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Relative Mutagenicity of Some Urinary Metabolites of the Antitumor Drug Cyclophosphamide¹

Departments of Chemistry [J. K., R. F., T. J., A. B.] and Genetics and Carcinogenesis [E. B., C. I. R., D. S.], AMC Cancer Research Center and Hospital, Lakewood, Colorado 80214

Four urinary metabolites of the cytostatic drug cyclophosphamide were tested for mutagenicity in the Ames Salmonella assay: nornitrogen mustard (NM), 4-ketocyclophosphamide, 3-(2-chloroethyl)oxazolidone (OZ), and N,N'-bis(2-chloroethyl)piperazine. All four acted as direct base substitution mutagens although 4-ketocyclophosphamide showed an increase in mutagenicity after metabolic activation with S-9 rat liver fraction. Of the four compounds tested, NM was the strongest mutagen while all the others had weak mutagenic activity, with OZ being the weakest. We observed that, under conditions which facilitate the conversion of NM to OZ (presence of HCO₃^- at neutral pH), the former lost both mutagenic and alkylating activities. Our findings, taken together with other reports in the literature, indicate that NM could be a major cause of secondary bladder carcinoma since it is a potent mutagen and seems to be present in high levels in the urine of cyclophosphamide-treated patients. The fact that it can be detoxified to the weak mutagen OZ in the presence of HCO₃^- suggests the possibility that, by increasing the concentration of HCO₃^- in the urine of patients, that undesirable side effect of cyclophosphamide treatment can be alleviated.

¹ This research was supported by institutional funds of AMC Cancer Research Center and Hospital.

² To whom requests for reprints should be addressed.

³ Present address: Division of Molecular and Cellular Biology, National Jewish Hospital and Research Center, Denver, Colo. 80206.

⁴ Present address: Center for Environmental Sciences, University of Colorado at Denver, Denver, Colo. 80202.

Received 12/ 1/80. Accepted 4/15/81.