期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 109, 期 2, 页码 388-395出版社
WILEY
DOI: 10.1046/j.1365-2141.2000.02056.x
关键词
AraCTP; modulation; deoxycytidine kinase; cytokine; ribonucleotide reductase
类别
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 de novo AML were analysed for their formation of AraCTP under high-dose AraC conditions (20 mu M over 3 h) without prior modulation (n = 47) after a 2-h pre-exposure with fludarabine (50 mu g/ml) (n = 40) or gemcitabine (30 ng/ml) (n = 40) and after a 48-h preexposure to granulocyte colony-stimulating-factor (G-CSF: 100 ng/ml) (n = 27) or granulocyte-macrophage colony-stimulating-factor (GM-CSF: 100 U/ml) (n = 28), Unmodulated formation of AraCTP (median 239.8 ng/10(7) cells) could not be increased via modulation by gemcitabine (232.4 ng/10(7) cells) or fludarabine (247.8 ng/10(7) 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(7) cells, 2.31-fold increase, P < 0.001; GM-CSF 147.9 ng/10(7) cells, 1.87-fold increase, P < 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 (n = 33). In vivo 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 (P < 0.013).
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