DNA DAMAGE IN HUMAN ENDOMETRIUM BY TAMOXIFEN TREATMENT

描述：他莫昔芬(TMX)是一种抗雌激素化合物，用于 乳腺癌和其他癌症的治疗。接受TMX治疗的女性已经 据报道，罹患该病的风险增加了6倍 子宫癌。来自申请人实验室的研究表明 TMX的使用可能导致人类DNA损伤的形成 子宫内膜。在这些研究中，申请人建议：(1)收集 子宫内膜活检样本取自一组服用不同TMX的妇女。 患者的医疗记录将用于评估TMX的使用情况，并 问卷将被用来分析其他变量，包括年龄， 更年期状态和吸烟史。(2)测量TMX水平 子宫内膜样本中的代谢物和子宫过氧化物酶活性。 这些测量将被视为TMX内部剂量的生物标记物 以及个体激活TMX代谢物形成DNA损伤的能力。 (3)测定DNA加合物和8-羟基脱氧-7，8- 子宫内膜样本中的二氢鸟苷将尝试 确认在子宫内膜样本中检测到的加合物是衍生的 用高效液相色谱-质谱仪直接分析从TMX中提取。 (4)鉴定4-羟基-TMX形成的DNA加合物的结构。(5) 开发一个模型来测试TMX使用和 DNA加合物和8-羟基脱氧-7，8-二氢鸟苷的形成 子宫内膜样本。申请人将寻求确定是否有 相关性被TMX代谢物的任一水平改变 子宫内膜样本、子宫过氧化物酶活性或吸烟 历史。关于这一假设，已经考虑了统计能力。 服用TMX会导致脑组织中DNA损伤的形成 人子宫内膜。

DESCRIPTION: Tamoxifen (TMX) is an antiestrogenic compound used in the treatment of breast and other cancers. Women treated with TMX have been reported to show up to a 6-fold increased risk for the development of uterine cancer. Studies from the applicant's laboratory suggest that TMX usage may result in the formation of DNA damage in human endometrium. In these studies the applicant proposes to: (1) collect endometrial biopsy samples from a group of women with varying TMX usage. Patient medical records will be used to asses TMX usage and a questionnaire will be used to analyze other variables includin age, menopausal status, and tobacco history. (2) Measure levels of TMX metabolites and uterine peroxidase activity in the endometrial samples. These measurements will be treated as biomarkers of internal TMX dose and individual capacity to activate TMX metabolites to form DNA damage. (3) Measure levels of DNA adducts and 8-hydroxydeoxy-7,8- dihydroguanosine in the endometrial samples Attempts will be made to verify that the adducts detected in the endometrial samples are derived from TMX by direct analysis with liquid chromatography-mas spectrometry. (4) Identify the structure of the DNA adduct formed by 4-OH-TMX. (5) Develop a model to test for associations between TMX usage and the formation of DNA adducts and 8-hydroxydeoxy-7,8-dihydroguanosine in endometria samples. The applicant will seek to determine if any association is modified by either levels of TMX metabolites in endometrial samples, activity of uterine peroxidase, or tobacco smoking history. Statistical power has been considered regarding the hypothesis that administration of TMX results in the formation of DNA damage in human endometrium.