CARCINOGENIC METABOLITES FORMED FROM ANTIESTROGENS

他莫昔芬仍然是治疗内分泌疾病的内分泌治疗选择。 所有阶段的乳腺癌。 此外，大规模 临床试验正在进行中，以确定他莫昔芬的潜力 作为一种化学预防剂，用于被认为有高风险的女性， 患上了乳腺癌 然而，一些研究引起了人们的关注， 长期使用这种药物的安全性 替代 抗雌激素药包括屈洛昔芬、托瑞米芬和艾多昔芬， 可能由于不同的代谢途径而具有遗传毒性， 可能会导致最终数量和/或类型的减少 致癌物质。 该项目的核心假设是， 反应性中间体的形成是一个重要的机制， 致癌作用和/或某些抗雌激素的细胞毒性。 为 例如，他莫昔芬可以被代谢成至少三种亲电子物质， 反应性非常不同的代谢物：醌甲基化物， 碳阳离子和邻醌。 建议的具体目标如下： 1.醌甲基化物、碳阳离子和/或邻醌在抗氧化剂中的作用 抗雌激素的致癌和细胞毒性作用。 致癌 他莫昔芬，屈洛昔芬， 托瑞米芬和艾多昔芬将在C3 H1 OT 1/2细胞中进行研究， 在JB 6细胞中检测肿瘤促进能力。 生物化学效应 抗雌激素及其代谢产物的研究将在人类 乳腺癌和子宫内膜癌细胞系。2.探讨了影响 反应性代谢物结构对亲电和/或氧化还原反应性的影响。 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 它们能够烷基化/氧化DNA。 氧化还原活性代谢物将 通过监测还原型辅因子的变化和确定 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DNA损伤程度。 的 将使用石川细胞系统来确定雌激素 抗雌激素和/或毒性作用 代谢物和最终的活性中间体。 细胞DNA来自 分离雌激素受体阳性和阴性细胞系 在用测试化合物处理之后。 DNA会被水解成 脱氧核苷（从目标2中鉴定），并检查共价 加合物和氧化损伤。 这些研究将大大有助于 保持有益特性的雌激素拮抗剂的设计 而不产生遗传毒性代谢物。

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.