Circumvention of glutathione-mediated mitomycin C resistance by a novel mitomycin C analogue, KW-2149.
A novel antitumor antibiotic 7-N-[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl] mitomycin C (KW-2149), an analogue of mitomycin C (MMC), is activated by thiol molecules, such as glutathione (GSH). To clarify the relationship between cellular GSH levels and the cytotoxicity of KW-2149, a murine fibroblast cell line (NIH/3T3) was transfected with human gamma-glutamylcysteine synthetase (gamma-GCS) cDNA, which codes a rate-limiting enzyme of GSH synthesis. Transfected cells (3T3/GCS) displayed increased gamma-GCS mRNA levels, gamma-GCS activity and GSH content, compared with NIH/3T3 cells. 3T3/GCS cells exhibited a 4.4-fold resistance to MMC, but not to KW-2149 (x 0.69), using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, suggesting that the increased cellular GSH levels did not affect the growth-inhibitory effect of KW-2149. KW-2149 exerted a greater growth-inhibitory effect than MMC on cisplatin- and doxorubicin-resistant cells with cross-resistance to MMC. KW-2149 exhibited a greater growth inhibitory effect than MMC not only on cells with GSH-mediated MMC resistance but also on cells with acquired resistance. We thus conclude that KW-2149 might be a clinically useful drug.
Ishida
T
T
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Nishio
K
K
Kurokawa
H
H
Arioka
H
H
Fukumoto
H
H
Fukuoka
K
K
Nomoto
T
T
Yokote
H
H
Hasegawa
S
S
Saijo
N
N
D016475:3T3 Cells; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003432:Cross-Linking Reagents; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology*; D008937:Mitomycins; D014162:Transfection; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D008937:Mitomycins; C057625:KW 2149; D016685:Mitomycin; D004247:DNA; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione