[gamma-Glutamylcysteine synthetase and chemosensitivity]

The gene transfectant with gamma-glutamylcysteine synthetase (gamma-GCS) gene, a rate limiting enzyme in GSH biosynthesis, exerted increased GSH content and ATP-dependent glutathione S-conjugate export pump (GS-X pump) decreased intracellular platinum and sensitivity against cisplatin. It is suggested that GS-X pump expression is related to cellular GSH metabolism and involved in cisplatin resistance. gamma-GCS transfectant also showed the resistance to MMC with the decreased DNA-MMC adduct. On the other hand, a MMC derivative, KW-2149, which is activated by thiol molecule, exhibited high cytotoxicity against the transfectant with an equal amount of DNA-MMC adduct compared with parental cells. It is suggested that KW-2149 could circumvent the GSH-mediated drug resistance.