Biointeractions of antiestrogens with nitric oxide

选择性雌激素受体调节剂(SERM)，他莫昔芬仍然是患者内分泌治疗的首选药物 治疗所有阶段的激素依赖型乳腺癌，并于近期完成大规模临床 试验已经证实他莫昔芬是一种乳腺癌化学预防药物。有几项研究引起了人们的关注 关于SERM慢性治疗的安全性，特别是在诱导子宫内膜方面 癌症。替代的SERM，包括雷洛昔芬，可能没有遗传毒性，可能是因为不同的途径 可能导致最终致癌物数量和/或类型减少的代谢(S)。雷洛昔芬是 在一项大型化学预防试验中与他莫昔芬进行比较，用于治疗骨质疏松症和临床 检查心血管疾病预防效果的试验。SERM的心血管活性是 通过细胞内一氧化氮(NO)的升高而介导。这项提议的中心假设是 SERM在不同组织中组织NO水平的升高与其内在联系 具有细胞保护、细胞毒性和致癌特性。血清诱导的组织中NO的升高 氧化应激会产生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。血清代谢物 能够共价修饰生物分子，包括DNA和雌激素受体(ER)，在 除了产生超氧化物外，还会通过耗尽细胞还原而导致氧化应激 等价物，并导致蛋白质S亚硝化。具体目标：1.评估细胞毒途径 亚细胞系统中的SERM/NO相互作用。2.评估反应产物的细胞毒性 NO和过氧亚硝酸盐与SERM及其代谢物在细胞中的相互作用及评价其拮抗剂/激动剂活性 细胞系中的SERM及其代谢物和纯化的雌激素受体。3.评估细胞毒性和 SERM/NO相互作用产物在血管和子宫组织中的活性。这些项目的完成 特定的目标将确定SERM和NO与细胞之间潜在的细胞/遗传毒性相互作用 目标。

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 tumour 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 peroxynitritewith 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 cytotoxicityand 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.