Successful modulation of high‐dose cytosine arabinoside metabolism in acute myeloid leukaemia by haematopoietic growth factors: no effect of ribonucleotide reductase inhibitors fludarabine and gemcitabine
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Titel:
Successful modulation of high‐dose cytosine arabinoside metabolism in acute myeloid leukaemia by haematopoietic growth factors: no effect of ribonucleotide reductase inhibitors fludarabine and gemcitabine
Beschreibung:
<jats:p>High‐dose cytosine arabinoside (AraC)‐containing regimens have shown the highest antileukaemic efficacy of all currently used regimens in the treatment of acute myeloid leukaemia (AML). This study aimed at increasing the antileukaemic potential of high‐dose AraC by raising intracellular levels of AraC triphosphate (AraCTP), which is the mediator of cytotoxicity, via biochemical modulation by inhibitors of ribonucleotide reductase (RR) or haematopoietic growth factors (HGFs). Blasts from patients with <jats:italic>de novo</jats:italic> AML were analysed for their formation of AraCTP under high‐dose AraC conditions (20 µ<jats:sc>m</jats:sc> over 3 h) without prior modulation (<jats:italic>n</jats:italic> = 47) after a 2‐h pre‐exposure with fludarabine (50 µg/ml) (<jats:italic>n</jats:italic> = 40) or gemcitabine (30 ng/ml) (<jats:italic>n</jats:italic> = 40) and after a 48‐h pre‐exposure to granulocyte colony‐stimulating‐factor (G‐CSF; 100 ng/ml) (<jats:italic>n</jats:italic> = 27) or granulocyte–macrophage colony‐stimulating‐factor (GM‐CSF; 100 U/ml) (<jats:italic>n</jats:italic> = 28). Unmodulated formation of AraCTP (median 239·8 ng/10<jats:sup>7</jats:sup> cells) could not be increased via modulation by gemcitabine (232·4 ng/10<jats:sup>7</jats:sup> cells) or fludarabine (247·8 ng/10<jats:sup>7</jats:sup> cells). The lack of effect of RR inhibitors was also observed for all other known metabolites of AraC [Ara‐cytosine monophosphate (CMP), Ara‐cytosine diphosphate (CDP), AraCDP‐choline, Ara‐uridine monophosphate (UMP), Ara‐uridine diphosphate (UDP) and Ara‐uridine triphosphate (UTP)]. In contrast, pre‐exposure to HGFs led to significant increases in AraCTP formation (G‐CSF 556·0 ng/10<jats:sup>7</jats:sup> cells, 2·31‐fold increase, <jats:italic>P</jats:italic> < 0·001; GM‐CSF 447·9 ng/10<jats:sup>7</jats:sup> cells, 1·87‐fold increase, <jats:italic>P</jats:italic> < 0·0001). To establish the mechanism responsible for these effects, the activity of the rate‐limiting enzyme of AraC metabolism, deoxycytidine kinase (dCK), was investigated (<jats:italic>n</jats:italic> = 33). <jats:italic>In vivo</jats:italic> exposure to GM‐CSF led to increases in dCK activity from unmodulated values at 0 h (29·8 pmol/min/mg protein) to 34·3 pmol/min/mg protein at 24 h (1·15‐fold increase) and 54·5 pmol/min/mg protein at 48 h (1·83‐fold increase). The raise in dCK activity over 48 h was significant (<jats:italic>P</jats:italic> < 0·013).</jats:p>