Biointeractions of antiestrogens with nitric oxide

抗雌激素与一氧化氮的生物相互作用

• 批准号: 7007301
• 负责人: Gregory R. J Thatcher
• 金额: $ 23.65万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7007301
• 关键词: DNA damage; cancer prevention; cardiovascular disorder prevention; cell line; cytoprotection; cytotoxicity; drug adverse effect; drug carcinogenesis; drug interactions; drug metabolism; drug related neoplasm /cancer; estrogen inhibitor; estrogen receptors; hormone regulation /control mechanism; hormone related neoplasm /cancer; laboratory rat; mutagen testing; neoplasm /cancer pharmacology; nitric oxide; oxidative stress; peroxynitrites; raloxifene; selective estrogen receptor modulators; tamoxifen; uterus neoplasms

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.

描述（由申请人提供）：作为选择性雌激素受体调节剂（SERM），他莫昔芬仍然是治疗激素依赖性乳腺癌各阶段的首选内分泌疗法，最近完成的大规模临床试验已验证他莫昔芬作为乳腺癌化学预防剂。一些研究引起了人们对 SERM 长期治疗安全性的担忧，特别是在诱发子宫内膜癌方面。包括雷洛昔芬在内的替代 SERM 可能不具有基因毒性，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/或类型减少。在一项大型化学预防试验中，雷洛昔芬与他莫昔芬进行了比较，雷洛昔芬已用于骨质疏松症的临床治疗，并在临床试验中检验其预防心血管疾病的功效。 SERM 的心血管活性是通过细胞一氧化氮 (NO) 的升高介导的。该提议的中心假设是，SERM 在各种组织中所表现出的组织 NO 水平升高与其细胞保护、细胞毒性和致癌特性有着内在的联系。 SERM 诱导氧化应激下组织中 NO 升高，会产生 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 代谢物除了产生超氧化物外，还能够共价修饰生物分子，包括 DNA 和雌激素受体 (ER)，通过消耗细胞还原当量来促进氧化应激，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NO和过氧亚硝酸盐与细胞系中SERM及其代谢物反应产物的细胞毒性，并评估细胞系中SERMS及其代谢物以及与纯化的雌激素受体的拮抗剂/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。这些具体目标的完成将确定 SERM 与 NO 和细胞靶标之间细胞/基因毒性相互作用的潜力。