INDUCTION OF HEPATIC ANEUPLOIDY IN-VIVO BY TAMOXIFEN, TOREMIFENE AND IDOXIFENE IN FEMALE SPRAGUE-DAWLEY RATS

Since tamoxifen is efficacious for the prevention of second primary br east neoplasms in humans and has a low reported incidence of acute sid e effects, several structurally related compounds have been developed for the treatment of breast cancer including toremifene and idoxifene, We have compared the karyotypic alterations that occur after a single per os administration of 35 mg/kg of tamoxifen, toremifene or idoxife ne to female Sprague-Dawley rats, One day following treatment, the rat s were sacrificed and the hepatocytes isolated and cultured, After 47 h in culture, colcemid was added for 3 h prior to harvest of the hepat ocytes for karyotypic evaluation, At least 100 metaphase spreads mere examined for each of five rats per treatment, Toremifene resulted in a neuploidy in 50+/-7% of the cells examined and idoxifene induced a 57/-4% aneuploidy compared with the 85+/-7% level induced by tamoxifen, Since the level of aneuploidy in solvent-treated rats was 3+/-3%, the induction of aneuploidy in at least 50% of the cells from rats treated with tamoxifen, toremifene or idoxifene was highly significant, Analy sis of electron micrographs of cultures treated with these antiestroge ns demonstrated a range of phenotypes including multipolar spindles in toremifene-treated rats and condensed chromosomes in the presence of an intact nuclear envelope in occasional idoxifene-treated rat hepatoc ytes. The exclusion of chromosomes from the spindle apparatus and the lagging of some chromosomes on the metaphase plate correlate with the high rate of induction of aneuploidy in the rat liver as determined by karyotypic analysis of hepatocytes from rats treated with these triph enylethylenes.