucleoside analogues in combination with chemotherapy in the developing world has not been studied and is necessary before any large scale efficacy trials are conducted. Patients and Methods Children 3–15 years old meeting inclusion criteria were assigned to a 3+3 dose escalation trial of combination valacyclovir (15 and 30 mg/kg, 3 times daily for 40 days) and cyclophosphamide (CPM) (40 mg/kg day 1, 60 mg/kg on days 8, 18, and 28) or CPM monotherapy. Subjects were monitored for clinical and laboratory toxicity and had EBV levels measured regularly. Dose-limiting toxicity (DLT) was our primary outcome. Results We found that the combination of valacyclovir and CPM was safe and did not lead to any DLT compared with CPM monotherapy. The most common side effects were vomiting, abdominal pain, and tumor site pain, which were similar in both arms. Patients with measurable serum EBV showed decreased loads over their treatment course. Conclusions We recommend a phase II valacyclovir dose of 30 mg/kg 3 times daily for 40 days. We also observed that 6 of our 12 patients with presumed Burkitt lymphoma had measurable EBV viral

  7. Protective effects of a by-product of the pecan nut industry (Carya illinoensis) on the toxicity induced by cyclophosphamide in rats Carya illinoensis protects against cyclophosphamide-induced toxicity.

    PubMed

    Benvegnú, D; Barcelos, R C S; Boufleur, N; Reckziegel, P; Pase, C S; Müller, L G; Martins, N M B; Vareli, C; Bürger, M E

    2010-01-01

    This study investigated the antioxidant effects of pecan nut (Carya illinoensis) shell aqueous extract (AE) on toxicity induced by cyclophosphamide (CP) in the heart, kidney, liver, bladder, plasma and erythrocytes of rats. Rats were treated with water or pecan shell AE (5%) ad libitum, replacing drinking water for 37 days up to the end of the experiment. On day 30, half of each group received a single administration of vehicle or CP 200 mg/kg-ip. After 7 days, the organs were removed. Rats treated with CP showed an increase in lipid peroxidation (LP) and decrease in reduced glutathione (GSH) levels in all structures. Catalase (CAT) activity was increased in the heart and decreased in liver and kidney. Besides, CP treatment decreased plasmatic vitamin C (VIT C) levels and induced bladder macroscopical and microscopical damages. In contrast, co-treatment with pecan shell AE prevented the LP development and the GSH depletion in all structures, except in the heart and plasma, respectively. CAT activity in the heart and liver as well as the plasmatic VIT C levels remained unchanged. Finally, AE prevented CP-induced bladder injury. These findings revealed the protective role of pecan shell AE in CP-induced multiple organ toxicity. PMID:21303326

  8. Comparison of toxicity following different conditioning regimens (busulfan/melphalan and carboplatin/etoposide/melphalan) for advanced stage neuroblastoma: Experience of two transplant centers.

    PubMed

    Elborai, Yasser; Hafez, Hanafy; Moussa, Emad A; Hammad, Mahmoud; Hussein, Hany; Lehmann, Leslie; Elhaddad, Alaa

    2016-03-01

    The outcome for advanced neuroblastoma has improved with combined modality therapy: induction chemotherapy, surgery, and consolidation with high-dose chemotherapy/autologous HSCT, followed by local radiation, cisretinoic acid, and recently antibody therapy. In the United States, the most common conditioning regimen is CEM, while in Europe/Middle East, Bu/Mel has been widely used; it remains unclear which regimen has the best outcome. Assess renal, hepatic, and infectious toxicity through Day+100 in 2 different regimens. Retrospective comparison between CEM-DFCHCC Boston and Bu/Mel- CCHE-57357. Thirty-five patients, median age 4, in Boston (2007-2011) and 38 patients, median age 3, in Cairo (2009-2011). Renal toxicity; creatinine was significantly higher in CEM than Bu/Mel: 57% (median day+90) vs. 29% (median>day+100), p = 0.004. One CEM patient died from renal dialysis at day+19. Hepatic toxicity was significantly higher in CEM than Bu/Mel: 80% (median day+26) vs. 58% (median day+60), p = 0.04. In infectious complications with CEM 14%, bacteremia (n = 4) and fungemia (n = 1), 3 had culture-negative sepsis requiring vasopressors. With Bu/Mel 18%, bacteremia (n = 7), none required pressors, p = 0.4. Bu/Mel was associated with less acute hepatic and renal toxicity and thus may be preferable for preserving organ functions. PMID:26614402

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

    PubMed

    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. PMID:25079140

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

    PubMed Central

    Chabra, Aroona; Naghshvar, Farshad; Ahmadi, Amirhossein

    2013-01-01

    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. PMID:24324391

  11. Investigation on Immunomodulatory Activity of Calf Spleen Extractive Injection in Cyclophosphamide-induced Immunosuppressed Mice and Underlying Mechanisms.

    PubMed

    Jia, D; Lu, W; Wang, C; Sun, S; Cai, G; Li, Y; Wang, G; Liu, Y; Zhang, M; Wang, D

    2016-07-01

    Calf spleen extractive injection (CSEI), extracted from the spleen of healthy cows (within 24 h of birth), is a small peptides enriched extraction while the ratio between peptide and ribose is 76 ± 15.2 mg/μg. CSEI is usually used as an ancillary agent to assist cancer patients with immune dysfunction. The present study aims to evaluate the immunomodulatory activity of CSEI in cyclophosphamide (CTX)-induced mice model of immunosuppression and its underlying mechanisms. During the experiment, thymosin ɑ1 (0.16 mg/kg) was served as the positive control drug. In CTX-induced immunosuppressed mice, CSEI significantly increased bodyweights and spleen indexes, and upgraded the natural killer activity together with lymphocytes proliferation. CSEI regulated the production of IgG and IgA, and the levels of IL-2, 6, 10, 12 and IFN-ɑ, γ and TNF-ɑ in serum of CTX-induced immunosuppressed mice. Furthermore, CSEI markedly downregulated nuclear factor kappa-B (NF-κB) expression which was controlled by IKKβ. Taken together, CSEI effectively improved immune function in CTX-induced immunosuppression related to NF-κB signalling pathway via regulating the production of immunoglobulins, interleukins and some inflammatory factors. PMID:27104480

  12. Two Cases of Refractory Thrombocytopenia in Systemic Lupus Erythematosus that Responded to Intravenous Low-Dose Cyclophosphamide

    PubMed Central

    Park, Hee-Jin; Kang, Mi-il; Kang, Yoon; Chung, Soo-jin; Park, Yong-Beom; Lee, Soo-Kon

    2013-01-01

    Treatment of thrombocytopenia in systemic lupus erythematosus (SLE) is considered in cases of current bleeding, severe bruising, or a platelet count below 50,000/µL. Corticosteroid is the first choice of medication for inducing remission, and immunosuppressive agents can be added when thrombocytopenia is refractory to corticosteroid or recurs despite it. We presented two SLE patients with thrombocytopenia who successfully induced remission after intravenous administration of low-dose cyclophosphamide (CYC) (500 mg fixed dose, biweekly for 3 months), followed by azathioprine (AZA) or mycophenolate mofetil (MMF). Both patients developed severe thrombocytopenia in SLE that did not respond to pulsed methylprednisolone therapy, and started the intravenous low-dose CYC therapy. In case 1, the platelet count increased to 50,000/µL after the first CYC infusion, and remission was maintained with low dose prednisolone and AZA. The case 2 achieved remission after three cycles of CYC, and the remission continued with low dose prednisolone and MMF. PMID:23487584

  13. Ferulic Acid against Cyclophosphamide-Induced Heart Toxicity in Mice by Inhibiting NF-κB Pathway

    PubMed Central

    Song, Yafan; Zhang, Chunyan; Wang, Congxia; Zhao, Ling; Wang, Zheng; Dai, Zhijun; Lin, Shuai; Kang, Huafeng; Ma, Xiaobin

    2016-01-01

    The purpose of the present study was to elucidate the protective effects of ferulic acid (FA) against cyclophosphamide- (CTX-) induced changes in mice. Forty-eight male ICR mice were divided into four groups. Control group was intraperitoneally (i.p.) injected with 200 μL of phosphate buffer saline (PBS). Model group was intraperitoneally injected with a single dose of CTX (200 mg/kg). FA (50 mg/kg) and FA (100 mg/kg) groups were intraperitoneally injected with a single dose of CTX (200 mg/kg) followed by the intragastric treatment with FA (50, 100 mg/kg) for 7 consecutive days. After 12 d, the mice were sacrificed to analyze the hematological, biochemical, histological parameters and mechanism research. The results indicated that FA significantly decreased the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), lactate dehydrogenase (LDH), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) in CTX-injected mice. In addition, FA effectively reduced the total numbers of white blood cells (WBCs), red blood cells, platelets, and hemoglobin content. FA also obviously attenuated the histological changes of the heart tissues caused by CTX. Moreover, Western blot demonstrated that FA inhibited the phosphorylations of NF-κB signaling pathway in CTX-stimulated cardiac tissues. In conclusion, FA might be considered as an effective agent in the amelioration of the heart toxicity resulting from CTX treatment. PMID:26881001

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

    PubMed

    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. PMID:26482705

  15. CYP2B6rs2279343 Is Associated with Improved Survival of Pediatric Rhabdomyosarcoma Treated with Cyclophosphamide

    PubMed Central

    A. Abdelrahim, Mohamed E.; Elnadi, Enas; Hesham, Reem M.; Yassin, Dina

    2016-01-01

    Background Rhabdomyosarcoma (RMS) is a small round blue cell malignant tumor, representing 7% of childhood malignancies, and over 50% of all soft tissue sarcomas. Cyclophosphamide (CPA) is a prodrug and is the mainstay of RMS treatment. CYP2B6 is a highly polymorphic drug metabolizing enzyme involved in CPA bioactivation. The influence of CYP2B6 single nucleotide polymorphisms (SNPs) on the survival of RMS is still unknown. Methods We genotyped CYP2B6SNPs rs2279343, rs3745274, and rs3211371 by restriction fragment polymorphism (RFLP) after PCR amplification in a cohort of 73 pediatric RMS patients treated with CPA-based first line treatment. We then analyzed the association between those genotypes and survival outcome of RMS. Results The frequencies of CYP2B6 rs2279343, rs3745274, and rs3211371 were 63%, 45.2%, and 5.5%, respectively. There was no association between rs3745274, rs3211371 genotypes and survival outcomes of RMS. However, the carriers of at least one mutant allele CYP2B6rs2279343 had significantly longer event-free survival (p-value = 0.03). Conclusion Our results demonstrated that CYP2B6 rs2279343 may predict EFS in RMS patients and warrants future studies to clarify the pharmacogenetics of CPA in pediatrics. If validated, integration of genetic factors with clinical and molecular characteristics could be used for a composite algorithm to better stratify risk prior to treatment. PMID:27388155

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

    PubMed

    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. PMID:25904411

  17. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma

    PubMed Central

    Micallef, Ivana N. M.; Maurer, Matthew J.; Wiseman, Gregory A.; Nikcevich, Daniel A.; Kurtin, Paul J.; Cannon, Michael W.; Perez, Domingo G.; Soori, Gamini S.; Link, Brian K.; Habermann, Thomas M.

