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.
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