MRP/GST Synergy in MDR

描述(申请人提供)：该实验室的工作研究了谷胱甘肽(GSH)与GSH结合和MRP介导的外排过程如何相互作用，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，我们已经测试了GSH转移酶(GST)和MRP1-3协同作用的假设，以赋予对亲电毒素的抗性。事实上，我们已经证明，GST同工酶和MRP同工酶的结合表达对一些亲电抗癌药物和致癌物的细胞毒性和基因毒性具有抵抗力。基于这些和其他最近的研究结果，这些研究建议扩展GSH、GSH结合和MRP相互作用调节细胞对外源物质的反应-与治疗和预防癌症密切相关的反应。概述了四个新的具体目标。 1)特定目的1将我们以前的细胞和生化研究结果应用于临床。这些先导性研究的长期目标是验证阿尔法类GST和MRP1的联合过度表达将对慢性淋巴细胞性白血病患者的治疗反应产生不利影响的假设。2)特异性目的2研究MRP1和GSH在抗癌药物米托蒽醌(MX)耐药和转运中的作用。这一目标是基于初步研究表明，MX是MRP1的底物，具有区别于其他MRP1底物的独特性质。3)特异性靶点3验证了GSTP1的特异性等位基因变异和表达的特异性MRP亚型是细胞对铂类抗癌药物耐药的重要决定因素的假设。 4)特殊目的4检验假设，在混合的肿瘤细胞群体中，基于GST和MRP表达的耐药细胞将影响不表达GST和MRP的邻近细胞的药物敏感性。

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.