    2011-01-01

    Approximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m2 intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821. PMID:21673350

  18. Lactobacillus plantarum NCU116 attenuates cyclophosphamide-induced intestinal mucosal injury, metabolism and intestinal microbiota disorders in mice.

    PubMed

    Xie, Jun-Hua; Fan, Song-Tao; Nie, Shao-Ping; Yu, Qiang; Xiong, Tao; Gong, Deming; Xie, Ming-Yong

    2016-03-16

    Anticancer drugs at high doses often damage the intestinal mucosa and metabolism. Lactobacillus plantarum NCU116 (NCU116) isolated from pickled vegetables was orally given to cyclophosphamide-treated mice to determine its effects on intestinal mucosal injury, nutrient metabolism and colon microbiota, and investigate the mechanisms accounting for its effects. Mice treated with the bacterium were found to favorably recover intestine morphology of villus height and crypt depth, and have improved mucins expression and quantity of goblet cells, as well as intestinal metabolism by increasing the level of short-chain fatty acids and reducing the concentration of ammonia in the colon feces. In addition, NCU116-treated mice showed a higher diversity of colonic microbiota than the group without bacterium supplementation. The number of Lactobacillus and Bifidobacterium in the mouse colon was increased after bacterium intake, which decreased the number of potentially pathogenic bacteria, Escherichia coli and Pseudomonas. These results indicated that NCU116 could be of significant advantage in reducing intestinal mucosal injury and improving the intestinal metabolism and the intestinal microbiota. PMID:26906433

  19. Effects of Spirulina on Cyclophosphamide-Induced Ovarian Toxicity in Rats: Biochemical and Histomorphometric Evaluation of the Ovary

    PubMed Central

    Yener, Nese Arzu; Sinanoglu, Orhun; Ilter, Erdin; Celik, Aygen; Sezgin, Gulbuz; Midi, Ahmet; Aksungar, Fehime

    2013-01-01

    Cyclophosphamide (Cyc) is known to cause ovotoxicity and infertility in women. Our aim is to investigate the possible ovotoxic effects of Cyc and possible antioxidant and protective effects of blue-green algae, Spirulina (Sp), in rat ovaries. Eighteen rats were given: group I (n = 6, control); group II (n = 6, CP), a single dose Cyc; group III (n = 6, Sp+Cyc), 7 days Sp+single dose Cyc. Tissue malondialdehyde (MDA) levels, superoxide dismutase (SOD), and catalase (CAT) activities are assessed biochemically. Normal and atretic primordial and primary follicle counts for all sections obtained for each ovary are calculated. Mean number of follicle counts for each group are compared. In Sp+Cyc group, tissue MDA levels were significantly lower than those in the CP and higher than those in the C group (CP > Sp+Cyc > C). Tissue SOD activity was significantly higher in Sp+Cyc group than that in the CP group and lower than that in the C group (C > Sp+Cyc > C). No statistically significant difference was found between the ovarian CAT activities in any group. Histomorphometrically, there was also no significant difference between the mean numbers of normal and atretic small follicle counts. Our results suggest that single dose Cyc has adverse effects on oxidant status of the ovaries and Sp has protective effects in Cyc-induced ovotoxicity. PMID:23762559

  20. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplantation for Patients with Acute Leukemia.

    PubMed

    Holter-Chakrabarty, Jennifer L; Pierson, Namali; Zhang, Mei-Jie; Zhu, Xiaochun; Akpek, Görgün; Aljurf, Mahmoud D; Artz, Andrew S; Baron, Frédéric; Bredeson, Christopher N; Dvorak, Christopher C; Epstein, Robert B; Lazarus, Hillard M; Olsson, Richard F; Selby, George B; Williams, Kirsten M; Cooke, Kenneth R; Pasquini, Marcelo C; McCarthy, Philip L

    2015-07-01

    Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI, n = 948; TBICy, n = 821) recipients of related or unrelated hematopoietic cell transplantation who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome-positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk, .89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk, .93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk, .9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk, .96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning. PMID:25840335

  1. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia

    PubMed Central

    Terzi-di-Bergamo, Lodovico; De Paoli, Lorenzo; Cerri, Michaela; Ghilardi, Guido; Chiarenza, Annalisa; Bulian, Pietro; Visco, Carlo; Mauro, Francesca R.; Morabito, Fortunato; Cortelezzi, Agostino; Zaja, Francesco; Forconi, Francesco; Laurenti, Luca; Del Giudice, Ilaria; Gentile, Massimo; Vincelli, Iolanda; Motta, Marina; Coscia, Marta; Rigolin, Gian Matteo; Tedeschi, Alessandra; Neri, Antonino; Marasca, Roberto; Perbellini, Omar; Moreno, Carol; Del Poeta, Giovanni; Massaia, Massimo; Zinzani, Pier Luigi; Montillo, Marco; Cuneo, Antonio; Gattei, Valter; Foà, Robin; Gaidano, Gianluca

    2015-01-01

    Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant treatment advancement in chronic lymphocytic leukemia (CLL). In the new scenario of targeted agents, there is an increasing interest in identifying patients who gain the maximum benefit from FCR. In this observational multicenter retrospective analysis of 404 CLL patients receiving frontline FCR, the combination of three biomarkers that are widely tested before treatment (IGHV mutation status, 11q deletion and 17p deletion; available in 80% of the study cohort) allowed to identify a very low-risk category of patients carrying mutated IGHV genes but neither 11q or 17p deletion that accounted for 28% of all cases. The majority of very low-risk patients (71%) remained free of progression after treatment and their hazard of relapse decreased after 4 years from FCR. The life expectancy of very low-risk patients (91% at 5 years) was superimposable to that observed in the matched normal general population, indicating that neither the disease nor complications of its treatment affected survival in this favorable CLL group. These findings need a prospective validation and may be helpful for the design of clinical trials aimed at comparing FCR to new targeted treatments of CLL, and, possibly, for optimized disease management. PMID:26276669

  2. Removal of antineoplastic drugs cyclophosphamide, ifosfamide, and 5-fluorouracil and a vasodilator drug pentoxifylline from wastewaters by ozonation.

    PubMed

    Lin, Angela Yu-Chen; Hsueh, Julia Han-Fang; Hong, P K Andy

    2015-01-01

    We investigated the ozonation of the antineoplastic drugs cyclophosphamide (CP), ifosfamide (IF), and 5-fluorouracil (5-FU) and of the vasodilator pentoxifylline (PEN) in distilled water, in pharmaceutical wastewater, and in hospital effluent at pH 5-11. Under an alkaline pH of 11, all of the target compounds rapidly degraded through the attack of hydroxyl radicals, which resulted in their complete removal within 5 min at an ozone supply rate of 3 g O3/h. Under acidic pH conditions, such as pH 5.6, CP and IF exhibited slower removal rates; however, compounds with unsaturated C-C bonds, such as 5-FU and PEN, were still removed at rapid rates under acidic conditions. Although the parent compounds were removed within minutes, the resulting ozonation byproducts were resistant to further ozonation and possessed increased Microtox acute toxicity. In distilled water, the resulting ozonation products exhibited minimal mineralization but high acute toxicity, whereas in naturally buffered pharmaceutical and hospital effluents, the byproducts were more amenable to removal and detoxification. PMID:25087496

  3. Study on the therapeutic effects of low-energy laser therapy combined with cyclophosphamide on the mouse ascites sarcoma

    NASA Astrophysics Data System (ADS)

    Wang, Hongbin; Huang, Baoxu; Liu, Huanqi; Qu, Zhina; Liu, Xifeng; Cheng, Shaohui

    2004-07-01

    By using the experimental model of mouse S180 ascites sarcoma, the feasibility and mechanism of low-energy laser therapy combined with the traditional antitumor drug of cyclophosphamide in the treatment of malignant tumors were discussed. The S180 ascites sarcoma suffering BALB/c mice were irradiated upon the Harder's glands with the dosages of 11.00, 14.67 and 22.00 J/cm2 respectively, and/or injected with CYT intraperitoneally to evaluate the therapeutic effects of CYT/LELT combination on malignant tumors. The three dosages of LELT combined with CYT all showed remarkably therapeutic effects on the mouse S180 ascites sarcoma. Comparatively, the dosage of 14.67J/cm2 LELT combined with CYT showed the most ideal therapeutic effects and the survival time was up to 20.80 days, and the life prolongation ratio was 33.33% which was remarkably higher than those of the CYT and tumor control groups. CYT/LELT combined therapy had remarkably inhibiting effects on the mice ascites growth because of the existence of CYT.

