Toxicity of cyclophosphamide

Stekar, J., Hilgard, P. and Klenner, T. (1995) Opposite effect of miltefosine on the antineoplastic activity and hematological toxicity of cyclophosphamide. EurJ. Cancer, 31A(3), 372-374. 

Cyclophosphamide (Cytoxan and Endoxan) is used in the treatment of Hodgkin s disease, lymphosarcoma, and other lymphomas. It is employed as a secondary drug in patients with acute leukemia and in combination with doxorubicin in women with breast cancer. A drug combination effective in the treatment of breast cancer is cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP). Cyclophosphamide is also an immunosuppressive agent. The toxicity of cyclophosphamide causes alopecia, bone marrow depression, nausea and vomiting, and hemorrhagic cystitis. 

Plowchalk DR Mattison DR (1991) Phosphoramide mustard is responsible for the ovarian toxicity of cyclophosphamide. Toxicol Appl Pharmacol, 107 472-481. 

Au W, Sokova Ol, Kopnin B, et al. 1980. Cytogenetic toxicity of cyclophosphamide and its metabolites in vitro. Cytogenet Cell Genet 26 108-116. 

Gurtoo HL, Berrigan MJ, Love J, et al. 1985. Metabolism-dependent toxicities of cyclophosphamide and protection by N-acetylcysteine and other thiols. Cancer Treat Res 24 61-79. 

Pool BL, Bos RP, Niemeyer U, et al. 1988. In vitro/in vivo effects of MESNA on the genotoxicity and toxicity of cyclophosphamide-- A study aimed at clarifying the mechanism of MESNA s anticarcinogenic activity. Toxicol Lett 41 49-56. 

The risk of bone marrow depression by cytostatic drugs is potentiated by allopurinol, which also appears to potentiate the therapeutic effect of purine cytostatic drugs, since it competitively inhibits their metabolic breakdown. Studies in animals suggest that this reaction occurs only with oral mercaptopurine (28), although there is older evidence that the toxicity of cyclophosphamide and other cytostatic drugs can be increased by allopurinol (SED-9, 156). The danger of combining allopurinol with azathioprine has been confirmed by cases of bone marrow suppression, particularly in patients with impaired renal function (SEDA-16,114). 

Ranitidine, and probably famotidine, appear not to increase the bone marrow toxicity of cyclophosphamide. Animal studies suggest that cimetidine might. 

A clinical study that was started to find out if pentostatin would improve the immunosuppressive effects of cyclophosphamide, carmustine and etoposide in bone marrow transplant patients was stopped when acute and fatal cardiovascular collapse developed in the first 2 patients. Both patients had been given cyclophosphamide 800mg/m and etoposide 200 mg/m, both every 12 hours for 8 doses, and carmustine 112 mg/m daily for 4 doses. On day 3 pentostatin 4 mg/m, given over 4 hours, was added. Within 8 to 18 hours after completion of chemotherapy both patients developed confusion, hypothermia, hypotension, respiratory distress, pulmonary oedema, and eventually fatal ventricular fibrillation within 45 to 120 minutes of the first symptoms. A later study in rats similarly found that pentostatin markedly increased the acute toxicity of cyclophosphamide. The reasons for this cardiotoxicity are not understood. Neither of the 2 patients had previously shown any evidence of cardiac abnormalities. ... 

Ramu K, Fraiser LH, Mamiya B, Ahmed T, Kehrerh JP. Acrolein mercapturates Synthesis, characterization, and assessment of their role in the bladder toxicity of cyclophosphamide. Chem Res Toxicol 1995 8(4) 515—524. 

Alkylating Agents. Figure 2 Biotransformation of cyclophosphamide - formation of inactive ( ) and toxic ( metabolites. 

Novel nitroxide malonate methanofullerenes (Fig. 1.3), thanks to the presence of nitroxide radicals and fullerene moiety, are able to protect cells from toxic side effects of cyclophosphamide (Gubskaya et al., 2007). Experiments were carried out on mice, in which leukemia P-388 was transplanted. Cyclophosphamide or fullerene individually injected did not increase the average life span of the animals, while the combination of the anticancer drug and nitroxide fullerene derivative resulted in the survival of 70% animals, classifying these compounds as promising modifiers of biological reaction for tumor therapy. 

Mechlorethamine was the first nitrogen mustard. It is directly toxic. With its half-life of only a few minutes infusion directly into arteries supplying the tumor is the preferred mode of administration. Its spectrum of adverse effects is similar to that of cyclophosphamide. 

With chlorambucil and melphalan, although administered orally complaints of nausea and vomiting are minimal. The other toxic effects are comparable to those of cyclophosphamide. Chlorambucil has marked immunosuppressant activity. 

Senthilkumar, S., Yogeeta, S. K., Subashini, R., and Devaki, T. (2006). Attenuation of cyclophosphamide induced toxicity by squalene in experimental rats. Chem. Biol. Interact. 160, 252-260. 

In animal studies, NAC has been shown to prevent hemorrhagic cystitis that results from administration of cyclophosphamide or its position isomer ifosfamide. Hemorrhagic cystitis results from the toxic effect of acrolein, a metabolic product of cyclophosphamide or its position isomer ifosfamide. The mechanism whereby NAC prevents this toxicity may be prevention of the intracellular depletion of antioxidants, such as GSH, by acrolein. Concomitant administration of NAC with cyclophosphamide or ifosfamide does not impair antineoplastic activity, because both anticancer drugs are inactive until they are metabolized by the liver to their phosphoramide mustard metabolites. 

Fat-soluble vitamins, in addition to their antioxidative effects on lipids, appear to exert a general protective effect in animals. Vitamin A and beta-carotenes protect lab animals from toxicity of citral, cyclophosphamide and some hydrocarbons (Seifter et al, (A2.) In related but independent studies, it was observed that high levels of vitamin A inhibit tumorogenesis and that low levels of vitamin A appear to enhance tumorogenesis (Baird, (1 ). vitamin E inhibited chemically-induced carcinogenesis in test systems (Shamberger, ) and also reduced the susceptibility of rats to cigarette smoke (Chow,... 

Gurtoo HL, Hipkens HJ, Sharma SD. 1981. Role of glutathione in the metabolism-dependent toxicity and chemotherapy of cyclophosphamide. Cancer Res 41 (9 Part 1 ) 3584-3591. 

Gurtoo HL, Marinello AJ, Berrigan MJ, et al. 1983. Effect of thiols on toxicity and carcinostatic activity of cyclophosphamide. Semin Oncol 10(1 Suppl. 1) 35-45. 

Ohno Y, Ormstad K. 1985. Formation, toxicity and inactivation of acrolein during biotransformation of cyclophosphamide as studies in freshly isolated cells from rat liver and kidney. Arch Toxicol 57 99-103. 

Patel JM, Block ER, Hood Cl. 1984. Biochemical indexes of cyclophosphamide- induced lung toxicity. Toxicol Appl Pharmacol 767 128-138. 

CYCLOPHOSPHAMIDE H2 RECEPTOR BLOCKERS-CIMETIDINE t adverse effects of alkylating agent, e.g. myelosuppression 1. Additive toxicity 2. Possible minor inhibition of cyclophosphamide metabolism via CYP2C9 Avoid co-administration of cimetidine with cyclophosphamide... 

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