GLUTATHIONE S TRANSFERASE MEDIATED MECHANISMS OF DRUG RESISTANCE

各种抗癌药物的成功可能会受到严重限制， 对这些药物产生了抗药性。 越来越多的证据 这强烈表明谷胱甘肽S-转移酶（GST）可能发挥作用， 在对烷基化的耐药性发展中的关键作用 化疗药物 GST在5种烷基化药物中的过表达 耐药细胞可能表明，这些多功能酶提供了 增强解毒机制，从而降低细胞毒性 化疗药物。 在某些细胞系中抑制GST， 至少部分逆转了 烷基化剂 根据这些和其他一些研究， 人们普遍认为烷化剂是细胞内失活的， 通过GSH/GST依赖的代谢，然而，GST- 在耐药细胞中的依赖性药物解毒尚未得到证实。 因此，在目前的研究中，我们建议纯化，表征和 比较与野生型相关的GST同工酶的性质 和耐药HS-Sultan骨髓瘤和人类小细胞肺癌 (NCI H-69）细胞。 我们还将量化烷基化的效率 这些同工酶在体外以及在野生环境中的试剂偶联 型和耐药细胞在培养物中生长，通过分离和 定量药物-GSH缀合物。 此外，各种磺胺 将评估它们对癌细胞的抑制作用 相关GST同工酶。 最后，最有效的各种 建议的GST磺酰胺抑制剂，将进行评估， 在抗性细胞中烷化剂细胞毒性的增强， 以及在耐药细胞在裸鼠体内生长的肿瘤中。 这将 通过培养耐药细胞或注射裸鼠 （具有来自耐药）细胞的肿瘤）沿着烷化剂。 这些研究的结果预计将有助于界定的作用， GST在烷化剂耐药方面也将提供无价的 在制定有效治疗癌症的策略方面提供信息。

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.