title: Evidence for a critical role of DNA topoisomerase IIalpha in drug sensitivity revealed by inducible antisense RNA in a human leukaemia cell line.
abstract: 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.
authors.affiliation: First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Towatari
authors.forename: K
authors.initials: K
authors.lastname: Adachi
authors.forename: T
authors.initials: T
authors.lastname: Marunouchi
authors.forename: H
authors.initials: H
authors.lastname: Saito
mesh_terms: 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
chemical_list: 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