Effect of interleukin 3 on cytosine arabinoside-mediated cytotoxicity of leukemic myeloblasts.
The concept of biologic modification of proliferation and differentiation of myeloid leukemia cells has attracted much attention over the past years. One promising strategy involves the recruitment of leukemic cells into the cell cycle by hematopoietic growth factors in combination with cycle-specific cytotoxic drugs. Because cytosine arabinoside (Ara-C), which targets only cells in S-phase of the mitotic cell cycle, is included in most chemotherapeutic regimens for the treatment of acute myelogenous leukemia, we explored the hypothesis that the recruitment of quiescent immature leukemic blasts into the cell cycle by the early acting growth factor interleukin 3 (IL-3) can increase the efficacy of Ara-C for kill of leukemic stem cells. We show that IL-3 increases the fraction of blasts in S-phase, as assessed by DNA histogram analysis with propidium iodide staining, leading to an enhancement of kill of clonogenic blast cells when combined with Ara-C. Expression of the protooncogenes c-myc, c-fms, and c-fos, known to be linked to cellular proliferation and differentiation, was also altered by IL-3 in Ara-C-treated cultures, further substantiating the role that IL-3 plays as an enhancer of the cytotoxicity of Ara-C.
Brach
M
M
Department of Hematology and Oncology, University of Freiburg, FRG.
Klein
H
H
Platzer
E
E
Mertelsmann
R
R
Herrmann
F
F
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D000943:Antigens, Differentiation / Q000032:analysis; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage*; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D007377:Interleukin-3 / Q000008:administration & dosage*; D007399:Interphase / Q000187:drug effects; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D009195:Peroxidase / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011994:Recombinant Proteins; D003561:Cytarabine; D009195:Peroxidase; D016186:Receptor, Macrophage Colony-Stimulating Factor