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PubMed1985

Treatment of high-risk gestational trophoblastic disease with methotrexate, actinomycin D, and cyclophosphamide chemotherapy.

Seventy-three patients with metastatic high-risk gestational trophoblastic disease were treated with methotrexate, actinomycin D, and cyclophosphamide chemotherapy at the Brewer Trophoblastic Disease Center between 1968 and 1982. Forty-six patients were treated primarily with methotrexate, actinomycin D, and cyclophosphamide because of the presence of one or more high-risk factors. Twenty-seven additional patients who had not responded to initial single-agent chemotherapy with methotrexate and/or actinomycin D were subsequently treated with methotrexate, actinomycin D, and cyclophosphamide. Adjuvant surgery and radiotherapy were used in selected patients. The overall cure rate was 51% (37 of 73): 63% (29 of 46) for primary treatment and 30% (eight of 27) for secondary treatment (P less than .01). Several factors that influenced response to primary treatment with methotrexate, actinomycin D, and cyclophosphamide chemotherapy were determined: 1) clinicopathologic diagnosis of choriocarcinoma versus invasive mole (59 versus 100%), 2) metastases to sites other than the lung and/or vagina (44 versus 74%), 3) antecedent term gestation compared with hydatidiform mole or abortion (50 versus 75%), and 4) presence of three or more high-risk factors (27 versus 74%). There were no significant differences in cure rates during the course of the study period.

Abortion, Spontaneous↗

PubMed1988

Cyclophosphamide-induced liver necrosis: a possible interaction with azathioprine.

Cyclophosphamide is a valuable drug for the treatment of vasculitis and hepatic toxicity resulting from its use has been reported rarely. We describe four patients in whom cyclophosphamide was associated with liver injury when its administration had been preceded by azathioprine. Microscopy of hepatic biopsy material in three of these cases showed liver cell necrosis. In two of the patients, cyclophosphamide had been given previously without earlier azathioprine and hepatic damage had not been noted. An apparent interaction of cyclophosphamide with azathioprine to cause liver cell necrosis has important implications for the treatment of patients with vasculitis and related disorders.

Adult↗

PubMed1987

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

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.

Animals↗

PubMed1977

The effect of cyclophosphamide on the splecific unresponsiveness to skin allografts induced in ALS-treated mice infused with donor bone marrow.

Specific unresponsiveness to skin allografts can be induced in ALS-treated mice by the injection of bone marrow from the graft-donor strain. Mice bearing long-term grafts in perfect condition have evidence of cell-mediated immunity against donor antigens and also serum-blocking factors. The effect of cyclophosphamide on graft prolongation was investigated in this model. Cyclophosphamide was given either before or after marrow. Cyclophosphamide given before marrow abrogated the enhancing effect of marrow possibly due to a depletion of antibody-forming cells. Cyclophosphamide given after marrow potentiated the effect of marrow probably due to the destruction of immunocompetent cells responding to the challenge of marrow.

Animals↗

PubMed1977

[Influence of centrophenoxine on the effect of cyclophosphamide and chloramphenicol in teratological experiment].

Cyclophosphamide and chloramphenicol underwent a teralogical test in the animal experiment. The prenatal changes in the application of cyclophosphamide reveal the cytostatic remedy as a strong teratogenic remedy, whereas chloramphenicol in the first place has an embryotoxic effect and only a weak teratogenic one. The possibility of an influence on the prenatal changes caused by cyclophosphamide and chloramphenicol was tried with centrophenoxin. Apart from the weight of the foetuses the induced changes remained without influence in cyclophosphamide, whereas in chloramphenicol even in increase of the toxic effect could be observed.

Abnormalities, Drug-Induced↗

PubMed1988

Immunotherapy with Chinese medicinal herbs. II. Reversal of cyclophosphamide-induced immune suppression by administration of fractionated Astragalus membranaceus in vivo.

