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Sample records for radiation cyclophosphamide busulfan

  1. Busulfan

    MedlinePlus

    (bue sul' fan)Busulfan can cause a severe decrease in the number of blood cells in your bone marrow. Tell your ... rash itching and dry skin darkened skin hair loss Some side effects can be ... online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

  2. 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.

  3. 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

  4. Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

    PubMed Central

    Ye, YongBin; Wang, Jing; Huang, YuXian; Weng, GuangYang; Zhang, MingWan

    2016-01-01

    Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a major cause of nonrelapse mortality after allo-HSCT. A conditioning regimen plays a pivotal role in the development of aGVHD. To provide a platform for studying aGVHD and evaluating the impact of different conditioning regimens, we established a murine aGVHD model that simulates the clinical situation and can be conditioned with Busulfan-Cyclophosphamide (Bu-Cy) and Fludarabine-Busulfan (Flu-Bu). In our study, BALB/c mice were conditioned with Bu-Cy or Flu-Bu and transplanted with 2 × 107 bone marrow cells and 2 × 107 splenocytes from either allogeneic (C57BL/6) or syngeneic (BALB/c) donors. The allogeneic recipients conditioned with Bu-Cy had shorter survivals (P < 0.05), more severe clinical manifestations, and higher hepatic and intestinal pathology scores, associated with increased INF-γ expression and diminished IL-4 expression in serum, compared to allogeneic recipients conditioned with Flu-Bu. Moreover, higher donor-derived T-cell infiltration and severely impaired B-cell development were seen in the bone marrow of mice, exhibiting aGVHD and conditioned with Flu-Bu. Our study showed that the conditioning regimen with Bu-Cy resulted in more severe aGVHD while the Flu-Bu regimen was associated with more extensive and long standing bone marrow damage. PMID:27843940

  5. Busulfan, cyclophosphamide, and melphalan conditioning for autologous bone marrow transplantation in hematologic malignancy.

    PubMed

    Phillips, G L; Shepherd, J D; Barnett, M J; Lansdorp, P M; Klingemann, H G; Spinelli, J J; Nevill, T J; Chan, K W; Reece, D E

    1991-10-01

    Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent conditioning with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (BUCY-2) plus melphalan (90 or 135 mg/m2) and autologous bone marrow transplantation (AuBMT) in a phase I study. At the melphalan dose of 90 mg/m2, grade greater than or equal to 3 regimen-related toxicity (RRT) was observed in five patients (31%; 95% confidence interval [CI], 11% to 59%), with hepatic (venoocclusive disease [VOD]) and urinary (hemorrhagic cystitis) RRT being the most frequent complications. Further escalation of the melphalan dose to 135 mg/m2 was deemed excessively toxic, as three of five patients had grade greater than or equal to 3 RRT. Following this experience, 21 patients with multiple myeloma (MM) and chronic myelogenous leukemia (CML) were treated with BUCY-2 plus melphalan 90 mg/m2 and AuBMT in separate studies. Three of these patients--all with extensively pretreated MM--had grade greater than or equal to 3 RRT (14%; 95% CI, 3% to 36%); no others had grade greater than or equal to 3 RRT. Therefore, a total of eight of the 37 patients (22%; 95% CI, 10% to 38%) who received BUCY-2 plus melphalan 90 mg/m2 conditioning developed grade greater than or equal to 3 RRT; three of these patients (8%; 95% CI, 3% to 25%) died of RRT. Although limited by the relatively small number of patients, our analysis of the patients receiving this regimen showed that the presence of parameters denoting the lymphoid diagnostic group (ie, ALL, NHL, and MM), more extensive pretreatment, and/or more advanced disease status were associated with a higher incidence of grade greater than or equal to 3 RRT. Response data on the AML, ALL, and NHL patients who received BUCY-2 plus melphalan 90 mg/m2 were analyzed: three patients (all with AML in first or second remission) are leukemia-free at 3.0, 2.8, and 1.4 years after AuBMT. The actuarial 2-year

  6. 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

  7. Comparison of total body irradiation plus cyclophosphamide with busulfan plus cyclophosphamide as conditioning regimens in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplant.

    PubMed

    Eroglu, Celalettin; Pala, Cigdem; Kaynar, Leylagül; Yaray, Kadir; Aksozen, M Tarkan; Bankir, Mehmet; Zararsız, Gökmen; Orhan, Okan; Gündog, Mete; Yıldız, Oguz G; Eser, Bülent; Cetin, Mustafa; Unal, Ali

    2013-11-01

    Conditioning regimens used during stem cell transplant provide prolonged control or cure of the disease in patients with acute lymphoblastic leukemia (ALL). In this study, we present a comparison of treatment results for 95 patients with ALL who underwent allogeneic hematopoietic stem cell transplant (AHSCT) with total body irradiation plus cyclophosphamide (TBI + Cy) or busulfan plus cyclophosphamide (Bu + Cy) as conditioning regimen. Median age was 25 (range: 9-54) years. Median follow-up was 24 (range: 3-107) months. Median overall survival (OS) was found to be 29 months. Median event-free survival (EFS) was 9 months. Median OS was 37 months in the TBI + Cy arm, while it was 12 months in the Bu + Cy arm, suggesting a significant advantage favoring the TBI + Cy arm (p = 0.003). Median EFS was 13 months in the TBI + Cy arm, while it was 4 months in the Bu + Cy arm, indicating a significant difference (p = 0.006). In univariate and multivariate analysis, it was found that high OS and EFS were significantly correlated with TBI + Cy conditioning regimen and lack of transplant-related mortality (p < 0.05). The TBI + Cy conditioning regimen was found to be superior to the Bu + Cy regimen in patients with ALL undergoing AHSCT regarding both OS and EFS.

  8. A Comprehensive Assessment of Toxicities in Patients with Central Nervous System Lymphoma Undergoing Autologous Stem Cell Transplantation Using Thiotepa, Busulfan, and Cyclophosphamide Conditioning.

    PubMed

    Scordo, Michael; Bhatt, Valkal; Hsu, Meier; Omuro, Antonio M; Matasar, Matthew J; DeAngelis, Lisa M; Dahi, Parastoo B; Moskowitz, Craig H; Giralt, Sergio A; Sauter, Craig S

    2017-01-01

    High-dose therapy and autologous stem cell transplantation (ASCT) with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning has emerged as an effective postinduction treatment strategy for patients with primary central nervous system lymphoma (PCNSL) or secondary central nervous system lymphoma (SCNSL), but it is associated with considerable toxicity and transplantation-related mortality (TRM) in the modern era. Forty-three adult patients with chemosensitive PCNSL or SCNSL underwent TBC-conditioned ASCT between 2006 and 2015. Twenty-eight of these patients received pharmacokinetically (PK)-targeted busulfan dosing. The median number of clinically relevant individual grade ≥3 nonhematologic toxicities per patient was 5. We found no association between pretransplantation patient characteristics and the presence of more than 5 grade ≥3 nonhematologic toxicities. Patients with elevated first-dose busulfan area under the curve values did not experience more toxicity. Paradoxically, patients treated with more than 2 regimens before undergoing ASCT had lower first-dose busulfan AUC values. With a median follow-up among survivors of 20 months, 1-year progression-free survival (PFS) and overall survival (OS) from the time of ASCT were 83% and 87%, respectively. Although this study reaffirms the favorable PFS and OS associated with TBC-conditioned ASCT for PCNSL or SCNSL, this treatment strategy carries a large toxicity burden.

  9. Phase I-II study of high-dose busulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation for hematological malignancies: toxicities and hematopoietic recovery.

    PubMed

    Ballester, O F; Agaliotis, D P; Hiemenz, J W; Janssen, W E; Fields, K K; Zorksy, P E; Goldstein, S C; Perkins, J B; Elfenbein, G J

    1996-07-01

    In a phase I-II study, we evaluated toxicities, tolerability, pace of engraftment, and tumor responses to high-dose bulsulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with hematological malignancies. We treated 51 patients with various hematological malignancies involving the bone marrow with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of autologous peripheral blood stem cells. Stem cells were previously collected during hematopoietic recovery after cyclophosphamide (100 mg/kg) and etoposide (600 mg/m2) followed by G-CSF (5 micrograms/kg/day). Neutrophil recovery (>0.5 x 10(9)/I) was rapid in the majority of patients (median 10 days after transplant, range 7-91 days), resulting in a low number of days with severe neutropenia (median 7 days, range 5-85 days) and with fever (median 5 days, range 1-13 days). Platelet recovery, however, was delayed in 60% of patients. There was one acute transplant-related death (2%). Four patients died of late, presumed infections, pulmonary complications (interstitial pneumonia). Tumor responses were documented in a significant proportion of these patients with high-risk hematological malignancies. We conclude that peripheral blood stem cell transplantation results in rapid recovery of neutrophils but variable recovery of platelets after high-dose busulfan and cyclophosphamide, when stem cells are harvested following priming with cyclophosphamide/etoposide and G-CSF. The regimen is well-tolerated with limited non-hematological toxicities and transplant-related mortality. While significant tumor responses were documented in this trial, the ultimate efficacy of the regimen needs to be further defined.

  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. Using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning: results of a dose de-escalation trial.

    PubMed

    Horan, John T; Haight, Ann; Dioguardi, Jacqueline Lagerlof; Brown, Clark; Grizzle, Audrey; Shelman, Chiani; Kanter, Julie; Hale, Greg; Nieder, Michael; Benton, Melody; Kasow, Kimberly A; Abraham, Allistair; Chiang, Kuang-Yueh

    2015-05-01

    High-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide. We conducted a multicenter dose de-escalation trial with the objective of decreasing the doses of busulfan and cyclophosphamide by 50% and 55%, respectively. Using day +28 donor-predominant chimerism as a surrogate endpoint for sustained engraftment, we completed the first 2 of 4 planned levels, enrolling 6 patients at each and reducing the total dose of cyclophosphamide from 200 mg/kg to 90 mg/kg. On the third level, which involved a reduction of i.v. busulfan from 12.8 mg/kg to 9.6 mg/kg, the first 2 patients had host-predominant T cell chimerism, which triggered trial-stopping rules. All 14 patients survive disease-free. No patients suffered severe regimen-related toxicity. Our results suggest BU-FLU-CY-ATG using lower dose CY could be a less toxic yet effective regimen. Further evaluation of this regimen in a full-scale clinical trial is warranted.

  12. HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide after Busulfan-Containing Reduced-Intensity Conditioning.

    PubMed

    Sugita, Junichi; Kawashima, Naomi; Fujisaki, Tomoaki; Kakihana, Kazuhiko; Ota, Shuichi; Matsuo, Keitaro; Miyamoto, Toshihiro; Akashi, Koichi; Taniguchi, Shuichi; Harada, Mine; Teshima, Takanori

    2015-09-01

    Allogeneic hematopoietic stem cell transplantation (allo-SCT) using post-transplant cyclophosphamide (PTCy) is increasingly performed. We conducted a multicenter phase II study to evaluate the safety and efficacy of PTCy-based HLA-haploidentical peripheral blood stem cell transplantation (PTCy-haploPBSCT) after busulfan-containing reduced-intensity conditioning. Thirty-one patients were enrolled; 61% patients were not in remission and 42% patients had a history of prior allo-SCT. Neutrophil engraftment was achieved in 87% patients with a median of 19 days. The cumulative incidence of grades II to IV and III to IV acute graft-versus-host disease (GVHD) and chronic GVHD at 1 year were 23%, 3%, and 15%, respectively. No patients developed severe chronic GVHD. Day 100 nonrelapse mortality (NRM) rate was 19.4%. Overall survival, relapse, and disease-free survival rates were 45%, 45%, and 34%, respectively, at 1 year. Subgroup analysis showed that patients who had a history of prior allo-SCT had lower engraftment, higher NRM, and lower overall survival than those not receiving a prior allo-SCT. Our results suggest that PTCy-haploPBSCT after busulfan-containing reduced-intensity conditioning achieved low incidences of acute and chronic GVHD and NRM and stable donor engraftment and low NRM, particularly in patients without a history of prior allo-SCT.

  13. Cyclophosphamide

    MedlinePlus

    ... medications or in children who experienced intolerable side effects with other medications. Cyclophosphamide is in a class ... on your response to treatment and any side effects that you experience. Talk to your doctor about ...

  14. Busulfan Injection

    MedlinePlus

    Busulfex® Injection ... Busulfan injection is used to treat a certain type of chronic myelogenous leukemia (CML; a type of cancer of ... of 16 doses) before bone marrow transplant.Busulfan injection may cause seizures during therapy with the medication. ...

  15. 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.

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

    ClinicalTrials.gov

    2016-12-27

    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

  17. Cyclophosphamide Injection

    MedlinePlus

    ... medications or in children who experienced intolerable side effects with other medications. Cyclophosphamide is in a class ... adjust your dose if you experience certain side effects. It is important for you to tell your ...

  18. Toxicity of abdominopelvic radiation in advanced ovarian carcinoma patients after cisplatin/cyclophosphamide therapy and second-look laparotomy

    SciTech Connect

    Shelley, W.E.; Starreveld, A.A.; Carmichael, J.A.; O'Connell, G.; Roy, M.; Swenerton, K.

    1988-03-01

    Twenty-seven advanced ovarian carcinoma patients who had received six courses of cyclophosphamide/cisplatin and had either microscopic disease (15 patients) or no pathologically detectable disease (12 patients) after second-look laparotomy were treated with abdominopelvic radiation (2250 cGy to the abdomen and pelvis and a 2250-cGy pelvic boost). Acute myelosuppression or gastrointestinal toxicity prevented completion of treatment in only three patients. However, bowel obstruction occurred in 13 (48%), ten of whom required surgery. Five of these ten had recurrent tumor, but the other five did not. Subsequently two of the latter five did develop a recurrence, one in the lung and one in the liver. A third patient died as an indirect result of radiation damage to the bowel. Median follow-up duration is 17 months from completion of radiation. So far, 13 (48%) have developed progressive disease: four (33%) of the 12 who had a negative second-look laparotomy and nine (60%) of the 15 who had microscopic disease before radiation. While acute toxicity is tolerable, the incidence of serious chronic bowel toxicity is high. Efforts should be made to alter this therapy in order to decrease the frequency of long-term morbidity.

  19. 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.

  20. Some cell kinetic effects of combined injury with ionizing radiation and cyclophosphamide on mouse bladder urothelium.

    PubMed

    Reitan, J B

    1985-01-01

    Cyclophosphamide was given intraperitoneally to groups of eight female mice 48 h after local electron irradiation to the bladder with 0, 10 and 20 Gy respectively. The reactions in the urothelium were monitored by histology, incorporation of tritiated thymidine and flow cytometry. A wave of increased thymidine incorporation combined with an increase in the proportion of diploid S-phase cells was seen in the unirradiated bladders 24 h after the drug treatment, followed by normalization after 1 week. This response was significantly less pronounced in the irradiated animals. In the unirradiated animals a similar wave characterized by an increased proportion of octaploid cells was also seen, but this wave occurred later in the irradiated animals. Severe injury was observed in the rectum of the 20 Gy-irradiated animals. Irradiation prior to drug treatment led to only small effects, but a decreased ability for regenerative DNA synthesis after drug injury seems to persist. This affects both proliferation and the building up of polyploidy.

  1. 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.

  2. 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.

  3. 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.

  4. Treatment of patients with secondary central nervous system lymphoma with high-dose busulfan/thiotepa-based conditioning and autologous stem cell transplant.

    PubMed

    Oh, Danielle H; Chua, Neil; Street, Lesley; Stewart, Douglas A

    2016-01-01

    Although the survival rates are extremely low for patients with secondary central nervous system lymphoma (SCNSL) treated with conventional chemotherapy and radiotherapy, more encouraging outcomes have recently been reported in small series with high-dose (HD) therapy and autologous stem cell transplant (ASCT). The optimal HD regimen for SCNSL is unknown. Despite reports of thiotepa/busulfan-based conditioning for primary CNS lymphoma, very little data exist regarding the use of this regimen for SCNSL. We analyzed 23 patients with SCNSL (median age 62 years) who underwent ASCT at two Alberta centers using thiotepa, busulfan, cyclophosphamide (TBC) in six patients prior to 2011 and rituximab-busulfan, melphalan, thiotepa (R-BuMelTt) in 17 patients after 2011. At a median follow-up of 27.8 months (4.2-113.6), the 2-year actuarial rate of progression-free survival was 76.1%. In conclusion, our results demonstrate encouraging survival outcomes for patients with SCNSL treated with R-BuMelTt and ASCT.

  5. 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.

  6. IV busulfan dose individualization in children undergoing hematopoietic stem cell transplant: limited sampling strategies.

    PubMed

    Dupuis, L Lee; Sibbald, Cathryn; Schechter, Tal; Ansari, Marc; Gassas, Adam; Théorêt, Yves; Kassir, Nastya; Champagne, Martin A; Doyle, John

    2008-05-01

    We currently calculate area under the busulfan concentration time curve (AUC) using 7 plasma busulfan concentrations (AUC7) drawn after the first of 16 i.v. busulfan doses given as a 2-hour infusion every 6 hours. The aim of this study was to develop and validate limited sampling strategies (LSSs) using 3 or fewer busulfan concentration values with which to reliably calculate AUC in children undergoing hematopoietic stem cell transplant (HSCT). Children in the development group (44) received i.v. busulfan at Sick Kids; the validation group consisted of 35 children who received care at CHU Ste-Justine. Busulfan doses given and subsequent plasma busulfan concentrations were recorded. LSSs using 1 to 3 concentration-time points were developed using multiple linear regression. LSS were considered to be acceptable when adjusted r(2) > 0.9, mean bias <15% and precision <15%. Extent of agreement between the AUC7 values and the LSS AUC was assessed by the intraclass correlation coefficient (ICC) and Bland-Altman (BA) analysis. Agreement was considered to be excellent when the lower limit of the 95% confidence limit of the ICC exceeded 0.9 and when the limits of agreement in the BA analysis were +/-15% for both AUC and dose. Administration of the theoretic adjusted busulfan doses based on each LSS was simulated and cases where the resulting AUC was >1500 or <900 microM x min were noted. LSSs using 1, 2, or 3 plasma busulfan concentrations were developed that showed excellent agreement with AUC7 and adjusted busulfan doses. In the validation sample, only the 2- and 3-point LSSs demonstrated acceptable precision and lack of bias. LSSs using 2 or 3 plasma busulfan concentrations can be used to reliably estimate busulfan AUC after IV administration in children undergoing HSCT.

  7. Molecular mechanism of prostate cancer cell apoptosis induced by busulfan via adjustment of androgen receptor phosphatization

    PubMed Central

    Liu, Jun; Jiang, Guojun; Yang, Aiping; Yang, Guohui; Yang, Wenjuan; Fang, Yi

    2016-01-01

    Objective: To probe killing effect of busulfan to prostate cancer cell without androgen and the influence of androgen receptor phosphatization and analyze its molecular mechanism. Methods: prostate cancer cell line 22RV1, LAPC4 and LNCaP treated with busulfan under androgen-free condition underwent CCK-8 examination to probe killing ability of the medicine. Flow cytometry was used to check the influence of busulfan on apoptosis rate of prostate cancer cell line LAPC4. Expression level of androgen receptor (AR), Src and Ack1 and change in phosphatization of AR after busulfan treatment were measured by RT-PCR and Western blotting. Finally, influence o proliferation ability and apoptosis of LAPC4 were measured using EGF-busulfan co-processing. Results: Significant dose-dependency was observed as killing ability rises with higher busulfan concentration (p<0.05). Significant improvement in prostate cancer cell inhibition ability of busulfan was also observed with prolonging of time (p<0.05). Then we discovered, as indicated by flow cytometry, that busulfan inhibits prostate cancer cell LAPC4 proliferation by strengthening its apoptosis (p<0.05), which showed significant dose- and time-dependency. Detection of AR expression and phosphatization level showed no significant influence on mRNA and protein expression level of AR made by busulfan. However, decline of phosphatization level at AR Y534 site was positively related to busulfan treatment time. Busulfan was found to be inhibitory to Src kinase induced by EGF and level of resulting AR phosphatization in our further probe into the mechanism of busulfan influence on phosphatization level at AR Y534 site. Nude mice experiment indicated that busulfan was inhibitory to protein expression of AR downstream target gene prostate specific antigen (PSA) and human tissue kallikrein2 (hk-2), thus inhibited in vivo tumorigenic ability of prostate cancer cells. Conclusion: Busulfan was significantly inhibitory to prostate cancer cell

  8. Haploidentical Related Donor Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency Using Post-Transplantation Cyclophosphamide.

    PubMed

    Shah, Nirali N; Freeman, Alexandra F; Su, Helen; Cole, Kristen; Parta, Mark; Moutsopoulos, Niki M; Baris, Safa; Karakoc-Aydiner, Elif; Hughes, Thomas E; Kong, Heidi H; Holland, Steve M; Hickstein, Dennis D

    2017-03-10

    Dedicator-of-Cytokinesis-8 (DOCK8) deficiency, a primary immunodeficiency disease, can be reversed by allogeneic hematopoietic stem cell transplant (HSCT); however, there are few reports describing the use of alternative donor sources for HSCT in DOCK8 deficiency. We describe HSCT for patients with DOCK8 deficiency who lack a matched related or unrelated donor using bone marrow from haploidentical related donors and post-transplantation cyclophosphamide (PT/CY) for GVHD prophylaxis. Seven patients with DOCK8 deficiency (median age 20 years, range 7-25 years) received a haploidentical related donor HSCT. The conditioning regimen included 2 days of low-dose cyclophosphamide, 5 days of fludarabine, three days of busulfan, and 200 cGy TBI. Graft-versus host disease (GVHD) prophylaxis consisted of post-transplant cyclophosphamide (PT/CY) 50 mg/kg/day on days +3 and +4, and tacrolimus and mycophenolate mofetil starting at day +5. The median times to neutrophil and platelet engraftment were 15 and 19 days, respectively. All patients attained >90% donor engraftment by day +30. Four subjects developed acute GVHD (one with maximum grade 3). No patient developed chronic GVHD. With a median follow-up time of 20.6 months (range 9.5 - 31.7 months), 6 of 7 patients are alive and disease-free. Haploidentical related donor HSCT with PT/CY represents an effective therapeutic approach for patients with DOCK8 deficiency who lack a matched related or unrelated donor.

  9. Quantification of busulfan in plasma by gas chromatography-mass spectrometry following derivatization with tetrafluorothiophenol.

    PubMed

    Quernin, M H; Poonkuzhali, B; Montes, C; Krishnamoorthy, R; Dennison, D; Srivastava, A; Vilmer, E; Chandy, M; Jacqz-Aigrain, E

    1998-05-08

    A specific and highly sensitive method has been developed for the determination of busulfan in plasma by gas chromatography-mass spectrometry using a deuterium-labeled busulfan (busulfan-d8) as internal standard. Plasma containing busulfan and busulfan-d8 were extracted with ethyl acetate and derivatized with 2,3,5,6-tetrafluorothiophenol prior to the monitoring of specific ions. The limit of quantification of the assay was 20 ng/ml and the calibration curve was linear over the range of 10 to 2000 ng/ml of derivatized busulfan. This method was in good agreement with the GC-MS assay using derivatization with sodium iodide and measuring diiodobutane. In addition, a pharmacokinetic study of busulfan was conducted in six children. The apparent oral clearance was 5.7+/-1.9 ml/kg/min and the volume of distribution was 1.0+/-0.4 l/kg and were similar to those previously reported in pediatric patients.

  10. Antifertility effect of busulfan and procarbazine in male and female coyotes.

    PubMed

    Stellflug, J N; Green, J S; Leathers, C W

    1985-12-01

    Antifertility effects of two cytostatic agents, busulfan and procarbazine, were evaluated using 43 captive breeding pairs of adult coyotes. Nineteen pairs served as untreated controls. Only the male or female of remaining pairs was treated. Females received either 8 mg busulfan/kg or 6 mg procarbazine/kg just prior to onset of the breeding season. Males were treated once with either 8 mg busulfan/kg just before onset of breeding or with 4 mg busulfan/kg or 6 mg procarbazine/kg about 1 mo before onset of the breeding season. Uterine implantation sites were counted in females of all breeding pairs postpartum via laparotomy. Busulfan given to males at 4 mg/kg or to either females or males at 8 mg/kg significantly reduced implantation sites compared to untreated controls. Thus, busulfan may be successful in controlling population in coyotes in the field where both the male and female of a breeding pair may ingest the compound. However, multiple doses at a lower rate would be preferred because dosages greater than 10 mg/kg resulted in mortality. Although procarbazine has a mode of action similar to busulfan, doses of 6 mg procarbazine/kg did not reduce implantation sites or disrupt normal spermatogenesis. Increased doses need to be evaluated before effectiveness of procarbazine for coyote population control can be determined.

  11. 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.

  12. 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

  13. Evaluation of the Pharmacokinetics and Efficacy of a Busulfan Test Dose in Adult Patients Undergoing Myeloablative Hematopoietic Cell Transplantation.

    PubMed

    Weil, Elizabeth; Zook, Felicia; Oxencis, Carolyn; Canadeo, Angela; Urmanski, Angela; Waggoner, Mindy; Eastwood, Daniel; Pasquini, Marcelo; Hamadani, Mehdi; Hari, Parameswaran

    2017-03-10

    Owing to interpatient variability in busulfan exposure, therapeutic monitoring of busulfan is often used in myeloablative allogeneic transplantation to ensure that patients are near the optimal steady-state goal of 900 ng/mL. One challenge in therapeutic monitoring of busulfan is the brief course of busulfan treatment, requiring prompt analysis and dose adjustments as needed. Pharmacokinetic evaluation of a busulfan test dose before the start of the conditioning regimen would allow for all conditioning regimen doses to be given at the calculated optimized dose. An observational study was completed to evaluate the effects of a busulfan test dose of .9 mg/kg administered before the start of a myeloablative intravenous busulfan-based conditioning regimen. Sixty adult patients who received a busulfan conditioning regimen were reviewed, including 30 patients who had not yet received the busulfan test dose (pretest dose group) and 30 patients who had received the busulfan test dose (posttest dose group). The primary objective was a pharmacokinetic evaluation of the percentage of patients who achieved the desired steady-state goal using the test dose strategy. The safety and efficacy of the busulfan test dose were evaluated as well. The average busulfan steady-state level after the first dose of the conditioning regimen was significantly lower in the pre-test dose group compared with the post-test dose group (660 ng/mL versus 879.9 ng/mL; P < .001). Compared with the post-test dose group, significantly fewer patients in the pre-test dose group were within 10% of the busulfan steady-state goal (10% versus 73.3%; P < .001) or within 5% of the goal (0% versus 53%; P < .001). Requirements for parenteral nutrition and/or patient-controlled analgesia owing to mucositis and veno-occlusive disease rates were not significantly different between the pre-test dose group and the post-test dose group. The rates of disease relapse, mortality, and acute graft

  14. 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

  15. The effects of temperature and busulfan (Myleran) on the yellowtail tetra Astyanax altiparanae (Pisces, Characiformes) spermatogenesis.

    PubMed

    de Siqueira-Silva, Diógenes Henrique; Silva, Amanda Pereira dos Santos; Ninhaus-Silveira, Alexandre; Veríssimo-Silveira, Rosicleire

    2015-10-01

    We aimed to standardize a protocol to suppress spermatogenesis in the characiform fish, Astyanax altiparanae, for future use as a host in germ cell transplant research, opening opportunities for a range of studies, such as spermatogenesis analyses and transgenesis because this species presents livestock characteristics to be used as a biological model. The effects of the chemotherapeutic busulfan (formulated as Myleran), which is used as medicine, therefore not as toxic to humans manipulation as analytical grade busulfan (Fluka) used in previous studies, were evaluated at physiological temperature of 28 °C, ideal for growth and reproduction of A altiparanae, and also at increased temperature 35 °C. The temperature groups were divided into three treatment groups: busulfan, DMSO only, and an untreated control. Macroscopic, histologic, stereological, and ultrastructure analysis showed that, at 28 °C, busulfan did not cause depletion of germ cells in A altiparanae. However, at 35 °C, sterilization was observed 3 weeks after the initial application. Similar results were obtained with maintenance of fish at 35 °C for a longer period with no accompanying Myleran treatment. This procedure allows reduction in stress and lower mortality resulting from manipulation during busulfan injection and is also suitable for mass treatment because large numbers of fish can be incubated in warm water.

  16. A swine model of acute thrombocytopenia with prolonged bleeding time produced by busulfan

    PubMed Central

    Abe, Tomoyuki; Kono, Shota; Ohnuki, Takahiro; Hishikawa, Shuji; Kunita, Satoshi; Hanazono, Yutaka

    2016-01-01

    Animal models of thrombocytopenia are indispensable for evaluating the in vivo efficacy of hemostatic agents, cryopreserved platelets, and artificial platelets, but no large animal models are available. In this study, we generated a swine model of acute thrombocytopenia with prolonged bleeding times by administering the chemotherapeutic drug busulfan. First, we tested multiple doses of busulfan (4, 6, and 8 mg/kg) in pigs, and found that 6 mg/kg of busulfan is an optimal dose for producing a safe and moderate thrombocytopenia, with a platelet count of less than 30,000/µl. The pigs administered 6 mg/kg of busulfan (n=8) reached half their initial counts at day 7, counts below 30,000/µl at day 12, and their nadirs at day 15 (on average). The minimal platelet count was 14,000/µl. With this dose of busulfan (6 mg/kg), bleeding times were significantly prolonged in addition to the decrease in platelet counts (r=−0.63, P<0.01), while there were no cases of apparent hemorrhage. White blood cell counts were maintained at over 5,000/µl, and there were no infections or other adverse events including anemia or appetite or body weight loss. All pigs were sacrificed on day 16, with subsequent examination showing a significant reduction in cellularity and colony-forming units in the bone marrow, indicating that thrombocytopenia was the result of myelosuppression. In summary, administration with 6 mg/kg of busulfan induces safe and moderate thrombocytopenia with a prolonged bleeding time in swine. PMID:27333841

  17. Characterization and intramolecular bonding patterns of busulfan: Experimental and quantum chemical approach

    NASA Astrophysics Data System (ADS)

    Karthick, T.; Tandon, Poonam; Singh, Swapnil; Agarwal, Parag; Srivastava, Anubha

    2017-02-01

    The investigations of structural conformers, molecular interactions and vibrational characterization of pharmaceutical drug are helpful to understand their behaviour. In the present work, the 2D potential energy surface (PES) scan has been performed on the dihedral angles C6sbnd O4sbnd S1sbnd C5 and C25sbnd S22sbnd O19sbnd C16 to find the stable conformers of busulfan. In order to show the effects of long range interactions, the structures on the global minima of PES scan have been further optimized by B3LYP/6-311 ++G(d,p) method with and without empirical dispersion functional in Gaussian 09W package. The presence of n → σ* and σ → σ* interactions which lead to stability of the molecule have been predicted by natural bond orbital analysis. The strong and weak hydrogen bonds between the functional groups of busulfan were analyzed using quantum topological atoms in molecules analysis. In order to study the long-range forces, such as van der Waals interactions, steric effect in busulfan, the reduced density gradient as well as isosurface defining these interactions has been plotted using Multiwfn software. The spectroscopic characterization on the solid phase of busulfan has been studied by experimental FT-IR and FT-Raman spectra. From the 13C and 1H NMR spectra, the chemical shifts of individual C and H atoms of busulfan have been predicted. The maximum absorption wavelengths corresponding to the electronic transitions between the highest occupied molecular orbital and the lowest unoccupied molecular orbital of busulfan have been found by UV-vis spectrum.

  18. Targeted busulfan and fludarabine-based conditioning for bone marrow transplantation in chronic granulomatous disease

    PubMed Central

    Ju, Hee Young; Hong, Che Ry; Lee, Ji Won; Kim, Hyery; Song, Sang Hoon; Yu, Kyung-Sang; Jang, In-Jin; Park, June Dong; Park, Kyung Duk; Shin, Hee Young; Kim, Joong-Gon; Ahn, Hyo Seop

    2016-01-01

    Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by impaired phagocytic function. Hematopoietic stem cell transplantation (HSCT) is a definitive cure for CGD; however, the use of HSCT is limited because of associated problems, including transplantation-related mortality and engraftment failure. We report a case of a patient with CGD who underwent successful HSCT following a targeted busulfan and fludarabine reduced-toxicity myeloablative conditioning. Intravenous busulfan was administered once daily for 4 consecutive days (days –8 to –5), and the target area under the curve was 75,000 µg·hr/L. Fludarabine (40 mg/m2) was administered once daily for 6 consecutive days from days –8 to –3. Antithymocyte globulin (2.5 mg/kg/day) was administered from days –4 to –2. The patient underwent successful engraftment and did not have any severe toxicity related to the transplantation. Conditioning with a targeted busulfan and fludarabine regimen could provide a better outcome for HSCT in CGD, with close regulation of the busulfan dose. PMID:28018447

  19. 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

  20. Cyclophosphamide treatment in polyarteritis nodosa.

    PubMed

    Oriente, P; Riccio, A; Farinaro, C; Farinaro, E; Scarpa, R; Vignone, L; Pucino, A

    1986-06-01

    Five male patients with polyarteritis nodosa were treated with cyclophosphamide as follows: 3 mg/Kg/die i.v. up to maximum of 3 g.; subsequently, 200 mg/die per os for two weeks, then 100 mg per os every other day for three months; finally, 100 mg every fourth day until the 18th month. One patient, who also had fever, received 25 mg/die of prednisone for the initial three weeks of treatment. Before treatment ESR, WBC, and circulating immune-complexes were increased, while C3a, C3c and C4 serum complement components levels were normal. Skin ulcers healed within 4 months. A progressive marked improvement of visceral damages in the first months of therapy have been noted (e.g. blood pressure values in normal range after suspension of concomitant antihypertensive treatment, regression of peripheral neuropathy, etc. etc.). No further ischemic lesions occurred during treatment. Significant decreases of ESR and serum immune-complexes levels were detected. No untoward effects due to cyclophosphamide were observed. These findings support the effectiveness of this drug in polyarteritis. The possibility of association with glucocorticoids during the acute phase of disease is also discussed.

  1. Radiation-Sensitive Severe Combined Immunodeficiency: The arguments for and against conditioning prior to hematopoietic cell transplantation – What to do?

    PubMed Central

    Cowan, MJ; Gennery, AR

    2015-01-01

    Defects in DCLRE1C, PRKDC, LIG4, NHEJ1, and NBS1, involving the non-homologous end joining (NHEJ) DNA repair pathway, result in radiation-sensitive severe combined immunodeficiency (RS-SCID). Results of hematopoietic cell transplantation for RS-SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of pre-conditioning with alkylating agents is associated with a greater likelihood of full T and B cell reconstitution compared to no conditioning or immunosuppression alone. A reduced intensity regimen using fludarabine and low dose cyclophosphamide may be effective for patients with LIG4, NHEJ1 and NBS1 defects although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose alkylating agents without significant late effects. Until non-chemotherapy agents, e.g., anti-CD45 or anti-CD117 become available, options include minimizing exposure to alkylators, e.g., single agent low dose targeted Busulfan or achieving T cell reconstitution followed several years later with a conditioning regimen to restore B cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and GvHD. Prospective multi- center studies are needed to evaluate these approaches in this rare but highly vulnerable patient population. PMID:26055221

  2. 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

  3. Glutathione conjugation of busulfan produces a hydroxyl radical-trapping dehydroalanine metabolite.

    PubMed

    Peer, Cody J; Younis, Islam R; Leonard, Stephen S; Gannett, Peter M; Minarchick, Valerie C; Kenyon, Allison J; Rojanasakul, Yon; Callery, Patrick S

    2012-12-01

    The Phase 2 drug metabolism of busulfan yields a glutathione conjugate that undergoes a β-elimination reaction. The elimination product is an electrophilic metabolite that is a dehydroalanine-containing tripeptide, γ-glutamyldehydroalanylglycine (EdAG). In the process, glutathione lacks thiol-related redox properties and gains a radical scavenging dehydroalanine group. EdAG scavenged hydroxyl radical generated in the Fenton reaction in a concentration-dependent manner was monitored by electron paramagnetic resonance (EPR) spectroscopy. The apparent rate of hydroxyl radical scavenging was in the same range as published values for known antioxidants, including N-acyl dehydroalanines. A captodatively stabilized carbon-centered radical intermediate was spin trapped in the reaction of EdAG with hydroxyl radical. The proposed structure of a stable product in the Fenton reaction with EdAG was consistent with that of a γ-glutamylserylglycyl dimer. Observation of the hydroxyl trapping properties of EdAG suggests that the busulfan metabolite EdAG may contribute to or mitigate redox-related cytotoxicity associated with the therapeutic use of busulfan, and reaffirms indicators that support a role in free radical biology for dehydroalanine-containing peptides and proteins.

  4. Computational approaches to find the active binding sites of biological targets against busulfan.

    PubMed

    Karthick, T; Tandon, Poonam

    2016-06-01

    Determination of electrophilic and nucleophilic sites of a molecule is the primary task to find the active sites of the lead molecule. In the present study, the active sites of busulfan have been predicted by molecular electrostatic potential surface and Fukui function analysis with the help of dispersion corrected density functional theory. Similarly, the identification of active binding sites of the proteins against lead compound plays a vital role in the field of drug discovery. Rigid and flexible molecular docking approaches are used for this purpose. For rigid docking, Hex 8.0.0 software employing fast Fourier transform (FFT) algorithm has been used. The partial flexible blind docking simulations have been performed with AutoDock 4.2 software; where a Lamarckian genetic algorithm is employed. The results showed that the most electrophilic atoms of busulfan bind with the targets. It is clear from the docking studies that busulfan has inhibition capability toward the targets 12CA and 1BZM. Graphical Abstract Docking of ligand and protein.

  5. Involvement of ICAM-1 in impaired spermatogenesis after busulfan treatment in mice.

    PubMed

    Cai, Y; Liu, T; Fang, F; Shen, S; Xiong, C

    2016-02-01

    Expression of adherence proteins, such as P-cadherin, has been identified in the normal testis and changed in impaired testis induced by alkylating agents. Intercellular adhesion molecule-1 (ICAM-1), a member of the immunoglobulin superfamily of cell adhesion molecules, is a constituent component of the blood-testis barrier and a multifunctional molecule in homeostasis of spermatogenesis. However, the distribution of ICAM-1 in the testis of mice and expression changes after busulfan treatment remain unclear. In this study, ICAM-1 immunoreaction was detected in Sertoli and germinal cells, particularly in spermatogonia, and elongating and elongated spermatids of normal testes. Accompanied with degeneration of spermatogenesis (decrease in testicular and epididymal weights, as well as loss of germ cells in histological morphology), ICAM-1 expression declined significantly in the seminiferous tubules during a 4-week experimental period, particularly in the first 2 weeks (40 mg kg(-1) busulfan, single injection). Compared with the control group, busulphan-treated testes showed a significant increase in lipid peroxidation during weeks 1 and 2. Thus, ICAM-1 may play an important role in the homeostasis of spermatogenesis, and busulfan treatment can lead to adhesion disintegration.

  6. 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

  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.

  8. 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.

  9. 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.

  10. Low-dose cyclophosphamide-induced acute hepatotoxicity

    PubMed Central

    Subramaniam, S. Ravih; Cader, Rizna Abdul; Mohd, Rozita; Yen, Kong Wei; Ghafor, Halim Abdul

    2013-01-01

    Patient: Male, 48 Final Diagnosis: Low dose cyclophosphamide-induced acute hepatotoxicity Symptoms: Epigastric pain Medication: Withdrawal of cyclophosphamide Clinical Procedure: — Specialty: Nephrology • Hepatology • Gastroenterology • Toxicology Objective: Unexpected drug reaction Background: Cyclophosphamide is commonly used to treat cancers, systemic vasculitides, and kidney diseases (e.g., lupus nephritis and focal segmental glomerulosclerosis). Acute adverse effects include bone marrow suppression, hemorrhagic cystitis, nausea, vomiting, and hair loss. Hepatotoxicity with high dose cyclophosphamide is well recognized but hepatitis due to low dose cyclophosphamide has rarely been described. Case Report: We report the case of a 48-year-old Chinese man with a rapidly progressive glomerulonephritis secondary to granulomatosis with polyangiitis who developed severe acute hepatic failure within 24 hours of receiving low-dose intravenous cyclophosphamide. The diagnosis of granulomatosis with polyangiitis was supported with a positive c-ANCA serology. The patient was treated with high dose methylprednisolone, plasmapheresis, intermittent hemodialysis, and low-dose intravenous cyclophosphamide. Conclusions: Hepatotoxicity may occur even after low-dose intravenous cyclophosphamide treatment. To the best of our knowledge, this is the first report of severe, non-viral, liver inflammation developing within 24 hours of administration of low-dose intravenous cyclophosphamide (200 mg). Physicians should be aware of this serious adverse reaction and should not repeat the cyclophosphamide dose when there is hepatotoxicity caused by the first dose. Initial and follow-up liver function tests should be monitored in all patients receiving cyclophosphamide treatment. PMID:24023976

  11. Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation--what to do?

    PubMed

    Cowan, Morton J; Gennery, Andrew R

    2015-11-01

    Defects in DNA cross-link repair 1C (DCLRE1C), protein kinase DNA activated catalytic polypeptide (PRKDC), ligase 4 (LIG4), NHEJ1, and NBS1 involving the nonhomologous end-joining (NHEJ) DNA repair pathway result in radiation-sensitive severe combined immunodeficiency (SCID). Results of hematopoietic cell transplantation for radiation-sensitive SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of preconditioning with alkylating agents is associated with a greater likelihood of full T- and B-cell reconstitution compared with no conditioning or immunosuppression alone. A reduced-intensity regimen using fludarabine and low-dose cyclophosphamide might be effective for patients with LIG4, NHEJ1, and NBS1 defects, although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose-alkylating agents without significant late effects. Until nonchemotherapy agents, such as anti-CD45 or anti-CD117, become available, options include minimizing exposure to alkylators, such as single-agent low-dose targeted busulfan, or achieving T-cell reconstitution, followed several years later with a conditioning regimen to restore B-cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and graft-versus-host disease. Prospective multicenter studies are needed to evaluate these approaches in this rare but highly vulnerable patient population.

  12. Busulfan and total body irradiation as antihematopoietic stem cell agents in the preparation of patients with congenital bone marrow disorders for allogenic bone marrow transplantation

    SciTech Connect

    Parkman, R.; Rappeport, J.M.; Hellman, S.; Lipton, J.; Smith, B.; Geha, R.; Nathan, D.G.

    1984-10-01

    The capacity of busulfan and total body irradiation to ablate hematopoietic stem cells as preparation for the allogeneic bone marrow transplantation of patients with congenital bone marrow disorders was studied. Fourteen patients received 18 transplants; busulfan was used in the preparatory regimen of eight transplants and total body irradiation in the regimens of six transplants. Sustained hematopoietic ablation was achieved in six of eight patients prepared with busulfan and in all six patients prepared with total body irradiation. Three patients prepared with total body irradiation died with idiopathic interstitial pneumonitis, whereas no patients receiving busulfan developed interstitial pneumonitis. The optimal antihematopoietic stem cell agent to be used for the preparation of patients with congenital bone marrow disorder for bone marrow transplantation is not certain.

  13. High-Throughput Quantitation of Busulfan in Plasma Using Ultrafast Solid-Phase Extraction Tandem Mass Spectrometry (SPE-MS/MS).

    PubMed

    Langman, Loralie J; Danso, Darlington; Robert, Enger; Jannetto, Paul J

    2016-01-01

    Busulfan is a commonly used antineoplastic agent to condition/ablate bone marrow cells before hematopoietic stem cell transplant. While intravenous (IV) formulations of busulfan are now available and have lower incidences of toxicity and treatment related mortality compared to oral dosing, it still displays large pharmacokinetic variability. As a result, studies have shown that therapeutic drug monitoring is clinically useful to minimize graft failure, disease reoccurrence, and toxicities like veno-occlusive disease and neurologic toxicity. Current methods for assaying busulfan include the use of GC/MS, HPLC, and LC-MS/MS. The clinical need for faster turnaround times and increased testing volumes has required laboratories to develop faster methods of analysis for higher throughput of samples. Therefore, we present a method for the quantification of busulfan in plasma using an ultrafast SPE-MS/MS which has much faster sample cycle times (<20 s per sample) and comparable analytical results to GC/MS.

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

    ClinicalTrials.gov

    2016-11-14

    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)

  15. 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.

  16. Pulmonary toxicity of cyclophosphamide: a 1-year study

    SciTech Connect

    Morse, C.C.; Sigler, C.; Lock, S.; Hakkinen, P.J.; Haschek, W.M.; Witschi, H.P.

    1985-01-01

    The development of cyclophosphamide-induced pulmonary lesions over a 1-year period was studied in mice. Male BALB/c mice received a single intraperitoneal injection of 100 mg/kg of cyclophosphamide. Within 3 weeks there were scattered foci of intraalveolar foamy macrophages. With time, these foci increased in size and, 1 year later, occupied large areas in all lung lobes. There was also diffuse interstitial fibrosis. Chemical determination done 3, 12, 24, and 52 weeks after cyclophosphamide showed that lungs of animals treated with cyclophosphamide had significantly more hydroxyproline per lung than controls. One year after cyclophosphamide pressure - volume curves measured in vivo were shifted down and to the right and total lung volumes were decreased. A single injection of cyclophosphamide produced an irreversible and progressive pulmonary lesion. 16 references, 5 figures, 3 tables.

  17. Differential effects of busulfan on gonadal development in five divergent anuran species.

    PubMed

    Piprek, Rafał P; Pecio, Anna; Kubiak, Jacek Z; Szymura, Jacek M

    2012-11-01

    The aim of this paper was to investigate the effects of germ cell depletion on the sexual differentiation of gonads in five anuran species. We used busulfan to eliminate the germ cells. Our results indicate that germ cells are not required for gonadal ridge formation or the development of the undifferentiated gonads. We observed a gradual degeneration of gonads in studied species and the transdifferentiation of the whole gonads into large fat bodies in Xenopus laevis. In the latter the sexual differentiation of gonads or seminiferous tubules were not impaired in the absence of germ cells. Thus, the X. laevis may serve as a model to study the human Del Castillo syndrome. Our study shows that in anuran amphibians the germ cells are not necessary for the formation of the testis, but they are crucial for development of the ovaries and are required for the maintenance of the gonadal structure.

  18. Water Intoxication Following Low-Dose Intravenous Cyclophosphamide

    PubMed Central

    Koo, Tai Yeon; Bae, Sang-Cheol; Park, Joon Sung; Lee, Chang Hwa; Park, Moon Hyang; Kang, Chong Myung

    2007-01-01

    Cyclophosphamide is frequently used for the treatment of severe lupus nephritis, but is very rarely associated with dilutional hyponatremia. Recently we experienced a case of water intoxication following low-dose intravenous cyclophosphamide. Five hours after one dose of intravenous pulse cyclophosphamide 750 mg, the patient developed nausea, vomiting, and general weakness. Serum sodium concentration revealed 114 mEq/L and her hyponatremia was initially treated with hypertonic saline infusion. Then her serum sodium concentration rapidly recovered to normal with water restriction alone. During the course of intravenous pulse cyclophosphamide therapy, one must be aware of the possibility of significant water retention. PMID:24459501

  19. Water intoxication following low-dose intravenous cyclophosphamide.

    PubMed

    Koo, Tai Yeon; Bae, Sang-Cheol; Park, Joon Sung; Lee, Chang Hwa; Park, Moon Hyang; Kang, Chong Myung; Kim, Gheun-Ho

    2007-06-01

    Cyclophosphamide is frequently used for the treatment of severe lupus nephritis, but is very rarely associated with dilutional hyponatremia. Recently we experienced a case of water intoxication following low-dose intravenous cyclophosphamide. Five hours after one dose of intravenous pulse cyclophosphamide 750 mg, the patient developed nausea, vomiting, and general weakness. Serum sodium concentration revealed 114 mEq/L and her hyponatremia was initially treated with hypertonic saline infusion. Then her serum sodium concentration rapidly recovered to normal with water restriction alone. During the course of intravenous pulse cyclophosphamide therapy, one must be aware of the possibility of significant water retention.

  20. An HPLC-UV method for determining plasma dimethylacetamide concentrations in patients receiving intravenous busulfan.

    PubMed

    Cendana, Mildred; Lee, Samiuela; Upadhyay, Parth J; Byrne, Jennifer A; Shaw, Peter J; Earl, John; Nath, Christa E

    2016-12-07

    Dimethylacetamide (DMA) is a solvent used in the preparation of intravenous busulfan, an alkylating agent used in blood or marrow transplantation. DMA may contribute to hepatic toxicity, so it is important to monitor its clearance. The aim of this study was to develop an HPLC-UV assay for measurement of DMA in human plasma. After precipitation of plasma proteins with acetonitrile followed by dilution (1:4) with water, the extract was injected onto the HPLC and detected at 195 nm. Separation was performed using a Cogent-HPS 5 μm C18 column (250 × 4.6 mm) preceded by a Brownlee 7 μm RP18 , pre-column (1.5 cm × 3.2 mm). The mobile phase was 25 mm sodium phosphate buffer (pH 3), containing 2.5% (v/v) acetonitrile and 0.0005% (v/v) sodium-octyl-sulfonate. Using a flow rate of 1 mL/min, the retention times of DMA and the internal standard (IS), 2-chloroacetamide, were 9.5 and 3.5 min, respectively. Peak area ratio (DMA:IS) was a linear function of concentration from 1 to 1000 μg/mL. There was excellent intraday precision (<5% for 5-700 μg/mL DMA), accuracy (<3% deviation from the true concentration) and recovery (74-98%). The limits of detection and quantification were 1 and 5 μg/mL, respectively. In eight children who received intravenous busulfan, DMA concentrations ranged from 110 to 438 μg/mL.

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

    PubMed

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

    1981-01-01

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

  2. HLA Haplotype Mismatch Transplants and Posttransplant Cyclophosphamide.

    PubMed

    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.

  3. 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

  4. Phase I controlled trials of WR-2721 and cyclophosphamide

    SciTech Connect

    Glick, J.H.; Glover, D.; Weiler, C.; Norfleet, L.; Yuhas, J.; Kligerman, M.M.

    1984-09-01

    WR-2721 is an organic thiophosphate compound which in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Controlled Phase I trials of WR-2721 and cyclophosphamide were initiated to determine if WR-2721 protected against cyclophosphamide's hematolgic toxicity. Fifteen patients received WR-2721 prior to cyclophosphamide and were subsequently retreated 4 weeks later with the same cyclophosphamide dose alone. With WR-2721 pretreatment, 11/15 (73%) patients had improved WBC counts. In the second trial, 25 patients received the reverse sequence: an initial dose of cyclophosphamide alone, followed 4 weeks later by WR-2721 prior to the same dose of cyclophosphamide. With WR-2721 pretreatment, 12/25 (48%) patients had improved nadir WBC counts. No patient developed microscopic or gross hematuria or inappropriate antidiuretic hormone secretion. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced granulocytopenia, but the dose modification factors and degree of clinical benefit remain to be established. The current recommended WR-2721 dose for Phase II trials is 740 mg/m/sup 2/ administered over 15 minutes.

  5. Bioavailability of cyclophosphamide and vincristine after intraperitoneal administration in cats.

    PubMed

    Voorhorst, Marieke J; van Maarseveen, Erik M; van Lankveld, Adriaan J; Teske, Erik

    2014-11-01

    Cyclophosphamide and vincristine are widely used intravenous chemotherapeutic agents in both human and veterinary oncology. Although intravenous administration of these chemotherapeutics is the gold standard in most treatment protocols, this route of administration has several disadvantages (e.g. long infusion times and risk of extravasation). Therefore, alternative routes have been explored in the past. Recently, good clinical results were achieved with intraperitoneal (i.p.) administration of cyclophosphamide and vincristine in cats. However, the bioavailability following i.p. administration of cyclophosphamide and vincristine providing proof of principle has not been investigated and is the focus of the present study. The pharmacokinetics of cyclophosphamide and vincristine after i.p. and intravenous administration was investigated in six cats in a cross-over study by analysis of plasma levels of cyclophosphamide and vincristine after simultaneously administration of 0.6 mg/m vincristine and 200 mg/m cyclophosphamide. The median bioavailability on i.p. administration was 76% for cyclophosphamide and 100% for vincristine. Median areas under the curve for i.p. and intravenous administration were 11.4 and 16.0 ng h/ml for cyclophosphamide and 16.7 and 16.5 ng h/ml for vincristine, respectively. No specific i.p. administration-related adverse events were observed after i.p. administration. The high bioavailability of both cyclophosphamide and vincristine after i.p. administration and the absence of specific i.p. administration-related side effects suggest that i.p. administration is a suitable route of systemic chemotherapy for both chemotherapeutics. These results are promising and may serve as a stepping stone for the investigation of the pharmacology, safety, and efficacy of i.p. administration of cyclophosphamide and vincristine in humans.

  6. 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

  7. A New Harmonized Approach to Estimate Busulfan Exposure Predicts Survival and Toxicity after Hematopoietic Cell Transplantation in Children and Young Adults: a Multicenter Retrospective Cohort Analysis

    PubMed Central

    Bartelink, I.H.; Lalmohamed, Arief; van Reij, Elisabeth M.L.; Dvorak, Chris C.; Savic, Rada M.; Zwaveling, Juliette; Bredius, Robbert. G.M.; Egberts, Antoine C.G.; Bierings, M.; Kletzel, M.; Shaw, Peter J.; Nath, Christa E.; Hempel, George; Ansari, M.; Krajinovic, M.; Theoret, Yves; Duval, Michel; Keizer, Ron J.; Bittencourt, Henriette; Hassan, Moustapha; Güngör, Tayfun; Wynn, Robert F.; Veys, Paul; Cuvelier, Geoff D.E.; Marktel, Sarah; Chiesa, Robert; Cowan, Morton J.; Slatter, Mary A.; Stricherz, Melisa K.; Jennissen, Cathryn; Long-Boyle, Janel R.; Boelens, Jaap Jan

    2016-01-01

    Background Intravenous-busulfan (IV-busulfan) combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). The best method to estimate busulfan exposure and the optimal exposure in children/young adults remains unclear. We therefore evaluated three approaches to estimate IV-Bu exposure (expressed as cumulative-area-under-the-curve; AUC) and associated busulfan-AUC with clinical outcomes in children/young adults undergoing allo-HCT. Methods In this retrospective analysis, patients (0.1–30.4 years) receiving busulfan-based conditioning regimen from 15 centers were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modeling (AUCNONMEM), non-compartmental analysis (AUC0-infinity and AUC to the end of the dose interval AUC0-tau) and by individual centers using a variety of approaches (AUCcenter). Main outcome of interest was event-free survival (EFS). Other outcomes of interest were overall survival, graft-failure, relapse, transplantation related mortality (TRM), acute toxicity (veno-occlusive disease (VOD) and/or acute graft versus-host disease (aGvHD), chronic GvHD (cGvHD) and cGVHD-free event-free survival (GEFS). Propensity score adjusted cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions were used. Results 674 patients were included (41% malignant, 59% non-malignant) Estimated 2-year EFS was 69.7%. The median busulfan AUCNONMEM was 74.4 mg*h/L (CI95% 31.1–104.6 mg*h/L). The median AUCNONMEM correlated poorly with AUCcenter (R2 = 0.254). Patients with optimal IV-busulfan AUC of 78–101 mg*h/L showed 81% EFS at 2 years compared to 66.1% and 49.5% in the low (<78 mg*h/L) and high (>101 mg*h/L) busulfan AUC group respectively (P=0.011). Graft-failure/relapse occurred more frequently in the low AUC group (HR=1.75 P<0.001). Acute toxicity, cGvHD and TRM was significantly higher in the high AUC group (HR 1

  8. 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.

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

    PubMed

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

    2016-09-17

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

  10. Synergistic cytotoxicity of the DNA alkylating agent busulfan, nucleoside analogs and SAHA in lymphoma cell lines

    PubMed Central

    Valdez, Benigno C.; Murray, David; Nieto, Yago; Li, Yang; Wang, Guiyun; Champlin, Richard E.; Andersson, Borje S.

    2013-01-01

    Hematopoietic stem cell transplantation (HSCT) is a promising treatment for lymphomas. Its success depends on effective pre-transplant conditioning regimens. We previously reported on the efficacy of DNA alkylating agent-nucleoside analog (NA) combinations for conditioning in AML. We hypothesized that a similar combinatory approach can be used for lymphomas. A combination of busulfan (Bu) with two NAs – clofarabine (Clo), fludarabine (Flu) or gemcitabine (Gem) – resulted in synergistic cytotoxicity in lymphoma cell lines. We demonstrated that the [2 NAs+Bu] combination activates a DNA damage response through the ATM-CHK2 and ATM-CHK1 pathways, leading to cell cycle checkpoint activation and apoptosis. Histone modifications and KAP1 phosphorylation are indicative of chromatin relaxation mediated by the nucleoside analogs which sequentially increase Bu alkylation. Addition of suberoylanilide hydroxamic acid (SAHA) enhanced chromatin relaxation through increased histone acetylation and further augmented the cytotoxicity of [2 NAs+Bu]. Our results provide a preclinical basis for a clinical trial on using [2 NAs+Bu±SAHA] combinations as conditioning therapy for chemotherapy-refractory lymphoma patients undergoing HSCT. PMID:22023523

  11. Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update.

    PubMed

    Bacigalupo, A; Dominietto, A; Ghiso, A; Di Grazia, C; Lamparelli, T; Gualandi, F; Bregante, S; Van Lint, M T; Geroldi, S; Luchetti, S; Grasso, R; Pozzi, S; Colombo, N; Tedone, E; Varaldo, R; Raiola, A M

    2015-06-01

    This is a report of 148 patients with hematologic malignancies who received an unmanipulated haploidentical bone marrow transplant (BMT), followed by post-transplant high-dose cyclophosphamide (PT-CY). All patients received a myeloablative conditioning consisting of thiotepa, busulfan, fludarabine (n=92) or TBI, fludarabine (n=56). The median age was 47 years (17-74); 47 patients were in first remission (CR1), 37 in second remission (CR2) and 64 had an active disease; all patients were first grafts. The diagnosis was acute leukemia (n=75), myelodisplastic syndrome (n=24), myelofibrosis (n=16), high-grade lymphoma (n=15) and others (n=18). GVHD prophylaxis consisted in PT-CY on days +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median day for neutrophil engraftment was day +18 (13-32). The cumulative incidence of grades II-IV acute GVHD was 24%, and of grades III-IV GVHD 10%. The incidence of moderate-severe chronic GVHD was 12%. With a median follow-up for the surviving patients of 313 days (100-1162), the cumulative incidence of transplant-related mortality (TRM) is 13%, and the relapse-related death is 23%. The actuarial 22 months overall survival is 77% for CR1 patients, 49% for CR2 patients and 38% for patients grafted in relapse (P<0.001). Major causes of death were relapse (22%), GVHD (2%) and infections (6%). We confirm our initial results, suggesting that a myeloablative conditioning regimen followed by unmanipulated haploidentical BMT with PT-CY, results in a low risk of acute and chronic GVHD and encouraging rates of TRM and overall survival, also for patients with active disease at the time of transplant.

  12. Cyclophosphamide-associated enteritis: A rare association with severe enteritis

    PubMed Central

    Yang, Linda S; Cameron, Karla; Papaluca, Tim; Basnayake, Chamara; Jackett, Louise; McKelvie, Penelope; Goodman, David; Demediuk, Barbara; Bell, Sally J; Thompson, Alexander J

    2016-01-01

    Cyclophosphamide is a potent cytotoxic agent used in many clinical settings. The main risks of cyclophosphamide therapy include hematological disorders, infertility, hemorrhagic cystitis and malignancies. Gastrointestinal side effects reported to date are often non-specific and not severe. We present the first case of a fatal small bowel enteritis and pan-colitis which appears to be associated with cyclophosphamide. We aim to raise the readers’ awareness of this significant adverse event to facilitate clinical suspicion and early recognition in potential future cases. PMID:27818600

  13. The effect of cyclophosphamide on MSV-H oncogenesis.

    PubMed Central

    Branca, M.; Nicoletti, L.

    1977-01-01

    The effect of cyclophosphamide on MSV-H oncogensis and the immune response of young mice has been investigated. A single, sublethal dose (100 and 50 mg/kg of cyclophosphamide) in 8-day-old mice given 24 h before or after MSV-H infection led to an earlier and lower incidence of tumours in comparison with controls infected only with MSV-H. The protective effect of cyclophosphamide, and the mechanism of action of both cyclophosphamide and MSV-H on the target cells, mesenchymal cells in rapid replication, as well the immunological implications of the findings are discussed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:201258

  14. Conditioning with targeted busulfan for autologous peripheral blood stem cells transplantation for acute myelogenous leukemia in an XYY male.

    PubMed

    Sada, Eriko; Henzan, Hideho; Ohtani, Ryoko; Takase, Ken; Miyamoto, Toshihiro; Fukuda, Takahiro; Nagafuji, Koji; Yamauchi, Keita; Takamatsu, Yasushi; Inaba, Shoichi; Harada, Mine

    2005-01-01

    We report herein a 19-year-old Japanese male with XYY syndrome who developed acute myelogenous leukemia. During three courses of cytotoxic chemotherapy, he suffered repeated hepatic and renal insufficiencies, possibly related to latent dysfunction from the XYY syndrome. The patient was treated with granulocyte colony-stimulating factor combined with etoposide, cytarabine, and busulfan (the latter adjusted to a targeting dose) followed by autologous peripheral blood stem cell transplantation. He had no severe regimen-related toxicities and is now free of leukemia.

  15. Stability-indicating high-performance liquid chromatographic assay of busulfan in aqueous and plasma samples.

    PubMed

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

    1997-12-19

    A sensitive, specific and stability-indicating high-performance liquid chromatographic (HPLC) assay, involving pre-column derivatization and solid-phase extraction (SPE), was developed and validated for the quantitation of busulfan (BU) in aqueous and plasma samples. The linearity of the assay was in the concentration ranges of 0.15-10 microg/ml and 0.15-3 microg/ml for aqueous and plasma samples, respectively. The within-day and between-day variations were 2.90 and 3.31%, respectively, for the aqueous samples, and 9.24 and 14.56%, respectively, for the plasma samples. The overall recovery, derivatization yield and SPE efficiency of BU from plasma samples were 82.03, 108.01 and 86.69%, respectively. Forced degraded samples, either in highly acidic, neutral or basic medium, produced no interfering peaks in the chromatogram. The reported assay requires only 0.2 ml of plasma for the analysis, and its sensitivity is 150 ng/ml by monitoring samples at a wavelength of 254 nm, sufficient to study the plasma pharmacokinetics of BU in rats after a clinically relevant oral dose. Moreover, the sensitivity of the assay can be significantly increased to 30 ng/ml by monitoring samples at a wavelength of 278 nm. The applications of the assay were demonstrated with BU solubility measurements in two aqueous systems and with plasma samples from a Sprague-Dawley rat for an in vivo pharmacokinetic study. In addition, the assay has been employed in the development of a patented intravenous formulation, and in evaluations of stability, preclinical pharmacokinetics in rats and dogs, and clinical phase I trial of the formulation. The assay is readily adaptable to clinical therapeutic drug monitoring.

  16. Damage to rat spermatozoal DNA after chronic cyclophosphamide exposure.

    PubMed

    Qiu, J; Hales, B F; Robaire, B

    1995-12-01

    Treatment of male rats with low dosages of cyclophosphamide causes a dramatic increase in early embryo death among their progeny without significantly affecting the general health of the male. It is hypothesized that cyclophosphamide exerts its effects by targeting specific components of spermatozoal nuclei. The purpose of the present studies was to investigate the effects of chronic cyclophosphamide treatment on spermatozoal DNA. Two approaches were pursued. The first was to determine total DNA damage by using the alkaline elution method. The second was to study spermatozoal DNA template function by using an in vitro DNA synthesis system. Adult male rats were treated with saline or cyclophosphamide (6.1 mg/kg/day) daily for 1 or 6 wk. Cauda epididymal spermatozoa were collected and subjected to alkaline elution using DNA-DNA dot hybridization to quantify the fractionated DNA. One week of treatment with cyclophosphamide caused DNA single strand breaks that could be detected only in the presence of proteinase K in the lysis solution; no DNA cross-links were observed in the animals that received 1-wk drug treatment. In contrast, 6 wk of treatment with cyclophosphamide induced a significant increase in both DNA single strand breaks and cross-links in spermatozoal nuclei; the cross-links were attributable primarily to DNA-DNA linkages. The availability of spermatozoal DNA for template function was not affected by 1 wk of treatment with cyclophosphamide but was markedly affected after 6 wk of treatment with this drug. It is proposed that during chromatin transition processes the male genome may be in an open dynamic state with many exposed sites that are vulnerable to alkylating agents. Since there is no DNA repair during spermiogenesis, damage to the genome by alkylation at this stage may be cumulative, resulting in the production of dysfunctional germ cells.

  17. 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.

  18. The use of emoxipin for correction of cyclophosphamide cytotoxicity in experimental animals.

    PubMed

    Siprov, A V; Kinzirskaya, Yu A

    2008-07-01

    In experiments on animals with Lewis lung carcinoma, emoxipin decreased hematotoxicity of cyclophosphamide without reducing its antitumor efficiency (effect on primary tumor node). Combined administration of emoxipin and cyclophosphamide more effectively prevented the development of metastases compared to cytostatic monotherapy.

  19. Repetitive busulfan administration after hematopoietic stem cell gene therapy associated with a dominant HDAC7 clone in a nonhuman primate.

    PubMed

    Xie, Jianjun; Larochelle, Andre; Maric, Irina; Faulhaber, Marion; Donahue, Robert E; Dunbar, Cynthia E

    2010-06-01

    The risk of genotoxicity of retroviral vector-delivered gene therapy targeting hematopoietic stem cells (HSCs) has been highlighted by the development of clonal dominance and malignancies in human and animal gene therapy trials. Large-animal models have proven invaluable to test the safety of retroviral vectors, but the detection of clonal dominance may require years of follow-up. We hypothesized that hematopoietic stress may accelerate the proliferation and therefore the detection of abnormal clones in these models. We administered four monthly busulfan (Bu) infusions to induce hematopoietic stress in a healthy rhesus macaque previously transplanted with CD34+ cells transduced with retroviral vectors carrying a simple marker gene. Busulfan administration resulted in significant cytopenias with each cycle, and prolonged pancytopenia after the final cycle with eventual recovery. Before busulfan treatment there was highly polyclonal marking in all lineages. After Bu administration clonal diversity was markedly decreased in all lineages. Unexpectedly, we found no evidence of selection of the MDS1/EVI1 clones present before Bu administration, but a clone with a vector integration in intron 1 of the histone deacetylase-7 (HDAC7) gene became dominant in granulocytes over time after Bu administration. The overall marking level in the animal was increased significantly after Bu treatment and coincident with expansion of the HDAC7 clone, suggesting an in vivo advantage for this clone under stress. HDAC7 expression was upregulated in marrow progenitors containing the vector. Almost 5 years after Bu administration, the animal developed progressive cytopenias, and at autopsy the marrow showed complete lack of neutrophil or platelet maturation, with a new population of approximately 20% undifferentiated blasts. These data suggest that chemotherapeutic stress may accelerate vector-related clonal dominance, even in the absence of drug resistance genes expressed by the vector

  20. Cyclophosphamide and Doxorubicin Induced Melanonychia: A Case Report

    PubMed Central

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

    2017-01-01

    Chemotherapeutic agents may rarely cause discoloration and hyperpigmentation of the nails. We present a patient who developed blackish discoloration of nails also referred as melanonychia during six cycles of R-CHOP chemotherapy regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) for the treatment of Non Hodgkin Lymphoma (NHL) follicular type. The patient developed blackish brown discoloration in all the nails. As suggested by previous literature evidence the melanonychia could be associated with cyclophosphamide and doxorubicin. According to the Naranjo causality assessment scale, we established that there was a ‘probable’ association of nail discoloration with the drug. PMID:28273993

  1. Cyclophosphamide in the treatment of toxic epidermal necrolysis.

    PubMed

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

    1996-10-01

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

  2. Busulfan and melphalan as conditioning regimen for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia in first complete remission

    PubMed Central

    Bueno, Nadjanara Dorna; Dulley, Frederico Luiz; Saboya, Rosaura; Amigo Filho, José Ulysses; Coracin, Fabio Luiz; Chamone, Dalton de Alencar Fischer

    2011-01-01

    Background Allogeneic hematopoietic stem cell transplantation with HLA-identical donors has been established for the treatment of acute myeloid leukemia patients for over 30 years with a cure rate of 50% to 60%. Objectives To analyze the overall survival of patients and identify factors that influence the outcomes of this type of transplant in patients in 1st complete remission who received a busulfan and melphalan combination as conditioning regimen. Methods Twenty-five consecutive patients with acute myeloid leukemia were enrolled between 2003 and 2008. The median age was 34 years old (Range: 16 - 57 years). All patients received cyclosporine and methotrexate for prophylaxis against graft-versus-host disease. Median neutrophil engraftment time was 16 days (Range: 7 - 22 days) and 17 days (Range: 7 - 46 days) for platelets. Sinusoidal obstructive syndrome was observed in three patients, seven had grade II acute graft-versus-host disease and one extensive chronic graft-versus-host disease. Results The overall survival by the Kaplan-Meier method was 48% after 36 months with a plateau at 36 months after transplantation. Intensive consolidation with high-dose arabinoside resulted in an improved survival (p-value = 0.0001), as did grade II acute graft-versus-host disease (p-value = 0.0377) and mild chronic graft-versus-host disease (p-value < 0.0001). Thirteen patients died, five due to infection within 100 days of transplant, two due to hemorrhages, one to infection and graftversus-host disease and three relapses followed by renal failure (one) and infection (two). The cause of death could not be determined for two patients. Conclusion The busulfan and melphalan conditioning regimen is as good as other conditioning regimens providing an excellent survival rate. PMID:23049292

  3. 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

  4. Long-Term Cyclophosphamide Treatment in a Case with Serpiginous Choroiditis.

    PubMed

    Sahin, Ozlem G

    2010-10-05

    PURPOSE: To report the effect of long-term therapy with the alkylating agent cyclophosphamide in a case with serpiginous choroiditis and thus to contribute to the previously reported few cases showing the beneficial effect of long-term cyclophosphamide therapy for serpiginous choroiditis. PROCEDURES: Oral cyclophosphamide therapy for 12 months in a case with unilateral active serpiginous choroiditis. RESULTS: The active lesion responded well to long-term therapy with cyclophosphamide without recurrences and significant systemic side-effects. CONCLUSIONS: Long-term therapy with cyclophosphamide for serpiginous choroiditis is effective for improving vision and preventing recurrences.

  5. Clinicopathologic features of late-onset veno-occlusive disease/sinusoidal obstruction syndrome after high dose intravenous busulfan and hematopoietic cell transplant.

    PubMed

    Pai, Rish K; van Besien, Koen; Hart, John; Artz, Andrew S; O'Donnell, Peter H

    2012-08-01

    Most cases of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) occur <21 days after allogeneic hematopoietic stem cell transplant (HCT). Rarely, however, VOD/SOS can occur later, and can be confused with other causes. We report the clinicopathologic features of eight patients with advanced hematologic malignancies developing VOD/SOS >30 days after dose-escalated busulfan/fludarabine/alemtuzumab and HCT. Median time to diagnosis was 52 days (range: 33-77). For seven patients, VOD/SOS was confirmed by liver biopsies showing classical features including reticulin deposition within sinusoids, central vein occlusions, hepatocyte atrophy/necrosis, sinusoidal/perivenular hemorrhage and sparing of portal tracts. VOD/SOS risk was directly related to higher busulfan plasma exposures. Two patients died from VOD/SOS, and in another two patients VOD/SOS was contributory to death. Late-onset VOD/SOS may be underrecognized and should be considered in the differential diagnosis of patients undergoing HCT, particularly after high dose busulfan. Liver biopsy should be entertained even late in the course if appropriate signs/symptoms exist.

  6. Role of recombinant human erythropoietin loading chitosan-tripolyphosphate nanoparticles in busulfan-induced genotoxicity: Analysis of DNA fragmentation via comet assay in cultured HepG2 cells.

    PubMed

    Ghassemi-Barghi, Nasrin; Varshosaz, Jaleh; Etebari, Mahmoud; Jafarian Dehkordi, Abbas

    2016-10-01

    Busulfan is one of the most effective chemotherapeutic agents used for the treatment of chronic myeloid leukemia. Busulfan is involved in secondary malignancy due to its genotoxic potential in normal tissues. As an alkylating agent busulfan can cause DNA damage by cross-linking DNAs and DNA and proteins, induces senescence in normal cells via transient depletion of intracellular glutathione (GSH) and subsequently by a continuous increase in reactive oxygen species (ROS) production. Erythropoietin, a glycoprotein widely used against drug induced anemia in cancerous patients and regulates hematopoiesis, has been shown to exert an important cyto-protective effect in many tissues. Recombinant human erythropoietin has been demonstrated to directly limit cell injury and ROS generation during oxidative stress. Furthermore, rhEPO decreased levels of pro-apoptotic factor (Bax) and also increased expression of the anti-apoptotic factor Bcl2. According to EPO's short half-life and requirements for the frequently administration, finding the new strategies to attenuate its side effects is important. The aim of this study was to explore whether rhEPO loading chitosan-tripolyphosphate nanoparticles protects against busulfan-induced genotoxicity in HepG2 cells. For this purpose cells were incubated with busulfan alone, regular rhEPO alone and regular rhEPO and CS-TPP-EPO nanoparticles along with busulfan in pre and co-treatment condition. Our results showed that busulfan induced a noticeable genotoxic effects in HepG2 cells (p<0.0001). Both regular rhEPO and CS-TPP-EPO nanoparticles reduced the effects of busulfan significantly (p<0.0001) by reduction of the level of DNA damage via blocking ROS generation, and enhancement intracellular glutathione levels. CS-TPP-EPO nanoparticles were more effective than regular rhEPO in both pre and co-treatment conditions. In conclusion, our results show that administration of rhEPO and CS-TPP-EPO nanoparticles especially in the pre

  7. Protective effect of berberine on cyclophosphamide-induced haemorrhagic cystitis in rats.

    PubMed

    Xu, X; Malavé, A

    2001-05-01

    The urotoxicity of cyclophosphamide and the protective effect of the herb berberine were investigated in this study. Administration of 150 mg/kg cyclophosphamide intraperitoneally caused a serious haemorrhagic cystitis in rats after 12 hr, including bladder oedema, haemorrhage, and dramatic elevation of nitric oxide metabolites (nitrite+nitrate) in urine and in plasma. To explore whether cyclophosphamide-induced cystitis could be prevented by berberine, rats were pretreated with a single dose or two doses of berberine at 50, 100, or 200 mg/kg intraperitoneally then challenged with cyclophosphamide (150 mg/kg, intraperitoneally). The results indicated that pretreatment of rats with berberine could reduce cyclophosphamide-induced cystitis in a dose-dependent manner. Furthermore, we found that two doses of berberine showed greater protection against cyclophosphamide urotoxicity than when given a single dose. In addition, our data shows that a single dose of 200 mg/kg berberine, or two doses of 100, and 200 mg/kg berberine could completely block cyclophosphamide-induced bladder oedema and haemorrhage, as well as nitric oxide metabolites increase in rat urine and plasma. In conclusion, our findings suggest that berberine could be a potential effective drug in the treatment of cyclophosphamide-induced cystitis, and provides us with the bright hope in the prevention and treatment of cyclophosphamide urotoxicity.

  8. Successful engraftment of mismatched unrelated cord blood transplantation following reduced intensity preparative regimen using fludarabine and busulfan.

    PubMed

    Komatsu, Tsunehiko; Narimatsu, Hiroto; Yoshimi, Ai; Kurita, Naoki; Kusakabe, Manabu; Hori, Akiko; Murashige, Naoko; Matsumura, Tomoko; Kobayashi, Kazuhiko; Yuji, Koichiro; Tanaka, Yuji; Kami, Masahiro

    2007-01-01

    We conducted a pilot study to evaluate the feasibility of reduced-intensity cord blood transplantation (RI-CBT) using a non-total body irradiation (TBI) regimen in adult patients with advanced hematologic malignancies. Seventeen patients with a median age of 58 years (range, 38-74) underwent RI-CBT at Tsukuba Memorial Hospital between April 2004 and November 2005. Preparative regimens were fludarabine 30 mg/m(2) for 6 days, and busulfan 4 mg/kg for 2 days. Tacrolimus was used for prophylaxis of graft-vs-host disease (GVHD). Median numbers of infused total nucleated were 2.6 x 10(7)/kg (range, 2.0-3.3). HLA disparity was found in 2/6 antigens (n=16) and 1/6 antigens (n=1). Underlying diseases progressed despite preparative regimens in four patients. Of the remaining 13 patients, nine patients achieved engraftment at a median of day 18 (range, 17-28). Six of the nine patients with engraftment achieved complete donor-type chimerism by day 100. Six patients were alive in remission at median follow-up of 13.1 months (range, 1.0-19.0). This study demonstrated the feasibility of RI-CBT using a non-TBI regimen in adults. When disease progression is controlled by the preparative regimen, RI-CBT carries a clinically significant graft-vs-tumor effect. Further studies are required to identify patients who benefit from this regimen.

  9. Radiation

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    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...

  10. Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study

    PubMed Central

    Lahuerta, Juan José; Mateos, Maria Victoria; Martínez-López, Joaquin; Grande, Carlos; de la Rubia, Javier; Rosiñol, Laura; Sureda, Anna; García-Laraña, José; Díaz-Mediavilla, Joaquín; Hernández-García, Miguel T.; Carrera, Dolores; Besalduch, Joan; de Arriba, Felipe; Oriol, Albert; Escoda, Lourdes; García-Frade, Javier; Rivas-González, Concepción; Alegre, Adrían; Bladé, Joan; San Miguel, Jesús F.

    2010-01-01

    Background The aim of this study was to compare the long-term safety and efficacy of oral busulfan 12 mg/kg plus melphalan 140 mg/m2 and melphalan 200 mg/m2 as conditioning regimens for autologous stem cell transplantation in newly diagnosed patients with multiple myeloma in the GEM2000 study. Design and Methods The first 225 patients received oral busulfan 12 mg/kg plus melphalan 140 mg/m2; because of a high frequency of veno-occlusive disease, the protocol was amended and a further 542 patients received melphalan 200 mg/m2. Results Engraftment and hospitalization times were similar in both groups. Oral busulfan 12 mg/kg plus melphalan 140 mg/m2 resulted in higher transplant-related mortality (8.4% versus 3.5%; P=0.002) due to the increased frequency of veno-occlusive disease in this group. Response rates were similar in both arms. With respective median follow-ups of 72 and 47 months, the median progression-free survival was significantly longer with busulfan plus melphalan (41 versus 31 months; P=0.009), although survival was similar to that in the melphalan 200 mg/m2 group. However, access to novel agents as salvage therapy after relapse/progression was significantly lower for patients receiving busulfan plus melphalan (43%) than for those receiving melphalan 200 mg/m2 (58%; P=0.01). Conclusions Conditioning with oral busulfan 12 mg/kg plus melphalan 140 mg/m2 was associated with longer progression-free survival but equivalent survival to that achieved with melphalan 200 mg/m2 but this should be counterbalanced against the higher frequency of veno-occlusive disease-related deaths. This latter fact together with the limited access to novel salvage therapies in patients conditioned with oral busulfan 12 mg/kg plus melphalan 140 mg/m2 may explain the absence of a survival difference. Oral busulfan was used in the present study; use of the intravenous formulation may reduce toxicity and result in greater efficacy, and warrants further investigation in myeloma

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

    PubMed

    1987-08-15

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

  12. [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.

  13. 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

  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. Ultrastructural Changes in Murine Peritoneal Cells Following Cyclophosphamide Administration

    PubMed Central

    Chin, K. N.; Hudson, G.

    1974-01-01

    Peritoneal cells were studied at intervals of between 6 h and 30 days following a single intravenous injection of a sublethal dose of cyclophosphamide. With the electron microscope, evidence of cell damage and death could be seen at 6 h, and by 12 h large numbers of dead cells were noted, either lying free or within the cytoplasm of macrophages. Most of the damaged cells were lymphocytes but degenerating blast cells, eosinophils, neutrophils and mast cells were also identified. Nuclei were seen in which margination of chromatin had occurred but nuclei of uniform density were also prominent and showed irregular shape and lobulation. Macrophages exhibited all stages of phagocytosis and digestion and a few phagocytes of atypical appearance were noted. By 24 h most of the dead cells lay within the cytoplasm of macrophages which showed many phagocytic inclusions as well as lipid droplets. By 6 days, the peritoneal cells had regained normal appearances although the proportion of lymphoid cells was still reduced. By the 18th day, all features were indistinguishable from normal. The changes observed showed a general similarity to those noted previously in the lymphoreticular cells of the Peyer's patch; they provide no evidence that the environment of the peritoneal cavity protects cells against the action of cyclophosphamide. ImagesFigs. 4-6Figs. 7-9Figs. 10-12Figs. 1-3 PMID:4447790

  16. 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

  17. 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.

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

    PubMed

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

    2011-07-01

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

  19. Lung damage following bone marrow transplantation. II. The contribution of cyclophosphamide

    SciTech Connect

    Varekamp, A.E.; de Vries, A.J.; Zurcher, C.; Hagenbeek, A.

    1987-10-01

    The effect of high-dose cyclophosphamide (Cy), either alone or in combination with irradiation, upon the development of interstitial pneumonitis (IP) after bone marrow transplantation (BMT) was investigated in a Brown Norway rat model. The parameters that were examined included ventilation rate, mortality, and histopathology. No damage to the lungs was observed in rats given Cy alone in supralethal dosages plus BMT, and mortality resulted from severe aplasia of hemopoietic and lymphoid tissues with multifocal hemorrhages, secondary infections, and sepsis. Two separate periods of mortality were observed within the first 180 days following whole thorax irradiation with a high dose rate (HDR; 0.8 Gy/min) or a low dose rate (LDR; 0.05 Gy/min). The addition of Cy prior to irradiation resulted in an increased mortality in the first period (before day 100) in all experimental groups. The influence of Cy on mortality at 180 days however, was different for the HDR and LDR experiments. The LD50-180 after HDR irradiation, dose range 8 to 18 Gy, was not significantly altered by the addition of Cy (100 mg/kg) 1 day prior to irradiation, whereas Cy (100 mg/kg) 1 day prior to LDR irradiation, dose range: 16 to 24 Gy, caused an enhancement of radiation damage with a decrease of the LD50-180 by 1.33 Gy. The dose modification factor (DMF) was 1.07. This enhancement was no longer significant after splitting up the dose of Cy in two dosages of 50 mg/kg given on 2 consecutive days prior to irradiation with a LDR. The extrapolation of the data in this rat model to available dose-response curves on IP after BMT and radiation pneumonitis in humans, implied that non-infectious IP is a radiation pneumonitis that is only slightly enhanced by Cy.

  20. Recrudescence of Anaplasma marginale induced by immunosuppression with cyclophosphamide.

    PubMed

    Corrier, D E; Wagner, G G; Adams, L G

    1981-01-01

    Eight doses of cyclophosphamide (5 mg/kg), at 2-day intervals between doses, were administered IV to Anaplasma-carrier splenectomized calves. Significant decreases in serum immunoglobulins, diminished complement-fixing antibody response, and transitory leukopenia were associated with the treatment. Recrudescence of clinical Anaplasma infection occurred after the 5th dose of cyclophosphate was given and was characterized by rapid increase in parasitemia, marked decrease in PCV, and mortality. The results of the present study indicated that humoral mediated immunity may contribute to the maintenance of a state of equilibrium in the host-parasite relationship and that suppression of humoral immune responses may alter the course and outcome of infection in Anaplasma carriers.

  1. Effect of millimeter waves on cyclophosphamide induced suppression of the immune system.

    PubMed

    Logani, Mahendra K; Anga, Altaf; Szabo, Imre; Agelan, Alexis; Irizarry, Armando R; Ziskin, Marvin C

    2002-12-01

    The effect of millimeter electromagnetic waves (MWs) on cyclophosphamide (CPA) induced toxicity to leukocytes, bone marrow cells, and T-cell-mediated immunity was examined. For studying the effect of MWs on CPA induced leukopenia and myelosuppression, BALB/C mice were irradiated for 3 days, 30 min each day, prior to administration of CPA (200 mg/kg). MWs were produced with a Russian made YAV-1 generator. The device produced 42.2 +/- 0.2 GHz modulated wave radiation through a 10 mm x 20 mm rectangular output horn. The animals were irradiated on the nose area. Peak SAR and incident power density were measured as 622 +/- 100 W/kg and 31 +/- 5 mW/cm(2), respectively. For studying the effect of MWs on CPA induced suppression of T-cell mediated immunity, a delayed type hypersensitivity (DTH) assay in mouse skin was used. The DTH reaction in mouse skin was induced by topical application of dinitrochlorobenzene (DNCB) and quantified by measuring the increase in ear thickness and by histological examination. Treatment of animals with CPA significantly (P < 0.05) reduced leukocyte and bone marrow cell population, but MW irradiation did not show any significant protection from the immunosuppressive effects of CPA. Furthermore, MW irradiation did not protect the animals from CPA induced suppression of T-cell mediated immunity.

  2. Combined millimeter wave and cyclophosphamide therapy of an experimental murine melanoma.

    PubMed

    Logani, Mahendra K; Bhanushali, Ashok; Anga, Altaf; Majmundar, Amar; Szabo, Imre; Ziskin, Marvin C

    2004-10-01

    The objective of the present studies was to investigate whether millimeter wave (MMW) therapy can increase the efficacy of cyclophosphamide (CPA), a commonly used anti-cancer drug. The effect of combined MMW-CPA treatment on melanoma growth was compared to CPA treatment alone in a murine model. MMWs were produced with a Russian made YAV-1 generator. The device produced 42.2 +/- 0.2 GHz modulated wave radiation through a 10 x 20 mm rectangular output horn. The animals, SKH-1 hairless female mice, were irradiated on the nasal area. Peak SAR and incident power density were measured as 730 +/- 100 W/kg and 36.5 +/- 5 mW/cm2, respectively. The maximum skin surface temperature elevation measured at the end of 30 min irradiation was 1.5 degrees C. B16F10 melanoma cells (0.2 x 10(6)) were implanted subcutaneously into the left flank of mice on day 1 of the experiment. On days 4-8, CPA was administered intraperitoneally (30 mg/kg/day). MMW irradiation was applied concurrently with, prior to or following CPA administration. A significant reduction (P < .05) in tumor growth was observed with CPA treatment, but MMW irradiation did not provide additional therapeutic benefit as compared to CPA alone. Similar results were obtained when MMW irradiation was applied both prior to and following CPA treatment.

  3. Phase II Study of CD4+-Guided Pentostatin Lymphodepletion and Pharmacokinetically Targeted Busulfan as Conditioning for Hematopoietic Cell Allografting

    PubMed Central

    Kharfan-Dabaja, Mohamed A.; Anasetti, Claudio; Fernandez, Hugo F.; Perkins, Janelle; Ochoa-Bayona, Jose L.; Pidala, Joseph; Perez, Lia E.; Ayala, Ernesto; Field, Teresa; Alsina, Melissa; Nishihori, Taiga; Locke, Frederick; Pinilla-Ibarz, Javier; Tomblyn, Marcie

    2015-01-01

    One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4+ lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ≥50% CD3+ donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m2 i.v. on days −28, −21, and −14 when the CD4+ cell count was >100 cells/µL and on days −4 and −3 regardless of CD4+ level. Rituximab 375 mg/m2 was administered to patients with CD20+ malignancies on days −21, −14, −7, +1, and +8. Busulfan 200 mg/m2 i.v. was administered on days −4 and −2 at a dose to target a cumulative AUC dose of 16,000 (−10%) µmol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4+ cell count decrease from baseline (day −28) was 52% to day −21, 66% to day −14, 62% to day −7, and 91% to day 0. At day +28, all 42 patients (100%) had ≥50% CD3+ donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II–IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Non-relapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse. PMID:23632090

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

    PubMed

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

    2017-01-13

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

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

    PubMed

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

    2014-08-01

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

  6. Ovarian failure in systemic lupus erythematosus patients treated with pulsed intravenous cyclophosphamide.

    PubMed

    Katsifis, G E; Tzioufas, A G

    2004-01-01

    Pulsed intravenous cyclophosphamide is considered as standard therapy for lupus nephritis and several other severe manifestations of systemic lupus erythematosus (SLE). While the response rate to intravenous cyclophosphamide is substantial, concern has arisen about its toxicity. In addition to increased susceptibility to infection, bone marrow suppression, alopecia, hemorrhagic cystitis and malignancy, ovarian failure is an important side effect associated with the use of cyclophosphamide. Prior research on cyclophosphamide-treated women has consistently demonstrated that the risk of sustained amenorrhea depends on the age of the patient and the cumulative dose received. Sustained amenorrhea is difficult to avoid in women 32 years or older, even with very short intravenous cyclophosphamide courses. Younger women seem to have a substantially lower incidence of ovarian failure, but this side effect may be far more problematic for these patients. In these young women the risk may be modulated by the prior SLE disease duration, the presence of anti-U1RNP antibodies and anti-Ro antibodies. Co-treatment with gonadotropin-releasing hormone agonists may preseserve the future fertility and ovarian function in young women. Ovarian banking before administration of cyclophosphamide should be considered in selected patients.

  7. 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.

  8. Veno-occlusive disease of the liver after high-dose cytoreductive therapy with busulfan and melphalan for autologous blood stem cell transplantation in multiple myeloma patients.

    PubMed

    Carreras, Enric; Rosiñol, Laura; Terol, Maria José; Alegre, Adrián; de Arriba, Felipe; García-Laraña, José; Bello, José Luis; García, Raimundo; León, Angel; Martínez, Rafael; Peñarrubia, M Jesús; Poderós, Concha; Ribas, Paz; Ribera, Josep Maria; San Miguel, Jesús; Bladé, Joan; Lahuerta, Juan José

    2007-12-01

    Veno-occlusive disease of the liver (VOD) is a potentially severe complication of high-dose cytoreductive therapy (HDT) used for stem cell transplantation (SCT). This complication is uncommon after HDT for autologous SCT (ASCT) in patients with multiple myeloma (MM). The Spanish Myeloma Group/PETHEMA conducted a study (MM2000) for patients with newly diagnosed MM consisting of induction with alternating VBMCP/VBAD chemotherapy followed by intensification with busulfan/melphalan (Bu/MEL) with a second high-dose therapy procedure in patients not achieving at least near-complete remission with the first procedure. After 2 years of the trial, a number of episodes resembling classical VOD but with a late onset were recognized. Consequently, the protocol was modified, and Bu/MEL was replaced by melphalan 200 mg/m(2) (MEL-200). Three years later, after a total of 734 patients had undergone first autologous SCT, the incidence and characteristics of VOD episodes were analyzed in the whole series. Nineteen cases of VOD (8%) were observed among the first 240 patients receiving Bu/MEL, whereas only 2 (0.4%) were observed among the 494 patients treated with MEL-200 (P < .0001). VOD manifestations in the Bu/MEL group appeared at a median of 29 days (range, 3-57 days) after ASCT. Mortality directly attributable to VOD was 2% in the Bu/MEL group and 0.2% in the MEL-200 group (P = .026). This high incidence of severe VOD probably had a multifactorial origin (busulfan followed by melphalan and previous use of BCNU). This observation should be kept in mind when designing future trials for the treatment of MM.

  9. Congenital Malformations Attributed to Prenatal Exposure to Cyclophosphamide.

    PubMed

    Rengasamy, Padmanabhan

    2016-12-06

    Cyclophosphamide (CPA) remains one of the most widely prescribed anticancer drugs. It is also used in the treatment of rheumatoid arthritis, childhood nephrotic syndrome and systemic lupus erythematosus. It is a potent immunosuppressive agent. It is commonly used in blood and bone marrow transplantation. With the growing trend among women postponing childbearing, the number of women who are diagnosed with breast cancer is also increasing thus escalating the chances of exposure of the unborn child to antineoplastic drugs. A review of the literature provides strong evidence for the teratogenic effects on infants prenatally exposed to CPA. Both sporadic case reports and larger case series have demonstrated that babies with cyclophosphamide embryopathy are afflicted with intrauterine growth restriction, small for gestational age, and craniofacial malformations including eye anomalies, cleft/arched palate, hydrocephaly, micrognathia, low set microtia, hearing defects, craniosynostosis, and facial asymmetry. Also observed in these cases are limb defects such as radial, ulnar and tibial hypoplasia, club foot, digital defects of the hand and feet as well as vertebral fusion, brevicolis, and occasional Sprengel's deformity. These anomalies vary in consistency of occurrence and severity of the phenotype across cases and lack the specificity of thalidomide embryopathy or rubella embryopathy. However, that they do occur is no longer in doubt. First trimester of pregnancy seems to be particularly susceptible to fetal malformations, although CPA effects on fetuses of later stages of gestation (hearing defects, growth restriction for example) are also reported occasionally. One of the major concerns from a mechanistic point of view is our inability to dissect the teratogenic effects of CPA from those of other drugs administered together with CPA as combination therapy. Animal experiments have been of particular value in that they are able to circumvent the numerous extraneous

  10. Risk factors for development of sterile haemorrhagic cystitis in canine lymphoma patients receiving oral cyclophosphamide: a case-control study.

    PubMed

    Gaeta, R; Brown, D; Cohen, R; Sorenmo, K

    2014-12-01

    Sterile haemorrhagic cystitis (SHC) is a known risk of cyclophosphamide treatment; however, most canine reports are case series. This case-control study examined risk factors for SHC in dogs with lymphoma receiving oral cyclophosphamide. Twenty-two dogs with SHC and 66 control dogs were identified. On univariate analysis, SHC risk factors included age (P = 0.041), induction protocol (P = 0.021) and cumulative cyclophosphamide dose (P = 0.002). On multivariate analysis, increasing cumulative cyclophosphamide dose was associated with increased risk of SHC and the 'short' induction protocol (protocol 1) was associated with decreased risk. Controlling for age and induction protocol, odds of SHC increased by 2.21 per 750 mg m(-2) increase in cyclophosphamide dose (P = 0.001). SHC from oral cyclophosphamide is a predominately delayed toxicity resulting from high cumulative doses.

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

    PubMed

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

    1998-01-01

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

  12. 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.

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

    PubMed

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

    2015-07-01

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

  14. 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

    2003-03-03

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

  15. Restraint stress augments antibody production in cyclophosphamide-treated mice.

    PubMed

    Karp, J D; Smith, J; Hawk, K

    2000-01-01

    These studies evaluated the effects of a psychological stressor (restraint, RST) on antibody production in male BALB/cByJ mice. In Experiment 1, mice were immunized with keyhole limpet hemocyanin (KLH, 100 microg i.p.) 8 h prior to 15 h of RST or food and water deprivation (FWD). RST mice exhibited higher serum anti-KLH IgM and IgG antibodies than FWD mice. In Experiment 2, mice were given either cyclophosphamide (CY, 15 mg/kg) or saline (SAL) prior to immunization with KLH and RST or FWD. ANOVA revealed serum anti-KLH IgG antibody titers in CY+RST animals to be significantly higher than in CY+FWD, SAL+FWD, and SAL+RST mice. Anti-KLH IgM titers of CY+RST mice were higher than those of other groups before and after a second immunization with KLH. In Experiment 3, we show that these changes in antibody production are not likely to be mediated via CY-induced alterations in the reactivity of the hypothalamo-pituitary-adrenal axis to RST. Together, these results indicate two potentially immunomodulatory parameters (RST and CY) can interact to alter a humoral immune response. In addition, these data support the hypothesis that humoral immune response of mice can be more reactive to stress when the mice are given a low dose of an immunomodulatory drug prior to stressor exposure.

  16. 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.

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

    PubMed

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

    2014-10-24

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

  18. 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

  19. 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

  20. Promotion of the Toxic Action of Cyclophosphamide by Digestive Tract Luminal Ammonia in Rats

    PubMed Central

    Ivnitsky, Jury Ju.; Schäfer, Timur V.; Rejniuk, Vladimir L.

