MRP/GST Synergy in MDR

MDR 中的 MRP/GST 协同作用

• 批准号: 7404439
• 负责人: CHARLES S MORROW
• 金额: $ 26.02万
• 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/7404439
• 关键词: ABCC1 gene; ATP-Binding Cassette Transporters; Affect; Antineoplastic Agents; Biochemical; Biological; Carcinogens; Cells; Class; Clinic; DNA; Drug resistance; Enzymes; Family; GSTP1 gene; Genetic Variation; Glutathione; Goals; Isoenzymes; Laboratories; Ligand Binding; Measurable; Mediating; Mitoxantrone; Nuclear Receptors; Patients; Pharmaceutical Preparations; Pilot Projects; Population; Process; Property; Protein Isoforms; Protein Overexpression; Resistance; Role; Testing; Toxin; Transferase; Work; Xenobiotics; base; cancer cell; cancer prevention; cytotoxicity; drug sensitivity; genotoxicity; glutathione S-transferase pi; member; neoplastic cell; response

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) 以及 GSH 结合过程和 MRP 介导的外排如何相互作用，从而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，我们测试了 GSH 转移酶 (GST) 和 MRP1-3 协同作用以赋予对亲电子毒素的抗性的假设。事实上，我们已经证明，GST 同工酶与 MRP 同工酶的联合表达赋予对某些亲电子癌症药物和致癌物的细胞毒性和基因毒性的抵抗力。基于这些和其他最近的结果，这些研究提出了以下主题：GSH、GSH-结合和 MRP 相互作用调节细胞对异生素的反应，这与癌症的治疗和预防密切相关。概述了四个新的具体目标。 1) 具体目标 1 将我们之前的细胞和生化研究获得的结果应用于临床。这些试点研究的长期目标是检验以下假设：α 类 GST 和 MRP1 联合过度表达会对 CLL 患者的治疗反应产生不利影响。 2) 具体目标 2 检查 MRP1 和 GSH 在抗癌药物米托蒽醌 (MX) 的抵抗和转运中的作用。这一目标基于初步研究，表明 MX 是 MRP1 的底物，具有独特的特性，将其运输与其他 MRP1 底物的运输区分开来。 3) 具体目标 3 检验以下假设：GSTP1 的特定等位基因变体以及表达的特定 MRP 亚型是细胞对 Pt 抗癌药物耐药性的重要决定因素。 4) 具体目标4检验了以下假设：在肿瘤细胞的混合群体中，基于GST和MRP表达而产生耐药性的细胞将影响不表达GST和MRP的邻近细胞的药物敏感性。