A partially purified fraction (F3) with an estimated molecular weight of 20,000 to 25,000 derived from the traditional Chinese medicinal herb Astragalus membranaceus, was found to possess a potent immunorestorative activity in vitro. Its capacity to aborogate the local xenogeneic graft versus host reaction (XGVHR) following injection in vivo was further studied in a newly developed animal model designed for preclinical evaluation of various biological response modifiers. F3 was injected intravenously into cyclophosphamide-primed rats at varied concentrations and schedules prior to grafting of mononuclear cells from healthy normal donors. Maximal abrogation of the local XGVHR mounted by the mononuclear cells, was observed following injection of 5.55 mg of F3 daily for eight days. This abrogation of XGVHR indicates a reversal of the immunosuppressive effect of cyclophosphamide as manifested by a significant decline in the local XGVHR volume from 99.42 +/- 9.2 mm3 (positive control) to 39.78 +/- 8.3 mm3 (p less than 0.001). This reversal of cyclophosphamide-induced immunosuppression by the administration of F3 was complete, since the volume of the abrogated local XGVHR (39.78 +/- 8.3 mm3) was comparable to 34.79 +/- 5.69 mm3 (p greater than 0.1) in the negative control group (no cyclophosphamide-priming; saline injection only). These data indicate that F3 administration markedly enhances the rats' ability to reject the xenogeneic graft and therefore possesses a strong immune potentiating activity in vivo. These preclinical data also provide the rational basis for the use of extracts of Astragalus membranaceus in phase I clinical trials among patients suffering from iatrogenic or inherent immune deficiency states.

Adjuvants, Immunologic↗

PubMed1977

Characterization of the direct effects of cyclophosphamide on cell-mediated immunological responses.

The direct immunosuppressive effects of cyclophosphamide were examined by incubating normal guinea-pig mononuclear cells with activated cyclophosphamide prepared from the serum of separate animals which were treated with cyclophosphamide in vivo. Treated cells were subsequently assayed in a panel of tests of cell-mediated immunity either immediately or following recovery during variable periods of incubation. It was found that cyclophosphamide (1) induces changes in lymphocyte functions which are not due simply to cell death; (2) is markedly antiproliferative in mitogen-induced blastogenesis; (3) depresses migration inhibitory factor production only after a delay of several hours and (4) depresses certain cytotoxicity reactions immediately following treatment, such responses are subsequently normalized when the cells are allowed to recover in culture.

Animals↗

PubMed1988

Experience with cyclophosphamide in multiple sclerosis: the cons.

Neurologists in the Kaiser-Permanente Medical Care Program recently designed a study to evaluate the utility of intensive immunosuppression with cyclophosphamide compared with folic acid in 44 patients with chronic progressive multiple sclerosis (MS). Although preliminary results based on incomplete data suggest cyclophosphamide may be safely administered in an outpatient clinic setting and modest benefits cannot be ruled out, it is doubtful that there are very substantial benefits to that therapy. Although several other studies have been cited as evidence of cyclophosphamide's favorable effect on the clinical course of patients with MS, many of these studies have had design shortcomings. If these flaws are considered, the hypothesis that cyclophosphamide has a favorable effect on the course of MS must be considered weak.

Adult↗

PubMed1987

Second marrow transplants in patients with aplastic anemia rejecting the first graft: use of a conditioning regimen including cyclophosphamide and antithymocyte globulin.

Sixteen (11%) of 146 consecutive patients with severe aplastic anemia prepared for engraftment with cyclophosphamide (200 mg/kg) rejected marrow grafts from their HLA-identical siblings. They were given a second marrow transplant from either the same (n = 13) or a second (n = 3) HLA-identical sibling between 23 and 743 (median 86) days after the first transplant. The preparation for the second transplant included cyclophosphamide, 50 mg/kg, on each of four successive days. Twelve hours after each of the first three doses of cyclophosphamide, antithymocyte globulin, 30 mg/kg/dose, was infused. One of the 16 patients died from infection too early after the second transplant to be evaluated, two had failure of engraftment and died with infection, one rejected the second graft and is surviving almost 5 years later with full autologous marrow recovery, and 12 had successful and sustained second grafts. Of these 12, six are surviving between 11 months and 7 3/4 years. Four of the six have no graft-v-host disease (GVHD), while two have chronic GVHD requiring treatment. Five have Karnofsky scores of 100% and one of 90%. Six of the 12 patients with sustained grafts died between 63 days and 38 months after transplantation, four with infections (related in two patients to chronic GVHD), one with acute GVHD, and one with hemorrhage. The average interval from first to second transplant was 308 days during the past five years, compared to 61 days in earlier patients. Five of seven recent patients are surviving, compared to two of nine earlier patients. In conclusion, successful second transplants after cyclophosphamide and antithymocyte globulin are possible in most patients with aplastic anemia who have rejected their first marrow grafts; however, mortality remains high, with only 40% of the patients becoming long-term survivors.

Adolescent↗

PubMed1987

[Modification by cyclophosphamide of the effect of autovaccination in chronic pyelonephritis in an animal experiment].

