The Role of Deoxycytidine Kinase in DNA Synthesis and Nucleoside Analog Activation

  • Maria Staub
  • Staffan Eriksson
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Deoxycytidine kinase (dCK) is the main enzyme in the salvage of deoxyribonucleosides as a consequence of its broad substrate specificity. dCK is the only enzyme that can supply cells with all four precursors of DNA; is capable of 5′-phosphorylation of the natural substrates deoxycytidine (dCyt), deoxyadenosine, and deoxyguanosine; and can be interconverted into thymine nucleotides. The deoxycytidine triphosphate (dCTP), in addition to DNA, can be utilized for special processes, such as for synthesis of “Cliponucleotides, ”which are precursors of membrane phospholipids. The expression of dCK is highest in lymphoid cells/tissues (e.g., such as thymus, spleen, lymph nodes, stimulated peripheral blood mononuclear and bone marrow cells) and in all malignancies of these cells. The cell cycle dependence of the expression of dCK has been a matter of discussion; even higher dCK activity and dCyt metabolism were found in undifferentiated rather than in differentiated human lymphocytes. An enhancement of dCK activity occurred on preincubation of cells with a variety of nucleoside derivatives and nonnucleoside genotoxic agents, such as aphidicolin, etoposide (VP16), taxol, and even the G protein modulator sodium fluoride. γ-Irradiation and ultraviolet (UV) C irradiation also augmented dCK activity in different cells. The decrease of dCK activity was observed with protein phosphatase inhibitors, suggesting a regulatory role for reversible protein phosphorylation in the activation process. Cytosolic Ca2+ ion and p53 protein are necessary for the increase of dCK activity in cells after toxic treatments. The reason for the increase of dCK activity after toxic treatment of cells seems to be a compensatory mechanism induced by “metabolic stress” signals; cells need deoxynucleotides to repair damaged DNA. A positive correlation was found between dCK activity and the sensitivity of malignant cells to chemotherapy; thus, dCK has an outstanding importance in human chemotherapy. dCK is often the rate-limiting enzyme in the activation of these analogs. L-2′3′-dideoxy-3′-thiacytidine (lamivudine, 3TC); arabinosylcytosine (Cytosar, ara-C); 2-chlorodeoxyadenosine (cladribine, CdA); and 2′,2′-difluorodeoxycytidine (gemcitabine, dFdC), the first a human immunodeficiency virus drug and the last three valuable anticancer agents, are all substrates for dCK, and they are between 5% and 50% as efficient as dCyt as substrates for the enzyme. dCK prefers nucleoside sugars in the S-conformation (C2′-endo-C3′-exo) because α-2′,3′-dideoxycytidine adopts that conformation preferentially. dCK is composed by two identical polypeptides of 261 amino acids (54), and it shows some significant sequence similarity with the herpes simplex type 1 virus thymidine kinase, as well as about 40% sequence identity to the mitochondrial thymidine kinase 2. In 2003, the structure of dCK in complex with dCyt and ADP-Mg2+ was solved.

Key Words

Deoxycytidine kinase deoxyguanosine kinase deoxynucleoside analogs deoxynucleoside kinases deoxynucleosides thymidine kinases. 


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  1. 1.
    Arnér ES, Eriksson S. Mammalian deoxyribonucleoside kinases. Pharmacol Ther 1995;67:155–186.PubMedCrossRefGoogle Scholar
  2. 2.
    Eriksson S, Arn#x00E9;r ES, Spasokoukotskaja T, et al. Prospective and levels of deoxynucleoside kinases in normal and tumor cells: implications for chemother-apy. Adv Enzyme Regul 1994;34:13–45.PubMedCrossRefGoogle Scholar
  3. 3.
    Eriksson S, Wang L. The role of the cellular deoxynucleoside kinases in activation of nucleoside analogs used in chemotherapy. In:Chu CK, ed. Recent Advances in Nucleosides: Chemistry and Chemotherapy. Elsevier, 2002:455–475.Google Scholar
  4. 4.
    Eriksson S, Munch-Petersen B, Johansson K, Ekhlund H. Structure and function of cellular deoxyribonucleoside kinases. Cell Mol Life Sci 2002;59:1327–1346.PubMedCrossRefGoogle Scholar
  5. 5.
    Mathews CK. Deoxycytidylate deaminase, human. In:Wiley Encyclopedia of Molecular Medicine. Vol. 5. Wiley, 2002:1327–1346.Google Scholar
  6. 6.