    2011-01-01

    To estimate the influence of the digestive tract luminal ammonia pool on acute toxic effects of cyclophosphamide, the dynamics of blood ammonia, glutamine and urea level, symptoms of toxic action and the survival time have been studied in rats, intraperitoneally treated with cyclophosphamide, at the background of the gavage with non-lethal dose of ammonium acetate (12 mmol/kg, i.e., 0.35 LD50). Ammonium acetate enhanced the hyperammonaemic action of cyclophosphamide while promoting its lethal action: the mean survival time decreased 1.5, 2.1, 2.8, or 6.1 times at the background of cyclophosphamide i/p doses 200, 600, 1000, or 1400 mg/kg, respectively. Animals exposed to the combination of toxicants, manifested symptoms which were characteristic of the effect of lethal doses of ammonia salts. These data provide the evidence of the detrimental role of gastrointestinal luminal ammonia in the acute high-dose cyclophosphamide toxicity. PMID:23724282

  1. Activation of Nrf2-ARE signaling mitigates cyclophosphamide-induced myelosuppression.

    PubMed

    Que, Linling; He, Liu; Yu, Chenshu; Yin, Wencheng; Ma, Liwen; Cao, Baoshan; Yu, Siwang

    2016-11-16

    Myelosuppression is the most common dose-limiting adverse effect of chemotherapies. In the present study, we investigated the involvement of nuclear erythroid 2-related factor 2 (Nrf2) in cyclophosphamide-induced myelosuppression in mice, and evaluated the potential of activating Nrf2 signaling as a preventive strategy. The whole blood from Nrf2(-/-) mice exhibited decreased antioxidant capacities, while the bone marrow cells, peripheral blood mononuclear cells and granulocytes from Nrf2(-/-) mice were more susceptible to acrolein-induced cytotoxicity than those from wild type mice. Single dosage of cyclophosphamide induced significantly severer acute myelosuppression in Nrf2(-/-) mice than in wild type mice. Furthermore, Nrf2(-/-) mice exhibited greater loss of peripheral blood nucleated cells and recovered slower from myelosuppression nadir upon multiple consecutive dosages of cyclophosphamide than wild type mice did. This was accompanied with decreased antioxidant and detoxifying gene expressions and impaired colony formation ability of Nrf2(-/-) bone marrow cells. More importantly, activation of Nrf2 signaling by CDDO-Me significantly alleviated cyclophosphamide-induced myelosuppression, while this alleviation was diminished in Nrf2(-/-) mice. In conclusion, the present study shows that Nrf2 plays a protective role in cyclophosphamide-induced myelosuppression and activation of Nrf2 is a promising strategy to prevent or treat chemotherapy-induced myelosuppression.

  2. 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.

  3. 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

  4. Nitric oxide synthases and cyclophosphamide-induced cystitis in rats.

    PubMed

    Alfieri, A B; Malave, A; Cubeddu, L X

    2001-03-01

    The role of inducible (iNOS) and neuronal nitric oxide (nNOS) synthases and of tachykinin NK1 receptors on the pathogenesis of cyclophosphamide (CYP)-induced cystitis was investigated, in rats. CYP-induced cystitis was characterized by large increases in bladder-protein plasma extravasation (PPE), increases in the urinary excretion of nitric oxide (NO) metabolites and histological evidences of urothelial damage, edema, extensive white blood cell infiltrates and vascular congestion of the bladder. The specific iNOS inhibitor, S-methylthiourea (MITU), produced marked inhibition (>90%) of CYP-induced increases in PPE associated with amelioration of tissue inflammatory changes. Treatment with 7-nitroindazole (7-NI; 20, 40 and 80 mg/kg), a selective nNOS inhibitor, did not significantly reduce CYP-induced increases in PPE and failed to produce histological improvement. In addition, treatment with MITU, but not with 7-NI, inhibited the increases in the urinary excretion of NO metabolites induced by CYP treatment. WIN 51,708 (17-beta-hydroxy-17-alpha-ethynyl-androstano[3,2-b]pyrimido[1,2-a]benzimidazole; WIN), a selective NK1-receptor antagonist, reduced the increases in EPP and ameliorated the inflammatory changes in the bladder induced by CYP. However, the maximal degree of protection achieved with WIN was significantly less than that produced by MITU. Combined treatment with the iNOS inhibitor and the NK1 antagonist produced no greater effect than that produced by the iNOS inhibitor alone. Our results suggest that NO plays a fundamental role in the production of the cystitis associated with CYP treatment. The iNOS, and not nNOS, seems responsible for the inflammatory changes. Part of the increases in NO may due to activation of NK1 receptors by neuropeptides such as substance P possibly released from primary afferent fibers.

  5. 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

  6. 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.

  7. 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.

  8. Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers.

    PubMed

    Lehmann-Che, Jacqueline; André, Fabrice; Desmedt, Christine; Mazouni, Chafika; Giacchetti, Sylvie; Turpin, Elisabeth; Espié, Marc; Plassa, Louis-François; Marty, Michel; Bertheau, Philippe; Sotiriou, Christos; Piccart, Martine; Symmans, W Fraser; Pusztai, Lajos; de Thé, Hugues

    2010-01-01

    The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response.

  9. Nitric oxide and NK(1)-tachykinin receptors in cyclophosphamide-induced cystitis, in rats.

    PubMed

    Alfieri, A B; Cubeddu, L X

    2000-11-01

    The present study was conducted to investigate the role of NK(1) receptors and of nitric oxide (NO) on the pathogenesis of cyclophosphamide-induced cystitis, in rats. This bladder toxicity was characterized by marked increases in protein plasma extravasation, urothelial damage, edema, white blood cell infiltrates, and vascular congestion. These changes were associated with appearance of Ca(2+)-independent NO-synthase (NOS) activity [characteristic of inducible NOS (iNOS)] in the bladder and with increases in urinary NO metabolites. GR205171, a selective NK(1) antagonist (10-20 mg/kg, i.p.) reduced cyclophosphamide-induced increases in protein plasma extravasation and in the urinary excretion of NO metabolites. N(G)-Nitro-L-arginine (L-NNA) (10 mg/kg, i.p.), a NOS inhibitor, reduced basal and cyclophosphamide-induced increases in NO metabolites and protected against cyclophosphamide-induced protein plasma extravasation. GR205171 had no effect, whereas L-NNA reduced basal NO metabolite excretion. Combined treatment with the NK(1) antagonist and the NO-synthesis inhibitor produced comparable reduction in protein plasma extravasation than that achieved with each drug given separately. Combined drug treatment ameliorated cyclophosphamideinduced urothelial damage, and the extent of edema, vascular congestion, and white blood cell infiltrates in the bladder. In summary, NK(1) receptors and iNOS play a role in NO formation and on cyclophosphamide-induced cystitis. Activation of NK(1) receptors mainly acts through the formation of NO. It is proposed that cyclophosphamide and/or its metabolites would stimulate primary afferent capsaicin-sensitive fibers in the bladder, releasing neuropeptides, which would activate NK(1) receptors. However, additional mechanisms are involved, because neither the NK(1) receptor antagonist nor the NO synthesis inhibitor, either alone or in combination, were able to completely prevent the toxicity.

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

    PubMed

    Li, Dong; He, Song

    2015-01-01

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

  11. 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)

  12. Does cyclophosphamide still have a role in the treatment of severe inflammatory eye disease?

    PubMed

    Wakefield, Denis

    2014-08-01

    Cyclophosphamide is a highly effective immunosuppressive drug that has proven efficacy in the treatment of patients with severe inflammatory eye disease. It has the advantage of being able to be used either orally or intravenously, has a potent steroid-sparing effect, and is effective in inducing disease remission. The major limitations to the use of this alkylating agent are its frequent side effects. With the increasing availability of alternate forms of therapy it is time to review the therapeutic regimen for cyclophosphamide use in patients with inflammatory eye disease.

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

    PubMed

    Erban, S B; Sokas, R K

    1988-05-01

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

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

    PubMed

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

    1984-01-01

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

  15. 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

  16. Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients.

    PubMed

    Andersson, B S; Thall, P F; Valdez, B C; Milton, D R; Al-Atrash, G; Chen, J; Gulbis, A; Chu, D; Martinez, C; Parmar, S; Popat, U; Nieto, Y; Kebriaei, P; Alousi, A; de Lima, M; Rondon, G; Meng, Q H; Myers, A; Kawedia, J; Worth, L L; Fernandez-Vina, M; Madden, T; Shpall, E J; Jones, R B; Champlin, R E

    2017-04-01

    We hypothesized that IV busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and that this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation. To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine 40 mg/m(2) once daily x4, each dose followed by IV Bu, randomized to 130 mg/m(2) (N=107) or PK-guided to average daily SE, AUC of 6000 μM min (N=111), stratified for remission status and allo-grafting from HLA-matched donors. Toxicity and GvHD rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease control, leading to improved overall and PFS, most prominently in MDS patients and in AML patients not in remission at allogeneic stem cell transplantation. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu dosing. This could be considered an alternative to fixed-dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.

  17. PLasma half-life and urinary excretion of cyclophosphamide in children.

    PubMed

    Sladek, N E; Priest, J; Doeden, D; Mirocha, C J; Pathre, S; Krivit, W

    1980-01-01

    The plasma half-life and urinary excretion of cyclophosphamide were determined in 13 children who had various malignancies and/or who were being prepared for bone marrow transplantation. Disappearance from the plasma following iv infusion over a 1-2 hour period was first-order. Urinary excretion was maximal during the first 8 hours after administration and was essentially complete in 24 hours. The plasma half-life in children not receiving known inducers of hepatic microsomal mixed-function oxygenase activity or cyclophosphamide in the 3-week period prior to each determination ranged from 145 to 390 minutes. These values are lower than those ordinarily found in adult patients. The fraction of the total dose excreted in the urine as the parent compound ranged from 4% to 27%. Repeated administration of cyclophosphamide at approximately 30-60 day intervals did not appear to alter its plasma half-life but did appear to increase its urinary excretion. Daily administration of cyclophosphamide (approximately 50 mg/kg/day x 2 or 4) significantly decreased its plasma half-life and urinary excretion suggesting that it may reversibly induce its own metabolism.

  18. 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

    ... (cyclophosphamide) for Injection (lyophilized formulations), 100 milligrams (mg)/vial, 200 mg/vial, 500 mg/vial, 1... formulations), 100 mg/vial and 200 mg/vial, were not withdrawn from sale for reasons of safety or effectiveness... Injection (lyophilized formulations), 100 mg/vial, 200 mg/vial, 500 mg/vial, 1 g/vial, and 2 g/vial,...

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

    PubMed Central

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

    2011-01-01

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

  20. Hyperoxia, but not thoracic X-irradiation, potentiates bleomycin- and cyclophosphamide-induced lung damage in mice

    SciTech Connect

    Hakkinen, P.J.; Whiteley, J.W.; Witschi, H.R.

    1982-08-01

    The intraperitoneal administration of cyclophosphamide or bleomycin to BALB/c mice resulted in lung cell damage followed by cellular proliferation, which was quantitated by measuring the increase in thymidine incorporation into pulmonary DNA. We have previously shown that administration of the antioxidant butylated hydroxytoluene produces lung damage that can be potentiated by both hyperoxia and thoracic X-irradiation. In the present study we show that hyperoxic exposure also potentiates bleomycin- and cyclophosphamide-induced acute lung damage. However, thoracic X-irradiation does not potentiate bleomycin- and cyclophosphamide-induced lung toxicity.

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

    SciTech Connect

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

    1983-08-01

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

  2. Effect of cyclophosphamide and 61.22 GHz millimeter waves on T-cell, B-cell, and macrophage functions.

    PubMed

    Makar, V R; Logani, M K; Bhanushali, A; Alekseev, S I; Ziskin, M C

    2006-09-01

    The present study was undertaken to investigate whether millimeter waves (MMWs) at 61.22 GHz can modulate the effect of cyclophosphamide (CPA), an anti-cancer drug, on the immune functions of mice. During the exposure each mouse's nose was placed in front of the center of the antenna aperture (1.5 x 1.5 cm) of MMW generator. The device produced 61.22 +/- 0.2 GHz wave radiation. Spatial peak Specific Absorption Rate (SAR) at the skin surface and spatial peak incident power density were measured as 885 +/- 100 W/kg and 31 +/- 5 mW/cm(2), respectively. Duration of the exposure was 30 min each day for 3 consecutive days. The maximum temperature elevation at the tip of the nose, measured at the end of 30 min, was 1 degrees C. CPA injection (100 mg/kg) was given intraperitoneally on the second day of exposure to MMWs. The animals were sacrificed 2, 5, and 7 days after CPA administration. MMW exposure caused upregulation in tumor necrosis factor-alpha (TNF-alpha) production in peritoneal macrophages suppressed by CPA administration. MMWs also caused a significant increase in interferon-gamma (IFN-gamma) production by splenocytes and enhanced proliferative activity of T-cells. Conversely, no changes were observed in interleukin-10 (IL-10) level and B-cell proliferation. These results suggest that MMWs accelerate the recovery process selectively through a T-cell-mediated immune response.

  3. Long-term follow-up of busulfan, etoposide, and nimustine hydrochloride (ACNU) or melphalan as conditioning regimens for childhood acute leukemia and lymphoma.

    PubMed

    Izaki, Sakurako; Goto, Hiroaki; Okuda, Kumiko; Matsuda, Motoi; Watanabe, Yuka; Fujioka, Kenichirou; Hanzawa, Noriyuki; Sumita, Hiroko; Takahashi, Hiroyuki; Goto, Shoko; Kai, Sumio; Sekiguchi, Haruyuki; Funabiki, Tetsunori; Sasaki, Hideki; Ikuta, Koichiro; Yokota, Shumpei

    2007-10-01

    We retrospectively evaluated early and long-term complications of an intensified conditioning regimen consisting of busulfan and etoposide in combination with either nimustine hydrochloride (ACNU) (BVA regimen, n = 18) or melphalan (BVL regimen, n = 34) in 52 children with acute leukemia or non-Hodgkin's lymphoma. With a median follow-up of 13.2 years after the BVA regimen and 8.1 years after the BVL regimen, 61% and 76% of patients, respectively, are in continuous complete remission. Transplantation-related mortality was 17% and 6% after the BVA and BVL regimens, respectively, and the corresponding relapse rates were 17% and 15%. The most common and severe toxicity was pulmonary complication in the BVA regimen, which was seen in 67% of patients and was life-threatening in 20%. Thirty-three percent of patients after the BVA regimen and 24% after BVL died of relapse or disease progression (n = 9), interstitial pneumonia (n = 2), fungal pneumonia (n = 1), or chronic graft-versus-host disease (n = 2). One of the long-term survivors developed secondary leukemia. A significant decrease in the height standard deviation score of more than 2 SD from diagnosis to the last follow-up was seen in 17% of the patients, with hypothyroidism in 15%, and alopecia in 42%. Because our experience is limited to a small heterogeneous population of patients who mainly underwent transplantation in the first remission, we cannot draw conclusions on the treatment's effectiveness. The BVL regimen is tolerable, however, because no regimen-related death was observed, whereas the BVA regimen is not recommended because of the high incidence of pulmonary complications. The effectiveness of the BVL regimen requires further study.

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

    ClinicalTrials.gov

    2017-04-04

    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

  5. 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

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

    PubMed

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

    2009-01-01

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

  7. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells

    PubMed Central

    1982-01-01

    On the basis of preceding studies showing that tumor-induced, T cell- mediated immunosuppression serves as an obstacle to adoptive immunotherapy of the Meth A fibrosarcoma, it was predicted that cyclophosphamide treatment of tumor bearers would remove this obstacle and allow passively transferred immune T cells to cause tumor regression. It was found that infusion of immune spleen cells alone had no effect on tumor growth, and cyclophosphamide alone caused a temporary halt in tumor progression. In contrast, combination therapy consisting of intravenous injection of 100 mg/kg of cyclophosphamide followed 1 h later by intravenous infusion of tumor-immune spleen cells caused small, as well as large tumors, to completely and permanently regress. Tumor regression caused by combination therapy was completely inhibited by intravenous infusion of splenic T cells from donors with established tumors, but not by spleen cells from normal donors. These suppressor T cells were eliminated from the spleen by treating the tumor-bearing donors with 100 mg/kg of cyclophosphamide. Immune T cells, in contrast, were resistant to this dose of cyclophosphamide. These results show that failure of intravenously-infused, tumor- sensitized T cells to cause regression of the Meth A fibrosarcoma growing in its syngeneic or semi-syngeneic host is caused by the presence of a tumor-induced population of cyclophosphamide-sensitive suppressor T cells. PMID:6460831

  8. 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.

  9. THE INDUCTION OF GRAFT VERSUS HOST DISEASE IN MICE TREATED WITH CYCLOPHOSPHAMIDE

    PubMed Central

    Owens, Albert H.; Santos, George W.

    1968-01-01

    In these studies adult mice treated with cyclophosphamide and foreign immunologically competent cells developed a graft versus host disease which outwardly resembled that encountered in other experimental systems. Progressively larger doses of cyclophosphamide produced an increasingly severe disease whereas comparable doses of mechlorethamine were ineffective. Increasingly larger cell inocula from parental, allogeneic, and xenogeneic donors resulted in a correspondingly more severe disease. Nucleated cells obtained from the peripheral blood were found to be the most potent inducers of this syndrome, while cells from the spleen, bone marrow, and thymus displayed lesser degrees of reactivity in that order. No such graft versus host disease occurred in mice given saline, lysed, or heat-killed cells in place of viable foreign cells. Neither did the disorder develop when comparable inocula of isogeneic cells were used. PMID:4873022

  10. The effect of immunosuppression with cyclophosphamide on an experimental porcine enterovirus infection in piglets.

    PubMed Central

    Derbyshire, J B

    1983-01-01

    Eleven specific pathogen-free, five week old piglets were infected orally with the T80 strain of porcine enterovirus type 2. Three days after infection, five of the piglets were treated with cyclophosphamide, together with two of four uninfected control piglets. The treated, infected piglets developed severe diarrhea, and one showed signs of encephalomyelitis. These piglets showed no virological evidence of recovery from the infection, since the virus persisted throughout the intestinal tract, and they failed to mount a serological response. It was concluded that immunosuppression with cyclophosphamide impaired the normal recovery mechanisms in this infection, providing further evidence that the humoral immune response is an important defence mechanism against porcine enterovirus infection in piglets. PMID:6224548

  11. Regulation of secondary antibody responses in rodents. I. Potentiation of IgG production by cyclophosphamide.

    PubMed Central

    Gagnon, R F; MacLennan, I C

    1979-01-01

    This paper describes the effects of a single dose of cyclophosphamide on specific IgG production in rats during an established secondary immune response. (PVG X Agus)F1 rats were immunized twice (days 0 and 28) with chicken erythrocytes (CRBC), received cyclophosphamide (100 mg/m2 of body surface area) on day 33 and were killed 8 days later. The production of anti-CRBC IgG antibodies was assessed by testing the supernatants of spleen cell cultures in a cytotoxicity assay with 51Cr-labelled CRBC as target cells and normal rat spleen cells as effector cells. In observations of fifty-nine pairs of treated and untreated rats from eight separate experiments, the administration of cyclophosphamide resulted in: (1) a decrease in the number of spleen cell to a median of 10(8.63) from a median of 10(8.7) (P less than 0.0025); (2) an increase in the anti-CRBC IgG antibody titre of the supernatants of cultured spleen cells to a median of 10(0.67) from a median of 10(0.27 (P less than 0.0025); and (3) the calculated anti-CRBC. IgG antibody production per spleen to be increased in the drug-treated rats to a median of 10(2.26) from a median of 10(2.0) (P less than 0.005). In a cyclophosphamide dose-response study, it was shown that some enhancement of antibody production was induced by doses between 12.5 and 50 mg/m2 and consistently elevated levels of antibody production were associated with doses between 100 and 400 mg/m2. PMID:487659

  12. 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.

  13. The Effects of Electroacupuncture on Cyclophosphamide-Induced Emesis in Ferrets.

    DTIC Science & Technology

    1996-07-01

    serotonin ( 5 - HT3 ) receptor antagonists have been shown to be effective antiemetics for cyclophosphamide-induced emesis in ferrets (1) and humans (2,3,5,8...the 5 - HT3 receptor in the gastrointestinal tract and the chemoreceptor trigger zone (Fraschini et al., 1991; Hawthorn et al., 1988). The 5 -HT 3...possibly through release of serotonin to stimulate the 5 - HT3 receptor in the gastrointestinal tract and the chemoreceptor trigger zone (5,6). The

  14. Evaluation of the immunosuppressive effects of cyclophosphamide in patients with multiple sclerosis.

    PubMed Central

    ten Berge, R J; van Walbeek, H K; Schellekens, P T

    1982-01-01

    In a group of eight patients suffering from clinically definite multiple sclerosis, we studied the effects of treatment with cyclophosphamide on the immune reactivity in vitro and in vivo. The results are compared with those obtained in a control group consisting of eight patients who received no drug therapy and who were matched with the former group for age, sex and severity of disease. The results indicate that therapy with cyclophosphamide at a mean dose of 100 mg/day induces a profound lymphocytopenia in peripheral blood involving both T and B cells. Serum levels of immunoglobulins as well as primary and secondary antibody responses were depressed. In tests with standardized cell numbers, proliferative responses of lymphocytes in vitro and cytotoxic T cell function remained normal, whereas K and NK cell activities were diminished. Secondary cellular immune responses in vivo remained intact; however, the primary cellular immune response in vivo was markedly depressed. From these data, it is concluded that therapy with cyclophosphamide in man mainly affects humoral immune functions, but also cellular immunity, although to a lesser extent. PMID:7165996

  15. Cyclophosphamide pulses with oral prednisolone in the treatment of pemphigus: a pilot study.

    PubMed

    Bhat, Radhakrishna; Sharma, Vinod K; Ramam, M; Kumar, Ashok

    2005-12-01

    An open labeled clinical trial aimed at assessing the efficacy and safety of pulse intravenous cyclophosphamide with daily oral prednisolone in the treatment of pemphigus was carried out. Twenty-six patients (12 men, 14 women; mean age, 48.4 years), comprising 25 cases with pemphigus vulgaris and 1 with pemphigus vegetans (< 10% body surface area involvement) who did not achieve adequate control on corticosteroids with or without other adjuvants were included. After baseline evaluation, monthly intravenous boluses of cyclophosphamide (15 mg/kg) along with daily oral prednisolone (starting dose 1 mg/kg/day, tapered according to clinical response) were administered. Patients were assessed monthly for clinical activity and side-effects. All patients experienced significant clinical improvement within 1 month of starting treatment. Healing of skin and mucosal lesions occurred respectively at mean durations of 2.1 and 3.6 months. Three weeks to 8 months later, 9 patients had recurrences of activity on tapering/withdrawal of prednisolone, mainly in the oral mucosa. Side effects of treatment included amenorrhea (3 patients), microscopic hematuria (3) which cleared with co-administration of mesna, vomiting (1), weight gain (10), gastritis (1), and cataract (2). It is concluded that treatment with monthly intravenous cyclophosphamide boluses along with daily oral prednisolone clears lesions of pemphigus with < 10 percent body surface involvement, and this may be an alternative regimen for pemphigus. Monitoring for adverse effects is essential.

  16. Effects of multiple doses of cyclophosphamide on mouse testes: accessing the germ cells lost, and the functional damage of stem cells.

    PubMed

    Drumond, Ana Luiza; Weng, Connie C; Wang, Gensheng; Chiarini-Garcia, Helio; Eras-Garcia, Leticia; Meistrich, Marvin L

    2011-12-01

    Spermatogenesis is sensitive to the chemotherapeutic drug cyclophosphamide, which decreases the patients' sperm count. Since the recovery of fertility is dependent on regeneration from stem cells, in the present study we evaluated the ability of cyclophosphamide-exposed stem spermatogonia from mice to regenerate spermatogenesis in situ and after transplantation. When seven doses of cyclophosphamide were given at 4-day intervals, the differentiating germ cells were largely eliminated but ~50% of the undifferentiated type A spermatogonia remained. We monitored the recovery and found that sperm production recovered to 64% of control within the time expected. When the cyclophosphamide-surviving spermatogonia were transplanted into recipient mice, recovery of spermatogenesis from the cyclophosphamide-exposed donor cells was observed, but was reduced when compared to cells from cryptorchid donors. Thus, multidose regimens of cyclophosphamide did not eliminate the stem spermatogonia, but resulted in cell loss and residual damage.

  17. Spinal astrocytic activation contributes to mechanical allodynia in a rat model of cyclophosphamide-induced cystitis

    PubMed Central

    Liu, Bolong; Su, Minzhi; Tang, ShaoJun; Zhan, Hailun; Yang, Fei; Li, Wenbiao; Li, Tengcheng; Xie, Juncong

    2016-01-01

    Background Previous studies have demonstrated that glial cells play an important role in the generation and maintenance of neuropathic pain. Activated glial cells produce numerous mediators such as proinflammatory cytokines that facilitate neuronal activity and synaptic plasticity. Similarly, bladder pain syndrome/interstitial cystitis shares many characteristics of neuropathic pain. However, related report on the involvement of spinal glia in bladder pain syndrome/interstitial cystitis-associated pathological pain and the underlying mechanisms are still lacking. The present study investigated spinal glial activation and underlying molecular mechanisms in a rat model of bladder pain syndrome/interstitial cystitis. Results A rat model of bladder pain syndrome/interstitial cystitis was established via systemic injection with cyclophosphamide. Mechanical allodynia was tested with von Frey monofilaments and up-down method. Moreover, Western blots and double immunofluorescence were used to detect the expression and location of glial fibrillary acidic protein, OX42/Iba1, P-P38, NeuN, interleukin (IL)-1β, phosphorylation of N-methyl-D-aspartate receptor 1 (P-NR1), and IL-1 receptor I (IL-1RI) in the L6-S1 spinal cord. We found that glial fibrillary acidic protein rather than OX42/Iba1 or P-P38 was significantly increased in the spinal cord of cyclophosphamide-induced cystitis. L-alpha-aminoadipate but not minocycline markedly attenuated the allodynia. Furthermore, we found that spinal IL-1β was dramatically increased in cyclophosphamide-induced cystitis, and activated astrocytes were the only source of IL-1β release, which contributed to allodynia in cystitis rats. Besides, spinal P-NR1 was statistically increased in cyclophosphamide-induced cystitis and only localized in IL-1RI positive neurons in spinal dorsal horn. Additionally, NR antagonist significantly attenuated the cystitis-induced pain. Interestingly, the time course of the P-NR1 expression paralleled to that

  18. A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas

    PubMed Central

    Kummar, Shivaani; Ji, Jiuping; Morgan, Robert; Lenz, Heinz-Josef; Puhalla, Shannon L.; Belani, Chandra P.; Gandara, David R.; Allen, Deborah; Kiesel, Brian; Beumer, Jan H.; Newman, Edward M.; Rubinstein, Larry; Chen, Alice; Zhang, Yiping; Wang, Lihua; Kinders, Robert J.; Parchment, Ralph E.; Tomaszewski, Joseph E.; Doroshow, James H.

    2012-01-01

    Purpose Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. Poly(ADP-ribose) polymerase (PARP) inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics; measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMCs); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTCs). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels; γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared to single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma. PMID:22307137

  19. 5-Aza-2′-deoxycytidine Sensitizes Busulfan-resistant Myeloid Leukemia Cells By Regulating Expression of Genes Involved in Cell Cycle Checkpoint and Apoptosis

    PubMed Central

    Valdez, Benigno C.; Li, Yang; Murray, David; Corn, Paul; Champlin, Richard E.; Andersson, Borje S.

    2009-01-01

    Busulfan (Bu) is a DNA-alkylating drug used in myeloablative pretransplant conditioning therapy for patients with myeloid leukemia (ML). A major obstacle to successful treatment is cellular Bu-resistance. To investigate the possible contribution of DNA hypermethylation to Bu-resistance, we examined the cytotoxic activity of combined 5-aza-2′-deoxycytidine (DAC) and Bu. Exposure of Bu-resistant B5/Bu2506 ML cells to 0.5 μM DAC resulted in G2-arrest and apoptosis. The observed G2-arrest was associated with hypomethylation and subsequent expression of epigenetically controlled genes including p16INK4A, activation of the p53 pathway, and phosphorylation of CDC2. The DAC-mediated apoptosis was partly due to hypomethylation and up-regulation of XAF1, which resulted in down-regulation of the anti-apoptotic proteins XIAP, cIAP1 and cIAP2. The pro-apoptotic PUMA and BNIP3 proteins were up-regulated while pro-survival STAT3 and c-MYC were suppressed. Combination of 0.05 μM DAC and 5 μg/ml Bu resulted in synergistic cytotoxicity, which was associated with PARP1 cleavage and activation of caspases 3 and 8, suggesting induction of an apoptotic response. P53 inhibition in B5/Bu2506 cells using pifithrin-α alleviated these effects, suggesting a role for p53 therein; this observation was supported by the relative resistance of p53-null K562 cells to [DAC+Bu] combinations and by the effects of an anti-p53 shRNA on the OCI-AML3 cell line. We conclude that the synergistic effects of [DAC+Bu] are p53-dependent and involve cell-cycle arrest, apoptosis induction and down-regulation of pro-survival genes. Our results suggest that, depending on tumor p53 status, incorporation of DAC might synergistically improve the cytoreductive efficacy of Bu-based pre-transplant regimen in patients with ML. PMID:19732952

  20. Safety and efficacy of targeted-dose busulfan and bortezomib as a conditioning regimen for patients with relapsed multiple myeloma undergoing a second autologous blood progenitor cell transplantation.

    PubMed

    Freytes, César O; Toro, Juan J; Yeh, Rosa F; Stadtmauer, Edward A; Ratanatharathorn, Voravit; Akpek, Görgün; Sahovic, Entezam; Tricot, Guido J; Shaughnessy, Paul J; White, Darrell J; Rodriguez, Tulio E; Solomon, Scott R; Yu, Louie H; Zhao, Cathy; Patil, Shiva; Armstrong, Elizabeth; Smith, Angela; Elekes, Agnes; Kato, Kazunobu; Reece, Donna E

    2014-12-01

    Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase IIa study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration-time curve (AUC) of 20,000 μM × minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n = 24). Individualized Bu dose, based on test dose .8 mg/kg pharmacokinetics (PK), was administered daily for 4 consecutive days starting 5 days before transplantation, followed by a single dose of bortezomib (1.3 mg/m(2)) 1 day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 14.2 mg/kg (standard deviation = 2.48; range, 8.7 to 19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59 years (range, 48 to 73). Median time from first to second transplantation was 28.0 months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months after transplantation, with 2 patients attaining a complete response. At 6 months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one

  1. p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-kappaB DNA binding.

    PubMed

    Pekar, Olga; Molotski, Nataly; Savion, Shoshana; Fein, Amos; Toder, Vladimir; Torchinsky, Arkady

    2007-08-01

    The tumor suppressor protein p53 regulates the sensitivity of embryos to such human teratogens as ionizing radiation, diabetes, and cytostatics. Yet, the molecular mechanisms whereby it fulfills this function remain undefined. We used p53 heterozygous (p53(+/-)) female mice mated with p53(+/-) males and then exposed to cyclophosphamide (CP) to test whether caspases 3, 8, and 9 and the transcription factor nuclear factor (NF)-kappaB may serve as p53 targets. Mice were exposed to CP on day 12 of pregnancy and killed on days 15 and 18 of pregnancy to evaluate CP-induced teratogenic effect. The brain and limbs of embryos harvested 24 h after CP treatment were used to evaluate NF-kappaB (p65) DNA-binding activity by an ELISA-based method, the activity of the caspases by appropriate colorimetric kits, apoptosis, and cell proliferation by TUNEL, and 5'-bromo-2'-deoxyuridine incorporation respectively. We observed that the activation of caspases 3, 8, and 9 and the suppression of NF-kappaB DNA binding following CP-induced teratogenic insult took place only in teratologically sensitive organs of p53(+/+) but not p53(-/-) embryos. CP-induced apoptosis and suppression of cell proliferation were also more intensive in the former, and they exhibited a higher incidence of structural anomalies, such as open eyes, digit, limb, and tail anomalies. The analysis of the correlations between the p53 embryonic genotype, the activity of the tested molecules, and the CP-induced dysmorphic events at the cellular and organ level suggests caspases 3, 8, and 9 and NF-kappaB as components of p53-targeting mechanisms in embryos exposed to the teratogen.

  2. Cyclophosphamide, ara-C and topotecan (CAT) for patients with refractory or relapsed acute leukemia.

    PubMed

    Cortes, J; Estey, E; Beran, M; O'Brien, S; Giles, F; Koller, C; Keating, M; Kantarjian, H

    2000-02-01

    Topotecan is a topoisomerase I inhibitor with significant activity in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical data suggest a synergistic activity with DNA damaging agents such as cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide-induced DNA damage. We thus designed a combination including cyclophosphamide 500 mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL) (refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79 years). Eleven patients (17%) achieved a complete remission (CR), and two patients (3%) had a hematologic improvement (HI; met all criteria for CR except for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23 episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin complicating 74 courses of CAT. Non-hematologic toxicity was mostly gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was severe in only 8%. In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation.

  3. Effects of phosphoramide mustard and acrolein, cytotoxic metabolites of cyclophosphamide, on mouse limb development in vitro.

    PubMed

    Hales, B F

    1989-07-01

    Phosphoramide mustard and acrolein are toxic and reactive metabolites of the widely used anticancer drug and known teratogen cyclophosphamide. To study the mechanism(s) involved and to determine which of the active metabolites of cyclophosphamide is responsible for the production of limb malformations, the effects of exposure of cultured limb buds to phosphoramide mustard and acrolein were investigated. Fore- and hindlimbs were excised from ICR mice on day 12 of gestation and cultured in roller bottles for 6 days. Limbs were exposed to either phosphoramide mustard or acrolein (10 or 50 micrograms/ml) for the first 20 hours of the culture period. Exposure to phosphoramide mustard produced limb reduction malformations in both the fore- and hindlimbs; total limb bone area was greatly reduced, while the relative contribution of the paw to this area in forelimbs was increased. There was a fourfold reduction in both DNA and RNA; protein content was reduced only by one-half. Alkaline phosphatase activity was significantly decreased in fore- and hindlimbs exposed to phosphoramide mustard, whereas creatine phosphokinase activity was only reduced in hindlimbs in the limbs exposed to the higher concentration of phosphoramide mustard. Exposure to acrolein also produced malformed limbs with a mangled appearance; however, total limb bone area and the relative contribution of the long bones versus paw structures were not altered. Acrolein exposure had little effect on growth parameters such as DNA (decreased only in hindlimbs exposed to 50 micrograms/ml), RNA (increased in hindlimbs exposed to 50 micrograms/ml), or protein content. Alkaline phosphatase and creatine phosphokinase activities were not altered in acrolein-exposed fore- or hindlimbs. Thus, phosphoramide mustard and acrolein have dramatically different effects on developing limbs in vitro; this observation may indicate that they have different targets and/or mechanisms of action as teratogens in the limb. The effects

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

    PubMed

    Prakash; Singh, Gajendra; Singh, Sukh Mahendra

    2007-07-01

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

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

    PubMed

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

    2012-09-01

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

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

    PubMed Central

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

    2017-01-01

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

  7. 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

  8. Long-Term Follow-Up of Cyclophosphamide Compared with Azathioprine for Initial Maintenance Therapy in ANCA-Associated Vasculitis

    PubMed Central

    Faurschou, Mikkel; Berden, Annelies; Flossmann, Oliver; Bajema, Ingeborg; Hoglund, Peter; Smith, Rona; Szpirt, Wladimir; Westman, Kerstin; Pusey, Charles D.; Jayne, David R.W.

    2014-01-01

    Background and objectives Treatment with azathioprine within 3 months of remission induction with cyclophosphamide is a common treatment strategy for patients with ANCA-associated vasculitis. This study comprised patients undergoing long-term follow-up who were randomly allocated to azathioprine after 3–6 months or after 12 months of cyclophosphamide treatment. Design, setting, participants, & measurements Patients from 39 European centers between 1995 and 1997 with a new diagnosis of ANCA-associated vasculitis that involved the kidneys or another vital organ were eligible. At the time of diagnosis, participants were randomly allocated to convert to azathioprine after 3–6 months (the azathioprine group) or after 12 months of cyclophosphamide (the cyclophosphamide group). Patients who did not achieve a remission within 6 months were excluded. This study assessed relapses, ESRD, and death during long-term follow-up. Results Patients were allocated to the azathioprine group (n=71) and the cyclophosphamide group (n=73). Of these patients, 63 (43.8%) developed a relapse, 35 (24.3%) developed a renal relapse, 13 (9.0%) developed ESRD, and 21 (14.6%) died. Although there were worse outcomes in the azathioprine group, none were statistically significant. The subdistribution hazard ratio [sHR] for relapse was 1.63 (95% confidence interval [95% CI], 0.99 to 2.71), the composite of relapse or death hazard ratio [HR] was 1.59 (95% CI, 1.00 to 2.54), the ESRD sHR was 1.71 (95% CI, 0.56 to 5.19), and the death HR was 0.75 (95% CI, 0.32 to 1.79). Conclusions It remains uncertain whether converting to azathioprine after 3–6 months of induction cyclophosphamide therapy is as effective as converting after 12 months. Outcomes are still poor for this group of patients and further research is required to determine the optimal timing of maintenance therapy. PMID:24970876

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

    PubMed Central

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

    2017-01-01

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

  10. 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

  11. 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

  12. Quantitative prediction of catalepsy induced by amoxapine, cinnarizine and cyclophosphamide in mice.

    PubMed

    Nasu, R; Matsuo, H; Takanaga, H; Ohtani, H; Sawada, Y

    2000-05-01

    Parkinsonism can be a side effect of antipsychotic drugs, and has recently been reported with peripherally acting drugs such as calcium channel blockers, antiarrhythmic agents and so on. In this study, we examined the quantitative prediction of drug-induced catalepsy by amoxapine, cinnarizine and cyclophosphamide, which have been reported to induce parkinsonism. Dose-dependent catalepsy was induced by these drugs in mice. In vivo dopamine D(1), D(2) and muscarinic acetylcholine (mACh) receptor occupancies by these drugs in the striatum were also examined. The in vitro binding affinities (K(i) values) of amoxapine and cinnarizine to dopamine D(1), D(2) and mACh receptors in rat striatal synaptic membrane were 200 and 2900 nM, 58.4 and 76.4 nM and 379 and 290 nM, respectively. Cyclophosphamide did not bind to these receptors at concentrations up to 100 microM. Twenty drugs, including those mentioned above, showed a significant correlation between the observed intensity of catalepsy and the values predicted with a pharmacodynamic model (Haraguchi K, Ito K, Kotaki H, Sawada Y, Iga T. Prediction of drug-induced catalepsy based on dopamine D(1), D(2), and muscarinic acetylcholine receptor occupancies. Drug Metab Disp 1997; 25: 675-684) based on in vivo occupancy of dopamine D(1), D(2) and mACh receptors. We conclude that occupancy of dopamine D(1) and D(2) receptors contributes to catalepsy induction by amoxapine and cinnarizine.

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

    PubMed

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

    2012-01-01

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

  14. 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.

  15. Comparative Metabolism of Cyclophosphamide and Ifosfamide in the Mouse Using UPLC-ESI-QTOFMS-Based Metabolomics

    PubMed Central

    Li, Fei; Patterson, Andrew D.; Höfer, Constance C.; Krausz, Kristopher W.; Gonzalez, Frank J.; Idle, Jeffrey R.

    2010-01-01

    Ifosfamide (IF) and cyclophosphamide (CP) are common chemotherapeutic agents. Interestingly, while the two drugs are isomers, only IF treatment is known to cause nephrotoxicity and neurotoxicity. Therefore, it was anticipated that a comparison of IF and CP drug metabolites in the mouse would reveal reasons for this selective toxicity. Drug metabolites were profiled by ultra-performance liquid chromatography-linked electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS), and the results analyzed by multivariate data analysis. Of the total 23 drug metabolites identified by UPLC-ESI-QTOFMS for both IF and CP, five were found to be novel. Ifosfamide preferentially underwent N-dechloroethylation, the pathway yielding 2-chloroacetaldehyde, while cyclophosphamide preferentially underwent ring-opening, the pathway yielding acrolein (AC). Additionally, S-carboxymethylcysteine and thiodiglycolic acid, two downstream IF and CP metabolites, were produced similarly in both IF- and CP-treated mice. This may suggest that other metabolites, perhaps precursors of thiodiglycolic acid, may be responsible for IF encephalopathy and nephropathy. PMID:20541539

  16. Cyclophosphamide (Cytoxan)

    MedlinePlus

    ... Septra) or, in patients who are allergic to sulfa medications, dapsone. Warts — The picture below shows a ... their occurrence diminishes greatly after discontinuation of the drug. In contrast, the risk of cancer associated with ...

  17. Idiopathic Relapsing Thrombotic Thrombocytopenic Purpura with Persistent ADAMTS13 Inhibitor Activity Treated Sequentially with Plasmapheresis, Rituximab, Cyclophosphamide and Splenectomy.

    PubMed

    Musa, Faisal; Baidas, Said

    2015-01-01

    We here describe a patient with an idiopathic thrombotic thrombocytopenic purpura (TTP) secondary to an ADAMTS13 inhibitor that continued to be dependent on plasmapheresis until the patient was treated with rituximab. TTP manifestations subsided with rituximab treatment in spite of a persistently low ADAMTS13 activity and continued a detectable inhibitor activity until the patient developed an intolerance to rituximab due to an allergic reaction when cyclophosphamide was added; this resulted in a normalization of ADAMTS13 activity and the disappearance of the inhibitor. Later, the patient developed an intolerance to rituximab due to a severe allergic reaction. Soon after stopping rituximab, the ADAMTS13 activity level dipped below 5% in addition to the appearance of the ADAMTS13 inhibitor. The patient had a splenectomy after rituximab and cyclophosphamide treatment; the medication was stopped based on several case reports of a complete remission of TTP after splenectomy. We believe that the reason TTP went into remission in our patient was because of rituximab treatment, in spite of both persistently low ADAMTS13 activity and a detectable inhibitor activity due to reducing the release of von Willebrand factor large multimers from the endothelial cells. We found that ADAMTS13 activity normalized and the inhibitor activity became undetectable when cyclophosphamide was added to rituximab. We suggest adding cyclophosphamide to rituximab for the treatment of patients with persistent ADAMTS13 inhibitors in order to prolong the remission period and lower the rate of relapse.

  18. 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

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

    PubMed

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

    2015-07-01

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

  1. Phase 1 and Extension Study of Clofarabine plus Cyclophosphamide in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

    PubMed Central

    Faderl, S; Balakrishnan, K; Thomas, DA; Ravandi, F; Borthakur, G; Burger, J; Ferrajoli, A; Cortes, J; O’Brien, S; Kadia, T; Feliu, J; Plunkett, W; Gandhi, V; Kantarjian, HM

    2014-01-01

    Background Clofarabine is a nucleoside analog with activity in children with ALL. Based on the hypothesis that clofarabine inhibits DNA repair following exposure to DNA damaging agents, we designed a phase 1 and extension study to evaluate the combination of clofarabine with cyclophosphamide in adult patients with relapsed/refractory ALL. Methods The continual reassessment method (CRM) was used to define the maximum tolerated dose (MTD). Results Fifty patients with a median age of 30 years (range 21–72 years) were enrolled of whom 30 patients were part of the phase 1 group. Clofarabine 40 mg/m2 iv daily x 3 days and cyclophosphamide 200 mg/m2 iv q 12 hours x 3 days were established as the MTD. Dose limiting toxicities were diarrhea, transaminase elevations, and skin rashes. The response rate of the whole study group was 14% including 10% of patients who achieved complete remission (CR) or CR without platelet recovery. Three responses occurred in patients with primary refractory disease. Early mortality (< 30 days) was 6%. The median response duration was 69 days (range 5–315 days). Median overall survival was about 3 months. Compared to day 1 (cyclophosphamide alone), H2AX phosphorylation was increased on day 2 when clofarabine and cyclophosphamide were administered as a couplet (n = 8). Conclusions The combination of clofarabine plus cyclophosphamide at the doses used in this study and in a group of heavily pretreated patients with ALL is only moderately effective. Other doses, alternative schedules, or a more favorable patient population may achieve better results. (Word count: 248) PMID:24440659

  2. 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.

  3. 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.

  4. 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.

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

    PubMed

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

    1977-01-01

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

  6. 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.

  7. 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.

  8. Effect of Chuanminshen violaceum polysaccharides and its sulfated derivatives on immunosuppression induced by cyclophosphamide in mice

    PubMed Central

    Zhao, Xinghong; Zhang, Yuetian; Song, Xu; Yin, Zhongqiong; Jia, Renyong; Zhao, Xingfang; Lai, Xin; Wang, Guangxi; Liang, Xiaoxia; He, Changliang; Yin, Lizi; Lv, Cheng; Zhao, Ling; Shu, Gang; Ye, Gang; Shi, Fei

    2015-01-01

    One hundred mice were randomly divided into five groups. The mice in one group were injected with physiological saline as the normal control group. The mice in the other four groups were injected with physiological saline, sulfated Chuanminshen violaceum polysaccharides (SCVP), Chuanminshen violaceum polysaccharide (CVP) and astragalus polysaccharide (AP) once daily for 7 d and then with cyclophosphamide (CY) in the last 3 d. The serum cytokine level, apoptosis protein expressions, spleen lymphocyte proliferation, changes in peripheral blood T-cell subsets, and immune organ index were then measured. Results showed that SCVP and CVP can overcome CY-induced immunosuppression by promoting spleen lymphocyte proliferation, raising serum IFN-γ and IL-2 levels, enlarging immune organ indexes, and decreasing excessive apoptosis. Moreover, SCVP and CVP showed the potential to treat autoimmune diseases based on CD4+/CD8+ ratios. Results suggested that SCVP and CVP exhibited the potential to treat autoimmune and immunosuppression diseases. PMID:25785030

  9. Complete remission of Schnitzler syndrome and Waldenström macroglobulinemia under rituximab-cyclophosphamide-dexamethasone.

    PubMed

    Aouba, Achille; Pressiat, Claire; Pricopi, Maria; Georgin-Lavialle, Sophie; Boue, François; Lievre-Castilla, Maria-Angela; Marfaing-Koka, Anne; Prevot, Sophie; Decottignies, Audrey

    2015-01-01

    In Schnitzler syndrome, which is mostly diagnosed with a low and asymptomatic monoclonal peak, anakinra has always exhibited a complete but only transient control of the auto-inflammatory signs, which are induced by interleukin (IL)-1 auto-activation. We focused on the treatment of a case of Schnitzler syndrome with moderate macroglobulinemia peak. Anakinra failed to improve the severe inflammatory anaemia and the dysglobulinemia, but rituximab-dexamethasone-cyclophosphamide chemotherapy alone allowed a complete response. The correlation between the clinical, pro-inflammatory cytokines and dysglobulinemia complete controls with chemotherapy proves the following: (1) the dual action of this treatment in both the auto-inflammatory and dysglobulinemia components of the syndrome and (2) a different but entangled cytokine network in the pathogenesis of the auto-inflammatory and dysglobulinemia components of the syndrome.

  10. 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.

  11. 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.

  12. 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.

  13. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia

    PubMed Central

    Zhang, Mei-Jie; Bacigalupo, Andrea A.; Bashey, Asad; Appelbaum, Frederick R.; Aljitawi, Omar S.; Armand, Philippe; Antin, Joseph H.; Chen, Junfang; Devine, Steven M.; Fowler, Daniel H.; Luznik, Leo; Nakamura, Ryotaro; O’Donnell, Paul V.; Perales, Miguel-Angel; Pingali, Sai Ravi; Porter, David L.; Riches, Marcie R.; Ringdén, Olle T. H.; Rocha, Vanderson; Vij, Ravi; Weisdorf, Daniel J.; Champlin, Richard E.; Horowitz, Mary M.; Fuchs, Ephraim J.; Eapen, Mary

    2015-01-01

    We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation. PMID:26130705

  14. Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Sakellari, Ioanna; Mallouri, Despina; Gavriilaki, Eleni; Batsis, Ioannis; Kaliou, Maria; Constantinou, Varnavas; Papalexandri, Apostolia; Lalayanni, Chrysavgi; Vadikolia, Chrysanthi; Athanasiadou, Anastasia; Yannaki, Evangelia; Sotiropoulos, Damianos; Smias, Christos; Anagnostopoulos, Achilles

    2017-03-01

    Treosulfan has been incorporated in conditioning regimens for sustained remission without substantial toxicity and treatment-related mortality (TRM). We aimed to analyze the safety and efficacy of a fludarabine 150 mg/m(2) and treosulfan 42 g/m(2) (FluTreo) conditioning regimen in medically infirm patients. Outcomes were compared with those of a similar historical group treated with fludarabine 150 mg/m(2) to 180 mg/m(2), busulfan 6.4 mg/kg, and antithymocyte globulin (ATG) 5 mg/kg to 7.5 mg/kg (FluBuATG). Thirty-one consecutive patients with acute myeloid leukemia (AML; n = 21), myelodysplastic syndrome (MDS; n = 6), or treatment-related AML (n = 4) received FluTreo conditioning. The historical group consisted of 26 consecutive patients treated with FluBuATG. In the FluTreo group, engraftment was prompt in all patients and 74% achieved >99% donor chimerism by day +30. No grades III or IV organ toxicities were noted. One-year cumulative incidences (CI) of acute and chronic graft-versus-host disease (GVHD) were 19.4% and 58.4%. The groups were similar for age, disease risk, lines of treatment, hematopoietic cell transplantation-specific comorbidity index, and acute or chronic GVHD incidence, except that there were more matched unrelated donor recipients in the FluTreo group (P < .001). With 20 (range, 2 to 36) months follow-up for FluTreo and 14 (range, 2 to 136) for FluBuATG, the 1-year cumulative overall survival (OS) probability was 76% versus 57%, respectively (P = .026); 1-year disease-free survival (DFS) was 79% versus 38% (P < .001). In multivariate analysis, the only significantly favorable factor for OS and DFS was FluTreo (P = .010 and P = .012). The CI of relapse mortality was markedly decreased in FluTreo versus FluBuATG (7.4% versus 42.3%, P < .001). In conclusion, the treosulfan-based regimen resulted in favorable OS and DFS with acceptable toxicity and low relapse rates compared with busulfan-based conditioning.

