The ultimate aim of these studies is to develop potent antiestrogens capable of controlling growth of estrogen-dependent tumors in humans by non-invasive endocrine therapy. We will monitor, in a comparative manner, the effects of a number of structurally related antiestrogens and proestrogens on estrogen-stimulated growth responses in the immature rat uterus and vagina, where the biosynthetic sequence or events following estrogen has been well characterized. In this model system we will attempt to elucidate the cellular (receptor occupancy) and pharmacodynamic factors (uptake, distribution, metabolism, rates of clearance) influencing antiestrogen effectiveness. Utilizing this information, we will then conduct studies to elucidate the probable bases of antiestrogenic inhibition of tumor development and growth in the dimethylbenzanthracene (DMBA)-induced rat mammary tumor system with our most effective antiestrogens.