Single-dose and multiple-dose intravenous toxicity studies of BMY-25282 in rats

Single-dose and multiple-dose (daily X 5 and weekly X 5) intravenous toxicity studies in rats were conducted to determine the possible acute and delayed toxicity of BMY-25282 (7-N-(dimethylaminomethylene) mitomycin C), a potential anticancer drug. Rats in the single-dose study received either 0.05, 0.25, or 0.50 mg/kg (0.3, 1.5, or 3.0 mg/m2) of BMY-25282; rats in the daily X 5 multiple-dose study received doses of 0.005, 0.025, or 0.050 mg/kg (0.03, 0.15, and 0.3 mg/m2) of BMY-25282 once each day for 5 days; and rats in the weekly X 5 multiple-dose study received 0.05 mg/kg of BMY-25282. All doses were in 0.1% Pluronic F-68 diluent. Acute toxicities included gastrointestinal epithelial necrosis, myelosuppression, and splenic lymphoid depletion in the high and intermediate dose groups in the single-dose study and myelosuppression in the high dose group of the daily X 5 multiple-dose study. One death in a high dose male of the single-dose study was attributed to acute gastrointestinal and lymphoid toxicity. Between the interim necropsy on Day 5 or 9 and termination of the 9-week dose-free observation period, 9/20 rats of the high and intermediate dose groups of the single-dose study and 4/10 high dose rats in the daily X 5 multiple-dose study died, primarily due to hydrothorax and congestive heart failure caused by delayed, drug-related myocardial degeneration. The most prominent drug-related histopathologic changes observed in rats of both the single-dose study and the daily X 5 studies were myocardial degeneration (cardiomyopathy), glomerulopathy with tubular degeneration, and necrotizing arteritis. These three changes, observed at 0.5 and 0.25 mg/kg in the single-dose study and at 0.05 mg/kg/day in the multiple-dose (daily X 5) study, were delayed in onset and irreversible. Drug-related tubular degeneration and slight glomerulopathy were observed in male BMY-25282-treated rats in the weekly X 5 study, but cardiotoxicity, pulmonary arteritis, hydrothorax, and lethality were not observed. The diluent, Pluronic F-68, was not associated with any morphologic or clinico-pathologic changes. A single-dose of 0.05 mg/kg or 5 daily doses of 0.025 and 0.005 mg/kg of BMY-25282 were considered nontoxic doses in rats. A cumulative dose of 0.25 mg/kg, which caused cardiotoxicity in the daily X 5 study, was not cardiotoxic in the weekly X 5 study. These results indicate that the delayed cardiotoxicity of BMY-25282 is schedule dependent.