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The relationship of Ara-C metabolism in vitro to therapeutic response in acute myeloid leukaemia


Ara-C phosphorylation and Ara-C deamination was measured in vitro, using intact marrow myeloblasts from 25 patients with previously untreated acute myeloid leukaemia. At Ara-C concentrations above 10 μM there was no longer a linear relationship of phosphorylation to Ara-C concentration. Ara-U production was measured by sampling the incubation medium. This method showed greater Ara-U production than previous methods sampling the cell pellet alone. However, Ara-CTP/Ara-U ratios from intact myeloblasts were much higher than those recorded in studies using lysed myeloblasts. Using 1 μM Ara-C, a concentration representative of in vivo concentrations, deamination and phosphorylation were related to therapeutic response to Ara-C-containing drug regimens. There was no significant correlation of these variables with response, although 5/16 non-responders had low Ara-C phosphorylation (<1.5 pmol/106 cells/45 min/l pm Ara-C) compared with 0/9 responders. Measuring deaminase activity did not help in selecting non-responders. Even in patients with low phosphorylation increasing Ara-C concentration increased Ara-CTP levels proportionally, but up to 10 times conventional doses may be necessary to exceed endogenous dCTP levels.

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  1. 1.

    Armentrout SA, Burns CP (1976) Cytosine arabinoside as a single agent in the therapy of adult care leukaemia. Am J Med Sci 268: 163–168

  2. 2.

    Bodey GP, Freireich EJ, Monto RW, Hewlett JS (1969) Cytosine arabinoside (NSC-63878) therapy for acute leukaemia in adults. Cancer Chemother Rep 53: 59–66

  3. 3.

    Camiener GW (1967) Studies of the enzymatic deamination of cytosine arabinoside-II. Properties of the deaminase of human liver. Biochem Pharmacol 16: 1681–1689

  4. 4.

    Chou TC, Arlin A, Clarkson BD, Philips FS (1977) Metabolism of 1-β-d-arabinofuranosylcytosine in human leukaemic cells. Cancer Res 37: 3561–3570

  5. 5.

    Coleman CN, Stoller RG, Drake JC, Chabner BA (1975) Deoxycytidine kinase: properties of the enzyme from human leukaemic granulocytes. Blood 46: 791–803

  6. 6.

    Dicioccio RA, Srivastava BIS (1977) Kinetics of inhibition of deoxynucleotide polymerising enzyme activities from normal and leukaemic human cells by 9-β-d-arabinofuranosyladenine 5-triphosphate. Eur J Biochem 79: 411–418

  7. 7.

    Durham JP, Ives DH (1970a) Deoxycytidine kinase. II. Purification and properties of the calf thymus enzyme,. J Biol Chem 245: 2276–2284

  8. 8.

    Durham JP, Ives DH (1970b) Deoxycytidine kinase. III. Kinetics and allosteric regulation of the calf thymus enzyme. J Biol Chem 245: 2285–2294

  9. 9.

    Hall TC (1971) Selecting drug regimens in human leukaemia. Prediction of response in cancer therapy. Natl Cancer Inst Monogr 34: 145–151

  10. 10.

    Harris AL, Grahame-Smith DG (1980) Variation in sensitivity of DNA synthesis to Ara-C in acute myeloid leukaemia. Br J Haematol 45: 371–379

  11. 11.

    Harris AL, Potter C, Bunch C, Boutagy J, Harvey DJ, Grahame-Smith DG (1979) Pharmacokinetics of cytosine arabinoside in patients with acute myeloid leukaemia. Br J Clin Pharmacol 8: 219–227

  12. 12.

    Hart JS, Ho DH, George SL, Salem P, Gohlieb JA, Frei E III (1972) Cytokinetic and molecular pharmacology studies of arabinosylcytosine in metastatic melanoma. Cancer Res 32: 2711–2716

  13. 13.

    Hederson JF, Brox LW, Fraser JH, Lomax CA, McCoy EE, Snyder F, Zombor G (1975) Models and methods for biochemical studies of resistance in man. Pharmacological basis of cancer chemotherapy. Williams & Wilkins, Baltimore, pp 663–680

  14. 14.

    Kessel D, Hall TC, Rosenthal D (1969) Uptake and phosphorylation of cytosine arabinoside by normal and leukaemic blood cells in vitro. Cancer Res 29: 459–463

  15. 15.

    Kreiss W, Hession C, Soricelli A, Scully K (1977) Combinations of tetrahydouridine and cytosine arabinoside in mouse tumours. Cancer Treat Rep 61: 1355–1364

  16. 16.

    Mauer AM, Fisher V (1962) Comparison of the proliferative capacity of acute leukaemia cells in marrow and in blood. Nature 193: 1085

  17. 17.

    Randerath K, Randerath E (1966) Ion-exchange thin-layer chromatography. XV. Preparation properties and applications of paper-like PE1-cellulose sheets. J Chromatogr 22: 110–117

  18. 18.

    Smyth JF, Robins AB, Leese LL (1976) The metabolism of cytosine arabinoside as a predictive test for clinical response to the drug in acute myeloid leukaemia. Eur J Cancer 12: 567–575

  19. 19.

    Stuart DC, Burke PJ (1971) Cytidine deaminase and development of resistance to arabinosylcytosine. Nature New Biol 233: 109–110

  20. 20.

    Stoller RG, Coleman CN, Chang P, Chabner BA (1975) Biochemical pharmacology of cytidine analog metabolism in human leukaemic cells. In: Clemmesen J, Yohn DS (eds) Comparative leukaemia research. Bibl Haematol 43: 531–533

  21. 21.

    Tattersall MNH, Ganeshaguru K, Hoffbrand AV (1974) Mechanism of resistance of human acute leukaemic cells to cytosine arabinoside. Br J Haematol 27: 39–46

  22. 22.

    Thorell B (1947) Studies on the formation of cellular substances during blood cell production. Acta Med Scand [Suppl 200]

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Correspondence to Adrian L. Harris.

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Harris, A.L., Grahame-Smith, D.G. The relationship of Ara-C metabolism in vitro to therapeutic response in acute myeloid leukaemia. Cancer Chemother. Pharmacol. 9, 30–35 (1982).

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  • Cancer Research
  • Linear Relationship
  • Method Sampling
  • Myeloid Leukaemia
  • Cell Pellet