Gaté Laurent, Tew Kenneth D
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Expert Opin Ther Targets. 2001 Aug;5(4):477-489. doi: 10.1517/14728222.5.4.477.
Glutathione S-transferases (GST) represent a large family of Phase II detoxification enzymes widely expressed in animals and plants. These enzymes catalyse the conjugation of glutathione with some endogenous molecules and a broad range of exogenous substrates including various anticancer drugs. Due to high expression of GSTs in tumours when compared to normal tissues and their high level in plasma from cancer patients, these enzymes are considered to be cancer markers. Their involvement in resistance to anticancer drugs and an inverse correlation between expression and prognosis in many tumours provided a rationale for the design of inhibitors and prodrugs to enhance therapeutic index. The first generation of GST inhibitors included ethacrynic acid and showed promising potentiating activity in vitro but lack of isoenzyme specificity and diuretic side effects restricted clinical use. Novel GST inhibitors include glutathione analogues and demonstrate better specificities with fewer limiting toxicities. One lead compound is a potent inhibitor of the GSTP1-1 isoform in both cell lines and animal models. A GSTP1-1 activated prodrug has also been developed. Testing of the preclinical and clinical efficacy of these agents is presently in progress. Their rational design provides a promising new approach to targeting tumour-specific characteristics in a manner consistent with improving therapeutic index.
谷胱甘肽S-转移酶（GST）是一类在动植物中广泛表达的Ⅱ相解毒酶大家族。这些酶催化谷胱甘肽与一些内源性分子以及包括各种抗癌药物在内的多种外源性底物结合。与正常组织相比，GST在肿瘤中高表达，且在癌症患者血浆中含量也很高，因此这些酶被认为是癌症标志物。它们参与对抗癌药物的耐药性，并且在许多肿瘤中其表达与预后呈负相关，这为设计增强治疗指数的抑制剂和前药提供了理论依据。第一代GST抑制剂包括依他尼酸，在体外显示出有前景的增效活性，但缺乏同工酶特异性且有利尿副作用，限制了其临床应用。新型GST抑制剂包括谷胱甘肽类似物，具有更好的特异性，且毒性限制较少。一种先导化合物在细胞系和动物模型中都是GSTP1-1同工型的有效抑制剂。还开发了一种GSTP1-1激活的前药。目前正在对这些药物的临床前和临床疗效进行测试。它们的合理设计为以提高治疗指数的方式靶向肿瘤特异性特征提供了一种有前景的新方法。
