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Deoxypyrimidine-induced inhibition of the cytokinetic effects of 1-β-d-arabinofuranosyluracil


Ara-U-induced S-phase accumulation and the interaction between high concentrations of ara-U (HiCAU) and ara-C were investigated in L1210 leukemia cells in vitro. Treatment of exponentially growing L1210 murine leukemia cells with ara-U (200–1000 μm) for 48 h caused a dose-dependent accumulation of cells in the S-phase. The extent of this ara-U-induced S-phase accumulation correlated with ara-U incorporation into DNA and with increases of up to 172% and 464% in the specific activities of deoxycytidine kinase and thymidine kinase, respectively, over control values. Metabolism of 1 μm ara-C following the exposure of cells to ara-U (1mm) resulted in 4.5 pmol ara-C DNA/mg protein vs 2.1 pmol/mg protein in control cells. Although 48-h exposure of cells to 200 and 400 μm ara-U is not cytotoxic, it enhances the cytotoxicity of ara-C (10–100 μm) 4- to 10-fold. Ara-U-induced S-phase accumulation is inhibited by deoxypyrimidine nucleosides but not by pyrimidine or deoxypurine nucleosides. Some of the ara-U and ara-C concentrations used in this study are achievable in clinical practice, and ara-U/ara-C interactions may explain in part the unique therapeutic utility of high-dose ara-C.

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1-β-d-arabinofuranosylcytidine triphosphate


high-dose ara-C


high concentrations of ara-U


deoxycytidine triphosphate


high-dose ara-U




deoxyuridine diphosphate


deoxyuridine triphosphate


thymidine triphosphate



dCyd kinase:

deoxycytidine kinase


  1. 1.

    Caminier GW, Smith CG (1965) Studies of the enzymatic deamination of cytosine arabinoside. Biochem Pharmacol 14: 1405

  2. 2.

    Capizzi RL, Powell BL (1987) Sequential high dose ara-C and asparaginase versus high dose ara-C alone in the treatment of patients with relapsed and refractory acute leukemias. Semin Oncol 14 [Suppl 1]: 40

  3. 3.

    Capizzi RL, Yang J-L, Cheng E, Bjornson D, Sahasrabudhe D, Tan R-S, Cheng Y-C (1983) Alteration of the pharmacokinetics of high dose ara-C by its metabolite high ara-U in patients with acute leukemia. J Clin Oncol 1: 763

  4. 4.

    Capizzi RL, Yang J-L, Rathmell JP, White JC, Cheng E, Cheng Y-C, Kute T (1985) Dose-related pharmacologic effects of high dose ara-C and its self-potentiation. Semin Oncol 12 [Suppl 3]: 65

  5. 5.

    Caradonna SJ, Cheng Y-C (1980) The role of deoxyuridine triphosphate nucleotidohydrolase, uracil-DNA glycosylase, and DNA polymerase α in the metabolism of FUdR in human tumor cells. Mol Pharmacol 18: 513

  6. 6.

    Caradonna SJ, Cheng YC (1980) Uracil DNA-glycosylase. Purification and properties of this enzyme isolated from blast cells of acute myelocytic leukemia patients. J Biol Chem 255: 2293

  7. 7.

    Chandrasekaran B, Capizzi RL, Thomas MJ (1986) Ara-U metabolism in murine and human leukemias (abstract). Proc Am Assoc Cancer Res 27: 304

  8. 8.

    Chandrasekaran B, Capizzi RL, Kute TE, Morgan T, Dimling J (1989) Modulation of the metabolism and pharmacokinetics of 1-β-d-arabinofuranosylcytosine by 1-β-d-arabinofuranosyluracil in leukemic mice. Cancer Res 49: 3259

  9. 9.

    Cheng Y-C, Prusoff WH (1974) A new rapid assay for measuring deoxycytidylate- and deoxythymidylate-kinase activities. Anal Biochem 60: 545

  10. 10.

    Cheng Y-C, Domin B, Lee L-S (1977) Human deoxycytidine kinase: purification and characterization of the cytoplasmic and mitochondrial isozymes derived from blast cells of acute myelocytic leukemia patients. Biochim Biophys Acta 481: 481

  11. 11.

    Chiba P, Tihan T, Eher R, Koller U, Wallner C, Gobl R, Linkesch W (1989) Effect of cell growth and cell differentiation on 1-β-d-arabinofuranosylcytosine metabolism in myeloid cells. Br J Haematol 71: 451

  12. 12.

    Dolbeare F, Beisker W, Pallavicini MG, Vanderlaan M, Gray JW (1985) Cytochemistry for bromodeoxyuridine/DNA analysis. Cytometry 6: 521

  13. 13.

    Domena JD, Mosbaugh DW (1985) Purification of nuclear and mitochondrial uracil-DNA glycosylase from rat liver. Identification of two subcellular forms. Biochemistry 24: 7320

  14. 14.

