Carcinogenicity of the anticancer topoisomerase inhibitor, amsacrine, in Wistar rats.
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 of the skin tumors were located on the tail, suggesting a localized tissue concentration effect. In the 3 mg/kg females, significantly increased tumor incidences also included all tumors of the mammary gland, adenocarcinoma of the mammary gland, all tumors of the uterine horn, and endometrial stromal polyps of the uterine horn. The 1 mg/kg males had significantly increased incidences of all tumors of the small intestine and skin, adenocarcinoma 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 increased in the 1 mg/kg females. There were no significantly increased tumor incidences in the 0.25 mg/kg females. The results of this study show that amsacrine is carcinogenic in Wistar rats. Target organs for tumorigenicity include small intestine, skin, mammary gland, thymus, and uterus.
Graziano
M J
MJ
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Courtney
C L
CL
Meierhenry
E F
EF
Kheoh
T
T
Pegg
D G
DG
Gough
A W
AW
D000677:Amsacrine / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D005260:Female; D007414:Intestinal Neoplasms / Q000139:chemically induced; D007421:Intestine, Small / Q000473:pathology; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D012878:Skin Neoplasms / Q000139:chemically induced
D000970:Antineoplastic Agents; D002273:Carcinogens; D000677:Amsacrine