  4. Treatment of Walker ascites tumor cells by combination of photodynamic therapy with cyclophosphamide and interleukin-2 entrapped in liposomes

    NASA Astrophysics Data System (ADS)

    Dima, Vasile F.; Ionescu, Mircea D.; Balotescu, Carmen; Dima, V. S.

    2003-12-01

    The purpose of this study was to investigate the beneficial and adverse local effects of PDT associated with chemoimmunotherapy on rats bearing Walker ascites tumor cells. Experiments were performed on five batches of Wistar inbred rats with ascites tumor cells receiving intraperitoneally PDT (Photofrin II and 18 hrs later HeNe laser irradiation); Cyclophosphamide (CY); interleukin-2 (IL-2) or associated therapy (PDT+CY+IL-2). The control batch consisted of untreated rats (HBSS). The following results were noticed: (a) sole administration of PDT, IL-2 or CY reduced tumor growth, gave survival rates between 28.4 and 56.5% and cure rates ranging from 12.4 to 33.3%; (b) combined therapy (PDT+CY+IL-2) decreased tumor growth, increased survival rates (88.5%) and cure rates were 73.1% forty-two days post-transplantation. Summing up, in this study we noticed that PDT associated with chemoimmunotherapy reduced mortality as well as tumor volumes and increased cure rates in rats with ascites tumor cells. This approach points to the need for further evaluation in patients with peritoneal malignancies.

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

    PubMed

    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

  6. Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female, but not male mice.

    PubMed

    Philpot, Rex M; Ficken, Melissa; Wecker, Lynn

    2016-07-01

    Self-reports of chemotherapy-related cognitive deficits (CRCDs) are more prevalent among women than men, suggesting that women may be more vulnerable to the cognitive-impairing effects of chemotherapy. However, there have been no direct comparisons of females and males using objective measures of cognitive function either during or following exposure to the same chemotherapeutic regimen. The present study used an animal model, and a prospective longitudinal design, to assess sex differences in the manifestation and persistence of spatial memory deficits resulting from exposure to doxorubicin (DOX) and cyclophosphamide (CYP), commonly used anticancer drugs. The spatial memory of female and male BALB/C mice was assessed using the Morris water maze prior to, during and following 4 weekly intravenous injections of DOX (2.5mg/kg) and CYP (25mg/kg) or vehicle. Females receiving DOX+CYP experienced significant deficits in spatial memory during and following injections when compared to baseline or females receiving vehicle. These deficits persisted for at least 34 days following the final injection. In contrast, males receiving DOX+CYP injections did not exhibit alterations in spatial memory relative to baseline or males receiving vehicle. These findings indicate that females may be more vulnerable than males to the cognitive-impairing effects of DOX+CYP and demonstrate that deficits in females persist for at least several weeks following drug exposure. Preclinical studies of CRCDs should parallel clinical work by including females and examine sex specific factors as potential mechanisms. PMID:27083301

  7. Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS

    PubMed Central

    Kanakry, Christopher G.; Tsai, Hua-Ling; Bolaños-Meade, Javier; Smith, B. Douglas; Gojo, Ivana; Kanakry, Jennifer A.; Kasamon, Yvette L.; Gladstone, Douglas E.; Matsui, William; Borrello, Ivan; Huff, Carol Ann; Swinnen, Lode J.; Powell, Jonathan D.; Pratz, Keith W.; DeZern, Amy E.; Showel, Margaret M.; McDevitt, Michael A.; Brodsky, Robert A.; Levis, Mark J.; Ambinder, Richard F.; Fuchs, Ephraim J.; Rosner, Gary L.; Jones, Richard J.

    2014-01-01

    High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched–related or –unrelated T-cell–replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse. PMID:25316679

  8. Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies.

    PubMed

    El-Serafi, I; Fares, M; Abedi-Valugerdi, M; Afsharian, P; Moshfegh, A; Terelius, Y; Potácová, Z; Hassan, M

    2015-10-01

    The role of cytochrome P450 2J2 (CYP2J2) in cyclophosphamide (Cy) bioactivation was investigated in patients, cells and microsomes. Gene expression analysis showed that CYP2J2 mRNA expression was significantly (P<0.01) higher in 20 patients with hematological malignancies compared with healthy controls. CYP2J2 expression showed significant upregulation (P<0.05) during Cy treatment before stem cell transplantation. Cy bioactivation was significantly correlated to CYP2J2 expression. Studies in HL-60 cells expressing CYP2J2 showed reduced cell viability when incubated with Cy (half maximal inhibitory concentration=3.6 mM). Inhibition of CYP2J2 using telmisartan reduced Cy bioactivation by 50% and improved cell survival. Cy incubated with recombinant CYP2J2 microsomes has resulted in apparent Km and Vmax values of 3.7-6.6 mM and 2.9-10.3 pmol/(min·pmol) CYP, respectively. This is the first study demonstrating that CYP2J2 is equally important to CYP2B6 in Cy metabolism. The heart, intestine and urinary bladder express high levels of CYP2J2; local Cy bioactivation may explain Cy-treatment-related toxicities in these organs. PMID:25601761

  9. Ferulic Acid against Cyclophosphamide-Induced Heart Toxicity in Mice by Inhibiting NF-κB Pathway.

    PubMed

    Song, Yafan; Zhang, Chunyan; Wang, Congxia; Zhao, Ling; Wang, Zheng; Dai, Zhijun; Lin, Shuai; Kang, Huafeng; Ma, Xiaobin

    2016-01-01

    The purpose of the present study was to elucidate the protective effects of ferulic acid (FA) against cyclophosphamide- (CTX-) induced changes in mice. Forty-eight male ICR mice were divided into four groups. Control group was intraperitoneally (i.p.) injected with 200 μL of phosphate buffer saline (PBS). Model group was intraperitoneally injected with a single dose of CTX (200 mg/kg). FA (50 mg/kg) and FA (100 mg/kg) groups were intraperitoneally injected with a single dose of CTX (200 mg/kg) followed by the intragastric treatment with FA (50, 100 mg/kg) for 7 consecutive days. After 12 d, the mice were sacrificed to analyze the hematological, biochemical, histological parameters and mechanism research. The results indicated that FA significantly decreased the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), lactate dehydrogenase (LDH), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) in CTX-injected mice. In addition, FA effectively reduced the total numbers of white blood cells (WBCs), red blood cells, platelets, and hemoglobin content. FA also obviously attenuated the histological changes of the heart tissues caused by CTX. Moreover, Western blot demonstrated that FA inhibited the phosphorylations of NF-κB signaling pathway in CTX-stimulated cardiac tissues. In conclusion, FA might be considered as an effective agent in the amelioration of the heart toxicity resulting from CTX treatment. PMID:26881001

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

    PubMed Central

    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

  11. [Safety and Tolerance of Dose-Dense Epirubicin and Cyclophosphamide (EC) with Pegfilgrastim for Japanese Patients with Early Breast Cancer].

    PubMed

    Watanabe, Kenichi; Sato, Masako; Yamamoto, Mitsugu; Ikarashi, Mayuko; Hagio, Kanako; Tomioka, Nobumoto; Tamaki, Shinya; Takahashi, Yumi; Takahasi, Masato

    2016-04-01

    With the approval of pegfilgrastim, the use of dose-dense epirubicin and cyclophosphamide (EC) for breast cancer has become acceptable in Japan. Thus, we aimed to evaluate its safety and tolerability in Japanese patients. Nine breast cancer patients with a high risk of preoperative or postoperative recurrence received EC therapy(epirubicin 90 mg/m(2) and cyclo- phosphamide 600 mg/m(2))for 4 cycles every 2 weeks in combination with a subcutaneous injection of pegfilgrastim (3.6 mg) on day 2 of each cycle. Treatment was discontinued in 1 and extended in 1 of the 9 patients, and the mean relative dose intensity(RDI)was good at 0.93. No serious adverse events were observed, indicating good tolerability. The regimen has potential for use in cases in which the treatment dose needs to be increased. grade 4 neutropenia was observed in all the 9 patients on day 8, with 6 patients developing febrile neutropenia. In Japan, data on changes in neutrophil count associated with pegfilgrastim administration under anthracycline-based chemotherapy are currently insufficient, and further study is required. PMID:27220788

  12. [Determination of airborne and surface contamination with cyclophosphamide at the Masaryk Memorial Cancer Institute, Brno, Czech Republic].

    PubMed

    Gorná, Lucie; Odráska, Pavel; Dolezalová, Lenka; Piler, Pavel; Oravec, Michal; Bláha, Ludek

    2011-02-01

    Manipulation with cytotoxic drugs (CDs) during the preparation and administration of chemotherapy to cancer patients can potentially lead to contamination of working areas and consequently to occupational exposure of hospital staff. This study aimed to assess the potential of inhalation and dermal contact with CDs. For this purpose, distribution of the marker drug (cyclophosphamide, CP) in the working environment of the Masaryk Memorial Cancer Institute (Czech Republic) was studied. The study determined airborne and surface contamination of the hospital pharmacy and the outpatient clinic. Determination of airborne contamination was based on active stationary sampling of air using a PTFE filter, an impinger filled with distilled water and two solid sorbent tubes (Anasorb 708 and Strata-X) as sampling devices. Surface contamination was determined by the wipe sampling method. The airborne contamination was rare and the concentrations were many times lower than the maximal value calculated from the vapour pressure (0.36 mg/m3 at 20 degrees C). Detectable airborne CP was found in Strata-X samples collected at the outpatient clinic (n = 5, all samples positive at concentrations from 0.3 to 4.3 ng/m3). Surface contamination was determined at 75% of wipe samples (n = 65) with a median concentration of 750 ng/m2. In conclusion, inhalation of CDs seems to be of low importance at our hospital, which is up to the standard specified by current legislation (drug preparation performed in a clean room equipped with negative pressure isolators). The main proportion of contamination was present on the surfaces at all workplaces studied. Consequently, attention should be given to the elimination of the sources of surface contamination and to the prevention of dermal contact with contaminated material. PMID:21650015

  13. Activation of soluble guanylyl cyclase by BAY 58-2667 improves bladder function in cyclophosphamide-induced cystitis in mice.

