Biointeractions of antiestrogens with nitric oxide

描述（由申请人提供）：选择性雌激素受体调节剂（SERM），他莫昔芬仍然是激素依赖性乳腺癌所有阶段治疗的内分泌治疗选择，最近完成的大规模临床试验已经证实他莫昔芬是乳腺癌化学预防剂。一些研究已经引起了对SERMs慢性治疗安全性的关注，特别是关于子宫内膜癌的诱导。包括雷洛昔芬在内的其他serm可能没有遗传毒性，这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/或类型减少。在一项大型化学预防试验中，雷洛昔芬正在与他莫昔芬进行比较，在骨质疏松症的临床应用中，在临床试验中检验预防心血管疾病的功效。SERMs的心血管活性是通过细胞一氧化氮（NO）的升高介导的。该提案的中心假设是，serm在各种组织中显示的组织NO水平升高与其细胞保护，细胞毒性和致癌特性具有内在联系。serm诱导的氧化应激组织中NO的升高会产生RNOS和过氧亚硝酸盐，这是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代谢物除了产生超氧化物外，还具有共价修饰生物分子的能力，包括DNA和雌激素受体（ER），通过消耗细胞还原等价物导致氧化应激，并导致蛋白质s -亚硝基化。具体目标：1；评估亚细胞系统中SERM/NO相互作用的细胞毒性途径。2. 评估一氧化氮和过氧亚硝酸盐与细胞系中SERMs及其代谢物的反应产物的细胞毒性，评估SERMs及其代谢物在细胞系和纯化雌激素受体中的拮抗剂/激动剂活性。3. 评估血管和子宫组织中SERM/NO相互作用产物的细胞毒性和活性。这些特定目标的完成将确定serm与NO和细胞靶标之间细胞/基因毒性相互作用的潜力。

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.