A 2-YEAR DIETARY CARCINOGENICITY STUDY OF THE ANTIESTROGEN TOREMIFENEIN SPRAGUE-DAWLEY RATS

The carcinogenic potential of the nonsteroidal triphenylethylene antie strogen toremifene (Fareston (R)) was evaluated in a standard 104-week rat dietary carcinogenicity study. The doses were 0, 0.12, 1.2, 5.0 a nd 12 mg/kg/day and the number of animals 50/sex/dose group. The body weight gain and food consumption were monitored once weekly (study wee ks 1-16) or once every four weeks thereafter (study weeks 17-104). Blo od samples were taken at weeks 34, 52 and 104 and the plasma concentra tions of toremifene, as well as the two main metabolites (deaminohydro xy)toremifene and N-demethyltoremifene, were measured. All doses of to remifene reduced food intake and body weight gain. Toremifene caused a significant reduction in mortality, which was mainly due to reduced i ncidences of pituitary tumors. This was evident in all dose groups. Dr ug-related decrease of mammary tumors in females (at all doses) and te sticular tumors in male rats (doses greater than or equal to 1.2 mg/kg /day) were also evident. The incidence of the preneoplastic foci of ba sophilic hepatocytes were significantly decreased in treated female gr oups. Toremifene induced no preneoplastic or neoplastic lesions. Based on histopathology, no obvious toxicity could be observed. Drug-relate d changes were observed in the genital organs, thyroid, spleen, mammar y gland, adrenal, kidney, stomach and lung. These changes were due to hormonal disturbances or as a result of reduced food consumption or re duced incidences of pituitary, mammary or testicular tumors. This stud y indicates that toremifene is an efficient antiestrogen in long-term treatment, is well tolerated and has no tumorigenic potential in rats.