  15. Activation of cathepsins B and L in mouse lymphosarcoma tissue under the effect of cyclophosphamide is associated with apoptosis induction and infiltration by mononuclear phagocytes.

    PubMed

    Zhanaeva, S Ya; Mel'nikova, E V; Trufakin, V A; Korolenko, T A

    2013-11-01

    We analyzed activities of lysosomal cystein cathepsins B and L in mouse LS lymphosarcoma and its drug-resistant RLS 40 strain and their correlations with the dynamics of the percentage of cells with fragmented DNA and CD14 (+) phagocytes over 3 days after cyclophosphamide injection. LS regression and inhibition of RLS 40 growth after cyclophosphamide injection were paralleled by an increase in cathepsins B and L activities in tumor tissues. The antitumor effect of cyclophosphamide associated with apoptosis intensity and protease activities were significantly higher in LS. Positive correlations between activities of cathepsins B and L and the LS tissue content of cells with fragmented DNA and CD14 (+) phagocytes and negative correlations thereof with tumor weight were detected. It seems that the increase in cathepsins B and L activities in LS tissues was caused by cyclophosphamide induction of apoptosis and depended on the level of tumor cell infiltration with mononuclear phagocytes.

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

    PubMed

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

    2017-04-01

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

  17. CpG-1826 immunotherapy potentiates chemotherapeutic and anti-tumor immune responses to metronomic cyclophosphamide in a preclinical glioma model.

    PubMed

    Jordan, Marie; Waxman, David J

    2016-04-01

    Cyclophosphamide administered on an intermittent metronomic schedule induces strong immune-dependent regression in several glioma models. Here we investigate whether this immunogenic chemotherapy can be potentiated by combination with the immune stimulatory TLR9 agonist CpG-1826. CpG-1826 treatment of GL261 gliomas implanted in immune competent mice induced tumor growth delay associated with increased tumor recruitment of macrophages and B cells. Anti-tumor responses varied between individuals, with CpG-1826 inducing robust tumor growth delay in ~50% of treated mice. Both high and low CpG-1826-responsive mice showed striking improvements when CpG-1826 was combined with cyclophosphamide treatment. Tumor-associated macrophages, B cells, dendritic cells, and cytotoxic T cells were increased, T regulatory cells were not induced, and long-term GL261 glioma regression with immune memory was achieved when CpG-1826 was combined with either single cyclophosphamide dosing (90 mg/kg) or metronomic cyclophosphamide treatment (two cycles at 45 mg/kg, spaced 12-days apart). B16F10 melanoma, a low immunogenic tumor model, also showed enhanced immune and anti-tumor responses to cyclophosphamide/CpG-1826 chemoimmunotherapy, but unlike GL261 tumors, did not regress. TLR9-based immunotherapy can thus be effectively combined with immunogenic cyclophosphamide treatment to enhance immune-based anti-tumor responses, even in poorly immunogenic cancer models.

  18. Cyclophosphamide treatment of steroid dependent nephrotic syndrome: comparison of eight week with 12 week course. Report of Arbeitsgemeinschaft für Pädiatrische Nephrologie.

    PubMed Central

    1987-01-01

    In a prospective study (Cytotoxic Drug Study II), 18 children with steroid dependent nephrotic syndrome and steroid toxicity were treated with cyclophosphamide (2 mg/kg body weight/day) for 12 weeks in combination with reducing doses of prednisone (group A). This group was compared retrospectively with 18 children with steroid dependent nephrotic syndrome, studied as part of the Cytotoxic Drug Study I, and who had received cyclophosphamide for eight weeks (group B). There were no differences between the groups in age at the onset of the nephrotic syndrome, age at entry into the study, and duration of the nephrotic syndrome before entry into the study. The number of relapses during the six months before the treatment was the same in both groups. Two years after treatment 12 of 18 children treated with cyclophosphamide for 12 weeks were still in remission. By contrast, only four of of 18 children treated with cyclophosphamide for eight weeks were still in remission. The cumulative rates of sustained remissions were significantly higher (67% and 22%, respectively) in group A. All relapses were observed within 400 days of stopping cytotoxic treatment. No severe side effects of cyclophosphamide occurred up to two years after treatment had been stopped. We conclude that for children with steroid dependent nephrotic syndrome and steroid toxicity cyclophosphamide treatment should be prolonged to 12 weeks to increase the likelihood of a prolonged remission. PMID:3688915

  19. [An advanced metastatic breast cancer patient successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy].

    PubMed

    Sato, Yasushi; Takayama, Tetsuji; Sagawa, Tamotsu; Sato, Tsutomu; Okamoto, Kumiko; Takahashi, Shou; Abe, Seiichiro; Iyama, Satoshi; Murase, Kazuyuki; Kato, Junji; Niitsu, Yoshiro

    2008-03-01

    We reported here a case of advanced breast cancer successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy. A 56-year-old male was referred to our hospital for treatment of recurrent metastatic breast cancer. When he was admitted, his general condition was poor due to massive intraperitoneal metastasis. We administered TAC chemotherapy (docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2), every 3 weeks). During chemotherapy, he showed no major adverse effects except grade 3 neutropenia, which could be easily managed with G-CSF administration. Metastatic lesions almost disappeared after 4 cycles of TAC. TAC therapy was considered to be acceptable as salvage therapy for a metastatic male breast cancer patient.

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

    PubMed

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

    1978-09-01

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

  1. Water intoxication associated with moderate dose of cyclophosphamide pulse therapy in an elderly patient: a case report and literature review.

    PubMed

    Yanagisawa, Kunio; Hiromura, Keiju; Yagi, Hiroaki; Yokohama, Akihiko; Kaneko, Yoriaki; Kuroiwa, Takashi; Ueki, Kazue; Nojima, Yoshihisa

    2005-01-01

    Intravenous high-dose cyclophosphamide infusion, usually performed to treat malignant neoplasms, is known to cause water intoxication. Intravenous cyclophosphamide pulse therapy (IVCY) is increasingly being employed for the treatment of rheumatic diseases as well. Recently, water intoxication has been reported to occur even after low-to-moderate doses of IVCY. In the present paper, we describe a case of polyarteritis nodosa in a patient in whom water intoxication developed after IVCY at a moderate dose. Hydration is usually performed to maintain sufficient urine flow to avoid cystitis. Based on our case and a review of the literature, it is recommended that hydration should be carefully performed during IVCY in order to avoid water intoxication, especially when treating elderly patients.

  2. 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

  3. The role of combined fludarabine, cyclophosphamide and rituximab chemoimmunotherapy in chronic lymphocytic leukemia: current evidence and controversies

    PubMed Central

    Skarbnik, Alan P.; Faderl, Stefan

    2016-01-01

    Chemoimmunotherapy (CIT) has become a cornerstone in the treatment of patients with chronic lymphocytic leukemia (CLL). The combination of fludarabine, cyclophosphamide and rituximab (FCR) has emerged as the standard of care for therapy of previously untreated patients with CLL who are younger than 65 years and have no significant comorbidities. In this article, we review the role of FCR in the current treatment paradigm for CLL. PMID:28246553

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

    SciTech Connect

    Gambone, L.M.; Elbon, C.L.; Fryer, A.D.

    1994-09-01

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

  5. Cyclophosphamide-induced oxidative stress in brain: protective effect of hot short pepper (Capsicum frutescens L. var. abbreviatum).

    PubMed

    Oboh, Ganiyu; Ogunruku, Omodesola O

    2010-05-01

    This study sought to characterize the distribution of phenols and antioxidant activities in hot short pepper (Capsicum frutescens var. abbreviatum) and their inhibition of cyclophosphamide-induced oxidative stress in rat's brain. The total phenol content and antioxidant activities of pepper flesh (pericarp) and seeds were determined in vitro and in vivo. The results of the study revealed that intraperitoneal administration of cyclophosphamide (75mg/kg of body weight) caused a significant increase (P<0.05) in the malondialdehyde (MDA) content of the brain; however, there was a significant decrease (P<0.05) in the brain MDA content, in those of rats fed diet containing pepper; the flesh showed a higher inhibitory effect. In addition, dietary inclusion of the pepper (seed and flesh) also caused a dose-dependent inhibition of serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase and total bilirubin; likewise, dietary inclusion of the flesh inhibited MDA production than the seeds. The higher inhibition of oxidative stress in brain and serum enzymes and metabolites by the flesh could be attributed to its significantly higher (P<0.05) total phenol content, reducing power and free-radical scavenging ability. Therefore, dietary hot short pepper (Capsicum frutescens L. var. abbreviatum) could prevent cyclophosphamide-induced oxidative stress in brain; although the flesh is a better protectant, the possible contributory role of the seeds cannot be neglected. However, this protective effect of the pepper could be attributed to their antioxidant properties.

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

    PubMed

    Bolaños-Meade, Javier; Fuchs, Ephraim J; Luznik, Leo; Lanzkron, Sophie M; Gamper, Christopher J; Jones, Richard J; Brodsky, Robert A

    2012-11-22

    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.

  7. [The application of SCGE-KIAS in monitoring of DNA damage in lymphocytes of tumor patients treated with cyclophosphamide].

    PubMed

    Cheng, Shao-Hui; Ma, Xiao-Hui; Bu, Li-Ming; Liu, Ning; Sun, Dian-Jun

    2003-10-01

    Single cell gel electrophoresis assay (SCGE), also named as alkaline comet assay, was a simple, rapid and sensitive method to evaluate DNA damage. In this study SCGE technique was used to monitor DNA damage difference in tumor patients caused by chemotherapy, DNA damage distribution frequency and DNA damage characters were analyzed by komet image analysis system (KIAS). The results showed that cyclophosphamide greatly caused DNA damage in lymphocytes of tumor patients. There was significant difference of peripheral blood lymphocyte DNA damage between tumor patients and healthy controls. Tail length of lymphocytes were 33.69 +/- 7.56 micro m, and tail DNA% we re 31.51 +/- 5.4 6% in 10 cancer patients treated with cyclophosphamide, while Tail length were 1 6.2 +/- 1.5 micro m and tail DNA% were 7.46 +/- 1.15% in healthy controls. there was great significant difference on tail length and tail DNA% values between cancer patients and healthy controls (P < 0.01). In conclusion, the successful measurement of DNA damage caused by Cyclophosphamide treatment means that the alkaline comet assay as a valuable tool can be very useful in cancer epideminology study, and also be valuable to evaluate DNA damage status of patients in clinic.

  8. [The determination of urinary cyclophosphamide at low concentration levels by liquid-liquid extraction and HPLC/MS/MS analysis].

    PubMed

    Sottani, C; Turci, R; Perbellini, L; Minoia, C

    1998-01-01

    A sensitive, specific and accurate high-performance liquid chromatography-ion spray-tandem mass spectrometry procedure (HPLC/MS/MS) has been developed to quantify cyclophosphamide in human urine. This methodology, which includes the liquid-liquid extraction with ethyl acetate, requires no derivatization procedures, preventing cyclophosphamide from possible thermal and chemical decomposition reactions. This methodology was validated by the use of ifosfamide as internal standard (I.S.). The assay was linear over the range 0 to 3.2 ng mL-1 urine, having a low limit of quantification of 0.2 ng mL-1. The low limit of detection was assessed at 0.05 ng mL-1 urine. This method is characterized by a coefficient of variation < 10%. Standard calibration curves, performed on three different days, had correlation coefficient always greater than 0.998. The intra and inter-day precision were within 11%, and accuracy was included in the range 99-103%. The mean extracted recovery assessed at three different concentrations (0.5, 0.8, 3.2 ng mL-1) was always more than 85%. The extraction efficiency of cyclophosphamide from urine samples was also studied at six different pH values (pH 4, 5, 6, 7, 8, 10). CP gave the maximum extraction efficiency when pH urine solutions was adjusted to 7.0 and somewhat lower at the other considered values.

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

    PubMed

    Guthrie, T H

    1987-04-01

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

  10. 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

  11. 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.

  12. Fludarabine, cyclophosphamide, and rituximab in salvage therapy of Waldenström's macroglobulinemia.

    PubMed

    Tedeschi, Alessandra; Ricci, Francesca; Goldaniga, Maria Cecilia; Benevolo, Giulia; Varettoni, Marzia; Motta, Marina; Pioltelli, Pietro; Gini, Guido; Barate', Claudia; Luraschi, Annamaria; Vismara, Eleonora; Frustaci, Anna Maria; Nichelatti, Michele; Vitolo, Umberto; Baldini, Luca; Morra, Enrica

    2013-04-01

    The combination FCR (fludarabine, cyclophosphamide, and rituximab) proved to be active in Waldenström's macroglobulinemia in a mixed population of untreated and previously treated patients. Prolonged myelosuppression and concerns about purine analogue treatment led to the conclusion that this regimen should be avoided in younger patients in first-line treatment. In this retrospective study on 40 patients we observed a response rate of 80% (32) after FCR salvage treatment with 32.5% (13) of patients reaching at least a very good partial remission. None of the prognostic variables had a significant effect on response or good quality of response achievement. Median event-free survival was reached at 77 months; median progression-free survival was not reached after a median follow-up of 51 months with any difference when categorizing patients according to quality of response. The results of this study suggest that the FCR regimen might overcome poor prognostic features and should be taken into account as salvage treatment. Tardive immunosuppression and myelosuppression warrant accurate patient follow-up.

  13. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study.

    PubMed

    Bringhen, Sara; Petrucci, Maria Teresa; Larocca, Alessandra; Conticello, Concetta; Rossi, Davide; Magarotto, Valeria; Musto, Pellegrino; Boccadifuoco, Luana; Offidani, Massimo; Omedé, Paola; Gentilini, Fabiana; Ciccone, Giovannino; Benevolo, Giulia; Genuardi, Mariella; Montefusco, Vittorio; Oliva, Stefania; Caravita, Tommaso; Tacchetti, Paola; Boccadoro, Mario; Sonneveld, Pieter; Palumbo, Antonio

    2014-07-03

    This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) ≥65 years of age or who were ineligible for autologous stem cell transplantation. Patients (N = 58) received CCyd for up to 9 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required carfilzomib dose reductions. In summary, results showed high complete response rates and a good safety profile. This trial was registered at clinicaltrials.gov as #NCT01346787.

  14. Interventional effects of squid ink polysaccharides on cyclophosphamide-associated testicular damage in mice.

    PubMed

    Le, X Y; Luo, P; Gu, Y P; Tao, Y X; Liu, H Z

    2015-01-01

    Cyclophosphamide (CP) is a commonly used antitumour and immunosuppressive drug, but it is inevitable that the chemotherapeutic agent may cause long-term or permanent reproductive damage on young male patients through inducing oxidative stress in the testes. Squid ink polysaccharides (SIP), a newly found marine glycosaminoglycon have been proved to have antioxidant capabilities and chemotherapy-protective activities on model animals in our recent investigations. This study was conducted to assess whether or not SIP could protect male mice against gonadotoxicity during CP exposure. Sexually mature male Kunming mice were allocated to one of four groups. CP was abdominally administered at dose of 15 mg/kg body weight to two groups of mice for ten weeks, once a week, one group of mice received SIP at dose of 80 mg/kg body weight by gavage for ten weeks, once a day. The other two groups comprised a vehicle treated group and an SIP treated group. Toxicity of CP and protective activity of SIP on the testes were assessed by: sperm parameters, organ index, testicular antioxidant ability, activities of marker enzymes, sex hormone content, and histopathological features. Data showed CP-induced, serious negative changes on murine sperm parameters, organ index, testicular antioxidant ability, activities of marker enzymes, sexual hormone contents, and histopathological features which were all significantly impaired by SIP. This study found that SIP were demonstrated to offer protective effects against CP-induced toxicity on testes in mice (Tab. 2, Fig. 3, Ref. 29).

  15. Using clinically approved cyclophosphamide regimens to control the humoral immune response to oncolytic viruses

    PubMed Central

    Peng, K-W; Myers, R; Greenslade, A; Mader, E; Greiner, S; Federspiel, MJ; Dispenzieri, A; Russell, SJ

    2013-01-01

    Oncolytic viruses can be neutralized in the bloodstream by antiviral antibodies whose titers increase progressively with each exposure, resulting in faster virus inactivation and further reductions in efficacy with each successive dose. A single dose of cyclophosphamide (CPA) at 370 mg m−2 was not sufficient to control the primary antiviral immune responses in mice, squirrel monkeys and humans. We therefore tested clinically approved multidose CPA regimens, which are known to kill proliferating lymphocytes, to determine if more intensive CPA therapy can more effectively suppress antiviral antibody responses during virotherapy. In virus-susceptible mice, primary antibody responses to intravenously (i.v.) administered oncolytic measles virus (MV) or vesicular stomatitis virus (VSV) were partially or completely suppressed, respectively, by oral (1 mg × 8 days) or systemic (3 mg × 4 days) CPA regimens initiated 1 day before virus. When MV- or VSV-immune mice were re-challenged with the respective viruses and concurrently treated with four daily systemic doses of CPA, their anamnestic antibody responses were completely suppressed and antiviral antibody titers fell significantly below pre-booster levels. We conclude that the CPA regimen of four daily doses at 370 mg m−2 should be evaluated clinically with i.v. virotherapy to control the antiviral antibody response and facilitate effective repeat dosing. PMID:22476202

  16. Using clinically approved cyclophosphamide regimens to control the humoral immune response to oncolytic viruses.

    PubMed

    Peng, K-W; Myers, R; Greenslade, A; Mader, E; Greiner, S; Federspiel, M J; Dispenzieri, A; Russell, S J

    2013-03-01

    Oncolytic viruses can be neutralized in the bloodstream by antiviral antibodies whose titers increase progressively with each exposure, resulting in faster virus inactivation and further reductions in efficacy with each successive dose. A single dose of cyclophosphamide (CPA) at 370 mg m(-2) was not sufficient to control the primary antiviral immune responses in mice, squirrel monkeys and humans. We therefore tested clinically approved multidose CPA regimens, which are known to kill proliferating lymphocytes, to determine if more intensive CPA therapy can more effectively suppress antiviral antibody responses during virotherapy. In virus-susceptible mice, primary antibody responses to intravenously (i.v.) administered oncolytic measles virus (MV) or vesicular stomatitis virus (VSV) were partially or completely suppressed, respectively, by oral (1 mg × 8 days) or systemic (3 mg × 4 days) CPA regimens initiated 1 day before virus. When MV- or VSV-immune mice were re-challenged with the respective viruses and concurrently treated with four daily systemic doses of CPA, their anamnestic antibody responses were completely suppressed and antiviral antibody titers fell significantly below pre-booster levels. We conclude that the CPA regimen of four daily doses at 370 mg m(-2) should be evaluated clinically with i.v. virotherapy to control the antiviral antibody response and facilitate effective repeat dosing.

  17. 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

  18. Protective effects of boron on cyclophosphamide induced lipid peroxidation and genotoxicity in rats.

    PubMed

    Ince, Sinan; Kucukkurt, Ismail; Demirel, Hasan Huseyin; Acaroz, Damla Arslan; Akbel, Erten; Cigerci, Ibrahim Hakki

    2014-08-01

    The aim of the present study was to evaluate the possible protective effect of boron (B) on cyclophosphamide (CYC) induced oxidative stress in rats. Totally, thirty Wistar albino male rats were fed standard rodent diet and divided into 5 equal groups: physiological saline was given intraperitoneally (i.p.) to the control group (vehicle treated), to the second group only 75 mg kg(-1) CYC was given i.p. on the 14th d, and boron was administered (5, 10, and 20 mg kg(-1), i.p.) to the other groups for 14 d and CYC (75 mg kg(-1), i.p.) on the 14th d. CYC caused increase of malondialdehyde and decrease of glutathione levels, decrease of superoxide dismutase activities in erythrocyte and tissues, decrease of erythrocyte, heart, lung, and brain catalase, and plasma antioxidant activities. Also, CYC treatment caused to DNA damage in mononuclear leukocytes. Moreover, B exhibited protective action against the CYC-induced histopathological changes in tissues. However, treatment of B decreased severity of CYC-induced lipid peroxidation and genotoxicity on tissues. In conclusion, B has ameliorative effects against CYC-induced lipid peroxidation and genotoxicity by enhancing antioxidant defence mechanism in rat.

  19. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL

    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

    Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute–Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population. PMID:21245487

  20. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia

    PubMed Central

    Parikh, Sameer A.; Keating, Michael J.; O'Brien, Susan; Wang, Xuemei; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Estrov, Zeev; Badoux, Xavier; Lerner, Susan

    2011-01-01

    Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation. PMID:21750315

  1. Activation of the anticancer drugs cyclophosphamide and ifosfamide by cytochrome P450 BM3 mutants.

    PubMed

    Vredenburg, Galvin; den Braver-Sewradj, Shalenie; van Vugt-Lussenburg, Barbara M A; Vermeulen, Nico P E; Commandeur, Jan N M; Vos, J Chris

    2015-01-05

    Cyclophosphamide (CPA) and ifosfamide (IFA) are widely used anticancer agents that require metabolic activation by cytochrome P450 (CYP) enzymes. While 4-hydroxylation yields DNA-alkylating and cytotoxic metabolites, N-dechloroethylation results in the generation of neuro- and nephrotoxic byproducts. Gene-directed enzyme prodrug therapies (GDEPT) have been suggested to facilitate local CPA and IFA bioactivation by expressing CYP enzymes within the tumor cells, thereby increasing efficacy. We screened bacterial CYP BM3 mutants, previously engineered to metabolize drug-like compounds, for their ability to catalyze 4-hydroxylation of CPA and IFA. Two CYP BM3 mutants showed very rapid initial bioactivation of CPA and IFA, followed by a slower phase of product formation. N-dechloroethylation by these mutants was very low (IFA) to undetectable (CPA). Using purified CYP BM3 as an extracellular bioactivation tool, cytotoxicity of CPA and IFA metabolism was confirmed in U2OS cells. This novel application of CYP BM3 possibly provides a clean and catalytically efficient alternative to liver microsomes or S9 for the study of CYP-mediated drug toxicity. To our knowledge, the observed rate of CPA and IFA 4-hydroxylation by these CYP BM3 mutants is the fastest reported to date, and might be of potential interest for CPA and IFA GDEPT.

  2. Acrolein: unwanted side product or contribution to antiangiogenic properties of metronomic cyclophosphamide therapy?

    PubMed

    Günther, M; Wagner, E; Ogris, M

    2008-12-01

    Tumour therapy with cyclophosphamide (CPA), an alkylating chemotherapeutic agent, has been associated with reduced tumour blood supply and antiangiogenic effects when applied in a continuous, low-dose metronomic schedule. Compared to conventional high-dose scheduling, metronomic CPA therapy exhibits antitumoural activity with reduced side effects. We have studied potential antiangiogenic properties of acrolein which is released from CPA after hydroxylation. Acrolein adducts were found in tumour cells and tumour endothelial cells of CPA-treated mice, suggesting an in vivo relevance of acrolein. In vitro, acrolein inhibited endothelial cell proliferation, endothelial cell migration and tube formation. Moreover, acrolein caused disassembly of the F-actin cytoskeleton and inhibition of alphavbeta3 integrin clustering at focal adhesions points in endothelial cells. Acrolein treatment modulated expression of thrombospondin-1 (TSP-1), an endogenous inhibitor of angiogenesis known to be linked to antiangiogenic effects of metronomic CPA therapy. Further on, acrolein treatment of primary endothelial cells modified NF-(kappa)B activity levels. This is the first study that points at an antiangiogenic activity of acrolein in metronomically scheduled CPA therapy.

  3. 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

  4. 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

  5. [Adjuvant chemotherapy with mitoxantrone, cyclophosphamide and 5-fluorouracil in breast neoplasms: therapeutic life].

    PubMed

    Genre, D; Macquart-Moulin, G; Bouscary, M L; Viens, P; Cowen, D; Packer y Comyn, I; Moatti, J P; Maraninchi, D

    1997-03-01

    The chemotherapy side-effects are insufficiently documented while they strongly condition patients' quality of life. The aim of the study was to assess by means of a self-administered questionnaire the somatic symptoms experienced by breast cancer patients during their NCF (mitoxantrone + cyclophosphamide + 5-fluorouracil) chemotherapy and to demonstrate the interest of this self-report by comparing the frequency of side-effects assessed by the patients to that noted by the physicians in medical records. The study was carried out among 44 patients receiving their chemotherapy + radiotherapy at the Paoli-Calmettes Institute (marseille) between July 1994 and May 1995. The questionnaire comprized of 17 symptoms evaluated in terms of frequency, duration/severity and distress. The most frequent symptoms are: hair loss and nausea (75%), hot flush (57%), lack of appetite and headache (46%) associated with distress in 67 to 100% of cases. Their frequency was underestimated by the physicians in medical records. This study showed a large discordance patient-physician in the assessment of chemotherapy side-effects. The type of tool presented in this study could complement the usual scales of toxicity that do not provide an estimation of true patients' experience.

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

    PubMed

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

    2017-04-01

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

  7. Haploidentical transplantation with post-infusion cyclophosphamide in advanced Hodgkin lymphoma.

    PubMed

    Castagna, L; Bramanti, S; Devillier, R; Sarina, B; Crocchiolo, R; Furst, S; El-Cheikh, J; Granata, A; Faucher, C; Harbi, S; Morabito, L; Mariotti, J; Puvinathan, S; Weiller, P J; Chabannon, C; Mokart, D; Carlo-Stella, C; Bouabdallah, R; Santoro, A; Blaise, D

    2017-01-16

    We investigated the use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of advanced Hodgkin lymphoma (HL). Sixty-two consecutive HL patients underwent haplo-HSCT. Unmanipulated stem cells and post-transplant cyclophosphamide were given to all patients as GVHD prophylaxis. At 100 days, the cumulative incidence of grades 2-3 and grades 3-4 acute GVHD was 23% and 4%, respectively. The chronic GVHD (cGVHD) cumulative incidence was 16%, with one patient experiencing severe cGVHD. The 3-year OS, PFS, relapse rates and 1-year non-relapse mortality (NRM) were 63%, 59%, 21% and 20%, respectively. Uncontrolled disease status and high hematopoietic cell transplantation comorbidity index (HCT-CI) were associated with lower OS, whereas PBSC was an independent protective factor. Uncontrolled disease and HCT-CI >2 was predictive for NRM. Finally, disease status other than CR was predictive of relapse. In conclusion, haplo-HSCT is a valid treatment in advanced HL, offering excellent rates of survival and acceptable toxicities.Bone Marrow Transplantation advance online publication, 16 January 2017; doi:10.1038/bmt.2016.348.

  8. Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus.

    PubMed

    Salido, M; Macarron, P; Hernández-García, C; D'Cruz, D P; Khamashta, M A; Hughes, G R V

    2003-01-01

    Cyclophosphamide (CY) is an alkylating agent used to treat a variety of autoimmune disorders. Water intoxication is a well-known complication of high-dose intravenous (i.v.) CY, but is rare in patients treated with low dose i.v. CY. We describe two patients with lupus nephritis and water intoxication following low dose i.v. CY. The first patient was treated with oral prednisolone and azathioprine for eight weeks with inadequate response and persistent renal inflammatory activity. Eight hours after the first i.v. CY pulse she had a grand mal seizure. The second patient had WHO class III lupus nephritis, and after a single i.v. CY pulse developed vomiting, diarrhoea and grand mal seizures. They were both fluid-restricted and their serum sodium levels returned to normal. In conclusion, even at low doses i.v. CY may induce hyponatremia related to inappropriate antidiuretic hormone secretion. This potentially life-threatening complication of i.v. CY could be minimized by avoidance of overhydration following pulse i.v. CY.

  9. 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

  10. 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; Robins, Harlan S.; O’Donnell, Paul V.; 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

  11. Comparison of doxorubicin-cyclophosphamide with doxorubicin-dacarbazine for the adjuvant treatment of canine hemangiosarcoma.

    PubMed

    Finotello, R; Stefanello, D; Zini, E; Marconato, L

    2017-03-01

    Canine hemangiosarcoma (HSA) is a neoplasm of vascular endothelial origin that has an aggressive biological behaviour, with less than 10% of dogs alive at 12-months postdiagnosis. Treatment of choice consists of surgery followed by adjuvant doxorubicin-based chemotherapy. We prospectively compared adjuvant doxorubicin and dacarbazine (ADTIC) to a traditional doxorubicin and cyclophosphamide (AC) treatment, aiming at determining safety and assessing whether this regimen prolongs survival and time to metastasis (TTM). Twenty-seven dogs were enrolled; following staging work-up, 18 were treated with AC and 9 with ADTIC. Median TTM and survival time were longer for dogs treated with ADTIC compared with those receiving AC (>550 versus 112 days, P = 0.021 and >550 versus 142 days, P = 0.011, respectively). Both protocols were well tolerated, without need for dose reduction or increased interval between treatments. A protocol consisting of combined doxorubicin and dacarbazine is safe in dogs with HSA and prolongs TTM and survival time.

  12. 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.

  13. Cardiorenal protective effect of taurine against cyclophosphamide-induced toxicity in albino rats.

    PubMed

    Alhumaidha, Khaled A; Saleh, Dalia O; Abd El Fattah, Mai A; El-Eraky, Wafaa I; Moawad, Helmy

    2015-07-18

    Cyclophosphamide (CP) is a cytotoxic alkylating agent used in the treatment of malignant diseases and autoimmune disorders. Its clinical use is limited to its marked cardiorenal toxicity. The present study aimed to investigate the possible protective role of taurine (Tau; 200 mg·kg(-1) per day, i.p.) on CP-induced cardiorenal toxicity. CP (200 mg·kg(-1)) was administered as a single intraperitoneal injection whereas; Tau was administered for 3 weeks on a daily basis. The results showed that CP produced an elevation in serum activities of creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase, creatinine as well as blood urea nitrogen. CP also induced an elevation in the oxidative stress markers viz. elevation in the serum lipid peroxides level (measured as malondialdehyde; MDA) and reduction in reduced glutathione level and superoxide dismutase activity in both heart and renal tissue. On the other hand, administration of Tau attenuated the CP-evoked disturbances in the above mentioned parameters. In addition, CP exhibited electrocardiographic (ECG) changes, which were significantly reversed by Tau treatment. Finally, the histopathological examination emphasized the obtained results. In conclusion, Tau is suggested to be a potential candidate to ameliorate CP-induced cardiorenal toxicity that may be related to its antioxidant activity.

  14. 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

  15. 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

  16. Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus.

    PubMed

    Cerullo, Vincenzo; Diaconu, Iulia; Kangasniemi, Lotta; Rajecki, Maria; Escutenaire, Sophie; Koski, Anniina; Romano, Valentina; Rouvinen, Noora; Tuuminen, Tamara; Laasonen, Leena; Partanen, Kaarina; Kauppinen, Satu; Joensuu, Timo; Oksanen, Minna; Holm, Sirkka-Liisa; Haavisto, Elina; Karioja-Kallio, Aila; Kanerva, Anna; Pesonen, Sari; Arstila, Petteri T; Hemminki, Akseli

    2011-09-01

    Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50 mg/day, N = 21), intravenously (single 1,000 mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral + intravenous schedules) decreased regulatory T cells (T(regs)) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P < 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral + intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P < 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial.

  17. [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

  18. 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

  19. Antagonism of the transient receptor potential ankyrin 1 (TRPA1) attenuates hyperalgesia and urinary bladder overactivity in cyclophosphamide-induced haemorrhagic cystitis.

    PubMed

    Meotti, Flavia C; Forner, Stefânia; Lima-Garcia, Juliana F; Viana, Alice F; Calixto, João B

    2013-04-25

    The aim of this study was to investigate the involvement of the transient receptor potential ankyrin 1 (TRPA1) in haemorrhagic cystitis, the main side effect of cyclophosphamide-based chemotherapy. Hannover female rats received intraperitoneal (i.p.) injection of cyclophosphamide (three doses of 100 mg/kg, every other day, in a total of five days). This treatment was followed by the treatment with TRPA1 antagonist HC 030031 (50 mg/kg, p.o.). The threshold for hindpaw withdrawal or abdominal retraction to von Frey Hair and the locomotor activity were measured. The treatment with the TRPA1 antagonist HC 030031 significantly decreased mechanical hyperalgesia induced by cyclophosphamide without interfere with locomotor activity. Urodynamic parameters were performed by cystometry 24 h after a single treatment with cyclophosphamide (200 mg/kg, i.p.) in control and HC 030031 treated rats. Analyses of the urodynamic parameters showed that a single dose of cyclophosphamide was enough to significantly increase the number and amplitude of non-voiding contractions and to decrease the voided volume and voiding efficiency, without significantly altering basal, threshold or maximum pressure. The treatment with HC 030031 either before (100 mg/kg, p.o.) or after (30 mg/kg, i.v.) cyclophosphamide inhibited the non-voiding contractions but failed to counteract the loss in voiding efficiency. Our data demonstrates that nociceptive symptoms and urinary bladder overactivity caused by cyclophosphamide, in part, are dependent upon the activation of TRPA1. In this context, the antagonism of the receptor may be an alternative to minimise the urotoxic symptoms caused by this chemotherapeutic agent.

  20. Plasma concentrations of 4-hydroxycyclophosphamide and phosphoramide mustard in patients repeatedly given high doses of cyclophosphamide in preparation for bone marrow transplantation.

    PubMed

    Sladek, N E; Doeden, D; Powers, J F; Krivit, W

    1984-10-01

    Plasma half-life and area under the curve (AUC) values for cyclophosphamide were determined in patients given this agent iv at doses of 50-60 mg/kg/infusion. Apparent plasma half-life and AUC values for the metabolites 4-hydroxycyclophosphamide and phosphoramide mustard were also determined in some of these patients. Disappearance from the plasma of the parent compound as well as that of the metabolites was approximately first-order. Plasma half-life values for cyclophosphamide ranged from 45 to 480 mins; AUC values ranged from 10 to 188 mM X min. As expected, AUC values for cyclophosphamide increased approximately linearly with an increase in its plasma half-life. Apparent plasma half-life values for 4-hydroxycyclophosphamide and phosphoramide mustard increased approximately linearly with an increase in plasma half-life values for cyclophosphamide; the slopes of these relationships were 1.35 and 1.97, respectively, but did not quite extrapolate to zero. AUC values for 4-hydroxycyclophosphamide and phosphoramide mustard remained approximately constant at about 5 and 15 mM X min, respectively, over the relatively wide range of plasma half-life and AUC values obtained for cyclophosphamide. On the basis of these observations we suggest that (a) changes in the rate of cyclophosphamide hydroxylation, effected by whatever means, will not alter the systemic therapeutic and toxic responses to a given dose of cyclophosphamide, given that the cytotoxic effects of this agent are directly proportional to AUC values of 4-hydroxycyclophosphamide and/or phosphoramide mustard, and (b) in most cases, 4-hydroxycyclophosphamide, and not phosphoramide mustard, is likely to be the circulating metabolite of therapeutic importance in humans since the AUC values for phosphoramide mustard exceeded those for 4-hydroxycyclophosphamide by only a factor of 3 and tumor and bone marrow cells proliferating in culture are generally substantially (8-25-fold) more sensitive to 4

  1. 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.

  2. Timing of platelet recovery is associated with adequacy of leukapheresis product yield after cyclophosphamide and G-CSF in patients with lymphoma.

    PubMed

    Zimmerman, T M; Michelson, G C; Mick, R; Grinblatt, D L; Williams, S F

    1999-01-01

    A subgroup of patients with refractory Hodgkin's (HD) or non-Hodgkin's (NHL) lymphoma may be cured with high-dose chemotherapy and peripheral blood progenitor cell rescue. To investigate the relationship of adequate leukapheresis yield and time course of platelet recovery after mobilization chemotherapy, we retrospectively analyzed the leukapheresis yields in seven patients with Hodgkin's disease and fifteen patients with non-Hodgkin's lymphoma undergoing high-dose chemotherapy. Our goal was to develop a rule to determine when to initiate leukapheresis and then to prospectively validate this rule. All patients were mobilized with cyclophosphamide and G-CSF (granulocyte-colony stimulating factor). A total of 144 leukaphereses were completed and analyzed. Based on the CD34 content in the initial harvest product, fifteen patients were defined as poor mobilizers (CD34 < 0.15 x 10(6)/kg) and seven were good mobilizers. The platelet count on the first day of harvesting was significantly associated with the poor mobilizers (P = .03). Age, sex, marrow involvement, disease (HD vs. NHL), prior radiation, time since last chemotherapy, and total number of cycles of prior chemotherapy were not predictive of poor mobilizers. By using a platelet count cut off of 35 x 10(9)/L, we retrospectively analyzed 144 individual leukapheresis products, to test whether CD34 yield was predicted by the peripheral blood platelet count on the day of leukapheresis. This rule had an excellent sensitivity, 91%, and a specificity of 67%. Subsequently, we validated this rule with the next twenty-four patients undergoing leukapheresis of which there were 143 leukaphereses. The prediction rule exhibited a sensitivity of 72% and a specificity of 68% in the validation set. There does appear to be utility in using the platelet count to guide the initiation of leukapheresis after chemotherapy and G-CSF mobilization.

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

    PubMed Central

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

    2016-01-01

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

  4. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study.

    PubMed

    Schey, Stephen A; Morgan, Gareth J; Ramasamy, Karthik; Hazel, Beth; Ladon, Dariusz; Corderoy, Sophie; Jenner, Matthew; Phekoo, Karen; Boyd, Kevin; Davies, Faith E

    2010-08-01

    We report the results of a Phase I/II dose escalation study to determine the maximum tolerated dose (MTD) of cyclophosphamide when combined with lenalidomide and dexamethasone in relapsed/refractory myeloma. Thirty-one patients were enrolled in cohorts of 3, at five dose levels of cyclophosphamide to a maximum of 700 mg on days 1 and 8 of a 28-d cycle. Patients received lenalidomide 25 mg days 1-21 and dexamethasone 20 mg orally days 1-4 and 8-11. The MTD was 600 mg cyclophosphamide, days 1 and 8. Grade 3/4 haematological complications occurred in 26% of patients, grade 3/4 infection in 3% (both at 700 mg cyclophosphamide), with thromboembolic complications in 6% of patients. Overall complete response (CR) rate was 29%, very good partial response rate 7% and partial response rate 45% giving an overall response rate of 81%. After 21 months median follow-up, projected 2-year progression-free survival was 56%, with 80% overall survival at 30 months. Ten further patients were treated at MTD with a 40% CR rate. No dose reductions for any study drugs or deaths occurred during cycles 1-9. Lenalidomide, cyclophosphamide and dexamethasone is a safe, effective combination in relapsed myeloma inducing a high response rate, warranting further investigation in phase III trials.

  5. 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

    2015-09-25

    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.

  6. 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

  7. Exposure to Green Tea Extract Alters the Incidence of Specific Cyclophosphamide-Induced Malformations

    PubMed Central

    Logsdon, Amanda L.; Herring, Betty J.; Lockard, Jarrett E.; Miller, Brittany M.; Kim, Hanna; Hood, Ronald D.; Bailey, Melissa M.

    2012-01-01

    BACKGROUND Green tea extract (GTE) has been shown to have antioxidative properties due to its high content of polyphenols and catechin gallates. Previous studies indicated that catechin gallates scavenge free radicals and attenuate the effects of reactive oxidative species (ROS). Cyclophosphamide (CP) produces ROS, which can have adverse effects on development, causing limb, digit, and cranial abnormalities. The current study was performed to determine if exposure to GTE can decrease teratogenic effects induced by CP in CD-1 mice. METHODS From gestation days (GD) 6–13, mated CD-1 mice were dosed with 400 or 800 mg/kg/d GTE; 100, 200, 400, or 800 mg/kg/d GTE + CP; CP alone, or the vehicle. GTE was given by gavage. CP (20 mg/kg) was given by intraperitoneal injection on GD 10. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. RESULTS The highest GTE dose did not effectively attenuate, and in some cases exacerbated the negative effect of CP. GTE alone was also associated with an increased incidence of microblepharia. Conversely, moderate GTE doses (200 &/or 400 mg/kg/d) attenuated the effect of CP on fetal weight and (GTE 200 mg/kg/d) decreased the incidences of certain defects resulting from CP exposure. CONCLUSIONS Exposure of a developing mammal to moderate doses of GTE can modulate the effects of exposure to CP during development, possibly by affecting biotransformation, while a higher GTE dose tended to exacerbate the developmental toxicity of CP. GTE alone appeared to cause an adverse effect on eyelid development. PMID:22447743

  8. Acacia ferruginea inhibits cyclophosphamide-induced immunosuppression and urotoxicity by modulating cytokines in mice.

    PubMed

    Sakthivel, K M; Guruvayoorappan, Chandrasekaran

    2015-01-01

    Cyclophosphamide (CTX), commonly used as an anti-neoplastic drug, can cause adverse side-effects including immunotoxicity and urotoxicity. Increasingly, plants have become sources of therapeutics that can help to restore host immunity to normal. In this study, Acacia ferruginea was assessed for an ability to protect mice against/mitigate CTX-induced toxicity. Co-administration of an extract of A. ferruginea (10 mg/kg BW, IP daily) for 10 consecutive days reduced CTX (25 mg/kg BW, IP daily)-induced toxicity. Apart from improvements in bladder and small intestine morphology, there was marked improvement in anti-oxidant (glutathione) levels in the bladder, suggesting a role for the anti-oxidant in reducing CTX-induced urotoxicity. Moreover, use of the extract significantly increased total leukocyte counts and bone marrow cellularity/α-esterase activity in CTX-treated mice which suggested a protective effect on the hematopoietic system. Co-treatment with the extract also prevented decreases in organ (liver, kidney, spleen, thymus) weight as well as body weight, thereby seemingly lessening the potential impact of CTX on the host immune system. Further, CTX-induced increases in serum aspartate transanimase, alanine transaminase, and alkaline phosphatase were reversed by extract co-treatment, as were alterations in in situ formation/release of interferon (IFN)-γ, interleukin (IL)-2, granulocyte-macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-α. Overall, this study indicated there were some protective effects from use of an extract of A. ferruginea against CTX-induced toxicities, in part through modulation of levels of anti-oxidants and pro-inflammatory cytokines.

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

    PubMed Central

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

    2013-01-01

    Summary Background and objectives Induction therapy with oral cyclophosphamide (CYP) has been a mainstay of treatment in patients with severe renal failure secondary to ANCA-associated vasculitis (AAV). Recent evidence proposes using pulsed intravenous CYP in less severe disease to minimize adverse events. It is unclear if this can be translated to those with dialysis-dependent renal insufficiency. Design, setting, participants, & methods All AAV patients presenting between 2005 and 2010 requiring dialysis at presentation were retrospectively analyzed. Patients were treated with plasma exchange, corticosteroids, and intravenous CYP. Rate of dialysis independence at 3 and 12 months and adverse effects were assessed and compared with the outcome of the plasmapheresis, prednisolone, and oral CYP arm of the randomized MEPEX (methylprednisolone versus plasma exchange) trial. Results Forty-one patients were included. At 3 months, 3 (7.3%) patients had died on dialysis, 12 (29.3%) remained dialysis dependent, and 26 (63.4%) were dialysis independent (creatinine, 2.5 mg/dl; GFR, 26 ml/min per 1.73 m2). Four patients subsequently reached ESRD at a median time of 83 days. Thirty-seven (90%) patients reached 1 year follow-up, 13 (35%) remained dialysis dependent, and 24 (65%) had independent renal function. Eleven patients (27%) had episodes of leukopenia (white cell count <4×109/L) during CYP therapy and 17 (41%) experienced infectious complications. This compares favorably with the dialysis-dependent cohort treated with plasmapheresis in the MEPEX study in which 51% were alive with independent renal function at 1 year. Conclusions Intravenous CYP used with corticosteroids and plasmapheresis may be an effective alternative to oral CYP in patients with dialysis-dependent AAV. PMID:23160261

  10. Protective effect of Selenium nanoparticle against cyclophosphamide induced hepatotoxicity and genotoxicity in Swiss albino mice.

    PubMed

    Bhattacharjee, Arin; Basu, Abhishek; Ghosh, Prosenjit; Biswas, Jaydip; Bhattacharya, Sudin

    2014-08-01

    Cyclophosphamide (CP) is the most commonly used chemotherapeutic drug for various types of cancer. However, its use causes severe cytotoxicity to normal cells in human. It is well known that the undesirable side effects are caused due to the formation of reactive oxygen species. Selenium is an essential micronutrient for both animals and humans and has antioxidant and membrane stabilizing property, but selenium is also toxic above certain level. Nano selenium has been well proved to be less toxic than inorganic selenium as well as certain organoselenium compounds. The objective of the study is to evaluate the protective role of Nano-Se against CP-induced hepatotoxicity and genotoxicity in Swiss albino mice. CP was administered intraperitoneally (25 mg/kg b.w.) and Nano-Se was given by oral gavages (2 mg Se/kg b.w.) in concomitant and pretreatment scheme. Intraperitoneal administration of CP induced hepatic damage as indicated by the serum marker enzymes aspartate and alanine transaminases and increased the malonaldehyde level, depleted the glutathione content and antioxidant enzyme activity (glutathione peroxidase, glutathione-s-transferase, superoxide dismutase and catalase), and induced DNA damage and chromosomal aberration. Oral administration of Nano-Se caused a significant reduction in malonaldehyde, ROS level and glutathione levels, restoration of antioxidant enzyme activity, reduction in chromosomal aberration in bone marrow, and DNA damage in lymphocytes and also in bone marrow. Moreover, the chemoprotective efficiency of Nano-Se against CP induced toxicity was confirmed by histopathological evaluation. The results support the protective effect of Nano-Se against CP-induced hepatotoxicity and genotoxicity.

  11. 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.

  12. 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

  13. 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.

  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. Fludarabine, Cyclophosphamide, and Multiple-Dose Rituximab as Frontline Therapy for Chronic Lymphocytic Leukemia

    PubMed Central

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

    2016-01-01

    Background Fludarabine, cyclophosphamide and rituximab (FCR) results in durable responses in patients with previously untreated chronic lymphocytic leukemia (CLL). Previous reports suggest that in patients with relapsed CLL a dose-intensified rituximab regimen increases response rates compared to standard-dose rituximab. It is unknown whether rituximab intensification of the FCR regimen will result in improved response rates and patient outcomes in patients with previously untreated CLL. Methods We conducted a single-arm study to evaluate the safety and efficacy of a modified FCR regimen with multiple-dose rituximab (FCR3) in 65 patients with previously untreated CLL. Results were compared to an historical cohort treated with FCR. Results The overall response rate to FCR3 was 97%, with 75% of patients achieving a complete remission. Minimal residual disease negativity was achieved in 62% of patients by flow cytometry. Median time to progression (TTP) was 81 months, and median overall survival (OS) was not reached, with 58% of patients still alive at a median survivor follow-up of 9.7 years. Grade 3-4 neutropenia, grade 3-4 thrombocytopenia and major infection were observed with 45%, 5% and 1.9% of FCR3 courses, respectively. Therapy-related myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML) developed in 7 patients (11%) (P <0.01 compared to the historical FCR cohort). Conclusions In patients with previously untreated CLL, FCR3 resulted in similar response rates, TTP and OS compared to a historical cohort of patients treated with FCR. FCR3 was associated with an increased incidence of t-MDS/AML. PMID:26218678

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

    PubMed Central

    Strati, Paolo; Wierda, William; Burger, Jan; Ferrajoli, Alessandra; Tam, Constantine; Lerner, Susan; Keating, Michael J.; O’Brien, Susan

    2015-01-01

    BACKGROUND The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced improved response rates and a prolonged survival in patients with chronic lymphocytic leukemia (CLL). However, its therapeutic power is counterbalanced by significant hematologic toxicity. Persistent and new-onset cytopenia after the completion of FCR raise concern about disease recurrence, the development of therapy-related myeloid malignancies (TRMM), and infections. METHODS A total of 207 patients with CLL who achieved complete response, complete response with incomplete bone marrow recovery, or nodular partial remission were analyzed after frontline FCR therapy. RESULTS Three months after the completion of therapy, 35% of patients had developed grade 2 to 4 cytopenia (according to Common Terminology Criteria for Adverse Events [version 4.0]). Factors found to be associated with cytopenia at 3 months after therapy were older age, advanced Rai stage disease, and lower baseline blood counts. Moreover, patients with cytopenia were less likely to have completed 6 courses of therapy with FCR. At 6 months and 9 months after therapy, the prevalence of grade 2 to 4 cytopenia was 24% and 12%, respectively. No differences in progression-free survival and overall survival were noted between cytopenic and noncytopenic patients or between patients with persistent and new-onset cytopenia. The prevalence of TRMM was 2.3% and did not differ significantly between cytopenic and noncytopenic patients or between those with persistent and new-onset disease. Late infections were more common in patients who were cytopenic at 9 months (38%) and were mostly bacterial (67%). CONCLUSIONS Cytopenia after the completion of therapy is a common complication of frontline FCR that improves over time, particularly for new-onset cases. The presence of persistent cytopenia (lasting up to 9 months after the completion of therapy) should not raise concern about CLL recurrence of the development of TRMM, but

  17. Correlation of Cough With Disease Activity and Treatment With Cyclophosphamide in Scleroderma Interstitial Lung Disease

    PubMed Central

    Tseng, Chi-Hong; Li, Ning; Elashoff, Robert M.; Tashkin, Donald P.

