Cardiac, renal, and pulmonary toxicity of several mitomycin derivatives in rats

The potential cardiotoxicity, nephrotoxicity, and pulmonary toxicity of several mitomycin (MMC) derivatives, BMY-25067 ( N-7-[2-(4-nitrophenyl-dithio)ethyl]MMC), BMY-26107 ( N-7-[2-(4-aminophenyldithio)ethyl]MMC), BMY-26605 ( N-7acetyl-MMC), BMY-25690(7- N-(dimethylaminomethylene)-10-[1-morpholinomethyleneamino)carbonyl-oxy]MMC), BMY-26646 ( N-7-[2-(4-fluorophenyldithio)ethyl]MCC), and BMY-25551 (7-(2-hydroxyethyl)mitosane), were evaluated in rats. Groups of 10 male Sprague-Dawley rats were given single intravenous doses of the test compounds and were then observed for 10 weeks. Doses represented 67 and 33% of the respective mouse LD10 (corrected for body size on a mg/m 2 basis) of each test compound. BMY-25282 (7- N-(dimethylaminomethylene)MMC), a mitomycin derivative that produces cardiac, renal, and arterial lesions, was used as a reference drug. Hematologic and blood chemical parameters were monitored at 3 days and at 3,6, and 10 weeks after drug administration. Heart, kidney, and lung were examined histopathologically. Drug-related cardiac changes with late onset were seen histopathologically in rats treated with BMY-26605, BMY-25282, BMY-25551, and BMY-25690 (in order of decreasing severity). Drug-related renal changes, consisting of tubular degeneration and glomerulopathy, were seen in rats treated with BMY-25690, BMY-26107, BMY-25282, BMY-25551, BMY-26605, and BMY025067 (in order of decreasing severity). Pulmonary arterial lesions were noted inconsistently in rats treated with BMY-26605, BMY-25282, and BMY-25551. Neither cardiac, renal, nor pulmonary changes were seen in rats administered BMY-26646, and only minor drugrelated renal changes were seen in rats treated with BMY-25067.