UNLIKE TAMOXIFEN, DROLOXIFENE PRODUCES NO HEPATIC-TUMORS IN THE RAT

The chronic toxicity of droloxifene (DROL) and tamoxifen (TAM) was exa mined in two studies. In the first, groups of 25 rats per sex were dos ed daily for 26 weeks with DROL at dose levels of 0, 2, 20 and 200 mg/ kg in 0.25% agar vehicle by gavage. Identical groups were dosed with T AM at 3 times lower dose levels of 0.6, 6, and 60 mg/kg. After 26 week s of exposure 5 animals/sex/group were retained for a further 6 weeks without treatment in order to assess the reversibility of the effects. The histopathological examination revealed exclusively in the 60-mg/k g TAM group irreversible hyper- and neoplastic transformations of hepa tocytes in nearly all test animals. Many characteristic stages of hepa tocellular tumor development could be demonstrated, starting from pren eoplastic dedifferentiation disorders up to anaplastic hepatomas. Sign ificant changes of nuclear sizes, nucleus:plasma relations and an incr ease in mitotic rates characterized these proliferations. Preneoplasti c changes could be distinguished as clear-cell, acidophilic or basophi lic main types. It was evident that all the nodular changes observed a t the end of treatment tended increasingly to heterogenicity during th e recovery period and resulted in mixed tumor forms with distinct anap lastic tendencies. Trabecular and glandular tumor types developed in a cidophilic and basophilic nodes, which could be classified as adenocar cinomas. These alterations were more pronounced in females than in mal es. In contrast to TAM, DROL did not induce any morphologically and/or morphometrically significant liver lesions. This was confirmed by a s econd experiment over a dosing period of 2 years. DROL did not induce any macroscopical liver lesion up to a dose of 90 mg/kg, whereas nearl y all animals exposed to 36 mg/kg TAM displayed clearly visible hepati c tumors. The corresponding histopathological examination is still ong oing.