© 1996 Oxford University Press
research-article |
Carcinogenicity of the Anticancer Topoisomerase Inhibitor, Amsacrine, in Wistar Rats1
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company Ann Arbor, Michigan 48105
Received November 20, 1995; accepted March 27, 1996
Amsacrine is an antineoplastic drug used in the treatment of acute adult leukemias. To assess its carcinogenic potential, groups of 50 male and 50 female rats were administered amsacrine by lateral tail vein injection at 0 (vehicle control), 0.25, 1, or 3 mg/ kg once daily for 5 days, followed by a 23–day recovery period. This cycle of dosing and recovery was repeated a total of six times. The animals were then maintained without dosing for an 18–month observation period. During the dosing phase, signs of toxicity were limited to the 3 mg/kg animals and included alopecia, diarrhea, injection site lesions, and skin and subcutaneous nodules. Statistically significant reductions in body weight gain and food consumption also occurred at 3 mg/kg during each 5–day dosing period followed by recovery during the latter 3 weeks of each cycle. Except for skin and subcutaneous nodules, signs of toxicity in the 3 mg/kg animals ultimately disappeared during the 18–month observation phase. Survival at study termination for the vehicle control, 0.25, 1, and 3 mg/kg groups was 56, 52, 34, and 0%, respectively, in males, and 64, 48, 54, and 4%, respectively, in females. Mortality was primarily due to bone marrow suppression during the dosing phase, chronic progressive nephropathy, or development of tumors. Incidences of the following tumors were significantly increased in the 3 mg/kg groups of both sexes (Fisher exact test, two–tailed,p < 0.01): all malignancies; all tumors of the small intestine, adenocarcinoma and adenoma of the small intestine, all tumors of the skin, and squamous cell papilloma. Other tumor incidences that were significantly increased in the 3 mg/kg males were thymoma and multiple neoplastic histotypes of the skin and adnexa including basal cell tumor, fibroma, sebaceous gland adenoma, and squamous cell carcinoma. A disproportionate number