2-METHOXYESTRADIOL & HORMONAL CANCER

2-甲氧基二醇

• 批准号: 6612121
• 负责人: BAO-TING ZHU
• 金额: $ 20.72万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6612121
• 关键词: SDS polyacrylamide gel electrophoresis; affinity chromatography; angiogenesis; apoptosis; breast neoplasms; catechol methyltransferase; cell growth regulation; cell line; cell proliferation; cell surface receptors; enzyme inhibitors; estradiol; high performance liquid chromatography; hormone related neoplasm /cancer; laboratory rat; mass spectrometry; neoplastic growth; polymerase chain reaction; tissue /cell culture

DESCRIPTION (provided by applicant): 2-Methoxyestradiol (2-MeO-E2) is a nonpolar endogenous estrogen metabolite formed by metabolic O-methylation of 2-hydroxyestradiol (the most abundant hydroxyestrogen metabolite in humans). 2-MeO-E2 has anti-proliferative, apoptotic, and antiangiogenic actions at nonphysiological high concentrations. This grant application has two overall goals: (i) to study the molecular mechanism(s) of 2-MeO-E2's action by searching for its specific cellular receptor in human breast cancer cell lines. We will isolate a specific, high-affinity cellular receptor for 2-MeO-E2 present in human breast cancer cells, and we will determine its protein and DNA sequences (described under Specific Aim 1). (ii) To determine whether the endogenously-formed or exogenously-administered 2-MeO-E2 (at physiologically-relevant concentrations) has chemoprotective effects against estrogen-induced mammary tumor formation in a commonly-used animal model. We will determine the potency and efficacy of the exogenously-administered 2-MeO-E2 for protection against estradiol-induced mammary tumorigenesis in female ACI rats, and we will also evaluate the mammary cancer-protective effects of the endogenously-formed 2-MeO-E2 by determining whether chronic administration of entacapone (a selective COMT inhibitor) alters estradiol-induced mammary carcinogenesis in the female ACI rats. These studies are described under Specific Aims 2, 3, and 4. Our proposed studies are expected to advance our knowledge on the mammary cancer-protective effects of 2- MeO-E2, a nonpolar endogenous estrogen metabolite formed in large amounts in humans. This knowledge will form the basis for future development of new approaches to the prevention of human mammary cancer by administration of "physiological doses" of 2-MeO-E2 (or its synthetic analogs), or by using agents that can alter the metabolic formation and/or disposition of endogenous 2-MeO-E2 in beneficial ways. The results will also provide novel mechanistic understanding for the biological actions of 2-MeO-E2.

描述（由申请人提供）：2-甲氧基雌二醇（2-MeO-E2）是一种非极性内源性雌激素代谢产物，该代谢物是由2-羟基雌二醇的代谢O-甲基化形成的（人类最丰富的羟基酯代谢物）。 2-MeO-E2在非生理学高浓度下具有抗增殖，凋亡和抗血管生成作用。该赠款应用有两个总体目标：（i）通过在人类乳腺癌细胞系中寻找其特定的细胞受体来研究2-MeO-E2作用的分子机制。我们将分离出人类乳腺癌细胞中2-MeO-E2的特异性高亲和力细胞受体，并确定其蛋白质和DNA序列（在特定目标1中进行了描述）。 （ii）确定内源形成或外源性化的2-MeO-E2（在生理上与生理含量相关的浓度）是否具有对雌激素诱导的乳腺肿瘤形成的化学保护作用。 We will determine the potency and efficacy of the exogenously-administered 2-MeO-E2 for protection against estradiol-induced mammary tumorigenesis in female ACI rats, and we will also evaluate the mammary cancer-protective effects of the endogenously-formed 2-MeO-E2 by determining whether chronic administration of entacapone (a selective COMT inhibitor) alters estradiol-induced mammary雌性ACI大鼠的致癌作用。这些研究是在特定目标2、3和4中描述的。我们提出的研究有望提高我们对2-MEO-E2的乳腺癌保护作用的了解，这是一种非极性内源性雌激素代谢物，在人类中大量形成。这些知识将构成未来开发新方法来预防人类乳腺癌的基础，该方法通过给予2-MeO-E2（或其合成类似物）的“生理剂量”，或者使用可以改变内源性2-Meo-E2的代谢形成和/或以有益的方式改变代谢形成和/或处置的药物。结果还将为2-MEO-E2的生物学作用提供新的机械理解。