The close association of pi-class glutathione S-transferase with drug sensitivity to alkylating agents and cisplatin in human cancer cells.

Buthionine sulfoximine (BSO) is a synthetic amino acid that irreversibly inhibits glutathione biosynthesis. A BSO-resistant line, KB/BSO3, was established from human epidermoid cancer KB cells; and other BSO-resistant lines, HLE/BSO1 and HLE/BSO2, were from human hepatic cancer HLE cells. Cellular level of pi-class glutathione S-transferase (GSTP1) in KB/BSO3 was less than 10% of the parental KB, and those in HLE/BSO1 and HLE/BSO2 wa 30-40% of the parental HLE cells. KB/BSO3, HLE/BSO1 and HLE/BSO2 had collateral sensitivities to a potent anticancer agent, cisplatin, and alkylating agents including melphalan and nitrosourea. The GSTP1 cDNA transfectant KB/BSO3-pi established from KB/BSO3, and also HLE/BSO1-pi and HLE/BSO2-pi established from HLE/BSO1 and HLE/BSO2, restored cellular sensitivities to cisplatin and alkylating agents to similar levels as KB and HLE cells. Our present results indicate that GSTP1 levels apparently limit cellular sensitivities to cisplatin and alkylating agents, suggesting that GSTP1 is a useful diagnostic marker for drug sensitivities to these agents in human cancer cells.