Characterization of drug resistance to VM-26 in A2780 ovarian carcinoma cells

Human ovarian carcinoma A2780 cells resistant to VM-26, a topoisomerase II-targeting drug, were cloned. Cross-resistance test showed that the resistant cells were 300 fold more tolerant toward VM-26 than were parental cells, whereas tolerance towards other drugs increased only 3 to 10 fold. VM-26 triggered apoptosis in a variety of cells including rodent cells, but not in resistant cells. This resistance might not be due to multidrug resistance (MDR). The topoisomerase II mRNA levels showed only a slight variation between VM-26-treated and -untreated resistant cells, and the difference in protein levels was about 2 fold. This implies that the level of topoisomerase IIβ expression may be unrelated to drug resistance. The DNA strand-passing activity of topoisomerase II affected by VM-26 was measured by K-SDS precipitation of the topoisomerase II-DNA complex, and topoisomerase II decatenation of kinetoplastic DNA (K-DNA). The results showed that the VM-26 influence on topoisomerase II cleavable activity was much less in resistant cells. Alteration of drug targeting sites in topoisomerase II might be a factor contributing to VM-26 drug resistance in these resistant cells.