Carcinogenicity of Bleomycin Sulfate and Peplomycin Sulfate after Repeated Subcutaneous Application to Rats

Abstract

Bleomycins (BLM) are widely used as antineoplastic agents either alone or in combination regimens. Results of earlier studies in experimental animals were said to be inadequate to evaluate the carcinogenicity of BLM, which is a known mutagen. In a dose-response study, BLM and peplomycin (PEP) were investigated in Sprague-Dawley rats of both sexes. For the first 10 wk weekly doses of 0.35, 0.70, 1.40 and 2.80 mg/kg BLM and of 0.32, 0.63, 1.25, 2.50 and 5.0 mg/kg PEP were applied s.c. (BLM: 30 male and 30 female rats/group; PEP: 25 male and 25 female rats/group). In the case of BLM, thereafter the doses were given once every fortnight either for 1 yr (BLM: 1.40 and 2.80) or for life (lower doses). In the case of PEP, application of the high doses was stopped after the 13th time (5.0: 10 .times. 1/wk and 3 .times. 1 every 2 wk) and the 19th application (2.5 mg: 10 .times. 1/wk and 9 .times. 1/every 2 wk). After the 10th dosing, the remaining groups were treated once every fortnight for life. Male (60) and 60 female rats served as solvent-treated (physiological saline) controls. The animals were observed for life. Repeated doses of BLM and PEP reduced body weight and life expectancy of the animals in a dose-related pattern. Tubular cell damages and cell proliferations were seen as a symptom of major toxicity in the kidneys. In this model BLM and PEP are carcinogenic; treatments resulted in significant dose-related incidences of animals with tumors at the site of application (fibrosarcomas) and with renal tumors (adenomas, adenocarcinomas, sarcomas).