Granulocyte-macrophage colony-stimulating factor and interleukin-3 enhance the incorporation of cytosine arabinoside into the DNA of leukemic blasts and the cytotoxic effect on clonogenic cells from patients with acute myeloid leukemia.
In the present study the effects of the 48-hour administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) (100 U/mL) or interleukin-3 (IL-3) (100 U/mL) on the proliferative activity of leukemic cells and on the intracellular metabolism and cytotoxic efficacy of a subsequent 12-hour application of cytosine arabinoside (ara-C) at doses of 0.1, 1.0, 10.0, and 100.0 mumol/L were evaluated on bone marrow cells from 17 patients with acute myeloid leukemia. After GM-CSF or IL-3, a 1.2- to 2.4-fold increase in S-phase cells was observed in nine of 14 GM-CSF and seven of 11 IL-3 cases. 3H-Cytosine arabinoside incorporation into the DNA was enhanced 1.33- to 18.3-fold over respective controls in 14 of 17 patients. While in control specimens are ara-C dose-dependent increase in 3H-ara-C uptake was accompanied by a corresponding rise in intracellular ara-C-5' triphosphate (ara-CTP) levels, ara-CTP concentrations were not increased after GM-CSF or IL-3 exposure, resulting in a higher ara-C to ara-CTP ratio over controls. This finding may be explained by a stimulatory effect of GM-CSF and IL-3 on ara-C phosphorylating enzymes and a more rapid incorporation of ara-CTP into the DNA of leukemic blasts. These effects translated into a 2.2- to 229.0-fold increase in the cytotoxic activity of ara-C against clonogenic leukemic cells after GM-CSF or IL-3 pretreatment. Hence, GM-CSF and IL-3 enhance the intracellular metabolism of ara-C and its incorporation into the DNA of leukemic cells leading to a higher antileukemic activity of ara-C on clonogenic leukemic cells (CFU-L).
Hiddemann
W
W
Department of Internal Medicine, University of Münster, Germany.
Kiehl
M
M
Zühlsdorf
M
M
Busemann
C
C
Schleyer
E
E
Wörmann
B
B
Büchner
T
T
D000208:Acute Disease; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001752:Blast Crisis / Q000188:drug therapy* / Q000378:metabolism; D003561:Cytarabine / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism* / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016196:S Phase / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D004273:DNA, Neoplasm; D007377:Interleukin-3; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor