NOVEL MECHANISM FOR TAMOXIFEN-INDUCED ENDOMETRIAL ATYPIA

他莫昔芬引起的子宫内膜异型性的新机制

• 批准号: 2896283
• 负责人: Kimberly K. Leslie
• 金额: $ 14.84万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896283
• 关键词: breast neoplasms; chemical carcinogenesis; clinical research; drug adverse effect; endometrium; enzyme activity; enzyme induction /repression; estrogen receptors; human genetic material tag; human subject; hyperplasia; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; oxygenases; progesterone receptors; protein isoforms; receptor expression; tamoxifen; uterus neoplasms

DESCRIPTION (Adapted from the Investigator's Abstract): Tamoxifen is the most common prescribed adjuvant therapy for breast cancer, and is taken daily by women throughout this nation and the world. The development of endometrial hyperplasia, cellular atypia, and new endometrial cancers are the most serious side effects of tamoxifen treatment. Our research team has been studying tamoxifen using endometrial and breast cancer cells grown in vitro, and our preliminary findings point to a novel mechanism by which tamoxifen causes cellular damage. An enzyme, flavin-containing monoxygenase 5 (FMO5), converts tamoxifen into a metabolic by-product tmf* that damages DNA. Tmf* binds to DNA and causes structural damage called adducts. Our preliminary data indicate that the production of FMO5 is controlled by the hormone progesterone, which in turn acts through the progesterone receptor. Progesterone receptors exist in two forms, A and B. Interestingly, we have shown that only the B form of the progesterone receptor stimulates the production of FMO5. We hypothesize that women who develop atypical endometrial growth or cancers in response to tamoxifen do so because their endometrial cells contain relatively high levels of the B form of the progesterone receptor, which under the influence of progesterone, stimulate the production of the enzyme FMO5. The steps in our hypothesis are: (1) Progesterone binds to progesterone receptor B - (2) Production of FMO5 - (3) Tamoxifen is metabolized into a reactive by-product, tmf* - (4) Tmf* binds to DNA causing structural damage (adducts) - (5) DNA mutations occur - (6) In rare cases, endometrial cancer develops. We now wish to test this hypothesis in patients. Using a safe and simple office technique, we have already begun to sample the endometria of women taking tamoxifen. We propose to test the endometrial samples for the presence of the B form of the progesterone receptor; we will then determine if FMO5 and DNA adducts indicative of structural DNA damage are increased. In addition, we will assay for estrogen receptors and other growth factors through which tamoxifen may act. Our long-term goal is to determine which factors best correlate with the eventual appearance of tamoxifen-induced endometrial abnormalities. By screening for these factors, we hope to identify those women who are at risk for developing endometrial cancer. A reliable screening test for endometrial cancer would make tamoxifen an even safer medicine for future generations of women who need it.

描述（改编自研究者摘要）：他莫昔芬是 最常见的处方辅助治疗乳腺癌，并采取 全国乃至全世界的妇女每天都在谈论这个问题。 的发展 子宫内膜增生、细胞增生和新发子宫内膜癌， 他莫昔芬治疗最严重的副作用。 我们的研究团队 一直在研究他莫昔芬使用子宫内膜和乳腺癌细胞生长在 我们的初步发现指出了一种新的机制， 他莫昔芬导致细胞损伤。 一种酶，含黄素的单加氧酶 5（FMO 5），将他莫昔芬转化为代谢副产物tmf*， DNA. Tmf* 与DNA结合并引起称为加合物的结构损伤。 我们 初步数据表明，FMO 5的生产是由 激素孕酮，这反过来又通过孕酮受体的作用。 孕激素受体存在两种形式，A和B。有趣的是， 表明只有孕激素受体的B型刺激 生产FMO 5。 我们假设那些发展成非典型性的女性 子宫内膜生长或癌症对他莫昔芬的反应是这样的， 子宫内膜细胞含有相对高水平的B型 孕酮受体，在孕酮的影响下，刺激 FMO 5酶的产生。 我们假设的步骤是：（1） 孕激素与孕激素受体B结合-（2）产生FMO 5-（3） 他莫昔芬被代谢成反应性副产物，tmf* -（4）Tmf* 结合 对DNA造成结构损伤（加合物）-（5）DNA突变发生-（6） 在极少数情况下，会发生子宫内膜癌。 我们现在想测试一下 患者的假设。 使用安全和简单的办公室技术，我们有 已经开始对服用他莫昔芬的妇女的尿道进行取样。 我们 建议检测子宫内膜样本中是否存在B型 孕酮受体;然后我们将确定FMO 5和DNA加合物 结构性DNA损伤的指标增加。 此外，我们将 雌激素受体和其它生长因子的测定， 他莫昔芬可能起作用。 我们的长期目标是确定哪些因素最适合 与他莫昔芬诱导的子宫内膜最终出现相关 异常 通过筛选这些因素，我们希望能够识别出 有患子宫内膜癌风险的妇女。 一个可靠 子宫内膜癌的筛查测试将使他莫昔芬更安全 为未来需要的女性提供药物。