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PubMed1984

Effect of cyclophosphamide on oocyte and follicle number in Sprague-Dawley rats, C57BL/6N and DBA/2N mice.

Oocyte and follicle destruction produced by cyclophosphamide was investigated in Sprague-Dawley (SD) rats, and inbred C57BL/6N (B6) and DBA/2N (D2) mice. Primordial oocytes were the most sensitive to destruction after intraperitoneal treatment with cyclophosphamide. A delayed decrease in the number of medium-sized follicles occurred between 1 and 2 weeks after treatment. No reduction in the number of large follicles was observed over the 3-week period of this experiment. Primordial oocyte destruction produced by cyclophosphamide occurred in a time-, dose-, strain-, and species-dependent fashion. The threshold for primordial oocyte/follicle destruction in B6 and D2 mice, and SD rats was less than 10, 40, and greater than 500 mg/kg, respectively. ED50S for primordial oocyte/follicle destruction were 49 and 137 mg/kg in B6 and D2 mice, respectively. The ED50 for oocyte destruction was greater than 500 mg/kg in SD rats. Primordial oocyte destruction occurred rapidly and was completed between 48 and 72 hours after treatment with cyclophosphamide in both murine strains. Oocyte destruction and premature ovarian failure is a significant side effect in women treated with alkylating agents. The rodent ovotoxicity model used in these experiments may be useful in elucidating mechanisms of ovotoxicity and evaluating treatment protocols designed to protect the ovary.

Animals↗

PubMed1977

Cyclophosphamide-induced specific suppression of the protective immune response to rodent malaria.

Nonspecific and specific chemosuppression of the immune response to Plasmodium berghei protective antigens were investigated. Specific immunosuppression was defined operationally as the selective suppression of the protective response to the parasite in mice injected with a combination of gamma-irradiated infected mouse erythrocytes (gammaPb) and cyclophosphamide (CY) with continued responsiveness to sheep erythrocytes (SRBC). After initial treatment (gammaPb + CY), mice were injected with gammaPb in potentially immunogenic doses. These and appropriate control animals were later challenged with nonirradiated infected mouse erythrocytes. The influence of the initial treatment regimens on the protective response was evaluated by parasitemia, and mortality was observed after challenge. Specificity of suppression was measured by evaluating the ability of mice to produce antibody to SRBC. Both specific and nonspecific suppression of the protective response to malaria were noted. Initial treatment with drug alone resulted in increased parasitemia and mortality and suppression of the SRBC antibody synthesis in drug-pretreated immunized mice as compared with immunized mice not pretreated with the drug. On the other hand, suppression of the response to the parasite, but not to SRBC, in animals pretreated with gammaPb + CY was clearly greater than that induced by drug alone. Thus, animals treated with malarial antigen and cyclophosphamide develop a measurable specific immunosuppression. These studies indicate that immunity to malaria is influenced by both cyclophosphamide alone (general immunosuppression) and cyclophosphamide in combination with antigen (specific immunosuppression) in a manner analogous to other immune responses.

Animals↗

PubMed1980

Factor VIII antibodies in rheumatoid arthritis. Effect of cyclophosphamide.

Three patients with rheumatoid arthritis had bleeding and bruising and were found to have circulating antibodies specifically directed against factor VIII. Review of the literature indicates that this is an unusual but serious complication of rheumatoid arthritis. In two of our three cases, disappearance of the factor VIII antibody coincided with the oral administration of cyclophosphamide; in the third patient, antibody titers declined several weeks after cyclophosphamide therapy was discontinued. Our collected experience involving 11 nonhemophilic patients with factor VIII antibodies indicates that a good response to cyclophosphamide therapy may be expected if the antibody titer is less than 10 Bethesda units at the initiation of treatment. While optimum treatment of these patients is not yet established, we suggest an initial trial of prednisone and, if there is no response, then therapy with cyclophosphamide.

Aged↗

PubMed1982

Suppression of human B lymphocyte function by cyclophosphamide.

