Cytosine Arabinoside Triphosphate Production in Human Leukaemic Myeloblasts: Interactions with Deoxycytidine

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 1981 Jan 1

PMID 6945922

Citations 2

Authors

A L Harris

D G Grahame-Smith

Affiliations

Soon will be listed here.

Abstract

The effect of 1 mu M deoxycytidine (dC) on Ara-C conversion to Ara-CTP and on inhibition of DNA synthesis by Ara-C was measured in intact leukaemic myeloblasts. dC decreased Ara-CTP production in blasts with high Ara-C phosphorylation, but not those with low activity. The Ki for dC was similar to values found with partially purified deoxycytidine kinase. The change in Ara-CTP concentration was associated with a proportional reduction in inhibition of DNA synthesis. dC decreased the effects of Ara-C by inhibition of Ara-CTP production, rather than by production of dCTP and competition with Ara-CTP. Since low Ara-CTP production in patients' blasts is a predictor of poor therapeutic response to Ara-C, the use of dC with Ara-C may improve the therapeutic index in this group of patients.

Citing Articles

Effect of deoxycytidine on the in vitro response of human leukemia cells to inhibitors of de novo pyrimidine biosynthesis.

Bhalla K, Grant S Cancer Chemother Pharmacol. 1987; 19(3):226-32.

PMID: 3581416 DOI: 10.1007/BF00252977.

Modulation of the effect of 1-beta-D-arabinofuranosylcytosine based on changes of cytidine deaminase activity in HL60 cells.

Mejer J, Mortensen B, Christensen I Med Oncol Tumor Pharmacother. 1990; 7(1):25-9.

PMID: 2338846 DOI: 10.1007/BF03000487.

References

Ahern T, Taylor G, Sanderson C . An evaluation of an assay for DNA synthesis in lymphocytes with [3H]thymidine and harvesting on to glass fibre filter discs. J Immunol Methods. 1976; 10(4):329-36. DOI: 10.1016/0022-1759(76)90027-2. View

Hande K, Chabner B . Pyrimidine nucleoside monophosphate kinase from human leukemic blast cells. Cancer Res. 1978; 38(3):579-85. View

Durham J, IVES D . Deoxycytidine kinase. II. Purification and general properties of the calf thymus enzyme. J Biol Chem. 1970; 245(9):2276-84. View

Durham J, IVES D . Deoxycytidine kinase. I. Distribution in normal and neoplastic tissues and interrelationships of deoxycytidine and 1-beta-D-arabinofuranosylcytosine phosphorylation. Mol Pharmacol. 1969; 5(4):358-75. View

Harris A, Potter C, BUNCH C, Boutagy J, Harvey D, Grahame-Smith D . Pharmacokinetics of cytosine arabinoside in patients with acute myeloid leukaemia. Br J Clin Pharmacol. 1979; 8(3):219-27. PMC: 1429786. DOI: 10.1111/j.1365-2125.1979.tb01005.x. View

Chabner B, Johns D, Coleman C, Drake J, Evans W . Purification and properties of cytidine deaminase from normal and leukemic granulocytes. J Clin Invest. 1974; 53(3):922-31. PMC: 333075. DOI: 10.1172/JCI107633. View

Mourad N, Parks Jr R . Erythrocytic nucleoside diphosphokinase. II. Isolation and kinetics. J Biol Chem. 1966; 241(2):271-8. View

Coleman C, Stoller R, Drake J, Chabner B . Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes. Blood. 1975; 46(5):791-803. View

Kessel D, Hall T, Rosenthal D . Uptake and phosphorylation of cytosine arabinoside by normal and leukemic human blood cells in vitro. Cancer Res. 1969; 29(2):459-63. View

10.

Randerath K, RANDERATH E . Ion-exchange thin-layer chromatography. XV. Preparation, properties and applications of paper-like PEI-cellulose sheets. J Chromatogr. 1966; 22(1):110-7. DOI: 10.1016/s0021-9673(01)97076-1. View

11.

IVES D, Durham J . Deoxycytidine kinase. 3. Kinetics and allosteric regulation of the calf thymus enzyme. J Biol Chem. 1970; 245(9):2285-94. View

12.

Plagemann P, Marz R, Wohlhueter R . Transport and metabolism of deoxycytidine and 1-beta-D-arabinofuranosylcytosine into cultured Novikoff rat hepatoma cells, relationship to phosphorylation, and regulation of triphosphate synthesis. Cancer Res. 1978; 38(4):978-89. View

13.

Tattersall M, Ganeshaguru K, Hoffbrand A . Mechanisms of resistance of human acute leukaemia cells to cytosine arabinoside. Br J Haematol. 1974; 27(1):39-46. DOI: 10.1111/j.1365-2141.1974.tb06772.x. View

14.

Kozai Y, Sugino Y . Enzymatic phosphorylation of 1-beta-D-arabinofuranosylcytosine. Cancer Res. 1971; 31(10):1376-82. View

15.

SCHRECKER A . Metabolism of 1-beta-D-arabinofuranosylcytosine in leukemia L1210: nucleoside and nucleotide kinases in cell-free extracts. Cancer Res. 1970; 30(3):632-41. View

16.

MEYERS M, Kreis W . Purification of deoxycytidine kinases from two P815 murine neoplasms and their separation from deoxyguanosine kinase. Arch Biochem Biophys. 1976; 177(1):10-5. DOI: 10.1016/0003-9861(76)90409-4. View

17.

Stoller R, Myers C, Chabner B . Analysis of cytidine deaminase and tetrahydrouridine interaction by use of ligand techniques. Biochem Pharmacol. 1978; 27(1):53-9. DOI: 10.1016/0006-2952(78)90256-3. View

18.

Harris A, Grahame-Smith D, Potter C, BUNCH C . Cytosine arabinoside deamination in human leukaemic myeloblasts and resistance to cytosine arabinoside therapy. Clin Sci (Lond). 1981; 60(2):191-8. DOI: 10.1042/cs0600191. View

19.

Young R, Fischer G . The action of arabinosylcytosine on synchronously growing populations of mammalian cells. Biochem Biophys Res Commun. 1968; 32(1):23-9. DOI: 10.1016/0006-291x(68)90420-8. View

20.

Bodey G, Freireich E, MONTO R, HEWLETT J . Cytosine arabinoside (NSC-63878) therapy for acute leukemia in adults. Cancer Chemother Rep. 1969; 53(1):59-66. View