Evidence for a critical role of DNA topoisomerase IIα in drug sensitivity revealed by inducible antisense RNA in a human leukaemia cell line

Abstract

To examine the role of human DNA topoisomerase IIα (topo IIα) in drug resistance, we selectively inhibited topo IIα gene expression in U937 human monocytic leukaemia cells stably transfected with a plasmid that allowed for Zn-mediated conditional expression of a human α-topo IIα antisense sequence. Expression of topo IIα mRNA was reduced to <30%, whereas no significant alteration of topo IIβ mRNA expression was observed. Under these conditions, drug sensitivity to the topo-II-directed agents, etoposide and daunorubicin, was reduced to approximately 50%, whereas sensitivity to 4-hydroperoxy-cyclophosphamide (4-HC) was not altered. This suggests that a reduced amount of topo IIα mRNA may be sufficient for the resistance to topo II inhibitors in leukaemia cells.