Development of Nuclear Antioxidants for the Treatment of Endometriosis

描述（由申请人提供）：RU 486已被证明在子宫内膜异位症的医学管理中具有显著的临床潜力。我们的研究表明，至少有一部分的能力，这种代理商调节子宫内膜细胞的生长是通过其证明抗氧化活性。这种活性在结构上可以与其抗白细胞介素的特性分离，这引起了我们对“靶向特异性核抗氧化剂”的概念，这些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，可以开发出对子宫内膜异位症具有治疗功效而不干扰正常月经周期、生育力或其他激素依赖性过程的RU 486衍生物。这项探索性R21资助的总体目标是开发此类化合物，了解其对子宫内膜细胞生长的作用模式，并在子宫内膜异位症的体内动物模型中测试其疗效。这一目标将通过两个具体目标来实现。基于我们的工作表明，还原型RU 486，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将表征这种活动的性质和特异性。我们将合成新的RU 486衍生物与不同的抗氧化剂和抗孕酮的性能，这将提供新的见解，这类独特的化合物的结构与功能的关系。目的2将评估RU 486化合物在免疫活性小鼠模型中对子宫内膜异位症发展的作用。使用模拟大量逆行月经的方法，该模型将揭示我们影响异位子宫内膜细胞的植入/侵入潜力和子宫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存在局限性，迫切需要更有效的治疗方案。从我们的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.