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PubMed2002

Phase II evaluation of 3-day topotecan with cyclophosphamide in the treatment of recurrent ovarian cancer.

OBJECTIVE: The aim of this trial was to investigate the toxicity and efficacy of a 3-day topotecan administration schedule in combination with cyclophosphamide in the management of recurrent ovarian cancer. METHODS: Patients with recurrent measurable ovarian cancer who had up to two prior chemotherapy regimens for the management of their disease participating in this phase II trial were to receive topotecan at a dose of 1.25 mg/m(2)/day x 3 days in combination with cyclophosphamide at 600 mg/m(2) on Day 1 every 21 days. Dose escalation and reductions were permitted. RESULTS: A total of 36 patients (median age = 65; range 37-84) were treated with this combination regimen. Seventeen were platinum-sensitive and 19 were platinum-resistant. A total of 169 cycles of chemotherapy was administered (median = 4; range 1-10). Major toxicity included grade 4 neutropenia (68.6%), neutropenic fever (7.1%), grade 3 thrombocytopenia (18.3%), and requirement for blood transfusion (19.5%). Dose escalation was possible in 3 (8.3%), and dose reduction was required in 14 (38.9%) patients. Overall response rate was 25 and 44.5% stable disease. Median progression-free interval and overall survival was 5.4 and 23.5 months, respectively, independent of platinum sensitivity. CONCLUSION: The 3-day topotecan schedule in combination with cyclophosphamide appears to have good activity in recurrent ovarian cancer regardless of platinum sensitivity. Neutropenia was the only severe toxicity and was less prevalent than other reported trials of topotecan. This tolerable regimen offers patients more convenience and appears to have moderate activity.

Adult↗
PubMed2002

Kinetic modeling and efficacy of intraperitoneal paclitaxel combined with intravenous cyclophosphamide and carboplatin as first-line treatment in ovarian cancer.

OBJECTIVE: The purpose of this study was to determine the efficacy, tolerability, and pharmacokinetics of intraperitoneal (ip) paclitaxel combined with intravenous (iv) carboplatin and cyclophosphamide. PATIENTS AND METHODS: Twenty-five newly diagnosed patients with Stage IC-IV epithelial ovarian cancer received ip paclitaxel with iv carboplatin and cyclophosphamide as a first-line treatment. Paclitaxel pharmacokinetics was determined during the first cycle on day 1 or 8. RESULTS: This regimen was well tolerated, as abdominal pain and hematological toxicities were minor, while neurotoxicity grade I/II was reported in only 20% and myalgia in 24% of patients and were fully reversible. After treatment 13 of 18 (72%) of the patients had no evidence of disease. At a median follow-up of 30 months patients with residual disease after surgery (n = 10) had a median progression-free survival (PSF) of 13 months; for the optimally debulked group (n = 15) the actuarial PFS was 60% at 48 months. The elimination of paclitaxel from the peritoneal cavity and plasma followed first-order kinetics and was not influenced by adding carboplatin with cyclophosphamide. CONCLUSION: This regimen was well tolerated, with minimal hematologic or neurotoxicity, and allowed the application of a triple-drug schedule without compromising dose intensity. To judge its efficacy, comparison with a standard iv paclitaxel-based schedule should be performed in a formal phase III study.

Adult↗
PubMed1979

The effect of cyclophosphamide on a secondary ocular immune response in rabbits.

Treatment of rabbits with immunosuppressive doses of cyclophosphamide during the primary response to intravitreally injected bovine gamma globulin did not prevent priming for a secondary response to the same antigen. High antibody titers were found in the aqueous humor and serum of most of the treated rabbits. Ocular tissue plaque forming cell numbers were similar to those of the controls in many of the rabbits, and slightly lower in others. Treatment with cyclophosphamide completely suppressed the ocular immune response in many rabbits that had undergone a primary response following intravitreal injection of BGC. The response in other animals was depressed but not completely inhibited. The presence of ocular inflammation and lymphocytes in the challenged eyes of the treated rabbits suggested a differential effect of cyclophosphamide on cells stimulated to divide after challenge.

