INDUCTION OF SMALL-INTESTINAL ADENOCARCINOMAS IN WISTAR RATS ADMINISTERED AMSACRINE

Amsacrine is an aminoacridine that binds to DNA by intercalation. Beca use amsacrine interferes with DNA synthesis it has potent genotoxic an d cytotoxic properties. To define its tumorigenic nature, amsacrine wa s studied in a 104-week carcinogenicity bioassay using Wistar rats. Tr eatment regimen consisted of 6 cycles of intravenous administration ov er 5 consecutive days followed by 23 days without drug to allow for re covery from cytotoxicity. Doses were 0.25, 1 and 3 mg/kg. At 3 mg/kg m ortality was excessive reaching 100 % of males by Week 90 and 96 % of females at Week 104. Deaths were associated with either tumor inductio n or cytotoxicity. Multisystemic tumor development manifested in a dos e-related fashion. The incidence of small intestinal adenocarcinomas w as particularly striking owing to the rarity of these neoplasia in Wis tar rats. Small intestinal adenocarcinomas that were well-differentiat ed presented as pedunculated masses or were sessile masses derived fro m flat mucosa. Mucin-secreting adenocarcinomas showed poorly-different iated histologic pattern with absence of crypt or villus structures. W e postulate that they are variants of the neoplasia derived from flat mucosa wherein the loss of histologic architecture is the sequela of p rotracted secretion and accumulation of mucin leading ultimately to ex tensive tumor remodeling. As amsacrine is primarily excreted in bile, direct exposure to this genotoxic agent was a probable factor in tumor igenesis like small intestinal carcinogens such as 1,2-dimethylhydrazi ne and azoxymethane.