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 multidrug resistance protein (MRP) gene is involved in acquisition of multidrug‐resistant phenotypes in human cancer cells. In this study we examined whether selection for resistance to the epipodophyllotoxins, etoposide/teniposide (VP16/VM26), could induce overexpression of MDR1 or MRP. We have previously isolated two VP16/VM26‐resistant KB cell lines. Two VP16/VM26‐resistant KB cell lines, KB/VM‐1 and KB/VM‐4, which were selected by stepwise exposure to VM26 had decreased accumulation of [(3)H]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, KB/VP‐2, had decreased accumulation of [(3)H]VP16 and showed overexpression of MRP gene, but not that of MDR1 gene. We also isolated a VP16‐resistant cell line, IN157/VP‐1, from a human glioma cell line IN157. IN157/VP‐1 cells showed decreased accumulation of [(3)H]VP16 and overexpression of MRP gene, but not of MDR1. These findings suggest that selection for resistance to VP16/VM26, preferentially induces overexpression of MRP gene.