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

Br J Haematol. 1998 Jun;101(3):548-51. doi: 10.1046/j.1365-2141.1998.00713.x.


To examine the role of human DNA topoisomerase IIalpha (topo IIalpha) in drug resistance, we selectively inhibited topo IIalpha gene expression in U937 human monocytic leukaemia cells stably transfected with a plasmid that allowed for Zn-mediated conditional expression of a human alpha-topo IIalpha antisense sequence. Expression of topo IIalpha mRNA was reduced to <30%, whereas no significant alteration of topo IIbeta 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 IIalpha mRNA may be sufficient for the resistance to topo II inhibitors in leukaemia cells.

MeSH terms

  • Antibiotics, Antineoplastic / therapeutic use
  • Antigens, Neoplasm
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Blotting, Southern
  • Cell Survival
  • Cyclophosphamide / analogs & derivatives
  • Cyclophosphamide / therapeutic use
  • DNA Topoisomerases, Type II* / genetics
  • DNA Topoisomerases, Type II* / metabolism*
  • DNA-Binding Proteins
  • Daunorubicin / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / genetics
  • Etoposide / therapeutic use
  • Gene Expression
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Leukemia, Myeloid / drug therapy
  • Leukemia, Myeloid / enzymology*
  • RNA, Antisense / metabolism*
  • RNA, Messenger / metabolism
  • Tumor Cells, Cultured


  • Antibiotics, Antineoplastic
  • Antigens, Neoplasm
  • Antineoplastic Agents, Phytogenic
  • DNA-Binding Proteins
  • Isoenzymes
  • RNA, Antisense
  • RNA, Messenger
  • Etoposide
  • Cyclophosphamide
  • DNA Topoisomerases, Type II
  • perfosfamide
  • Daunorubicin