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PubMed1984

Busulfan versus cyclophosphamide treatment in the early and late stages of granulocytic leukemia in guinea pigs.

A transplantable granulocytic leukemia (GL-13-BC) in strain 13 guinea pigs, which has many similarities to human CML, was used to test the antineoplastic effects of two alkylating agents, busulfan and cyclophosphamide, administered in the late and early stages of the disease. Busulfan had a pronounced cytoreductive effect on circulating leukemic cells in the late, pre-blast crisis stage of this disease but all treated animals, succumbed to the leukemia with only a marginal increase in survival time relative to that of untreated controls. In this respect the guinea pig model resembles human CML. Survival time was moderately increased with early busulfan treatment but, as in the late treatment group, all animals succumbed to the leukemia. A pronounced cytoreductive action on leukemic cells was also observed in guinea pigs treated with cyclophosphamide. Late treatment with this drug produced highly variable effects on the survival time of leukemic guinea pigs; of the nine animals treated, no effect was observe in five, three showed a significant increase in survival time and one animal was still in remission without treatment when the experiment was concluded. Early treatment with cyclophosphamide produced the most striking finding of this study. Two treatments with this drug produced a complete remission in all of the treated guinea pigs. This remission lasted without further treatment for the duration of the study (greater than 200 days) while all untreated controls died within 27-37 days after receiving leukemic cell transplants. The relevance of these findings to the treatment of human CML is discussed.

Animals↗
PubMed1982

Age dependent differential effects of cyclophosphamide on natural antibody levels in chickens.

Administration of 5 mg of cyclophosphamide per day for 4 days into neonatal chicks resulted in suppression of natural agglutinin titers up to at least 12 weeks of age. When the administration of cyclophosphamide was delayed until 7 days post-hatching suppression was found up to 8 weeks but titers rose to normal by 10 weeks after initial injections. Injections of cyclophosphamide after 21 days of age did not suppress natural agglutinin titers unless the drug was administered daily for 2 or more weeks.

Agglutinins↗
PubMed1992

Immunosuppression in goats by dexamethasone and cyclophosphamide.

The influence of dexamethasone and cyclophosphamide on the goat immune system was investigated. Seven goats, with a previous contact with caprine herpesvirus type 1 (CHV-1), were used. All had been vaccinated with live Mycobacterium paratuberculosis vaccine. Six goats were injected intravenously (i.v.) with dexamethasone daily for 5 days (2.5-4 mg/kg BW per day). Three also received 25 mg/kg BW of cyclophosphamide on day 0. The seventh goat was not treated. Dexamethasone alone caused depression, slight lymphopenia and fall in tuberculin reaction. Dexamethasone plus cyclophosphamide caused a severe clinical reaction, marked leukopenia (lymphopenia and polymorphopenia), fall in tuberculin reaction and significant increase in CHV-1 neutralizing antibody titres. M. paratuberculosis antibody reaction was variable and thus difficult to be assessed. CHV-1 was not isolated.

Animals↗
PubMed1989

Use of the cytokinesis-block method for the analysis of micronuclei in V79 Chinese hamster lung cells: results with mitomycin C and cyclophosphamide.

The cytochalasin B (CYB)-blocked binucleated cell assay has been explored to analyze micronuclei and cell cycle kinetics using 2 known mutagenic carcinogens in V79 Chinese hamster lung cells. To determine the optimum time to obtain the maximum number of binucleated cells for micronucleus analysis, duplicate cultures of exponentially growing cells were treated with 3 micrograms/ml CYB for varying durations (8-48 h). A peak appearance of binucleated cells at 16 h in the presence of CYB suggested this as an optimum time for micronucleus analysis in binucleated V79 cells. To evaluate the capacity for induction of micronuclei in V79 cells, 2 mutagenic carcinogens, mitomycin C (0.125-1.0 micrograms/ml) and cyclophosphamide (2-12 micrograms/ml) were tested in duplicate cultures. Mitomycin C, a direct-acting alkylating agent, caused approximately an 18-fold increase in micronucleus frequency over controls at the highest concentration tested (1.0 micrograms/ml), and this increase occurred in a dose-related manner (r = 0.92). The concentrations of mitomycin C tested also caused a significant dose-related cell cycle delay, thus suggesting cytotoxicity to V79 cells. Cyclophosphamide, an indirect-acting alkylating agent, requiring the presence of S9 mix, caused approximately a 17-fold increase in micronucleus frequency over controls at the highest tested concentration (12 micrograms/ml), with a clear dose response (r = 0.99). The various concentrations of cyclophosphamide also caused cytotoxicity in a dose-related fashion. Thus, this study demonstrates the usefulness of the cytokinesis-block method in V79 cells as a possible screen to analyze micronucleus induction and cytotoxicity. Because this approach is much less labor intensive than conducting a structural chromosomal analysis, this assay has great potential both as an initial screen for clastogenic activity and as a tool for investigating the underlying mechanisms for clastogenicity.

