Action of Novel Retinyl Ethers in Breast Cancer Control

新型视黄基醚在乳腺癌控制中的作用

• 批准号: 7119590
• 负责人: BRAHMA P SANI
• 金额: $ 29.03万
• 依托单位: CHEMOPREVENTIA, LLC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119590
• 关键词: MCF7 cell; breast neoplasms; chemical synthesis; chemoprevention; drug metabolism; fluorescence microscopy; gel mobility shift assay; glutathione transferase; high performance liquid chromatography; laboratory rat; nuclear receptors; prodrugs; protein isoforms; protein purification; protein structure function; protein transport; receptor binding; retinoid binding proteins; retinoids

DESCRIPTION (provided by applicant): Retinoids are in clinical trials in the prevention and treatment of different types of cancer. We observed that a group of retinoids called retinyl ethers exhibit tissue-specific chemopreventive activity against carcinogen-induced mammary tumors in rats. We also observed that the active retinyl ethers specifically bind to cellular retinol binding protein (CRBP) even though they lack an active OH group. We are now focusing, through a multidisciplinary approach, on the development of two novel series of retinyl ethers and elucidation of their mechanism of action in cancer prevention. The new retinoic acid receptor (RAR and RXR)-selective all-trans- and 9-cis-retinoids will be evaluated for their chemopreventive potential against methylnitrosourea-induced mammary cancer in rats. We will determine the binding affinity of the ethers for CRBP and serum retinol binding protein (RBP), and assess whether a correlation exists between these affinities and their biological potency in different assays. We will evaluate, in MCF-cells as well as in a reconstituted system, whether the retinyl ethers act as such, or as pro-drugs that are metabolized to an active form subsequent to CRBP-binding. We will also study, analogous to retinoic acid (RA) import, the possible existence of a CRBP-dependent channeling for transmigration of the ethers/retinol to the nuclei of MCF cells. We will further elucidate the role, if any, for the ethers, albeit poor binders of RARs/RXRs, in RAR/RXR homo- and hetero-dimerization, as well as transcriptional complex formation with the RA-response elements. By using gel mobility shift assays and glutathione S-transferase assays, we will also evaluate if the antagonistic action of retinyl ethers is via a modulation of co-activators/co-repressors of RARs/RXRs. An understanding of the metabolic fate and the mode of action of retinyl ethers is critical for the rational development of the new retinoids in the control of breast cancer.

描述（由申请人提供）：类视黄素在预防和治疗不同类型癌症的临床试验中。我们观察到，一组称为视乙烯基醚的类维生素类动物表现出针对致癌物诱导的大鼠乳腺肿瘤的组织特异性化学预防活性。我们还观察到，活性视网膜乙醇具有特异性结合与细胞视黄醇结合蛋白（CRBP），即使它们缺乏活性OH组。现在，我们通过一种多学科的方法将重点放在开发两个新型的视网膜类醚系列，并阐明其在癌症预防中的作用机理。新的视黄酸受体（RAR和RXR）选择性全反trans和9-Cis-类替素的方法将被评估，以针对大鼠甲基硝基苯甲酸诱导的乳腺癌的化学预防潜力。我们将确定乙醇对CRBP和血清视黄醇结合蛋白（RBP）的结合亲和力，并评估这些亲和力之间是否存在相关性及其在不同测定中的生物效能之间存在相关性。我们将在MCF细胞以及重建的系统中评估视网膜醚的作用，还是在CRBP结合后代谢为活性形式的亲毒品。我们还将研究类似于视黄酸（RA）的进口，可能存在CRBP依赖性通道，用于将乙醇/视黄醇迁移到MCF细胞的核。我们将进一步阐明Ethers的作用（如果有的话），尽管RAR/RXRS的较差的粘合剂在RAR/RXR HOMO-和异方差二聚体中以及与RA-RESPONSE元件的转录复合物形成。通过使用凝胶迁移率转移测定和谷胱甘肽S-转移酶测定，我们还将评估视网膜醚的拮抗作用是否是通过调节RARS/RXRS的共激活器/共抑制器的调节。对新陈代谢的命运和视黄乙基醚的作用方式的理解对于在控制乳腺癌中的新类维生素类动物的合理发展至关重要。