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PubMed1986

Interferon alfa-2b-cyclophosphamide combination studies: in vitro and phase I-II clinical results.

Since interferon alfa-2b (Intron A) is useful as a single agent, it is important to determine if interferon can be combined with standard chemotherapy to improve both response and survival in patients with cancer. Using clonogenic assays, interferon was tested alone and in combination with cyclophosphamide (Cytoxan) or melphalan (Alkeran) using several dose and exposure schedules to evaluate cytotoxicity. In vitro, continuous-exposure interferon produced optimal cell kill. Maximum enhancement of cytotoxicity occurred with cyclophosphamide or melphalan pretreatment (1 hour) and/or simultaneous interferon treatment. Based upon these data, a phase I-II study was designed to determine the tolerance of cancer patients to a fixed dose of cyclophosphamide (150 mg/m2 p.o. daily X 4 days [days 2 to 5]) combined with increasing doses of interferon. Interferon was administered subcutaneously on treatment cycle days 1 to 5, plus days 8, 10, 12, 15, 17, and 19 of the 21-day regimen. Three patients had partial responses: one breast cancer, one angiosarcoma, and one myeloma (mixed). All patients reported mild flu-like symptoms, fatigue, and anorexia. Leukopenia occurred in all patients; three required treatment interruption to allow recovery. Eight patients had a fall in hemoglobin (mean decrease 1.4 g/dL). The combination of cyclophosphamide and interferon was safe and deserves further trial in cancer treatment. However, using this combination schedule, interferon doses greater than or equal to 5 X 10(6) IU were poorly tolerated and compromised administration of full-dose cyclophosphamide.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1979

Administration of cyclophosphamide during late pregnancy and early lactation: a case report.

Burkitt lymphoma was diagnosed in a patient during the third trimester of pregnancy. Treatment with a low-dose, seven-day course of intravenous cyclophosphamide gave a good response which permitted the pregnancy to be carried to term, with delivery of a normal infant. When the mother received cyclophosphamide during lactation while the baby was breast-fed, the infant's leukocyte and platelet counts were rapidly depressed. Results in this patient and a survey of reported cases in which cyclophosphamide was administered during pregnancy and lactation lead to the conclusions that (1) low-dose intravenous cyclophosphamide therapy is not hazardous to the fetus during late pregnancy; (2) mammary concentration of the drug is too toxic to the infant's bone marrow; and (3) breast-feeding the baby should be suspended during the period the mother is receiving cyclophosphamide treatment.

Adolescent↗

PubMed1979

Cyclophosphamide alone in the treatment of adult patients with minimal change glomerulonephritis.

Eight adult patients with the nephrotic syndrome due to "minimal change" glomerulonephritis have been treated with cyclophosphamide alone. The effects of therapy have been compared with a similar group of patients treated with conventional diuretic therapy. Complete remission was achieved in seven of the cyclophosphamide treated patients as compared to only two spontaneous remissions in the untreated group. After a mean follow up period of 6 years none of these 9 patients relapsed. The eighth patient treated with cyclophosphamide remitted spontaneously 21 months after stopping cyclophosphamide and relapsed 36 months later. No serious side effects were encountered in the treated patients. The results suggest that cyclophosphamide is an effective agent in the management of adults with the nephrotic syndrome due to "minimal change" glomerulonephritis.

Adolescent↗

PubMed1979

The effect of drug schedule on mouse neuroblastoma treated with cyclophosphamide.

The potential difference in survival due to scheduling of cyclophosphamide treatment was examined in A/J mice inoculated with neuroblastoma C1-1300 cells. Treatment was started on the third day post tumor implantation. There were four groups of animals each consisting of 30 mice: Group A, a control group, was injected with 0.3 cc of normal saline for a week. Group B was injected with cyclophosphamide 50 mg/kg/day every other day for five doses. This cycle was repeated in the same fashion starting on day 17. Group C was injected with cyclophosphamide 250 mg/kg on day 3 and this was repeated on day 17. Group D was injected with cyclophosphamide 50 mg/kg/day for five consecutive days. This cycle was repeated on day 17-21. The median survival for group B was 26.2 days (the same as the control group), for group C 47.7 days (87% increased survival) and for group D 63.2 days (143% increased survival with 30% possible cures). Twenty-three percent of the mice in group B died of pneumonia and another 23% had minor evidence of lung infection. Only three mice in this group had tumor at the time of death. The study suggests that the response of murine neuroblastoma as well as the development of pneumonia in A/J mice treated with cyclophosphamide might be schedule dependent.

