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Topoisomerase IIalpha expression in acute myeloid leukaemia cells that survive after exposure to daunorubicin or ara-C
Örebro University, School of Health and Medical Sciences.
Örebro University, School of Health and Medical Sciences.
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2009 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 22, no 6, 1527-1531 p.Article in journal (Refereed) Published
Abstract [en]

Patients diagnosed with acute myeloid leukaemia are often treated with a combination of daunorubicin and 1-β-D-arabinofuranosylcytosine (ara-C). Both daunorubicin and ara-C exert their effects in the cell nucleus but by different mechanisms, i.e. daunorubicin causes double stranded DNA breaks by inhibition of the nuclear enzyme, topoisomerase (topo) IIα, whereas ara-C is an anti-metabolite that integrates with DNA during DNA synthesis and causes cell cycle arrest. Despite the initial efficacy of these drugs, resistance often develops in the clinical setting. The mechanisms underlying clinical resistance to these drugs are poorly understood, but may be associated with an increase in the proportion of topo IIα negative cells. Therefore, the aim of this study was to determine whether daunorubicin treatment results in increased numbers of topo IIα negative subpopulations in vitro. Acute myeloid leukaemia cells isolated from 12 consenting patients were treated for 24 h with increasing concentrations of daunorubicin or ara-C and the proportion of topo IIα-negative cells in surviving cell populations determined by flow cytometry. Treatment with daunorubicin, but not ara-C, resulted in a significant increase in the proportion of topo IIα negative cells (p=0.0023). These results suggest that daunorubicin may act by cell cycle arrest and/or by selection of pre-existing topo IIα negative subpopulations. Both of these mechanisms can theoretically contribute to a reduced efficacy of a second dose of daunorubicin. The clinical relevance of these interactions should be further elucidated in experimental and clinical studies.

Place, publisher, year, edition, pages
Athen: Spandidos Publications , 2009. Vol. 22, no 6, 1527-1531 p.
Keyword [en]
acute myeloid leukaemia, topoisomerase, daunorubicin, 1-b-D-arabinofuranosylcytosine, flow cytometry
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine; Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-10517DOI: 10.3892/or_00000597ISI: 000271732300035PubMedID: 19885609Scopus ID: 2-s2.0-70449353711OAI: oai:DiVA.org:oru-10517DiVA: diva2:313643
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2017-02-17Bibliographically approved
In thesis
1. Biological markers in breast cancer and acute leukaemia with focus on drug resistance
Open this publication in new window or tab >>Biological markers in breast cancer and acute leukaemia with focus on drug resistance
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2010. 68 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 43
Keyword
Breast cancer, acute leukaemia, drug resistance, toposiomerase IIa, BCRP, HER2, SLC25A43, flow cytometry, real time PCR, whole genome screening
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-10519 (URN)978-91-7668-724-6 (ISBN)
Public defence
2010-05-21, Bohmanssonsalen, Universitetssjukhuset, Örebro, 13:00 (Swedish)
Opponent
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Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2011-04-26Bibliographically approved

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CiteExportLink to record
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