Granulocyte-macrophage colony-stimulating factor enhances the cytotoxic effects of cytosine arabinoside in acute myeloblastic leukemia and in the myeloid blast crisis phase of chronic myeloid leukemia.
A strategy designed to stimulate myeloid leukemic blasts into active cell cycle may increase the effectiveness of S phase-specific agents such as cytosine arabinoside (ARA-C). Since recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) is known to stimulate the growth of myeloid leukemic cells in vitro, we have evaluated the ability of this growth factor to enhance leukemic clonogenic cell kill in the presence of ARA-C. In seven patients studied, GM-CSF increased the fraction of myeloid leukemic blasts in S phase as measured by propidium iodide DNA staining, bromodeoxyuridine incorporation, or ARA-C suicide techniques. Six of these seven patients demonstrated clonogenic cell growth in agar in response to GM-CSF. In five of these six patients, the combination of GM-CSF and ARA-C treatment in vitro resulted in a significant increase in leukemic clonogenic cell kill when compared to treatment with ARA-C in the absence of GM-CSF. Similar results were observed with the combination of GM-CSF and hydroxyurea, another S phase specific agent, further suggesting that the observed enhancement of cytotoxicity was due to the ability of GM-CSF to increase the number of leukemic cells in S phase. These data provide a rationale for investigating the toxicity and efficacy of combined GM-CSF and ARA-C therapy in patients with high-risk myeloid leukemia.
Cannistra
S A
SA
Division of Tumor Immunology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Groshek
P
P
Griffin
J D
JD
D001752:Blast Crisis / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007399:Interphase / Q000187:drug effects; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor