Genotoxicity of Estrogen-and Anti-estrogen-DNA Adducts

描述（由申请方提供）：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，可诱导啮齿动物肝癌，并与女性子宫内膜癌相关。雌激素也与子宫内膜癌和乳腺癌的病因有关。这些物质的致癌性可能通过其遗传毒性效应介导。本研究的目的是建立他莫昔芬和雌激素的遗传毒性机制，并找到一个更安全的替代他莫昔芬。将通过自动化DNA合成制备含有单一确定DNA加合物的寡脱氧核苷酸。使用这些位点特异性修饰的寡脱氧核苷酸，将确定哺乳动物细胞中雌激素和抗雌激素DNA加合物的致突变和修复潜力。还将建立他莫昔芬和雌激素加合物在DNA双链体中的三维结构，使我们能够了解在损伤部位发生的致突变和修复事件的过程。这种修饰的寡脱氧核苷酸也将被用作超灵敏的32 P-后标记和HPLC/电化学检测器分析的标准品，这些分析旨在量化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。总之，这些信息可用于预测遗传毒性。已设计转化研究来检测接受他莫昔芬或托瑞米芬治疗的患者的子宫内膜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志物，并探索他莫昔芬治疗与接受这种药物治疗的妇女发生子宫内膜癌之间的关系。这项研究应该为接受乳腺癌治疗和化学预防的妇女提供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.