Abstract 4528: Genotoxic and estrogenic properties of new antiestrogens

Abstract

Abstract Long-term administration of tamoxifen (TAM) to breast cancer patients and women at high risk of developing this disease gives serious side effects, including endometrial cancer. These side-effects are due to the DNA damaging and/or estrogenic action of the drug. Several antiestrogens have been developed in last three decades, but were dropped out from the clinical trials due to their undesirable effects on the uterus. To avoid this serious side-effect, we have synthesized a new triphenylethylene antiestrogen, E-3-{4-[(E)-4-chloro-1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]-phenyl} acrylic acid (SS1020) and a new benzopyran antiestrogen, 2E-3-{4-[(7-hydroxy-2-oxo-3-phenyl-2H-chromen-4-yl)-methyl]-phenyl}-acrylic acid (SS5020). SS1020 and SS5020 had antitumor potential much higher than that of TAM or other antiestrogens at the human equivalent doses (TAM 0.3-1.0 mg/kg/day), against 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats or human MCF-7 breast cancer xenograft implanted into athymic nude mice. To evaluate their genotoxic activity, the capability of forming hepatic DNA adducts in rats was determined. When rats were treated orally at a dose molar equivalent to TAM (20 mg/kg/day), a high level (∼1 adduct/105 nucleotides) of DNA adducts was detected in TAM-treated rats whereas no DNA adducts were observed in rats treated with SS1020 or SS5020. To evaluate the estrogenic potential, the uterotrophic activity of our compounds was determined in ovariectomized (OVX) rats at a dose molar equivalent to TAM (10 mg/kg/day), which is 30 times higher than the human equivalent dose of TAM. TAM had high uterotrophic activity while SS1020 and SS5020 did not present significant uterotrophic activity. Therefore, SS1020 and SS5020, lacking estrogenic and genotoxic actions, are expected not to induce reproductive cancers. Interestingly, the antitumor activities of several antiestrogens examined were, rather, increased significantly to the lowering uterotrophic activity evaluated with OVX-rats, but not to their antiproliferative activities against cultured estrogen receptor positive human MCF-7 breast cancer cells. The use of uterotrophic assay, not antiproliferative assay, may be a suitable screening system to exploit antiestrogen alternatives. Non-genotoxic and non-estrogenic SS1020 and SS5020, having strong antitumor potency superior to that of TAM, could be safer alternatives for breast cancer therapy and prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4528. doi:10.1158/1538-7445.AM2011-4528