Animals↗
PubMed1989

Chemoimmunotherapy with cyclophosphamide and bestatin in experimental metastasis in mice.

Bestatin has significant therapeutic activity (even following oral administration) for the treatment of metastatic disease, an activity which is limited by tumor burden. Therefore, the therapeutic potential of bestatin was examined in combination with chemotherapy to determine if there is additive activity for heavy tumor burdens. Bestatin significantly increased therapeutic activity and decreased the myelotoxicity of cyclophosphamide following a single injection of cyclophosphamide or split daily doses. In immune function studies, in tumor-bearing animals, bestatin increased the number of colony-forming units (granulocyte-macrophage) (CFU) and alveolar macrophage tumoricidal activity. However, when bestatin was combined with cyclophosphamide, which depressed bone marrow and macrophage activity, it did not show apparent augmentation of macrophage and NK cell activity, but did significantly increase bone marrow CFU activity. Thus, in combined chemoimmunotherapy, bestatin appears to enhance therapeutic activity by accelerating the recovery of hematopoiesis. We suggest, therefore, that a combination chemotherapy protocol, with oral bestatin, may facilitate myelorestoration following aggressive chemotherapy. The majority of biological response modifiers require parental administration; thus, the identification of an orally active, synthetic immunoaugmenting agent with a defined receptor is of particular interest.

Adjuvants, Immunologic↗
PubMed1982

The effects of cyclophosphamide on in vitro cytotoxic responses to a syngeneic tumour.

We have studied the effects of treating DBA/2 mice with high doses of cyclophosphamide upon their subsequent ability to generate cytotoxic cells in vitro against syngeneic tumour antigens or alloantigens. High doses of cyclophosphamide (100-200 mg/kg body weight) eliminated the response to both antigens. The addition of normal DBA/2 thymocytes into these cultures restored the response to allogeneic cells but not to tumour cells. The anti-tumour response could be restored by the addition of interleukin 2 to the cultures. Treatment with high doses of cyclophosphamide decreased the number of anti-tumour cytotoxic cell precursors in the spleen, but did not affect the capacity of bulk cultures of spleen cells to produce interleukin 2 when stimulated with the mitogen concanavalin A.

Animals↗
PubMed1989

A phase-II study of low-dose cyclophosphamide and recombinant human interleukin-2 in metastatic renal cell carcinoma and malignant melanoma.

Recent preclinical and clinical studies that have demonstrated antitumor activity of high-dose recombinant interleukin-2 (rIL-2), and animal models that demonstrated a synergistic effect of low-dose cyclophosphamide, led us to study rIL-2 (Cetus Corp., Emeryville, Calif) in a phase II clinical trial in combination with low-dose cyclophosphamide in 32 patients, 18 with malignant melanoma and 14 with renal cell carcinoma. rIL-2 was given once daily at 3 x 10(6) U/m2, as a 30-min infusion for 14 days in cycle I and for 2 x 5 days in cycles II and III respectively; if tolerated, the dose was increased to a maximum of 6 x 10(6) U m-2 day-1; the cycles, separated by 1 week treatment-free intervals, were preceded each by a single i.v. bolus of cyclophosphamide at 350 mg/m2. The most prominent side-effects encountered in this trial consisted of a capillary leak syndrome, myalgia and fever that required dose reduction during the first cycle in one-half of the patients. Given the limit of tolerable toxicities in a standard care unit, the regimen employed achieved minor antitumor activity. No remission was achieved in patients with renal cell carcinoma, and 15% of melanoma patients showed objective responses (partial response + minor response).

Adult↗
PubMed1987

Combination trial of subcutaneous interferon alfa-2b and oral cyclophosphamide in favorable histology, non-Hodgkin's lymphoma.

