Genotoxic effects of the novel mixed antiestrogen FC-1271a in comparison to tamoxifen and toremifene

Tamoxifen has been used for the treatment of breast cancer since the 1970s, but is considered a carcinogen because it has been linked to liver cancer in rats and an increased risk of endometrial cancer in patients. In rats, D NA adducts appear to be responsible for carcinogenesis, but their contribut ion to carcinogenesis in humans is not clear. FC-1271a and toremifene are m ixed antiestrogens similar to tamoxifen. In order to compare the genotoxici ty of these different triphenylethylenes, we treated mice for 28 days with 50 mg/kg of either tamoxifen, toremifene, FC-1271a or vehicle control. DNA from liver and uterus was assayed by standard P-32-postlabeling and thin la yer chromatography for the presence of DNA adducts. Two methods of drug adm inistration (oral and subcutaneous) and two strains of mice were compared a nd the plasma and tissue concentrations of the drugs and three metabolites of tamoxifen and toremifene were determined. Regardless of the conditions, only tamoxifen-treated mice showed DNA adducts in the liver. Adduct levels did not correlate with drug or metabolite levels and adducts were present e ven when drug was not detectable. Mice were also treated orally with either 50, 100, or 200 mg/kg of drug for 7 days. Again, adducts were found only i n liver tissue of mice treated with tamoxifen, and adduct levels were dose- dependent. In conclusion, the chlorinated triphenylethylene FC-1271a did no t cause DNA adducts under various conditions in mice, suggesting a low carc inogenic potential.