Genotoxicity of Estrogen-and Anti-estrogen-DNA Adducts

描述(申请人提供)：他莫昔芬是一种用于乳腺癌内分泌治疗和化学预防的抗雌激素，可诱发啮齿类动物的肝癌，并与女性的子宫内膜癌有关。雌激素也与子宫内膜癌和乳腺癌的病因学有关。这些药物的致癌作用可能是通过它们的遗传毒性作用来实现的。这项研究的目的是建立他莫昔芬和雌激素的遗传毒性机制，并找到比他莫昔芬更安全的替代品。含有单一定义的DNA加合物的寡聚脱氧核苷酸将通过自动DNA合成来制备。利用这些定点修饰的寡核苷酸，将确定哺乳动物细胞中雌激素和抗雌激素DNA加合物的诱变和修复潜力。还将建立DNA双链中他莫昔芬和雌激素加合物的三维结构，使我们能够了解发生在病变部位的诱变和修复事件的过程。这种修饰的寡核苷酸还将被用作超灵敏的32P-后标记和高效液相/电化学检测器分析的标准，旨在定量使用这些药物治疗的啮齿动物和猴子组织中的DNA加合物和氧化损伤损伤。综上所述，这些信息可以用于预测遗传毒性。翻译研究的目的是检测接受他莫昔芬或托瑞米芬治疗的患者子宫内膜DNA中的加合物。这些实验将为分子流行病学研究提供生物标记物，并探索三苯氧胺治疗与使用该药物治疗的妇女子宫内膜癌发展的关系。这项研究应该会为接受乳腺癌治疗和化学预防的女性带来一种更安全的替代方案。

DESCRIPTION (provided by applicant): Tamoxifen, an antiestrogen used in the endocrine therapy and chemoprevention of breast cancer, induces liver cancer in rodents and is associated with endometrial cancer in women. Estrogens also are implicated in the etiology of endometrial and breast cancer. The carcinogenicity of these agents may be mediated through their genotoxic effects. The goals of this research are to establish a mechanism for the genotoxicities of tamoxifen and estrogen and to find a safer alternative to tamoxifen. Oligodeoxynucleotides containing a single defined DNA adduct will be prepared by automated DNA synthesis. Using these site-specifically modified oligodeoxynucleotides, the mutagenic and repair potential of estrogen and anti-estrogen DNA adducts in mammalian cells will be determined. The three dimensional structure of tamoxifen- and estrogen adducts in DNA duplex also will be established, permitting us to understand the process of mutagenic and repair events which occur at lesion sites. Such modified oligodeoxynucleotides also will be employed as standards in ultrasensitive 32P-postlabeling and HPLC/electrochemical detector analyses designed to quantify DNA adducts and oxidatively damaged lesions in the tissues of rodents and monkeys treated with these drugs. Taken together, this information can be used to predict genotoxicity. Translational studies have been designed to detect adducts in the endometrial DNA of patients undergoing treatment with tamoxifen or toremifene. These experiments will provide biomarkers for molecular epidemiological studies and explore the relationship between tamoxifen therapy and the development of endometrial cancer in women treated with this drug. This research should lead to a safer alternative for women undergoing breast cancer therapy and for chemoprevention.