OVEREXPRESSION OF MULTIDRUG-RESISTANCE PROTEIN GENE IN HUMAN CANCER CELL-LINES SELECTED FOR DRUG-RESISTANCE TO EPIPODOPHYLLOTOXINS

Overexpression of either the multidrug resistance 1 (MDR1) gene or mul tidrug resistance protein (MRP) gene is involved in acquisition of mul tidrug-resistant phenotypes in human cancer cells. In this study we ex amined whether selection for resistance to the epipodophyllotoxins, et oposide/teniposide (VP16/VM26), could induce overexpression of MDR1 or MRP. We have previously isolated two VP16/VM26-resistant KB cell line s. Two VP16/VM26-resistant KB cell lines, KB/VM-1 and KB/VM-4, which w ere selected by stepwise exposure to VM26 had decreased accumulation o f [H-3]VP16 and increased levels of MRP, but no apparent expression of MDR1 gene was observed, Another VP16/VM26-resistant KB cell line, KB/ VP-4, which was further isolated from a VP16-resistant KB cell line, K B/Vp-2, had decreased accumulation of [3H]VP16 and showed overexpressi on of MRP gene, but not that of MDR1 gene. We also isolated a VP16-res istant cell line, IN157/VP-1, from a human glioma cell line IN157. IN1 57/VP-1 cells showed decreased accumulation of [H-3]VP16 and overexpre ssion of MRP gene, but not of MDR1. These findings suggest that select ion for resistance to VP16/VM26, preferentially induces overexpression of MRP gene.