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: 8184309
• 负责人: Gregory R. J Thatcher
• 金额: $ 23.49万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8184309
• 关键词: Adverse effects; Affinity; Agonist; Alkylation; Apoptosis; Attenuated; Biological Assay; Biological Markers; Breast; Breast Cancer Cell; Cell Culture Techniques; Cell Line; Cell Nucleus; Cells; Characteristics; Chemicals; Clinical; DNA Adduction; DNA Adducts; DNA Damage; DNA Modification Process; Data; Deamination; Depurination; Development; Epithelial Cells; Estrogen Antagonists; Estrogen Metabolism; Estrogen Receptor Modulators; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Foundations; Funding; Goals; Grant; Growth; Hormonal; Hormonal Carcinogenesis; Hormone replacement therapy; Human; In Vitro; Inbred ACI Rats; Libraries; Link; MCF7 cell; Malignant - descriptor; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Measurement; Measures; Menopausal Symptom; Modeling; Nitric Oxide; Nitric Oxide Synthase; Nitrosation; Normal Cell; Nucleic Acids; Oxidation-Reduction; Pharmaceutical Preparations; Plasma; Post-Translational Protein Processing; Postmenopause; Prevention therapy; Process; Production; Property; Proteins; Quinones; Raloxifene; Receptor Cell; Reporting; Risk; Selective Estrogen Receptor Modulators; Structure; Syndrome; System; T47D; Tamoxifen; Techniques; Therapeutic; Therapeutic Agents; Time; Tissues; Tumor Promotion; Writing; adduct; attenuation; base; benzothiophene; cancer chemoprevention; cancer risk; carcinogenesis; chemical carcinogenesis; cytotoxic; design; expectation; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; novel; oxidation; oxidative DNA damage; receptor; research study; response; risk benefit ratio; sensor; therapy development; tumor; tumor initiation; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Use of estrogen/hormone replacement therapy (HRT) for post-menopausal symptoms has plummeted because of increased breast cancer risk associated with hormonal and chemical carcinogenesis. Selective estrogen receptor modulators (SERMs) could provide an alternative to HRT, but development has stalled because of the risk of side effects including carcinogenesis. The benzothiophene SERM (BT-SERM) raloxifene is currently the sole SERM in clinical use for postmenopausal syndrome and breast cancer chemoprevention. SERMs act as estrogen agonists in some tissues and both estrogens and SERMs are oxidatively metabolized to electrophilic quinones with potential to generate ROS. Estrogen agonists have been shown to elevate cellular NO; NO is implicated in breast cancer tumorigenesis. Quinones, ROS, and NO can interact chemically and also modify proteins and damage DNA. This proposal is directed at understanding how estrogen-dependent carcinogenesis can be attenuated by NO modulation and by appropriately designed SERMs that are redox-active but not themselves carcinogenic, to provide a basis for design of safe, non-carcinogenic SERMs for HRT and beyond. In Aim 1, new BT-SERMs will be synthesized and profiled as cellular probes. In vitro DNA damage and protein modification will be studied by LC-MS/MS. This aim will determine the protein and nucleic acid adducts of the chemical interaction with quinones, NO, and ROS generated by (anti)estrogens, and the influence of quinone structure on these products, allowing comparison with Aim 2 results in cell cultures. Aim 2 will study modulation of oxidative DNA damage in mammary cell cultures leading to apoptosis or malignant transformation. We hypothesize that malignant transformation of breast cancer cells reflects estrogen chemical carcinogenesis and therefore will be predictive for BT-SERM and NO modulating treatments that will attenuate tumorigenesis in experiments planned in Aim 3. In Aim 3, the ACI rat, an established model for estrogen-induced mammary carcinogenesis will be used to study the effect of one BT-SERM and NO modulation on carcinogenesis and tumor regression. PUBLIC HEALTH RELEVANCE: SERMs are a drug class used for postmenopausal syndromes and for prevention and therapy of estrogen dependent breast cancer. Risk-benefit ratios associated with estrogen replacement therapy and side effects of SERMs may be associated with tissue levels of nitric oxide (NO). The importance of this drug class demands a better understanding of the interactions of SERMs, estrogens, and NO as the foundation for improved therapeutic agents.

描述（由申请人提供）：由于与激素和化学致癌作用相关的乳腺癌风险增加，用于治疗绝经后症状的雌激素/激素替代疗法（HRT）的使用量急剧下降。选择性雌激素受体调节剂（SERM）可以提供 HRT 的替代方案，但由于存在包括致癌在内的副作用风险，开发已陷入停滞。苯并噻吩SERM（BT-SERM）雷洛昔芬是目前临床上用于绝经后综合征和乳腺癌化学预防的唯一SERM。 SERM 在某些组织中充当雌激素激动剂，雌激素和 SERM 都氧化代谢为亲电醌，有可能产生 ROS。雌激素激动剂已被证明可以升高细胞一氧化氮（NO）； NO 与乳腺癌肿瘤发生有关。醌、ROS 和 NO 可以发生化学相互作用，还可以修饰蛋白质并损伤 DNA。该提案旨在了解如何通过 NO 调节和适当设计的具有氧化还原活性但本身不致癌的 SERM 来减弱雌激素依赖性致癌作用，为设计用于 HRT 及其他安全、非致癌性 SERM 提供基础。在目标 1 中，将合成新的 BT-SERM 并作为细胞探针进行分析。将通过 LC-MS/MS 研究体外 DNA 损伤和蛋白质修饰。该目标将确定与（抗）雌激素产生的醌、NO 和 ROS 发生化学相互作用的蛋白质和核酸加合物，以及醌结构对这些产物的影响，从而可以与细胞培养物中的 Aim 2 结果进行比较。目标 2 将研究乳腺细胞培养物中氧化 DNA 损伤的调节，导致细胞凋亡或恶性转化。我们假设乳腺癌细胞的恶性转化反映了雌激素化学致癌作用，因此将预测 BT-SERM 和 NO 调节治疗，从而在目标 3 计划的实验中减弱肿瘤发生。在目标 3 中，将使用 ACI 大鼠，一种已建立的雌激素诱导乳腺癌模型来研究 BT-SERM 和 NO 调节对癌发生和肿瘤的影响 回归。 公众健康相关性：SERM 是一类用于治疗绝经后综合征以及预防和治疗雌激素依赖性乳腺癌的药物。与雌激素替代疗法和 SERM 副作用相关的风险效益比可能与组织中一氧化氮 (NO) 水平有关。此类药物的重要性要求更好地了解 SERM、雌激素和 NO 的相互作用，作为改进治疗药物的基础。