Differential Effect of GM-CSF on the Intracellular Ara-C Metabolism in Normal Bone Marrow Mononuclear Cells and Acute Myeloid Leukemia (AML) Blasts
This study examines the effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the intracellular metabolism of cytosine arabinoside (ara-C) in mononuclear bone marrow cells (NBMMC) from 8 healthy volunteers and leukemic blasts from 50 patients with acute myeloid leukemia (AML). Pretreatment with rh GM-CSF (100 U/ml) for 48 hrs significantly enhanced DNA synthesis: Median 3H-TdR uptake into the DNA increased from 2.15 to 3.68 pmol/105 cells in AML blasts and from 3.09 to 7.4 pmol/105 cells in NBMMC (p<0.05). 14 AML cases did not respond to GM-CSF. Median ara-C mediated inhibition of DNA synthesis was significantly higher in AML blasts as compared to NBMMC (76.5 vs 55.0% and 99.0 vs 96.0% at 0.05 and 5.0 μM ara-C, respectively, p<0.01). Similarly, intracellular ara-CTP levels were higher in AML blasts as compared to NBMMC (46.5 vs 18.7,167.8 vs 48.0 and 59.5 ng/107 cells at 1, 10, 100 μM extracellular ara-C, respectively, p< 0.01). Overall DNA polymerase and DNA polymerase α activity increased from median 80.9 to 94.1 and from 3.1 to 5.7 pmol/min × mg in AML blasts as compared to median 96.7 to 189.8 and 1.2 to 2.2 pmol/min × mg in NBMMC (p < 0.05). Median deoxycytidine and thymidine kinase activity were only slightly increased in the presence of GM-CSF. The GM-CSF induced increase of the 3H-ara-C incorporation into the DNA was slightly higher in GM-CSF responding AML blasts as compared to NBMMC (median 2.0 vs 1.7 fold at 0.06 μM ara-C, p < 0.05). The differential effect of GM-CSF on the metabolism of ara-C in normal versus leukemic cells may cause a selective increase in the antileukemic cytotoxicity of ara-C in the presence of GM-CSF.
KeywordsLeukemia Oncol Doxorubicine Thymidine Cytosine
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- 2.Hiddemann W, Kiehl M, Zuehlsdorf M, Busemann C, Schleyer E, Woermann B, Buechner T. Granulocyte-macrophage colony-stimulating factor and interleukin-3 enhance the incorporation of cytosine arabinoside into the DNA of leukemic blasts and the cytotoxic effect on clonogenic cells from patients with acute myeloid leukemia. Sem. Oncol. 1992; 19: 31–37.Google Scholar
- 4.Miyauchi J, Kelleher CA, Wang C, Minkin S, McCulloch EA. Growth factors influence the sensitivity of leukemic stem cells to cytosine arabinoside in culture. Blood 1989; 73: 1271–1278.Google Scholar
- 10.Van Der Lely N, Witte T, Muus P, Raymakers R, Preijers F, Haanen C. Prolonged exposure to cytosine arabinoside in the presence of hematopoietic growth factors preferentially kills leukemic versus normal clonogenic cells. Exp. Hematol. 1991; 19: 267–272.Google Scholar
- 15.te Boekhorst PAW, Loewenberg B, Vlastuin M, Sonneveld P. Enhanced chemosensitivity of clonogenic blasts from patients with acute myeloid leukemia by G-CSF, IL-3 or GM-CSF stimulation. Leukemia 1993; 7: 1191–1198.Google Scholar
- 17.Reuter C, Auf Der Landwehr U I, Auf Der Landwehr U II, Schleyer E, Zuehlsdorf M, Ameling C, Rolf C, Woermann B, Buechner T, Hiddemann W. Modulation of intracellular metabolism of cytosine arabinoside in acute myeloid leukemia by granulocyte macrophage colony stimulating factor. Leukemia 1994; 8: 217–225.PubMedGoogle Scholar
- 20.Kufe D, Spriggs D. Biochemical and cellular pharmacology of cytosine arabinoside. Sem. Oncol. 1985; 12(2): 34–48.Google Scholar
- 21.Aglietta M, De Felice L, Stacchini A, Petti MC, Bianchi ACM, Aloe Spiriti MA, Sanavio F, Apra F, Piacibello W, Stern AC, Gavosto F, Mandelli F. In vivo effect of granulocyte-macrophage colony stimulating factor on the kinetics of human acute myeloid leukemia cells. Leukemia 1991; 5: 979–984.PubMedGoogle Scholar
- 22.Bettelheim P, Valent P, Andreeff M, Tafuri A, Haimi J, Gorischek C, Muhm M, Sillaber Ch, Haas O, Vieder L, Maurer D, Schulz G, Speiser W, Geissler K, Kier P, Hinterberger W, Lechner K. Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia. Blood 1991; 77: 700–711.PubMedGoogle Scholar
- 24.Estey E, Thall PF, Kantarjian H, O’Brien S, Koller CA, Beran M, Gutterman J, Deisseroth A, Keating M. Treatment of newly diagnosed acute myelogenous leukemia with granulocyte-macrophage colony-stimulating factor (GM-CSF) before and during continous-infusion high-dose ara-C + daunorubicin: comparison to patients treated without GM-CSF. Blood 1992; 79: 2236–2255.Google Scholar