Multidrug resistance due to impaired DNA cleavage in a VP-16-resistant human leukemia cell line.

We established a VP-16-resistant line of human leukemia cells, K562/VP-H2, derived from K562 cells. K562/VP-H2 cells were 44-fold more resistant to VP-16 than were K562 cells. K562/VP-H2 cells were also resistant to doxorubicin, daunorubicin and mitoxantrone, but showed little or no resistance to vincristine, aclarubicin, idarubicin, idarubicinol, cytosine arabinoside, cis-platinum or camptothecin. K562/VP-H2 cells did not over-express P-glycoprotein or multidrug resistance protein, and showed intracellular accumulation of VP-16 similar to that in K562 cells. While the expressions of topoisomerase II-alpha gene and topoisomerase II-beta gene, or catalytic activity in nuclear extract of K562/VP-H2 cells were similar to that of K562 cells, the VP-16 induced DNA cleavage was reduced in K562/VP-H2 cells compared to K562 cells, suggesting that the reduction of topoisomerase II-mediated DNA cleavage through qualitative alteration of topoisomerase II may be the main mechanism of acquired multidrug resistance for K562/VP-H2 cells. The K562/VP-H2 cell line is an interesting model for studying resistance to antileukemia drugs targeting topoisomerase II.