A New Safer and More Effective Triphenylethylene Antiestrogen (SS1020) for the Treatment and Prevention of Breast Cancer.

Abstract

Abstract Background: 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. Besides the significant benefit, 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. RAL has a poor bioavailability. This makes it difficult to achieve adequate bioavailability by oral administration in humans. High doses are required to obtain an efficacy quivalent to that achieved with TAM. Several other antiestrogens 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 for breast cancer therapy and prevention.Results: SS1020 was developed as a new triphenylethylene antiestrogen in our laboratory. Although TAM is a hepatic carcinogen and produces a high level of DNA damage in rats, SS1020 did not produce such DNA damage. Unlike TAM and RAL, SS1020 had no detectable uterotrophic activity in OVX-rats even treated with a high dose (10 mg/kg). These indicate that SS1020 is free of genotoxic and estrogenic activities. The antitumor potential of SS1020 against 7,12-dimethyl-benz(a)anthracene (DMBA)-induced mammary carcinoma in rats and human MCF-7 breast cancer xenograft in athymic nude mice was superior to that of TAM and 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. The bioavailability of SS1020 was approximately 35 times higher than that of RAL. The maximum blood concentration (493 ng/ml serum) of SS1020 was observed at 2 hour after the oral treatment while that of RAL (15.6 ng/ml) was at 6 hours, indicating that SS1020 is absorbed rapidly into the body. SS1020 has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL.Conclusion: Taken together, SS1020 lacking genotoxic and estrogenic actions has anti-breast cancer activity superior to that of TAM and RAL and has a preventive potential. SS1020 is a safer and more effective antiestrogen candidate for breast cancer therapy and prevention. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4085.