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Metallothionein (MT) is known to play an important role in the resistance of tumor cells to cis-diamminedichloroplatinum (II) (cisplatin). To identify non-MT factors of cisplatin resistance, we characterized cisplatin-resistant cell lines derived from MT-null cells. All of the cisplatin-resistant MT- null cell lines, namely MKCr-1, -3, -4, -12, and -13, showed strong cisplatin resistance and decreased platinum accumulation. Some multidrug resistance proteins (MRPs) have been reported to contribute to cisplatin resistance. However, no significant difference of the MRPs was observed in any of these cell lines. The MKCrs showed cross-resistance to other metals such as arsenite, arsenate, cadmium and antimony. The arsenate and arsenite sensitivities were highly correlated with sensitivity to cisplatin. In addition, the degree of arsenite accumulation was correlated with the degree of cisplatin accumulation. These results suggest that the cisplatin resistance was strongly correlated with the arsenite transport mechanism in these cells.

ARSENIC ACCUMULATION DECREASED IN METALLOTHIONEIN NULL CISPLATIN-RESISTANT CELL LINES