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PubMed1982

Diminution of cyclophosphamide-induced suppression of antitumor immunity by an immunomodulator PS-K and combined therapeutic effects of PS-K and cyclophosphamide on transplanted tumor in rats.

An immunomodulator PS-K was shown to diminish the cyclophosphamide (CY)-induced suppression of specific antitumor transplantation resistance in WKA rats immunized with X-irradiated KMT-17 tumor cells when PS-K was given before treatment of CY. In the immunochemotherapy of transplanted KMT-17 tumor in WKA rats by a combination of CY and PS-K, an enhanced therapeutic effect was also observed when PS-K was given before treatment of CY, with different doses of CY and at different days of CY treatment. However, when PS-K was given just after treatment of CY, the therapeutic effect was rather diminished in comparison with the group having CY treatment alone. By means of the Winn assay, spleen cells obtained from KMT-17-bearing rats (TBR) treated with PS-K followed by CY inhibited the admixed tumor cells more strongly than did spleen cells obtained from TBR treated with CY alone. Recovery of thymus weight from the damage caused by CY was accelerated in TBR treated with PS-K followed for CY and was delayed in TBR treated with CY followed by PS-K. These observations suggest that diminution of CY-induced immunosuppression by PS-K possibly results in an enhanced therapeutic effect in WKA rats treated with PS-K followed by CY.

Adjuvants, Immunologic↗
PubMed1981

Elimination of tumor-enhancing cells by cyclophosphamide and its relevance to cyclophosphamide therapy of the murine mammary tumor.

The antitumor effect of cyclophosphamide (CY) on a syngeneic mouse mammary tumor, MM46, was found to be due to selective elimination of host lymphoid cell populations as well as a direct cytotoxic effect of CY on tumor cells. marked inhibition of tumor growth after a single ip injection of CY on day 12 lasted for more than 3 weeks, unless the host was infused iv with spleen cells from tumor-bearing mice. The tumor-enhancing activity of spleen cells from tumor-bearing mice appeared to be mainly due to Thy 1.2 positive T lymphocytes and was no longer seen after CY treatment on day 12. The extent of tumor growth inhibition achieved with CY was critically dependent on the time of drug administration. CY had no antitumor effect when given before tumor inoculation. Associated with the antitumor effect of CY, augmentation of the antitumor delayed hypersensitivity reaction, or the cellular immune response, was observed. In contrast, the titer of antitumor antibody in the blood, or the humoral immune response, decreased. Cell transfer experiments showed that suppressor T cells for antitumor delayed hypersensitivity reaction specifically induced by the tumor inoculum were eliminated after CY treatment on day 12.

Animals↗
PubMedDate not supplied

High-dose cyclophosphamide versus cyclophosphamide, methotrexate, 5-FU, and hydroxyurea (CMFH) in the treatment of stage III non-small cell bronchogenic carcinoma: a randomized trial.

Fifty-eight patients with non-small cell carcinoma of the lung (33 with epidermoid carcinoma, 22 with adenocarcinoma, and three with large cell anaplastic carcinoma) were treated with high-dose cyclophosphamide (CTX) or, alternatively, with CTX, methotrexate, 5-FU, and hydroxyurea (CMFH) in a controlled study. Two partial remissions were achieved (one in each regimen [13%]. Seventeen of 29 patients treated with CTX and 14 of 29 patients treated with CMFH showed no change (differences were not statistically significant). Toxicity was moderate in both regimens. Median survival was 24 weeks for patients treated with CTX and 26 weeks for patients treated with CMFH (differences were not significant). The results show that the therapeutic activity of CMFH is not higher than that of CTX alone.

Aged↗
PubMed1994

Cyclophosphamide-induced tumour regression of cyclophosphamide-resistant L5178Y lymphoma through suppressor cells elimination.

The series of experiments here described show that injection of cyclophosphamide (Cy) into mice bearing the L5178Y lymphoma caused partial or complete regression of this tumour. This effect was dependent on both the size of lymphoma and on the dose of drug administered. Cy-induced tumour regression was observed in mice in which L5178Y lymphoma had been implanted at least 10 days previously, and the dose required to cause neoplasm regression was found to be 100 mg/kg i.v., lower doses having no therapeutic effect. A key additional finding was that this same dose administered to lethally irradiated mice, or to T-cell-deficient mice bearing a 14-days neoplasm, failed to cause the L5178Y lymphoma regression. It was also demonstrated that this Cy-induced permanent or complete regression of L5178Y tumour is mediated by releasing memory antineoplasm effector cells from the inhibitory influence of suppressor Ly 1+ T cells. Tumour regression induced by Cy administration may be associated with elimination of Ly 1+ suppressor T lymphocytes, since the therapeutic effect of Cy was reversed by passive transfer of Ly 1+ T cells obtained from donor mice bearing a 14-days L5178Y lymphoma; thus, these results suggest that the therapeutic effect of Cy in this model is through its capability to preferentially eliminate Ly 1+ suppressor T lymphocytes, thereby permitting memory antitumour immune cells to generate a strong secondary immune response against this immunogenic lymphoma.

