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-nitrophenyldithio)ethyl]MMC), BMY-26107 (N-7-[2-(4-aminophenyldithio)ethyl]MMC), BMY-26605 (N-7 acetyl-MMC), BMY-25690 (7-N-(dimethylaminomethylene)-10-[1-morpholinomethyleneamino)carbo nyl- 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/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 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 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.
Bregman
C L
CL
Department of Pathology and Toxicology, Bristol-Myers Company, Syracuse, New York 13221-4755.
Buroker
R A
RA
Bradner
W T
WT
Hirth
R S
RS
Madissoo
H
H
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008937:Mitomycins / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012519:Sarcoplasmic Reticulum / Q000648:ultrastructure
D008937:Mitomycins