Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells.
Human recombinant GM-CSF (rGM-CSF) is under investigation as a growth-protective agent for normal hematopoietic elements in phase I trials of myelosuppressive chemotherapy and in bone marrow transplantation. We determined the effect of rGM-CSF on the metabolism of high dose Ara-C in bone marrow mononuclear cells (BMMCs) from healthy volunteers and patients with ANLL. Cells were incubated with rGM-CSF alone, Ara-C alone, or a combination of the two drugs. Treatment with rGM-CSF alone yielded approximately a twofold increment in intracellular dCTP pools in normal BMMCs but not in leukemic blasts. Exposure to rGM-CSF in conjunction with Ara-C corrected Ara-C-mediated declines in dCTP levels and decreased cytosine arabinoside triphosphate (Ara-CTP) accumulation in normal BMMCs but not in their leukemic counterparts. Furthermore, when exposure to Ara-C was preceded by treatment with rGM-CSF for 18 hr, an even greater reduction in the Ara-CTP/dCTP pool ratio was observed in normal versus leukemic elements; however, this did not significantly change Ara-C DNA incorporation in the two cell types. The differential effect of rGM-CSF on the phosphorylation of Ara-C in normal BMMCs versus leukemic blasts has potential implications for the use of a regimen consisting of rGM-CSF and high dose Ara-C in the treatment of ANLL with chemotherapy or autologous bone marrow transplantation.
Bhalla
K
K
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032.
Birkhofer
M
M
Arlin
Z
Z
Grant
S
S
Lutzky
J
J
Graham
G
G
D001853:Bone Marrow / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003561:Cytarabine / Q000378:metabolism*; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D004357:Drug Synergism; D006098:Granulocytes; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
D003115:Colony-Stimulating Factors; D003845:Deoxycytosine Nucleotides; D011994:Recombinant Proteins; D003561:Cytarabine; C024107:2'-deoxycytidine 5'-triphosphate