Animals↗
PubMed1994

Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide.

A prospective randomized study was conducted comparing two conditioning regimens for the treatment of patients with chronic myeloid leukemia in chronic phase by marrow transplantation from HLA identical siblings. Sixty-nine patients received 60 mg/kg of cyclophosphamide on each of 2 successive days followed by 6 fractions of total body irradiation each of 2.0 Gy (CY-TBI), and 73 patients received 16 mg/kg of busulfan delivered over 4 days followed by 60 mg/kg CY on each of 2 successive days (BU-CY). There was no significant difference between the CY-TBI and the BU-CY groups in the 3-year probabilities of survival (0.80 for both), relapse (0.13 for both), or event-free survival (CY-TBI, 0.68; BU-CY, 0.71) or in speed of engraftment or incidence of venocclusive disease of the liver. The 4-year probabilities of survival and event-free survival for patients transplanted within 1 year of diagnosis were 0.86 and 0.72, respectively, for each group. Significantly more patients in the CY-TBI group experienced major creatinine elevations. There was significantly more acute graft-versus-host disease in the CY-TBI group. Fever days, positive blood cultures, hospitalizations, and inpatient hospital days were significantly more common in the CY-TBI group than in the BU-CY group. In conclusion, the BU-CY regimen was better tolerated than, and associated with survival and relapse probabilities that compare favorably with, the CY-TBI regimen.

Adolescent↗
PubMed1996

Urinary elimination of cyclophosphamide alkylating metabolites and free thiols following two administration schedules of high-dose cyclophosphamide and mesna.

Twenty patients with a variety of neoplastic diseases were treated with preparative regimens containing high-dose cyclophosphamide (CY) administered as a 2-h infusion (60 mg/kg) for 2 days or by continuous infusion (1500 mg/m2/day) for 4 days. In patients receiving CY by 2-h infusion, the uroprotectant 2-mercaptoethane sulfonate (MESNA) was administered as an intermittent, bolus intravenous infusion (20% of CY dose) every 6 h. In patients receiving continuous infusion CY, MESNA was administrated concomitantly at an equivalent dose to CY by continuous infusion. During the first 24 h of CY administration, urine was collected at 2-h intervals and analyzed for free thiols and CY-alkylating metabolites. In patients receiving CY by short infusion and MESNA by intermittent bolus infusion, urinary concentrations of alkylating metabolites peaked at 4-8 h. During each dose of MESNA, urinary free thiols peaked at 2 h following administration but fell to pre-treatment levels at subsequent intervals. In patients receiving CY by continuous infusion, CY alkylating metabolites increased gradually over the 24-h study period while free thiols remained at a constant level during this period. With bolus administration of CY and intermittent bolus administration of MESNA every 6 h, there are periods where urinary CY-alkylating metabolites are elevated and free thiol concentrations are diminished. During continuous infusion of CY and MESNA, urinary CY alkylating metabolites reached peak concentrations at 18-22 h while the exposure of the bladder to free thiols remained constant. Recommendations are provided to increase the exposure of free thiols in the bladder when MESNA is administered by bolus or continuous infusion.

Adult↗
PubMed1997

Meta-analysis of chemotherapy regimens for ovarian carcinoma: a reassessment of cisplatin, cyclophosphamide and doxorubicin versus cisplatin and cyclophosphamide.

