Prolonged exposure to cytosine arabinoside in the presence of hematopoietic growth factors preferentially kills leukemic versus normal clonogenic cells.
We investigated the cytotoxic effect of the cell cycle-specific agent cytosine arabinoside (Ara-C) on clonogenic leukemic and normal bone marrow cells. To overcome kinetic resistance and to increase cytotoxicity, the cells were exposed to Ara-C in liquid culture medium for extended time periods, that is, 5 and 10 days. Subsequently the number of surviving clonogenic cells was determined in a semi-solid assay. All cultures were stimulated with the combination of recombinant human interleukin 3 (rhIL-3), granulocyte-macrophage colony-stimulating factor (rhGM-CSF), and granulocyte colony-stimulating factor (rhG-CSF) to induce optimal cell proliferation. In comparison to normal clonogenic bone marrow cells (granulocyte-macrophage colony-forming units, CFU-GM) 5-day Ara-C exposure resulted in an equal to a slightly more effective kill of leukemic colony-forming cells (CFU-L). The Ara-C dose resulting in 50% inhibition (ID50) was 1.6 +/- 1.6 x 10(-8) M for CFU-L (n = 9) and 6.7 +/- 4.3 x 10(-8) M for CFU-GM (n = 4, p = 0.096). Prolongation of the Ara-C exposure time from 5 to 10 days increased the cytotoxicity towards the majority of the leukemic clonogenic cells (ID50: 0.8 +/- 0.6 x 10(-8) M) but not towards CFU-GM (ID50: 5.7 +/- 2.8 x 10(-8) M). Overall, significantly more leukemic clonogenic cells than normal CFU-GM were killed after 10 days of exposure to Ara-C (p = 0.039). These results indicate that leukemic clonogenic cells can be eradicated preferentially by prolonged exposure to low dosages of Ara-C in the presence of hematopoietic growth factors with relative preservation of the normal hematopoietic progenitor cells.
Van Der Lely
N
N
Department of Internal Medicine, University Hospital Nijmegen, The Netherlands.
De Witte
T
T
Muus
P
P
Raymakers
R
R
Preijers
F
F
Haanen
C
C
D001853:Bone Marrow / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells; D003561:Cytarabine / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000503:physiopathology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
D016298:Hematopoietic Cell Growth Factors; D003561:Cytarabine