GLUTATHIONE/GLUTATHIONE S TRANSFERASE MEDIATED MECHANISMS OF DRUG RESISTANCE

尽管对化疗的初步反应令人印象深刻，但大多数 患者最终对他们的疾病有所缓解，主要是因为 对引起感染的化疗药物产生抗药性 治疗失败。在过去的十年里，人们越来越关注 重点是确定谷胱甘肽(GSH)和GSH依赖的作用 解毒系统，特别是谷胱甘肽-S-转移酶的作用， 谷胱甘肽过氧化物酶(GSH-Px)、谷氨酰半胱氨酸合成酶(GTP) 谷胱甘肽连接-谷胱甘肽共轭外排泵对沙门氏菌的耐药性 烷基化试剂。谷胱甘肽与DNA竞争药物的能力 有约束力的。GST介导的GSH与不同烷基化试剂的偶联反应 已经建立了。我们对顺铂耐药的初步研究 耐药骨髓瘤细胞系中少量GSH含量表明 抗性细胞中GSH含量明显升高。虽然 GST活性在野生型和抗性细胞中是相同的，两者 细胞系表现出明显的K/m值差异和对 GST的抑制剂。这些研究表明，细胞的初级结构 在获得抗性期间，抗性细胞的GST可能会改变 或者，在我的抗性细胞中，GST的一个多态变体过度表达。 因此，我们建议研究GST的一级结构 用经典化学方法鉴定野生型和抗性细胞 和基因测序方法，并比较了它们的微观结构 异质性。由于抗性细胞被认为保持了相对 高水平的GSH，我们还建议研究GSH水平和 谷胱甘肽代谢酶的活性及其mRNA水平。在……里面 此外，谷胱甘肽结合转运蛋白在出口中的作用 潜在的细胞毒结合物及其在耐药中的意义 将会被评估。预计拟议的研究将显著 有助于了解烷基化剂的作用机理 并为长期目标提供宝贵的信息 制定策略以防止对烷基化的耐药性 化疗期间的药物。

Despite impressive initial response to chemotherapy, the majority of the patients eventually relent to their disease primarily because of acquisition of resistance against the chemotherapeutic drugs which cause treatment failure. In the last decade, increasing attention has been focused on establishing the role of glutathione (GSH) and GSH-dependent detoxification system, particularly the role of GSH-S-transferase (GST), GSH-peroxidase (GSH-PX), gamma-glutamyl cysteine synthetase (gamma-GTP) and GSH-linked-GSH conjugate efflux pump in drug resistance against alkylating agents. An ability of GSH to compete with the DNA for drug binding. GST mediated conjugation of GSH with various alkylating agents has been established. Our preliminary studies with cisplatin resistant small levels of GSH content in the resistant myeloma cell line indicated distinctly higher levels of GSH content in the resistant cells. Although the GST activity is same in the wild type and resistant cells, the two cell lines show apparent differences in K/m values and sensitivities to inhibitors of the GST. These studies suggest that primary structures of GST of the resistant cells may be altered during acquisition of resistance or a polymorphic variant of a GST is over expressed in my resistant cells. We are, therefore proposing to investigate the primary structure GST of the wild type and resistant cells by classical chemical characterization and gene sequencing methods, and compare their structures of micro- heterogeneity. Since resistant cells are believed to maintain relatively high levels of GSH, we also proposes to investigate the GSH levels and activities of enzymes of GSH metabolism and their mRNA levels. In addition, the role of the GSH-conjugate transporter protein in the export of potentially cytotoxic conjugates and it significance in drug resistance will be evaluated. The proposed studies are expected to significantly contribute towards understanding the mechanism of alkylating agent resistance and provide invaluable information for the long term goals of developing strategies to prevent drug resistance against the alkylating agents during chemotherapy.