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

It was previously shown that the potent new DNA-binding antibiotic, CC-1065, prolonged life span, but was not curative, when administered to mice bearing a variety of transplantable tumors. In this paper we show results of preliminary studies indicating that CC-1065 caused lethal delayed hepatotoxicity at therapeutic antineoplastic doses. In non-tumor-bearing mice toxic deaths were delayed ca 50 days after a single iv dose of 12.5 micrograms/kg and as much as 70 days after 10 micrograms/kg was given ip. Intravenous mouse LD50's were 9 micrograms/kg, single dose, and 0.3 microgram/kg/day, five daily doses. Intraperitoneal LD50's were 0.53 approximately 6.90 micrograms/kg, single dose, and 0.14 microgram/kg/day, five daily doses. Mice treated with high doses iv died within 12 days with frank hepatic necrosis, whereas delayed deaths at lower doses were associated with changes in hepatic mitochondrial morphology. This suggested that separate mechanisms of hepatotoxicity were operative at high and low dose ranges. Attempts to prevent the delayed toxicity of CC-1065 in the mouse by treatment with WR-2721, N-acetylcysteine, phenobarbital, Aroclor 1254, and 3-methylcholanthrene were unsuccessful; no effect on the LD50 or the times of death was observed. Lethal doses in the rabbit were similar on a body surface area basis to those in the mouse; evidence of hepatotoxicity was also observed in the rabbit.