Patients with follicular non-Hodgkin's lymphoma (NHL) respond well to chemotherapy but frequently relapse and progress with conversion to more aggressive histology lymphomas. In a prior Cancer and Leukemia Group B (CALGB) trial, oral cyclophosphamide, given as a single agent, was found to be equivalent to a five-drug regimen in remission induction in patients with follicular NHL who had not received prior chemotherapy. Recently, interferon alfa-2b (Intron A; Schering Plough) has been demonstrated to elicit complete or partial responses in up to 50% of patients with nodular NHL who had received prior chemotherapy. In the current CALGB pilot trial, oral cyclophosphamide (100 mg/m2 daily) combined with interferon alfa-2b (2 X 10(6) IU/m2 s.c. on alternate days) is being evaluated, both in previously treated and untreated patients with stage III or IV follicular NHL, for toxicity, safety and efficacy in remission induction. A total of 68 patients have been entered into this study. Four patients are ineligible on pathology review, and 60 have on-study data currently available. Forty-one (60%) had not received prior chemotherapy and 19 (32%) had previously received some form of chemotherapy. Leukopenia was found to be the single, most common toxicity experienced by all patients. Previously untreated patients experienced leukopenia of less than 2,000 WBC/microliter at a significantly higher rate (53% versus 14%) than a similar patient population receiving oral cyclophosphamide as a single agent in the prior CALGB trial. Leukopenia was found to be promptly reversible, however, by dose suspension or adjustment, and other toxicities were demonstrated to be mild and tolerable.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Cyclophosphamide cystitis as a model of visceral pain in rats: model elaboration and spinal structures involved as revealed by the expression of c-Fos and Krox-24 proteins.

The evoked expression of the immediate early gene (IEG)-encoded proteins c-Fos and Krox-24 was used to monitor spinal visceronociceptive processing that results from cyclophosphamide cystitis in behaving rats. Animals received a single dose of 100 mg/kg i.p. of cyclophosphamide and survived for 30 min to 5 h. Longer survival times were not considered because of ethical considerations. Cyclophosphamide-injected animals developed characteristic behavioral signs in parallel with development of bladder lesions and spinal evoked expression of IEG-encoded proteins. Histological examination of the urinary bladder was used to evaluate the degree of cystitis and as a criterion for selection of groups of animals to be quantitatively analyzed. Controls consisted of freely behaving animals including control (un-injected), sham (saline-injected) or diuretic (furosemide-injected) animals. Behavioral modifications consisted of lacrimation, piloerection, assumption of a peculiar "rounded-back" posture, which was accompanied by head immobility and various brief "crises" (tail hyperextension, abdominal retractions, licking of the lower abdomen, backward withdrawal movements). Abnormal behaviors, which first appeared (lacrimation, piloerection) at the end of postinjection hour 1, progressively increased in severity (rounded-back posture) over the following 90 min to reach a plateau at about postinjection hour 2; the rounded-back posture was maintained up to time of death. Histological modifications of bladder tissue were assessed using a 4-grade scale in a blind setting. The 1st grade consisted of control or sham animals with no bladder lesion; 2nd grade, animals with simple chorionic edema; 3rd grade, animals with chorionic edema associated with mucosal abrasion, fibrin deposit, and onset of polymorphonuclear leukocyte infiltration; 4th grade, animals with complete cystitis corresponding to an increase in severity and spread of all the signs of cystitis described above plus petechial hemorrhage. Simple chorionic edema was observed from 30 min to 3 h postinjection, but with a progressive increase in severity over time. Edema accompanied by epithelial abrasion was observed for animals that survived 3-4 h postinjection; complete inflammation was observed in animals that survived 4-5 h postinjection. The study of c-Fos- and Krox-24-encoded protein expression demonstrated that few lumbosacral spinal areas were specifically involved in the processing of visceral inputs in response to bladder stimulation. These areas were the parasympathetic column (SPN), the dorsal gray commissure (DGC as the caudal extent of lamina X), and superficial layers of the dorsal horn.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

A proposed mechanism of resistance to cyclophosphamide and phosphoramide mustard in a Yoshida cell line in vitro.

