Genotoxicity of Estrogen-and Anti-estrogen-DNA Adducts

描述（由申请人提供）：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，在啮齿动物中诱发肝癌，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是通过其遗传毒性作用介导的。本研究的目的是建立他莫昔芬和雌激素的基因毒性机制，并寻找一种更安全的他莫昔芬替代品。含有单一定义的DNA加合物的寡脱氧核苷酸将通过自动DNA合成制备。利用这些位点特异性修饰的寡脱氧核苷酸，雌激素和抗雌激素DNA加合物在哺乳动物细胞中的诱变和修复潜力将被确定。DNA双链中他莫昔芬和雌激素加合物的三维结构也将被建立，使我们能够了解发生在病变部位的致突变和修复事件的过程。这些修饰的寡脱氧核苷酸也将被用作超灵敏32p后标记和HPLC/电化学检测器分析的标准，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。综合起来，这些信息可用于预测遗传毒性。翻译研究已经被设计用来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志物，并探索他莫昔芬治疗与子宫内膜癌发展之间的关系。这项研究将为接受乳腺癌治疗和化学预防的妇女提供一种更安全的选择。

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.