Topoisomerase IIalpha expression in acute myeloid leukaemia cells that survive after exposure to daunorubicin or ara-C

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

acute myeloid leukaemia

topoisomerase

daunorubicin

1-b-D-arabinofuranosylcytosine

flow cytometry

MEDICINE

MEDICIN

Oncology

Onkologi

Medicin

Medicine

Biomedicin

Biomedicine

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