In an existing chronic pyelonephritis the influence of cyclophosphamide on the efficacy of an immunisation with autopathogenic antigens and the surface antigen of an E. coli rough strain was tested in an animal experiment. After an existence of the infection of about five weeks a decisive decrease of the antibody production by cyclophosphamide was not to be observed. The animals treated with cyclophosphamide did not show any improved elimination of germs. The histological findings of the kidneys documented the cytotoxical effect of the cyclophosphamide on the renal tissues and the epithelium of the urinary tract. The immunisation of animals with chronic pyelonephritis with various autopathogenic antigens altogether led to a statistically significant decrease of inflammatorily changed kidneys.

Animals↗

PubMed1987

[Autovaccination in chronic pyelonephritis in the animal experiment--effect of cyclophosphamide on splenic and thymus lymphocytes].

In rats with experimental pyelonephritis, cyclophosphamide leads to changes in the spleen and thymus lymphocyte populations. When cyclophosphamide was given five times a week from the fifth week of infection on, the population of electrophoretically slow moving spleen lymphocytes, which are believed to be B-lymphocytes, decreased in the seventh week. This effect is independent of autovaccination. During the same period the number of immature slow moving thymus lymphocytes decreased. Further treatment with cyclophosphamide until the twelfth week of infection led to the differences almost disappearing in the histogramm. Cyclophosphamide showed a slight effect on antibody production and did not influence the elimination of infective agents from the kidneys of animals with pyelonephritis.

Animals↗

PubMed1988

Type 2 pneumocyte responses to cyclophosphamide-induced pulmonary injury: functional and morphological correlation.

We investigated the correlation between the functional and morphological responses of type 2 pneumocytes to experimentally induced subacute lung damage. BALB/c mice were injected with a single dose of 300 mg/kg of cyclophosphamide intraperitoneally to induce alveolar epithelial injury. Groups of six cyclophosphamide-treated animals and three untreated controls were killed at 3 days and 1, 2, 3, 4, 6, 8 and 12 weeks after drug treatment. The net secretory response of type 2 pneumocytes to injury was assessed by an enzyme immunoassay for the surfactant-associated protein alveolyn in bronchoalveolar lavage fluid and the morphological responses of the alveolar epithelial cells were evaluated by light and electron microscopy. Early type I pneumocyte injury occurred without significant endothelial damage and was accompanied by intra-alveolar fibrinous exudation. This was followed by focal hypertrophy and apparent hyperplasia of type 2 pneumocytes, together with the progressive accumulation of large foamy intra-alveolar macrophages and focal pleural fibrosis. In a minority of animals these lesions progressed to intra-alveolar fibrosis with marked epithelial hyperplasia. The type 2 pneumocyte response was initially paralleled by an increase in the concentration of alveolyn in bronchoalveolar lavage fluid, which was significantly greater than control values at 1 and 2 weeks (P less than 0.005) as well as at 3 and 4 weeks (P less than 0.05) after injury induced by cyclophosphamide, but thereafter fell to control levels. This study demonstrates that cyclophosphamide induces morphological alterations of type 2 pneumocytes and altered secretory activity of these cells manifested as an increased net secretion of a surfactant-associated protein.

Animals↗

PubMed1988

Effect of cyclophosphamide on the pathophysiology of RIF-1 solid tumors.

The present experiments were conducted to determine the effects of cyclophosphamide (150 mg/kg) on the pathophysiology of RIF-1 solid tumors and to determine the temporal relationship between treatment mediated changes in tumor vascular physiology, cell proliferation, and chemoresponsiveness in vivo. Capillary permeability and plasma and extracellular water volumes were determined by a 125I-bovine serum albumin, 51Cr-EDTA double isotope dilution assay at various intervals after cyclophosphamide. Tumor blood flow and exchangeable erythrocyte vascular volumes were determined by 86RbCl distribution and 51Cr-labeled erythrocyte dilution methods. Cell proliferation in RIF-1 tumors, assessed by [3H]thymidine labeling index and tumor growth fraction (primer-dependent DNA polymerase labeling assay) measurements, was inhibited for up to 3 days by cyclophosphamide. Although tumor regrowth was not apparent until Day 10, cell kinetic studies indicated proliferative recovery in the surviving cell population on Days 4 and 5 after treatment. Increases in tumor blood flow and tumor vascular volumes were temporally coincident with this proliferative response. In split-dose experiments, the time-dependent increases in the chemoresponsiveness of RIF-1 tumors, after cyclophosphamide, may be due not only to the increased proliferation of repopulating cells, but also to vascular responses attendant with cytoreduction.

Animals↗

PubMed1987

[Do endothelial cells participate in the biotransformation of cyclophosphamide?].