Animals↗
PubMed1988

Short-term effect of cyclophosphamide and azathioprine on selected aspects of the canine blastogenic response.

The short-term, in vitro responses of canine peripheral blood lymphocytes to mitogenic stimulation and serum immunoglobulin concentrations were evaluated following treatment with currently recommended doses of cyclophosphamide and azathioprine. Cyclophosphamide had no significant effect on either the serum immunoglobulin concentrations or the blastogenic response of lymphocytes to mitogenic stimulation. Serum immunoglobulin concentrations remained unchanged following azathioprine treatment. The blastogenic response was significantly suppressed following one week of azathioprine therapy and returned to baseline values one week following cessation of treatment. The response to phytohemagglutinin was most suppressed, followed, in order, by the response to concanavalin A, and to pokeweed mitogen. These results suggest that the short-term use of azathioprine, but not cyclophosphamide, in clinically used dosages, does suppress selective aspects of the canine immune system, and the T cells appear to be more susceptible than B cells to the immunosuppressive effect of this drug.

Animals↗
PubMed1987

Mechanisms in cyclophosphamide induction of cytogenetic damage in human lymphocyte cultures.

Low-dose cyclophosphamide treatment of human lymphocyte cultures in concentrations ranging from 0.001 to 0.00001 microgram/ml produced a statistically significant dose response in chromosome breakage and cell death. However, a dose as high as 0.2 micrograms/ml did not produce significant damage in comparably treated whole blood cultures. These results suggest that lymphocytes in culture have the ability to metabolize the nonmutagenic cyclophosphamide parent compound to its more mutagenic metabolite, but that such conversion may be prevented by binding of cyclophosphamide to red blood cells.

Biotransformation↗
PubMed1991

Cyclophosphamide alters the clinical and pathological expression of experimental autoimmune gray matter disease.

Guinea pigs inoculated with bovine spinal cord ventral horn homogenate develop a syndrome termed experimental autoimmune gray matter disease (EAGMD) characterized by extremity weakness, bulbar signs, and a loss of lower and upper motoneurons. To provide evidence for the role of autoimmune mechanisms, we have administered the immunosuppressant cyclophosphamide prior to and after gray matter immunization. Pretreatment with cyclophosphamide prevented the appearance of clinical signs of disease and decreased the loss of spinal cord motoneurons, the appearance of damaged motoneurons, and the antibody titer to motoneurons. Treatment 7 days after immunization attenuated the expression of disease. Treatment immediately after signs also improved the clinical and pathological findings. In all cyclophosphamide-treated animals there was less IgG within motoneurons and less inflammation. These results support the role for autoimmune mechanisms in motoneuron loss and degeneration in EAGMD.

Animals↗
PubMed1990

Increased frequency of 6-thioguanine-resistant lymphocytes in peripheral blood of workers employed in cyclophosphamide production.

The frequency of 6-thioguanine-resistant peripheral blood lymphocytes has been determined by autoradiography in a control population and a population of cyclophosphamide-exposed individuals. The mean variant frequency in a non-exposed population was found to be 2.76 +/- 1.48 X 10(-5). Subpopulations of smokers and non-smokers revealed statistically significant differences in the variant frequencies, i.e. 3.52 +/- 1.55 X 10(-5) and 2.07 +/- 1.05 X 10(-5) respectively. In 20 out of a total of 23 individuals employed in cyclophosphamide synthesis and manufacturing, the variant frequency of 6-thioguanine-resistant lymphocytes was found to be higher than the maximum individual frequency found in the control population. The mean variant frequency in the cyclophosphamide-exposed population was 13.64 +/- 13.56 X 10(-5), a statistically significant increase as compared to the mean control frequency. There was no correlation between variant frequency and duration of employment suggesting that this test reflects the actual exposure and not a cumulative effect.

Adult↗
PubMed1980

Recovery of the capacity for cytotoxic T cell generation in cyclophosphamide-treated mice by the addition of LYT-1/2- helper cells.

Spleen cells from mice treated with cyclophosphamide (150 mg/kg) and cultured at suboptimal concentrations do not generate cytotoxic T lymphocytes to allogeneic tumor cells. The reduced response of spleen cells from cyclophosphamide-treated mice is not due to the elimination of cytotoxic T cell precursors because normal responses are obtained by the addition of Lyt-1+2- T helper cells to the culture system. These results indicate that helper cells, required for the development of cytotoxic T cell responses to tumor alloantigens, are eliminated by cyclophosphamide in the absence of evident toxicity to cytotoxic T cell precursors.

