Ospemifene as a chemopreventive agent

Selective estrogen receptor modulators, or SERMs, act as estrogen receptor agonists in some tissues, while having antagonistic effects in others. The FDA has approved several SERMs, including tamoxifen and raloxifene to treat and prevent breast cancer and osteoporosis, respectively; however, due to adverse effects such as thromboembolic disease and tamoxifen's associated risk of endometrial cancer, other SERMs may be better alternatives for prophylactic use. Ospemifene is currently in phase III trials for the treatment and prevention of osteoporosis, and previous trials have demonstrated that it is well tolerated in healthy postmenopausal women. It has primarily been studied for its effects on improving bone mass, however, ospemifene has also been shown to have antiestrogenic effects on breast tissue and appears to have fewer adverse effects than currently used SERMs; it does not cause uterine stimulation or thromboembolic events, and causes fewer climacteric symptoms. Thus, ospemifene may be a potential chemopreventive agent to reduce the risk of breast cancer in healthy postmenopausal women. The presently described research includes (1) a characterization of ospemifene's metabolites in vitro, (2) an investigation of ospemifene as a breast cancer chemopreventive agent in mice, and (3) an evaluation of the distribution of ospemifene. In vitro, the antiestrogenic activity of ospemifene and several of its metabolites were characterized by evaluating cell growth stimulation or inhibition in MCF-7 human breast cancer cells and measuring the expression of pS2, an estrogen-regulated gene. Ospemifene inhibited cell growth and pS2 expression. Ospemifene's metabolites had mixed activity. OSP VI and OSP VIII were antiestrogenic, while OSP XIII and OSPXVIII had slight to no antiestrogenic activity. The breast cancer chemopreventive activity of ospemifene was compared to tamoxifen and raloxifene using a mouse model. Ospemifene prevented the occurrence of mammary tumors induced by the chemical carcinogen, dimethylbenz[a]anthracene, as effectively as tamoxifen, suggesting that ospemifene may have a role as a breast cancer chemopreventive agent. HPLC analysis confirmed the presence of ospemifene in a variety of target tissues in the mouse, suggesting extensive distribution. The results of the above mentioned studies have further characterized the activity of ospemifene as a breast cancer chemopreventive agent.