    2012-01-01

    Background: Cough is a significant symptom in patients with scleroderma interstitial lung disease (SSc-ILD), affecting 73% of the 158 patients enrolled in the Scleroderma Lung Study (SLS), a multicenter randomized trial of oral cyclophosphamide (CYC) vs placebo (PLA) in patients with active interstitial lung disease. Methods: We examined the correlation of cough frequency and severity and phlegm production at baseline in 156 SLS participants with other baseline variables representing SSc-ILD disease activity and the cough response to 1 year of treatment with CYC vs PLA. Results: Patients with cough at baseline had significantly lower diffusing capacity of the lung for carbon monoxide, dyspnea, the quality-of-life physical component summary, and the maximal fibrosis score on high-resolution CT imaging compared with those without cough at baseline. Cough severity and frequency correlated with FVC % predicted. After 12 months of treatment, cough frequency decreased in the CYC group compared with the PLA group and was significantly different from the PLA group at 18 months (6 months after discontinuation of CYC). However, the decreases in cough frequency did not correlate with the changes in FVC or diffusing capacity of the lung for carbon monoxide observed in the CYC group. Treatment-related improvements in cough frequency, as well as in FVC, were no longer apparent 12 months after discontinuation of CYC. Conclusions: Cough is a common symptom in SSc-ILD and correlates with the extent of fibrosis. Cough frequency decreases significantly in response to treatment with CYC but returns to baseline 1 year after withdrawal of treatment. Cough may be a symptom of ongoing fibrosis and an independent variable in assessing therapeutic response to CYC. Trial registry: ClinicalTrials.gov; No.: NCT000004563; URL: www.clinicaltrials.gov PMID:22156609

  18. The effects of oral glutamine on cyclophosphamide-induced nephrotoxicity in rats.

    PubMed

    Abraham, Premila; Isaac, Bina

    2011-07-01

    Nephrotoxicity is one of the adverse side effects of cyclophosphamide (CP) chemotherapy. In a recent study, we have demonstrated that oxidative stress and glutathione depletion play important roles in CP-induced renal damage. The aim of the study was to verify whether glutamine, the precursor for glutathione synthesis, prevents CP-induced oxidative stress and renal damage using a rat model. Adult male rats were administered a single dose of 150 mg/ kg body weight of CP intraperitoneally. The glutamine-pretreated rats were administered 1 gm/kg body weight of glutamine orally 2 h before the administration of CP. Vehicle/glutamine-treated rats served as controls. All the rats were killed 16 h after the dose of CP/vehicle. The kidneys were removed and used for light microscopic and biochemical studies. The markers of oxidative stress including malondialdehyde content, protein carbonyl content, protein thiol, reduced glutathione and myeloperoxidase activity, a marker of neutrophil infiltration, were measured in kidney homogenates. CP treatment-induced damage to kidney involved the glomeruli and the tubules. Pretreatment with glutamine reduced CP-induced glutathione depletion and increased myeloperoxidase activity. However, it did not prevent CP-induced lipid peroxidation, protein carbonylation and renal damage. The results of the present study suggest that glutamine pretreatment does not prevent CP-induced lipid peroxidation and renal damage, although it prevents CP-induced glutathione depletion and neutrophil infiltration significantly. It is suggested that mechanisms other than oxidative stress may also be involved and/or oxidative stress may be consequence and not the cause of CP induced renal damage.

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

    PubMed

    El-Naggar, Sabry A; Abdel-Farid, Ibrahim B; Germoush, Mousa O; Elgebaly, Hassan A; Alm-Eldeen, Abeer A

    2016-10-01

    Context Cyclophosphamide (CTX) is used to treat different cancer types, although it causes severe hepatotoxicity due to its oxidative stress effect. Rosmarinus officinalis, L. (Lamiaceae) has a therapeutic potential against hepatotoxicity due to its antioxidant activity. Objective The objective of this study is to investigate the phytochemical analysis of the methanol extract of Rosmarinus officianalis leaves (MEROL) and its efficacy against CTX-induced hepatotoxicity. Materials and methods The phytochemical analyses were assessed spectrophotometericaly. To assess the MEROL efficacy, 72 Swiss albino mice were divided into six groups. Group 1 was control, groups 2 and 3 included mice which were injected intraperitoneally (i.p.) with 100 or 200 mg/kg of MEROL at days 1, 4, 7, 10, 13 and 16; group 4 was injected (i.p.) with CTX (200 mg/kg) at day 17, groups 5 and 6 were injected (i.p.) with MEROL as groups 3 and 4 followed by 200 mg/kg CTX at day 17, respectively. At day 22, six mice from each group were sacrificed and the others were sacrificed at day 37. Results MEROL has a high content of total phenolics, saponins, total antioxidant capacity and DPPH radical scavenging activity. The median lethal dose (LD50) value of MEROL was 4.125 g/kg b.w. The inhibitory concentration 50 (IC50) value for DPPH radical scavenging was 55 μg/mL. Pretreatment with 100 mg/kg MEROL for 16 d ameliorated CTX-induced hepatotoxicity represented in lowering the levels of the aspartate aminotransferase (AST) and lipid profile and minimizing the histological damage. Conclusions Pretreatment with 100 mg/kg b.w. MEROL mitigated CTX-induced hepatotoxicity due to its antioxidant activity.

  20. Evaluation of antioxidant effects of crocin on sperm quality in cyclophosphamide treated adult mice

    PubMed Central

    Bakhtiary, Zahra; Shahrooz, Rasoul; Ahmadi, Abbas; Zarei, Leila

    2014-01-01

    Cyclophosphamide (CP) is one of the anti-neoplastic drugs. Despite its numerous clinical applications, it has devastating effects on the testicles and declines the sperm quality in treated patients. This study was aimed to investigate the protective effect of crocin in improving the toxicity induced by CP in reproductive system. In this study, 24 male adult mice (6 to 8 weeks) were randomly divided into three groups, control group received normal saline (0.1 mL, IP, daily), the CP group received CP (15 mg kg-1, IP, weekly) and the CP + crocin group received CP along with crocin (200 mg kg-1, IP, daily). After 35 days of treatment, animals were sacrificed. The samples of epididymis in human tubal fluid medium incubated for 30 min in 5% CO2 for flotation of sperm. Sperm were obtained from caudal epididymis using dissecting method. Then, the parameters of sperm quality including sperm count, motility, viability, DNA damage, nuclear maturation, and sperm morphology were evaluated. In CP group, the sperm count, motility, viability, nuclear maturation and sperm morphology were significantly decreased compared to control group (p < 0.05) and in the CP + crocin group all of these parameters significantly increased compared to CP group (p < 0.05). The percentage of sperm with DNA damage in the CP group significantly increased compared to other groups (p < 0.05). The results of this study indicated that the crocin was able to suppress free radicals and enhance the quality of sperm in CP treated animals. PMID:25568721

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

    PubMed

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

    2015-09-01

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

  2. Rituximab versus cyclophosphamide for ANCA-associated vasculitis with renal involvement.

    PubMed

    Geetha, Duvuru; Specks, Ulrich; Stone, John H; Merkel, Peter A; Seo, Philip; Spiera, Robert; Langford, Carol A; Hoffman, Gary S; Kallenberg, Cees G M; St Clair, E William; Fessler, Barri J; Ding, Linna; Tchao, Nadia K; Ikle, David; Jepson, Brett; Brunetta, Paul; Fervenza, Fernando C

    2015-04-01

    Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown. This is a post hoc analysis of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immune GN, red blood cell casts in the urine, and/or a rise in serum creatinine concentration attributed to vasculitis). Remission-induction regimens were RTX at 375 mg/m(2) × 4 or CYC at 2 mg/kg/d. CYC was replaced by AZA (2 mg/kg/d) after 3-6 months. Both groups received glucocorticoids. Complete remission (CR) was defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG)=0 off prednisone. Fifty-two percent (102 of 197) of the patients had renal involvement at entry. Of these patients, 51 were randomized to RTX, and 51 to CYC/AZA. Mean eGFR was lower in the RTX group (41 versus 50 ml/min per 1.73 m(2); P=0.05); 61% and 75% of patients treated with RTX and 63% and 76% of patients treated with CYC/AZA achieved CR by 6 and 18 months, respectively. No differences in remission rates or increases in eGFR at 18 months were evident when analysis was stratified by ANCA type, AAV diagnosis (granulomatosis with polyangiitis versus microscopic polyangiitis), or new diagnosis (versus relapsing disease) at entry. There were no differences between treatment groups in relapses at 6, 12, or 18 months. No differences in adverse events were observed. In conclusion, patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids.

  3. 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

  4. Biochemical and connective tissue changes in cyclophosphamide-induced lung fibrosis in rats.

    PubMed

    Venkatesan, N; Punithavathi, D; Chandrakasan, G

    1998-10-01

    The present investigation was designed to characterize the biochemical and connective tissue components and to correlate the significance of morphological and biochemical perturbations in cyclophosphamide (CP)-induced lung fibrosis in rats. Lung fibrosis was induced in male Wistar rats by intraperitoneal injection of 20 mg/100 g body weight of CP, and their pneumotoxic derangements were characterized during an early destructive phase followed by a proliferative and synthetic phase. Serum angiotensin-converting enzyme (ACE) activity was higher in CP-treated rats at days 2, 3, 5, 7, and 11, but there was a significant decrease in lung ACE activity during the same time period. Elevated levels of beta-glucuronidase activity were observed in the lung lavage fluid of CP-administered rats days 2, 3, 5, and 7. Lung myeloperoxidase activity was higher in CP rats. Of significance was the presence of collagenase and collagenolytic cathepsin in the lavage fluid of CP rats, when compared with the barely detectable levels in controls. A similar increase in these enzyme activities was also noticed in the lung tissue of CP rats during the same experimental period. Lavage fluid hydroxyproline content was higher in CP rats when compared with controls. Similarly, lung protein and DNA levels were elevated significantly after treatment with CP. The pulmonary histamine and serotonin contents were significantly higher in CP rats. The incorporation of [3H]thymidine into lung total DNA, [3H]proline into lung hydroxyproline, and [35S]sulphate into lung glycosaminoglycan, measured as indicators of lung DNA, collagen, and glycosaminoglycan synthesis, respectively, was also higher in CP groups. Increased levels of hydroxyproline, elastin, hexosamine, total hexose, fucose, sialic acid, and uronic acid in the lungs of rats 14, 28, and 42 days after CP insult were characterized as biomarkers of CP-induced interstitial changes. These findings indicate that CP-induced lung fibrosis results in

  5. 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

  6. Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis

    PubMed Central

    Brochet, Bruno; Deloire, Mathilde S. A.; Perez, Paul; Loock, Timothé; Baschet, Louise; Debouverie, Marc; Pittion, Sophie; Ouallet, Jean-Christophe; Clavelou, Pierre; de Sèze, Jérôme; Collongues, Nicolas; Vermersch, Patrick; Zéphir, Hélène; Castelnovo, Giovanni; Labauge, Pierre; Lebrun, Christine; Cohen, Mikael; Ruet, Aurélie

    2017-01-01

    Background Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far. Objective To compare CPM to methylprednisolone (MP) in SPMS. Methods Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area—MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model. Results Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31–1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14–4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17–0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected. Conclusion Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability. Trial Registration Clinicaltrials.gov NCT00241254 PMID:28045953

  7. 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.

  8. Effects of melatonin on DNA damage induced by cyclophosphamide in rats

    PubMed Central

    Ferreira, S.G.; Peliciari-Garcia, R.A.; Takahashi-Hyodo, S.A.; Rodrigues, A.C.; Amaral, F.G.; Berra, C.M.; Bordin, S.; Curi, R.; Cipolla-Neto, J.

    2013-01-01

    The antioxidant and free radical scavenger properties of melatonin have been well described in the literature. In this study, our objective was to determine the protective effect of the pineal gland hormone against the DNA damage induced by cyclophosphamide (CP), an anti-tumor agent that is widely applied in clinical practice. DNA damage was induced in rats by a single intraperitoneal injection of CP (20 or 50 mg/kg). Animals received melatonin during the dark period for 15 days (1 mg/kg in the drinking water). Rat bone marrow cells were used for the determination of chromosomal aberrations and of formamidopyrimidine DNA glycosylase enzyme (Fpg)-sensitive sites by the comet technique and of Xpf mRNA expression by qRT-PCR. The number (mean ± SE) of chromosomal aberrations in pinealectomized (PINX) animals treated with melatonin and CP (2.50 ± 0.50/100 cells) was lower than that obtained for PINX animals injected with CP (12 ± 1.8/100 cells), thus showing a reduction of 85.8% in the number of chromosomal aberrations. This melatonin-mediated protection was also observed when oxidative lesions were analyzed by the Fpg-sensitive assay, both 24 and 48 h after CP administration. The expression of Xpf mRNA, which is involved in the DNA nucleotide excision repair machinery, was up-regulated by melatonin. The results indicate that melatonin is able to protect bone marrow cells by completely blocking CP-induced chromosome aberrations. Therefore, melatonin administration could be an alternative and effective treatment during chemotherapy. PMID:23471360

  9. Effects of melatonin on DNA damage induced by cyclophosphamide in rats.

    PubMed

    Ferreira, S G; Peliciari-Garcia, R A; Takahashi-Hyodo, S A; Rodrigues, A C; Amaral, F G; Berra, C M; Bordin, S; Curi, R; Cipolla-Neto, J

    2013-03-01

    The antioxidant and free radical scavenger properties of melatonin have been well described in the literature. In this study, our objective was to determine the protective effect of the pineal gland hormone against the DNA damage induced by cyclophosphamide (CP), an anti-tumor agent that is widely applied in clinical practice. DNA damage was induced in rats by a single intraperitoneal injection of CP (20 or 50 mg/kg). Animals received melatonin during the dark period for 15 days (1 mg/kg in the drinking water). Rat bone marrow cells were used for the determination of chromosomal aberrations and of formamidopyrimidine DNA glycosylase enzyme (Fpg)-sensitive sites by the comet technique and of Xpf mRNA expression by qRT-PCR. The number (mean ± SE) of chromosomal aberrations in pinealectomized (PINX) animals treated with melatonin and CP (2.50 ± 0.50/100 cells) was lower than that obtained for PINX animals injected with CP (12 ± 1.8/100 cells), thus showing a reduction of 85.8% in the number of chromosomal aberrations. This melatonin-mediated protection was also observed when oxidative lesions were analyzed by the Fpg-sensitive assay, both 24 and 48 h after CP administration. The expression of Xpf mRNA, which is involved in the DNA nucleotide excision repair machinery, was up-regulated by melatonin. The results indicate that melatonin is able to protect bone marrow cells by completely blocking CP-induced chromosome aberrations. Therefore, melatonin administration could be an alternative and effective treatment during chemotherapy.

  10. 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.

  11. Long-Term Outcomes after Treatment with Clofarabine ± Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome.

    PubMed

    Alatrash, Gheath; Thall, Peter F; Valdez, Benigno C; Fox, Patricia S; Ning, Jing; Garber, Haven R; Janbey, Selma; Worth, Laura L; Popat, Uday; Hosing, Chitra; Alousi, Amin M; Kebriaei, Partow; Shpall, Elizabeth J; Jones, Roy B; de Lima, Marcos; Rondon, Gabriela; Chen, Julianne; Champlin, Richard E; Andersson, Borje S

    2016-10-01

    Pretransplant conditioning regimens critically determine outcomes in the setting of allogeneic stem cell transplantation (allo-SCT). The use of nucleoside analogs such as fludarabine (Flu) in combination with i.v. busulfan (Bu) has been shown to be highly effective as a pretransplant conditioning regimen in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). Because leukemia relapse remains the leading cause of death after allo-SCT, we studied whether clofarabine (Clo), a nucleoside analog with potent antileukemia activity, can be used to complement Flu. In a preliminary report, we previously showed the safety and efficacy of Clo ± Flu with i.v. Bu in 51 patients with high-risk AML, CML, and MDS. The study has now been completed, and we present long-term follow-up data on the entire 70-patient population, which included 49 (70%), 8 (11%), and 13 (19%) patients with AML, MDS, and CML, respectively. Thirteen patients (19%) were in complete remission, and 41 patients (59%) received matched unrelated donor grafts. Engraftment was achieved in all patients. Sixty-three patients (90%) achieved complete remission. There were no deaths reported at day +30, and the 100-day nonrelapse mortality rate was 4% (n = 3). Thirty-one percent of patients (n = 22) developed grades II to IV acute graft-versus-host disease, and the median overall survival and progression-free survival times were 2.4 years and .9 years, respectively. Our results confirm the safety and overall and progression-free survival advantage of the arms with higher Clo doses and lower Flu doses, which was most prominent in the AML/MDS group.

  12. Corticosteroid and cyclophosphamide in acute exacerbation of idiopathic pulmonary fibrosis: a single center experience and literature review.

    PubMed

    Novelli, Luca; Ruggiero, Roberto; De Giacomi, Federica; Biffi, Alice; Faverio, Paola; Bilucaglia, Luca; Gamberini, Silvia; Messinesi, Grazia; Pesci, Alberto

    2016-12-23

    Acute Exacerbation (AEx) is a frequent and severe complication of Idiopathic Pulmonary Fibrosis (IPF). In the absence of consensus regarding treatment, studies evaluating the efficacy of specific therapies, such as corticosteroids and immunosuppresant agents, are needed. In this case series we evaluated the outcome in terms of survival of intravenous pulse doses of high-dose corticosteroid (methylprednisolone 1000 mg per day for 3 consecutive days) followed by montlhy cyclophosphamide administration (maximum 6 doses) in a cohort of patients with AEx-IPF referred to the Respiratory Unit, San Gerardo University Hospital, Monza, Italy, from 2009 to 2013. A total of 11 patients (7 males, median age 65 years) were enrolled. A median of five monthly pulse doses of cyclophosphamide were administered, with four patients receiving all 6 doses. Four patients died before completion. Three patients developed adverse events. Overall survival at 3 months was 73%, at 6 months 63%, at 12 months 55%, at 18 months 45% and at 2 years 27%. In-hospital mortality was 9%. Causes of death were: six respiratory failures from disease progression, one lung cancer and one breast cancer. Two patients received lung transplantation and were excluded from the Kaplan-Meier analysis. In conclusion, combined intravenous pulse doses of high-dose corticosteroid and cyclophosphamide could be a reasonable add-on therapy for AEx-IPF, considering the few side effects and safe profile. A complete and rapid diagnostic work-up associated to the proper management (e.g. support of respiratory failure with non-invasive ventilation) in the right setting, may also have a positive effect on patients' outcome.

  13. A case study: surface contamination of cyclophosphamide due to working practices and cleaning procedures in two Italian hospitals.

    PubMed

    Acampora, Antonio; Castiglia, Loredana; Miraglia, Nadia; Pieri, Maria; Soave, Claudio; Liotti, Francesco; Sannolo, Nicola

    2005-10-01

    The efficacy of preventive and organisational measures implemented in Italy to prevent the contamination of cytotoxic drug preparation rooms has been investigated, and oncologic wards of two Italian hospitals were examined. The sampling strategy was based not only on potential sources of contamination but also on responses to detailed questionnaires on workplace practices and work organisation. Wipe samples were taken from different surfaces of preparation rooms, before and after the work shift, over a span of a month. Cyclophosphamide was taken as the marker drug that reflects exposure to cytotoxic drugs, being measurable by GC/MS. In one of the two hospitals (Hospital A), a large amount of cyclophosphamide was found, both before and after shift, on the workbench (median value, 2.55 microg dm(-2), before shift), on the floor between the operator working position and the waste bin (>10 microg dm(-2), after shift), as also on door handles and storage shelves. No quantifiable levels of cytotoxic drug were detected in the second hospital investigated (Hospital B). These results could be attributed to the efficacy of cleaning procedures and working practices. In fact, both hospitals were provided with vertical-laminar airflow hoods and the (male) nurses had attended special training courses; but in Hospital A, cleaning procedures were carried out without substances used specifically for the cleaning of surfaces contaminated by cytotoxic drugs such as sodium hypochlorite. Working practices did not include Luer Lock devices. Cyclophosphamide concentrations found in both hospitals, compared with the quantities of drug handled, gave evidence of the importance of the correct handling of cytotoxic agents as a major tool in reducing contamination levels. The results reveal the insufficiency of the risk management measures which do not take into account working practices that are prevailing, and stress the necessity for periodic environmental monitoring, indispensable for

  14. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up.

    PubMed

    Ludwig, Heinz; Greil, Richard; Masszi, Tamas; Spicka, Ivan; Shpilberg, Ofer; Hajek, Roman; Dmoszynska, Anna; Paiva, Bruno; Vidriales, María-Belén; Esteves, Graca; Stoppa, Anne Marie; Robinson, Don; Chaturvedi, Shalini; Ataman, Ozlem; Enny, Christopher; Feng, Huaibao; van de Velde, Helgi; Viterbo, Luisa

    2015-11-01

    This follow-up extension of a randomised phase II study assessed differences in long-term outcomes between bortezomib-thalidomide-dexamethasone (VTD) and VTD-cyclophosphamide (VTDC) induction therapy in multiple myeloma. Newly diagnosed patients (n = 98) were randomised 1:1 to intravenous bortezomib (1·3 mg/m(2); days 1, 4, 8, 11), thalidomide (100 mg; days 1-21), and dexamethasone (40 mg; days 1-4, 9-12), with/without cyclophosphamide (400 mg/m(2); days 1, 8), for four 21-day cycles before stem-cell mobilisation/transplantation. After a median follow-up of 64·8 months, median time-to-next therapy was 51·8 and 47·9 months with VTD and VTDC, respectively. Type of subsequent therapy was similar in both arms. After adjusting for asymmetric censoring, median time to progression was not significantly different between VTD and VTDC [35·7 vs. 34·5 months; Hazard ratio (HR) 1·26, 95% confidence interval: 0·76-2·09; P = 0·370]. Five-year survival was 69·1% and 65·3% with VTD and VTDC, respectively. When analysed by minimal residual disease (MRD) status, overall survival was longer in MRD-negative versus MRD-positive patients with bone marrow-confirmed complete response (HR 3·66, P = 0·0318). VTD induction followed by transplantation provides long-term disease control and, consistent with the primary analysis, there is no additional benefit from adding cyclophosphamide. This study was registered at ClinicalTrials.gov (NCT00531453).

  15. Photocatalytic oxidation of 5-fluorouracil and cyclophosphamide via UV/TiO2 in an aqueous environment.

    PubMed

    Lin, Hank Hui-Hsiang; Lin, Angela Yu-Chen

    2014-01-01

    Cytostatic drugs are a class of pharmaceuticals that are increasingly used in cancer therapies; 5-fluorouracil is one of the most commonly used cytostatic (antineoplastic) drugs in the world. This study applied photocatalytic oxidation to remove 5-fluorouracil. Degussa P25 showed a higher photocatalytic degradation efficiency for 5-fluorouracil removal than Aldrich TiO2 and ZnO. Under optimal conditions (20 mg L(-1) TiO2 at pH 5.8), 200 μg L(-1) 5-fluorouracil can be removed within 2 h (k = 0.0375 min(-1)). 5-fluorouracil was found to be decomposed by near-surface OH free radicals produced from valence holes (hvb(+)). At a relatively high concentration, 5-fluorouracil (27.6 mg L(-1)) is >99.9% removed within 4 h by 300 mg L(-1) Degussa P25, while 24 h is required to reach complete mineralization with 96.7% fluoride recovery. Cyclophosphamide is another widely used cancer drug that follows a similar decomposition pathway. Cyclophosphamide (27.6 mg L(-1)) was also >99.9% eliminated within 4 h, but dechlorination and mineralization reached only 79.9% and 55.1%, respectively, after 16 h of irradiation. Together with the results for Microtox(®), it is suggested that the oxidation products of cyclophosphamide are even more recalcitrant and toxic. For engineering practices, despite the fact that photocatalytic oxidation can rapidly remove target antineoplastic, it is also important to further evaluate the treatment efficiency of the photoproducts.

  16. Radiation dosimetry.

    PubMed Central

    Cameron, J

    1991-01-01

    This article summarizes the basic facts about the measurement of ionizing radiation, usually referred to as radiation dosimetry. The article defines the common radiation quantities and units; gives typical levels of natural radiation and medical exposures; and describes the most important biological effects of radiation and the methods used to measure radiation. Finally, a proposal is made for a new radiation risk unit to make radiation risks more understandable to nonspecialists. PMID:2040250

  17. 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.

  18. Cyclophosphamide and tamoxifen as adjuvant therapies in the management of breast cancer. CRC Adjuvant Breast Trial Working Party.

    PubMed Central

    1988-01-01

    In 1980 the Cancer Research Campaign launched a multi-centre breast cancer trial; aimed at repeating the Scandinavian Chemotherapy Study Group's cyclophosphamide trial, and the NATO tamoxifen study; thereby further evaluating the role of these two adjuvant regimens in patients with early breast cancer. Two thousand two hundred and thirty women were randomized into this trial between 1980 and 1985 and preliminary analyses demonstrate a significant improvement in event-free survival for both regimens. Results from this study closely parallel the two trials it set out to repeat. PMID:2900646

  19. Determination of cyclophosphamide and ifosfamide in sewage effluent by stable isotope-dilution liquid chromatography-tandem mass spectrometry.

    PubMed

    Llewellyn, N; Lloyd, P; Jürgens, M D; Johnson, A C

    2011-11-25

    A reliable and specific method was developed for the determination of the cytotoxic drugs cyclophosphamide and ifosfamide in sewage effluent. The most successful combination was found to be Strata-X solid-phase extraction followed by Florisil® clean-up with analysis by liquid chromatography-tandem mass spectrometry. Quantification by internal standardisation was achieved using custom synthesised d4-cyclophophosphamide. The mass spectrometer was operated in highly selective reaction monitoring (HSRM) mode, which significantly reduced matrix noise and improved sensitivity. Although it suffered from some ionisation suppression, electrospray ionisation (ESI) was found to give an order of magnitude better sensitivity in terms of limit of detection than atmospheric pressure chemical ionisation (APCI). Using final effluent from two different sewage treatment plants, the method was validated following official European guidelines and shown to be a high performance tool for routine analysis at the sub-nanogram per litre level. Depending on the matrix, the limit of detection for cyclophosphamide was between 0.03 ng/L and 0.12 ng/L and for ifosfamide between 0.05 ng/L and 0.09 ng/L. For cyclophosphamide the accuracy and precision, tested at 1.7 ng/L, were 98-109% and ≤ 13%, CV respectively. For ifosfamide the accuracy and precision, tested at 1.1 ng/L, were 98-113% and ≤ 15% CV, respectively. Depending on the sample matrix the absolute recovery of the internal standard was between 57% and 70%. The method was tested by analysis of spot samples taken from the final effluent discharges of two sewage treatment plants; the first using a conventional trickling filter treatment process and second employing activated sludge followed by ultra violet treatment. Cyclophosphamide was detected at 0.19 ng/L at the first plant and at the second detected at 3.7 ng/L and 3.5 ng/L, before and after the UV treatment process; ifosfamide was not detectable at either plant.

  20. Sequential cyclophosphamide-bortezomib-dexamethasone unmasks the harmful cardiac effect of dexamethasone in primary light-chain cardiac amyloidosis.

    PubMed

    Le Bras, Fabien; Molinier-Frenkel, Valerie; Guellich, Aziz; Dupuis, Jehan; Belhadj, Karim; Guendouz, Soulef; Ayad, Karima; Colombat, Magali; Benhaiem, Nicole; Tissot, Claire Marie; Hulin, Anne; Jaccard, Arnaud; Damy, Thibaud

    2017-03-20

    Chemotherapy combining cyclophosphamide, bortezomib and dexamethasone is widely used in light-chain amyloidosis. The benefit is limited in patients with cardiac amyloidosis mainly because of adverse cardiac events. Retrospective analysis of our cohort showed that 39 patients died with 42% during the first month. A new escalation-sequential regimen was set to improve the outcomes. Nine newly-diagnosed patients were prospectively treated with close monitoring of serum N-terminal pro-brain natriuretic peptide, troponin-T and free light chains. The results show that corticoids may destabilise the heart through fluid retention. Thus, a sequential protocol may be a promising approach to treat these patients.

  1. Treatment of Vasodilator-resistant Mixed Connective Tissue Disease-associated Pulmonary Arterial Hypertension with Glucocorticoid and Cyclophosphamide

    PubMed Central

    Sugawara, Eri; Kato, Masaru; Hisada, Ryo; Oku, Kenji; Bohgaki, Toshiyuki; Horita, Tetsuya; Yasuda, Shinsuke; Atsumi, Tatsuya

    2017-01-01

    Pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MTCD), in contrast to other types of PAH, may respond to immunosuppressive therapy. Most PAH cases with an immunosuppressant response were in the early stages of the disease (WHO functional class III or less). The present case was a 34-year-old woman with MCTD-associated PAH (WHO functional class IV) who was resistant to a combination of three vasodilators. Afterwards, she was treated with glucocorticoid and cyclophosphamide. This case suggested the potential benefit of immunosuppressants in patients with severe MCTD-associated PAH. PMID:28202869

  2. Treatment of Vasodilator-resistant Mixed Connective Tissue Disease-associated Pulmonary Arterial Hypertension with Glucocorticoid and Cyclophosphamide.

    PubMed

    Sugawara, Eri; Kato, Masaru; Hisada, Ryo; Oku, Kenji; Bohgaki, Toshiyuki; Horita, Tetsuya; Yasuda, Shinsuke; Atsumi, Tatsuya

    2017-01-01

    Pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MTCD), in contrast to other types of PAH, may respond to immunosuppressive therapy. Most PAH cases with an immunosuppressant response were in the early stages of the disease (WHO functional class III or less). The present case was a 34-year-old woman with MCTD-associated PAH (WHO functional class IV) who was resistant to a combination of three vasodilators. Afterwards, she was treated with glucocorticoid and cyclophosphamide. This case suggested the potential benefit of immunosuppressants in patients with severe MCTD-associated PAH.

  3. Treatment of steroid-resistant post-transplant nephrotic syndrome with cyclophosphamide in a child with congenital nephrotic syndrome.

    PubMed

    Flynn, J T; Schulman, S L; deChadarevian, J P; Dunn, S P; Kaiser, B A; Polinsky, M S; Baluarte, H J

    1992-11-01

    A child with congenital nephrotic syndrome underwent renal transplantation, was treated for acute rejection, and then developed nephrotic syndrome and renal failure. He was felt to have minimal change disease on allograft biopsy, but failed to respond to therapy with corticosteroids. Cyclophosphamide was substituted for cyclosporine and rapidly induced a complete remission of his nephrotic syndrome. We feel that this case not only represents an important example of a useful therapeutic approach to the child with congenital nephrotic syndrome who develops nephrotic syndrome post transplantation, and also raises questions concerning the pathogenesis of congenital nephrotic syndrome.

  4. Long-term results of a randomized trial comparing cisplatin with cisplatin and cyclophosphamide with cisplatin, cyclophosphamide, and adriamycin in advanced ovarian cancer. GICOG (Gruppo Interregionale Cooperativo Oncologico Ginecologia), Italy.

    PubMed

    1992-05-01

    We report the long-term results of a randomized trial comparing cisplatin (P) with cisplatin and cyclophosphamide (CP) with cisplatin, cyclophosphamide, and adriamycin (CAP) in advanced ovarian cancer. Overall, this update confirms previously published data on 529 cases. Median survival times for the three treatments--CAP, CP, and P--are, respectively, 23, 20, and 19 months. The differences among the three arms are still nonsignificant and the estimated percentage survival at 7 years and confidence limits are, respectively, 21.7 (14.9-28.4), 17.0 (11.0-22.9), and 12.2 (6.9-17.4). According to the results of the Cox regression model on prognostic factors, higher grading, a larger residual tumor size, and performance status less than 80 (Karnovsky) all were independently associated with a poorer outcome, while a serous histotype was related to a better prognosis. The other variables (age, stage, center, type of surgery) initially included in the model did not appear to be significantly related to prognosis. The implications of these long-terms results relative to the application of combination chemotherapy with CAP or CP are discussed.

  5. Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/metotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid.

    PubMed

    Vogt, Ulf; Bielawski, Krzysztof P; Bosse, Ulrich; Schlotter, Claus M

    2004-11-01

    Breast cancer has a significant capacity to metastasize to bone. Bisphosphonates are the standard treatment for hypocalcaemia of malignancy (HCM), which is a common complication of bone metastasis. The combination of bisphosphonates with standard anticancer drugs such as paclitaxel or tamoxifen results in a synergistic apoptotic effect greater than that produced by either single agent alone. Potential antitumour effects in vitro of the two bisphosphonates zoledronic acid (Zol) and ibandronate (Ib) (each at 30 microM) combined with different anticancer drug combinations: cyclophosphamide/metotrexate/5-fluorouracil (CMF), epirubicin/cyclophosphamide (EC), epirubicin/paclitaxel (ET), and epirubicin/docetaxel (EDoc) were investigated using ATP-cell viability assay (ATP-CVA). Twenty cases of female primary, invasive breast cancer were assessed. Ibandronate and zoledronic acid alone showed an inhibitory effect on breast cancer tumour cells in vitro. The breast tumour growth inhibition effect for those two drugs amounted to 22 and 25% respectively. Inhibitory effects were clearly visible for all four combinations of anticancer drugs together with both bisphosphonates. Combinations of anticancer drugs with zoledronic acid seem to be more effective with respect to tumour growth inhibition than combinations with ibandronate.

  6. Severe Hepatic Sinusoidal Obstruction Syndrome in a Child Receiving Vincristine, Actinomycin-D, and Cyclophosphamide for Rhabdomyosarcoma: Successful Treatment with Defibrotide

    PubMed Central

    Choi, Aery; Kang, Young Kyung; Lim, Sewon; Kim, Dong Ho; Lim, Jung Sub; Lee, Jun Ah

    2016-01-01

    Hepatic sinusoidal obstruction syndrome (SOS) is a life-threatening syndrome that generally occurs as a complication after hematopoietic stem cell transplantation or, less commonly, after conventional chemotherapy. Regarding SOS in rhabdomyosarcoma patients who received conventional chemotherapy, the doses of chemotherapeutic agents are associated with the development of SOS. Several cases of SOS in rhabdomyosarcoma patients after receiving chemotherapy with escalated doses of cyclophosphamide have been reported. Here, we report on a 9-year-old female with rhabdomyosarcoma who developed severe SOS after receiving chemotherapy consisting of vincristine, actinomycin-D, and a moderate dose of cyclophosphamide. She was treated successfully with defibrotide without sequelae to the liver. PMID:27034141

  7. Polymorphisms and Clinical Outcome in Recurrent Ovarian Cancer Treated with Cyclophosphamide and Bevacizumab

    PubMed Central

    Schultheis, Anne M; Lurje, Georg; Rhodes, Katrin E; Zhang, Wu; Yang, Dongyun; Garcia, Agustin A; Morgan, Robert; Gandara, David; Scudder, Sidney; Oza, Amit; Hirte, Hal; Fleming, Gini; Roman, Lynda; Lenz, Heinz-Josef

    2008-01-01

    Purpose This study was designed to evaluate the associations between angiogenesis gene polymorphisms and clinical outcome in ovarian cancer patients treated with low dose Cyclophosphamide and Bevacizumab. Experimental Design Seventy recurrent/metastatic epithelial ovarian cancer patients were enrolled in a phase II clinical trial. Genomic DNA (gDNA) was available from 53 blood samples. Polymorphisms were analyzed using the PCR-RFLP protocol. A 5′ end 33p γATP labeled PCR protocol was used to analyze dinucleotide repeats. Results Patients genotyped A/A or A/T for IL-8 T-251A gene polymorphism had a statistically significant lower response rate (19%; 0%) than those homozygous T/T (50%) (p=0.006, Fisher’s exact test). Patients carrying minimum one C allele (C/C;C/T) of CXCR2 C+785T polymorphism showed a median PFS of 7.4 months compared to those homozygous T/T; PFS of 3.7 months (p=0.026, log-rank test). Patients with VEGF C+936T polymorphism C/T genotype had a longer median PFS of 11.8 months, compared to those with C/C and T/T genotype, which had median PFS of 5.5 months, and 3.2 months, respectively (p=0.061, log-rank test). Patients carrying both AM 3′ end alleles <14CA repeats had shortest median PFS of 3.4 months; patients with at least one allele >14 repeats or both alleles >14 repeats showed a median PFS of 6.4 months and 7.2 months, respectively (p=0.008 log-rank test). Conclusion Our data suggest, the IL-8 A-251T polymorphism may be a molecular predictor of response to Bevacizumab based chemotherapy. The CXCR2 C+785T, VEGF C+936T single nucleotide polymorphisms and the AM 3′ dinucleotide repeat polymorphisms may be molecular markers for PFS in ovarian cancer patients. PMID:19010874

  8. Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors1

    PubMed Central

    Ziegler, David S.; Cohn, Richard J.; McCowage, Geoffrey; Alvaro, Frank; Oswald, Cecilia; Mrongovius, Robert; White, Les

    2006-01-01

    The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children’s Cancer Study Group—VETOPEC I, Baby Brain 91, and VETOPEC II—have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed

  9. Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors.

    PubMed

    Ziegler, David S; Cohn, Richard J; McCowage, Geoffrey; Alvaro, Frank; Oswald, Cecilia; Mrongovius, Robert; White, Les

    2006-01-01

    The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children's Cancer Study Group--VETOPEC I, Baby Brain 91, and VETOPEC II--have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed

  10. Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508.

    PubMed

    Chan, K K; Hong, P S; Tutsch, K; Trump, D L

    1994-12-15

    The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially with the appearance of transient saturation kinetics in some and a mean t1/2 of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 microM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 microM and a terminal t1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was detected. Mean urinary excretion was: CP, 10.8; 4-OH, CP, 0.5; PM, 39.0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation coefficient of 0

  11. 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

  12. Evaluation of the utility of popliteal lymph node examination in a cyclophosphamide model of immunotoxicity in the rat.

    PubMed

    Lapointe, Jean-Martin; Valdez, Reginald A; Ryan, Anne M; Haley, Patrick J

    2016-07-01

    The objective of this study was to characterize the variability of rat lymphoid organ weights and morphology following treatment with a known immunotoxicant, with a focus on the usefulness of evaluating popliteal lymph node weight and histology. Cyclophosphamide was administered to male Sprague-Dawley rats by oral gavage at doses of 2, 7 or 12 mg/kg/day for 10 consecutive days. Left and right popliteal lymph nodes (PLN), spleen and thymus were collected at necropsy, weighed, fixed and processed for histopathology. Femoral bone marrow was also collected, fixed and processed for histology. Organ weight variability was greater for PLN than for either spleen or thymus in control animals. There was a significant but weak correlation between paired left and right PLN weights (p < 0.005; r(2) = 0.2774). Significant treatment-related decreases in lymphoid organ weights were observed in spleen and thymus at ≥ 7 mg/kg/day (p < 0.01), whereas in PLN a significant decrease (p < 0.05) was noted only at 12 mg/kg/day. The inclusion of PLN did not enhance the sensitivity of detection of systemic treatment-related changes in lymphoid organs in a rat cyclophosphamide model.

  13. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma.

    PubMed

    García-Sanz, R; González-Porras, J R; Hernández, J M; Polo-Zarzuela, M; Sureda, A; Barrenetxea, C; Palomera, L; López, R; Grande-García, C; Alegre, A; Vargas-Pabón, M; Gutiérrez, O N; Rodríguez, J A; San Miguel, J F

    2004-04-01

    We evaluate the efficacy of the oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 71 refractory/relapsed multiple myeloma patients, including a prognostic analysis to predict both response and survival. Patients received thalidomide at escalating doses (200-800 mg/day), daily cyclophosphamide (50 mg/day) and pulsed dexamethasone (40 mg/day, 4 days every 3 weeks). On an intention-to-treat basis and using the EBMT response criteria, 2% patients reached complete response (CR), 55% partial response (PR) and 26% minor response (MR) yielding a total response (CR+PR+MR) rate of 83% after 3 months of therapy. After 6 months of therapy, responses were maintained including a 10% CR. The 2-year progression free and overall survival were 57 and 66%, respectively. A favorable response was associated with beta2 microglobulin < or =4 mg/dl, platelets >80 x 10(9)/l and nonrefractory disease. Regarding survival, low beta2 microglobulin (< or =4 mg/dl), age (< or =65 years) and absence of extramedullary myelomatous lesion were associated with a longer survival. Major adverse effects included constipation (24%), somnolence (18%), fatigue (17%) and infection (13%). Only 7% of patients developed a thrombo-embolic event. ThaCyDex is an oral regimen that induces a high response rate and long remissions, particularly in relapsing patients with beta2 microglobulin < or =4 mg/dl and < or =65 years.

  14. Protective effects of the antileishmanial extract of Tephrosia cinerea (L.) Pers. (Fabaceae) against cyclophosphamide-induced damage.

    PubMed

    Dias, A C S; Moreira, V R; Almeida, L P; Lima, M I S; Bezerra, J L; Ribeiro, M N S; Nascimento, F R F; Pereira, S R F

    2014-10-31

    Tephrosia cinerea L. (Pers.) is a tropical species that exhibits antileishmanial activity in Leishmania amazonensis promastigote cultures and is commonly used to treat infections, inflammations, ulcers, nervous conditions, and diarrhea. However, no studies have investigated its effects on genetic material. Therefore, we evaluated the genotoxic potential, antigenotoxic potential, and cytotoxic effects of hydroalcoholic extracts of T. cinerea leaves. In an in vitro genotoxicity study, human peripheral blood leukocytes were treated for 3, 24 (comet assay), or 48 h (cell death assay) with 22, 44, or 88 μg/mL plant extract. In the in vivo assay, Swiss mice were treated with 500, 1000, or 2000 mg extract/kg body weight by intraperitoneal injection and were evaluated 24 h later. Antigenotoxicity was investigated in pre- and post-treatment assays in which the animals received the plant extract (2000 mg/kg) 24 h before or after receiving cyclophosphamide (50 mg/kg), respectively. The extract had no genotoxic effects in the in vitro or in vivo assays. However, the extract reduced apoptotic cell death and induced necrotic cell death at concentrations that presented leishmanicidal activity in vitro. The extract also had an antigenotoxic effect, reducing the levels of genomic damage that were caused by cyclophosphamide in Swiss mice by more than 80%.

  15. 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%.

  16. Oral metronomic cyclophosphamide and methotrexate plus fulvestrant in advanced breast cancer patients: a mono-institutional case-cohort report.

    PubMed

    Aurilio, Gaetano; Munzone, Elisabetta; Botteri, Edoardo; Sciandivasci, Angela; Adamoli, Laura; Minchella, Ida; Esposito, Angela; Cullurà, Daniela; Curigliano, Giuseppe; Colleoni, Marco; Goldhirsch, Aron; Nolè, Franco

    2012-09-01

    Fulvestrant is effective in postmenopausal women with estrogen receptor-positive advanced breast cancer (ABC). So far, no published data exist on fulvestrant combined with chemotherapy. We retrospectively assessed the role of combining oral metronomic cyclophosphamide and methotrexate (CM) to fulvestrant in two cohorts (A and B) of heavily pre-treated estrogen receptor-positive advanced ABC patients. From October 2006 to September 2009, 33 postmenopausal patients received fulvestrant 250 mg via i.m. injection q28 days. In A, 20 patients added metronomic cyclophosphamide (50 mg p.o. daily) and methotrexate (2.5 mg p.o. twice daily on day 1 and day 4 weekly) after disease progression, continuing fulvestrant at the same dose. In B, 13 patients started fulvestrant plus metronomic CM upfront. Thirty-two patients were evaluable for response. Clinical benefit (partial response + stable disease >24 months) for A + B was 56% (95% CI 38-74%). The addition of metronomic CM did not determine relevant toxicities. Treatment with fulvestrant plus metronomic CM was effective in advanced ABC and was minimally toxic providing long-term disease control in a high proportion of patients. The prolonged clinical benefit, often desirable in such patients, supports this regimen as an additional and useful therapeutic tool.

  17. 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

  18. Protective effect of curcumin and chlorophyllin against DNA mutation induced by cyclophosphamide or benzo[a]pyrene.

    PubMed

    Ibrahim, Marwa A; Elbehairy, Adel M; Ghoneim, Magdy A; Amer, Hassan A

    2007-01-01

    The current study was carried out to evaluate the potency of curcumin and chlorophyllin as natural antioxidants to reduce the oxidative stress markers induced by cyclophosphamide (CP) and benzo[a]pyrene [B(a)P] which were used as free radical inducers. For this purpose, 126 male albino rats were used. The animals were assigned into 4 main groups: negative control group; oxidant-treated group (subdivided into two subgroups: cyclophosphamide-treated group and benzo[a]pyrene-treated group); curcumin-treated group; and chlorophyllin-treated group. Liver samples were collected after two days post the oxidant inoculation and at the end of the experimental period (10 weeks). These samples were examined for determination of liver microsomal malondialdehyde (MDA), DNA fragmentation, restriction fragment length polymorphism (RFLP) and 8-hydroxy deoxyguanosine (8-OHdG) concentration. Both CP and B(a)P caused increments in DNA fragmentation percentages, liver microsomal MDA, concentration of 8-OHdG and induced point mutation. Treatment of rats with either curcumin or chlorophyllin revealed lower DNA fragmentation percentages, liver microsomal MDA concentration, concentration of 8-OHdG and prevented induction of mutations, i.e., reversed the oxidative stress induced by CP and B(a)P and proved that they were capable of protecting rats against the oxidative damage evoked by these oxidants.

  19. 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.

  20. 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.

  1. 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

  2. Successful treatment of steroid and cyclophosphamide-resistant diffuse scleroderma-associated interstitial lung disease with rituximab.

    PubMed

    Yoo, Wan-Hee

    2012-03-01

    Scleroderma (SSc) is a multisystem disorder characterized by fibrosis and collagen deposition in the dermis, but affects multiple organ systems, leading to esophageal dysmotility, renal failure, and interstitial lung disease (ILD). ILD is common manifestation of diffuse type of SSc and may be life threatening, and require aggressive therapy with cytotoxic agents. Although high-dose steroid and cyclophosphamide are most commonly used therapy for SSc-associated ILD, the efficacy is questionable in some cases and more effective and less toxic therapies are needed. Rituximab (RTX) is a chimeric mAb against human CD20 that depletes peripheral B cells and introduced for systemic rheumatic diseases. However, there were no enough evidences for SSc-associated ILD. We report herein a case of 47-year-old female with diffuse type of SSc with steroid and cyclophosphamide-resistant ILD that was successfully treated with RTX. Thus, we suggested that RTX could be an efficacious therapeutic modality for severe, conventional treatment-resistant SSc-associated ILD.

