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 i s 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.
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