    PubMed

    de Oliveira, Mariana G; Calmasini, Fabiano B; Alexandre, Eduardo C; De Nucci, Gilberto; Mónica, Fabíola Z; Antunes, Edson

    2016-07-01

    Activators of soluble guanylyl cyclase (sGC) interact directly with its prosthetic heme group, enhancing the enzyme responsiveness in pathological conditions. This study aimed to evaluate the effects of the sGC activator BAY 58-2667 on voiding dysfunction, protein expressions of α1 and β1 sGC subunits and cGMP levels in the bladder tissues after cyclophosphamide (CYP) exposure. Female C57BL/6 mice (20-25 g) were injected with CYP (300 mg/kg ip) to induce cystitis. Mice were pretreated or not with BAY 58-2667 (1 mg/kg, gavage), given 1 h before CYP injection. The micturition patterns and in vitro bladder contractions were evaluated at 24 h. In freely moving mice, the CYP injection produced reduced the micturition volume and increased the number of urine spots. Cystometric recordings in CYP-injected mice revealed significant increases in basal pressure, voiding frequency, and nonvoiding contractions (NVCs), along with decreases in bladder capacity, intercontraction interval, and compliance. BAY 58-2667 significantly prevented the micturition alterations observed in both freely moving mice and cystometry and normalized the reduced in vitro carbachol-induced contractions in the CYP group. Reduced protein expressions of α1 and β1 sGC subunits and of cGMP levels were observed in the CYP group, all of which were prevented by BAY 58-2667. CYP exposure significantly increased reactive-oxygen species (ROS) generation in both detrusor and urothelium, and this was normalized by BAY 58-2667. The increased myeloperoxidase and cyclooxygenase-2 activities in the bladders of the CYP group remained unchanged by BAY 58-2667. Activators of sGC may constitute a novel and promising therapeutic approach for management of interstitial cystitis. PMID:27122537

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

    PubMed

    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. PMID:27489498

  15. A C-type lectin receptor pathway is responsible for the pathogenesis of acute cyclophosphamide-induced cystitis in mice.

    PubMed

    Dejima, Takashi; Shibata, Kensuke; Yamada, Hisakata; Takeuchi, Ario; Hara, Hiromitsu; Eto, Masatoshi; Naito, Seiji; Yoshikai, Yasunobu

    2013-12-01

    Hemorrhagic cystitis often arises after cyclophosphamide (CYP) administration. As yet, however, the mechanism involved in its pathogenesis is unknown. In this study, it was found that the Fc receptor γ chain (FcRγ)- caspase recruitment domain-containing protein 9 (CARD9)-dependent pathway rather than the myeloid differentiation primary response gene 88 (MyD88)-dependent pathway is involved in the pathogenesis of acute CYP-induced cystitis in mice. Rapid and transient production of interleukin (IL)-6 and IL-1β was detected in the bladder at 4 hr, preceding IL-23 and IL-17A production and an influx of neutrophils, which reached a peak at 24 hr after injection. As assessed by weight, edema and neutrophil infiltration, cystitis was significantly attenuated in CARD9 knockout (KO) and FcRγKO mice, this attenuation being accompanied by impaired production of IL-1β, IL-6, IL-23 and IL-17A. The major source of IL-17A is the vesical γδ T cell population: IL-17AKO, CδKO and Tyk2KO mice showed little IL-17A production and reduced neutrophil infiltration in the bladder after CYP injection. These results suggest that FcRγ-CARD9-dependent production of proinflammatory cytokines such as IL-1β, IL-6, and IL-23 and the subsequent activation of IL-17A-producing γδ T cells are at least partly involved in the pathogenesis of acute CYP-induced cystitis in mice. PMID:24102807

  16. Allogeneic hematopoietic stem cell transplantation for acquired aplastic anemia using cyclophosphamide and antithymocyte globulin: a single center experience.

    PubMed

    Ladeb, S; Abdelkefi, A; Torjman, L; Ben Neji, H; Lakhal, A; Kaabi, H; Ben Hamed, L; Ennigrou, S; Hmida, S; Ben Othman, T; Ben Abdeladhim, A

    2009-07-27

    Between February 1998 and October 2007, 97 (69 male, 28 female) patients with acquired aplastic anemia and a median age of 18 years (range, 2-39) received related allogeneic hematopoietic stem cell transplantation. Ninety-five patients received bone marrow grafts and two patients G-CSF primed peripheral blood stem cell transplantation. The donors were genotypically HLA-identical siblings in 94 cases, HLA-matched parents in 2 cases and a syngeneic twin in 1 case. Median time from diagnosis to transplantation was 2 months (range, 1-15). Conditioning regimen consisted of cyclophosphamide combined with antithymocyte globulin in all patients. For graft versus host disease (GVHD) prophylaxis, all patients received methotrexate and cyclosporine. Eighty-six patients showed evidence of hematopoietic engraftment. Eight patients died before engraftment. Rejection rate was 14.8% with three primary graft failures and eight secondary graft rejections occurring between 2 and 27 months post transplantation. Of the 11 rejecting patients, 3 died from infection and 8 proceeded to a second transplantation. Among the eight patients re-transplanted, seven are alive with successful second engraftments and one died from acute grade III GVHD. Acute GVHD occurred in 15.5% and extensive chronic GVHD in only 5.3% of patients. The 4-year overall probability of survival was 76.8%. Infection was the cause of 81.1% of deaths. The major factor affecting survival was onset of infection before transplantation. Major ABO donor-recipient incompatibility, disease severity and acute GVHD had also negative impact on survival. These results could be improved by reducing the time to transplant and by a more efficient supportive care policy.Bone Marrow Transplantation advance online publication, 27 July 2009; doi:10.1038/bmt.2009.175. PMID:19633695

  17. Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine.

    PubMed

    Peng, Shiwen; Lyford-Pike, Sofia; Akpeng, Belinda; Wu, Annie; Hung, Chien-Fu; Hannaman, Drew; Saunders, John R; Wu, T-C; Pai, Sara I

    2013-01-01

    Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8(+) T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8(+) T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8(+) T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8(+) T cells, which led to higher ratios of CD8(+)/Treg and CD8(+)/CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8(+) T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. PMID:23011589

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

    PubMed Central

    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. PMID:27489498

  19. GST-pi gene-transduced hematopoietic progenitor cell transplantation overcomes the bone marrow toxicity of cyclophosphamide in mice.

    PubMed

    Matsunaga, T; Sakamaki, S; Kuga, T; Kuroda, H; Kusakabe, T; Akiyama, T; Konuma, Y; Hirayama, Y; Kobune, M; Kato, J; Sasaki, K; Kogawa, K; Koyama, R; Niitsu, Y

    2000-08-10

    Autologous transplantation of bone marrow cells (BMCs) transduced with the multidrug resistance 1 (MDR1) gene or dihydrofolate reductase (DHFR) gene has already been applied in clinical chemoprotection trials. However, anticancer drugs frequently used in high-dose chemotherapy (HDC), such as alkylating agents, are not relevant to MDR1 or DHFR gene products. In this context, we have previously reported that glutathione S-transferase-pi (GST-pi) gene-transduced human CD34(+) cells showed resistance in vitro against 4-hydroperoxicyclophosphamide, an active form of cyclophosphamide (CY). In the present study, a subsequent attempt was made in a murine model to evaluate the effectiveness of transplantation of GST-pi-transduced BMCs to protect bone marrow against high-dose CY. The gene transfection was carried out retrovirally, employing a recombinant fibronectin fragment. Transfection efficiency into CFU-GM was 30%. After the transplantation, recipient mice (GST-pi mice) received three sequential courses of high-dose CY. As the chemotherapy courses advanced, both shortening of recovery period from WBC nadir and shallowing of WBC nadir were observed. In contrast to the fact that three of seven control mice died, possibly due to chemotoxicity, all seven GST-pi mice were alive after the third course, at which point the vector GST-pi gene was detected in 50% of CFU-GM derived from their BMCs and peripheral blood mononuclear cells. When BMCs obtained from these seven mice were retransplanted into secondary recipient mice, 20% of CFU-GM from BMCs showed positive signals for vector GST-pi DNA after 6 months. These data indicate that the GST-pi gene can confer resistance to bone marrow against CY by being transduced into long-term repopulating cells. PMID:10954901

  20. Dioscorea bulbifera polysaccharide and cyclophosphamide combination enhances anti-cervical cancer effect and attenuates immunosuppression and oxidative stress in mice.

    PubMed

    Cui, Hongxia; Li, Ting; Wang, Liping; Su, Yan; Xian, Cory J

    2016-01-01

    Cyclophosphamide (CTX) is commonly used in cancer chemotherapy, which causes immunosuppression and tissue oxidative stress at high doses. As potential protective agents, some polysaccharides were shown to have anti-tumor, anti-inflammatory and/or anti-oxidant properties. This study explored potential effects of oral treatment of Dioscorea bulbifera polysaccharides (DBLP at 100 or 150 mg/kg) in U14 cervical tumor-bearing mice treated with CTX (25 mg/kg). While CTX suppressed tumor growth (65.4% inhibition) and DBLP alone also inhibited tumor (25.6% at 100 mg/kg or 37.6% at 150 mg/kg), CTX+DBLP combination produced tumor inhibition rates of 5.6 (for 100 mg/kg DBLP) or 9% (for 150 mg/kg) higher than CTX alone. While tumor itself and CTX treatment reduced thymus and/or spleen/body weight indices, DBLP alone or CTX + DBLP combination attenuated this reduction. DBLP lowered peripheral blood T-cell subpopulation CD(4+)/CD(8+) ratio, and DBLP+CTX combination attenuated CTX effect in lifting CD(4+)/CD(8+) ratio. Tumor itself and CTX treatment heightened oxidative stress (with decreased superoxide dismutase but increased lactate dehydrogenase and malondialdehyde levels in serum and tissues), which was attenuated by DBLP treatment, and DBLP+CTX combination suppressed CTX-induced oxidative stress. Combination use of DBLP with CTX can potentially enhance CTX anti-tumor effect and can attenuate CTX-induced immunosuppression and oxidative stress in U14 cervical tumor-bearing mice. PMID:26753518

  1. Post-transplantation cyclophosphamide versus conventional graft-versus-host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation.

