title: 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.
abstract: 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).
authors.affiliation: Department of Internal Medicine, University of Münster, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Hiddemann
authors.forename: M
authors.initials: M
authors.lastname: Kiehl
authors.forename: M
authors.initials: M
authors.lastname: Zühlsdorf
authors.forename: C
authors.initials: C
authors.lastname: Busemann
authors.forename: E
authors.initials: E
authors.lastname: Schleyer
authors.forename: B
authors.initials: B
authors.lastname: Wörmann
authors.forename: T
authors.initials: T
authors.lastname: Büchner
mesh_terms: 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
chemical_list: D004273:DNA, Neoplasm; D007377:Interleukin-3; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor