Abstract
Metabolites of tritium labeled AraC (AraCMP, -CDP, CTP, -CDP-choline) were determined by HPLC analysis. No significant differences in the formation of these metabolites could be found between fresh leukemic blasts, mononuclear cells from normal bone marrow and CD34/ 38 positive hematopoetic stem cells. AraCTP half-life, which has previously been shown to correlate with clinical parameters like CR duration, was longest in leukemic blasts. The intracellular pool of AraCTP precursors (AraCMP, -CDP) was similar and of low abundance (13–20% of AraCTP at all tested AraC concentrations) in all investigated cell types and therefore did not explain the differences in AraCTP half-life.
AraCDP-choline formation seemed to be saturated at higher AraC incubation levels than AraCTP and might therefore have a significance for AraC pharmacodynamics of high dose AraC regimens. Since this metabolite is structurally similar to CDP-choline — a precursor of phospholipid metabolism — the effect of AraC on cellular lipid metabolism of HL60 cells was investigated: AraC induced a significant reduction (30%) in cellular phosphatidylcholine (PC) content. Antagonism of these alterations by lysoPC resulted in almost complete reversal of the AraC induced loss of viability (tested by trypan blue exclusion). The AraC induced loss of viability at high AraC concentrations might be caused partially by the de stabilization of cell membranes, which has also been observed after PC alterations from other causes.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Brach M, Herrmann F, Kufe D (1992) Activation of AP1 transcription factor by arabinofuronsylcytosine in myeloid leukemia cells. Blood 79: 728–734
Braess J, Pförtner J, Kaufmann CC, Ramsauer B, Unterhalt M, Hiddemann W, Schleyer E (1996) Detection and quantitation of the major metabolites of 3H-cytosine-arabinoside by high-performance liquid chromatography. J Chromatography 676: 131–140
Daley PF, Zugmaier G, Sandler D, Carpen M, Myers CE, Cohen JS (1990) Regulation of the cytidine phospholipid pathways in human cancer cells and effects of 1-β-D-arabinofuranosylcytosine: a non-invasive 31P nuclear resonance study. Cancer Res 50: 552–557
Emoto Y, Kisaki H, Manome Y, Kharbanda S, Kufe D (1996) Activation of protein kinase C delta in human myeloid leukemia cells treated with 1-β-arabinofuranosylcytosine. Blood 87(5): 1990–1996
Hiddemann W, Schleyer E, Unterhalt M, Zühlsdorf M, Rolf K, Reuter C, Kewer U, Uhrmeister C, Wörmann B, Büchner T (1992) Differences in the intracellular pharmacokinetics of cytosine arabinoside (araC) between circulating leukemic blasts and normal mononuclear blood cells. Leukemia 6: 1273–1280
Kucera GL, Capizzi RL (1992) 1-β-D-arabinofuranosylcytosine-diphosphate-choline is formed by the reversal of cholinephosphotransferase and not via cytidyltransferase. Cancer Res 52: 3886–3891
Hiddemann W, Aul C, Maschmeyer G, SchönrockNabulsi R, Ludwig WD, Bartholomäus A, Bettelheim P, Becker K, Balleisen L, Lathan B, Köppler H, Grüneisen T, Donhuis-Ant R, Reichle A, Hei-necke A, Sauerland C, Büchner T (1993) High-dose versus intermediate dose cytosine arabinoside combined with mitoxantrone for the treatment of relapsed and refractory acute myeloid leukemia: results of an age adjusted randomized comparison. Leukemia and Lymphoma 10: 133–137
Kufe DW, Major PP, Egan EM, Beardsley GP (1980) Correlation of cytotoxicity with incorporation of araC into DNA. J Biol Chem 255: 8897–9000
Kufe DW, Munroe D, Herrick D, Egan E, Spriggs D (1984) Effects of 1-β-D-arabinofuranosylcytosine incorporation on eukaryotic DNA template function. Molec Pharmacol 26 128–134
Nishizuka Y (1992) Intracellular signalling by hydrolysis of phospholipids and activation of protein kinase C. Science 258: 607–614
Plunkett W, Liliemark JO, Adams TM, Nowak DB, Estey E, Kantarjian H, Keating MJ (1987) Saturation of 1-β-D-arabinofuranosylcytosine therapy. Cancer Res 47: 3005–3011
Rustum YM, Riva C, Preissler HD (1987) Pharmacokinetic parameters of 1-ß-D-arabinofuranosylcytosine(araC) and their relationship to intracellular metabolism of araC, toxicity, and response of patients with conventional and high dose araC. Semin Oncol 14 (suppl.1) 141–148
Strum JC, Small GW, Pauig SB, Daniel LW (1994) 1-β-D-Arabinofuranosylcytosine stimulates ceramide and diglyceride formation in HL60 cells. J Biol Chem 269: 15493–15497
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Braess, J. et al. (1998). AraC Metabolism in Fresh Leukemic Blasts/ Normal Bone Marrow/ Hematopoetic Stem Cells and its Impact on the Lipid Composition of Leukemic Cells (HL60). In: Hiddemann, W., et al. Acute Leukemias VII. Haematology and Blood Transfusion / Hämatologie und Bluttransfusion, vol 39. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-71960-8_80
Download citation
DOI: https://doi.org/10.1007/978-3-642-71960-8_80
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-71962-2
Online ISBN: 978-3-642-71960-8
eBook Packages: Springer Book Archive