    Gribaudo G, Riera L, Caposio P, Maley F, Landolfo S. Human cytomegalovirus requires cellular deoxycytidylate deaminase for replication in quiescent cells. J Gen Virol 2003;84:1437–1441.PubMedCrossRefGoogle Scholar
  7. 7.
    Staub M, Spasokukotskaja T, Benczur M, Antoni F. DNA synthesis and nucleoside metabolism in human tonsillar lymphocyte subpopulations. Acta Otolaryngol 1987;454:118–124.Google Scholar
  8. 8.
    Spasokoukotskaja T, Sasvari-Szekely M, Taljanidisz J, Staub M. Compartmentation of dCTP pools disappears after hydroxyurea or araC treatment in lymphocytes. FEBS Lett 1992;297:151–154.CrossRefGoogle Scholar
  9. 9.
    Xu YZ, Huang P, Plunkett W. Functional compartmentation of dCTP pools. J Biol Chem 1995;270:631–637.PubMedCrossRefGoogle Scholar
  10. 10.
    Anglana M, Apiou F, Bensimon A, Debatisse M. Dynamics of DNA replication in mammalian somatic cells: nucleotide pool modulates origin choice and intero-rigin spacing. Cell 2003;114:385–394.PubMedCrossRefGoogle Scholar
  11. 11.
    Spasokoukotskaj a T, Spyrou G, Staub M. Deoxycytidine is salvaged not only into DNA but also into phospholipid precursors. Biochem Biophys Research Commun 1988;155:923–929.CrossRefGoogle Scholar
  12. 12.
    Spasokukotskaja T, Taljanidisz J, Sasv-Székely M, Staub M. Deoxycytidine is salvaged not only into DNA but also into phospholipid precursors III. dCDP-Diacylglycerol formation in tonsillar lymphocytes. Biochem Biophys Res Commun 1991;174:680–687.PubMedCrossRefGoogle Scholar
  13. 13.
    Sasvàri-Székely M, Spasokoukotskaja T, Staub M. Deoxyribocytidine is sal-vaged not only into DNA but also into phospholipid precursors IV. Exogenoue deoxycytidine can be used with the same efficacy as (ribo)cytidine for phospho-lipid activation. Biochem Biophys Res Commun 1993;194:966–723.PubMedCrossRefGoogle Scholar
  14. 14.
    Hrab A, Spasokukotskaja T, Temesi A, Staub M. The salvage of deoxycytidine into dCDP-diacylglycerol by macrophages and lymphocytes. Biochem Biophys Res Commun 1993;193:212–219.CrossRefGoogle Scholar
  15. 15.
    Martin DP, Wallace TL, Johnson EM Jr. Cytosine arabinoside kills postmitotic neurons in fashion resembling trophic factor deprivation: evidence that deoxycy-tidine dependent process may be required for nerve growth factor signal trans-duction. J Neurosci 1990; 10:184–193.PubMedGoogle Scholar
  16. 16.
    Nagy N, Magyar T, Spasokoukotskaja T, Virga S, Oláh I, Staub M. The neurotox-icity of 2-Cl-deoxyadanosine can be released by deoxycytidine. Fund Clin Pharmacol 1999; 13:46.Google Scholar
  17. 17.
    Taljanidisz J, Spasokukotskaja T, Sasvari-Szekely M, Antoni F, Staub M. Preferential utilisation of deoxycytidine by undifferentiated (peanut positive) tonsillar lymphocytes. Immunol Lett 1987;15:109–115.PubMedCrossRefGoogle Scholar
  18. 18.
    Horvath L, Sasvari-Szekely M, Spasokoukotskaja T, Antoni F, Staub M. Different utilisation of deoxycytidine and thymidine by tonsillar lymphocyte sub-populations. Immunol Lett 1989;22:161–166.PubMedCrossRefGoogle Scholar
  19. 19.
    Taub JW, Huang XM, Matherly LH, et al. Expression of chromosome 21 localised genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin. Blood 1999;94:1393–1400.PubMedGoogle Scholar
  20. 20.
    Taub JW, Huang X, Ge Y, et al. Cystathione-b-synthase cDNA transfection alters the sensitivity and metabolism of 1-β-D-arabinosylcytosine in CCRF-CEM leukemia cells in vitro and in vivo: a model of leukemia in Down syndrome. Cancer Res 2000;60:6421–6426.PubMedGoogle Scholar
  21. 21.
    van der Wilt CL, Kroep JR, Loves WJ, et al. Expression of deoxycytidine kinase in leukaemic cells compared with solid tumour cell lines, liver metastases and normal liver. Eur J Cancer 2003;39:691–697.PubMedCrossRefGoogle Scholar
  22. 22.