The immune responses of 16 patients with nonneoplastic immune mediated diseases including Wegener's granulomatosis, systemic necrotizing vasculitis, cutaneous vasculitis, and relapsing nodular panniculitis were evaluated before and during therapy with chronic low-dose (2 mg/kg/day) cyclophosphamide. A striking selective suppression of B cell function was noted as measured by PWM-induced immunoglobulin secretion. This suppression was a direct effect on the B cells themselves because T cell function, measured by blastogenic responses to the mitogens PHA, Con A, and PWM, was not significantly suppressed. Furthermore, the ability of T cells from cyclophosphamide-treated patients to provide helper function in T cell-dependent B cell assays remained intact. Treated patients manifested a total lymphocytopenia without a selective depletion of relative proportions of B cells or T cell subsets. However, the spontaneous secretion of immunoglobulin by peripheral blood B cells that is elevated in untreated patients was suppressed back to normal levels during cyclophosphamide therapy. This selective effect on spontaneous and induced secretion of immunoglobulin by human B cells may help explain the efficacy of cyclophosphamide therapy in certain antibody and immune complex-mediated diseases.

Adult↗

PubMedDate not supplied

Combination cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy for extensive non-small cell carcinomas of the lung.

Fifty consecutive patients with extensive non-small cell carcinoma of the lung were randomized to one of two chemotherapeutic regimens. Twenty-three patients (group 1) received cyclophosphamide (600 mg/mg(2)), doxorubicin (40 mg/m(2)), and cisplatin (50 mg/m(2)) every 3 weeks; 27 patients (group 2) received cyclophosphamide (600 mg/m(2)), doxorubicin (40 mg/m(2)), and cisplatin (100 mg/m(2)) every 3 weeks. The objective response rates were 4% and 7% in groups 1 and 2, respectively. Median survival duration was 15.2 weeks (group 1) and 21.7 weeks (group 2; P greater than or equal to 0.3). Hematologic toxicity was minimal in group 1 and moderate in group 2. Renal toxicity was moderate in group 2 only. Combination chemotherapy with cyclophosphamide, doxorubicin, and cisplatin as used in this study is not superior to previous studies in this institution using cyclophosphamide as a single agent.

Aged↗

PubMed1982

The course of nausea and vomiting after high-dose cyclophosphamide.

We studied the course of nausea and vomiting after high-dose cyclophosphamide (50-75 mg/kg) in 25 patients. Nausea was assessed with a visual analog scale and vomiting by patient report. The reliability and validity of these methods of assessment were established in separate studies of oncology patients. Nausea and vomiting developed between 6 and 12 hours after the start of a 1-hour cyclophosphamide infusion in about two thirds of the patients. Peak symptoms were at 12 hours. Vomiting had subsided in most of the patients by 24 hours, but nausea persisted. Although there was significant individual variation in the course of nausea and vomiting, we could identify no demographic, disease, drug, or treatment factors which were associated with more significant nausea and vomiting. Some of the variability in the onset, severity, and duration of nausea and vomiting may be related to individual differences in the metabolism of and susceptibility to cyclophosphamide. The visual analog scale may provide information about nausea not obtained by the more frequently employed categoric verbal rating scales. Suggestions for the treatment of nausea and vomiting after high-dose cyclophosphamide are made on the basis of the findings.

Adult↗

PubMedDate not supplied

Therapeutic response of human lung tumour xenografts to cyclophosphamide.

The effect of cyclophosphamide, given as a single i.p. injection (240 mg/kg) on 13 various fast growing human lung tumours, transplanted and passed serially in athymic nude mice, were studied. Cyclophosphamide showed activity against all tumours studied. The sensitivity of the different tumour lines tested varied considerably. The faster a tumor was growing, the more pronounced was the inhibitory effect of cyclophosphamide on growth, independent of the histological type. If different lung tumours were treated at the same size and site (8-10 mm, s.c. right anterior flank), growth rate was a factor of decisive importance for the sensitivity of a tumour to cyclophosphamide.

