Genotoxicity of Estrogen Compounds in Endocrine Therapy

描述（由申请人提供）：雌激素替代疗法（ERT）被广泛用于减少与绝经相关的症状，并保护妇女免受骨质疏松症。雌激素替代疗法由雌激素、马雌激素和马雌激素组成，与乳腺癌、卵巢癌和子宫内膜癌的风险增加有关。由于雌激素和马雌激素的主要代谢产物产生氧化性DNA损伤，并且在某些情况下与DNA反应形成共价加合物，因此DNA损伤可能在雌激素相关癌症的起始中起核心作用。拟定研究旨在测定用马雌激素或其代谢产物处理的大鼠乳腺和生殖组织中产生的共价DNA加合物和氧化损伤水平，以及确定马雌激素衍生DNA加合物的致突变和修复潜力。将从接受ERT的女性中收集白细胞和子宫内膜组织，并使用我们实验室开发的超灵敏32 P-后标记和HPLC/电化学检测技术分析DNA加合物。如果这种加合物没有完全修复，DNA损伤将在靶组织中持续存在，它们可能引发乳腺癌、卵巢癌和/或子宫内膜癌。通过证明ERT的某些成分具有遗传毒性，并通过定义所涉及的生化机制，应该可以设计出保留ERT理想治疗特性但不具有致癌作用的药物。这项研究还将提供生物标志物，可用于识别发展ERT诱发癌症的高风险女性亚组。

DESCRIPTION (provided by applicant): Estrogen replacement therapy (ERT) is widely used to decrease symptoms associated with menopause and to protect women against osteoporosis. ERT, composed of estrogens, equilin, and equilenin, is associated with increased risk of breast, ovarian, and endometrial cancers. As the major metabolites of estrogen and equine estrogen generate oxidative DNA damage and, in some cases react with DNA to form covalent adducts, it is possible that DNA damage plays a central role in the initiation of estrogen-associated cancers. The proposed studies are designed to determine the level of covalent DNA adducts and oxidative damage generated in mammary and reproductive tissues of rats treated with equine estrogens or their metabolites, as well as establish the mutagenic and repair potential of equine estrogen-derived DNA adducts. Leukocytes and endometrial tissue will be collected from women receiving ERT and analyzed for DNA adducts using ultrasensitive 32P-postlabeling and HPLC/electrochemical detection techniques developed in our laboratory. If such adducts are not fully repaired, DNA lesions will persist in target tissues where they may initiate breast, ovarian, and/or endometrial cancer. By demonstrating that certain components of ERT are genotoxic and by defining the biochemical mechanism involved, it should be possible to design drugs that retain desirable therapeutic properties of ERT but lack its carcinogenic effects. This research will also provide biomarkers that can be used to identify subgroups of women at high risk of developing ERT-induced cancer.