Biointeractions of antiestrogens with nitric oxide

描述(申请人提供)：选择性雌激素受体调节剂(SERM)，他莫昔芬仍然是治疗所有阶段的激素依赖型乳腺癌的内分泌疗法的选择，最近完成的大规模临床试验证实他莫昔芬是乳腺癌的化学预防药物。一些研究已经引起了人们对SERM慢性治疗的安全性的关注，特别是在诱发子宫内膜癌方面。替代的SERM包括雷洛昔芬，可能没有遗传毒性，可能是因为不同的代谢途径可能导致最终致癌物的数量和/或类型的减少(S)。雷洛昔芬正在一项大型化学预防试验中与他莫昔芬进行比较，该试验用于临床治疗骨质疏松症，并在临床试验中检查预防心血管疾病的效果。SERM的心血管活动是通过细胞内一氧化氮(NO)的升高而介导的。这一建议的中心假设是，SERM在不同组织中所展示的组织NO水平的升高与其细胞保护、细胞毒性和致癌特性内在地联系在一起。在氧化应激下，血清诱导组织中NO的升高将产生RNO和过氧亚硝酸盐，这是一种已知的肿瘤促进剂。RNO和过氧亚硝酸盐能够氧化和硝化各种生物分子以及SERM本身。SERM代谢物除了产生超氧化物外，还能够共价修饰生物分子，包括脱氧核糖核酸和雌激素受体(ER)，通过耗尽细胞还原当量而导致氧化应激，并导致蛋白质S亚硝化。具体目标：1.评估亚细胞系统中SERM/NO相互作用的细胞毒途径。2.评价NO和过氧亚硝酸根与SERMS及其代谢产物在细胞中的细胞毒性，评价SERMS及其代谢产物在细胞中和与纯化的雌激素受体的拮抗剂/激动剂活性。3.评价SERM/NO相互作用产物对血管和子宫组织的细胞毒性和活性。这些特定目标的完成将确定SERM与NO和细胞靶点之间的细胞/遗传毒性相互作用的可能性。

DESCRIPTION (provided by applicant): The Selective Estrogen Receptor Modulator (SERM), tamoxifen remains the endocrine therapy of choice in the treatment of all stages of hormone-dependent breast cancer, and recently completed large-scale clinical trials have validated tamoxifen as a breast cancer chemopreventive agent. Several studies have raised concern over the safety of chronic treatment with SERMs, in particular with respect to induction of endometrial cancer. Alternative SERMs including raloxifene, may not be genotoxic possibly because of different routes of metabolism which could lead to a decrease in amount and/or type of ultimate carcinogen(s). Raloxifene is being compared to tamoxifen in a large chemoprevention trial, is in clinical use in osteoporosis and in clinical trials to examine efficacy in prevention of cardiovascular disease. The cardiovascular activity of SERMs is mediated through elevation of cellular nitric oxide (NO). The central hypothesis of this proposal is that the demonstrated elevation of tissue NO levels by SERMs in various tissues is intrinsically linked with their cytoprotective, cytotoxic and carcinogenic properties. SERM-induced elevation of NO in tissue under oxidative stress will generate RNOS and peroxynitrite, a known tumor promoter. RNOS and peroxynitrite are capable of oxidation and nitration of various biomolecules, and of SERMs themselves. SERM metabolites have the capacity to covalently modify biomolecules, including DNA and the estrogen receptor (ER), in addition to generating superoxide, contributing to oxidative stress through depletion of cellular reducing equivalents, and leading to protein S-nitrosylation. Specific aims: 1. Assess cytotoxic pathways for SERM/NO interactions in subcellular systems. 2. Assess the cytotoxicity of products from the reactions of NO and peroxynitrite with SERMs and their metabolites in cell lines and assess antagonist/agonist activity of SERMS and their metabolites in cell lines and with purified estrogen receptor. 3. Assess the cytotoxicity and activity of products from SERM/NO interactions in vascular and uterine tissue. The completion of these specific aims will define potential for cyto/genotoxic interactions between SERMs and NO and cellular targets.