Evidence for a critical role of DNA topoisomerase IIalpha in drug sensitivity revealed by inducible antisense RNA in a human leukaemia cell line.
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.
Towatari
M
M
First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Adachi
K
K
Marunouchi
T
T
Saito
H
H
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D015139:Blotting, Southern; D002470:Cell Survival; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D003630:Daunorubicin / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology*; D016372:RNA, Antisense / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D016372:RNA, Antisense; D012333:RNA, Messenger; D005047:Etoposide; D003520:Cyclophosphamide; D004250:DNA Topoisomerases, Type II; C011272:perfosfamide; D003630:Daunorubicin