[Anti-cancer Drug Resistance and Glutathione S-transferases]

Glutathione S-transferase (GST) is a family of multimolecular forms with multi-functions for detoxication of drugs, and certain GST forms have been reported to concern multidrug resistance (MDR) mechanisms of neoplastic cells to anticancer drugs. In this paper, recent studies of GSTs concerning MDR are briefly reviewed, and the problems to be clarified are discussed. The reduced glutathione (GSH) is known to play important roles in the inactivation (detoxication) of the anticancer drugs. Most of them, especially alkylating agents, are conjugated with GSH by GSTs and detoxified, and the peroxides from drugs such as adriamycin are also reduced with GSH and detoxified by the GSH peroxidase activity of certain GST forms. Rat GST-P (GST 7-7) and human GST-pi, both of which belong to Class pi in the species-independent classification of GST, have been known as a marker enzyme for rat and human (pre) neoplastic lesions, respectively. GST-P is increased in rat hepatic preneoplastic foci resistant to cytotoxic agents. GST-pi is also increased not only in cancer cells such as colon carcinoma and non-small cell lung carcinoma, which exhibit "natural resistance" to anticancer drugs, but also increased in breast, ovarian and other tissue carcinomas with increased "acquired resistance" to certain drugs. A few research groups have attempted to confirm by transfection of a vector expressing a GST form such as GST-pi into non-resistant cell lines whether there is a direct relationship between the expression of a specific GST form and the appearance of MDR. However, MDR did not always appear. Recently, it was found in our laboratory that GST-P, GST-pi and even mouse GST II in Class pi, all are very strongly inactivated by SH-modifiers and active oxygens, indicating that these properties may be useful for overcoming MDR, if the forms really are involved with MDR.