CIRCUMVENTION OF GLUTATHIONE-MEDIATED MITOMYCIN-C RESISTANCE BY A NOVEL MITOMYCIN-C ANALOG, KW-2149

A novel antitumor antibiotic -[2-[[2-(gamma-L-glutamylamino)ethyl]dith io]ethyl] mitomycin C (KW-2149), an analogue of mitomycin C (MMC), is activated by thiol molecules, such as glutathione (GSH). To clarify th e relationship between cellular GSH levels and the cytotoxicity of KW- 2149, a murine fibroblast cell line (NIH/3T3) was transfected with hum an gamma-glutamylcysteine synthetase (gamma-GCS) cDNA, which codes a r ate-limiting enzyme of GSH synthesis. Transfected cells (3T3/GCS) disp layed increased gamma-GCS mRNA levels, gamma-GCS activity and GSH cont ent, compared with NIH/3T3 cells. 3T3/GCS cells exhibited a 4.4-fold r esistance to MMC, but not to KW-2149 (x 0.69), using the (4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, suggesting that t he 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-resis tance to MMC. KW-2149 exhibited a greater growth inhibitory effect tha n MMC not only on cells with GSH-mediated MMC resistance but also on c ells with acquired resistance. We thus conclude that KW-2149 might be a clinically useful drug. (C) 1997 Wiley-Liss, Inc.