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Topoisomerase II alpha expression in acute myeloid leukaemia cells that survive after exposure to daunorubicin or ara-C
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Hematologi)
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2009 (English)In: Oncology Reports, ISSN 1021-335X, 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-beta-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) IIalpha, 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 IIalpha negative cells. Therefore, the aim of this study was to determine whether daunorubicin treatment results in increased numbers of topo IIalpha 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 IIalpha-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 IIalpha negative cells (p=0.0023). These results suggest that daunorubicin may act by cell cycle arrest and/or by selection of pre-existing topo IIalpha 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
2009. Vol. 22, no 6, 1527-1531 p.
Keyword [en]
1-β-D-arabinofuranosylcytosine, Acute myeloid leukaemia, Daunorubicin, Flow cytometry, Topoisomerase
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-124537DOI: 10.3892/or_00000597ISI: 000271732300035PubMedID: 19885609OAI: oai:DiVA.org:uu-124537DiVA: diva2:317652
Available from: 2010-05-04 Created: 2010-05-04 Last updated: 2011-04-20Bibliographically approved

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