Inhibitors of glutathione S-transferases as therapeutic agents

Glutathione S-transferases (GST) are a family of phase II detoxification enzymes with broad substrate specificities. They catalyze the conjugation of glutathione with many different types of xenobiotics, rendering the compound more water soluble and thus more easily eliminated. Resistance to cancer chemotherapeutic drugs, such as the alkylating agents, has been directly correlated with the overexpression of GSTs. Subsequently, a rationale has been established to utilize agents that inhibit GST in combination with alkylating agents to circumvent this resistance. Two such agents, ethacrynic acid (EA) and Terrapin 199 (TER 199), have been examined for this purpose. EA, an inhibitor of all classes of GST isozymes, has been used clinically in combination with thiotepa. More recently, TER 199, a glutathione analog-based GST inhibitor, has been modeled specifically to inhibit GST pi, an enzyme which is commonly found at high levels in human tumor biopsies. Furthermore, a therapeutic strategy has been designed to take advantage of GST pi activation of a prodrug, TER 286. Recent studies have investigated the molecular mechanisms involved in the cellular response to GST inhibitors and have employed techniques such as differential display to examine altered gene expression as well as to identify novel genes induced by these agents. Overall, this strategy may provide further insight into the action of these agents in the cell as well as prove useful in endeavors to modulate anticancer drug resistance.