[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.
Nishio
K
K
Pharmacology Division, National Cancer Center Research Institute.
Kurokawa
H
H
Ishida
T
T
Fukuoka
K
K
Saijo
N
N
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology*; D008937:Mitomycins; D012333:RNA, Messenger / Q000378:metabolism*
D000970:Antineoplastic Agents; D008937:Mitomycins; D012333:RNA, Messenger; C057625:KW 2149; D016685:Mitomycin; D005721:Glutamate-Cysteine Ligase; D002945:Cisplatin