Development of Nuclear Antioxidants for the Treatment of Endometriosis

描述(由申请人提供)：RU486已被证明在子宫内膜异位症的医疗管理中具有显著的临床潜力。我们的研究表明，该制剂调节子宫内膜细胞生长的能力至少部分是通过其已证明的抗氧化活性来实现的。这种活性在结构上可以与它的抗孕激素特性分开，这引发了我们的概念，即靶向特定的核抗氧化剂，这种化合物可以通过与某些类固醇激素受体结合而转移到细胞核中。这一假设表明，可以开发出RU486衍生物，在不干扰正常月经周期、生育能力或其他激素依赖过程的情况下，对子宫内膜异位症具有治疗效果。这项探索性的R21基金的总体目标是开发这种化合物，了解它们对子宫内膜细胞生长的作用方式，并在子宫内膜异位症的活体动物模型中测试它们的有效性。这一目标将通过两个具体目标来实现。根据我们的工作表明，Reduced-RU486作为一种“核抗氧化剂”，可以调节子宫内膜细胞的生长，目标1将表征这一活性的性质和特异性。我们将合成具有不同抗氧化剂和抗孕酮性质的新RU486衍生物，这将为这类独特化合物的结构与功能关系提供新的见解。目的2评价RU486化合物对免疫活性小鼠子宫内膜异位症发生发展的影响。使用模拟大规模逆行月经的方法，该模型将阐明我们影响异位内膜细胞的植入/侵袭潜力和异位内膜病变的进行性生长的能力。公共卫生相关性：子宫内膜异位症是一个主要的公共卫生问题。由于目前的药物治疗有局限性，迫切需要更有效的治疗方案。我们从研究中获得的信息将为治疗这种疾病的新一代药物的合理药物设计提供基本框架。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.