Animals↗

PubMed1978

In vitro sensitivity testing of cells of histologically typified ovarian carcinomas and carcinoma of corpus with 3H-cyclophosphamide-metabolites in the serum of man after massive dose therapy.

Cells of a carcinoma of the uterine corpus and of five ovarian carcinomas were cultured in vitro with monolayer and sandwich methods, respectively. After 24-hours-incubation with serum samples of patients treated with a massive dose of 3H-cyclophosphamide (60 mg/kg body weight i.v.)-the samples were taken at different times after application-these cultures with a chromatographically defined content of free metabolites were interpreted, guided by morphological criteria. Incubation of the cultures with serum samples taken 5 hours after application of the massive dose turned out to be a practical system for detection, before the start of therapy, of the sensitivity of malignant tumors to cyclophosphamide. Statements about the proliferation kinetics of the malignant cells, about the active ultimate form of the antitumor agent and its way of action, which are not guaranteed experimentally, are largely eliminated by this method. The justification for using 4-hydroxy- and 4-hydroperoxy-cyclophosphamide to test the sensitivity of malignant cells in vitro to cyclophosphamide was critically examined.

Carcinoma↗

PubMed1981

Effect of cyclophosphamide-induced elimination of lymphocytes from the spleen and lymph node on immune response in mice.

A single dose of 300 mg of cyclophosphamide was injected intraperitoneally (i.p.). During the highest cyclophosphamide-induced elimination of lymphocytes from the spleen and lymph node, sheep red blood cells (SRBC) were injected either intravenously (i.v.) in a dose of 4 X 10(8) or into the hind foot-pads in a dose of 2 X 10(8). At consecutive days after cyclophosphamide administration, the number of cells producing 19S and 7S antibodies in the spleen and lymph node as well as antibody titer in the serum were determined. As observed, cyclophosphamide-induced depletion of the lymphoid tissue did not change the kinetics of appearance of cells producing antibodies in the spleen and lymph node but only diminished their number as well as the titer of antibodies in the serum.

Animals↗

PubMed1980

[Studies of diarrhea in young calves. 3. Effect of cyclophosphamide on histomorphology and microbial flora of the gastrointestinal tract in the calf].

One single intravenous injection of 60 mg/kg of cyclophosphamide caused the development of moderate to medium catarrhal enteritis in calves, within two to four days from injection. --Distally aggravating damage to epithelial cells in the small intestine, accompanied by shortening of villi, as well as usually complete lymphocyte depletion of the lymph follicles of Peyer's patches were the most conspicuous pathohistological findings obtained from the intestinal tract. Regular epithelial damage, including ulcerations and necroses, were recordable also from the colonic mucous membrane. --No remarkable change in the gastro-intestinal flora was recordable from calves killed two days from cyclophosphamide application, but the quantitative composition of the gastro-intestinal germ flora was found to be remarkably altered in those animals which had been killed four days after administration of the cytostatic. --Elevated coli counts in the rumen as well as in the proximal and distal parts of the jejunum and ileum and reduced anaerobic overall germ counts and bacteroides values in the cecum and rectum were the most conspicuous bacteriological findings. --The direct damaging action of cyclophosphamide on the mucous membrane as well as altered immunological reactivity of the experimental animals should be considered the triggering factors which actually caused considerable displacement in the quantitative composition of the gastro-intestinal flora in those calves which had been killed four days after cyclophosphamide application.

Animals↗

PubMedDate not supplied

PLasma half-life and urinary excretion of cyclophosphamide in children.

The plasma half-life and urinary excretion of cyclophosphamide were determined in 13 children who had various malignancies and/or who were being prepared for bone marrow transplantation. Disappearance from the plasma following iv infusion over a 1-2 hour period was first-order. Urinary excretion was maximal during the first 8 hours after administration and was essentially complete in 24 hours. The plasma half-life in children not receiving known inducers of hepatic microsomal mixed-function oxygenase activity or cyclophosphamide in the 3-week period prior to each determination ranged from 145 to 390 minutes. These values are lower than those ordinarily found in adult patients. The fraction of the total dose excreted in the urine as the parent compound ranged from 4% to 27%. Repeated administration of cyclophosphamide at approximately 30-60 day intervals did not appear to alter its plasma half-life but did appear to increase its urinary excretion. Daily administration of cyclophosphamide (approximately 50 mg/kg/day x 2 or 4) significantly decreased its plasma half-life and urinary excretion suggesting that it may reversibly induce its own metabolism.

