Success of various anticancer drugs could be severely limited due to acquired resistance against these drugs. Increasing body of evidence strongly suggests that glutathione S-transferase (GSTs) might play a crucial role in the development of drug resistance against alkylating chemotherapeutic drugs. Over-expression of GST in may alklylating drug resistant cells may suggest that these multi-functional enzymes provide enhanced detoxification mechanisms and thereby reduce the cytotoxicity of chemotherapeutic drugs. Inhibition of GSTs in some cells lines, has been shown to at least partially reverse the resistance against alkylating agents. Based on these and a number of other studies, it is widely assumed that alkylating drugs are intracellularly inactivated through GSH/GST-dependent metabolism, however, direct role of GST- dependent drug detoxification in resistant cells in not proved. Therefore, in the present studies we propose to purify, characterize and compare the properties of GST isoenzyme(s) associated with the wild type and drug resistant HS-Sultan myeloma and human small cell lung cancer (NCI H-69) cells. We will also quantitate the efficiency for alkylating agent conjugation by these isoenzymes in vitro as well as in the wild type and drug resistant cells growth in culture, by isolating and quantitating the drug-GSH conjugates. In addition, various sulfonamides will be evaluated for their inhibitory effects on the cancer cell associated GST isoenzymes. Finally, the most effective of the various proposed sulfonamide inhibitors of GST, will be evaluated for potentiation of alkylating agent cytotoxicity in the resistant cells as well as in tumors grown in nude mice from the resistant cells. This will be achieved by incubating the resistant cells or injecting the nude mice (having tumors from resistant) cells) along with the alkylating drugs. The results of these studies are expected to help delineate the role of GST in alkylating agent drug resistance and will also provide invaluable information in developing strategies for effective treatment of cancer.
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