Animals↗

PubMed1984

Modulation of bleomycin-induced pulmonary fibrosis in the BALB/c mouse by cyclophosphamide-sensitive T cells.

Endotracheal bleomycin treatment is an effective inducer of pneumonitis and pulmonary fibrosis. Certain strains of mice, however, develop only minimal or no pulmonary fibrosis after treatment with bleomycin. The mechanism of unresponsiveness or low responsiveness in the BALB/c strain of mice is examined in this article. Pretreatment with cyclophosphamide (100 mg/kg) 2 days prior to bleomycin instillation significantly augmented the fibrotic response in these mice. Treatment by cyclophosphamide alone at the same dosage caused no significant pulmonary disease or fibrosis. Furthermore, suppression of fibrosis in the cyclophosphamide-pretreated animals could be reconstituted with spleen cells from normal untreated donor mice. If the donor spleen cells were depleted of T cells by cytotoxic anti-Thy-1.2 antisera prior to infusion into recipient animals, no such reconstitution was observed, suggesting that a population of splenic T cells was responsible for the effect. Since this dose of cyclophosphamide is known to be cytotoxic for suppressor T cells, these data would signify that the intensity of the lung fibrogenic response to bleomycin in BALB/c mice can be modulated by a population of this T cell subset. Furthermore, the cell reconstitution data would exclude the possibility that cyclophosphamide augments the bleomycin response by non-T-cell-mediated synergistic effects on lung injury. Nevertheless, the results conclusively demonstrate the ability of T cells to modulate pulmonary fibrosis in vivo, at least in the BALB/c mouse.

Animals↗

PubMed1982

The effect of cyclophosphamide on the myocardial oxidase system of mitochondria.

The authors studied the effect of immunosuppressive doses of cyclophosphamide (5 mg/kg b. w.) on the activity of myocardial NADH, succinate and cytochrome oxidases in the mitochondria of rabbit myocardium on two experimental models: a) after a single dose of cyclophosphamide (acute model); b) after cyclophosphamide given daily for a period of 10 weeks (chronic model). A single dose of cyclophosphamide did not affect the myocardial oxidase systems of mitochondria, whereas its chronic administration significantly increased the succinate oxidase activity and decreased cytochrome oxidase activity. The drug did not interfere with NADH- oxidase activity. It is concluded that long-term administration of cytostatic and immunosuppressive doses of cyclophosphamide may result in severe myocardial lesions on subcellular level. This should be taken into account in clinical practice.

Animals↗

PubMed1983

Efficacy of high-dose cyclophosphamide in combination with total-body irradiation in the treatment of acute myelocytic leukemia: studies in a relevant rat model.

The efficacy of current clinical leukemia treatment with high-dose cyclophosphamide, supralethal total-body irradiation (TBI), and bone marrow transplantation was evaluated in a rat model for human acute myelocytic leukemia. In rats, both at an early stage of disease and in an advanced stage after remission-induction with 1-beta-D-arabinofuranosylcytosine, treatment with cyclophosphamide (100 mg/kg i.p.) followed by either acute, unfractionated TBI (900 centigrays) or fractionated TBI (200 centigrays for seven doses; 450 centigrays for three doses) achieved cure in 90 to 100% and 75% of the animals, respectively. The remaining rats died from treatment-related toxicity despite isologous bone marrow transplantation. Applying the cyclophosphamide-TBI treatment regimens in advanced stage leukemia (tumor load, 5 X 10(9) cells) resulted in death from leukemia relapse in the majority of rats (71%). From the increase in life span after treatment, it was deduced that a 9-log leukemic cell kill was achieved at the most. There was no significant difference between the regimens using fractionated or unfractionated TBI. Toxicity-related deaths occurred mainly in the TBI group receiving 450 centigrays for three doses (38%). In another approach, (repeated) low-dose cyclophosphamide was given subsequent to high-dose cyclophosphamide-TBI treatment applied in advanced stage leukemia. This proved to be effective in eradicating residual leukemia in 80 to 90% of the rats without destroying the bone marrow graft. In general, the outcome of the various treatment regimens was predictable through accurate information on the tumor load at various stages of disease. The major obstacle in extrapolating the present experimental results to clinical practice is the lack of similar quantitative data in human leukemia.

Animals↗

PubMedDate not supplied

Polarographic and colorimetric methods for determination of cyclophosphamide.

