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Effect of Disulfiram (Tetraethylthiuram Disulfide) and Diethyldithiocarbamate on the Bladder Toxicity and Antitumor Activity of Cyclophosphamide in Mice¹

Departments of Pharmacology [M. P. H., R. A. N.], Medicine [W. B. E., R. A. N.], and Surgery [R. L. G.], Vermont Regional Cancer Center, College of Medicine, University of Vermont, Burlington, Vermont 05405

Cyclophosphamide is the most commonly prescribed alkylating agent in clinical medicine. The usefulness of cyclophosphamide is often limited, however, by its propensity to cause hemorrhagic cystitis especially in children or patients receiving concomitant radiotherapy. Administration i.p. of cyclophosphamide at doses of 100 mg/kg or more to mice produced a significant increase in urinary bladder weight within 48 hr of treatment. The present studies demonstrate that disulfiram prevented cyclophosphamide-induced bladder damage when administered p.o. within 1 hr of cyclophosphamide treatment. Diethyldithiocarbamate, a sulfhydryl-containing metabolite of disulfiram, had identical uroprotective activity. Unlike disulfiram, diethyldithiocarbamate was effective only when administered 2 to 4 hr after cyclophosphamide. Disulfiram augmented slightly the antitumor activity of cyclophosphamide against L1210 murine leukemia in vivo when administered 30 min prior to cyclophosphamide. In contrast, diethyldithiocarbamate had no effect on the antitumor activity of cyclophosphamide when administered 4 hr after cyclophosphamide.

¹ Supported in part by Grant PO 1 CA 24543 from the National Cancer Institute, NIH.

² To whom requests for reprints should be addressed, at Vermont Regional Cancer Center, University of Vermont, 1 South Prospect Street, Burlington, Vt. 05401.

Received 4/23/82. Accepted 8/ 3/82.