Induction of small intestinal adenocarcinomas in Wistar rats administered amsacrine.
Amsacrine is an aminoacridine that binds to DNA by intercalation. Because amsacrine interferes with DNA synthesis it has potent genotoxic and cytotoxic properties. To define its tumorigenic nature, amsacrine was studied in a 104-week carcinogenicity bioassay using Wistar rats. Treatment regimen consisted of 6 cycles of intravenous administration over 5 consecutive days followed by 23 days without drug to allow for recovery from cytotoxicity. Doses were 0.25, 1 and 3 mg/kg. At 3 mg/kg mortality was excessive reaching 100% of males by Week 90 and 96% of females at Week 104. Deaths were associated with either tumor induction or cytotoxicity. Multisystemic tumor development manifested in a dose-related fashion. The incidence of small intestinal adenocarcinomas was particularly striking owing to the rarity of these neoplasia in Wistar rats. Small intestinal adenocarcinomas that were well-differentiated presented as pedunculated masses or were sessile masses derived from flat mucosa. Mucin-secreting adenocarcinomas showed poorly-differentiated histologic pattern with absence of crypt or villus structures. We postulate that they are variants of the neoplasia derived from flat mucosa wherein the loss of histologic architecture is the sequela of protracted secretion and accumulation of mucin leading ultimately to extensive tumor remodeling. As amsacrine is primarily excreted in bile, direct exposure to this genotoxic agent was a probable factor in tumorigenesis like small intestinal carcinogens such as 1,2-dimethylhydrazine and azoxymethane.
Gough
A
A
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Ann Arbor, MI 48105.
Courtney
C
C
Graziano
M
M
D000230:Adenocarcinoma / Q000139:chemically induced* / Q000473:pathology; D000677:Amsacrine / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007414:Intestinal Neoplasms / Q000139:chemically induced* / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000677:Amsacrine