CARCINOGENIC METABOLITES FORMED FROM ANTIESTROGENS

抗雌激素形成的致癌代谢物

• 批准号: 6342124
• 负责人: Judy L Bolton
• 金额: $ 19.17万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-08 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342124
• 关键词: DNA damage; animal genetic material tag; carcinogen testing; chemical carcinogen; chemical carcinogenesis; chemical structure function; cytochrome P450; dihydrolipoamide dehydrogenase; drug metabolism; enzyme activity; estrogen receptors; glutathione; laboratory rat; mutagen testing; mutagens; neoplasm /cancer genetics; oxidation reduction reaction; quinones; tamoxifen; tissue /cell culture

Tamoxifen remains the endocrine therapy of choice in the treatment of all stages of hormone-dependent breast cancer. In addition, large-scale clinical trials are in progress to determine the potential of tamoxifen to act as a chemopreventive agent in women considered at high risk for developing breast cancer. However, several studies have raised concern over the safety of chronic treatment with this drug. Alternate antiestrogens including droloxifene, toremifene, and idoxifene, may not be genotoxic probably because of different routes of metabolism which could lead to a decrease in amount and/or type of ultimate carcinogen(s). The central hypothesis of this project is that the formation of reactive intermediates is an important mechanism of carcinogenesis and/or cytotoxicity for certain antiestrogens. For example, tamoxifen can be metabolized to at least three electrophilic metabolites of very different reactivity: quinone methides, carbocations, and o-quinones. The following specific aims are proposed: 1. Role of quinone methides, carbocations, and/or o-quinones in the carcinogenic and cytotoxic effects of antiestrogens. The carcinogenic potential of the proximate carcinogens from tamoxifen, droloxifene, toremifene, and idoxifene will be studied in C3H1 OT1/2 cells and their tumor promoting ability examined in JB6 cells. The biochemical effects of the antiestrogens and their metabolites will be investigated in human breast and endometrial cancer cell lines. 2. Investigate the effect of reactive metabolite structure on electrophilic and/or redox reactivity. The substituent effects on the electrophilicity/redox ability of the antiestrogen reactive intermediates will be investigated by measuring their ability to alkylate/oxidize DNA. Redox active metabolites will be tested by monitoring changes in reduced cofactors and by determining the formation of reactive oxygen species. 3. Determine if the antagonist/agonist activity of antiestrogen metabolites correlates with the extent of DNA damage in estrogen receptor positive cell lines. The Ishikawa cell system will be used to determine the estrogenic antiestrogenic and/or toxic effects of the proximate hydroxylated metabolites and the ultimate reactive intermediates. Cellular DNA from estrogen receptor positive and negative cells lines will be isolated after treatment with the test compound. The DNA will be hydrolyzed to deoxynucleosides (identified from Aim 2) and examined for covalent adducts and oxidative damage. These studies will greatly assist in the design of estrogen antagonists that maintain beneficial properties without generating genotoxic metabolites.

他莫昔芬仍然是治疗以下疾病的首选内分泌疗法 激素依赖性乳腺癌的所有阶段。 此外，大规模 临床试验正在进行中以确定他莫昔芬的潜力 作为高风险女性的化学预防剂 发展为乳腺癌。 然而多项研究引起了人们的担忧 超过这种药物长期治疗的安全性。 备用 抗雌激素药物，包括屈洛昔芬、托瑞米芬和艾多昔芬，可能不会 具有遗传毒性，可能是因为代谢途径不同 可能导致最终数量和/或类型的减少 致癌物质。 该项目的中心假设是 反应中间体的形成是一个重要机制 某些抗雌激素的致癌作用和/或细胞毒性。 为了 例如，他莫昔芬可以代谢成至少三种亲电子 反应性截然不同的代谢物：醌甲基化物， 碳正离子和邻醌。 提出以下具体目标： 1. 醌甲基化物、碳正离子和/或邻醌在 抗雌激素的致癌和细胞毒性作用。 致癌的 他莫昔芬、屈洛昔芬、 托瑞米芬和艾多昔芬将在 C3H1 OT1/2 细胞及其 在JB6细胞中检测肿瘤促进能力。 生化效应 抗雌激素及其代谢物的研究将在人体中进行 乳腺癌和子宫内膜癌细胞系。 2. 调查效果 亲电子和/或氧化还原反应性的反应性代谢结构。 取代基对亲电性/氧化还原能力的影响 抗雌激素活性中间体将通过测量进行研究 它们烷基化/氧化 DNA 的能力。 氧化还原活性代谢物将 通过监测还原辅因子的变化并确定 活性氧的形成。 3. 确定是否 抗雌激素代谢物的拮抗剂/激动剂活性与 雌激素受体阳性细胞系中 DNA 损伤的程度。 这 Ishikawa 细胞系统将用于测定雌激素 近羟基化物的抗雌激素和/或毒性作用 代谢物和最终的反应中间体。 细胞DNA来自 分离雌激素受体阳性和阴性细胞系 用测试化合物处理后。 DNA 将被水解为 脱氧核苷（从目标 2 中鉴定）并检查共价键 加合物和氧化损伤。 这些研究将极大地帮助 设计保持有益特性的雌激素拮抗剂 不产生遗传毒性代谢物。