MRP/GST Synergy in MDR

MDR 中的 MRP/GST 协同作用

• 批准号: 7069519
• 负责人: CHARLES S MORROW
• 金额: $ 26.8万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-10 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069519
• 关键词: antineoplastics; antitoxins; cell free system; chemical conjugate; chronic lymphocytic leukemia; clinical research; detoxification; drug interactions; drug metabolism; drug screening /evaluation; enzyme activity; enzyme substrate; flow cytometry; fluorescence microscopy; gene expression; glutathione transferase; isozymes; melphalan; membrane transport proteins; mitoxantrone; multidrug resistance; neoplasm /cancer pharmacology; pharmacokinetics; protein protein interaction; tissue /cell culture

DESCRIPTION (provided by applicant): Work in this laboratory has examined how glutathione (GSH) and the processes of GSH conjugation and MRP-mediated efflux interact to influence the sensitivities of cells to anticancer drugs, carcinogens and other cellular toxins. In particular, we have tested the hypothesis that GSH transferases (GST) and MRP1-3 act in synergy to confer resistance to electrophilic toxins. Indeed, we have shown that combined expression of isozymes of GST with isoforms of MRP confers resistance to the cytotoxicities and genotoxicities of some electrophilic cancer drugs and carcinogens. Based upon these and other recent results, the studies proposed expand upon the theme that GSH, GSH-conjugation, and MRP interactions modulate cellular responses to xenobiotics-responses that are germane to the treatment and prevention of cancer. Four new specific aims are outlined. 1) Specific aim 1 applies to the clinic the results obtained from our previous cellular and biochemical studies. The long-term goal of these pilot studies is to test the hypothesis that combined overexpression of alpha class GST and MRP1 will adversely affect treatment response in patients with CLL. 2) Specific aim 2 examines the role of MRP1 and GSH in resistance to and transport of the anticancer drug mitoxantrone (MX). This aim is based upon preliminary studies suggesting that MX is a substrate of MRP1 with unique properties that distinguish its transport from that of other MRP1 substrates. 3) Specific aim 3 tests the hypothesis that the specific allelic variants of GSTP1 as well as the particular MRP isoform expressed are important determinants of cellular resistance to Pt-based anticancer drugs. 4) Specific aim 4 examines the hypothesis that, in a mixed population of tumor cells, cells that are drug resistant on the basis of expression of GST and MRP will influence the drug sensitivities of neighboring cells that do not express GST and MRP.

描述（由申请人提供）：本实验室的工作研究了谷胱甘肽（GSH）和GSH结合过程以及MRP介导的外排如何相互作用，以影响细胞对抗癌药物、致癌物和其他细胞毒素的敏感性。特别是，我们已经测试的假设，谷胱甘肽转移酶（GST）和MRP 1 -3的协同作用，赋予亲电毒素的抗性。事实上，我们已经表明，GST同工酶与MRP同工酶的联合表达赋予了对某些亲电子癌症药物和致癌物的细胞毒性和遗传毒性的抗性。基于这些和其他最近的结果，这些研究扩展了GSH，GSH结合和MRP相互作用调节细胞对外源性物质的反应的主题，这些反应与癌症的治疗和预防密切相关。提出了四个新的具体目标。 1)具体目标1适用于临床从我们以前的细胞和生化研究中获得的结果。这些初步研究的长期目标是检验α类GST和MRP 1的联合过表达将对CLL患者的治疗反应产生不利影响的假设。 2)具体目标2检查MRP 1和GSH在抗癌药物米托蒽醌（MX）的耐药性和转运中的作用。这一目标是基于初步研究，表明MX是MRP 1的底物，具有独特的性质，将其转运与其他MRP 1底物的转运区分开来。 3)具体目标3测试了以下假设：GST 1的特定等位基因变体以及表达的特定MRP同种型是细胞对基于Pt的抗癌药物的耐药性的重要决定因素。 4)具体目标4检验了这样的假设，即在肿瘤细胞的混合群体中，基于GST和MRP表达的耐药细胞将影响不表达GST和MRP的相邻细胞的药物敏感性。