Polarographic and colorimetric methods for analysis of cyclophosphamide and its dosage forms were investigated. Both methods are based on the reaction of cyclophosphamide with nitrous acid. A single cathodic diffusion-controlled wave was used for dc polarographic determination of cyclophosphamide, with an accuracy of 99.98 +/- 1.09%. The wave was well defined and irreversible. By differential pulse polarographic analysis, as little as 10 ppm cyclophosphamide was determined; overall accuracy at 10-60 ppm was 100.16 +/- 0.99%. The linear relationship between absorbance for the lemon-yellow nitroso derivative and the concentration of cyclophosphamide was further used in colorimetric analysis; overall accuracy was 100.2 +/- 0.99%.

Chemical Phenomena↗

PubMed1984

Cyclophosphamide resistance developed in a human melanoma cell line.

The Mer- human melanoma cell line MM253c1 was treated four times with cyclophosphamide activated in situ with rat liver microsomes, the fourth cycle being preceded by treatment with the mutagenic methylating agent N-methyl-N1-nitro-N-nitrosoguanidine. The resulting subline (MM253c1-4CG) showed increased resistance to activated cyclophosphamide; the resistance of seven allogeneic human tumor lines and of a fibroblast strain spanned the two extremes represented by the autologous MM253c1 lines. MM253c1-4CG cells were highly resistant to killing by methylating agents, a property indicative of conversion to the Mer+ phenotype. Compared with the parent line, MM253c1-4CG cells were resistant to DNA cross-linking agents having different structures and transport mechanisms (melphalan, mechlorethamine, and mitomycin) and were slightly more resistant to doxorubicin, gamma rays, and hydroxyurea, but were not resistant to killing by acrolein, cytarabine, hydrogen peroxide, 254 nm UV, [3H]thymidine, or vincristine. No difference in the intracellular concentration of potential alkylation targets (RNA, protein, and SH groups) was found, and neither cell line appeared able to activate cyclophosphamide or detoxify its metabolites. Caffeine and 3-aminobenzamide had no synergistic effect upon cyclophosphamide toxicity in either cell line. 3-Aminobenzamide showed synergism with the methylating agent 5-(3-methyl-1-triazeno)imidazole-4-carboxamide, the effect being greater in MM253c1-4CG than in MM253c1 cells. These results suggest that in vitro activation of cyclophosphamide produces a metabolite similar in stability to phosphoramide mustard, resistance to such toxicity being associated not with conversion to the Mer+ phenotype but with some intracellular change with confers resistance to a variety of DNA cross-linking agents.

Benzamides↗

PubMed1983

Comparison of approaches for augmenting the serologic response to the individually specific methylcholanthrene-induced sarcoma-Meth A: pretreatment with cyclophosphamide is most effective.

We have previously reported the production of antisera against a highly restricted antigen expressed on the BALB/c sarcoma Meth A. Because induction of the antibody required many vaccinations with irradiated and unirradiated Meth A cells over a prolonged period, we have investigated methods of improving the efficiency of producing Meth A antibody in BALB/c mice. Three general approaches were used: immunizing with irradiated Meth A cells mixed with adjuvants, immunizing with irradiated Meth A cells modified by treatment with chemicals, or administration of tumor cell vaccines in conjunction with low dose cyclophosphamide. These vaccine preparations were injected subcutaneously into groups of BALB/c mice five to six times at 2-wk intervals. Sera from all mice were screened for reactivity to Meth A by complement-dependent cytotoxicity, protein A, and mixed hemadsorption assays. Twenty-three vaccine preparations containing adjuvants or modified cells were tested in individual groups of mice. Mice in some groups receiving adjuvants and in all groups receiving modified cells produced antibody, but only after four to six vaccinations. In contrast, nine of the 14 mice immunized with irradiated Meth A cells (unmodified and without adjuvant) in conjunction with 10 or 100 mg/kg body weight of cyclophosphamide, and all nine of the mice receiving 25 mg/kg cyclophosphamide made Meth A antibodies after only one or two vaccinations. The titer of antibodies produced after one treatment with cyclophosphamide and irradiated Meth A cells was at least as high as that achieved after five or six vaccinations in our other trials. The specificity of these antibodies for the Meth A antigen was established by absorption analysis. We conclude that treatment with cyclophosphamide before vaccination is highly effective in augmenting the humoral immune response to the Meth A antigen.

Adjuvants, Immunologic↗

PubMed1983

Longterm effects of cyclophosphamide on granulocyte colony formation in patients with rheumatoid arthritis.