  3. Phase I clinical trial of a five-peptide cancer vaccine combined with cyclophosphamide in advanced solid tumors.

    PubMed

    Murahashi, Mutsunori; Hijikata, Yasuki; Yamada, Kazunari; Tanaka, Yoshihiro; Kishimoto, Junji; Inoue, Hiroyuki; Marumoto, Tomotoshi; Takahashi, Atsushi; Okazaki, Toshihiko; Takeda, Kazuyoshi; Hirakawa, Masakazu; Fujii, Hiroshi; Okano, Shinji; Morita, Masaru; Baba, Eishi; Mizumoto, Kazuhiro; Maehara, Yoshihiko; Tanaka, Masao; Akashi, Koichi; Nakanishi, Yoichi; Yoshida, Koji; Tsunoda, Takuya; Tamura, Kazuo; Nakamura, Yusuke; Tani, Kenzaburo

    2016-05-01

    We designed a phase I trial to investigate the safety, immune responses and clinical benefits of a five-peptide cancer vaccine in combination with chemotherapy. Study subjects were patients positive for HLA-A2402 with locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer. Eighteen patients including nine cases of colorectal cancer were treated with escalating doses of cyclophosphamide 4days before vaccination. Five HLA-A2402-restricted, tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1 and MPHOSPH1 were injected weekly for 4weeks. Treatment was well tolerated without any adverse events above grade 3. Analysis of peripheral blood lymphocytes showed that the number of regulatory T cells dropped from baseline after administration of cyclophosphamide and confirmed that TAA-specific T cell responses were associated significantly with longer overall survival. This phase I clinical trial demonstrated safety and promising immune responses that correlated with vaccine-induced T-cell responses. Therefore, this approach warrants further clinical studies.

  4. 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

  5. Busulfan and fludarabine conditioning regimen given at hematological nadir of cytoreduction fludarabine, cytarabine, and idarubicin chemotherapy in patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation: a single arm pilot consort study.

    PubMed

    Tang, Wei; Fan, Xing; Wang, Ling; Hu, Jiong

    2015-04-01

    To improve the outcome of allogeneic stem cell transplantation in refractory acute myeloid leukemia (AML), we conducted a single-arm phase II clinical trial to evaluate the efficacy and feasibility of conditioning regimen following cytoreduction chemotherapy with 7-day interval. Adult patients with refractory AML were enrolled in the study and received fludarabine, cytarabine, and idarubicin (FLAG-IDA) as cytoreductive chemotherapy followed by busulfan and fludarabine (Flu-BU) conditioning regimen and transfusion of mobilized peripheral stem cells from human leukocyte antigen-matched sibling or unrelated donor. The primary endpoint of the study was 2-year leukemia-free survival (LFS) and secondary endpoints included complete-remission rate, 2-year overall survival (OS), nonrelapse mortality (NRM), and relapse rate. A total of 16 patients were enrolled with median age of 36 (16-60), which included 9 primary induction failure, 2 early relapse, and 5 with relapse/refractory disease. The median cycles of previous chemotherapy were 4 (3-10) with a median of 55% (1%-90%) blasts in bone marrow. Six patients received transplantation from matched sibling and 10 from matched unrelated donors. After transplantation, 15 patients achieved bone marrow remission (11 complete remissions [CRs] and 4 bone marrow remissions without platelet recovery) at day +28. A total of 8 patients remained alive in CR with median LFS of 29.5 months (9.5-40.5 months). Four patients relapsed and 3 of them died of disease and another 4 patients died because of transplantation-related toxicity. The 2-year NRM and relapse rates were 25.0% ± 10.8% and 33.4% ± 13.8%, respectively with 2-year OS at 53.5% ± 13.1% and LFS at 50.0% ± 12.5%. Based on the Simon 2-stage design, 5 out of first eligible 14 patients remained leukemia-free for more than 2 years after allogeneic hematopoietic stem cell transplantation; thus, the null hypothesis of the study will be rejected and the study protocol

  6. 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.

  7. Radiation Therapy

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Radiation Therapy KidsHealth > For Teens > Radiation Therapy A A ... how to cope with side effects. What Is Radiation Therapy? Cancer is a disease that causes cells ...

  8. 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

  9. [A case of possible retroperitoneal metastasis of breast cancer successfully treated with oral S-1 and cyclophosphamide therapy after TC therapy].

    PubMed

    Yoneyama, Kimiyasu; Takeshita, Toshio; Suzuki, Hiroshi; Morise, Masaki; Suzuki, Tetsutarou; Kishi, Shinya; Tsutsui, Atsuko; Matsumoto, Akiko

    2011-03-01

    We report a case of possible retroperitoneal metastasis of breast cancer successfully treated with oral S-1 and cyclophosphamide therapy after docetaxel and cyclophosphamide (TC) therapy. A 57-year-old woman with a history of bilateral breast cancer showed an increase in tumor markers during treatment with oral anastrozole as postoperative adjuvant therapy 4 years after her second cancer surgery. After careful examination, the patient was diagnosed as having multiple bone metastases and her medication was changed to oral letrozole. After 3 months, the patient developed left back pain and was referred to our hospital. CT scanning showed an enhanced mass in the region from the left perirenal and posterior pararenal spaces to the left psoas major muscle and the anterior aspect of the left iliacus muscle, suggesting retroperitoneal metastasis. TC therapy was performed and, as a result, tumor markers decreased and the mass disappeared on CT imaging. After discontinuation of TC therapy, the tumor markers increased again, following which oral S-1 and cyclophosphamide therapy were administered, and the tumor markers decreased. At the time of this writing, the patient is still undergoing therapy, and no recurrence has been observed. We concluded that oral S-1 and cyclophosphamide therapy were useful in the present case and were associated with few adverse effects.

  10. 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.

  11. Effect of irradiation, cyclophosphamide, and etoposide (VP-16) on number of peripheral blood and peritoneal leukocytes in mice under normal conditions and during acute inflammatory reaction

    SciTech Connect

    van't Wout, J.W.; Linde, I.; Leijh, P.C.; van Furth, R.

    1989-02-01

    In order to develop a suitable model for studying the role of granulocytes and monocytes in resistance against pathogenic microorganisms, we investigated the effect of irradiation and cytostatic treatment (cyclophosphamide and VP-16) on the number of both peripheral blood and peritoneal leukocytes in male Swiss mice. Irradiation and cyclophosphamide treatment severely decreased the number of both granulocytes and monocytes in peripheral blood, whereas VP-16 only lowered the number of blood monocytes to a significant degree and had little effect on the number of blood granulocytes or lymphocytes. When normal mice were injected intraperitoneally with newborn calf serum (NBCS) the number of peritoneal granulocytes rose about 100-fold within 6 h. In irradiated and cyclophosphamide-treated mice, this influx of granulocytes into the peritoneal cavity was virtually eliminated, as was the concomitant increase in the number of blood granulocytes; in VP-16-treated mice, on the other hand, the number of peripheral blood and peritoneal granulocytes increased to the same degree as in normal mice. An increase in the number of peripheral blood monocytes and peritoneal macrophages occurred 24-48 h after injection of NBCS in normal mice. This increase was significantly impaired by irradiation as well as by treatment with cyclophosphamide or VP-16.

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

    PubMed Central

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

    2006-01-01

    Background Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. Methodology This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. Main Findings 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5mC content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. Conclusions Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well

  13. Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide

    PubMed Central

    McCurdy, Shannon R.; Kasamon, Yvette L.; Kanakry, Christopher G.; Bolaños-Meade, Javier; Tsai, Hua-Ling; Showel, Margaret M.; Kanakry, Jennifer A.; Symons, Heather J.; Gojo, Ivana; Smith, B. Douglas; Bettinotti, Maria P.; Matsui, William H.; Dezern, Amy E.; Huff, Carol Ann; Borrello, Ivan; Pratz, Keith W.; Gladstone, Douglas E.; Swinnen, Lode J.; Brodsky, Robert A.; Levis, Mark J.; Ambinder, Richard F.; Fuchs, Ephraim J.; Rosner, Gary L.; Jones, Richard J.; Luznik, Leo

    2017-01-01

    Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02–11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III–IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41–55%) and 53% (95% CI: 46–61%) after myeloablative HLA-matched related, 42% (95% CI: 34–52%) and 52% (95% CI: 44–62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40–50%) and 50% (95% CI: 45–55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related

  14. Radiation Protection

    MedlinePlus

    Jump to main content US EPA United States Environmental Protection Agency Search Search Radiation Protection Share Facebook Twitter Google+ Pinterest Contact Us Radiation Protection Document Library View ...

  15. Atmospheric radiation

    SciTech Connect

    Harshvardhan, M.R. )

    1991-01-01

    Studies of atmospheric radiative processes are summarized for the period 1987-1990. Topics discussed include radiation modeling; clouds and radiation; radiative effects in dynamics and climate; radiation budget and aerosol effects; and gaseous absorption, particulate scattering and surface reflection. It is concluded that the key developments of the period are a defining of the radiative forcing to the climate system by trace gases and clouds, the recognition that cloud microphysics and morphology need to be incorporated not only into radiation models but also climate models, and the isolation of a few important unsolved theoretical problems in atmospheric radiation.

  16. 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.

  17. 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

  18. 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.

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

    PubMed

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

    2016-11-15

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

  20. Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony-stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia.

    PubMed

    Strati, Paolo; Ferrajoli, Alessandra; Lerner, Susan; O'Brien, Susan; Wierda, William; Keating, Michael J; Faderl, Stefan

    2014-04-01

    Fludarabine, cyclophosphamide and rituximab (FCR), the standard of care for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), is associated with a high rate of neutropenia and infectious complications. Granulocyte macrophage colony-stimulating factor (GM-CSF) reduces myelosuppression and can potentiate rituximab activity. We conducted a clinical trial combining GM-CSF with FCR for frontline treatment of 60 patients with CLL. Eighty-six percent completed all six courses and 18% discontinued GM-CSF for toxicity: grade 3-4 neutropenia was observed in 30% of cycles, and severe infections in 16% of cases. The overall response rate was 100%. Both median event-free survival (EFS) and overall survival (OS) have not been reached. Longer EFS was associated with favorable cytogenetics. GM-CSF led to a lower frequency of infectious complications than in the historical FCR group, albeit similar EFS and OS.

  1. Treatment of acute myeloblastic leukemia in adults: remission induction with a combination of cyclophosphamide, cytarabine and vincristine

    PubMed Central

    Abu-Zahra, H.; Clarysse, A.; Cowan, D. H.; Hasselback, R.; Bergsagel, D. E.

    1972-01-01

    A regimen of intravenous cyclophosphamide, cytarabine and vincristine, given over a four-day period and repeated every two to three weeks, was used to treat 33 patients with acute myeloblastic leukemia. Of the 30 evaluable patients 9/18 previously untreated patients achieved complete remission and two others marked improvement, and 4/12 previously treated patients achieved complete remission. Twelve of 16 patients under the median age of 38 responded while only 3/14 patients over this age responded. There was no difference in response between those with elevated muramidase levels and those with normal levels. Three patients developed a previously unrecognized syndorme of fever, malaise, rash and orbital suffusion. Cytarabine was probably responsible. At least four courses of treatment are required before abandoning this regimen of therapy. Patients who achieve a complete remission and live for more than 150 days spend about 25% of their total survival time from diagnosis in hospital. PMID:4509017

  2. 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

  3. 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.

  4. Fludarabine, cyclophosphamide, doxorubicin (FCD), and rituximab: a remission induction therapy for aggressive pediatric post-transplant lymphoproliferative disease (PTLD).

    PubMed

    Giraldi, Eugenia; Provenzi, Massimo; Fiocchi, Roberto; Colledan, Michele; Cornelli, Pieremilio; Torre, Giuliano; Rambaldi, Alessandro; Conter, Valentino

    2011-08-01

    Management of aggressive, usually late-occurring, post-transplant lymphoproliferative disorders (PTLDs), a life-threatening complication after solid organ transplants, remains controversial. Four children affected by aggressive CD20+ PTLDs received a chemo-immunotherapy regimen for remission induction based on fludarabine, cyclophosphamide, doxorubicin, and rituximab, associated with a rapid discontinuation of immunosuppression (IS). Subsequent consolidation chemotherapy consisted of Berlin-Frankfurt-Münster-modified blocks. All patients achieved a complete remission, which persisted for 25, 68+, 80+, and 103+ months after diagnosis. Therapy was well tolerated. No patients developed allograft rejection during PTLD treatment. Our experience suggests that this chemo-immunotherapeutic approach may be an effective treatment strategy while allowing for a concomitant discontinuation of IS.

  5. Pelvic radiation - discharge

    MedlinePlus

    Radiation of the pelvis - discharge; Cancer treatment - pelvic radiation; Prostate cancer - pelvic radiation; Ovarian cancer - pelvic radiation; Cervical cancer - pelvic radiation; Uterine cancer - pelvic radiation; Rectal cancer - ...

  6. Attenuation of ozone-induced airway permeability in rats by pretreatment with cyclophosphamide, FPL 55712, and indomethacin

    SciTech Connect

    Bhalla, D.K.; Daniels, D.S.; Luu, N.T. )

    1992-07-01

    Exposure of rats to ozone (O3) produces an increase in airway permeability and a concomitant influx of polymorphonuclear leukocytes in the lung. These observations raise the possibility that the inflammatory cells play a role in the cellular injury and increased airway permeability after O3 exposure. This study was therefore designed to determine if the inflammatory cells or their products are essential for the O3 effect. In a series of experiments, rats were rendered leukopenic with cyclophosphamide, treated with leukotriene B4 (LTB4), or with the inhibitors of lipoxygenase or cyclooxygenase products of arachidonic acid, followed by exposure to O3. A 2-h exposure to 0.8 ppm O3 caused a significant increase in the flux of proteins and albumin in bronchoalveolar lavage (BAL) and elevated the transport of 99mTc-diethylenetriaminepentaacetate (99mTc-DTPA) from trachea to blood. The treatment with cyclophosphamide caused a significant reduction in the circulating and pulmonary leukocytes and prevented an increase in tracheal mucosal permeability to 99mTc-DTPA and the protein and albumin flux in BAL. While the intratracheal instillation of LTB4 did not affect the permeability, tracheal permeability and albumin levels in BAL in rats treated with LTD4 antagonist FPL 55712 and exposed to O3 were lower than in the untreated O3-exposed rats. Pretreatment with indomethacin also prevented the O3 effects, as reflected by the decreased protein and albumin flux in BAL and 99mTc-DTPA transport from trachea to blood. These data show a reduction in the effect of O3 by agents that affect leukocytes or their products. The results support a mechanism of increased permeability that is dependent upon inflammatory cells and their products.

  7. A new monitoring method using solid sorbent media for evaluation of airborne cyclophosphamide and other antineoplastic agents.

    PubMed

    Larson, Rodney R; Khazaeli, M B; Dillon, H Kenneth

    2003-02-01

    Cyclophosphamide is a known human carcinogen. In July 1999, in a report at a conference on cytotoxic drugs in Sweden, it was indicated that cyclophosphamide (CP) was not effectively controlled by high efficiency particulate air (HEPA) filters.((1)) This then raised a concern that the existing air monitoring methods, which utilize polytetrafluoroethylene (a.k.a. PTFE, or Teflon) or glass fiber filters for evaluation of antineoplastics such as CP in air may also be ineffective for collection and quantification of such agents. It was decided that further evaluation of the existing filter method for monitoring antineoplastics in air be conducted. This evaluation determined that the filter method of monitoring was minimally effective for some antineoplastic agents, and that an alternate method of monitoring should be sought. The method subsequently developed utilizes a solid sorbent tube, Anasorb 708, a methacrylic acid polymer. Evaluation of this sorbent tube for adsorption and desorption properties found it had a greater than 90 percent recovery for both CP and ifosfamide. Other agents evaluated included 5-fluorouracil, doxorubicin, and paclitaxel. All three agents were able to be detected and measured by use of Anasorb 708 solid sorbent tube. Validation of the method was then conducted with air pulled through the tubes via attachment to an air manifold system at air flows ranging from 1.5 to approximately 4.0 liters per minute for up to 24 hours. This evaluation did validate the Anasorb 708 tube as an effective media for collection of airborne concentrations of CP from less than 1 microgram up to approximately 2 mg (2000 microgram) per tube. This corresponds to a concentration range of approximately 0.7 microgram/m(3) (0.0007 mg/m(3)) to 0.7 mg/m(3) in a 5.76 m(3) volume of air. This method can provide accurate information on airborne concentrations of CP for purposes of conducting risk assessments or evaluation of risk management methods.

  8. Febrile neutropenia in adjuvant docetaxel and cyclophosphamide (TC) with prophylactic pegfilgrastim in breast cancer patients: a retrospective analysis.

    PubMed

    Ngamphaiboon, Nuttapong; O'Connor, Tracey L; Advani, Pooja P; Levine, Ellis G; Kossoff, Ellen B

    2012-09-01

    US Oncology Research Trial 9735 reported that TC improved overall survival when compared to doxorubicin and cyclophosphamide in early-stage breast cancer. Despite 61% grades 3-4 neutropenia in the TC arm, only 5% of patients developed febrile neutropenia (FN) without primary prophylactic GCSF (ppGCSF). TC has risen in popularity, particularly in older patients or in those where an anthracycline is contraindicated. Other studies examining the toxicity of TC without ppGCSF reported a higher incidence of FN between 23 and 46%. We reviewed our institutional experience with ppGCSF and the TC regimen. Women treated with adjuvant TC and pegfilgrastim at Roswell Park Cancer Institute were identified from the pharmacy database between 8/2006 and 11/2010. Patient characteristics and comorbidities were abstracted. Endpoints included incidence of FN, hematologic toxicities, relative dose intensity (RDI), and other acute complications. Docetaxel 75 mg/m(2) and cyclophosphamide 600 mg/m(2) were given every 21 day/cycle for a planned four cycles. All patients received pegfilgrastim 6 mg on day 3. One hundred and eleven women with median age of 56 years (27-79) were identified. Twenty-two percent of patients were ≥ 65 at diagnosis. Eight patients developed FN (7%). Ninety-five patients (86%) were able to complete four cycles. Completion rate was significantly lower in patients with age ≥ 65 (71% vs. 90%; P = 0.02). Incidence of hospitalization, delay, RDI <85%, and dose reduction were not significantly different between the age groups. The overall incidence of FN was 7%. Older patients were significantly less likely to complete four cycles of TC as planned. ppGCSF should be strongly considered in breast cancer patients receiving adjuvant TC chemotherapy.

  9. 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.

  10. Space Radiation

    NASA Technical Reports Server (NTRS)

    Wu, Honglu

    2006-01-01

    Astronauts receive the highest occupational radiation exposure. Effective protections are needed to ensure the safety of astronauts on long duration space missions. Increased cancer morbidity or mortality risk in astronauts may be caused by occupational radiation exposure. Acute and late radiation damage to the central nervous system (CNS) may lead to changes in motor function and behavior, or neurological disorders. Radiation exposure may result in degenerative tissue diseases (non-cancer or non-CNS) such as cardiac, circulatory, or digestive diseases, as well as cataracts. Acute radiation syndromes may occur due to occupational radiation exposure.

  11. Toxicity of fludarabine and cyclophosphamide with or without rituximab as initial therapy for patients with previously untreated mantle cell lymphoma: results of a randomised phase II study.

    PubMed

    Eve, Heather E; Linch, David; Qian, Wendi; Ross, Moira; Seymour, John F; Smith, Paul; Stevens, Lindsey; Rule, Simon A J

    2009-02-01

    The National Cancer Research Network (NCRN) is currently coordinating a Phase III randomised study (LY05) comparing fludarabine and cyclophosphamide (FC) with or without rituximab (R) for previously untreated mantle cell lymphoma (MCL). The combination of FC is well-recognised as significantly immunosuppressive and there are concerns that adding rituximab may increase infection risk further. The impact of rituximab on other markers of toxicity is also unclear. We analysed the toxicity data on 139 patients treated within the NCRN LY05 trial. Non-hematological toxicity was similar between the two treatment arms. The only difference in hematological toxicity was a higher rate of lymphocytopenia with fludarabine cyclophosphamide and rituximab (FCR), which did not translate into increased febrile episodes or infections. In conclusion, the addition of rituximab to FC for previously untreated MCL has no significant impact on toxicity.

  12. Successful Use of Cyclophosphamide as an Add-On Therapy for Multiple Myeloma Patients with Acquired Resistance to Bortezomib or Lenalidomide

    PubMed Central

    Ito, Shigeki; Oyake, Tatsuo; Murai, Kazunori; Ishida, Yoji

    2013-01-01

    Novel agents such as thalidomide, lenalidomide, and bortezomib have been shown to possess potent activity against multiple myeloma. However, the treatment strategy for patients who acquired resistance to these agents has not been established. In addition to switching drug classes, intensified treatment strategy, including increase in the dosage of current agents and addition of other agents, may be considered for these patients. We here describe 2 myeloma patients with acquired resistance to bortezomib or lenalidomide, in whom add-on therapy with low-dose cyclophosphamide was effective and tolerable. These cases suggest that add-on therapy with cyclophosphamide is one of the treatment options to overcome resistance to novel agents in patients with multiple myeloma. A larger prospective study is needed to clarify the efficacy and safety of this strategy for novel agent-resistant multiple myeloma. PMID:23607005

  13. 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.

  14. 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±0.003 mM and 3.419±0.518 mM, 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.

  15. Effects of a Shuangling Fuzheng anticancer preparation on the proliferation of SGC-7901 cells and immune function in a cyclophosphamide-treated murine model

    PubMed Central

    Chen, Hua-Sheng; Chen, Jue; Cui, De-Li; Zheng, Yuan-Yuan; Xu, Ai-Hua; Chen, Gang; Jia, Ling-Chang

    2007-01-01

    AIM: To study the inhibitory effects of a Shuangling Fuzheng anticancer preparation (SFAP) on the human gastric cancer cell line SGC-7901 in vitro as well as its immune-modulated effects in a cyclophosphamide-treated murine model. METHODS: MTT experiments and immunocytochemistry ABC experiments were performed for detecting the proliferation of SGC-7901 cells in vitro and protein expression of c-myc. The staphylococcal protein A (SPA) rosette test was utilized for measuring the ratio of T-lymphocyte subsets from peripheral blood in a cyclophosphamide-treated murine model. Enzyme-linked immunosorbant assay (ELISA) was performed for measuring the levels of serum sIL-2R in treated mice, while immunoturbidimetry was used for measuring the levels of immunoglobulins (Ig). RESULTS: SFAP (40-640 mg/L, 48 h) inhibited the proliferation of SGC-7901 cells, and a positive correlation was noted between inhibitory effects and dosage. At a dosage of 160-320 mg/L in cultured cells, the expression of c-myc was decreased. SFAP (50-200 mg/kg) increased the percentage of CD3+ and CD4+ T-lymphocytes, the ratio of CD4/CD8, and the contents of Ig such as IgM, IgG or IgA, but decreased the levels of serum sIL-2R in peripheral blood from cyclophosphamide-treated mice. CONCLUSION: SFAP can inhibit the proliferation of SGC-7901 cells via the c-myc gene. In addition, SFAP can modulat the cellular and humoral immunity in cyclophosphamide-induced immunosuppressed mice. PMID:18161930

  16. Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

    PubMed

    Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

    2017-03-01

    Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571.

  17. The effects of cyclophosphamide, melatonin and carvedilol on neural tube and skeletal system of mice fetuses in prenatal period.

    PubMed

    Khaksary Mahabady, M; Najafzadeh Varzi, H; Bakhtiari, E

    2011-10-20

    Cyclophosphamide (CP) as an alkylating agent is used for treatment of cancer and to prevent rejection of tissue transplantation. 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 melatonin and carvedilol are antioxidant.Therefore, in this study, the prophylactic effects of melatonin and carvedilol on teratogenic effects of CP was compared. This study was performed on 31 pregnant mice that were divided into six groups. The control group received normal saline and test groups received CP (20mg/kg), carvedilol (5mg/kg), melatonin (10mg/kg), CP (20mg/kg) pluscarvedilol (5mg/kg) and CP (20mg/kg) plus melatonin (10mg/kg) intraperitoneally on the 10th day of gestation, respectively. Fetuses were collected on the 19th day of gestation and after determination of weight and length; they were stained by Alizarin red-Alcian blue method. Cleft palate, spina bifida and exencephalyincidence were 62.79%, 62.79% and 30.23% in fetuses of mice that received only CP. Cleft palate,spina bifida, exencephaly, and incidence were 45.45%, 9.09% and 0% in group which received CP plus carvedilol (5mg/kg), respectively.However, cleft palate, spina bifida and exencephalyincidence were 62.5%, 45.83% and 4.16% range in the group which received CP plus melatonin (10mg/kg), respectively. In addition, theincidence of skeletal anomalies including limb, vertebral, and sternaldefects were decreased by melatonin and carvedilol. The mean weight and length of animal fetuses that had received melatonin and carvedilol were significantly greater than those receiving only CP. It is concluded; carvedilol has a significant effect in preventing CP-induced malformations and in cases like CP-induced exencephaly, cleft palate and spina bifidahas better prophylactic effect than melatonin, but this improvement is not significant.

  18. 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.

  19. Significant thrombocytopenia associated with the addition of rituximab to a combination of fludarabine and cyclophosphamide in the treatment of relapsed follicular lymphoma.

    PubMed

    Leo, Eugen; Scheuer, Lars; Schmidt-Wolf, Ingo G H; Kerowgan, Mohammed; Schmitt, Christina; Leo, Albrecht; Baumbach, Tanja; Kraemer, Alwin; Mey, Ulrich; Benner, Axel; Parwaresch, Reza; Ho, Anthony D

    2004-10-01

    Fludarabine in combination with cyclophosphamide is an effective treatment for newly diagnosed as well as relapsed follicular lymphoma. The anti-CD20 antibody rituximab has been employed successfully for the same indications. No such data were available on a combined use of these agents. Therefore, we conducted a phase II study to evaluate the safety and efficacy of a combination of rituximab (375 mg/m2), fludarabine (4 x 25 mg/m2) and cyclophosphamide (1 x 750 mg/m2), for the treatment of relapsed follicular lymphoma. An unexpected, severe hematologic toxicity with significant, prolonged thrombocytopenias WHO grade III/IV in 6 (35%) of 17 patients treated in total occurred, leading to early termination of the trial. Cytologic and serologic analyses point toward a direct toxic effect. Older patients (mean age 64.7 vs. 56.5 yr) were significantly (P = 0.02) more likely to suffer from this toxicity, whereas no other clinical or hematologic parameter differed statistically between the patients suffering from thrombocytopenia and those who did not. The addition of rituximab to fludarabine/cyclophosphamide employed at doses given above in relapsed follicular lymphoma may have led to this increase in thrombocytopenias. Therefore, caution should be exercised when combining these drugs for the treatment of patients with relapsed follicular lymphoma, especially when treating older patients.

  20. A monocentric retrospective study comparing pulse cyclophosphamide therapy versus low dose rituximab in the treatment of refractory autoimmune hemolytic anemia in adults.

    PubMed

    Fu, Rong; Yan, Siyang; Wang, Xiaoming; Wang, Guojin; Qu, Wen; Wang, Huaquan; Wu, Yuhong; Liu, Hong; Song, Jia; Guan, Jin; Xing, Limin; Ruan, Erbao; Li, Lijuan; Liu, Hui; Shao, Zonghong

    2016-10-01

    This retrospective study aims at confirming the efficacy and safety of low dose rituximab and pulse cyclophosphamide in the treatment of refractory AIHA in adults and making comparison of the two. Forty-nine adult patients with refractory AIHA have been enrolled. Results showed low dose rituximab combined with steroid therapy (group B) got more CR (78.9 %, 15/19) compared to that in intermittent intravenous cyclophosphamide combined with steroid therapy (group A) (42.1 %, 8/19) (P = 0.04) at 6 months after treatment. The hemoglobin level in group B was higher than group A at the time point of 1 month (P = 0.02) after treatments. The RFS in group A was 87.9 % at 6 months and 82.7 % at 12 months, which were no significant difference with group B (91.1 % at 6 months and 86.0 % at 12 months) (P = 0.81). Both the two therapies were well tolerated with pulmonary infections as the most common side effects. In conclusion, low dose rituximab combined with steroid therapy presents to be a better choice in the treatment of refractory AIHA in adults comparing with pulse cyclophosphamide therapy.

  1. 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

  2. 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.

  3. Radiation Proctopathy

    PubMed Central

    Grodsky, Marc B.; Sidani, Shafik M.

    2015-01-01

    Radiation therapy is a widely utilized treatment modality for pelvic malignancies, including prostate cancer, rectal cancer, and cervical cancer. Given its fixed position in the pelvis, the rectum is at a high risk for injury secondary to ionizing radiation. Despite advances made in radiation science, up to 75% of the patients will suffer from acute radiation proctitis and up to 20% may experience chronic symptoms. Symptoms can be variable and include diarrhea, bleeding, incontinence, and fistulization. A multitude of treatment options exist. This article summarizes the latest knowledge relating to radiation proctopathy focusing on the vast array of treatment options. PMID:26034407

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

    PubMed

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

    2015-06-01

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

  5. 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

  6. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma.

    PubMed

    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; Witzig, Thomas E

    2011-10-13

    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/m(2) 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.

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

    PubMed Central

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

    2014-01-01

    Although fludarabine, cyclophosphamide, and rituximab (FCR) together are established as a standard first-line treatment of younger patients with chronic lymphocytic leukemia (CLL), there is little information to guide the management of patients with CLL refractory to, or who have relapsed after, receiving frontline FCR treatment. To define optimal salvage strategy and identify patients unsuitable for retreatment with FCR, we examined the survival and treatment outcome of 300 patients enrolled in a phase 2 study of FCR. After a median 142 months of follow-up, 156 patients developed progressive CLL, with a median survival of 51 months after disease progression. The duration of first remission (REM1) was a key determinant of survival after disease progression and first salvage. Patients with a short REM1 (<3 years) had a short survival period, irrespective of salvage therapy received; these patients have high unmet medical needs and are good candidates for investigation of novel therapies. In patients with a long REM1 (≥3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care. PMID:25281606

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

    PubMed

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

    2015-06-01

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

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

    PubMed

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

    2014-11-13

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

  10. The constitutive androstane receptor is a novel therapeutic target facilitating cyclophosphamide-based treatment of hematopoietic malignancies

    PubMed Central

    Wang, Duan; Li, Linhao; Yang, Hui; Ferguson, Stephen S.; Baer, Maria R.; Gartenhaus, Ronald B.

    2013-01-01

    Cyclophosphamide (CPA) is one of the most widely used chemotherapeutic prodrugs that undergoes hepatic bioactivation mediated predominantly by cytochrome P450 (CYP) 2B6. Given that the CYP2B6 gene is primarily regulated by the constitutive androstane receptor (CAR, NR1I3), we hypothesize that selective activation of CAR can enhance systemic exposure of the pharmacologically active 4-hydroxycyclophosamide (4-OH-CPA), with improved efficacy of CPA-based chemotherapy. In this study, we have developed a unique human primary hepatocyte (HPH)–leukemia cell coculture model; the chemotherapeutic effects of CPA on leukemia cells can be directly investigated in vitro in a cellular environment where hepatic metabolism was well maintained. Our results demonstrated that activation of CAR preferentially induces the expression of CYP2B6 over CYP3A4 in HPHs, although endogenous expression of these enzymes in leukemia cells remains negligible. Importantly, coadministration of CPA with a human CAR activator led to significantly enhanced cytotoxicity in leukemia cells by inducing the apoptosis pathways, without concomitant increase in the off-target hepatotoxicity. Associated with the enhanced antitumor activity, a time and concentration-dependent increase in 4-OH-CPA formation was observed in the coculture system. Together, our findings offer proof of concept that CAR as a novel molecular target can facilitate CPA-based chemotherapy by selectively promoting its bioactivation. PMID:23160467

  11. 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

  12. Evaluation of a procedure for the simultaneous quantification of 4-ketocyclophosphamide, cyclophosphamide, and Ifosfamide in human urine.

    PubMed

    B'Hymer, C; Cheever, K L

    2010-01-01

    An accurate and precise analysis procedure is presented for the detection and quantification of cyclophosphamide (CP), 4-ketocyclophosphamide (4-keto-CP), a primary metabolite of CP, and ifosfamide (IF) in human urine. CP and IF are common antineoplastic drugs used for the treatment of many types of cancer. Workers in the healthcare field, including nurses and pharmacists who interact with or prepare prescriptions for patients, have potential low-level exposure to the parent drugs; therefore, an analysis procedure is needed. The main focus of this procedure is the quantitation of 4-keto-CP because it is a primary metabolite of CP exposure and stable under physiological conditions. Sample preparation consists of liquid-liquid extraction of urine with ethyl acetate, and the analysis consists of reversed-phase high-performance liquid chromatography coupled with tandem mass spectrometry for detection of the analytes. Accuracy and precision of this procedure is demonstrated by means of recovery experiments. Recoveries are between 97-105% of theory for the three target analytes at various concentrations (25, 50, 100, and 375 ng/mL for 4-keto-CP; 1, 2, 4, and 15 ng/mL for CP and IF) with relative standard deviations of 8.4% or less. The limit of detection for this procedure is 1 ng/mL for 4-keto-CP, 0.1 ng/mL for CP, and 0.05 ng/mL for IF in urine.

  13. 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

  14. Preserved learning and memory in mice following chemotherapy: 5-Fluorouracil and doxorubicin single agent treatment, doxorubicin-cyclophosphamide combination treatment.

    PubMed

    Fremouw, Thane; Fessler, Christy L; Ferguson, Robert J; Burguete, Yamil

    2012-01-01

    Clinical studies suggest that chemotherapy is associated with long-term cognitive impairment in some patients. A number of underlying mechanisms have been proposed, however, the etiology of chemotherapy-related cognitive dysfunction remains relatively unknown. As part of a multifaceted approach, animal models of chemotherapy induced cognitive impairment are being developed. Thus far, the majority of animal studies have utilized rats, however, mice may prove particularly beneficial in studying genetic risk factors for developing chemotherapy induced cognitive impairment. Thus, C57BL/6J mice were treated once a week for three weeks with saline, doxorubicin and cyclophosphamide (D&C), doxorubicin (Dox), or 5-fluorouracil (5-FU). Recent and remote contextual fear conditioning and novel object recognition (NOR) was assessed. Despite significant toxic effects as assessed by weight loss, the chemotherapy treated mice performed as well as control mice on all task. As are some humans, C57BL/6J mice may be resistant to at least some aspects of chemotherapy induced cognitive decline.

  15. 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.

  16. 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

  17. Investigation of antimutagenic potential of Foeniculum vulgare essential oil on cyclophosphamide induced genotoxicity and oxidative stress in mice.

    PubMed

    Tripathi, Pankaj; Tripathi, Rina; Patel, Rakesh K; Pancholi, Shyam S

    2013-01-01

    The present study investigated the protective effects of Foeniculum vulgare (fennel) essential oil (FEO) against genotoxicity induced by cyclophosphamide (CP). Mice bone marrow chromosomal aberration (CA), micronucleus, and sperm abnormality assays were employed to measure genotoxicity and cytotoxicity, respectively. The activities of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and malondialdehyde (MDA) content in the liver were also investigated spectrophotometrically. Animals were administered two different doses of FEO (1 and 2 mL/kg) continuously for 3 days at intervals of 24 hours by the oral route before tissue sampling. The results showed that CP produced a significant increase in the average percentage of aberrant metaphases and CAs, excluding gap and micronuclei formation in polychromatic erythrocytes (PCEs), produced cytotoxicity in mouse bone marrow cells, and induced abnormal sperms in the male germ line. CP also markedly inhibited the activities of SOD, CAT, and GSH and increased MDA content. Pretreatments with FEO significantly inhibited the frequencies of aberrant metaphases, CAs, micronuclei formation, and cytotoxicity in mouse bone marrow cells induced by CP and also produced a significant reduction of abnormal sperm and antagonized the reduction of CP-induced SOD, CAT, and GSH activities and inhibited increased MDA content in the liver. FEO inhibits genotoxicity and oxidative stress induced by CP.

  18. 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.

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

    PubMed

    Gómez-Meda, Belinda C; Bañales-Martínez, Luis R; Zamora-Perez, Ana L; Lemus-Varela, María de Lourdes; Trujillo, Xóchitl; Sánchez-Parada, María G; Torres-Mendoza, Blanca M; Armendáriz-Borunda, Juan; Zúñiga-González, Guillermo M

    2016-01-01

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

  20. Investigation of antigenotoxic potential of Syzygium cumini extract (SCE) on cyclophosphamide-induced genotoxicity and oxidative stress in mice.

    PubMed

    Tripathi, Pankaj; Patel, Rakesh K; Tripathi, Rina; Kanzariya, Nilesh R

    2013-10-01

    The present study investigated the protective effects of Syzygium cumini extract (SCE; 100 and 200 mg/kg) against genotoxicity and oxidative stress (OS) induced by cyclophosphamide (CP) in mice. Animals were received 14 days pretreatment (oral) of SCE, followed by induction of genotoxicity by CP (40 mg/kg), 24 hours before sacrifice. Mice bone marrow chromosomal aberration assay, micronucleus assay, and sperm abnormality assay were employed for the study. Activities of hepatic antioxidant enzymes were also investigated. Phytochemical investigation was done to determine total phenolic and flavonoid content in SCE. Results showed that CP produced a significant increase in average percentage of aberrant metaphases and chromosomal aberrations (CAs) excluding gap, and micronuclei (MN) formation in polychromatic erythrocytes produced cytotoxicity in mouse bone marrow cells and induced abnormal sperms in a male germ line. CP also markedly inhibited the activities of superoxide dismutase (SOD), catalase (CAT), and reduced glutahione (GSH) and increased malondialdehyde (MDA) content. Pretreatments with SCE significantly inhibited the frequencies of aberrant metaphases, CAs, MN formation, and cytotoxicity in mouse bone marrow cells induced by CP. SCE also produced a significant reduction of abnormal sperm and antagonized the reduction of CP-induced SOD, CAT, and GSH activities and inhibited increased MDA content in the liver. Total phenolic content present in SCE was 24.68%, whereas total flavonoids were calculated as 3.80%. SCE has a protective effect against genotoxicity and OS induced by CP.

  1. 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

    2016-03-01

    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.

  2. T-replete haploidentical allogeneic transplantation using post-transplantation cyclophosphamide in advanced AML and myelodysplastic syndromes.

    PubMed

    Devillier, R; Bramanti, S; Fürst, S; Sarina, B; El-Cheikh, J; Crocchiolo, R; Granata, A; Chabannon, C; Morabito, L; Harbi, S; Faucher, C; Santoro, A; Weiller, P-J; Vey, N; Carlo-Stella, C; Castagna, L; Blaise, D

    2016-02-01

    Unmanipulated haploidentical transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy) represents an alternative for patients with high-risk diseases lacking HLA-identical donor. Although it provides low incidences of GVHD, the efficacy of Haplo-SCT is still questioned, especially for patients with myeloid malignancies. Thus, we analyzed 60 consecutive patients with refractory (n=30) or high-risk CR (n=30) AML or myelodysplastic syndromes (MDSs) who underwent PT-Cy Haplo-SCT. The median age was 57 years (22-73 years), hematopoietic cell transplantation comorbidity index was ⩾3 in 38 patients (63%) and Haplo-SCT was the second allogeneic transplantation for 10 patients (17%). Although most of patients received PBSC as graft source (n=48, 80%), we found low incidences of grade 3-4 acute (2%) and severe chronic GVHD (4%). Among patients with high-risk CR diseases, 1-year non-relapse mortality, cumulative incidence of relapse, progression-free and overall survivals were 20%, 32%, 47% and 62%, respectively. In patients with refractory disease, corresponding results were 34%, 35%, 32% and 37%, respectively. We conclude that PT-Cy Haplo-SCT could provide promising anti-leukemic effect even in the setting of very advanced diseases. Thus, it represents a viable alternative for high-risk AML/MDS patients without HLA-identical donor.

  3. The mitigating effect of Citrullus colocynthis (L.) fruit extract against genotoxicity induced by cyclophosphamide in mice bone marrow cells.

    PubMed

    Shokrzadeh, Mohammad; 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.

  4. Synergistic antitumor efficacy of antibacterial helvolic acid from Cordyceps taii and cyclophosphamide in a tumor mouse model.

    PubMed

    Xiao, Jian-Hui; Zhang, Yao; Liang, Gui-You; Liu, Ru-Ming; Li, Xiao-Gang; Zhang, Ling-Tao; Chen, Dai-Xiong; Zhong, Jian-Jiang

    2017-01-01

    The antibacterial agent helvolic acid, which was isolated from the active antitumor fraction of Cordyceps taii, showed potent cytotoxicity against different human cancer cells. In the present study, the in vivo antitumor effect of helvolic acid was investigated in murine sarcoma S180 tumor-bearing mice. Doses of 10 and 20 mg/kg/day helvolic acid did not exert significant antitumor activity. Interestingly, co-administration of 10 mg/kg/day helvolic acid and 20 mg/kg/day cyclophosphamide (CTX) - a well-known chemotherapy drug - showed promising antitumor activity with a growth inhibitory rate of 70.90%, which was much higher than that of CTX alone (19.5%). Furthermore, the combination markedly prolonged the survival of tumor-bearing mice. In addition, helvolic acid enhanced the immune organ index. The protein expression levels of β-catenin, cyclin D1, and proliferating cell nuclear antigen were significantly suppressed in mice treated with 20 mg/kg/day helvolic acid and in those receiving combination therapy. Taken together, these results indicated that helvolic acid in combination with CTX showed potent in vivo synergistic antitumor efficacy, and its mechanism of action may involve the Wnt/ β-catenin signaling pathway.

  5. Aqueous extract of Trigonella foenum-graecum L. ameliorates additive urotoxicity of buthionine sulfoximine and cyclophosphamide in mice.

    PubMed

    Bhatia, K; Kaur, M; Atif, F; Ali, M; Rehman, H; Rahman, S; Raisuddin, S

    2006-10-01

    Cyclophosphamide (CP) is a commonly used anti-cancer drug which causes toxicity by its reactive metabolites such as acrolein and phosphoramide mustard. In the present study modulation of toxicity caused by concomitant exposure to CP and l-buthionine-SR-sulfoximine (BSO) by fenugreek (Trigonella foenum-graecum L.) extract was evaluated by measuring lipid peroxidation (LPO) and anti-oxidants in urinary bladder in mice. Fenugreek, a common dietary and medicinal herb, showed protective effect not only on LPO but also on the enzymatic anti-oxidants. CP-treated animals exhibited a significant decrease in the activities of glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GP) and catalase (CAT) when compared to the controls. Level of reduced glutathione (GSH) was also reduced with an increase in LPO in CP-treated animals. BSO treatment depicted an additive toxic effect in CP-treated animals. Pre-treatment of herbal extract restored activities of all the enzymes and thus showed an overall protective effect on additive effect of CP and BSO. Restoration of GSH by extract treatment may play an important role in reversing CP-induced apoptosis and free radical-mediated LPO in urinary bladder. Fenugreek, known for its hypoglycemic, anti-inflammatory and immunomodulatory activity, may be a promising protective medicinal herb for consideration in complementary therapy in cancer patients under chemotherapeutic interventions.

  6. Therapy-related myelodysplastic syndrome and acute myeloid leukemia in patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide.

    PubMed

    Colović, M; Suvajdžić, N; Janković, G; Tomin, D; Colović, N; Fekete, M Denčić; Palibrk, V

    2011-08-01

    We retrospectively studied four cases of t-MDS/AML among 210 (1.9%) consecutive patients with CLL treated at a single center with fludarabine and cyclophosphamide (FC) either as the first- or second-line therapy. The median follow-up of the whole cohort of patients was 46months (range: 7-60). Two of these patients (2/130, 1.7%) had been treated with FC only, and two more (2/80, 2.3%) with CHOP and CHOP+FND, respectively, prior to FC. The median age was 61.5years (range: 49-71); three were male. They developed t-MDS/AML after a median latency period of 41months (range: 7-56) from the FC completion. Chromosomal aberrations with an adverse prognostic impact were present in the karyotype of all four patients, including abnormalities of chromosome 5 in three of them, and a rare chromosomal translocation in one patient. Median survival after t-MDS/AML diagnosis was 4months (range: 2-8). Although the agents administered prior to FC make it difficult to assess the risk of t-MDS/AML attributable to FC, this report might be a valuable addition to the literature.

  7. 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.

  8. The use of low-dose cyclophosphamide followed by AZA/MMF treatment in childhood lupus nephritis.

    PubMed

    Baskin, Esra; Ozen, Seza; Cakar, Nilgun; Bayrakci, Umut S; Demirkaya, Erkan; Bakkaloglu, Aysin

    2010-01-01

    Cyclophosphamide (CYC) has been the landmark in the treatment of lupus nephritis. However, long-term treatment with CYC is associated with significant side effects. We aimed to evaluate the efficacy of short-term intravenous (IV) CYC treatment as a remission induction treatment followed by azathioprine (AZA) or mycophenolate mofetil (MMF) as a maintenance treatment. Twenty patients (18 girls) with biopsy-proven class III (5) and IV (15) lupus nephritis were included in to the study. Detailed clinical and laboratory data and patient outcomes were evaluated. All patients received three methylprednisolone (MP) IV pulses, followed by oral prednisone 0.5-1 mg/kg per day and one IV pulse of CYC per month for 6 months. Azathioprine was started as a remission-maintaining treatment. In ten of 20 patients, treatment was switched to MMF. The mean age at the time of diagnosis was 16.11 +/- 3.49 years, and the mean duration of follow-up was 49.6 +/- 27 months. Fourteen patients (70%) had complete remission, three (15%) had partial remission, one (5%) continued to have active disease, and two (10%) progressed to end-stage renal disease. Nine of the patients (45%) with complete remission had received AZA, and switching to MMF increased complete remission rate (additional five patients; 25%). In conclusion, short-term (6-month) IV bolus CYC treatment followed by AZA is a safe and effective treatment in children with severe lupus nephritis, and using MMF increases remission rate in resistant cases.

  9. Alleviation of genotoxic effects of cyclophosphamide using encapsulation into liposomes in the absence or presence of vitamin C.

    PubMed

    Tohamy, Amany A; Abdel Azeem, Amira A; Shafaa, Medhat W; Mahmoud, Wafaa S

    2012-03-01

    Cyclophosphamide (CP) is a widely used anticancer and immunosuppressant that induces oxidative stress. To ameliorate the side effects resulted from CP treatment, liposomes were tested as an efficient drug delivery system with or without vitamin C as an antioxidant. CP resulted in clastogenic and cytotoxic effects that significantly increased for the total chromosomal aberrations as well as the numerical ones in the CP group (150.8 and 6, respectively) than the control group (6.6 and 0.0) as mean values at p < 0.05. Micronucleus assay showed a significant increased micronucleated polychromatic erythrocytes percentage (MNPCEs% = 11.7%) and a significant decrease of polychromatic to normochromatic erythrocytes ratio (0.551) when compared to the group treated with liposomised CP and vitamin C (3.44%; 0.795, respectively) at p < 0.05. Also, the total glutathione S-transferase activity as a body antioxidant enzyme was decreased from 52.2 in the control to 16.09 nmol/min/mg protein in CP group at p < 0.05, while the highly significant amelioration results were observed in the liposomised vitamin C and CP group (40.88 nmol/min/mg protein). Our findings support the potential use of CP in a liposomal formulation doped with vitamin C to diminish the potential side effects of the agent.

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

    PubMed Central

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

    2016-01-01

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

  11. Radiation and concurrent chemotherapy for the treatment of Lewis lung tumor and B16 melanoma tumor in C57/BL mice

    SciTech Connect

    Pedersen, J.E.; Barron, G.

    1984-08-01

    C57/BL mice bearing either Lewis lung tumor or B16 melanoma tumor were treated with radiation and concurrent chemotherapy. The treatment results were determined in vivo by tumor regrowth delay assay. When continuous infusion of either Cyclophosphamide (CYCLO) or 5-Fluorouracil (5-FU) or Adriamycin (ADRIA) or Mitomycin-C (MITO-C) was used in combination with continuous radiation at 1 cGy/min, no increase in tumor regrowth delay was observed over that of radiation alone. When multiple drug chemotherapy, FAM (5-FU, ADRIA, MITO-C) was administered in combination with radiation at 80 cGy/min, no increase in tumor regrowth delay was observed over that of radiation alone. In these two murine tumor models, when clinically relevant concentrations of commonly used chemotherapy agents were combined with radiation, no therapeutic advantage was observed.

  12. Radiator technology

    NASA Technical Reports Server (NTRS)

    Juhasz, Albert J.

    1993-01-01

    Radiator technology is discussed in the context of the Civilian Space Technology Initiative's (CSTI's) high capacity power-thermal management project. The CSTI project is a subset of a project to develop a piloted Mars nuclear electric propulsion (NEP) vehicle. The following topics are presented in vugraph form: advanced radiator concepts; heat pipe codes and testing; composite materials; radiator design and integration; and surface morphology.

  13. Hawking radiation

    NASA Astrophysics Data System (ADS)

    Parentani, Renaud; Spindel, Philippe

    2011-12-01

    Hawking radiation is the thermal radiation predicted to be spontaneously emitted by black holes. It arises from the steady conversion of quantum vacuum fluctuations into pairs of particles, one of which escaping at infinity while the other is trapped inside the black hole horizon. It is named after the physicist Stephen Hawking who derived its existence in 1974. This radiation reduces the mass of black holes and is therefore also known as black hole evaporation.

