MECHANISM OF CROSS-RESISTANCE TO CISPLATIN IN A MITOMYCIN C-RESISTANTHUMAN BLADDER-CANCER CELL-LINE

This study was undertaken to elucidate the mechanism(s) of cross-resis tance to cisplatin (CDDP) in a mitomycin C (MMC)-resistant human bladd er cancer cell line, J82/MMC. The J82/MMC cell line displayed 2- to 3- fold cross-resistance to CDDP and carboplatin when compared to the par ental J82/WT cells. Drug uptake studies revealed that cross-resistance to CDDP in the J82/MMC cell line was independent of reduced platinum accumulation. The J82/MMC cell line exhibited approximately a 1.5-fold resistance to cadmium chloride, an indicator for increased metallothi onein (MT) content, when compared to the J82/WT cells. Northern blot a nalysis showed a 2.7-fold higher level of MT-IIA mRNA in the J82/MMC c ell line compared with J82/WT. We have reported previously that, where as glutathione (GSH) level is comparable in these cells, GSH transfera se (GST) activity is significantly higher in the J82/MMC cell line com pared with J82/WT. Results of the present study showed that the elevat ed GST activity in the J82/MMC cell line was due to an over-expression of pi-type GST protein. Although buthionine-S,R-sulfoximine (BSO)-ind uced GSH depletion significantly enhanced CDDP cytotoxicity in both ce ll lines, the magnitude of potentiation was markedly higher in J82/MMC cells (about 2.1-fold) relative to J82/WT (about 1.6-fold). Our resul ts suggest that cross resistance to CDDP in the J82/MMC cell line may be due to alterations in cellular thiols. (C) 1995 Wiley-Liss, Inc.