Adolescent↗

PubMed1981

Scanning electron microscopy of cyclophosphamide-induced hyperplasia of the rat urinary bladder.

Urinary bladder damage caused by cyclophosphamide in male F344 rats was studied by light microscopy, scanning electron microscopy, and autoradiography. Cyclophosphamide was injected intraperitoneally at doses of 50, 75, 100, 150, and 200 mg. per kg. of body weight, and rats were killed at several intervals following treatment. Extensive necrosis of the bladder was followed by regenerative hyperplasia of the epithelium. A dose response was evident in the number and size of lesions induced and the time of regeneration and repair. Scanning electron microscopy disclosed pleomorphic microvilli on the luminal surface of cells during the early phases of hyperplasia. The greatest number of cells with pleomorphic microvilli occurred 2, 5 and 7 to 8 days following injection of 75, 100, and 200 mg. per kg. of cyclophosphamide, respectively. The hyperplastic lesions also had cells with short, uniform microvilli and ropy or leafy microridges on their surfaces. Autoradiographs of the urinary bladders showed marked labeling of epithelial cells in the early phase of hyperplasia. Of the few rats surviving beyond 1 year after a single injection, none had bladder lesions at any of the dose levels. The changes in the epithelium observed by scanning electron microscopy following cyclophosphamide injection were compared to those observed during bladder carcinogenesis.

Animals↗

PubMed1995

[A case of nephrotic syndrome associated with severe interstitial pneumonitis due to cyclophosphamide whose life was saved by steroid pulse therapy].

A 53-year-old man was admitted for treatment of nephrotic syndrome due to membranous nephropathy. Since he did not improve with prednisolone alone, cyclophosphamide was administered concomitantly. However, this induced severe interstitial pneumonitis, which was not cured by discontinuation of the drug, but disappeared completely with six episodes of methylprednisolone pulse therapy. The incidence of cyclophosphamide-induced interstitial pneumonitis is low, but the mortality is high. Since cyclophosphamide is often used for the treatment of nephrotic syndrome, attention should be focused on the incidence of interstitial pneumonitis. Discontinuation of cyclophosphamide and intensive therapy are required when it occurs.

Anti-Inflammatory Agents↗

PubMed1995

Paclitaxel, cisplatin, and cyclophosphamide in human ovarian cancer: molecular rationale and early clinical results.

The three most active types of agents in the treatment of cancer of the ovary are platinum compounds (cisplatin or carboplatin), bifunctional alkylating agents (cyclophosphamide, melphalan, etc), and the recently developed natural product paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). In an effort to improve long-term disease-free survival in patients with advanced disease, we have developed a three-drug regimen consisting of cisplatin, paclitaxel, and cyclophosphamide. Granulocyte-colony stimulating factor is given as bone marrow support using a flexible dosing approach. The molecular basis for this approach is founded in the positive molecular interactions between cisplatin and bifunctional alkylating agents and between paclitaxel and DNA-damaging agents. Cisplatin and cyclophosphamide damage DNA by two very different mechanisms; the respective importance of DNA strand "kinking" versus DNA strand "cross-linking" may explain the positive cell kill interaction between these two drugs. Paclitaxel appears to markedly slow the repair of DNA lesions caused by DNA-damaging agents, which may include radiation-induced lesions, cisplatin adducts, and cyclophosphamide cross-links. Clinical data to date from several different groups strongly suggest that these molecular interactions translate into positive clinical benefit in human ovarian cancer. Preliminary data from our clinical trial show that these three agents are well tolerated in the doses administered and that this combination shows exceptional promise as a possible therapeutic advance in this disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1979

Splenic granulopoiesis in mice following administration of cyclophosphamide.

