CARCINOGENICITY OF THE ANTICANCER TOPOISOMERASE INHIBITOR, AMSACRINE,IN WISTAR RATS

Amsacrine is an antineoplastic drug used in the treatment of acute adu lt leukemias. To assess its carcinogenic potential, groups of 50 male and 50 female rats were administered amsacrine by lateral tail vein in jection at 0 (vehicle control), 0.25, 1, or 3 mg/kg once daily for 5 d ays, followed by a 23-day recovery period. This cycle of dosing and re covery was repeated a total of six times. The animals were then mainta ined without dosing for an 18-month observation period. During the dos ing phase, signs of toxicity were limited to the 3 mg/kg animals and i ncluded alopecia, diarrhea, injection site lesions, and skin and subcu taneous nodules. Statistically significant reductions in body weight g ain and food consumption also occurred at 3 mg/kg during each 5-day do sing period followed by recovery during the latter 3 weeks of each cyc le. Except for skin and subcutaneous nodules, signs of toxicity in the 3 mg/kg animals ultimately disappeared during the 18-month observatio n 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 primar ily due to bone marrow suppression during the dosing phase, chronic pr ogressive nephropathy, or development of tumors. Incidences of the fol lowing tumors were significantly increased in the 3 mg/kg groups of bo th sexes (Fisher exact test, two-tailed, p < 0.01): all malignancies; all tumors of the small intestine, adenocarcinoma and adenoma of the s mall intestine, all tumors of the skin, and squamous cell papilloma. O ther 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 of the skin tum ors were located on the tail, suggesting a localized tissue concentrat ion effect. In the 3 mg/kg females, significantly increased tumor inci dences also included all tumors of the mammary gland, adenocarcinoma o f the mammary gland, all tumors of the uterine horn, and endometrial s tromal polyps of the uterine horn. The 1 mg/kg males had significantly increased incidences of all tumors of the small intestine and skin, a denocarcinoma of the small intestine, and fibroma of the skin. Fibroma of the skin was also significantly increased in the 0.25 mg/kg males. Incidences of all tumors and all benign tumors were significantly inc reased in the 1 mg/kg females. There were no significantly increased t umor incidences in the 0.25 mg/kg females. The results of this study s how that amsacrine is carcinogenic in Wistar rats. Target organs for t umorigenicity include small intestine, skin, mammary gland, thymus, an d uterus. (C) 1996 Society of Toxicology