    PubMed

    Mehta, Rohtesh S; Saliba, Rima M; Chen, Julianne; Rondon, Gabriela; Hammerstrom, Aimee E; Alousi, Amin; Qazilbash, Muzaffar; Bashir, Qaiser; Ahmed, Sairah; Popat, Uday; Hosing, Chitra; Khouri, Issa; Shpall, Elizabeth J; Champlin, Richard E; Ciurea, Stefan O

    2016-05-01

    Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent graft-versus-host disease (GVHD) after haploidentical haematopoietic cell transplantation (HCT). We determined the efficacy of PTCy-based GVHD prophylaxis in human leucocyte antigen (HLA)-mismatched unrelated donor (MMUD) HCT. We analysed 113 adult patients with high-risk haematological malignancies who underwent one-antigen MMUD transplantation between 2009 and 2013. Of these, 41 patients received PTCy, tacrolimus and mycophenolate mofetil (MMF) for GVHD prophylaxis; 72 patients received conventional prophylaxis with anti-thymocyte globulin, tacrolimus and methotrexate. Graft source was primarily bone marrow (83% PTCy vs. 63% conventional group). Incidence of grade II-IV (37% vs. 36%, P = 0·8) and grade III-IV (17% vs. 12%, P = 0·5) acute GVHD was similar at day 100. However, the incidence of grade II-IV acute GVHD by day 30 was significantly lower in the PTCy group (0% vs. 15%, P = 0·01). Median time to neutrophil (18 days vs. 12 days, P < 0·001) and platelet (25·5 days vs. 18 days, P = 0·05) engraftment was prolonged in PTCy group. Rates of graft failure, chronic GVHD, 2-year non-relapse mortality, relapse, progression-free survival or overall survival were similar. Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HCT. PMID:26947769

  2. The Cyclophosphamide Equivalent Dose as an Approach for Quantifying Alkylating Agent Exposure. A Report from the Childhood Cancer Survivor Study

    PubMed Central

    Green, Daniel M.; Nolan, Vikki G.; Goodman, Pamela J.; Whitton, John A.; Srivastava, DeoKumar; Leisenring, Wendy M.; Neglia, Joseph P.; Sklar, Charles A.; Kaste, Sue C.; Hudson, Melissa M.; Diller, Lisa R.; Stovall, Marilyn; Donaldson, Sarah S.; Robison, Leslie L.

    2014-01-01

    BACKGROUND Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses. METHODS We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS)outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike’s Information Criterion (AIC). RESULTS The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure. CONCLUSION The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure. PMID:23940101

  3. HLA-Haploidentical Bone Marrow Transplantation for Hematologic Malignancies Using Nonmyeloablative Conditioning and High-Dose, Posttransplantation Cyclophosphamide

    PubMed Central

    Luznik, Leo; O’Donnell, Paul V.; Symons, Heather J.; Chen, Allen R.; Leffell, M. Susan; Zahurak, Marianna; Gooley, Ted A.; Piantadosi, Steve; Kaup, Michele; Ambinder, Richard F.; Huff, Carol Ann; Matsui, William; Bolaños-Meade, Javier; Borrello, Ivan; Powell, Jonathan D.; Harrington, Elizabeth; Warnock, Sandy; Flowers, Mary; Brodsky, Robert A.; Sandmaier, Brenda M.; Storb, Rainer F.; Jones, Richard J.; Fuchs, Ephraim J.

    2008-01-01

    We evaluated the safety and efficacy of high-dose, posttransplantation cyclophosphamide (Cy) to prevent graft rejection and graft-versus-host disease (GVHD) after outpatient nonmyeloablative conditioning and T cell-replete bone marrow transplantation from partially HLA-mismatched (haploidentical) related donors. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received Cy 50 mg/kg i.v. on day 3 (n = 28) or on days 3 and 4 (n 5 40) after transplantation. The median times to neutrophil (>500/µL) and platelet recovery (>20,000/µL) were 15 and 24 days, respectively. Graft failure occurred in 9 of 66 (13%) evaluable patients, and was fatal in 1. The cumulative incidences of grades II–IV and grades III–IV acute (aGVHD) by day 200 were 34% and 6%, respectively. There was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttransplantation Cy (P = .05), the only difference between these groups. The cumulative incidences of nonrelapse mortality (NRM) and relapse at 1 year were 15% and 51%, respectively. Actuarial overall survival (OS) and event-free survival (EFS) at 2 years after transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies had an improved EFS compared to those with myelogenous malignancies (P = .02). Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD. PMID:18489989

  4. Adjusting Cyclophosphamide Dose in Obese Patients with Lymphoma Is Safe and Yields Favorable Outcomes after Autologous Hematopoietic Cell Transplantation.

    PubMed

    Bachanova, Veronika; Rogosheske, John; Shanley, Ryan; Burns, Linda J; Smith, Sara M; Weisdorf, Daniel J; Brunstein, Claudio G

    2016-03-01

    No clear dosing guidelines exist for cyclophosphamide (Cy) dose adjustments in obese patients treated with high-dose chemoradiotherapy followed by autologous hematopoietic cell transplantation (HCT). We prospectively compared the outcomes of high-dose Cy/total body irradiation (TBI) conditioning in 147 non-Hodgkin lymphoma (NHL) patients in 3 weight groups: nonobese (<120% ideal body weight [IBW]; n = 72), overweight (120% to 149% IBW; n = 46), and obese (≥150% IBW; n = 29). Nonobese and overweight patients received Cy (120 mg/kg of total body weight, intravenously) and TBI (1320 cGy), whereas obese patients (median body mass index, 36) received an adjusted Cy dose based on IBW plus 50% of the difference between total body weight and IBW (AdjBW50). The median patient age was 57 years (range, 19 to 73). The most common diagnoses were diffuse large B cell lymphoma (n = 57) and mantle cell lymphoma (n = 51). Three-year overall survival was 61% (95% confidence interval [CI], 48% to 72%) for nonobese patients, 68% (95% CI, 52% to 82%) for overweight patients, and 80% (95% CI, 62% to 93%) for obese patients. Cumulative incidence of relapse (48%, 43%, and 38%, respectively) and nonrelapse mortality (∼4%) were similar in all groups. Hemorrhagic cystitis and cardiac toxicity were rare events. Our data show that the AdjBW50 formula can be safely and effectively used for Cy dose adjustments in obese patients treated for NHL with high-dose Cy/TBI conditioning followed by autologous HCT. PMID:26497907

  5. Cyclophosphamide-Induced Bladder Inflammation Sensitizes and Enhances P2X Receptor Function in Rat Bladder Sensory Neurons

    PubMed Central

    Dang, Khoa; Lamb, Kenneth; Cohen, Michael; Bielefeldt, Klaus; Gebhart, G. F.

    2009-01-01

    We studied sensitization of retrogradely labeled bladder sensory neurons and plasticity of P2X receptor function in a model of cystitis using patch-clamp techniques. Saline (control) or cyclophosphamide (CYP) was given intraperitoneally to rats on days 0, 2, and 4. On day 5, lumbosacral (LS, L6–S2) or thoracolumbar (TL, T12–L2) dorsal root ganglia were removed and dissociated. Bladders from CYP-treated rats showed partial loss of the urothelium and greater myeloperoxidase activity compared with controls. Bladder neurons from CYP-treated rats were increased in size (based on whole cell capacitance) compared with controls and exhibited lower activation threshold, increased action potential width, and greater number of action potentials in response to current injection or application of purinergic agonists. Most control LS bladder neurons (>85%) responded to ATP or α,β-metATP with a slowly desensitizing current; these agonists affected only half of TL neurons, producing predominantly fast/mixed desensitizing currents. CYP treatment increased the fraction of TL bladder neurons sensitive to purinergic agonists (>80%) and significantly increased current density in both LS and TL bladder neurons compared with control. Importantly, LS and TL neurons from CYP-treated rats showed a selective increase in the functional expression of heteromeric P2X2/3 and homomeric P2X3 receptors, respectively. Although desensitizing kinetics were slower in LS neurons from CYP-treated compared with control rats, recovery kinetics were similar. The present results demonstrate that bladder inflammation sensitizes and increases P2X receptor expression and/or function for both pelvic and lumbar splanchnic pathways, which contribute, in part, to the hypersensitivity associated with cystitis. PMID:17959738

  6. Increased Sensitivity of Glutathione S-Transferase P-Null Mice to Cyclophosphamide-Induced Urinary Bladder Toxicity

    PubMed Central

    Haberzettl, Petra; Lesgards, Jean-Francois; Prough, Russell A.; Srivastava, Sanjay; Bhatnagar, Aruni

    2009-01-01

    Hemorrhagic cystitis and diffuse inflammation of the bladder, common side effects of cyclophosphamide (CY) treatment, have been linked to the generation of acrolein derived from CY metabolism. Metabolic removal of acrolein involves multiple pathways, which include reduction, oxidation, and conjugation with glutathione. Herein, we tested the hypothesis that glutathione S-transferase P (GSTP), the GST isoform that displays high catalytic efficiency with acrolein, protects against CY-induced urotoxicity by detoxifying acrolein. Treatment of wild-type (WT) and mGstP1/P2 null (GSTP-null) mice with CY caused hemorrhagic cystitis, edema, albumin extravasation, and sloughing of bladder epithelium; however, CY-induced bladder ulcerations of the lamina propria were more numerous and more severe in GSTP-null mice. CY treatment also led to greater accumulation of myeloperoxidase-positive cells and specific protein-acrolein adducts in the bladder of GSTP-null than WT mice. There was no difference in hepatic microsomal production of acrolein from CY or urinary hydroxypropyl mercapturic acid output between WT and GSTP-null mice, but CY induced greater c-Jun NH2-terminal kinase (JNK) and c-Jun, but not extracellular signal-regulated kinase or p38, activation in GSTP-null than in WT mice. Pretreatment with mesna (2-mercaptoethane sulfonate sodium) abolished CY toxicity and JNK activation in GSTP-null mice. Taken together, these data support the view that GSTP prevents CY-induced bladder toxicity, in part by detoxifying acrolein. Because polymorphisms in human GSTP gene code for protein variants differing significantly in their catalytic efficiency toward acrolein, it is likely that GSTP polymorphisms influence CY urotoxicity. In addition, pretreatment with dietary or nutrient inducers of GSTP may be of use in minimizing bladder injury in patients undergoing CY therapy. PMID:19696094

  7. Relevance of the cyclophosphamide-induced cystitis model for pharmacological studies targeting inflammation and pain of the bladder.

    PubMed

    Augé, Céline; Chene, Gérald; Dubourdeau, Marc; Desoubzdanne, Denis; Corman, Bruno; Palea, Stefano; Lluel, Philippe; Vergnolle, Nathalie; Coelho, Anne-Marie

    2013-05-01

    This work aimed at establishing the relevance of using the in vivo model of cyclophosphamide (CYP)-induced bladder inflammation in rats for in vivo pharmacological studies. Specifically, we measured visceral nociception, identified key inflammatory mediators and evaluated the effects of relevant pharmacological treatments. Cystitis was induced in female rats by a single CYP injection. Sensitivity of the lower abdomen to von Frey mechanical stimulation was determined as a nociceptive parameter. Bladders were assessed for weight, wall thickness and macroscopic damage. Inflammatory mediators were quantified in bladders and urines. The effects of aspirin, ibuprofen and morphine were investigated on all these parameters. A single CYP injection increased nociceptive scores and decreased nociceptive threshold in response to mechanical stimuli between 1 and 4h post-administration. Increased bladder weight and wall thickness were associated with edema and hemorrhage. Bladder levels of IL-1β, IL-6, MCP-1 and VCAM, and urinary levels of PGE2 were increased. In contrast, a decrease in the urinary metabolites, indoxyl sulfate and pantothenic acid, was observed. Aspirin, ibuprofen and morphine decreased CYP-induced referred visceral pain. Aspirin and ibuprofen also reversed the increased wall thickness, macroscopic damage and levels of IL-1β, IL-6 and PGE2, and the decreased panthotenic acid levels. In contrast, morphine increased wall thickness, edema, hemorrhage, and bladder IL-6 and MCP-1 levels. This work presents a new and reliable method to evaluate visceral sensitivity in rats, and new relevant biomarkers identified in the bladder and urine to measure inflammation and pain parameters for in vivo pharmacological studies. PMID:23541724

  8. Cyclophosphamide-induced Hepatotoxicity in Wistar Rats: The Modulatory Role of Gallic Acid as a Hepatoprotective and Chemopreventive Phytochemical

    PubMed Central

    Oyagbemi, Ademola Adetokunbo; Omobowale, Olutayo Temidayo; Asenuga, Ebunoluwa Rachael; Akinleye, Akinrinde Stephen; Ogunsanwo, Rachael Omolola; Saba, Adebowale Bernard

    2016-01-01

    Background: Gallic acid (GA) is an endogenous plant phenol known to have antioxidant, free radical scavenging ability, anti-inflammatory, anti-cancer, and anti-fungal properties. The aim of this study was to assess the protective effect of GA on cyclophosphamide (CPA)-induced hepatotoxicity in male Wistar rats. Methods: Sixty rats were grouped into six groups of 10 rats per group. Group 1 received distilled water. Group 2 received CPA at 200 mg/kg single dose intraperitoneally on day 1. Groups 3 and 4 received a single dose of CPA (200 mg/kg) intraperitoneally on day 1 and then were treated with GA at 60 and 120 mg/kg body weight for 14 days, respectively. Rats in Groups 5 and 6 only received GA at 60 and 120 mg/kg body weight for 14 days, respectively. GA was administered orally. Results: CPA induced hepatic damage as indicated by significant elevation (P < 0.05) in aspartate aminotransferase, organ weight, and evidence by the histological study. CPA also induced hepatic oxidative stress as indicated by significant elevation (P < 0.05) in malondialdehyde content, hydrogen peroxide (H2O2) generation, nitrite level, and the level of glutathione (GSH) peroxidase crashed in the CPA-treated group. GA enhanced the antioxidant defense system as indicated by significant elevation (P < 0.05) in GSH level, catalase activity, and GSH-S-transferase activity. Conclusions: Taken together, the result of this present study shows that GA has a protective effect on CPA-induced hepatotoxicity. PMID:27076889

  9. Phase II Trial of Simple Oral Therapy with Capecitabine and Cyclophosphamide in Patients with Metastatic Breast Cancer: SWOG S0430

    PubMed Central

    Barlow, William E.; Albain, Kathy S.; Chew, Helen K.; Wade, James L.; Lanier, Keith S.; Lew, Danika L.; Hayes, Daniel F.; Gralow, Julie R.; Livingston, Robert B.; Hortobagyi, Gabriel N.

    2012-01-01

    Background. Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC. Methods. The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor–positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1–14, and capecitabine, 1,500 mg twice daily on days 8–21, in 21-day cycles. Results. In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7–8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1–22.0 months). The RR was 36% (95% CI, 26%–48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%–48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths. Conclusions. PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine. PMID:22267853

  10. Dioscorea bulbifera polysaccharide and cyclophosphamide combination enhances anti-cervical cancer effect and attenuates immunosuppression and oxidative stress in mice

    PubMed Central

    Cui, Hongxia; Li, Ting; Wang, Liping; Su, Yan; Xian, Cory J.

    2016-01-01

    Cyclophosphamide (CTX) is commonly used in cancer chemotherapy, which causes immunosuppression and tissue oxidative stress at high doses. As potential protective agents, some polysaccharides were shown to have anti-tumor, anti-inflammatory and/or anti-oxidant properties. This study explored potential effects of oral treatment of Dioscorea bulbifera polysaccharides (DBLP at 100 or 150 mg/kg) in U14 cervical tumor-bearing mice treated with CTX (25 mg/kg). While CTX suppressed tumor growth (65.4% inhibition) and DBLP alone also inhibited tumor (25.6% at 100 mg/kg or 37.6% at 150 mg/kg), CTX+DBLP combination produced tumor inhibition rates of 5.6 (for 100 mg/kg DBLP) or 9% (for 150 mg/kg) higher than CTX alone. While tumor itself and CTX treatment reduced thymus and/or spleen/body weight indices, DBLP alone or CTX + DBLP combination attenuated this reduction. DBLP lowered peripheral blood T-cell subpopulation CD4+/CD8+ ratio, and DBLP+CTX combination attenuated CTX effect in lifting CD4+/CD8+ ratio. Tumor itself and CTX treatment heightened oxidative stress (with decreased superoxide dismutase but increased lactate dehydrogenase and malondialdehyde levels in serum and tissues), which was attenuated by DBLP treatment, and DBLP+CTX combination suppressed CTX-induced oxidative stress. Combination use of DBLP with CTX can potentially enhance CTX anti-tumor effect and can attenuate CTX-induced immunosuppression and oxidative stress in U14 cervical tumor-bearing mice. PMID:26753518

  11. Neutrophil-guided dosing of anthracycline-cyclophosphamide-containing chemotherapy in patients with breast cancer: a feasibility study.

    PubMed

    Drooger, Jan C; van Pelt-Sprangers, Johanna M; Leunis, Corry; Jager, Agnes; de Jongh, Felix E

    2015-04-01

    The aim of this study was to investigate whether neutrophil-guided dose escalation of anthracycline-cyclophosphamide-containing chemotherapy (ACC) for breast cancer is feasible, in order to optimize outcome. Breast cancer patients planned for 3-weekly ACC were enrolled in this study. The first treatment cycle was administered in a standard BSA-adjusted dose. The absolute neutrophil count was measured at baseline and at day 8, 11 and 15 after administration of ACC. For patients with none or mild (CTC grade 0-2) neutropenia and no other dose-limiting toxicity, we performed a 10-25 % dose escalation of the second cycle with the opportunity to a further 10-25 % dose escalation of the third cycle. Thirty patients were treated in the adjuvant setting with either FE100C (n = 23) or AC (n = 4), or in the palliative setting with FAC (n = 3). Two out of 23 patients (9 %) treated with FEC did not develop grade 3-4 neutropenia after the first treatment cycle. Dose escalation was performed in these two patients (30 % in one and 15 % in the other patient). During dose escalation, there were no complications like febrile neutropenia. No patients treated with FAC or AC could be escalated, since all of them developed grade 3-4 neutropenia. We conclude that asymptomatic grade 3-4 neutropenia is likely to be achieved in the majority of patients with breast cancer treated with ACC according to presently advocated BSA-based dose levels. Escalation of currently advocated ACC doses without G-CSF, with a target of grade 3-4 neutropenia, is feasible, but only possible in a small proportion of patients. EudraCT 2010-020309-33. PMID:25772511

  12. Metronomic cyclophosphamide therapy in hormone-naive patients with non-metastatic biochemical recurrent prostate cancer: a phase II trial.

