CARCINOGENIC METABOLITES FORMED FROM ANTIESTROGENS

他莫昔芬仍是治疗慢性阻塞性肺疾病的首选内分泌疗法 激素依赖型乳腺癌的所有阶段。此外，大规模的 临床试验正在进行中，以确定他莫昔芬的潜力 在被认为是癌症高危人群的女性中充当化学预防药物 罹患乳腺癌。然而，有几项研究引起了人们的关注 使用这种药物进行慢性治疗的安全性。替代方案 包括屈洛昔芬、托瑞米芬和依多昔芬在内的抗雌激素药物可能不会 基因毒性可能是因为不同的代谢途径 可能会导致最终数量和/或类型的减少 致癌物(S)。这个项目的中心假设是 活性中间体的形成是一种重要的反应机制 某些抗雌激素的致癌和/或细胞毒性。为 例如，他莫昔芬可以被代谢成至少三个亲电的 反应性差异很大的代谢物：甲基苯醌， 碳正离子和邻苯二酚。提出了以下具体目标： 1.甲基对苯二酚、碳正离子和/或邻苯二酚在 抗雌激素的致癌和细胞毒性作用。致癌物质 他莫昔芬、屈洛昔芬、 托瑞米芬和依多昔芬将在C3H1 OT1/2细胞和他们的 在JB6细胞中检测促肿瘤能力。生化效应 抗雌激素及其代谢物的研究将在人类身上进行 乳腺和子宫内膜癌细胞株。2.调查 反应性代谢产物结构对亲电性和/或氧化还原反应性的影响。 取代基对体系亲电性/氧化还原能力的影响 将通过测量来研究抗雌激素活性中间体 它们使DNA烷化/氧化的能力。氧化还原活性代谢物将 通过监测减少的余因的变化和通过确定 活性氧物种的形成。3.确定是否 抗雌激素代谢产物的拮抗剂/激动剂活性与 雌激素受体阳性细胞系的DNA损伤程度。这个 石川细胞系统将用于测定雌激素 羟基化合物的抗雌激素和/或毒性作用 代谢物和最终的活性中间体。细胞DNA来自 将分离雌激素受体阳性和阴性细胞系 在用试验化合物处理后。DNA将被水解到 脱氧核苷(从目标2鉴定)并检查共价 加合物和氧化损伤。这些研究将极大地帮助 保持有益特性的雌激素拮抗剂的设计 不会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.