Daunorubicin-induced mammary tumors in the rat

Eleven of 24 female Sprague-Dawley rats given a single i.v. injection of daunorubicin (10 mg/kg) developed mammary tumors within 8 months after the injection. Four of 12 rats given an intramammary injection of daunorubicin (4 or 8 micrograms) developed five mammary tumors in the injected area within 6.5 months of injection. Tissue distribution studies using tritiated daunorubicin revealed that the liver, kidney, lung, heart, and intestine had higher daunorubicin concentrations than mammary tissue during the first 24 h after i.v. injection. However, depletion of the drug from the internal organs was more rapid than from mammary tissue. Differences in ability to metabolize daunorubicin were compared in homogenates of isolated mammary epithelial cells and hepatocytes by high-performance liquid chromatography: after 90 min, hepatocytes metabolized about 70% of daunorubicin, whereas mammary epithelial cells did not metabolize the drug. Tritiated daunorubicin injected directly into rat mammary gland showed no metabolism in 24 h, and the drug did not get into the circulation. These results suggest that retention of daunorubicin because of the inability of mammary tissue to metabolize the drug is a cause of drug-induced mammary tumors in female Sprague-Dawley rats.