  14. Radiation Therapy

    MedlinePlus

    ... can watch you during the procedure. As you go through radiation treatment, you may feel like you're all ... treatment. Avoid exposing the treated area to the sun during the weeks you're getting radiation therapy. And when the treatment's over, wear sunscreen ...

  15. Understanding Radiation.

    ERIC Educational Resources Information Center

    Department of Energy, Washington, DC. Nuclear Energy Office.

    Radiation is a natural energy force that has been a part of the environment since the Earth was formed. It takes various forms, none of which can be smelled, tasted, seen, heard, or felt. Nevertheless, scientists know what it is, where it comes from, how to measure and detect it, and how it affects people. Cosmic radiation from outer space and…

  16. Radiation Therapy

    MedlinePlus

    ... Tumors In Children Pediatric Brain Tumor Diagnosis Family Impact Late Effects After Treatment Returning to School Pediatric ... Una publicación de ABTA en español. Radiation Imaging Technology Information on Radiation and Imaging Technology Home Donor and ...

  17. Radiation Therapy

    MedlinePlus

    ... them from spreading. About half of all cancer patients receive it. The radiation may be external, from special machines, or internal, from radioactive substances that a doctor places inside your body. The type of radiation therapy you receive depends on many factors, including The ...

  18. Radiation Exposure

    MedlinePlus

    ... particles. It occurs naturally in sunlight. Man-made radiation is used in X-rays, nuclear weapons, nuclear power plants and cancer treatment. If you are exposed to small amounts of radiation over a long time, it raises your risk ...

  19. Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: Possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation.

    PubMed

    Kitamura, Yoshihisa; Hattori, Sayo; Yoneda, Saori; Watanabe, Saori; Kanemoto, Erika; Sugimoto, Misaki; Kawai, Toshiki; Machida, Ayumi; Kanzaki, Hirotaka; Miyazaki, Ikuko; Asanuma, Masato; Sendo, Toshiaki

    2015-10-01

    Many patients who have received chemotherapy to treat cancer experience depressive- and anxiety-like symptoms or cognitive impairment. However, despite the evidence for this, the underlying mechanisms are still not understood. This study investigated behavioral and biochemical changes upon treatment with doxorubicin and cyclophosphamide, focusing on mental and cognitive systems, as well as neurogenesis in male rats. Doxorubicin (2 mg/kg), cyclophosphamide (50 mg/kg), and the combination of doxorubicin and cyclophosphamide were injected intraperitoneally once per week for 4 weeks. In particular, the co-administration of doxorubicin and cyclophosphamide produced anhedonia-like, anxiety-like, and spatial cognitive impairments in rats. It also reduced both the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus and their survival. Serum brain-derived neurotrophic factor (BDNF) levels were decreased along with chemotherapy-induced decreases in platelet levels. However, hippocampal BDNF levels and Bdnf mRNA levels were not decreased by this treatment. On the other hand, hippocampal cyclin D1 levels were significantly decreased by chemotherapy. These results suggest that the co-administration of doxorubicin and cyclophosphamide induces psychological and cognitive impairment, in addition to negatively affecting hippocampal neurogenesis, which may be related to hippocampal cyclin D1 levels, but not hippocampal BDNF levels.

  20. Pure red cell aplasia (PRCA): Response of three patients of cyclophosphamide and/or antilymphocyte globulin (ALG) and demonstration of two types of serum IgG inhibitors to erythropoiesis.

    PubMed

    Marmont, A; Peschle, C; Sanguineti, M; Condorelli, M

    1975-02-01

    Three cases of adult pure red cell aplasia (PRCA) ARE REPORTED. All patients proved refractory to various combinations of androgens and corticosteroids. The first case, harboring a thymoma, showed a complete clinical remission following cyclophosphamide therapy. The second and third responded similarly to either a combined cyclophosphamide + antilymphocyte globulin (ALG) treatment or to ALG administration preceded by a small dosage of cyclophosphamide, which had proved ineffective when administered alone. Serum IgG inhibitors to erythropoiesis were demonstrated in all cases by means of in vivo and/or in vitro techniques. The inhibitor(s), although directed against the erythroid marrow in both the first and third patients (PRCA type A), apparently functioned as an antibody to circulating erythropoientin (Ep) in the second case (PRCA type B). The inhibitor(s) was always absent in postremission samples. Additionally, experimental models for both types of human PRCA were established in normal rodents. The present studies support the contention that adult PRCA is an autoimmune disease. The therapeutic role of cytotoxic-immunodepressive agents in PRCA patients is confirmed. It is emphasized that ALG may represent an additional therapeutic tool in cases resistant to cyclophosphamide and/or steroids. In addition, cyclophosphamide proved effective in a patient harboring a thymoma not amenable to surgery. Finally, it is postulated that IgG serum autoantibodies, directed against either an early erythroid precursor (PRCA type A) or, more rarely, circulating Ep (PRCA type B), play a major role in the pathogenesis of the disease.

  1. 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.

  2. Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma.

    PubMed

    Tuchman, Sascha A; Bacon, Wendi A; Huang, Li-Wen; Long, Gwynn; Rizzieri, David; Horwitz, Mitchell; Chute, John P; Sullivan, Keith; Morris Engemann, Ashley; Yopp, Amanda; Li, Zhiguo; Corbet, Kelly; Chao, Nelson; Gasparetto, Cristina

    2015-06-01

    High-dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony-stimulating factor; G-CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy-three patients were mobilized with G-CSF alone, and 94 patients with Cy plus G-CSF (Cy+G-CSF). We retrospectively analyzed Cy's impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 × 10(6) CD34+ cells/kg were collected from patients mobilized with Cy+G-CSF versus G-CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization-related toxicity was also, however, augmented by Cy; 14% of Cy+G-CSF patients were hospitalized because of complications versus none receiving G-CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long-term outcomes, multivariate analysis revealed no difference for Cy+G-CSF versus G-CSF (hazard ratio 0.8 for event-free survival [95% confidence interval {CI} 0.57-1.25] and 0.96 for overall survival [95% CI 0.61-1.54]). In summary, we show that mobilization with Cy increases toxicity without positively impacting long-term outcomes in MM. Our findings place into question Cy's benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively.

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

    PubMed

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

    2015-10-01

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

  4. Participation of TNF-alpha and IL-1 in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis.

    PubMed

    Gomes, T N; Santos, C C; Souza-Filho, M V; Cunha, F Q; Ribeiro, R A

    1995-10-01

    The involvement of cytokines TNF-alpha and IL-1 has been investigated in a mouse model of cyclophosphamide (CYP)-induced hemorrhagic cystitis. Male Swiss mice (25-30 g) received CYP in a single i.p. dose of 100, 200 or 400 mg/kg and were sacrificed 6, 12, 24, 48 and 72 h later. Cystitis was evaluated by determining the changes in bladder wet weight (BW) and plasma protein extravasation (PPE, measured by the Evans blue leakage technique). CYP treatment induced a marked increase in BW and in PPE, which was significant within 6 h and reached maximal values within 12 h (BW, 118%, P < 0.05; N = 11; and PPE, 824%, P < 0.05; N = 11), continuing to be significant until 48 h. Pretreatment of animals with whole anti-TNF-alpha serum (25 or 50 microliters diluted in 500 microliters 0.9% saline, i.p., 30 min earlier) caused a significant reduction in the CYP-induced BW increase in 6-h and 12-h cystitis (82% and 91%, respectively, P < 0.05; N = 6) and in the CYP-induced PPE increase (60% and 52%, respectively, P < 0.05; N = 6). In addition, the administration of whole anti-IL- 1 beta serum at the same dose promoted a significant blockage of the CYP-induced increase in BW (47%, P < 0.05; N = 6) and PPE increase (41%, P < 0.05; N = 6) only in 12-h cystitis. The control serum did not modify the effect of CYP. Histopathologic analysis of the bladders from anti-TNF-alpha- and anti-IL-1 beta-pretreated groups revealed a significant reduction of the following parameters compared to the control groups: mucosal erosion, hemorrhage, edema, leukocyte migration, fibrin deposition and ulcerations. These results suggests that TNF-alpha and IL-1 are crucial mediators involved in inflammatory events occurring in CYP-induced hemorrhagic cystitis.

  5. Busulphan-Cyclophosphamide Cause Endothelial Injury, Remodeling of Resistance Arteries and Enhanced Expression of Endothelial Nitric Oxide Synthase

    PubMed Central

    Al-Hashmi, Sulaiman; Boels, Piet J. M.; Zadjali, Fahad; Sadeghi, Behnam; Sällström, Johan; Hultenby, Kjell; Hassan, Zuzana; Arner, Anders; Hassan, Moustapha

    2012-01-01

    Stem cell transplantation (SCT) is a curative treatment for malignant and non malignant diseases. However, transplantation-related complications including cardiovascular disease deteriorate the clinical outcome and quality of life. We have investigated the acute effects of conditioning regimen on the pharmacology, physiology and structure of large elastic arteries and small resistance-sized arteries in a SCT mouse model. Mesenteric resistance arteries and aorta were dissected from Balb/c mice conditioned with busulphan (Bu) and cyclophosphamide (Cy). In vitro isometric force development and pharmacology, in combination with RT-PCR, Western blotting and electron microscopy were used to study vascular properties. Compared with controls, mesenteric resistance arteries from the Bu-Cy group had larger internal circumference, showed enhanced endothelium mediated relaxation and increased expression of endothelial nitric oxide synthase (eNOS). Bu-Cy treated animals had lower mean blood pressure and signs of endothelial injury. Aortas of treated animals had a higher reactivity to noradrenaline. We conclude that short-term consequences of Bu-Cy treatment divergently affect large and small arteries of the cardiovascular system. The increased noradrenaline reactivity of large elastic arteries was not associated with increased blood pressure at rest. Instead, Bu-Cy treatment lowered blood pressure via augmented microvascular endothelial dependent relaxation, increased expression of vascular eNOS and remodeling toward a larger lumen. The changes in the properties of resistance arteries can be associated with direct effects of the compounds on vascular wall or possibly indirectly induced via altered translational activity associated with the reduced hematocrit and shear stress. This study contributes to understanding the mechanisms that underlie the early effects of conditioning regimen on resistance arteries and may help in designing further investigations to understand the late

  6. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial

    PubMed Central

    O’Brien, Susan; Kingsley, C. Daniel; Eradat, Herbert; Pagel, John M.; Lymp, James; Hirata, Jamie; Kipps, Thomas J.

    2015-01-01

    Obinutuzumab is a type 2, glycoengineered, anti-CD20 antibody recently approved with chlorambucil for the initial therapy of chronic lymphocytic leukemia (CLL). In this nonrandomized, parallel-cohort, phase 1b, multicenter study, we explored the safety and preliminary efficacy of obinutuzumab-bendamustine (G-B) or obinutuzumab fludarabine cyclophosphamide (G-FC) for the therapy of previously untreated fit patients with CLL. Patients received up to 6 cycles of G-B (n = 20) or G-FC (n = 21). The primary end point was safety, with infusion-related reactions (88%, grade 3-4 20%) being the most common adverse event and grade 3-4 neutropenia in 55% on G-B and 48% on G-FC. Mean cycles completed were 5.7 for G-B and 5.1 for G-FC, with 2 and 7 early discontinuations, respectively. The objective response rate (ORR) for G-B was 90% (18/20) with 20% complete response (CR) and 25% CR with incomplete marrow recovery (CRi). The ORR for G-FC was 62% (13/21), with 10% CR and 14% CRi, including 4 patients not evaluable. With a median follow-up of 23.5 months in the G-B cohort and 20.7 months in the G-FC cohort, no patient has relapsed or died. We conclude that obinutuzumab with either B or FC shows manageable toxicity and has promising activity. This study was registered at www.clinicaltrials.gov as #NCT01300247. PMID:25769620

  7. Chemotherapy with cyclophosphamide, vincristine, and prednisolone (COP) in cats with malignant lymphoma: new results with an old protocol.

    PubMed

    Teske, Erik; van Straten, Giora; van Noort, Ronald; Rutteman, Gerard R

    2002-01-01

    This retrospective study in 61 cats with malignant lymphomas examined the efficacy of a well-established chemotherapy protocol (cyclophosphamide, vincristine, and prednisolone [COP]) in the Netherlands, a country with a low prevalence of feline leukemia virus (FeLV). Twenty-two cats (36.1%) had mediastinal lymphoma, 11 (18.0%) had alimentary lymphoma, 7 (11.5%) had peripheral lymphoma, 8 (13.1%) had nasal lymphoma, and 13 (21.3%) had miscellaneous lymphoma (including renal lymphoma in 2 [3.3%]). Of the 54 cats that were tested, only 4 (7.4%) were FeLV positive. Complete remission (CR) was achieved in 46 of the 61 cats (75.4%). The estimated 1- and 2-year disease-free periods (DFPs) in the 46 cats with CR were 51.4 and 37.8%, respectively, whereas the median duration of remission was 251 days. The overall estimated 1-year survival rate in all cats was 48.7%, and the 2-year survival rate was 39.9%, with a median survival of 266 days. The median survival time and the 1-year survival rate for mediastinal lymphoma were 262 days and 49.4%. respectively. Siamese cats had a more favorable prognosis for survival and remission than other breeds. Response to therapy in this study was shown to be a significant prognostic indicator. CR is necessary for long-term survival. Cats that did not achieve CR had little chance of survival for longer than I year. Young Siamese cats in this study had a greater tendency to develop mediastinal malignant lymphoma at a young age, and all were FeLV negative. In comparison with results reported in other studies with different combination chemotherapy protocols, these are among the highest percentages of remission and the longest survival rates for cats with malignant lymphoma.

  8. 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

    2016-01-12

    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.

  9. A randomized phase II trial of personalized peptide vaccine with low dose cyclophosphamide in biliary tract cancer.

    PubMed

    Shirahama, Takahisa; Muroya, Daisuke; Matsueda, Satoko; Yamada, Akira; Shichijo, Shigeki; Naito, Masayasu; Yamashita, Takuto; Sakamoto, Shinjiro; Okuda, Koji; Itoh, Kyogo; Sasada, Tetsuro; Yutani, Shigeru

    2017-02-11

    Since the prognosis of advanced biliary tract cancer (aBTC) still remains very poor, new therapeutic approaches, including immunotherapies, need to be developed. In the current study, we conducted an open-label randomized phase II study to test whether low dose cyclophosphamide (CPA) could improve antigen-specific immune responses and clinical efficacy of personalized peptide vaccination (PPV) in 49 previously treated aBTC patients. Patients with aBTC refractory to at least one regimen of chemotherapies were randomly assigned to receive PPV with low dose CPA (100 mg/ day for 7 days before vaccination) (PPV/CPA, n=24) or PPV alone (n=25). A maximum of four HLA-matched peptides were selected based on the pre-existing peptide-specific IgG responses, followed by subcutaneous administration. T cell responses to the vaccinated peptides in the PPV/CPA arm tended to be greater than those in the PPV alone arm. The PPV/CPA arm showed significantly better progression-free survival (median time: 6.1 vs 2.9 months; hazard ratio (HR): 0.427; P = 0.008) and overall survival (median time: 12.1 vs 5.9 months; HR: 0.376; P = 0.004), compared to the PPV alone arm. The PPV alone arm, but not the PPV/CPA arm, showed significant increase in plasma IL-6 after vaccinations, which might be associated with inhibition of antigen-specific T cell responses. These results suggested that combined treatment with low dose CPA could provide clinical benefits in aBTC patients under PPV, possibly through prevention of IL-6-mediated immune suppression. Further clinical studies would be recommended to clarify the clinical efficacy of PPV/CPA in aBTC patients. This article is protected by copyright. All rights reserved.

  10. Egyptian sweet marjoram leaves protect against genotoxicity, immunosuppression and other complications induced by cyclophosphamide in albino rats.

    PubMed

    Ramadan, Gamal; El-Beih, Nadia M; Zahra, Mai M

    2012-09-28

    Cyclophosphamide (CP) is one of the most popular alkylating anticancer drugs that show a high therapeutic index, despite the widespread side effects and toxicity particularly in high-dose regimens and long-term use. Here, we evaluated and compared the efficacy of two different doses (50 and 100 mg/kg body weight, given orally for 30 consecutive days) of Egyptian sweet marjoram leaf powder (MLP) and marjoram leaf aqueous extract (MLE) in alleviating the genotoxicity, immunosuppression and other complications induced by CP in non-tumour-bearing albino rats. The present study showed (probably for the first time) that both MLP and MLE significantly alleviated (P < 0·05-0·001) most side effects and toxicity of CP-treated rats including the increase in chromosomal aberrations of bone marrow cells and serum malondialdehyde level, the decrease in the level of serum Ig, the delayed type of hypersensitivity response as also the weights and cellularity of lymphoid organs, and myelosuppression, leucopenia, macrocytic normochromic anaemia as well as thrombocytopenia by reactivating the non-enzymic (reduced glutathione) and enzymic (catalase, glutathione peroxidase, glutathione S-transferase, superoxide dismutase) antioxidant system and increasing the mitotic index of bone marrow cells. The modulatory effects of marjoram leaves shown in the present study were dose dependent in most cases and much higher in MLE (21-23 % for all parameters taken together). In addition, the doses used in the present study were considered safe. In conclusion, sweet marjoram leaves (especially in the form of a herbal tea) may be useful as an immunostimulant and in reducing genotoxicity in patients under chemotherapeutic interventions.

  11. Urinary cyclophosphamide excretion and micronuclei frequencies in peripheral lymphocytes and in exfoliated buccal epithelial cells of nurses handling antineoplastics.

    PubMed

    Burgaz, S; Karahalil, B; Bayrak, P; Taşkin, L; Yavuzaslan, F; Bökesoy, I; Anzion, R B; Bos, R P; Platin, N

    1999-02-02

    In this study, urinary cyclophosphamide (CP) excretion rate, as well as micronuclei (MN) in peripheral lymphocytes and in buccal epithelial cells were determined for 26 nurses handling antineoplastics and 14 referents matched for age and sex. In urine samples of 20 out of 25 exposed nurses CP excretion rate was found in a range of 0.02-9.14 microg CP/24 h. Our results of the analyses of CP in urine demonstrates that when the nurses were handling CP (and other antineoplastic drugs) this particular compound was observed in urine. The mean values (+/-SD) of MN frequencies (%) in peripheral lymphocytes from the nurses and controls were 0.61 (+/-0. 32) and 0.28 (+/-0.16), respectively (p<0.01). The mean value (+/-SD) of MN frequency (%) in buccal epithelial cells of nurses was 0.16 (+/-0.19) and also mean MN frequency in buccal epithelial cells for controls was found to be as 0.08 (+/-0.08), (p>0.05). Age, sex and smoking habits have not influenced the parameters analyzed in this study. Handling time of antineoplastics, use of protective equipment and handling frequency of drugs have no effect on urinary and cytogenetic parameters analyzed. No correlation was found between the urinary CP excretion and the cytogenetic findings in nurses. Neither could we find any relationship between two cytogenetic endpoints. Our results have identified the possible genotoxic damage of oncology nurses related to occupational exposure to at least one antineoplastic agent, which is used as a marker for drug handling. As a whole, there is concern that the present handling practices of antineoplastic drugs used in the several hospitals in Ankara will not be sufficient to prevent exposure.

  12. Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients.

    PubMed

    Low, Siew-Kee; Kiyotani, Kazuma; Mushiroda, Taisei; Daigo, Yataro; Nakamura, Yusuke; Zembutsu, Hitoshi

    2009-10-01

    Cyclophosphamide (CPA)-based combination treatment has known to be effective for breast cancer, but often causes adverse drug reactions (ADRs). Hence, the identification of patients at risk for toxicity by CPA is clinically significant. In this study, a stepwise case-control association study was conducted using 403 patients with breast cancer who received the CPA combination therapy. A total of 143 genetic polymorphisms in 13 candidate genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, ALDH3A1, GSTA1, GSTM1, GSTP1, GSTT1, ABCC2 and ABCC4), possibly involved in the activation, metabolism and transport of CPA, were genotyped using 184 cases who developed either > or =grade 3 leukopenia/neutropenia or > or =grade 2 gastrointestinal toxicity and 219 controls who did not show any ADRs throughout the treatment. The association study revealed that one SNP, rs9561778 in ABCC4, showed a significant association with CPA-induced ADRs (Cochran-Armitage trend's P-value=0.00031; odds ratio (OR)=2.06). Subgroup analysis also indicated that the SNP rs9561778 was significantly associated with two major ADR subgroups; gastrointestinal toxicity and leukopenia/neutropenia (Cochran-Armitage trend's P-value=0.00019 and 0.014; OR=2.31 and 1.83). Furthermore, the SNP rs9561778 showed an association with breast cancer patients who were treated with CA(F) drug regimen-induced ADR (Cochran-Armitage trend's P-value=0.00028; OR=3.13). The SNPs in ABCC4 might be applicable in predicting the risk of ADRs in patients receiving CPA combination chemotherapy.

  13. 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

  14. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma.

    PubMed

    Mai, E K; Bertsch, U; Dürig, J; Kunz, C; Haenel, M; Blau, I W; Munder, M; Jauch, A; Schurich, B; Hielscher, T; Merz, M; Huegle-Doerr, B; Seckinger, A; Hose, D; Hillengass, J; Raab, M S; Neben, K; Lindemann, H-W; Zeis, M; Gerecke, C; Schmidt-Wolf, I G H; Weisel, K; Scheid, C; Salwender, H; Goldschmidt, H

    2015-08-01

    We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P<0.001). Neuropathy rates (⩾2°) were higher in the PAd group (14.9 versus 8.4%, P=0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P=0.04 and 2.8 versus 0.4%, P=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ⩾VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy.

  15. Infusional etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone +/- rituximab as first-line therapy for aggressive non-Hodgkin lymphoma

    PubMed Central

    Lamar, Zanetta S.; Fino, Nora; Palmer, Jodi; Gruber, Lindsey; Morris, Bonny B.; RaetskayaSolntseva, Olga; Kennedy, LeAnne; Vaidya, Rakhee; Hurd, David; Zamkoff, Kenneth

    2015-01-01

    Introduction Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH) was developed in an effort to overcome inadequate drug concentrations and to compensate for increased drug clearance. The goal of this study was to examine risk factors and outcomes in patients with aggressive non-Hodgkin lymphoma (aNHL) treated with DA-EPOCH. Patients and Methods We report 136 patients with previously untreated aNHL treated with infusional DA-EPOCH chemotherapy +/- rituximab from 2005-2013. Overall survival was estimated by Kaplan Meier methods. Univariate and multivariate logistic regression was used to determine factors associated with experiencing death, progression, or relapse at two years. Results The overall response rate was 82%. Relapse-free survival at 1, 3, and 5 years was 68%, 63%, and 52% with 95% CIs [0.59,0.85], [0.54,0.70], and [0.31,0.70], respectively. Patients with T-cell aNHL had increased risk of death, progression or relapse [OR:3.5, 95% CI: 1.4, 8.8] compared to those with B-cell aNHL. In multivariate analysis, current smoking, disease in the bone marrow and number of cycles completed were independent predictors of death or relapse. Conclusion Our data suggests EPOCH+/-R is active in both B and T-cell aNHL. Toxicity did not significantly delay treatment or negatively impact outcomes. Dose adjustment by hematopoietic nadir had no impact on outcomes. The impact of smoking during chemotherapy should be further evaluated. PMID:26725264

  16. 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

  17. Definitive activation of endogenous antitumor immunity by repetitive cycles of cyclophosphamide with interspersed Toll-like receptor agonists

    PubMed Central

    Manrique, Soraya Zorro; Dominguez, Ana L.; Mirza, Noweeda; Spencer, Christopher D.; Bradley, Judy M.; Finke, James H.; Lee, James J.; Pease, Larry R.; Gendler, Sandra J.; Cohen, Peter A.

    2016-01-01

    Many cancers both evoke and subvert endogenous anti-tumor immunity. However, immunosuppression can be therapeutically reversed in subsets of cancer patients by treatments such as checkpoint inhibitors or Toll-like receptor agonists (TLRa). Moreover, chemotherapy can leukodeplete immunosuppressive host elements, including myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). We hypothesized that chemotherapy-induced leukodepletion could be immunopotentiated by co-administering TLRa to emulate a life-threatening infection. Combining CpG (ODN 1826) or CpG+poly(I:C) with cyclophosphamide (CY) resulted in uniquely well-tolerated therapeutic synergy, permanently eradicating advanced mouse tumors including 4T1 (breast), Panc02 (pancreas) and CT26 (colorectal). Definitive treatment required endogenous CD8+ and CD4+ IFNγ-producing T-cells. Tumor-specific IFNγ-producing T-cells persisted during CY-induced leukopenia, whereas Tregs were progressively eliminated, especially intratumorally. Spleen-associated MDSCs were cyclically depleted by CY+TLRa treatment, with residual monocytic MDSCs requiring only continued exposure to CpG or CpG+IFNγ to effectively attack malignant cells while sparing non-transformed cells. Such tumor destruction occurred despite upregulated tumor expression of Programmed Death Ligand-1, but could be blocked by clodronate-loaded liposomes to deplete phagocytic cells or by nitric oxide synthase inhibitors. CY+TLRa also induced tumoricidal myeloid cells in naive mice, indicating that CY+TLRa's immunomodulatory impacts occurred in the complete absence of tumor-bearing, and that tumor-induced MDSCs were not an essential source of tumoricidal myeloid precursors. Repetitive CY+TLRa can therefore modulate endogenous immunity to eradicate advanced tumors without vaccinations or adoptive T-cell therapy. Human blood monocytes could be rendered similarly tumoricidal during in vitro activation with TLRa+IFNγ, underscoring the potential

  18. Chemoprotective and chemosensitizing properties of selenium nanoparticle (Nano-Se) during adjuvant therapy with cyclophosphamide in tumor-bearing mice.

    PubMed

    Bhattacharjee, Arin; Basu, Abhishek; Biswas, Jaydip; Sen, Tuhinadri; Bhattacharya, Sudin

    2017-01-01

    Cyclophosphamide (CP) is one of the widely used anticancer agents; however, it has serious deleterious effects on normal host cells due to its nonspecific action. The essential trace element Selenium (Se) is suggested to have chemopreventive and chemotherapeutic efficacy and currently used in pharmaceutical formulations. Previous report had shown Nano-Se could protect CP-induced hepatotoxicity and genotoxicity in normal Swiss albino mice; however, its role in cancer management is still not clear. The aim of present study is to investigate the chemoprotective efficacy of Nano-Se against CP-induced toxicity as well as its chemoenhancing capability when used along with CP in Swiss albino mice against Ehrlich's ascites carcinoma (EAC) cells. CP was administered (25 mg/kg b.w., i.p.) and Nano-Se was given (2 mg Se/kg b.w., p.o.) in concomitant and pretreatment schedule. Increase levels of serum hepatic marker, hepatic lipid peroxidation, DNA damage, and chromosomal aberration in CP-treated mice were significantly (P < 0.05) reversed by Nano-Se. The lowered status of various antioxidant enzymes in tumor-bearing mice after CP treatment was also effectively increased by Nano-Se. Administration of Nano-Se along with CP caused a significant reduction in tumor volume, packed cell volume, viable tumor cell count, and increased the survivability of the tumor-bearing hosts. The results suggest that Nano-Se exhibits significant antitumor and antioxidant effects in EAC-bearing mice. The potential for Nano-Se to ameliorate the CP-evoked toxicity as well as to improve the chemotherapeutic effect could have beneficial implications for patients undergoing chemotherapy with CP.

  19. 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

  20. Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model

    PubMed Central

    Wu, Junjie; Waxman, David J.

    2014-01-01

    Metronomic cyclophosphamide (CPA) treatment activates robust innate anti-tumor immunity and induces major regression of large, implanted brain tumor xenografts when administered on an intermittent, every 6-day schedule, but not on a daily low-dose or a maximum-tolerated dose CPA schedule. Here, we used an implanted GL261 glioma model to compare five intermittent metronomic CPA schedules to elucidate the kinetics and schedule dependence of innate immune cell recruitment and tumor regression. Tumor-recruited natural killer cells induced by two every 6-day treatment cycles were significantly ablated one day after a third CPA treatment, but largely recovered several days later. Natural killer and other tumor-infiltrating innate immune cells peaked 12 days after the last CPA treatment on the every 6-day schedule, suggesting that drug-free intervals longer than 6 days may show increased efficacy. Metronomic CPA treatments spaced 9 or 12 days apart, or on an alternating 6 and 9 day schedule, induced extensive tumor regression, similar to the 6-day schedule, however, the tumor-infiltrating natural killer cell responses were not sustained, leading to rapid resumption of tumor regrowth after day 24, despite ongoing metronomic CPA treatment. Increasing the CPA dose prolonged the period of tumor regression on the every 9-day schedule, but natural killer cell activation was markedly decreased. Thus, while several intermittent metronomic CPA treatment schedules can activate innate immune cell recruitment leading to major tumor regression, sustained immune and anti-tumor responses are only achieved on the 6-day schedule. However, even with this schedule, some tumors eventually relapse, indicating a need for further improvements in immunogenic metronomic therapies. PMID:25069038

  1. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial.

    PubMed

    Brown, Jennifer R; O'Brien, Susan; Kingsley, C Daniel; Eradat, Herbert; Pagel, John M; Lymp, James; Hirata, Jamie; Kipps, Thomas J

    2015-04-30

    Obinutuzumab is a type 2, glycoengineered, anti-CD20 antibody recently approved with chlorambucil for the initial therapy of chronic lymphocytic leukemia (CLL). In this nonrandomized, parallel-cohort, phase 1b, multicenter study, we explored the safety and preliminary efficacy of obinutuzumab-bendamustine (G-B) or obinutuzumab fludarabine cyclophosphamide (G-FC) for the therapy of previously untreated fit patients with CLL. Patients received up to 6 cycles of G-B (n = 20) or G-FC (n = 21). The primary end point was safety, with infusion-related reactions (88%, grade 3-4 20%) being the most common adverse event and grade 3-4 neutropenia in 55% on G-B and 48% on G-FC. Mean cycles completed were 5.7 for G-B and 5.1 for G-FC, with 2 and 7 early discontinuations, respectively. The objective response rate (ORR) for G-B was 90% (18/20) with 20% complete response (CR) and 25% CR with incomplete marrow recovery (CRi). The ORR for G-FC was 62% (13/21), with 10% CR and 14% CRi, including 4 patients not evaluable. With a median follow-up of 23.5 months in the G-B cohort and 20.7 months in the G-FC cohort, no patient has relapsed or died. We conclude that obinutuzumab with either B or FC shows manageable toxicity and has promising activity. This study was registered at www.clinicaltrials.gov as #NCT01300247.

  2. Immune function in cyclophosphamide-treated mice is restored by the T-cell-tropic isoxazole derivative R-13.

    PubMed

    Zimecki, Michał; Artym, Jolanta; Kocięba, Maja; Obmińska-Mrukowicz, Bożena; Mączyński, Marcin; Ryng, Stanisław

    2015-01-01

    Reconstitution of the immune function in chemotherapy patients will lead to decreases in post-operative complications. A preliminary investigation showed that an isoxazole derivative R-13 (3,5-dimethyl-isoxazole[5,4-e]8H-triazepin-4-one) hydrochloride, given in a single oral dose to normal mice, induced significant increases in the content of CD4(+) cells in the spleens and lymph nodes. That observation prompted the authors to assess the immune reconstituting effects of R-13 in mice pre-treated with cyclophosphamide (CP). Mice were given intraperitoneally (IP) a sublethal dose of CP (200 mg/kg) and then R-13 (as 20 µg IP doses, every 3 days post-CP treatment). Control mice, not treated with CP, received R-13 or the vehicle (DMSO in appropriate dilution). Blood leukocyte and splenocyte numbers, blood cell type levels, splenocyte spontaneous and ConA-induced proliferation, and delayed-type hypersensitivity (DTH) to ovalbumin (OVA) were investigated on day 15 post-CP treatment and five R-13 doses. The humoral immune response (antibody-forming cell development to sheep erythrocytes) was measured 30 days post-CP treatment and 10 R-13 doses. In CP-treated mice, five dosings with R-13 led to increases in numbers of splenocytes and blood leukocytes, as well as in spontaneous and ConA-induced splenocyte proliferation, relative to levels in mice that received only CP 15 days earlier. Blood analysis revealed decreases in neutrophil and eosinophil contents and an increased appearance of lymphocyte immature forms in all mice that received the R-13. Both cell-mediated responses to OVA and humoral immune response to sheep erythrocytes in CP-treated hosts were restored. Based on the data here, it is concluded that R-13 may be of potential value for reconstitution of the immune function of chemotherapy patients.

  3. Radiation detector

    DOEpatents

    Fultz, B.T.

    1980-12-05

    Apparatus is provided for detecting radiation such as gamma rays and x-rays generated in backscatter Moessbauer effect spectroscopy and x-ray spectrometry, which has a large window for detecting radiation emanating over a wide solid angle from a specimen and which generates substantially the same output pulse height for monoenergetic radiation that passes through any portion of the detection chamber. The apparatus includes a substantially toroidal chamber with conductive walls forming a cathode, and a wire anode extending in a circle within the chamber with the anode lying closer to the inner side of the toroid which has the least diameter than to the outer side. The placement of the anode produces an electric field, in a region close to the anode, which has substantially the same gradient in all directions extending radially from the anode, so that the number of avalanche electrons generated by ionizing radiation is independent of the path of the radiation through the chamber.

  4. Radiation detector

    DOEpatents

    Fultz, Brent T.

    1983-01-01

    Apparatus is provided for detecting radiation such as gamma rays and X-rays generated in backscatter Mossbauer effect spectroscopy and X-ray spectrometry, which has a large "window" for detecting radiation emanating over a wide solid angle from a specimen and which generates substantially the same output pulse height for monoenergetic radiation that passes through any portion of the detection chamber. The apparatus includes a substantially toroidal chamber with conductive walls forming a cathode, and a wire anode extending in a circle within the chamber with the anode lying closer to the inner side of the toroid which has the least diameter than to the outer side. The placement of the anode produces an electric field, in a region close to the anode, which has substantially the same gradient in all directions extending radially from the anode, so that the number of avalanche electrons generated by ionizing radiation is independent of the path of the radiation through the chamber.

  5. Radiation retinopathy.

    PubMed Central

    Zamber, R W; Kinyoun, J L

    1992-01-01

    Radiation therapy is effective against many cancerous and noncancerous disease processes. As with other therapeutics, side effects must be anticipated, recognized, and managed appropriately. Radiation retinopathy is a vision-threatening complication of ocular, orbital, periorbital, facial, nasopharyngeal, and cranial irradiation. Factors that appear important in the pathogenesis of radiation retinopathy include total radiation dosage, fraction size, concomitant chemotherapy, and preexisting vascular disorders. Clinical manifestations of the disorder include macular edema and nonproliferative and proliferative retinopathy, similar to changes seen in diabetic retinopathy. Argon laser photocoagulation has proved efficacious for managing macular edema and fibrovascular proliferation in some of these patients. Ongoing basic laboratory and clinical research efforts have led to a better understanding of the pathogenesis, natural history, and treatment response of radiation retinopathy. The ultimate goal of this knowledge is to improve the prevention, recognition, and management of this vision-threatening complication. Images PMID:1441494

  6. Diffuse radiation

    NASA Technical Reports Server (NTRS)

    1981-01-01

    A diffuse celestial radiation which is isotropic at least on a course scale were measured from the soft X-ray region to about 150 MeV, at which energy the intensity falls below that of the galactic emission for most galactic latitudes. The spectral shape, the intensity, and the established degree of isotropy of this diffuse radiation already place severe constraints on the possible explanations for this radiation. Among the extragalactic theories, the more promising explanations of the isotropic diffuse emission appear to be radiation from exceptional galaxies from matter antimatter annihilation at the boundaries of superclusters of galaxies of matter and antimatter in baryon symmetric big bang models. Other possible sources for extragalactic diffuse gamma radiation are discussed and include normal galaxies, clusters of galaxies, primordial cosmic rays interacting with intergalactic matter, primordial black holes, and cosmic ray leakage from galaxies.

  7. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS).

    PubMed

    Hájek, R; Masszi, T; Petrucci, M T; Palumbo, A; Rosiñol, L; Nagler, A; Yong, K L; Oriol, A; Minarik, J; Pour, L; Dimopoulos, M A; Maisnar, V; Rossi, D; Kasparu, H; Van Droogenbroeck, J; Yehuda, D B; Hardan, I; Jenner, M; Calbecka, M; Dávid, M; de la Rubia, J; Drach, J; Gasztonyi, Z; Górnik, S; Leleu, X; Munder, M; Offidani, M; Zojer, N; Rajangam, K; Chang, Y-L; San-Miguel, J F; Ludwig, H

    2017-01-01

    This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m(2) on days 1 and 2 of cycle 1; 27 mg/m(2) thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

  8. 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

  9. Inhibition of cyclophosphamide-induced oxidative stress in rat brain by polar and non-polar extracts of Annatto (Bixa orellana) seeds.

    PubMed

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

    2011-03-01

    Annatto (Bixa orellana) seeds are widely distributed throughout the Tropics and have been used to provide both colour and flavour to food. This study sought to assess the ability of dietary inclusion of polar (water) and non-polar (chloroform) extracts of Annatto (B. orellana) seeds on cyclophosphamide-induced oxidative stress in rat brain. The total phenol content and antioxidant activities of polar (water) and non-polar (chloroform) extracts of Annatto seeds were determined in vitro and in vivo. The results of the study showed that intraperitoneal administration of cyclophosphamide (75 mg/kg of body weight) caused a significant increase (P<0.05) in the malondialdehyde (MDA) content of the brain; however, dietary inclusion of Annatto seed extracts (0.1% and 0.2%) caused dose-dependent significant decrease (P<0.05) in the MDA content of the brain. Likewise, the extracts also caused dose-dependent inhibition of the elevated serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase and total bilirubin. However, the non-polar extract had significantly higher inhibitory effects on the elevated MDA production in brain and serum liver function markers. This higher protective effect of the non-polar extract could be attributed to its higher antioxidant properties as typified by its significantly higher (P<0.05) reducing power, free-radical scavenging and Fe (II) chelating ability. Therefore, dietary inclusion of Annato seed extracts as food colourant could prevent oxidative stress occasioned by cyclophosphamide administration, but the non-polar extract is a better protectant.

  10. Involvement of interleukin-6-regulated nitric oxide synthase in hemorrhagic cystitis and impaired bladder contractions in young rats induced by acrolein, a urinary metabolite of cyclophosphamide.

    PubMed

    Wang, Ching-Chia; Weng, Te-I; Wu, En-Ting; Wu, Mei-Hwan; Yang, Rong-Sen; Liu, Shing-Hwa

    2013-01-01

    Hemorrhagic cystitis is a common complication in children receiving cyclophosphamide, a chemotherapeutic alkylating agent. Acrolein is a urinary metabolite from cyclophosphamide and can induce hemorrhagic cystitis. Here, we investigated the effects and mechanisms of acrolein by intravesical instillation on urinary bladder muscle contractions and pathological alterations in rats. Acrolein instillation significantly increased the muscle contractions of rat bladder detrusor after 1 and 6 h but markedly decreased detrusor contractions after 24 h. Acrolein increased phosphorylated protein kinase C (pan-PKC) expressions in bladders after 1 and 6 h but inhibited it after 24 h. Inducible nitric oxide (NO) synthase (iNOS) protein expressions were markedly induced in bladders 24 h after acrolein treatment. Twenty-four-hour acrolein instillation increased the levels of nitrite/nitrate and interleukin-6 (IL-6) in the urinary bladder. The iNOS inhibitors significantly inhibited the acrolein-increased nitrite/nitrate levels, but not IL-6 levels. IL-6-neutralizing antibodies effectively inhibited the acrolein-increased NOx levels. The increased detrusor contractions by 1-h acrolein treatment were significantly reversed by the PKC inhibitor RO32-0432, and the decreased detrusor contractions by 24-h acrolein treatment were significantly reversed by the iNOS inhibitor and IL-6-neutralizing antibody. Both the iNOS inhibitor and IL-6-neutralizing antibody effectively reversed the increased iNOS expression, decreased PKC phosphorylation, increased bladder weight, and hemorrhagic cystitis in rats 24 h after acrolein treatment. Taken together, these results suggest that an IL-6-regulated iNOS/NO signaling pathway participates in the acrolein-triggered detrusor contraction inhibition and hemorrhagic cystitis. These findings may help us to find a new strategy to treat cyclophosphamide-induced hemorrhagic cystitis.

  11. 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.

  12. The PACOVAR-trial: A phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer

    PubMed Central

    2011-01-01

    Background The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC. Methods/design This study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject). Discussion The current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic

  13. 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

  14. Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma.

    PubMed

    Nijhof, Inger S; Franssen, Laurens E; Levin, Mark-David; Bos, Gerard M J; Broijl, Annemiek; Klein, Saskia K; Koene, Harry R; Bloem, Andries C; Beeker, Aart; Faber, Laura M; van der Spek, Ellen; Ypma, Paula F; Raymakers, Reinier; van Spronsen, Dick-Johan; Westerweel, Peter E; Oostvogels, Rimke; van Velzen, Jeroen; van Kessel, Berris; Mutis, Tuna; Sonneveld, Pieter; Zweegman, Sonja; Lokhorst, Henk M; van de Donk, Niels W C J

    2016-09-19

    The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/day) and prednisone (20 mg/day). At the MTD (n=67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median PFS and OS were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by FISH. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 non-hematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.

  15. Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study

    PubMed Central

    2014-01-01

    Introduction Pulmonary involvement represents a major cause of death of systemic sclerosis (SSc) patients. Recent data suggest that tyrosine kinase inhibitors, such as imatinib, may be a therapeutic option for SSc patients. However, preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects. The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy. Methods Thirty consecutive SSc patients with active pulmonary involvement, unresponsive to cyclophosphamide, were treated with imatinib 200 mg/day for 6 months followed by a 6-month follow-up. A “good response” was defined as an increase of forced vital capacity (FVC) by more of 15% and/or increase of diffusing capacity of carbon monoxide (DLCO) >15% and PaO2 > 90% of initial value and high-resolution computed tomography (HRCT)-scan pattern unchanged or improved. Results Twenty-six patients completed the study. Three patients died and one patient was lost to follow-up. Four patients (15.32%) had a good response, 7 worsened and 15 had a stabilized lung disease. Overall, 19 (73.07%) patients had an improved or stabilized lung disease. After a 6-month follow-up, 12 (54.5%) of the 22 patients showed an improved or stabilized lung disease. Conclusions Lung function was stabilized in a large proportion of patients unresponsive to cyclophosphamide therapy and a beneficial outcome emerged from the analysis of HRCT lung scans. There was no significant improvement of skin involvement, and the low dose was well tolerated. These data provide useful suggestions to design future randomized clinical trials for SSc therapeutics. Trial registration ClinicalTrials.gov NCT00573326. Registered 13 December 2007. PMID:25007944

  16. Liquid-liquid extraction procedure for trace determination of cyclophosphamide in human urine by high-performance liquid chromatography tandem mass spectrometry.

    PubMed

    Sottani, C; Turci, R; Perbellini, L; Minoia, C

    1998-01-01

    A sensitive, specific and accurate high performance liquid chromatography/ionspray-tandem mass spectrometry procedure (HPLC/MS/MS) has been developed to quantify cyclophosphamide in human urine from hospital personnel involved in drug preparation and administration of antineoplastic alkylating agents. This methodology, which includes liquid-liquid extraction with ethylacetate, requires no derivatization procedures, preventing cyclophosphamide (CP) from possible thermal and chemical decomposition reactions. We detected the excretion of this unmetabolized alkylating drug in 50% of all the study participants. The amount of CP ranged from 0.1 ng microL-1 to 1.9 ng microL-1 urine. This methodology was validated by the use of ifosfamide as internal standard. The assay was linear over the range 0 to 3.2 ng microL-1 urine, with a lower limit of quantification of 0.2 microL-1. The limit of detection was assessed at 0.05 ng microL-1 urine. This method is characterized by a coefficient of variation < 10%. Standard calibration curves, obtained on three different days, had correlation coefficients always greater than 0.998. The intra and interday precision were within 11%, and accuracy was in the range 99-103%. The mean extracted recovery assessed at three different concentrations (0.5, 0.8, 3.2 ng microL-1) was always more than 85%. The extraction efficiency of cyclophosphamide from urine samples was also studied at six different pH values (pH 4, 5, 6, 7, 8, 10). The maximum extraction efficiency was obtained when the pH of urine solutions was adjusted to 7.0

  17. 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 Central

    Mostafa, Heba H.; Vogel, Peter; Srinivasan, Ashok; Russell, Charles J.

    2016-01-01

    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

  18. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS)

    PubMed Central

    Hájek, R; Masszi, T; Petrucci, M T; Palumbo, A; Rosiñol, L; Nagler, A; Yong, K L; Oriol, A; Minarik, J; Pour, L; Dimopoulos, M A; Maisnar, V; Rossi, D; Kasparu, H; Van Droogenbroeck, J; Yehuda, D B; Hardan, I; Jenner, M; Calbecka, M; Dávid, M; de la Rubia, J; Drach, J; Gasztonyi, Z; Górnik, S; Leleu, X; Munder, M; Offidani, M; Zojer, N; Rajangam, K; Chang, Y-L; San-Miguel, J F; Ludwig, H

    2017-01-01

    This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4–14.4) vs 10.0 months (95% CI 7.7–12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760–1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients. PMID:27416912

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

    PubMed

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

    2016-01-15

    The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p < 0.001), and TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50-7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20-0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival.

  20. Randomised trial comparing combinations of cyclophosphamide and cisplatin without or with doxorubicin or 4'-epi-doxorubicin in the treatment of advanced ovarian cancer.

    PubMed

    Hernádi, Z; Juhász, B; Póka, R; Lampé, L G

    1988-10-01

    Forty-eight patients with FIGO stage III and IV epithelial carcinomas of the ovary were entered in this randomised trial. Radical surgery was performed and no residual tumor with a diameter greater than 2 cm was left behind. Of these patients 62.5% (10/16) had a complete or partial response on cyclophosphamide + cisplatin (CP) 87.5% (14/16) on cyclophosphamide + doxorubicin + cisplatin (CAP) and cyclophosphamide + 4'-epi-doxorubicin + cisplatin (CEP). The median time to progression was 3.5 months on CP, 12.5 months on CAP and 11.0 months on CEP. Patients treated with CAP combination chemotherapy had generally longer progression-free survival (log rank chi 2 = 5.4; P = 0.04). No significant difference was found, however, between patients on CAP and CEP. The median survival times were 12.5 months on CP, 26.5 months on CAP and 14.0 months on CEP. Patients treated with CAP combination chemotherapy had generally longer survival (logrank chi 2 = 9.08; P = 0.0099). No significant difference was found, however, between patients on CAP and CEP in terms of survival. Asymptomatic mild-to-moderate laboratory test toxicity occurred in 6-12% of patients on CP, 6-12% on CAP and no toxicity of this type and grade on CEP. Nausea and vomiting were also less severe and less frequent in the CEP group. Cardiotoxicity was seen in 12.5% (2/16) only in the CAP group.

  1. [Radiation carcinogenesis].

    PubMed

    Hosoi, Yoshio

    2013-11-01

    Misrepair of DNA damage induced by ionizing radiation is a potential cause of carcinogenesis following exposure to radiation. Radiation exposure increases the incidence of the same types of mutations that occur spontaneously in a given population. A high incidence of DNA double-strand breaks is characteristic of damage by ionizing radiation compared with those induced by other environmental mutagens. In China, residents living in areas with high level background radiation(6mSv/y) had a significantly higher frequency of dicentric and ring chromosomes compared to that for the residents living in the control areas(2mSv/y). Radiation-associated increases in risk were seen for most sites. Gender-averaged excess absolute risk rates estimated at age 70, after exposure at age 30, differ in the sites, and the risks of gastric cancer, breast cancer, colon cancer, and lung cancer were highly increased, in that order. Latent periods for the development of leukemia and thyroid cancer after radiation exposure at ages younger than 18 were shorter compared to those for other solid cancers.

  2. An investigation of the chest radiographs in a controlled trial of busulphan, cyclophosphamide, and a placebo after resection for carcinoma of the lung.

