Induction of hepatic aneuploidy in vivo by tamoxifen, toremifene and idoxifene in female Sprague-Dawley rats

Since tamoxifen is efficacious for the prevention of secondprimary breast neoplasms in humans and has a low reported incidenceof acute side effects, several structurally related compoundshave been developed for the treatment of breast cancer includingtoremifene and idoxifene. We have compared the karyotypic alterationsthat occur after a single per os administration of 35 mg/kgof tamoxifen, toremifene or idoxifene to female Sprague-Dawleyrats. One day following treatment, the rats were sacrificedand the hepatocytes isolated and cultured. After 47 h in culture,colcemid was added for 3 h prior to harvest of the hepatocytesfor karyotypic evaluation. At least 100 metaphase spreads wereexamined for each of five rats per treatment. Toremifene resultedin aneuploidy in 50±7% of the cells examined and idoxifeneinduced a 57±4% aneuploidy compared with the 85±7%level induced by tamoxifen. Since the level of aneuploidy insolvent-treated rats was 3±3%, the induction of aneuploidyin at least 50% of the cells from rats treated with tamoxifen,toremifene or idoxifene was highly significant Analysis of electronmicrographs of cultures treated with these antiestrogens demonstrateda range of phenotypes including multipolar spindles in toremifene-treatedrats and condensed chromosomes in the presence of an intactnuclear envelope in occasional idoxifene-treated rat hepatocytes.The exclusion of chromosomes from the spindle apparatus andthe lagging of some chromosomes on the metaphase plate correlatewith the high rate of induction of aneuploidy in the rat liveras determined by karyotypic analysis of hepatocytes from ratstreated with these triphenylethylenes.