Abstract 4617: Novel antiestrogens, SS1020 and SS5020, for breast cancer therapy and prevention

Tamoxifen (TAM) is widely used as a first-line endocrine therapy for breast cancer patients and as a prophylactic agent for women at high risk of developing this disease. Long-term administration of TAM has serious side effects, including endometrial cancer. These side-effects are due to the DNA damaging and/or estrogenic action of the drug. Raloxifene (RAL) approved as a chemopreventive agent for postmenopausal women at high risk for invasive breast cancer retains an estrogenic action. The poor bioavailability of RAL requires high doses to obtain an efficacy equivalent to that achieved with TAM. Several other antiestrogens developed were dropped out from the clinical trials due to their undesirable effects on the uterus. Therefore, development of new antiestrogen alternatives, but free of genotoxic and estrogenic potential, having significant antitumor potential beyond TAM and RAL is urgently required. SS1020 and SS5020 were developed as a new triphenylethylene antiestrogen and benzopyran antiestrogen, respectively, in our laboratory. Although TAM is a hepatic carcinogen and produces a high level of DNA damage in rats, both SS1020 and SS5020 did not produce such DNA damage. Unlike TAM and RAL, SS1020 and SS5020 had no detectable uterotrophic activity in OVX-rats treated even with a high dose (10 mg/kg). These indicate that SS1020 and SS5020 are free of genotoxic and estrogenic activities. The antitumor potential of SS1020 or SS5020 against 7,12-dimethyl-benz(a)anthracene-induced mammary carcinoma in rats and human MCF-7 breast cancer xenograft in athymic nude mice was superior to that of TAM and RAL. SS1020 has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL. In addition, the development of estrogen-induced mammary tumor in rats was completed inhibited by dietary intake of SS1020, indicating that this compound has preventive potential. Taken together, SS1020 and SS5020 lacking genotoxic and estrogenic actions have anti-breast cancer activity superior to that of TAM and RAL. Both SS1020 and SS5020 are safer and more effective antiestrogen candidates for breast cancer therapy and prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4617.