Preclinical toxicologic evaluation of bleomycin (NSC 125 066), a new antitumor antibiotic

Abstract

Bleomycin, a potent antitumor antibiotic obtained from Streptomyces verticillus, was administered to 14 dogs at doses from 0.312 to 5.0 mg/kg iv every 4 days for 6 to 28 wk. The resultant toxicity was atypical for most antitumor agents. Nondose-related interstitial pneumonia and pulmonary fibrosis restricted to pleural and subpleural areas were the treatment limiting toxicity and occurred in 93% of the dogs. Epithelial toxicity manifested as dermatitis, ulceration at friction sites, onychoptosis and alopecia also occurred in 70% of the animals. Hematologic changes and hepatotoxicity were minor and reversible, while dose-rlated anorexia and up to 60% weight loss were observed. Serum globulin changes in 2 dogs treated with 5.0 mg/kg included an increased α 2 level, a decreased α 1 level, and appearance of a second α 1 electrophoretic band. Severe nephrosis and/or nephritis also occurred in dogs treated with 2.5 or 5.0 mg/kg and contributed to the moribund condition of both dogs treated with the largest dose. Comparison of major toxic changes and clinical conditions. of the animals indicated that the primary toxicity was not identified. Preliminary results indicated that bleomycin may have affected cellular sulfhydryl or disulfide groups or availability of essential metals in those organs that concentrated the compound.