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© 1989 Oxford University Press

research-article

Cardiac, Renal, and Pulmonary Toxicity of Several Mitomycin Derivatives in Rats

C. L. BREGMAN, R. A. BUROKER, W. T. BRADNER, R. S. HIRTH and H. MADISSOO

Department of Pathology and Toxicology and Department of Preclinical Anticancer Research, Pharmaceutical Research and Development Division, Bristol-Myers Company Syracuse, New York 13221-4755

Received April 1, 1988; accepted September 13, 1988

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-[l-morpholinomethyl-eneamino)carbonyl-oxy]MMC), BMY-26646 (N-7-[2-(4-nuorophenyldithio)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/m2 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 histopatho-logically. 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 BMY-25067 (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 drug-related renal changes were seen in rats treated with BMY-25067.


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