A Yoshida sarcoma cell line (YR/cyclo) showing decreased sensitivity to metabolically activated cyclophosphamide in vitro has been shown to be cross-resistant to phosphoramide mustard, the ultimate alkylating agent formed from cyclophosphamide. Resistance to these alkylating agents has been shown to be associated with increased activity of the glutathione S-transferase group of enzymes, and with elevated levels of glutathione, the cosubstrate of the enzyme. The resistant cell line shows lower levels of cellular damage, as measured by alkaline elution following treatment with phosphoramide mustard, than the parental (YS) line. The mechanism of resistance is ascribed to increased deactivation of potentially damaging metabolites of cyclophosphamide by the glutathione S-transferase enzymes, resulting in decreased cellular damage in the resistant cell line.

Animals↗
PubMed1991

Immunomodulatory effect of cyclophosphamide on host humoral immunity in Dunning's R-3327 adenocarcinoma of the prostate.

The object of the present investigations was delineation of the exclusive effects of cyclophosphamide (Cytoxan) on host humoral response to tumor, as evaluated by the level of circulating antigen/antibody complexes (AACs), which may reflect the chemo-responsiveness of hosts and provide a rationale for new therapeutic strategies. Our data, recorded in Copenhagen X Fischer rats bearing Dunning's R-3327 Mat Ly-Lu adenocarcinoma of the prostate, show no modulatory effect of cyclophosphamide at 10 mg/kg, a nonspecific immunosuppressive effect at 30 mg/kg, and a definite immunostimulatory effect on host humoral immunity at 100 mg/kg. Sequential determination of AAC levels at different stages of tumor growth, i.e. from the primary to the metastatic stage, performed with the original purpose of demonstrating that any disturbance in the immunoregulatory mechanism of the host was due to cyclophosphamide rather than to changes in tumor load, revealed that levels of AACs parallel disease progression in the initial stages of primary tumor growth but rapidly decrease to near-normal levels in the presence of heavy tumor burden.

Adenocarcinoma↗
PubMed1986

A randomized trial of two regimens of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone in advanced breast cancer.

One-hundred evaluable patients with progressive advanced breast carcinoma untreated by cytotoxic chemotherapy but resistant to hormone therapy and irradiation were randomly allocated to receive either a combination of cyclophosphamide (600 mg/m2), methotrexate (40 mg/m2), 5-fluorouracil (600 mg/m2) IV every 3 weeks and prednisone 20 mg/m2 PO daily, with diminishing doses (intermittent group), or a combination of cyclophosphamide (100 mg/m2 PO on days 1-15, alternating with a 15-day rest period), methotrexate 20 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV weekly for 20 weeks and prednisone 20 mg/m2 PO daily, with diminishing doses in the remission induction period, followed by a maintenance regimen of cyclophosphamide 100 mg/m2 PO on days 1-15, methotrexate 20 mg/m2 IV on days 1, 8 and 15, 5-fluorouracil 500 mg/m2 IV on days 1, 8, and 15, and prednisone 20 mg/m2 PO on days 1-15, with a 3-week rest period between the courses (intensive group). Entry was from 1 December 1982 to 30 November 1983. Objective responses were seen in 20/49 (41%) patients in the intermittent group and 34/51 (67%) in the intensive group (chi 2 = 6.72; P less than 0.01). The estimated median duration of response was 11 months in the intermittent group and 14 months in the intensive group. The estimated median survival was greater in the intensive group, but the difference was not statistically significant, although this parameter can be influenced with alternative additional chemotherapy. Toxicity was similar in both groups. These data suggest there are no therapeutic and survival advantages to the 3-weekly IV protocol compared with our previous regimen CMFP.

