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

Abstract

Since tamoxifen is efficacious for the prevention of second primary breast neoplasms in humans and has a low reported incidence of acute side 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 idoxifene to female Sprague-Dawley rats. One day following treatment, the rats were sacrificed and the hepatocytes isolated and cultured. After 47 h in culture, colcemid was added for 3 h prior to harvest of the hepatocytes for karyotypic evaluation. At least 100 metaphase spreads were examined for each of five rats per treatment. Toremifene resulted in aneuploidy 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. Analysis of electron micrographs of cultures treated with these antiestrogens 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 hepatocytes. 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 triphenylethylenes.