A New Membrane Protein Associated with Resistance to cis-Platinum and Methotrexate
The mechanisms of resistance to alkylating drugs include defective transport across the cell membrane, intracellular bio-transformation to inactivate the drug, and repair of damaged DNA (Goldenberg et al, 1979; Hilton, 1984; Vistica et al, 1978). Thus, cis-diaminodichloroplatinum (CDDP)-resistant cell lines were found to have elevated glutathione (Hamilton et al, 1985; Hromas et al, 1987); increased metallothionein (Andrews et al, 1985); and increased DNA repair (Behrens et al, 1987). However, defects in membrane transport were also found to be an important mechanism of CDDP resistance. In ovarian carcinoma cells that were only 3.3 fold resistant to CDDP, showed 50% reduction in CDDP accumulation in a wide range of CDDP concentrations tested (Andrews et al, 1988). The rate of CDDP efflux and metabolic conversion of CDDP in these cells were unchanged. Decreased CDDP accumulation was an important mechanism of resistance that was expressed early in the development of CDDP resistance. In a human carcinoma cell line resistant to CDDP, there was at least a 3 fold decrease in the intracellular uptake and 10 fold decrease in nuclear accumulation of radioactive platinum complex(195mPt-CDDP) compared to the parent line (Teicher et al, 1987). The resistant cells did not differ in GSH (reduced glutathione) from the sensitive cells. The kinetics of release of radioactive CDDP was unchanged, suggesting that drug uptake was responsible for differences in drug accumulation.
KeywordsResistant Cell Line Human Ovarian Carcinoma Cell Human Carcinoma Cell Line CDDP Resistance Human Squamous Carcinoma Cell
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