Longterm cytotoxic therapy, particularly with alkylating agents, is frequently associated with the development of second neoplasms, particularly acute myeloid leukemia. Twelve patients with classic, progressive rheumatoid arthritis (RA), treated with a cytotoxic agent, cyclophosphamide, from 1969 to 1974 at the University of Colorado Health Sciences Center were reassessed for current status of the granulocytic system. Bone marrow biopsies were investigated histologically and the number of granulocyte precursor cells judged using colony forming cells in culture (CFU-C). Control bone marrow biopsies were done on 8 patients with classic, progressive RA who had not taken cyclophosphamide as well as 16 healthy controls. Colony forming cell numbers in patients with RA who had been treated with cyclophosphamide were significantly lower compared to patients with RA who had not received cyclophosphamide and normal controls. These data suggest that cyclophosphamide may cause suppression of the hematopoietic system that does not totally recover even after long periods of time.

Aged↗

PubMed1981

IgE antibody production in guinea pigs treated with cyclophosphamide.

Guinea pig anaphylactic responses usually involve IgG1 antibodies. Although IgE antibody production has been accomplished, a reliable and sustained method for production has not been described. We have investigated a method of enhancing IgE antibody production in guinea pigs. The criteria for IgE production were homologous passive cutaneous anaphylaxis (PCA) antibody activity that passed an affinity column of rabbit anti-guinea pig IgG1, heat lability (56 degrees C for 3 hr), and a long sensitization period in skin (7 days). Hartley guinea pigs were primed and boosted monthly with 1 microgram Picryl-Ascaris plus 1 mg of alum i.p. Some Hartley guinea pigs also received cyclophosphamide (250 mg/kg) before the first boost. English short-hair guinea pigs (previously shown to be good IgE producers) were immunized similarly but received no cyclophosphamide. Hartley animals receiving no cyclophosphamide inconsistently made low titered IgE anti-hapten antibody (1:100). Fifteen of 15 Hartley animals that received cyclophosphamide had high titers (1:2000) of IgE anti-hapten antibody. English short-hair animals had moderate titers (1:400), and not all animals responded. Thus, cyclophosphamide converted IgE nonresponder Hartley guinea pigs to uniformly high responders. This method provides material to study the biologic properties of IgE in this species, and also provides a model to study the apparent suppression of IgE responses in Hartley guinea pigs.

Animals↗

PubMed1981

Cardiotoxicity associated with high-dose cyclophosphamide therapy.

The cardiac effects of chemotherapeutic regimens using high doses of cyclophosphamide (180 mg/kg over four days) were assessed in 32 patients with hematologic malignant neoplasms. Left ventricular systolic function, determined by the fractional shortening on echocardiogram, declined substantially five to 16 days after the initiation of cyclophosphamide therapy. Although pericardial effusion on echocardiogram occurred in 33% of the patients studied, ECG voltage decreased five to 14 days after beginning cyclophosphamide therapy even in those patients without pericardial effusion. Congestive heart failure was noted in nine patients (28%) within three weeks of cyclophosphamide administration. Six of these patients (19%) died of myocardial failure. Pericardial tamponade occurred in six patients (19%), including five who died of myocardial failure. Histopathologic and electron microscopic findings showed endothelial injury and a hemorrhagic myopericarditis. Cyclophosphamide in this high dose is associated with a toxic, often fatal, pericardiomyopathy. Depression of ECG voltage and systolic left ventricular function, though common, do not necessarily predict clinical cardiac deterioration.

Adolescent↗

PubMed1981

Effect of cyclophosphamide on spleen lymphocytes in mice.

The experiments were carried out in the following groups of Swiss mice: 1. after administration of a single dose of cyclophosphamide (300 mg/kg); 2. after i.v. injection of sheep red blood cells (4 X 10(8)); 3. injected with SRBC on the 4th day after cyclophosphamide administration; 4. control group. In all mice, histologic evaluation of the spleen and determination of the percentage of Fc and C3 lymphocytes (EA and EAC rosettes) were performed on the days following cyclophosphamide administration. The results obtained revealed that cyclophosphamide caused fast elimination of lymphocytes from the spleen lymphoid tissue in thymus-dependent areas, most strongly pronounced on the 4th day after cyclophosphamide administration. Simultaneous injection of sheep red blood cells evoked changes in the spleen, typical of immune response. These changes, in respect to all parameters, were less pronounced in animals treated with antigen only.

Animals↗

PubMed1978

Stimulated autoantibody response and increased longevity in NZB/NZW mice treated with cyclophosphamide and tilorone.