Adult↗
PubMed1993

Effect of T-cell receptor V beta-specific monoclonal antibodies on cyclophosphamide-induced diabetes mellitus in non-obese diabetic mice.

The expression of specific T-cell receptor gene segments by T lymphocytes appears to be critically important for the induction of several experimental autoimmune diseases mediated by these cells. We examined whether this situation also applied to non-obese diabetic mice by using various T-cell receptor V beta-specific monoclonal antibodies. No significant age- or sex-related differences were observed in V beta usage by peripheral and splenic T lymphocytes. CD8+ T lymphocytes among the islet-derived mononuclear cells isolated from 20-week-old female non-obese diabetic mice showed heterogeneity of their V beta gene usage. In order to examine the role of T lymphocyte subsets expressing specific T-cell receptor V beta segments in the development of diabetes mellitus, T-cell receptor V beta-specific monoclonal antibodies were administered to 10-week-old male non-obese diabetic mice treated with cyclophosphamide. None of the antibodies used could significantly diminish the incidence of cyclophosphamide-induced diabetes and the severity of insulitis [anti-V beta 3 (11 of 22 mice became diabetic, 50%), anti-V beta 5 (9 of 14, 64%), anti-V beta 8 (9 of 21, 43%), anti-V beta 11 (12 of 23, 52%), anti-V beta 14 (7 of 12, 58%), and anti-V beta 5 + anti-V beta 11 (6 of 12, 50%)] when compared with control mice (12 of 21, 57%). In addition, there were no significant differences in T-cell receptor V beta usage between diabetic and non-diabetic cyclophosphamide-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Cyclophosphamide-resistant Yoshida ascites tumor cells and their cross resistance to some alkylating agents.

A cyclophosphamide-resistant subline of a Yoshida ascites tumor was developed by giving increasing doses of the drug after transplantation. The effect of several alkylating agents on the cell proliferation of both the sensitive and resistance cell line was compared establishind dose response curves and D50 values. The developed subline revealed a 260 fold resistance to cyclophosphamide. It was completely cross-resistant to hydroperoxycyclophosphamide, whereas for triaziquone, N-oxide-mustard, and N-methyl-mustard only a partial cross resistance existed. These results give further evidence that cyclophosphamide and hydropeoxycyclophosphamide have the same mechanism of action. Regarding the other alkylating agents the results demonstrate differences concerning either the molecular mode of action or protecting effects. A decreased activation or uptake of substance is probably not the base for resistance.

Alkylating Agents↗
PubMed1983

Delaying effect of cyclophosphamide on bone fracture healing chemical analyses of rat femora.

Hydroxyproline, calcium and inorganic phosphate contents of osteotomised rat femora were compared with those from rats treated with cyclophosphamide. The treatment consisted of 10 mg/kg/body weight injected intraperitoneally daily for 14 days after (group II) and before (group III) operation. The obtained results indicated a reduction in the hydroxyproline content of the callus and a diminution of the calcium and phosphate deposition upon it, thus inhibiting collagen formation and delaying mineralisation, retarding the healing process of the fraction. The degree of inhibition was decreased when the cyclophosphamide treatment discontinued before osteotomy was performed (group III). We would like to draw attention to these results, and suggest that cyclophosphamide treatment should not coincide with the healing of bone fracture.

Animals↗
PubMed1985

High-dose cyclophosphamide with autologous bone marrow rescue after conventional chemotherapy in the treatment of small cell lung carcinoma.