Animals↗
PubMed1983

The effect of cyclophosphamide on autoimmune response to rats immunized with modified accessory glands.

It was found that the organ specific hemagglutinating autoantibodies to rat male accessory glands can be suppressed by the injection of a single dose of cyclophosphamide applied 3 days after the first immunization. On the other hand, injection of the drug 3 days before immunization did not modify the response, that is, there were comparable incidence and titers in both treated and the control animals. Cyclophosphamide did not appear to act on the homocytotropic antibodies. These results indicate that cyclophosphamide acts only when it is administered after antigenic stimulation, to suppress hemagglutinating antibodies production.

Animals↗
PubMed1985

Extended immunosuppression with cyclophosphamide using controlled-release polymeric implants.

An effective method of prolonged immunosuppressive therapy using cyclophosphamide incorporated into acrylic bone cement has been developed. We have studied the effect of this form of administration of cyclophosphamide on circulating immune cells and the inflammatory response. When the slow release mode of cyclophosphamide administration was compared with conventional systemic therapy, it was found to produce a more rapid and prolonged immunosuppression. A dose-response relationship was established and the biological effects of varying the composition and surface area of the implant were determined. The inflammatory response, assessed by measuring the mobilisation of cells into subcutaneously implanted sponges, was also depressed using this mode of administration. These results, coupled with the commercial availability and existing clinical approval of Simplex P bone cement, suggest that the procedure could lead to useful clinical protocols.

Animals↗
PubMed1986

The selectivity of isoprinosine, NPT 15392, avridine and cyclophosphamide on multiple immune responses in rats.

Multiple concomitant immune responses were assessed in individual rats following treatment with the immunoenhancing drugs, isoprinosine (5 or 50 mg/kg), NPT 15392 (0.1 or 1.0 mg/kg) and avridine (1 or 25 mg/kg), or the immunosuppressant, cyclophosphamide (75 mg/kg). Immune responses assessed in each rat were specific antibody synthesis, delayed-type hypersensitivity (DTH), natural killer cell (NKC) cytotoxicity and production of three immunoregulatory cytokines, interleukin 1 (IL1), interleukin 2 (IL2) and prostaglandin E2 (PGE2). Spleen and thymus weights and numbers of splenocytes and resident peritoneal cells were also recorded. Rats treated with isoprinosine had dose-related, significant increases in spleen weights and DTH reactions. Rats treated with NPT 15392 had significantly enhanced DTH reactions at the 0.1 mg/kg dose. Rats treated with the 25 mg/kg dose of avridine had significantly increased spleen weights, DTH reactions and NKC cytotoxicity. The effect of avridine treatment on DTH reactions and IL1 and IL2 production was inverse to the dose administered, while the NKC response was directly related to the dose. Thymus weights, antibody production and PGE2 synthesis were not significantly altered in rats treated with isoprinosine, NPT 15392 or avridine. Cyclophosphamide-treated rats had significantly reduced spleen and thymus weights, antibody synthesis, DTH reactions, NKC cytotoxicity and IL2 production, but IL1 and PGE2 synthesis were significantly elevated. It can be concluded that isoprinosine, NPT 15392 and avridine act as general immunostimulants in the rat, with avridine having the greatest effect under these experimental conditions. It also appears that these drugs are differentially immunoselective in the rat and this effect is at least partially related to the dose administered. These results could be of significance in the selective therapeutic manipulation of different arms of the immune system. Also, enhanced production of PGE2 following cyclophosphamide treatment may contribute to the immunosuppressive effects of this drug.

Animals↗
PubMed1989

Antihypertensive effect of an immunosuppressive agent, cyclophosphamide, in genetically hypertensive rats of the Lyon strain.

The effect of a pharmacological immunosuppression on the development of hypertension and the part played by hormonal secretions of the thymus in this disease were investigated in genetically hypertensive rats (LH) of the Lyon strain. For this purpose, systolic blood pressure (SBP) was measured in cyclophosphamide-treated LH rats and in neonatally thymectomized LH rats receiving thymostimulin, a thymus extract. Cyclophosphamide treatment delayed the onset and attenuated the full development of hypertension in LH rats whereas it had no effect on SBP in normotensive rats (LN). Thymectomized LH rats also exhibited a significantly decreased SBP as compared to sham-operated controls. Thymostimulin treatment slightly increased the SBP of thymectomized LH rats but did not restore it to the level seen in sham-operated animals. These results showed that thymic hormonal secretions did not seem to be involved in the initiation of hypertension. By contrast, the fact that a reduction of hypertension could be obtained either by thymectomy or cyclophosphamide treatment suggested that immune disorders, mediated by thymus-dependent cellular reactions, could be of pathogenic importance in the development of hypertension in LH rats.

Aging↗
PubMed1996

Effect of hypothalamic lesion or chemical axotomy on restitution of immunoreactivity in mice after cyclophosphamide administration.

