Glutathione S-transferases as emerging therapeutic targets.
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.
Gaté
Laurent
L
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. KD_Tew@fccc.edu
Tew
Kenneth D
KD