The adult mouse spleen retains granulocytic progenitor cells that are capable of proliferation and maturation. In mice given cyclophosphamide, spleen weight and cell content increased. In vitro granulocyte progenitor cells increased more than 300-fold in the spleen and remained elevated 14 days following cyclophosphamide. Proliferative and nonproliferative granulocytes were increased above controls until Days 21 and 28, respectively. In splenectomized mice, blood neutrophil recovery was delayed when compared to nonsplenectomized mice following cyclophosphamide. Although marrow cell number was similar in both groups, maximum marrow granulocyte progenitor cells were 2-fold greater in nonsplenectomized animals. These studies demonstrate that the murine spleen becomes a markedly granulopoietic organ and is a major contributor to recovery of granulocytes following cyclophosphamide. Splenic granulopoiesis should be taken into account in studies which measure toxicity of various agents in murine hematopoiesis.

Animals↗

PubMed1995

[Cyclophosphamide during pregnancy: a safe prescription].

Cyclophosphamide is an alkylating agent used to treat haematologic malignant diseases and multisystem diseases with progressive glomerulonephritis. It is rarely prescribed during pregnancy. We report a case of Henoch-Schönlein purpura discovered at the end of the first trimester of pregnancy. Despite steroid therapy, glomerulonephritis worsened and 100 mg/day cyclophosphamide per os was administered from 28th week till delivery. The infant, prematurely born, was normal and did not have any haematological disorder. Congenital malformations are often reported (5 out of 19 newborns exposed in utero to cyclophosphamide), but in all those cases, there was another potentially teratogenic agent: either radiotherapy or another antineoplastic drug. Therefore, if mother's life is in jeopardy, cyclophosphamide therapy should be given and not postponed.

Adult↗

PubMed1994

[Monthly intravenous cyclophosphamide in the treatment of lupus nephritis].

21 patients with severe active lupus nephritis (LN) were treated with intravenous cyclophosphamide monthly doses 0.75 g/m2. The effects were compared with the results obtained in 22 patients by the oral prednisone administration in the dose 1 mg/kg/day. Both groups were not significantly different as regards the initial intensity of the LN symptoms. Complete or partial remission occurred in 17 patients (80.9%) receiving intravenous cyclophosphamide. End-stage renal failure in 2 patients and moderate renal insufficiency in other 2 patients from that group. In the prednisone treated group complete or partial remission was observed in 13 subjects (59.1%). The significant deterioration of the renal function occurred in 9 patients, in 6 into the phase of a moderate renal insufficiency and in 3 patients to the end-stage kidney failure. Additionally, the significant increase of the total serum complement activity and of the plasma platelets count was observed in the cyclophosphamide group, whereas those indicators did not improve in the patients receiving prednisone. The of intravenous pulse cyclophosphamide exhibits an advantage in the treatment of severe proliferative LN.

Adolescent↗

PubMed1994

Successful treatment of hemorrhagic cystitis secondary to cyclophosphamide chemotherapy with intravesical instillation of prostaglandin F2 alpha.

The treatment of cyclophosphamide-induced hemorrhagic cystitis is difficult. We report a successful case of severe cyclophosphamide-induced hemorrhagic cystitis treated with intravesical instillation of prostaglandin F2 alpha. A 32-year-old woman underwent high-dose cyclophosphamide conditioning before the autologous bone marrow transplantation. She developed clot retention which required continuous irrigation with normal saline. The patient had failed to respond to continuous bladder irrigation with saline and intravesical administration of 1% alum. Fifty ml of prostaglandin F2 alpha solution (1 mg in 100 ml normal saline) was instilled into the bladder, with a dwelling time of 60 minutes, three times a day for 5 days. The hematuria cleared completely 3 days after therapy. The only adverse effect was bladder spasm which was controlled with oxybutynin chloride. The success of this therapy suggests that prostaglandin F2 alpha is a safe and useful therapy for hemorrhagic cystitis secondary to cyclophosphamide chemotherapy.

Administration, Intravesical↗