Recombinant GM-CSF modulates the metabolism of cytosine arabinoside in leukemic cells in bone marrow

Abstract

The effect of human recombinant GM-CSF (rGM-CSF) on the metabolism of high dose ara-C was determined in bone marrow mononuclear cells (BMMCs) from eight normal volunteers and from seven patients with acute myelogenous leukemia (AML). We incubated the cells with rGM-CSF alone, ara-C alone, or a combination of the two drugs. Treatment with rGM-CSF for 16 h increased the percentage of cells in S-phase both in normal BMMCs and leukemic marrow cells. The treatment with rGM-CSF alone produced an approximately two-fold increase in the intracellular dCTP pools in normal BMMCs, but this increment was not observed in leukemic marrow cells. Simultaneous exposure to rGM-CSF in combination with ara-C increased cytosine arabinoside triphosphate (ara-CTP) pools in leukemic blasts. In contrast, this treatment decreased ara-CTP pools in normal BMMCs. Moreover, when the cells were preincubated with rGM-CSF for 16 h prior to the exposure to ara-C, leukemic blasts achieved a 7-fold higher ara-CTP/dCTP ratio as compared with normal marrow cells. Treatment of the cells with rGM-CSF, either simultaneously or sequentially, resulted in significantly greater amounts of ara-C incorporation into DNA in leukemic marrow cells than normal counterparts. The higher accumulation of ara-CTP and subsequent increased incorporation of ara-C into DNA in leukemic cells treated with rGM-CSF lead to the enhanced ara-C-mediated inhibition of DNA synthesis as compared with normal BMMCs. The selective accumulation of ara-CTP in leukemic vs normal cells have implications for the efficacy of the treatment of AML patients with high dose ara-C and rGM-CSF.