Preliminary toxicity studies with the DNA-binding antibiotic, CC-1065.

Abstract

The potent new DNA-binding antibiotic, CC-1065 [produced by microbial fermentation of Streptomyces zelensis] prolonged life-span but was not curative, when administered to mice bearing a variety of transplantable tumors. Results of preliminary studies indicate that CC-1065 caused lethal delayed hepatotoxicity at therapeutic antineoplastic doses. In non-tumor-bearing mice, toxic deaths were delayed .apprx. 50 days after a single i.v. dose of 12.5 .mu.g/kg and as much as 70 days after 10 .mu.g/kg was given i.p. I.v. mouse LD50 were 9 .mu.g/kg (single dose) and 0.3 .mu.g/kg per day (5 daily doses). Mice treated with high doses i.v. died within 12 days with frank hepatic necrosis; delayed deaths at lower doses were associated with changes in hepatic mitochondrial morphology. Separate mechanisms of hepatotoxicity were apparently operative at high and low dose ranges. Attempts to prevent the delayed toxicity of CC-1065 in the mouse of treatment wiht WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid], N-acetylcysteine, phenobarbital, Aroclor 1254 and 3-methylcholanthrene were unsuccessful; no effect on the LD50 or the times of death was observed. LD in the rabbit were similar on a body surface area basis to those in the mouse; hepatotoxicity was also observed in the rabbit.