TAS-108, a Novel Oral Steroidal Antiestrogenic Agent, Is a Pure Antagonist on Estrogen Receptor α and a Partial Agonist on Estrogen Receptor β with Low Uterotrophic Effect

Purpose: Investigators are currently conducting phase II trials on TAS-108, a novel oral steroidal antiestrogenic agent. The purpose of this study is to investigate the molecular and pharmacologic properties of TAS-108 comparedwith other antiestrogenic agents such as tamoxifen,raloxifene, and fulvestrant. Experimental Design: The antagonistic or agonistic activities of these agents against both estrogen receptors (ER) α and β were compared in the reporter assay systems. Their effects on the uterus were evaluated in ovariectomized rat models. The antitumor activity of TAS-108 given p.o. was evaluated in both dimethylbenzanthracene-induced mammary tumor model and human breast cancer MCF-7 cell line xenografts. Results: TAS-108 inhibited the transactivation of ERα under the presence of 17β-estradiol (E 2 ) and did not induce the transactivation of ERα in the absence of E 2 , unlike the agonistic activity of tamoxifen. On the other hand, it exhibited the most agonistic activity on ERβ among the antiestrogenic agents tested. When given p.o. in the ovariectomized rat, TAS-108 showed a much weaker estrogenic effect on utterine weight compared to tamoxifen, or with similar levels of raloxifene, a selective estrogen receptor modulator. Also, TAS-108 strongly inhibited tumor growth in dimethylbenzanthracene-induced mammary carcinomain the rat, the endogenous E 2 model, at a dosage of 1 to 3 mg/kg/day. It also inhibited high exogenous E 2 , inducing tumor growth against MCF-7 xenografts at a dosage of 1 mg/kg/day without any toxic manifestation. Conclusions: Taken together, p.o. treatment with TAS-108 has a novel mode of action on ERs and inhibits E 2 -dependent tumor growth with little uterotrophic effect.