Within an original consecutive series of 94 patients, 36 eligible patients with small cell lung carcinoma were treated with high-dose cyclophosphamide 7 g/m2 after conventional chemotherapy with VP16, adriamycin, and vincristine. The first 17 also underwent autologous bone marrow rescue. Treatment was well tolerated apart from one treatment-related death. Measurable tumour was still present in 15 patients before high-dose cyclophosphamide, and although 12 (80%) of these achieved further tumour response, these responses were all short-lived, with a median duration of 9 weeks. In 14 limited-disease patients already in complete remission before high-dose therapy the initial result was better, but 11 (79%) have now relapsed following overall median response duration of 10 months. High-dose cyclophosphamide after conventional chemotherapy is feasible and achieves a high response rate, but it does not appear to be associated with significant survival benefit either overall or in patient subgroup.

Adult↗
PubMed1989

High-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support. A clinical and pharmacologic study.

A total of 23 patients were treated at five dose escalations with high-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support. The maximum tolerated doses of cyclophosphamide, cisplatin, and melphalan were 5,625, 180, and 80 mg/m2, respectively. The dose-limiting toxicity was cardiac toxicity. Objective tumor regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5 months. Pharmacokinetic evaluation of melphalan in 20 patients revealed a dose-related increase in maximum plasma concentration (Cmax) and area under the curve (AUC). Perturbation of the melphalan plasma half-life and AUC, associated with severe toxicity, resulted when renal insufficiency occurred. The results suggest that high-dose combination cyclophosphamide, cisplatin, and melphalan produces frequent, rapid responses in breast cancer, melanoma, and sarcoma, although with significant extramedullary toxicity. The pharmacokinetics suggest that modification of the treatment schedule may result in a reduction of treatment-related toxicity.

Adult↗
PubMed1983

cis-Platinum, adriamycin, and hexamethylmelamine versus cyclophosphamide in advanced ovarian carcinoma.

Fifty-three evaluable patients with disseminated ovarian carcinoma (FIGO III or IV) not treated with prior chemotherapy were randomized to receive either combination chemotherapy consisting of cis-platinum 40 mg/m2 IV on day 1, adriamycin 40 mg/m2 IV on day 1, and hexamethylmelamine 150 mg/m2 PO on days 2-10 up to a maximum of 200 mg on a 4-weekly cycle, or moderate-dose cyclophosphamide alone 40 mg/kg given IV intermittently every 3 weeks. Entry was from 1. 11. 1978 until 30. 4. 1981 (last follow-up 31. 10. 1981). Pretreatment characteristics in both groups of patients, regarding median age at diagnosis, median time from diagnosis to chemotherapy, FIGO stage, histology, differentiation grade, type of surgery, residual disease, previous radiotherapy, and median performance status, were comparable. Objective responses were seen in 18 of 27 (66%) of patients receiving cyclophosphamide alone (range 5--32+ months) and in 10 of 26 (38%) of patients treated with the combination (range 3--30+ months), this difference being statistically significant (chi 2 = 4.228; P less than 0.05). The median duration of objective response (11 vs 10 months) and the median survival (12 vs 11 months) were greater in the cyclophosphamide group, but these differences were not statistically significant. The toxicity of the combination was more severe. It is concluded that there is no therapeutic advantage for this combination schedule over the alkylating agent used alone.

Adult↗
PubMed1984

Effect of liver failure on the pharmacokinetics of cyclophosphamide.

The pharmacokinetics of cyclophosphamide was investigated in 7 patients in severe liver failure. The pharmacokinetic data were compared with those derived from a matched control group of patients with normal liver function. The half-life (t1/2) of cyclophosphamide following intravenous administration in patients with liver failure was 12.5 +/- 1.0 h (m +/- SD), which was significantly longer than in the normal controls in whom it was 7.6 +/- 1.4 h (p less than 0.001). The mean total body clearance (Clt) was significantly smaller in liver failure at 44.8 + 8.61 X kg-1 than in the controls in whom it was 63.0 +/- 7.61 X kg-1 (p less than 0.01). It is concluded that severe liver disease has a significant effect on the disposition of cyclophosphamide, and that it could lead to accumulation of the drug in the body.

Adult↗