    PubMed Central

    Stott, H; Stephens, R; Fox, W; Simon, G; Roy, D C

    1976-01-01

    A standard series of radiographs of 588 patients allocated at random to treatment with busulphan (B patients), cyclophosphamide (C patients), or a placebo (P patients) for two years after surgery for bronchial carcinoma were viewed in three stages (following procedures which avoided bias) by an independent assessor, unaware of the allocated treatment of any patient, with a view to identifying pulmonary changes due to busulphan. Radiographic appearances consistent with busulphan lung were not reported in any of the 195 B patients (receiving a mean dosage of 464 mg of busulphan over 301 days) or of the 192 C patients but were present in one of the 201 patients receiving placebo. PMID:781905

  3. Water intoxication induced by low-dose oral cyclophosphamide in a patient with anti-neutrophil cytoplasmic antibody-related glomerulonephritis.

    PubMed

    Kato, Akihiko; Sugiura, Takeshi; Yamamoto, Tatsuo; Misaki, Taro; Tsuji, Takayuki; Sakao, Yukitoshi; Sakakima, Masaaki; Yasuda, Hideo; Fujigaki, Yoshihide; Hishida, Akira

    2008-10-01

    We reported the case of a 70-year-old woman with moderate renal failure due to anti-neutrophil cytoplasmic antibody-related glomerulonephritis who developed symptomatic water intoxication (serum Na: 108 mEq/L) following treatment with oral low-dose cyclophosphamide (CY) (50mg/day). Estimated glomerular filtration rate was 29.5 mL/min/1.73 m(2). She had drunk >2 L of fluid in 12 h prior to the development of cerebral oedema. This rare case suggests that oral low-dose CY could be an occult cause of water intoxication in patients with chronic kidney disease taking large fluid volumes.

  4. [Efficacy of rituximab combined with cyclophosphamide in a patient with systemic lupus erythematosus and peritoneal vasculitis refractory to conventional inmunosupressive therapy].

    PubMed

    Garrido Rasco, Rocío; García Hernández, Francisco José; González León, Rocío; Castillo Palma, María Jesús; Ocaña Medina, Celia; Sánchez Román, Julio

    2009-02-01

    Peritoneal vasculitis is a rare and severe clinical manifestation of systemic lupus erythematosus. We report a patient who presented with ascites due to peritoneal vasculitis and cutaneous, articular, hematological and renal inflammatory activity. Treatment with glucocorticoids and immunosuppressive drugs was ineffective. In view of the resistance to different therapies, 4 weekly infusions of 375mg/m2 of rituximab (RTX) were started, in association with cyclophosphamide pulses during the first and the third weeks. With this treatment strategy, the patient reached a complete response which was achieved in later flares of inflammatory activity (the second and third flares were multisystemic and with ascites again, and the fourth flare with nephritis).

  5. Plasma chromogranin A marks emesis and serotonin release associated with dacarbazine and nitrogen mustard but not with cyclophosphamide-based chemotherapies.

    PubMed Central

    Cubeddu, L. X.; O'Connor, D. T.; Hoffmann, I.; Parmer, R. J.

    1995-01-01

    Chromogranin A (CgA) is present in high concentrations in enterochromaffin cells, where it is co-localised with serotonin in the storage granules. Plasma CgA has been reported to mark emesis and serotonin release associated with cisplatin treatment. However, it is not known whether plasma CgA could be an indicator of emesis and of serotonin release in patients receiving non-cisplatin chemotherapies. Therefore, in this study we evaluated, in cancer patients, the temporal relationships between the increases in plasma CgA and urinary 5-hydroxyindoleacetic acid (5-HIAA) and the development of vomiting following dacarbazine, nitrogen mustard and cyclophosphamide treatments. Metoclopramide was used as antiemetic. With dacarbazine, nitrogen mustard and cyclophosphamide the median time to the onset of emesis was 2.3, 2.8 and 5.3 h and the duration of intense emesis was 3, 2 and 6 h respectively. Plasma CgA and urinary 5-HIAA increased after dacarbazine- and nitrogen mustard-based chemotherapies, with maximal increases between 4 and 6 h after initiation of drug infusion. The time course for the increases in plasma CgA paralleled that of urinary 5-HIAA and the period of intense emesis. A highly significant (P = 0.0009) positive correlation (r = 0.68) was found between the increases in plasma CgA and in urinary 5-HIAA. Cyclophosphamide treatment was not associated with increases in plasma CgA and in urinary 5-HIAA, despite inducing emesis; this indicates that the increases in CgA and 5-HIAA after dacarbazine and nitrogen mustard are not due to the act of vomiting per se. In summary, plasma CgA is a marker of serotonin release (most likely from enterochromaffin cells) after dacarbazine and nitrogen mustard-based chemotherapies, exocytosis being the most likely mechanism for the release of serotonin. Serotonin released from enterochromaffin cells seems to trigger the emetic response to dacarbazine and nitrogen mustard; however, cyclophosphamide may release serotonin from a

  6. Radiation dosimeter

    DOEpatents

    Fox, R.J.

    1981-09-01

    A radiation detector readout circuit is provided which produces a radiation dose-rate readout from a detector even through the detector output may be highly energy dependent. A linear charge amplifier including an output charge pump circuit amplifies the charge signal pulses from the detector and pumps the charge into a charge storage capacitor. The discharge rate of the capacitor through a resistor is controlled to provide a time-dependent voltage which when integrated provides an output proportional to the dose-rate of radiation detected by the detector. This output may be converted to digital form for readout on a digital display.

  7. Radiation dosimeter

    DOEpatents

    Fox, Richard J.

    1983-01-01

    A radiation detector readout circuit is provided which produces a radiation dose-rate readout from a detector even though the detector output may be highly energy dependent. A linear charge amplifier including an output charge pump circuit amplifies the charge signal pulses from the detector and pumps the charge into a charge storage capacitor. The discharge rate of the capacitor through a resistor is controlled to provide a time-dependent voltage which when integrated provides an output proportional to the dose-rate of radiation detected by the detector. This output may be converted to digital form for readout on a digital display.

  8. Radiation Hydrodynamics

    SciTech Connect

    Castor, J I

    2003-10-16

    The discipline of radiation hydrodynamics is the branch of hydrodynamics in which the moving fluid absorbs and emits electromagnetic radiation, and in so doing modifies its dynamical behavior. That is, the net gain or loss of energy by parcels of the fluid material through absorption or emission of radiation are sufficient to change the pressure of the material, and therefore change its motion; alternatively, the net momentum exchange between radiation and matter may alter the motion of the matter directly. Ignoring the radiation contributions to energy and momentum will give a wrong prediction of the hydrodynamic motion when the correct description is radiation hydrodynamics. Of course, there are circumstances when a large quantity of radiation is present, yet can be ignored without causing the model to be in error. This happens when radiation from an exterior source streams through the problem, but the latter is so transparent that the energy and momentum coupling is negligible. Everything we say about radiation hydrodynamics applies equally well to neutrinos and photons (apart from the Einstein relations, specific to bosons), but in almost every area of astrophysics neutrino hydrodynamics is ignored, simply because the systems are exceedingly transparent to neutrinos, even though the energy flux in neutrinos may be substantial. Another place where we can do ''radiation hydrodynamics'' without using any sophisticated theory is deep within stars or other bodies, where the material is so opaque to the radiation that the mean free path of photons is entirely negligible compared with the size of the system, the distance over which any fluid quantity varies, and so on. In this case we can suppose that the radiation is in equilibrium with the matter locally, and its energy, pressure and momentum can be lumped in with those of the rest of the fluid. That is, it is no more necessary to distinguish photons from atoms, nuclei and electrons, than it is to distinguish

  9. Radiation therapy

    MedlinePlus

    ... Intensity-modulated radiotherapy (IMRT) Image-guided radiotherapy (IGRT) Proton therapy is another kind of radiation used to ... than using x-rays to destroy cancer cells, proton therapy uses a beam of special particles called ...

  10. RADIATION DETECTOR

    DOEpatents

    Wilson, H.N.; Glass, F.M.

    1960-05-10

    A radiation detector of the type is described wherein a condenser is directly connected to the electrodes for the purpose of performing the dual function of a guard ring and to provide capacitance coupling for resetting the detector system.

  11. Radiation Basics

    MedlinePlus

    ... of the heaviest radioactive elements, such as uranium , radium and polonium. Even though alpha particles are very ... is roughly the activity of one gram of Radium-226. Curies are not used to measure radiation ...

  12. Anti-tumor innate immunity activated by intermittent metronomic cyclophosphamide treatment of 9L brain tumor xenografts is preserved by anti-angiogenic drugs that spare VEGF receptor 2

    PubMed Central

    2014-01-01

    Background Metronomic cyclophosphamide given on an intermittent, 6-day repeating schedule, but not on an exposure dose-equivalent daily schedule, activates an anti-tumor innate immune response that leads to major regression of large implanted gliomas, without anti-angiogenesis. Methods and approach Mice bearing implanted 9L gliomas were used to investigate the effects of this 6-day repeating, immunogenic cyclophosphamide schedule on myeloid-derived suppressor cells, which are pro-angiogenic and can inhibit anti-tumor immunity, and to elucidate the mechanism whereby the innate immune cell-dependent tumor regression response to metronomic cyclophosphamide treatment is blocked by several anti-angiogenic receptor tyrosine kinase inhibitors. Results Intermittent metronomic cyclophosphamide scheduling strongly increased glioma-associated CD11b+ immune cells but not CD11b+Gr1+ myeloid-derived suppressor cells, while bone marrow and spleen reservoirs of the suppressor cells were decreased. The inhibition of immune cell recruitment and tumor regression by anti-angiogenic receptor tyrosine kinase inhibitors, previously observed in several brain tumor models, was recapitulated in the 9L tumor model with the VEGFR2-specific inhibitory monoclonal antibody DC101 (p < 0.01), implicating VEGFR2 signaling as an essential step in metronomic cyclophosphamide-stimulated immune cell recruitment. In contrast, sorafenib, a multi-receptor tyrosine kinase inhibitor with comparatively weak VEGF receptor phosphorylation inhibitory activity, was strongly anti-angiogenic but did not block metronomic cyclophosphamide-induced innate immunity or tumor regression (p > 0.05). Conclusions The interference by receptor tyrosine kinase inhibitors in the immunogenic actions of intermittent metronomic chemotherapy is not a consequence of anti-angiogenesis per se, as demonstrated in an implanted 9L tumor model. Furthermore, this undesirable interaction with tyrosine kinase inhibitors can be

  13. Radiation Transport

    SciTech Connect

    Urbatsch, Todd James

    2015-06-15

    We present an overview of radiation transport, covering terminology, blackbody raditation, opacities, Boltzmann transport theory, approximations to the transport equation. Next we introduce several transport methods. We present a section on Caseology, observing transport boundary layers. We briefly broach topics of software development, including verification and validation, and we close with a section on high energy-density experiments that highlight and support radiation transport.

  14. Radiation enteritis.

    PubMed

    Harb, Ali H; Abou Fadel, Carla; Sharara, Ala I

    2014-01-01

    Radiation enteritis continues to be a major health concern in recipients of radiation therapy. The incidence of radiation enteritis is expected to continue to rise during the coming years paralleling the unprecedented use of radiotherapy in pelvic cancers. Radiation enteritis can present as either an acute or chronic syndrome. The acute form presents within hours to days of radiation exposure and typically resolves within few weeks. The chronic form may present as early as 2 months or as long as 30 years after exposure. Risk factors can be divided into patient and treatment-related factors. Chronic radiation enteritis is characterized by progressive obliterative endarteritis with exaggerated submucosal fibrosis and can manifest by stricturing, formation of fistulae, local abscesses, perforation, and bleeding. In the right clinical context, diagnosis can be confirmed by cross-sectional imaging, flexible or video capsule endoscopy. Present treatment strategies are directed primarily towards symptom relief and management of emerging complications. Recently, however, there has been a shift towards rational drug design based on improved understanding of the molecular basis of disease in an effort to limit the fibrotic process and prevent organ damage.

  15. Systemic sclerosis sera affect fibrillin-1 deposition by dermal blood microvascular endothelial cells: therapeutic implications of cyclophosphamide

    PubMed Central

    2013-01-01

    Introduction Systemic sclerosis (SSc) is a connective tissue disorder characterized by endothelial cell injury, autoimmunity and fibrosis. The following three fibrillin-1 alterations have been reported in SSc. (1) Fibrillin-1 microfibrils are disorganized in SSc dermis. (2) Fibrillin-1 microfibrils produced by SSc fibroblasts are unstable. (3) Mutations in the FBN1 gene and anti-fibrillin-1 autoantibodies have been reported in SSc. Fibrillin-1 microfibrils, which are abundantly produced by blood and lymphatic microvascular endothelial cells (B-MVECs and Ly-MVECs, respectively), sequester in the extracellular matrix the latent form of the potent profibrotic cytokine transforming growth factor β (TGF-β). In the present study, we evaluated the effects of SSc sera on the deposition of fibrillin-1 and microfibril-associated glycoprotein 1 (MAGP-1) and the expression of focal adhesion molecules by dermal B-MVECs and Ly-MVECs. Methods Dermal B-MVECs and Ly-MVECs were challenged with sera from SSc patients who were treatment-naïve or under cyclophosphamide (CYC) treatment and with sera from healthy controls. Fibrillin-1/MAGP-1 synthesis and deposition and the expression of αvβ3 integrin/phosphorylated focal adhesion kinase and vinculin/actin were evaluated by immunofluorescence and quantified by morphometric analysis. Results Fibrillin-1 and MAGP-1 colocalized in all experimental conditions, forming a honeycomb pattern in B-MVECs and a dense mesh of short segments in Ly-MVECs. In B-MVECs, fibrillin-1/MAGP-1 production and αvβ3 integrin expression significantly decreased upon challenge with sera from naïve SSc patients compared with healthy controls. Upon challenge of B-MVECs with sera from CYC-treated SSc patients, fibrillin-1/MAGP-1 and αvβ3 integrin levels were comparable to those of cells treated with healthy sera. Ly-MVECs challenged with SSc sera did not differ from those treated with healthy control sera in the expression of any of the molecules assayed

  16. Neoadjuvant Sequential Docetaxel Followed by High‐Dose Epirubicin in Combination With Cyclophosphamide Administered Concurrently With Trastuzumab. The DECT Trial

    PubMed Central

    Pizzuti, Laura; Barba, Maddalena; Giannarelli, Diana; Sergi, Domenico; Botti, Claudio; Marchetti, Paolo; Anzà, Michele; Maugeri‐Saccà, Marcello; Natoli, Clara; Di Filippo, Simona; Catenaro, Teresa; Tomao, Federica; Amodio, Antonella; Carpano, Silvia; Perracchio, Letizia; Mottolese, Marcella; Di Lauro, Luigi; Sanguineti, Giuseppe; Di Benedetto, Anna; Giordano, Antonio

    2016-01-01

    To report the results of the DECT trial, a phase II study of locally advanced or operable HER2‐positive breast cancer (BC) treated with taxanes and concurrent anthracyclines and trastuzumab. Eligible patients (stage IIA‐IIIB HER2‐positive BC, 18–75 years, normal organ functions, ECOG ≤1, and left ventricular ejection fraction (LVEF) ≥55%) received four cycles of neoadjuvant docetaxel, 100 mg/m2 intravenously, plus trastuzumab 6 mg/kg (loading dose 8 mg/kg) every 3 weeks, followed by four 3‐weekly cycles of epirubicin 120 mg/m2 and cyclophosphamide, 600 mg/m2, plus trastuzumab. Primary objective was pathologic complete response (pCR) rate, defined as ypT0/is ypN0 at definitive surgery. We enrolled 45 consecutive patients. All but six patients (13.3%) completed chemotherapy and all underwent surgery. pCR was observed in 28 patients (62.2%) overall and in 6 (66.7%) from the inflammatory subgroup. The classification and regression tree analysis showed a 100% pCR rate in patients with BMI ≥25 and with hormone negative disease. The median follow up was 46 months (8–78). Four‐year recurrence‐free survival was 74.7% (95%CI, 58.2–91.2). Seven patients (15.6%) recurred and one died. Treatment was well tolerated, with limiting toxicity being neutropenia. No clinical cardiotoxicity was observed. Six patients (13.4%) showed a transient LVEF decrease (<10%). In one patient we observed a ≥10% asymptomatic LVEF decrease persisting after surgery. Notwithstanding their limited applicability due to the current guidelines, our findings support the efficacy of the regimen of interest in the neoadjuvant setting along with a fairly acceptable toxicity profile, including cardiotoxicity. Results on BMI may invite further assessment in future studies. J. Cell. Physiol. 231: 2541–2547, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. PMID:27187274

  17. In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumor activity.

    PubMed

    Yu, L J; Drewes, P; Gustafsson, K; Brain, E G; Hecht, J E; Waxman, D J

    1999-03-01

    The widely used anticancer prodrug cyclophosphamide (CPA) is activated in liver by a 4-hydroxylation reaction primarily catalyzed by cytochrome P-4502B and P-4502C enzymes. An alternative metabolic pathway involves CPA N-dechloroethylation to yield chloroacetaldehyde (CA), a P-4503A-catalyzed deactivation/neurotoxication reaction. The in vivo modulation of these alternative, competing pathways of P-450 metabolism was investigated in pharmacokinetic studies carried out in the rat model. Peak plasma concentrations (Cmax) for 4-OH-CPA and CA were increased by 3- to 4-fold, and apparent plasma half-lives of both metabolites were correspondingly shortened in rats pretreated with phenobarbital (PB), an inducer of P-4502B and P-4503A enzymes. However, PB had no net impact on the extent of drug activation or its partitioning between these alternative metabolic pathways, as judged from AUC values (area-under-the-plasma concentration x time curve) for 4-OH-CPA and CA. The P-4503A inhibitor troleandomycin (TAO) decreased plasma Cmax and AUC of CA (80-85% decrease) without changing the Cmax or AUC of 4-OH-CPA in uninduced rats. In PB-induced rats, TAO decreased AUCCA by 73%, whereas it increased AUC4-OH-CPA by 93%. TAO thus selectively suppresses CPA N-dechloroethylation, thereby increasing the availability of drug for P-450 activation via 4-hydroxylation. By contrast, dexamethasone, a P-4503A inducer and antiemetic widely used in patients with cancer, stimulated large, undesirable increases in the Cmax and AUC of CA (8- and 4-fold, respectively) while reducing the AUC of the 4-hydroxylation pathway by approximately 60%. Tumor excision/in vitro colony formation and tumor growth delay assays using an in vivo 9L gliosarcoma solid tumor model revealed that TAO suppression of CPA N-dechloroethylation could be achieved without compromising the antitumor effect of CPA. The combination of PB with TAO did not, however, enhance the antitumor activity of CPA, despite the approximately 2

  18. Comparison of high and low dose of cyclophosphamide in lupus nephritis patients: a long-term randomized controlled trial.

    PubMed

    Mitwalli, Ahmed H; Al Wakeel, Jamal S; Hurraib, Sameer; Aisha, Abu; Al Suwaida, Abdulkaraem; Alam, Awatif; Hammad, Durdana; Sulimani, Fathia; Memon, Nawaz A; Askar, Akram; Al Tuwaijri, Ali; Qudsi, Abdo

    2011-09-01

    To evaluate the outcome of low doses of cyclophosphamide (Cyclo) therapy in lupus nephritis (LN) patients, we studied 117 biopsy-proven, de novo LN WHO class IV patients double-blinded and randomized in December 1997 to receive Cyclo in different doses; Group I (n=73) received Cyclo 10 mg/kg monthly for six months then every two months for 12 months. Group II (n=44) received Cyclo 5 mg/kg monthly for six months then every two months for 36 months. The patients were followed-up till January 2007. Six months post-induction values for creatinine clearance were significantly higher in Group I (67.7 ± 28.6 mL/min) compared with Group II (55.1 ± 30.1 mL/min), P = 0.026. Serum C4 and ANA were not significantly different between the groups (P > 0.05). At the mean follow-up of 6.77 ± 3.3 years, the mean creatinine clearance was 44.74 ± 31.7 mL/min in Group I vs. 49.3 ± 38.8 in Group II. Urinary protein was 1.65 ± 1.8 g/dL in Group I vs. 1.02 ± 1.01 in Group II (P = 0.03). The survival curve showed that kidney survival overtime was comparable in both groups (P = 0.2). Complete remission was observed in 25 (34.2%) patients in Group I vs. 11 (25%) in Group II (P = 0.288), while partial remission was similar in both groups; 43 (58.9%) patients in Group I vs. 26 (59%) patients in Group II. End-stage renal disease was observed in 10 (13.7%) patients in Group I vs. 9 (20.4%) patients in Group II (P = 0.359). Side-effects were more frequent in Group I patients than in Group II patients; gonadal toxicity and malignancy were lower in Group II patients (P = 0.0000). Moreover, different infections occurred in 23 (31.3%) patients vs. six (13.6%), digital infarcts occurred in 1.35% vs. 0%, diabetes in 4.1% vs. 2.27%, and vasculitis in 4.1% vs. 2.27% in Group I vs. Group II, respectively. Sustained amenorrhea without pregnancy was observed in both groups; however, significantly more in Group I patients, P ≤ 0.05. We conclude that low-dose Cyclo therapy is sufficiently effective

  19. Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia in Ukraine

    PubMed Central

    Mandrik, Olena; Corro Ramos, Isaac; Knies, Saskia; Al, Maiwenn; Severens, Johan L

    2015-01-01

    The aim of this study was to assess the cost-effectiveness, from a health care perspective, of adding rituximab to fludarabine and cyclophosphamide scheme (FCR versus FC) for treatment-naïve and refractory/relapsed Ukrainian patients with chronic lymphocytic leukemia. A decision-analytic Markov cohort model with three health states and 1-month cycle time was developed and run within a life time horizon. Data from two multinational, prospective, open-label Phase 3 studies were used to assess patients’ survival. While utilities were generalized from UK data, local resource utilization and disease-associated treatment, hospitalization, and side effect costs were applied. The alternative scenario was performed to assess the impact of lower life expectancy of the general population in Ukraine on the incremental cost-effectiveness ratio (ICER) for treatment-naïve patients. One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the robustness of the results. The ICER (in US dollars) of treating chronic lymphocytic leukemia patients with FCR versus FC is US$8,704 per quality-adjusted life year gained for treatment-naïve patients and US$11,056 for refractory/relapsed patients. When survival data were modified to the lower life expectancy of the general population in Ukraine, the ICER for treatment-naïve patients was higher than US$13,000. This value is higher than three times the current gross domestic product per capita in Ukraine. Sensitivity analyses have shown a high impact of rituximab costs and a moderate impact of differences in utilities on the ICER. Furthermore, probabilistic sensitivity analyses have shown that for refractory/relapsed patients the probability of FCR being cost-effective is higher than for treatment-naïve patients and is close to one if the threshold is higher than US$15,000. State coverage of rituximab treatment may be considered a cost-effective treatment for the Ukrainian population under conditions of economic

  20. Effects of dietary vitamin E type on the growth performance and antioxidant capacity in cyclophosphamide immunosuppressed broilers.

    PubMed

    Cheng, K; Song, Z H; Zheng, X C; Zhang, H; Zhang, J F; Zhang, L L; Zhou, Y M; Wang, T

    2016-09-24

    Reactive oxygen species and free radicals play multiple roles in some immune-pathological events. Vitamin E, as a very potent antioxidant, perhaps deceases the potentially negative effects of such oxidative stress to prevent immune-pathological damage to broilers. Therefore, the current study investigated the effects of dietary natural (D-α-tocopherol) and synthetic (DL-α-tocopherol acetate) vitamin E on the growth performance and antioxidant capacity in cyclophosphamide (CY) immunosuppressed broilers. 192 one-day-old male Arbor Acre broilers were randomly distributed into 4 groups: 1) non-CY-challenged control; 2) CY-challenged control; 3) CY-challenged group+20 IU DL-α-tocopherol acetate per kg feed; and 4) CY-challenged group+20 IU D-α-tocopherol per kg feed. The maize-soybean basal diet in the control group contained α-tocopherol (7.12 mg/kg). Broilers were intramuscularly injected with 80 mg/kg body weight of CY or sterile saline at 16, 17, and 18 d of age. CY decreased (P < 0.05) the average daily gain and average daily feed intake, but vitamin E did not alter the growth performance of broilers before or after CY injection (P > 0.05). The decreased absolute weight of the spleen, thymus and bursa, serum interleukin 2 (IL-2), and interleukin 6 (IL-2) concentrations in CY-treated broilers were alleviated by vitamin E (P < 0.05). The decreased relative weight (g/kg body weight) of the bursa in the CY-treated broilers was increased by natural vitamin E (P < 0.05). The CY-induced increases in malondialdehyde (MDA) content and decreases in total antioxidant capacity (T-AOC), glutathione, vitamin C, and α-tocopherol levels, and total superoxide dismutase and glutathione peroxidase activities in both serum and the liver were attenuated by vitamin E (P < 0.05). Additionally, natural vitamin E increased α-tocopherol and T-AOC levels and decreased MDA content in the liver of CY-treated broilers (P < 0.05) when compared to the synthetic form. In

  1. Cyclophosphamide causes activation of protein kinase A (PKA) in the brainstem of vomiting least shrews (Cryptotis parva).

    PubMed

    Alkam, Tursun; Chebolu, Seetha; Darmani, Nissar A

    2014-01-05

    Complete control of emesis caused by cyclophosphamide (CPA) is of immense interest to both patients and physicians. Serotonin 5-HT3- and tachykinin NK1-receptor antagonists are widely used antiemetics in clinic, but they fail to completely control CPA-induced emesis. New antiemetic targets for the full control of CPA-induced vomiting are lacking. We therefore examined the effects of CPA on emetic targets downstream of 5-HT3- and NK1- receptors in an attempt to better understand the molecular bases of CPA-induced emesis. Acute CPA (200 mg/kg, i.p.) administration in the least shrew caused a biphasic pattern of emesis over a 40 h observation period, with maximal peak vomit frequency during the 1st hour of treatment (acute phase), followed by a delayed-phase which peaks at 27th hour. The NK1 receptor mRNA levels increased significantly at 8 h post-CPA treatment in the brainstem, and at 28 h in the whole intestine. Substance P mRNA levels tended to increase both in the brainstem and intestine at most time-points post-CPA injection, however due to large variability, they failed to attain significance. Likewise, protein expression profiles of both NK1- and 5-HT3 -receptors in the brainstem were unchanged at any time-point. However, phosphorylation levels of protein kinase A (PKA), but not of extracellular signal-regulated protein kinase 1/2 (ERK1/2), were increased at 2, 8, 22, 28, and 33 h time-points after the treatment with CPA. Moreover, brainstem but not frontal cortex cAMP tissue levels tended to be elevated at most time-points, but significant increases occurred only at 1 and 2 h post-CPA treatment. The phosphodiesterase inhibitor, rolipram, caused significant increases in shrew brainstem cAMP levels which were associated with its capacity to produce vomiting, while pretreatment with SQ22536, an inhibitor of adenylyl cyclase, prevented rolipram-induced emesis. The results demonstrate that accumulation of cAMP and subsequent activation of PKA in the brainstem may

  2. Combination treatment with oncolytic Vaccinia virus and cyclophosphamide results in synergistic antitumor effects in human lung adenocarcinoma bearing mice

    PubMed Central

    2014-01-01

    Background The capacity of the recombinant Vaccinia virus GLV-1h68 as a single agent to efficiently treat different human or canine cancers has been shown in several preclinical studies. Currently, its human safety and efficacy are investigated in phase I/II clinical trials. In this study we set out to evaluate the oncolytic activity of GLV-1h68 in the human lung adenocarcinoma cell line PC14PE6-RFP in cell cultures and analyzed the antitumor potency of a combined treatment strategy consisting of GLV-1h68 and cyclophosphamide (CPA) in a mouse model of PC14PE6-RFP lung adenocarcinoma. Methods PC14PE6-RFP cells were treated in cell culture with GLV-1h68. Viral replication and cell survival were determined by plaque assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, respectively. Subcutaneously implanted PC14PE6-RFP xenografts were treated by systemic injection of GLV-1h68, CPA or a combination of both. Tumor growth and viral biodistribution were monitored and immune-related antigen profiling of tumor lysates was performed. Results GLV-1h68 efficiently infected, replicated in and lysed human PC14PE6-RFP cells in cell cultures. PC14PE6-RFP tumors were efficiently colonized by GLV-1h68 leading to much delayed tumor growth in PC14PE6-RFP tumor-bearing nude mice. Combination treatment with GLV-1h68 and CPA significantly improved the antitumor efficacy of GLV-1h68 and led to an increased viral distribution within the tumors. Pro-inflammatory cytokines and chemokines were distinctly elevated in tumors of GLV-1h68-treated mice. Factors expressed by endothelial cells or present in the blood were decreased after combination treatment. A complete loss in the hemorrhagic phenotype of the PC14PE6-RFP tumors and a decrease in the number of blood vessels after combination treatment could be observed. Conclusions CPA and GLV-1h68 have synergistic antitumor effects on PC14PE6-RFP xenografts. We strongly suppose that in the PC14PE6-RFP model the

  3. Synchrotron radiation with radiation reaction

    NASA Astrophysics Data System (ADS)

    Nelson, Robert W.; Wasserman, Ira

    1991-04-01

    A rigorous discussion is presented of the classical motion of a relativistic electron in a magnetic field and the resulting electromagnetic radiation when radiation reaction is important. In particular, for an electron injected with initial energy gamma(0), a systematic perturbative solution to the Lorentz-Dirac equation of motion is developed for field strengths satisfying gamma(0) B much less than 6 x 10 to the 15th G. A particularly accurate solution to the electron orbital motion in this regime is found and it is demonstrated how lowest-order corrections can be calculated. It is shown that the total energy-loss rate corresponds to what would be found using the exact Larmor power formula without including radiation reaction. Provided that the particle energy and field strength satisfy the same contraint, it is explicitly demonstrated that the intuitive prescription for calculating the time-integrated radiation spectrum described above is correct.

  4. Randomized trial comparing protracted infusion of 5-fluorouracil with weekly doxorubicin and cyclophosphamide with a monthly bolus FAC regimen in metastatic breast carcinoma (SPM90).

    PubMed Central

    Pierga, J. Y.; Jouve, M.; Asselain, B.; Livartowski, A.; Beuzeboc, P.; Diéras, V.; Scholl, S.; Dorval, T.; Palangié, T.; Garcia-Giralt, E.; Pouillart, P.

    1998-01-01

    Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical response rates when compared with conventional bolus therapy. As a first line of chemotherapy in proven metastatic breast carcinoma, 258 women were randomly assigned to receive FAC consisting of 5-fluorouracil (F) 600 mg m(-2) intravenously (i.v.) over 1 h on days 1, 2 and 3, doxorubicin (A) 50 mg m(-2) i.v. bolus on day 1 and cyclophosphamide (C), 400 mg m(-2) i.v. bolus on days 1, 2 and 3 or 'FULON' consisting of 5-fluorouracil 250 mg m(-2) day(-1) continuously infused from day 1 to day 22, doxorubicin 15 mg m(-2) i.v. bolus on days 1, 8, 15 and 22 and cyclophosphamide 300 mg m(-2) i.v. bolus on days 1, 8, 15 and 22. Chemotherapy courses were administered 4-weekly for the bolus regimen and 6-weekly for FULON. Pretreatment characteristics were identical between the two groups. Response rates were 54% in the FAC arm and 53% in the FULON arm. Time to progression was 14 months in the FAC arm and 12 months in the FULON arm. Differences were not statistically significant. Median overall survival duration for all patients was 22 months. Haematological toxicity was more severe in the bolus-treated group (P = 0.05), as were nausea and vomiting (P < or = 0.01). We conclude that the two regimens appeared equally effective but have different toxicities. PMID:9652764

  5. Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats.

    PubMed

    Fan, Chiaming; Georgiou, Kristen R; McKinnon, Ross A; Keefe, Dorothy M K; Howe, Peter R C; Xian, Cory J

    2016-05-01

    The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10 mg/kg, epirubicin at 2.5 mg/kg and 5-flurouracil at 10 mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation.

  6. Brain radiation - discharge

    MedlinePlus

    Radiation - brain - discharge; Cancer-brain radiation; Lymphoma - brain radiation; Leukemia - brain radiation ... Decadron) while you are getting radiation to the brain. It may make you hungrier, cause leg swelling ...

  7. Integration of chemotherapy and radiation therapy for small cell carcinoma of the lung

    SciTech Connect

    Holoye, P.Y.; Libnoch, J.A.; Byhardt, R.W.; Cox, J.D.

    1982-09-01

    Two chemotherapy trials using cyclophosphamide, doxorubicine hydrochloride and high-dose vincristine sulfate with or without methotrexate have induced a 93% incidence of complete remission in limited disease presentation of small cell bronchogenic carcinoma of the lung and 39% incidence in extensive disease. The first without consolidation radiotherapy had a local failure rate of 65%, which dropped to 17% with consolidation radiotherapy to the primary and mediastinum. Prophylactic whole brain radiotherapy prevented local recurrence in 98% of evaluable patients. One carcinomatous meningitis and 5 intraspinal recurrences were noted among the 38 patients in the CAV-M trial. We conclude that high-dose vincristine sulfate is associated with an improved incidence of complete remission; that prophylactic whole brain radiotherapy has been highly successful; that prevention of intraspinal recurrence will necessitate the use of craniospinal axis radiation therapy and consolidation radiation therapy improves local control of primary and mediastinum.

  8. Radiation myelopathy.

    PubMed Central

    Sanyal, B; Pant, G C; Subrahmaniyam, K; Agrawal, M S; Mohanty, S

    1979-01-01

    Five cases of radiation myelopathy were found in a total of 10,000 cases given radiotherapy from 1968 to 1977. The clinical presentation and treatment details including the total dose, treatment volume, number of fractionations, overall time, and the RET value at the spinal cord were calculated and compared with other reports on this subject. The total number of fractionations ranged from 20 to 26 with an overall time of 32 days to 37 days. The dose received by four patients ranged from 1030 to 1900 RET, a little higher than the tolerance level of the spinal cord as compared to reported values. Two patients in this series had high blood pressure. The incidence of radiation myelopathy, already acceptably low, could possibly be reduced further by meticulous planning of radiation. PMID:448380

  9. Radiation effects.

    PubMed

    Preston, R J

    2012-01-01

    International Commission on Radiological Protection (ICRP) Committee 1 (C1) considers the risk of induction of cancer and heritable disease; the underlying mechanisms of radiation action; and the risks, severity, and mechanisms of induction of tissue reactions (formerly 'deterministic effects'). C1 relies upon the interpretation of current knowledge of radio-epidemiological studies; current information on the underlying mechanisms of diseases and radiation-induced disease; and current radiobiological studies at the whole animal, tissue, cell, and molecular levels. This overview will describe the activities of C1 in the context of the 2007 Recommendations of ICRP. In particular, the conclusions from the most recent C1 Task Group deliberations on radon and lung cancer, and tissue reactions will be discussed. Other activities are described in summary fashion to illustrate those areas that C1 judge to be likely to influence the development of the risk estimates and nominal risk coefficients used for radiation protection purposes.

  10. Radiation receiver

    DOEpatents

    Hunt, A.J.

    1983-09-13

    The apparatus for collecting radiant energy and converting same to alternate energy form includes a housing having an interior space and a radiation transparent window allowing, for example, solar radiation to be received in the interior space of the housing. Means are provided for passing a stream of fluid past said window and for injecting radiation absorbent particles in said fluid stream. The particles absorb the radiation and because of their very large surface area, quickly release the heat to the surrounding fluid stream. The fluid stream particle mixture is heated until the particles vaporize. The fluid stream is then allowed to expand in, for example, a gas turbine to produce mechanical energy. In an aspect of the present invention properly sized particles need not be vaporized prior to the entrance of the fluid stream into the turbine, as the particles will not damage the turbine blades. In yet another aspect of the invention, conventional fuel injectors are provided to inject fuel into the fluid stream to maintain the proper temperature and pressure of the fluid stream should the source of radiant energy be interrupted. In yet another aspect of the invention, an apparatus is provided which includes means for providing a hot fluid stream having hot particles disbursed therein which can radiate energy, means for providing a cooler fluid stream having cooler particles disbursed therein, which particles can absorb radiant energy and means for passing the hot fluid stream adjacent the cooler fluid stream to warm the cooler fluid and cooler particles by the radiation from the hot fluid and hot particles. 5 figs.

  11. Radiation receiver

    DOEpatents

    Hunt, Arlon J.

    1983-01-01

    The apparatus for collecting radiant energy and converting same to alternate energy form includes a housing having an interior space and a radiation transparent window allowing, for example, solar radiation to be received in the interior space of the housing. Means are provided for passing a stream of fluid past said window and for injecting radiation absorbent particles in said fluid stream. The particles absorb the radiation and because of their very large surface area, quickly release the heat to the surrounding fluid stream. The fluid stream particle mixture is heated until the particles vaporize. The fluid stream is then allowed to expand in, for example, a gas turbine to produce mechanical energy. In an aspect of the present invention properly sized particles need not be vaporized prior to the entrance of the fluid stream into the turbine, as the particles will not damage the turbine blades. In yet another aspect of the invention, conventional fuel injectors are provided to inject fuel into the fluid stream to maintain the proper temperature and pressure of the fluid stream should the source of radiant energy be interrupted. In yet another aspect of the invention, an apparatus is provided which includes means for providing a hot fluid stream having hot particles disbursed therein which can radiate energy, means for providing a cooler fluid stream having cooler particles disbursed therein, which particles can absorb radiant energy and means for passing the hot fluid stream adjacent the cooler fluid stream to warm the cooler fluid and cooler particles by the radiation from the hot fluid and hot particles.

  12. RADIATION SOURCES

    DOEpatents

    Brucer, M.H.

    1958-04-15

    A novel long-lived source of gamma radiation especially suitable for calibration purposes is described. The source of gamma radiation is denoted mock iodine131, which comprises a naixture of barium-133 and cesium-137. The barium and cesium are present in a barium-cesium ratio of approximately 5.7/1 to 14/1, uniformly dispersed in an ion exchange resin and a filter surrounding the resin comprised of a material of atomic number below approximately 51, and substantially 0.7 to 0.9 millimeter thick.

  13. Radiation dermatitis

    SciTech Connect

    Shack, R.B.; Lynch, J.B.

    1987-04-01

    Even in this era of modern radiotherapy, injuries associated with the medical and industrial use of radiation devices will continue to pose a difficult problem for the reconstructive surgeon. It must be borne in mind that the single most serious hazard to surgery in irradiated tissue is the lodgement of bacteria in tissue rendered avascular by the radiation and the secondary necrosis from the infection itself. The basic principles of wound management must be augmented by thorough knowledge of the use of well-vascularized muscle and musculocutaneous flap to provide adequate, blood-rich, soft-tissue coverage.

  14. In vitro sensitivity testing of cells of histologically typified ovarian carcinomas and carcinoma of corpus with 3H-cyclophosphamide-metabolites in the serum of man after massive dose therapy.

    PubMed

    Wetzel, V; Schaumlöffel, E; Jankowski, R P

    1978-12-01

    Cells of a carcinoma of the uterine corpus and of five ovarian carcinomas were cultured in vitro with monolayer and sandwich methods, respectively. After 24-hours-incubation with serum samples of patients treated with a massive dose of 3H-cyclophosphamide (60 mg/kg body weight i.v.)-the samples were taken at different times after application-these cultures with a chromatographically defined content of free metabolites were interpreted, guided by morphological criteria. Incubation of the cultures with serum samples taken 5 hours after application of the massive dose turned out to be a practical system for detection, before the start of therapy, of the sensitivity of malignant tumors to cyclophosphamide. Statements about the proliferation kinetics of the malignant cells, about the active ultimate form of the antitumor agent and its way of action, which are not guaranteed experimentally, are largely eliminated by this method. The justification for using 4-hydroxy- and 4-hydroperoxy-cyclophosphamide to test the sensitivity of malignant cells in vitro to cyclophosphamide was critically examined.

  15. Radiation Emergencies

    MedlinePlus

    ... If the exposure is large enough, it can cause premature aging or even death. Although there are no guarantees of safety during a radiation emergency, you can take actions to protect yourself. You should have a disaster plan. Being prepared can help reduce fear, anxiety ...

  16. Ionizing radiation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This chapter gives a comprehensive review on ionizing irradiation of fresh fruits and vegetables. Topics include principles of ionizing radiation, its effects on pathogenic and spoilage microorganisms, shelf-life, sensory quality, nutritional and phytochemical composition, as well as physiologic and...

  17. Radiation Models

    ERIC Educational Resources Information Center

    James, W. G. G.

    1970-01-01

    Discusses the historical development of both the wave and the corpuscular photon model of light. Suggests that students should be informed that the two models are complementary and that each model successfully describes a wide range of radiation phenomena. Cites 19 references which might be of interest to physics teachers and students. (LC)

  18. Radiation accidents

    SciTech Connect

    Saenger, E.L.

    1986-09-01

    It is essential that emergency physicians understand ways to manage patients contaminated by radioactive materials and/or exposed to external radiation sources. Contamination accidents require careful surveys to identify the metabolic pathway of the radionuclides to guide prognosis and treatment. The level of treatment required will depend on careful surveys and meticulous decontamination. There is no specific therapy for the acute radiation syndrome. Prophylactic antibodies are desirable. For severely exposed patients treatment is similar to the supportive care given to patients undergoing organ transplantation. For high-dose extremity injury, no methods have been developed to reverse the fibrosing endarteritis that eventually leads to tissue death so frequently found with this type of injury. Although the Three Mile Island episode of March 1979 created tremendous public concern, there were no radiation injuries. The contamination outside the reactor building and the release of radioiodine were negligible. The accidental fuel element meltdown at Chernobyl, USSR, resulted in many cases of acute radiation syndrome. More than 100,000 people were exposed to high levels of radioactive fallout. The general principles outlined here are applicable to accidents of that degree of severity.

  19. Radiation Insulation

    NASA Technical Reports Server (NTRS)

    1987-01-01

    Radiation insulation technology from Apollo and subsequent spacecraft was used to develop superinsulators, used by makers of cold weather apparel, to make parkas, jackets, boots and outdoor gear such as sleeping bags. The radiant barrier technology offers warmth retention at minimal weight and bulk.

  20. Delivery and processing of exogenous double-stranded DNA in mouse CD34+ hematopoietic progenitor cells and their cell cycle changes upon combined treatment with cyclophosphamide and double-stranded DNA.

    PubMed

    Dolgova, Evgenia V; Efremov, Yaroslav R; Orishchenko, Konstantin E; Andrushkevich, Oleg M; Alyamkina, Ekaterina A; Proskurina, Anastasia S; Bayborodin, Sergey I; Nikolin, Valeriy P; Popova, Nelly A; Chernykh, Elena R; Ostanin, Alexandr A; Taranov, Oleg S; Omigov, Vladimir V; Minkevich, Alexandra M; Rogachev, Vladimir A; Bogachev, Sergey S; Shurdov, Mikhail A

    2013-10-10

    We previously reported that fragments of exogenous double-stranded DNA can be internalized by mouse bone marrow cells without any transfection. Our present analysis shows that only 2% of bone marrow cells take up the fragments of extracellular exogenous DNA. Of these, ~45% of the cells correspond to CD34+ hematopoietic stem cells. Taking into account that CD34+ stem cells constituted 2.5% of the total cell population in the bone marrow samples analyzed, these data indicate that as much as 40% of CD34+ cells readily internalize fragments of extracellular exogenous DNA. This suggests that internalization of fragmented dsDNA is a general feature of poorly differentiated cells, in particular CD34+ bone marrow cells. When linearized plasmid DNA was used as a source of exogenous DNA, we observed that exonucleolytic processing and ligation of double-stranded DNA termini occurred in the bone marrow cells that had this DNA internalized. We also recovered "hybrid" plasmids that encompass kanamycin-resistance gene from the exogenous plasmid DNA and the fragments of plasmids from host enterobacteria, which is suggestive of recombination events taking place upon DNA internalization. CD34+ cells make up the distinctive bone marrow cell population that internalizes extracellular DNA. Cell cycle analysis of CD34+ cells treated with cyclophosphamide only or in combination with dsDNA, suggests that these cells have distinct biologic responses to these treatments. Namely, whereas upon cyclophosphamide treatment bone marrow stem cells become arrested at S-G2 phases, combined cyclophosphamide+dsDNA treatment leads to cell cycle progression without any delay. This indicates that when the genome is undergoing repair of interstrand crosslinks, injection of fragmented exogenous dsDNA results in immediate reconstitution of genome integrity. We observe that cyclophosphamide-only or a combined cyclophosphamide+dsDNA treatment of cells lead to two distinct waves of apoptosis in CD34

  1. Radiation Therapy: Professions in Radiation Therapy

    MedlinePlus

    ... and typically one to two years of clinical physics training. They are certified by the American Board of Radiology or the American Board of Medical Physics . Radiation Therapist Radiation therapists work with radiation oncologists. ...

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

    PubMed Central

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

    2016-01-01

    A 73-year-old man with a history of lethargy, fever and dyspnea was admitted to Tottori University Hospital. A computed tomography (CT) scan revealed splenomegaly and diffusely spreading ground-glass opacities (GGOs) in both lungs. A video-assisted thoracoscopic surgery (VATS)-guided lung biopsy revealed intravascular proliferation of large atypical lymphoid cells in the arteries, veins and alveolar walls. The patient was diagnosed with intravascular large B-cell lymphoma (IVLBCL); he received 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) immunochemotherapy and has remained in complete remission for >1 year. Although IVLBCL is a rare disease, it should be considered in the differential diagnosis of pulmonary diffuse lesions that present with GGOs on CT scans. PMID:28105347

  3. Scleroderma renal crisis during intravenous cyclophosphamide pulse therapy for complicated interstitial lung disease was successfully treated with angiotensin converting enzyme inhibitor and plasma exchange

    PubMed Central

    Nagamura, Norihiro; Kin, Seikon

    2016-01-01

    ABSTRACT Systemic sclerosis (SSc) is a multiorgan disorder involving the skin, heart, lungs, kidneys, and intestines. Progressive interstitial lung disease (ILD) is a serious complication in SSc patients, and cyclophosphamide (CYC) is the only recommended therapy for this condition;1) however, its clinical effectiveness is not sufficient. Scleroderma renal crisis (SRC) is a rare complication, characterized by acute renal failure and progressive hypertension. Angiotensin-converting-enzyme inhibitor (ACE-i) is a widely accepted therapy for SRC. We report an SSc patient with SRC and progressive ILD who underwent treatment with CYC and successful treatment with ACE-i and plasma exchange (PE). SRC and ILD are significant contributors to morbidity and mortality among SSc patients, and the therapy for these disorders is of great interest to rheumatologists. This study presents the possibility of favorable effects of PE for SSc-associated ILD and SRC. PMID:27578917

  4. Dexamethasone, cyclophosphamide, idarubicin and etoposide (DC-IE): a novel, intensive induction chemotherapy regimen for patients with high-risk multiple myeloma.

    PubMed

    Ballester, O F; Moscinski, L C; Fields, K K; Hiemenz, J W; Zorsky, P E; Goldstein, S C; Saba, H I; Spiers, A S; Kronish, L; Sullivan, P; Elfenbein, G J

    1997-03-01

    We evaluated toxicities and responses to a novel, dose intensive and time sequenced, chemotherapy programme (DC-IE) in 45 patients with high-risk myeloma. DC-IE consisted of: dexamethasone (days 1-4); cyclophosphamide (day 5); idarubicin and etoposide (days 8-10). Complete response (CR) was achieved in four patients, six patients achieved near complete responses (nCR) and 21 patients achieved a partial remission (PR). Overall response rate was 76% (CI 56-94%) for newly diagnosed patients (n = 21) and 62% (CI 36-81%) for relapsed/refractory patients (n = 24). Toxicities were limited to myelosuppression; two patients died of sepsis during neutropenia (4%). DC-IE is active and tolerable for high-risk multiple myeloma, including patients with relapsed or refractory disease to anthracycline containing regimens.

  5. Water intoxication induced by low-dose oral cyclophosphamide in a patient with anti-neutrophil cytoplasmic antibody-related glomerulonephritis

    PubMed Central

    Kato, Akihiko; Sugiura, Takeshi; Yamamoto, Tatsuo; Misaki, Taro; Tsuji, Takayuki; Sakao, Yukitoshi; Sakakima, Masaaki; Yasuda, Hideo; Fujigaki, Yoshihide; Hishida, Akira

    2008-01-01

    We reported the case of a 70-year-old woman with moderate renal failure due to anti-neutrophil cytoplasmic antibody-related glomerulonephritis who developed symptomatic water intoxication (serum Na: 108 mEq/L) following treatment with oral low-dose cyclophosphamide (CY) (50mg/day). Estimated glomerular filtration rate was 29.5 mL/min/1.73 m2. She had drunk >2 L of fluid in 12 h prior to the development of cerebral oedema. Thi