Investigations with cyclophosphamide were done to answer the question of participation of the endothelium in biotransformation of xenobiotics. Cyclophosphamide inhibits the proliferation of cultivated endothelial cells only in high concentrations. Also after induction of the cells by phenobarbital or 2,5-diphenoxazole no increased toxicity of cyclophosphamide was observed. Though the endothelium disposes of cytochrome-P-450-dependent aryl-4-monooxygenases it does not take part in biotransformation of cyclophosphamide apparently. Further possibilities of biotransformation by endothelial cells will be discussed.

Animals↗

PubMed1978

Sequential combination chemotherapy (containing high-dose cyclophosphamide) for metastic osteogenic sarcoma.

Eleven patients with metastatic osteogenic sarcoma were treated with cyclophosphamide, adriamycin, and, in some cases, high-dose methotrexate. In the event of metastatic progression, the dose of cyclophosphamide was escalated by increasing the number of consecutive daily infusions (dose, 45 mg/kg/day). The results indicate that metastatic osteogenic sarcoma is marginally responsive to adriamycin and cyclophosphamide but rarely responsive to high-dose methotrexate as administered in this trial. The response of metastatic lesions was not improved by escalating the dose of cyclophosphamide.

Adolescent↗

PubMed1987

Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial.

Since cyclophosphamide is used by both oral and i.v. routes in the treatment of hematological and solid malignancies, we designed a randomized, crossover clinical trial to evaluate the pharmacokinetics of this anticancer agent after either administration route. Plasma levels of cyclophosphamide and its two cytotoxic metabolites, 4-hydroxycyclophosphamide and phosphoramide mustard, were determined in seven cancer patients randomly assigned to treatment initially with either orally or i.v. administered cyclophosphamide with a 30-day interim between alternate therapy courses. Oral treatment was used initially in five patients and i.v. treatment in two patients, and the pharmacokinetic parameter, area under the plasma disappearance curve, was determined for each metabolite in each patient for both routes of drug administration. Statistical comparison of area under the plasma disappearance curve values for this set of patients indicated no significant differences for either metabolite for oral versus i.v. drug treatment, suggesting equal efficacy for these two routes of cyclophosphamide administration.

Administration, Oral↗

PubMed1987

Weekly cyclophosphamide and alternate-day prednisone: an effective secondary therapy in multiple myeloma.

Intravenous or oral cyclophosphamide, 150-250 mg/m2 (500 mg maximum), once per week with alternate-day oral prednisone, 100 mg, was given to 57 myeloma patients resistant to melphalan and prednisone (MP). Seven responses in 28 primary MP-resistant patients and ten responses in 29 secondary MP-resistant patients were observed. Previous response to MP was not a significant factor in predicting response to weekly cyclophosphamide and alternate-day prednisone. The results suggest that the regimen of weekly cyclophosphamide and alternate-day prednisone may be as effective as more aggressive regimens in the treatment of patients with myeloma who have failed MP therapy. However, a randomized trial would be required to determine the relative contributions of cyclophosphamide and prednisone to the effectiveness of this regimen.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1986

Intracavitary chemotherapy with activated cyclophosphamides and simultaneous systemic detoxification with protector thiols in Sarcoma 180 ascites tumor.

Activated cyclophosphamides such as 4-sulfoethylthiocyclophosphamide (mafosfamide) are suitable for a local intracavitary chemotherapy, whereas cyclophosphamide requires a metabolic activation. Mafosfamide administered i.p. in mice was less toxic (50% lethal dose, 640 mg/kg) than its i.v. application (50% lethal dose, 480 mg/kg). A further remarkable reduction of toxicity with an increase of the 50% lethal dose of mafosfamide to 1500 mg/kg was obtained by the simultaneous i.v. application of the protector thiol cysteine (mafosfamide:cysteine ratio, 1:5 on molar weight basis). In comparison with the i.v. injection of mafosfamide, the local i.p. application resulted in a 20 times higher concentration versus time product of peritoneal drug levels. The molar ratio of sulfhydryl groups to activated cyclophosphamide (resorbed from the peritoneal cavity) remained high in blood. Therapy studies on Sarcoma 180 ascites tumor of mice revealed that the coadministration of cysteine i.v. in mafosfamide i.p. treatment is superior to mafosfamide i.p. application alone. On the contrary, the simultaneous i.p. application of cysteine is accompanied by a loss of antitumor efficacy. The regimen of local i.p. chemotherapy with activated cyclophosphamide and simultaneous systemic detoxification by an appropriate thiol allows the reduction of the systemic toxicity of treatment without influence on the cancerotoxic activity at the site of local injection and the exposing of the intraabdominal tumor to a much higher concentration of the cytostatic agent.

Animals↗