    PubMed

    Calcagno, Fabien; Mouillet, Guillaume; Adotevi, Olivier; Maurina, Tristan; Nguyen, Thierry; Montcuquet, Philippe; Curtit, E; Kleinclauss, F; Pivot, Xavier; Borg, Christophe; Thiery-Vuillemin, Antoine

    2016-08-01

    After curative local therapy, biochemical recurrence is a mode of relapse among patient with prostate cancer (PC). Deferring androgen deprivation therapy (ADT) or offering non-hormonal therapies may be an appropriate option for these non-symptomatic patients with no proven metastases. Metronomic cyclophosphamide (MC) has shown activity in metastatic PC setting and was chosen to be assessed in biochemical relapse. This prospective single-arm open-label phase II study was conducted to evaluate MC regimen in patients with biochemical recurrent PC. MC was planned to be administered orally at a daily dose of 50 mg for 6 months. Primary endpoint was PSA response. Thirty-eight patients were included and treated. Median follow-up was 45.5 months (range 17-100). Among them, 14 patients (37 %) achieved PSA stabilisation and 22 patients (58 %) experienced PSA progression. Response rate was 5 % with one complete response (2.6 %), and 1 partial response with PSA decrease >50 % (2.6 %). The median time until androgen deprivation therapy initiation was around 15 months. The treatment was well tolerated. Neither grade 3-4 toxicity nor serious adverse events were observed. This first prospective clinical trial with MC therapy in patients with non-metastatic biochemical recurrence of PC displayed modest efficacy when measured with PSA response rate, without significant toxicity. It might offer a new safe and non-expensive option to delay initiation of ADT. These results would need to be confirmed with larger prospective randomised trials. PMID:27400698

  13. Refractory acute lymphoblastic leukemia in Chinese children: bridging to stem cell transplantation with clofarabine, cyclophosphamide and etoposide.

    PubMed

    Liu, Anthony P Y; Lee, Vincent; Li, C K; Ha, S Y; Chiang, Alan K S

    2016-02-01

    Refractory or relapsed acute lymphoblastic leukemia (r/r ALL) represents the leading cause of cancer mortality in children. Clofarabine is effective in inducing remission thus enabling bridging to hematopoietic stem cell transplantation (HSCT). We report the results in treating Hong Kong Chinese pediatric patients with r/rALL by clofarabine/cyclophosphamide/etoposide (CLO-218) combination therapy. A retrospective review of patients treated between January 2009 and December 2014 in the two tertiary referral pediatric oncology units in Hong Kong. Thirteen patients were identified. All were Chinese and seven were male. Median age at clofarabine treatment was 8 years and the median duration of follow-up was 10 months. Nine patients had B-ALL and four had T-ALL. All were refractory to the preceding regimen(s). The median number of prior treatment regimens was 2; two patients had previous HSCT. Complete remission (CR) was achieved in five patients, Complete remission with incomplete counts (CRi) in two, PR in two, and non-remission (NR) in two. All four patients with T-ALL responded with three patients achieving CR. Eight out of nine patients who responded could be bridged to HSCT. Among those who were transplanted, four remained alive and in remission, three relapsed post-HSCT, and one died from transplant-related mortality. Treatment toxicities were common including febrile neutropenia in all subjects and culture-proven bacteremia in five patients. Hepatotoxicity was mild and reversible with no case of veno-occlusive disease. The clofarabine-based regimen is a promising strategy to induce disease remission in r/rALL and bridge to HSCT. Septic complications are, however, frequent necessitating prompt management with adequate supportive care in specialized centers. PMID:26666536

  14. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplant for Patients with Acute Leukemia

    PubMed Central

    Holter-Chakrabarty, Jennifer L.; Pierson, Namali; Zhang, Mei-Jie; Zhu, Xiaochun; Akpek, Görgün; Aljurf, Mahmoud D.; Artz, Andrew S.; Baron, Frédéric; Bredeson, Christopher N.; Dvorak, Christopher C.; Epstein, Robert B.; Lazarus, Hillard M.; Olsson, Richard F.; Selby, George B.; Williams, Kirsten M.; Cooke, Kenneth R.; Pasquini, Marcelo C.; McCarthy, Philip L.

    2015-01-01

    Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI N=948, TBICy N=821) recipients of related or unrelated hematopoietic cell transplantation (HCT) who received TBI (1200-1500cGY) for acute leukemia from 2003 to 2010. The two cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Ph+ ALL, HLA matched siblings, stem cell source, anti-thymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect TRM (24% vs. 23% at 3y, p=0.67; relative risk [RR] 1.01, p=0.91), leukemia relapse (27% vs. 29% at 3y, p=0.34; RR 0.89, p=0.18), leukemia-free survival (49% vs. 48% at3y, p=0.27; RR 0.93, p=0.29), chronic GVHD (45% vs. 47% at 1y, p=0.39; RR 0.9, p=0.11) or overall survival (53% vs. 52% at 3y, p=0.62; RR 0.96, p=0.57) for CyTBI and TBICy respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (p=0.08). This study demonstrates that the sequence of Cy and TBI does not impact transplant outcomes and complications in patients with acute leukemia undergoing HCT with myeloablative conditioning. PMID:25840335

  15. Timing of recombinant human granulocyte colony-stimulating factor administration on neutropenia induced by cyclophosphamide in normal mice.

    PubMed Central

    Misaki, M.; Ueyama, Y.; Tsukamoto, G.; Matsumura, T.

    1998-01-01

    The effects of altering the timing of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration on neutropenia induced by cyclophosphamide (CPA) were studied experimentally in a mouse model. Experimental mice were divided into three groups: (a) treatment with rhG-CSF after CPA administration (post-treatment group); (b) treatment with rhG-CSF both before and after CPA administration (pre- and post-treatment group); and (c) treatment with saline after CPA administration (control group). The results were as follows. Mice receiving rhG-CSF on the 2 days preceding CPA treatment, in which progenitor cell counts outside the S-phase when CPA was administered were the lowest of all the groups, showed accelerated neutrophil recovery but decreased neutrophil nadirs compared with the control group despite rhG-CSF treatment. The pre- and post-treatment group, consisting of mice who received rhG-CSF treatment on days -4 and -3 before CPA treatment, and in which progenitor cell counts when CPA was administered were increased to greater levels than in the other groups, showed remarkably accelerated neutrophil recovery and the greatest increase in the neutrophil nadirs of all the groups. These results suggested that the kinetics of progenitor cell populations when chemotherapeutic agents were administered seemed to play an important role in neutropenia after chemotherapy, and that not only peripheral neutrophil cell and total progenitor cell counts but also progenitor cell kinetics should be taken into consideration when administering rhG-CSF treatment against the effects of chemotherapy. PMID:9528829

  16. Synergestic effect of lycopene and melatonin against the genesis of oxidative stress induced by cyclophosphamide in rats.

    PubMed

    Al-Malki, Abdulrahman L

    2014-07-01

    Cyclophosphamide (CP) is an alkylating agent that has been considered effective for cancer treatment. Lycopene, the pigment in tomato fruits, has beneficial effect in the treatment of some diseases. The goal of this study is to evaluate the protective effect of lycopene alone or combined with melatonin (Mel) in inhibiting the oxidative stress and toxic effect of CP in rats. Five groups of rats were included in this study; Group I served as the control. Rats in groups II-V were administrated with single dose of CP (150 mg/kg B.W) interperitoneally for 3 days. On the same day of CP administration, the rats in group III were fed a diet supplemented with lycopene (50 mg/kg of diet), rats in group IV were administered with a dose of 2.5 mg Mel/kg body weight (bw) injected subcutaneously and rats in group V were supplemented with lycopene and a dose of 2.5 mg Mel/kg bw injected subcutaneously. After 15 days the blood samples were collected. Results obtained showed that CP exerted its toxic effect by increasing the free radicals and reactive oxygen species that causes lipid peroxidation and cell damage, and this in turn is detected by elevation in nitric oxide (NO) and malondialdehyde (MDA), while the activities of antioxidants enzymes including (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)) were significantly decreased as compared with the control rats. The combined treatment (Lyco + Mel) group showed potential reduction in these parameters more than those treated with lyco alone. The activities of SOD, CAT and GPx were found significantly high than lyco alone treated rats. A positive significant correlation between NO and MDA (r = .81). In conclusion, these results suggested that supplementation of diet with lycopene and Mel provided antioxidant defense with strong chemopreventive activity against Cp-induced cytotoxicity. PMID:23024110

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

    PubMed Central

    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 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. PMID:20684753

  18. Efficacy and safety of front-line therapy with fludarabine-cyclophosphamide-rituximab regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli CLL Study Group experience.