The experiment described in this report was designed to study the effects of immunostimulatory therapy in cyclophosphamide-treated hybrid New Zealand mice. Autoantibodies, renal histology and neoplasms were studied in seventeen female NZB/NZW mice treated with daily injections of the potent immunosuppressive drug, cyclophosphamide. Results were compared with fifteen female NZB/NZW mice who received both cyclophosphamide and tilorone, an interferon inducer which stimulates the immune system. Fifteen control mice received saline. The controls died with spontaneous arteritis and immune complex glomerulonephritis; their mean age at death was 46 weeks. In the cyclophosphamide group anti-DNA antibodies and renal disease were suppressed. Mean longevity was prolonged significantly to 80 weeks. Two mice died of iatrogenic causes, and the remaining fifteen mice died with neoplasms. Eleven mice had multiple neoplasms; a total of twenty-seven neoplasms appeared. In mice receiving combination therapy, autoantibody responses were not suppressed. Nevertheless, glomerulonephritis was controlled partially and the mean lifespan was prolonged to 82 weeks. Eighteen neoplasms appeared in ten mice in the combination treatment group, and five mice had more than one neoplasm. The appearance of lymphomas was delayed in mice receiving two drugs. It was concluded that concurrent therapy with tilorone stimulated autoantibody production and altered the expected pattern of neoplasia in cyclophosphamide-treated NZB/NZW mice.

Animals↗

PubMed1980

Effect of plasma from cyclophosphamide-treated mice on CFU-S in an in vivo culture system.

Various studies suggest that humoral substances, capable of stimulating CFU-S proliferation, are released into the plasma in response to depletion of the CFU-S population by cytotoxic substances such as cyclophosphamide. To test this hypothesis, we placed 0.25 ml of a murine marrow cell suspension with an equal volume of plasma from either normal mice or from mice previously injected with 5 mg of cyclophosphamide into cellulose dialysis tubing. These tubes were then incubated in the peritoneal cavity of mice for 1-7 days. The CFU-S content of the tubes was then assayed. The CFu-S content of suspensions in normal mouse plasma declined to one-fourth of the initial value after 7 days, whereas those in plasma from mice that received cyclophosphamide 7 days previously were essentially unchanged in number. These data suggest that 7 days after injection of cyclophosphamide, the plasma contains a factor that either prevents death of CFU-S or stimulates them to proliferate. An alternative explanation is that normal plasma contains an inhibitor of CFU-S growth that is lacking in plasma of cyclophosphamide-treated mice.

Animals↗

PubMed1976

Cytostatic treatment of glomerular diseases. III. A double-blind cross-over study of the effect of cyclophosphamide report from a copenhagen study group of renal diseases.

Fifty patients with renal glomerular diseases entered a double-blind cross-over study on the effect of cyclophosphamide; 38 had received neither corticosteroids nor cytostatic drugs before joining the study. Cyclophosphamide was given for 4 months in doses decreasing from 3 to 1.5 mg/kg b.wt. Cyclophosphamide caused a 46% decrease in the 24-hour excretion of urinary protein and a decrease in serum creatinine within the normal range. Albumin, transferrin and IgA in urine, as well as albumin clearance and the sieving coefficient of albumin, changed parallel to the total urinary protein. The initial values of proteinuria and serum complement were of prognostic significance for the effect of cyclophosphamide in serum creatinine. We were unable to demonstrate a prognostic significance for the variables: clinical diagnosis, renal histology, arterial BP, initial values of serum creatinine and IgG, IgA and IgM in serum and urine. ESR appeared to be the most reliable acute phase reactant. No differences were found between the changes in renal histology during cyclophosphamide or placebo.

Administration, Oral↗

PubMed1994

Veno-occlusive disease of the liver induced by low-dose cyclophosphamide.

A 2-yr-old child with idiopathic pulmonary hemosiderosis and autoimmune thrombocytopenia developed hepatic veno-occlusive disease after being treated with long-term, low-dose cyclophosphamide. The authors believe that the injury was induced by cyclophosphamide. Although transplant dosages of cyclophosphamide alone or in conjunction with other drugs have been shown to induce hepatic venocclusive disease, this is the first case of hepatic venocclusive disease associated with nontransplant dosages of cyclophosphamide. Histopathologically, the injury was characterized by occlusive lesions of intrahepatic veins, both the terminal hepatic venules and portal veins branches, together with necrosis (predominately involving Zones 3 and 2) and hemorrhages. An added risk factor could have been release of platelet-derived growth factor that in turn activated and promoted proliferation of fibroblasts and smooth muscle cells in the vessels. Previously reported cases of cyclophosphamide-related injury are reviewed.

Child, Preschool↗