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 doxorubic in, daunorubicin and mitoxantrone, but showed little or no resistance to vi ncristine, aclarubicin, idarubicin, idarubicinol, cytosine arabinoside, cis -platinum or camptothecin. K562/VP-H2 cells did not over express P-glycopro tein or multidrug resistance protein, and showed intracellular accumulation of VP-16 similar to that in K562 cells. While the expressions of topoisome rase II-alpha gene and topoisomerase II-beta gene, or catalytic activity in nuclear extract of K562/VP-H2 cells were similar ro that of K562 cells, th e VP-16 induced DNA cleavage was reduced in K562/VP-H2 cells compared to K5 62 cells, suggesting thar the reduction of topoisomerase II-mediated DNA cl eavage through qualitative alteration of topoisomerase II may be the main m echanism of acquired multidrug resistance for K5621VP-H2 cells. The K562/VP -H2 cell line is an interesting model for studying resistance to antileukem ia drugs targeting topoisomerase II.