    PubMed

    Herishanu, Yair; Goldschmidt, Neta; Bairey, Osnat; Ruchlemer, Rosa; Fineman, Riva; Rahimi-Levene, Naomi; Shvidel, Lev; Tadmor, Tamar; Ariel, Aviv; Braester, Andrea; Shapiro, Mika; Joffe, Erel; Polliack, Aaron

    2015-05-01

    This study aimed to evaluate the efficacy and safety of the fludarabine-cyclophosphamide-rituximab regimen for young physically fit patients with chronic lymphocytic leukemia in the "real-life" setting. We specifically focused on the impact of dose reduction on patient outcomes. The patient cohort consisted of 128 patients with chronic lymphocytic leukemia (≤ 70 years) treated at 10 Israeli centers with front-line fludarabine-cyclophosphamide-rituximab. We defined reduced chemotherapy as two-thirds or less of the total indicated dose. Patients treated with rituximab were divided into two groups and compared: those who received full dosages of 375 mg/m(2) or 500 mg/m(2), and patients given less than six cycles with either dose. Overall and clinical complete response rates (92.8% and 70.4%), as well as toxicities and overall survival (median not reached at 6 years), were similar to other reported clinical trials, but progression-free survival was shorter (42.5 months). Almost 50% of patients had some dose reduction of chemotherapy, 21% receiving less than two-thirds of the indicated dose, while close to 30% did not complete six cycles of rituximab. Reduced doses of chemotherapy and rituximab were independently associated with shorter progression-free survival (hazard ratio 3.6, P<0.0001 for reduced chemotherapy; hazard ratio 2.5, P=0.003 for incomplete-treatment with rituximab). Achieving a complete response was associated with longer overall survival but was not linked to the given dose of chemoimmunotherapy. In younger physically fit patients, front-line fludarabine-cyclophosphamide-rituximab therapy in the "real-life" setting achieves long remissions (albeit shorter than in clinical trials) and prolonged overall survival. However, dose reductions are commonly administered and may impact outcome. PMID:25661442

  19. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL

    PubMed Central

    Samoilova, Olga; Osmanov, Evgenii; Eom, Hyeon-Seok; Topp, Max S.; Raposo, João; Pavlov, Viacheslav; Ricci, Deborah; Chaturvedi, Shalini; Zhu, Eugene; van de Velde, Helgi; Enny, Christopher; Rizo, Aleksandra; Ferhanoglu, Burhan

    2015-01-01

    This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, all IV day 1, prednisone 100 mg/m2 orally days 1-5, plus either bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m2 (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; P = .80), overall response rate (93.4%, 98.6%; OR, 0.21; P = .11), progression-free survival (hazard ratio [HR], 1.12; P = .76), or overall survival (HR, 0.89; P = .75). Rates of grade ≥3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade ≥3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871. PMID:26232170

  20. Long-term follow-up of allogeneic stem cell transplantation in patients with severe aplastic anemia after conditioning with cyclophosphamide plus antithymocyte globulin.

    PubMed

    Kröger, N; Zabelina, T; Renges, H; Krüger, W; Kordes, U; Rischewski, J; Schrum, J; Horstmann, M; Ayuk, F; Erttmann, R; Kabisch, H; Zander, A R

    2002-11-01

    We investigated the efficacy of an antithymocyte globulin/cyclophosphamide preparative regimen prior to allogeneic stem cell transplantation from HLA-identical siblings in patients with severe aplastic anemia. Since 1990, 21 patients, 6 males and 15 females, with a median age of 25 years (range: 7-43) have been enrolled in the protocol consisting of 200 mg/kg cyclophosphamide and 90-120 mg/kg antithymocyte globulin (ATG, rabbit, Fresenius, Bad Homburg, Germany). For further graft-versus-host disease (GVHD) prophylaxis all patients received cyclosporin A and a short course of methotrexate (MTX). Only one patient had a primary graft failure (5%). All other patients engrafted with a leukocyte count >1.0 x 10(9)/l and a platelet count >20 x 10(9)/l after a median of 19 (range: 11-28) and 26 days (range: 13-67), respectively. No late graft failure or relapse was observed. Two patients experienced mild acute GVHD grade I (10%), and one patient developed grade II GVHD (5%). No severe grade III/IV GVHD was observed; 17% of the patients developed limited chronic GVHD. The treatment-related mortality was 14% and mainly due to fungal infection. After a median follow-up of 70 months (range: 2-139), the estimated overall and event-free survival at 10 years for all patients is 86% (95% confidence interval: 70-100%). We conclude that ATG plus cyclophosphamide is an effective conditioning regimen in patients with aplastic anemia undergoing stem cell transplantation with a low treatment-related mortality, resulting in an excellent outcome. PMID:12454700

  1. Apoptotic death induced by the cyclophosphamide analogue mafosfamide in human lymphoblastoid cells: Contribution of DNA replication, transcription inhibition and Chk/p53 signaling

    SciTech Connect

    Goldstein, Michael; Roos, Wynand P. Kaina, Bernd

    2008-05-15

    Cyclophosphamide is one of the most often used anticancer drugs. Although DNA interstrand cross-links are considered responsible for its cytotoxicity, the mechanism of initiation and execution of cell death is largely unknown. Using the cyclophosphamide analogue mafosfamide, which does not need metabolic activation, we show that mafosfamide induces apoptosis dose and time dependently in lymphoblastoid cells, with clearly more apoptosis in p53{sup wt} cells. We identified two upstream processes that initiate apoptosis, DNA replication blockage and transcriptional inhibition. In lymphoblastoid cells, wherein DNA replication can be switched off by tetracycline, proliferation is required for inducing apoptosis at low dose mafosfamide. At high dose, transcriptional inhibition also contributes to cell death. The RNA synthesis inhibitor {alpha}-amanitin induced similar to mafosfamide more apoptosis in p53{sup wt} than in p53{sup mt} cells. In combination with mafosfamide, however, {alpha}-amanitin had no additive effect. Mafosfamide caused p53 stabilization by phosphorylation of Ser15, 20 and 37, and activation of ATM/ATR and Chk1/Chk2. Inhibition of ATM/ATR, PI3-kinase and Chk1/Chk2 by CGK733, wortmannin and DBH, respectively, attenuated the apoptotic response in p53{sup wt} but not p53{sup mt} cells. Mafosfamide induced caspase dependent apoptosis and, for low dose treated cells, caspases were preferentially activated in the S-phase, whereas at high dose caspases were activated in all cell cycle stages. These data support the conclusion that at low dose level of mafosfamide, DNA replication blockage is the dominant apoptosis-inducing event, while at high dose, transcriptional inhibition comes into play. The data provide a mechanistic explanation of why cyclophosphamide applied at therapeutic doses preferentially kills replicating tumor cells.

  2. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL.

    PubMed

    Offner, Fritz; Samoilova, Olga; Osmanov, Evgenii; Eom, Hyeon-Seok; Topp, Max S; Raposo, João; Pavlov, Viacheslav; Ricci, Deborah; Chaturvedi, Shalini; Zhu, Eugene; van de Velde, Helgi; Enny, Christopher; Rizo, Aleksandra; Ferhanoglu, Burhan

    2015-10-15

    This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), and doxorubicin 50 mg/m(2), all IV day 1, prednisone 100 mg/m(2) orally days 1-5, plus either bortezomib 1.3 mg/m(2) IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m(2) (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; P = .80), overall response rate (93.4%, 98.6%; OR, 0.21; P = .11), progression-free survival (hazard ratio [HR], 1.12; P = .76), or overall survival (HR, 0.89; P = .75). Rates of grade ≥3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade ≥3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871. PMID:26232170

  3. Impact of Toceranib/Piroxicam/Cyclophosphamide Maintenance Therapy on Outcome of Dogs with Appendicular Osteosarcoma following Amputation and Carboplatin Chemotherapy: A Multi-Institutional Study

    PubMed Central

    Mathie, Tamra; Stingle, Nicole; Portela, Roberta; Pennell, Michael L.; Clifford, Craig A.; Rosenberg, Mona P.; Vail, David M.; Williams, Laurel E.; Cronin, Kim L.; Wilson-Robles, Heather; Borgatti, Antonella; Henry, Carolyn J.; Bailey, Dennis B.; Locke, Jennifer; Northrup, Nicole C.; Crawford-Jakubiak, Martin; Gill, Virginia L.; Klein, Mary K.; Ruslander, David M.; Thamm, Doug H.; Phillips, Brenda; Post, Gerald

    2015-01-01

    Background We hypothesized that the addition of toceranib to metronomic cyclophosphamide/piroxicam therapy would significantly improve disease-free interval (DFI) and overall survival (OS) in dogs with appendicular osteosarcoma (OSA) following amputation and carboplatin chemotherapy. Methods and Findings This was a randomized, prospective clinical trial in which dogs with OSA free of gross metastatic disease (n = 126) received carboplatin chemotherapy (4 doses) following amputation. On study entry, dogs were randomized to receive piroxicam/cyclophosphamide with or without toceranib (n = 63 each) after completing chemotherapy. Patient demographics were not significantly different between both groups. During or immediately following carboplatin chemotherapy, 32 dogs (n = 13 toceranib; n = 19 control) developed metastatic disease, and 13 dogs left the study due to other medical conditions or owner preference. Following carboplatin chemotherapy, 81 dogs (n = 46 toceranib; n = 35 control) received the metronomic treatment; 35 dogs (n = 20 toceranib; n = 15 control) developed metastatic disease during the maintenance therapy, and 26 dogs left the study due to other medical conditions or owner preference. Nine toceranib-treated and 11 control dogs completed the study without evidence of metastatic disease 1-year following amputation. Toceranib-treated dogs experienced more episodes of diarrhea, neutropenia and weight loss than control dogs, although these toxicities were low-grade and typically resolved with supportive care. More toceranib-treated dogs (n = 8) were removed from the study for therapy-associated adverse events compared to control dogs (n = 1). The median DFI for control and toceranib treated dogs was 215 and 233 days, respectively (p = 0.274); the median OS for control and toceranib treated dogs was 242 and 318 days, respectively (p = 0.08). The one year survival rate for control dogs was 35% compared to 38% for dogs receiving toceranib. Conclusions The

  4. 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.

    PubMed

    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. PMID:27589232

  5. Radiation sickness

    MedlinePlus

    ... to determine the amount of radiation exposure from nuclear accidents, the best signs of the severity of the ... doses of radiation, such as radiation from a nuclear power plant accident Exposure to excessive radiation for medical treatments

  6. Toxic epidermal necrolysis due to therapy with cyclophosphamide and mesna. A case report of a patient with seronegative rheumatoid arthritis and rheumatoid vasculitis.

    PubMed

    Chowdhury, A C; Misra, D P; Patro, P S; Agarwal, V

    2016-03-01

    Rheumatoid vasculitis usually occurs on