Biointeractions of antiestrogens with nitric oxide

选择性雌激素受体调节剂（SERM），他莫昔芬仍然是内分泌治疗的选择， 治疗所有阶段的乳腺癌依赖性，最近完成了大规模的临床 试验已经证实他莫昔芬是乳腺癌的化学预防剂。几项研究引起了人们的关注 关于SERM长期治疗的安全性，特别是在诱导子宫内膜异位症方面， 癌包括雷洛昔芬在内的替代SERM可能没有遗传毒性，这可能是因为不同的给药途径。 可能导致最终致癌物数量和/或类型减少的代谢。雷洛昔芬 在一项大型化学预防试验中与他莫昔芬进行了比较， 试验以检查预防心血管疾病的功效。SERMs的心血管活性是 通过升高细胞一氧化氮（NO）介导。这一建议的核心假设是， 在各种组织中，通过SERM证实的组织NO水平升高与它们的 细胞保护、细胞毒性和致癌特性。SERM诱导的组织中NO的升高 氧化应激将产生RNOS和过氧亚硝酸盐（一种已知的肿瘤促进剂）。RNOS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 具有共价修饰生物分子的能力，包括DNA和雌激素受体（ER）， 除了产生超氧化物外，还通过消耗细胞还原性 等价物，并导致蛋白质S-亚硝基化。具体目标：1.评估细胞毒性途径， 亚细胞系统中的SERM/NO相互作用。2.通过以下反应评估产品的细胞毒性 NO和过氧亚硝酸盐与SERMs及其代谢产物在细胞系中的作用，并评估 SERMS及其在细胞系中的代谢产物以及纯化的雌激素受体。3.评估细胞毒性， 血管和子宫组织中SERM/NO相互作用产物的活性。完成这些 具体目标将确定SERM和NO之间的细胞/遗传毒性相互作用的潜力， 目标的

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.