OBJECTIVE: To compare three year survival, median survival and improved longevity with the addition of doxorubicin to a chemotherapy regimen of cisplatin and cyclophosphamide used in the treatment of ovarian cancer and to integrate this with a previous meta-analysis that compared three year survival. METHODS: Twenty-three studies that evaluated either the control or test arms were combined for meta-analysis. Five studies were randomized with both arms. Inclusion criteria consisted of median survival data, three year survival data, no previous chemotherapy or radiation and adequate follow-up. The data were analyzed with a twotailed t test, a fixed effects odds ratio, a random effects odds ratio, logistic regression modeling for three year survival and standard regression modeling for median survival. RESULTS: A statistically significant improvement in three year survival was demonstrated with the fixed effects odds ratio analysis combining the five prospective randomized studies and with logistic regression model of all the studies. Random effects odds ratio and the two-tailed t test failed to show statistical significance. Standard regression modeling demonstrated statistically significant improvement in median survival for a doxorubicin dose intensity of 40 mg/m2 and near significance for a doxorubicin dose intensity of 50 mg/m2. Median survival was improved by 1.91 months with the addition of doxorubicin to the cisplatin/cyclophosphamide regimen. CONCLUSION: Although there appears to be statistically significant improvement in three year survival and median survival with the addition of doxorubicin to the cisplatin/cyclophosphamide regimen for ovarian cancer, the actual improvement in median survival is less than two months and therefore, the added toxicity of doxorubicin may not be warranted.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Cyclophosphamide and 4-Hydroxycyclophosphamide/aldophosphamide kinetics in patients receiving high-dose cyclophosphamide chemotherapy.

Using a recently developed gas chromatography and mass spectrometry method to determine whole-blood cyclophosphamide (CP) and 4-hydroxycyclophosphamide/aldophosphamide (4-HO-CP/AP) concentrations, we investigated their pharmacokinetics in women receiving CP therapy. Patients (n = 18) received one or two courses of CP: (a) a 90-min i.v. infusion (4 g/m2) followed by a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa; or (b) a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa. Whole-blood exposures to CP [area under the whole blood concentration versus time curve (AUCCP)] and 4-HO-CP/AP (AUC4HOCP) between courses 1 and 2 were compared after normalization to dose (g/m2). A nonproportional increase was observed for the AUCCP between the first course [1112 micrometer. h/g/m2 +/- 14% coefficient of variation (CV)] and the second course (1579 micrometer . h/g/m2 +/- 28% CV) (P < 0.001). In contrast, the AUC4HOCP (27 micrometer . h/g/m2 +/- 25% CV) determined for the first course was 29% higher than the AUC4HOCP (21 micrometer . h/g/m2 +/- 26% CV) for the second course (P < 0.01). The interpatient whole-blood exposures to both CP and 4-HO-CP/AP were remarkably consistent in this patient population with percent CVs ranging from 14 to 28%. Because thiotepa (800 mg/m2) was administered simultaneously with CP during the second course of treatment, possible inhibition of CP metabolism by thiotepa was investigated using human liver microsomes in vitro. IC50 values determined for inhibition of CP metabolism in three individual liver donors ranged from 1.0 to 40 micrometer. However, the clinical relevance of this observation has not been established.

Adolescent↗
PubMed1996

Adjuvant cyclophosphamide, methotrexate and 5-fluorouracil versus cyclophosphamide plus futraful for premenopausal patients with stage I-II and one- to three-node-positive breast cancer: results of a prospective randomized study.

A prospective randomized study was conducted to compare the adjuvant efficacy of 12 cycles of low-dose CMF (cyclophosphamide: CPA, methotrexate; MTX, 5-fluorouracil; 5-FU) with that of orally administered CPA plus FT (futraful) in premenopausal patients with stage I-II and one- to three-node-positive breast cancer. The 12-cycle CMF group (91 patients) received, 100 mg CPA orally on days 1 to 14 plus 20 mg MTX and 500 mg 5-FU intravenously (iv) on days 1 and 8 of each cycle. The CPA plus FT group (85 patients) received 100 mg CPA and 600 mg FT orally each day for one year. The background characteristics of the two groups were comparable. At 5 and 10 years, there were non-significant trends towards better disease-free and overall survival rates in the CMF group. Both treatments were well tolerated, but more patients in the CPA plus FT group refused to continue chemotherapy because of continuous gastrointestinal disturbances. No clear benefit of adding low-dose MTX to CPA and fluoropyrimidines was observed in this subgroup of Japanese patients. Further studies will be required to clarify the superiority of conventional-dose of CMF treatment to orally administered CPA plust FT treatment.

Adult↗
PubMed1980

Low-dose cyclophosphamide versus adriamycin plus cyclophosphamide in advanced ovarian cancer. A randomized clinical study.

After intensive staging 74 ovarian cancer patients were randomized to two arms balanced for stage and post-surgery residual tumor. The two regimens were CTX 100 mg/day continuously and ADM 50 mg/m2 IV every 4 weeks plus CTX 100 mg/day. The response rates were respectively 42% and 52%. Median survival times were 13 and 14 months. The incidence of side effects was significantly higher in the combination-treatment arm. No other statistical differences were found.

Adult↗