Mechanism of cross‐resistance to cisplatin in a mitomycin C‐resistant human bladder cancer cell line

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Abstract
This study was undertaken to elucidate the mechanism(s) of cross‐resistance to cisplatin (CDDP) in a mitomycin C (MMC)‐resistant human bladder cancer cell line, J82/MMC. The J82/MMC celi line displayed 2‐ to 3‐fold cross‐resistance to CDDP and carboplatin when compared to the parental 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 cetl line exhibited approximately a 1.5‐fold resistance to cadmium chloride, an indicator for increased metallothionein (MT) content, when compared to the J82/WT cells. Northern blot analysis showed a 2.7‐fold higher level of MT‐IIA mRNA in the J82/MMC ceil line compared with J82/WT. We have reported previously that, whereas glutathi‐one (GSH) level is comparable in these cells, GSH transferase (GST) activity is significantly higher in the J82/MMC eell line compared with J82/WT. Results of the present study showed that the elevated GST activity in the J82/MMC cell line was due to an over‐expression of π‐type GST protein. Although buthio‐nine‐S,R‐sulfoximine (BSO)‐induced GSH depletion significantly enhanced CDDP cytotoxicrty in both cell 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 results suggest that cross‐resistance to CDDP in the J82/MMC cell tine may be due to alterations in cellular thiols. © 1995 Wiley‐Liss, Inc.