Treatment with interleukin-3 plus granulocyte-macrophage colony-stimulating factors improves the selectivity of Ara-C in vitro against acute myeloid leukemia blasts.
Hematopoietic growth factors (HGFs) interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) individually have been shown to increase the percentage of acute myeloid leukemia (AML) blasts in S phase and enhance the cytotoxic effects of Ara-C against these blasts in culture. We compared in vitro the effects of a combined treatment with GM-CSF (10 ng/mL) plus IL-3 (10 ng/mL) on the metabolism and cytotoxicity of Ara-C in normal bone marrow mononuclear cells (NBMMC) and AML blasts. NBMMC from six healthy volunteers and AML blasts from 10 patients were incubated for 20 hours with or without IL-3 plus GM-CSF, followed by a concurrent treatment with Ara-C for 4 additional hours. Exposure to the HGFs and Ara-C produced significantly higher intracellular Ara-CTP levels as well as higher Ara-CTP/dCTP pool ratios in AML blasts as compared with NBMMC. Treatment with HGFs resulted in [3H] Ara-C DNA incorporation that was significantly higher in AML blasts versus NBMMC. This selective improvement of Ara-C metabolism in AML blasts was associated with an enhanced Ara-C-mediated leukemia colony-forming unit (CFU) growth inhibition. In contrast, exposure to HGFs resulted in an improved colony growth of normal CFU granulocyte-monocyte and CFU-granulocyte, erythroid, monocyte, megakaryocyte. These in vitro studies indicate that a combined treatment with IL-3 plus GM-CSF may improve the selectivity of Ara-C against AML blasts.
Bhalla
K
K
Department of Medicine, Medical University of South Carolina, Charleston 29425.
Holladay
C
C
Arlin
Z
Z
Grant
S
S
Ibrado
A M
AM
Jasiok
M
M
D000208:Acute Disease; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001752:Blast Crisis / Q000097:blood / Q000473:pathology*; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000378:metabolism* / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D007700:Kinetics; D007951:Leukemia, Myeloid / Q000097:blood / Q000473:pathology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D014407:Tumor Cells, Cultured
D007377:Interleukin-3; D011994:Recombinant Proteins; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor