Differential effect of interleukin 3 on the metabolism of high-dose cytosine arabinoside in normal versus leukemic human bone marrow cells.
We have examined the effect of recombinant interleukin 3 (rIL-3) on the metabolism of high-dose cytosine arabinoside (Ara-C), an S-phase-specific agent, in normal human bone marrow mononuclear cells (BMMC) and leukemic blasts from patients with acute myeloid leukemia (AML). Exposure to rIL-3 for 24 h significantly increased the percentage of cycling S-phase cells in normal BMMC as well as leukemic cells. A concomitant expansion of intracellular deoxycytidine triphosphate (dCTP) levels occurred to a significantly greater extent in normal BMMC. Compared to treatment with Ara-C (10 mumol/liter) alone, prior and coadministration of rIL-3 with Ara-C increased Ara-CTP levels in leukemic blasts. However, an identical treatment produced significantly higher dCTP levels in normal BMMC, resulting in a significantly lower mean Ara-CTP to dCTP pool ratio in normal BMMC compared to that observed in each of the samples of AML blasts. Following treatment with Ara-C plus rIL-3 versus Ara-C alone, the alteration in Ara-C DNA incorporation corresponded with the change in Ara-CTP to dCTP ratio observed in normal BMMC and AML blasts. The differential effect of rIL-3 on the metabolism of high-dose Ara-C in normal versus leukemic cells may indicate a role for rIL-3 in enhancing the selectivity of Ara-C toward leukemic myeloblasts.
Bhalla
K
K
Department of Medicine, Medical University of South Carolina, Charleston 29425.
Birkhofer
M
M
Arlin
Z
Z
Grant
S
S
Lutzky
J
J
Safah
H
H
Graham
G
G
D001853:Bone Marrow / Q000378:metabolism*; D003561:Cytarabine / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology
D003845:Deoxycytosine Nucleotides; D007377:Interleukin-3; D011994:Recombinant Proteins; D003561:Cytarabine; C024107:2'-deoxycytidine 5'-triphosphate; D004247:DNA