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: 6877220
• 负责人: Gregory R. J Thatcher
• 金额: $ 24.22万
• 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/6877220
• 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）：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乳腺癌依赖性乳腺癌的内分泌治疗的选择，最近完成的大规模临床试验已经验证了他莫昔芬作为乳腺癌化学预防剂。一些研究已经引起了对SERM长期治疗安全性的关注，特别是在诱导子宫内膜癌方面。替代SERM（包括雷洛昔芬）可能不具有遗传毒性，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。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，在骨质疏松症的临床应用中，以及在预防心血管疾病的临床试验中检查疗效。SERMs的心血管活性通过升高细胞一氧化氮（NO）来介导。该建议的中心假设是，在各种组织中通过SERM显示的组织NO水平的升高与其细胞保护、细胞毒性和致癌特性内在地相关。在氧化应激下，组织中的SERM诱导的NO升高将产生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（包括DNA和雌激素受体（ER））的能力，此外还产生超氧化物，通过消耗细胞还原当量促进氧化应激，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SERM及其代谢物在细胞系中反应的产物的细胞毒性，并评估SERM及其代谢物在细胞系中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。