Splenocytes harvested from mice that underwent chemical axotomy (by 6-hydroxydopamine) or that had electric lesions in their anterior hypothalami demonstrated a significant decrease in their proliferative ability after concanavalin-A stimulation in vitro. In axotomized mice pre-treated with cyclophosphamide, faster restitution of the proliferative activity was observed on days 6-8 after the drug's administration. Splenocytes isolated from mice treated with 6-hydroxydopamine did not exhibit any suppressive activity, which is characteristic of the restitution period following administration of cyclophosphamide. These results indicate that the autonomic nervous system exert a direct effect on immunoreactivity and on processes which are responsible for restitution after cyclophosphamide-induced immunodisorders.

Animals↗
PubMed1995

[Treatment of lupus glomerulonephritis with intravenous cyclophosphamide].

The treatment of severe lupus nephritis remains problematic. We have analysed retrospectively 17 patients with corticoresistant lupus nephritis treated with pulse cyclophosphamide. Single monthly doses (500 mg/m2) were given by intravenous infusion with a mean of 10.4 infusions per patient (3 to 18). A comparison of parameters at entry and at the end of the treatment revealed an improvement in proteinuria (4.8 vs 1.9 g/24 h; p < 0.013) whereas mean serum creatinine level and SLAM (Systemic Lupus Activity Measure) remained stable. The results were identical at follow up (mean: 14.5 months). Most of the therapeutic effect was achieved as soon as the 6th pulse. Further treatment was beneficial for four patients only. None of the studied parameters (serum creatinine level, renal biopsy, SLAM) was predictive of a response to an extended course of pulse cyclophosphamide. The infusions were definitively stopped in one patient and delayed in two others because of serious adverse effects. The data indicate that, in mean term, monthly intravenous cyclophosphamide was associated with a substantial amelioration of 24 hours urinary protein level. An amelioration of the renal function was however, uncommon.

Adult↗
PubMed1995

Successful cyclophosphamide treatment of cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection.

A 54-year-old man with cryoglobulinemia and chronic hepatitis C infection presented with progressive renal insufficiency caused by membranoproliferative glomerulonephritis. Because of a steady decline in renal function, cyclophosphamide therapy was instituted. Within 1 month of starting therapy, his cryoglobulins disappeared, and in 3 months, his creatinine clearance had improved from 56 mL/min to 89 mL/min. At no point in his course was there clinical evidence of liver disease. After 1 year, cyclophosphamide was successfully stopped. Fourteen months later, his creatinine clearance is 105 mL/min. These results suggest that cyclophosphamide may be useful therapy for patients with cryoglobulinemic membranoproliferative glomerulonephritis and hepatitis C virus infection who have progressive renal insufficiency.

Cryoglobulinemia↗
PubMed1982

High-dose cyclophosphamide treatment of acute myelocytic leukemia. Studies in the BNML rat model.

In view of its application in patients with acute leukemia prior to bone marrow transplantation, the toxicity and efficacy of high-dose cyclophosphamide treatment were evaluated in a rat model for human acute myelocytic leukemia (BNML). The LD50 in leukemic rats proved to be lower than that in normal rats (100 vs 164 mg/kg respectively). With dosages above 120 mg/kg, bone marrow transplantation was required to overcome irreversible aplasia. Additional causes of death were lung-, bladder- and intestinal tract hemorrhages (160-200 mg/kg) or acute cardiopulmonary failure (250-300 mg/kg). In leukemic rats, excessive leukemic cell kill leading to tumor cell embolism was another contributing factor. In this respect, treatment of late-stage leukemia proved invariably fatal. In leukemic rats, the highest therapeutic index was achieved with 100 mg/kg. Depending on the stage of disease, a 5-8.5 log leukemic cell kill was achieved. An increased proliferation rate of residual leukemic cells after cyclophosphamide treatment appeared likely. Finally, the present data are extrapolated to the current treatment of human acute myelocytic leukemia in complete remission with high-dose cyclophosphamide in combination with supralethal total-body irradiation.

Animals↗
PubMed1985

A randomised trial of cyclophosphamide pretreatment ('priming') before short-duration chemotherapy for small cell lung carcinoma.

Forty-five patients with small cell anaplastic carcinoma of the bronchus were treated with four four-weekly courses of a combination of cyclophosphamide, vincristine and methotrexate. Randomisation was carried out to determine whether they received in addition 1 g/m2 of cyclophosphamide 1 week before the three-drug therapy. Patients with limited disease received radiotherapy after their chemotherapy. Myelosuppression was similar in the two groups, but the additional cyclophosphamide did not improve remission duration or survival. Confining the chemotherapy to four courses did not give shorter survival times to those reported in other studies.

Adult↗