    Fietkau R, Friede H, Maurer-Schultze B (1984) Cell kinetic studies of the cytostatic cytocidal effect of 1-β-d-arabinofuranosylcytosine on the L1210 ascites tumor. Cancer Res 44: 1105

  15. 15.

    Ho DHW, Frei E (1971) Clinical pharmacology of 1-β-d-arabino-furanosylcytosine. Clin Pharmacol Ther 12: 944

  16. 16.

    Karon M, Shirakawa S (1969) The locus of action of 1-β-d-arabinofuranosylcytosine in the cell cycle. Cancer Res 29: 687

  17. 17.

    Kinahan JJ, Kowal EP, Grindey GB (1981) Biochemical and antitumor effects of the combination of thymidine and 1-β-d-arabinofuranosylcytosine against leukemia L1210. Cancer Res 41: 445

  18. 18.

    Koistinen P, Ferola E, Vilpo JA (1986) Uracil-DNA glycosylase activity in chronic lymphoproliferative disorders. Leuk Res 10: 1307

  19. 19.

    Koistinen P, Ferola E, Vilpo JA (1987) Uracil-DNA glycosylase activity in human acute leukemia. Leuk Res 11: 557

  20. 20.

    Kufe DW, Major PP, Egan ER, Beardsley P (1980) Incorporation of ara-C into L1210 DNA as a correlate of cytotoxicity. J Biol Chem 2355: 8997

  21. 21.

    Lampkin BC, Nagao T, Mauer AM (1971) Synchronization and recruitment in acute leukemia. J Clin Invest 50: 2204

  22. 22.

    Makino F, Munakata N (1979) Excision of uracil from bromodeoxyuridine-substituted and UV-irradiated DNA in cultured mouse lymphoma cells. Int J Radiat Biol 36: 349

  23. 23.

    Muller WEG, Zahn RK (1979) Metabolism of 1-β-d-arabinofuranosyluracil in mouse L5178Y cells. Cancer Res 39: 1102

  24. 24.

    Rudnick SA, Cadman EC, Capizzi RL, Skeel RT, Bertino JR, McIntosh S (1979) High dose cytosine arabinoside (HDARAC) in refractory acute leukemia. Cancer 44: 1189

  25. 25.

    Skipper HE, Schabel FM Jr, Wilcox WS (1967) Experimental evaluation of potential anticancer agents: XXI. Scheduling of arabinosylcytosine to take advantage of its S-phase specificity against leukemia cells. Cancer Chemother Rep 51: 125

  26. 26.

    Strauss BS (1985) Cellular aspects of DNA repair. Adv Cancer Res 45: 45

  27. 27.

    Townsend AJ, Cheng Y-C (1987) Sequence-specific effects of ara-5-aza-CTP and ara-CTP on DNA synthesis by purified human DNA polymerases in vitro: visualization of chain elongation on a defined template. Mol Pharmacol 32: 330

  28. 28.

    Vilpo JA (1988) The DNA-repair enzyme uracil-DNA glycosylase in the human hematopoietic system. Mutat Res 193: 207

  29. 29.

    Walsh CT, Craig RT, Agarwal RP (1980) Increased activation of 1-β-d-arabinofuranosylcytosine by hydroxyurea in L1210 cells. Cancer Res 40: 3286

  30. 30.

    Wan SH, Hoffman DH, Azarnoff DL (1974) Pharmacokinetics of 1-β-d-arabinofuranosylcytosine in humans. Cancer Res 34: 392

  31. 31.

    White JC, Rathmell JP, Capizzi RL (1987) Membrane transport influences the rate of accumulation of cytosine arabinoside in human leukemia cells. J Clin Invest 79: 380

  32. 32.

    Yang J-L, Cheng EH, Capizzi RL, Cheng Y-C, Kute T (1985) Effect of uracil arabinoside on metabolism and cytotoxicity of cytosine arabinoside in L5178Y murine leukemia. J Clin Invest 75: 141

  33. 33.

    Young RSK, Fischer GA (1968) The action of arabinosylcytosine on synchronously growing populations of mammalian cells. Biochem Biophys Res Commun 32: 23

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Correspondence to Robert L. Capizzi.

Additional information

Supported in part by grant CH-35H from the American Cancer Society, by Public Health Service grant CA-12197 from the National Cancer Institute, National Institutes of Health, and by the Gaston Cancer Society

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Chandrasekaran, B., Kute, T.E. & Capizzi, R.L. Deoxypyrimidine-induced inhibition of the cytokinetic effects of 1-β-d-arabinofuranosyluracil. Cancer Chemother. Pharmacol. 29, 455–460 (1992). https://doi.org/10.1007/BF00684847

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  • Pyrimidine
  • Nucleoside
  • Deoxycytidine
  • Thymidine Kinase
  • Therapeutic Utility