GM-CSF enhances sensitivity of leukemic clonogenic cells to long-term low dose cytosine arabinoside with sparing of the normal clonogenic cells.
Leukemic clonogenic cells (CFU-L) and normal myeloid progenitor cells (CFU-GM) were exposed to Ara-C in the presence of crude CSF obtained from placentas (HPCM) or recombinant human GM-CSF for varying periods. The cytotoxicity of Ara-C to CFU-L increased considerably when the exposure time to Ara-C in the presence of HPCM was extended from 20 hours to 10 days. The ID50 of the CFU-L was 1.5 +/- 2.2 x 10(-8) M Ara-C compared to 5.5 +/- 2.9 x 10(-8) M Ara-C for the CFU-GM after an exposure to Ara-C for 10 days (p less than 0.05). Replacement of crude CSF from placenta conditioned medium by rh GM-CSF resulted in identical observations. Interesting was the observation that secondary leukemic colony forming cells were more or at least equally sensitive to Ara-C in the presence of GM-CSF when compared to the primary leukemic clonogenic cells. This contrasted the secondary normal CFU-GM, which were less sensitive to Ara-C than the primary CFU-GM. This indicates that GM-CSF induces leukemic clonogenic cells with selfrenewal capacity into proliferation, and in doing so, it may enhance the cytotoxicity of a cell cycle specific drug like Ara-C with sparing of the normal clonogenic cells.
De Witte
T
T
Department of Hematology, University Hospital Nijmegen, The Netherlands.
Muus
P
P
Haanen
C
C
Van der Lely
N
N
Koekman
E
E
Van der Locht
A
A
Blankenborg
G
G
Wessels
J
J
D001853:Bone Marrow / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003115:Colony-Stimulating Factors / Q000302:isolation & purification / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D010920:Placenta; D011247:Pregnancy; D011994:Recombinant Proteins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D011994:Recombinant Proteins; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor