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，因为 对这些药物产生了抗药性。越来越多的证据 强烈提示谷胱甘肽S转移酶(GSTS)可能在 在烷基化耐药性形成中的关键作用 化疗药物。谷胱甘肽转移酶在五烷化药物中的过度表达 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。对某些细胞系中GSTs的抑制作用 已被证明至少部分逆转了对 烷基化试剂。基于这些和其他一些研究，它是 人们普遍认为烷基化药物在细胞内失活 然而，通过依赖于GSH/GST的代谢，GST- 依赖药物在耐药细胞中的解毒作用尚未得到证实。 因此，在目前的研究中，我们建议提纯、表征和 野生型谷胱甘肽转移酶同工酶S的性质比较 耐药HS-Sultan骨髓瘤和人小细胞肺癌 (NCI H-69)细胞。我们还将量化烷基化反应的效率。 这些同工酶在体外和野外对药物的偶联作用 通过分离和分离在培养中生长的类型和耐药细胞 定量药物-谷胱甘肽偶联物。此外，各种磺胺类药物 将评估它们对癌细胞的抑制作用 相关的GST同工酶。最后，在各种方法中，最有效的 将对GST的建议磺胺类抑制剂进行评估 烷化剂对AS耐药细胞的细胞毒性增强作用 耐药细胞在裸鼠体内生长的肿瘤也是如此。这将是 是通过培养耐药细胞或注射裸鼠来实现的 (有耐药细胞的肿瘤)以及烷化药物。 这些研究的结果预计将有助于描绘出 GST在烷化剂耐药性方面也将提供无可估量的 在制定有效治疗癌症的战略方面的信息。

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.