RU486 has been shown to have significant clinical potential in the medical management of endometriosis. Our studies have suggested that at least part of the ability of this agent to modulate the growth of endometrial cells is through its demonstrated antioxidant activity. This activity, which can be structurally separated from its antiprogestin properties, has given rise to our notion of """"""""target specific nuclear antioxidants"""""""", compounds which can be translocated into the nucleus through binding to certain steroid hormone receptors. This hypothesis suggests the possibility that RU486 derivatives can be developed that have therapeutic efficacy against endometriosis without interfering with the normal menstrual cycle, fertility, or other hormone dependent processes. The overall goal of this exploratory R21 grant is to develop such compounds, understand their mode of action against endometrial cell growth, and test their efficacy in an in vivo animal model of endometriosis. This goal will be accomplished by two specific aims. Based on our work showing that reduced- RU486, acting as a """"""""nuclear antioxidant"""""""", can regulate endometrial cell growth Aim 1 will characterize the nature and specificity of this activity. We will synthesize new RU486 derivatives with varying antioxidant and antiprogesterone properties which will provide new insight into structure-function relationships of this unique class of compounds.
Aim 2 will evaluate the effects of the RU486 compounds on the development of endometriosis in an immunocompetent mouse model. Using methodology that simulates a massive retrograde menses, this model will shed light on our ability to influence both the implantation/invasive potential of ectopic endometrial cells and the progressive growth of endometriotic lesions.
Endometriosis is a major public health issue. Since current medical therapy has limitations, more effective treatment options are desperately needed. The information gained from our studies will provide the basic framework for the rational drug design of a new generation of agents for treating this disease. ? ? ?