    Kroep JR, Loves WJ, van der Wilt CL, et al. Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther 2002; 1:371–376.PubMedGoogle Scholar
  23. 23.
    Galmarini CM, Mackey IR, Dumontet C. Nucleoside analogues: mechanism of drug resistance and reversal strategies. Leukemia 2001; 15:875–890.PubMedCrossRefGoogle Scholar
  24. 24.
    Beausejour CM, Tremblay G, Momparler RL. Potential of ribozymes against deoxycytidine kinase to confer drug resistance to cytosine nucleoside analogs. Biochem Biophys Res Commun 2000;278:569–575.PubMedCrossRefGoogle Scholar
  25. 25.
    Stegmann AP, Honders WH, Willemze R, Ruiz van Haperen VW, Landegent JE. Transfection of wild-type deoxycytidine kinase (dCK) cDNA into an AraC-and DAC-resistant rat leukemic cell line of clonal origin fully restores drug sensitiv-ity. Blood 1995;85:1188–1194.PubMedGoogle Scholar
  26. 26.
    Manome Y, Wen PY, Dong Y, et al. Viral vector transduction of the human deoxy-cytidine kinase cDNA sensitizes glioma cells to the cytotoxic effect of cytosine arabinoside in vitro and in vivo. Nat Med 1996;2:567–573.PubMedCrossRefGoogle Scholar
  27. 27.
    Johansson M, Brismar S, Karlsson A. Human deoxycytidine kinase is located in the cell nucleus. Proc Natl Acad Sci USA 1997;94:11,941–11,945.PubMedCrossRefGoogle Scholar
  28. 28.
    Hatzis P, Al-Madhoon AS, Jullig M, Petrakis TG, Eriksson S, Talianidis I. The intra-cellular localization of deoxycytidine kinase. JBiolChem 1998;273:30,239–30,243.Google Scholar
  29. 29.
    Mohammad RM, Beck FW, Katato K, Hamdy N, Wall N, Al-Katib A. Potentiation of 2-chlorodeoxyadenosine activity by bryostatin 1 in the resistant chronic lymphocytic leukemia cell line (WSU-CLL): association with increased ratios of dCK/5′-NT and Bax/Bcl-2. Biol Chem 1998;379:1253–1261.PubMedCrossRefGoogle Scholar
  30. 30.
    Sasvari-Szekely M, Spasokoukotskaja T, Szoke M, et al. Activation of deoxy-cytidine kinase during inhibition of DNA synthesis by 2-chloro-2′-deoxyadeno-sine (cladribine) in human lymphocytes. Biochem Pharmacol 1998;56:1175–1179.PubMedCrossRefGoogle Scholar
  31. 31.
    Csapo Z, Sasvari-Szekely M, Spasokoukotskaja T, Talianidis I, Eriksson S, Staub M. Activation of deoxycytidine kinase by inhibition of DNA synthesis in human lymphocytes. Biochem Pharmacol 2001;61:191–197.PubMedCrossRefGoogle Scholar
  32. 32.
    Wang LM, Kucera GL. Deoxycytidine kinase is phosphorylated in vitro by pro-tein kinase C alpha. Biochim Biophys Acta 1994; 1224:161–167.PubMedCrossRefGoogle Scholar
  33. 33.
    Spasokoukotskaja T, Csapo Z, Sasvari-Szekely M, et al. Effect of phosphoryla-tion on deoxycytidine kinase activity. Adv Exp Med Biol 2000;486:281–285.PubMedCrossRefGoogle Scholar
  34. 34.
    Arnér ES, Spasokoukotskaja T, Juliusson G, Eriksson S. Phosphorylation of 2-chlorodeoxyadenosine (CdA) in extracts of peripheral blood mononuclear cells of leukemic patients. Br J Haematol 1994;87:715–718.PubMedGoogle Scholar
  35. 35.
    Sasvari-Szekely M, Piroth Z, Kazimierczuk Z, Staub M. A novel effect of the new antileukemic drug, 2-chloro-2′-deoxyadenosine, in human lymphocytes. Biochem Biophys Res Commun 1994;203:1378–1384.PubMedCrossRefGoogle Scholar
  36. 36.
    Spasokoukotskaja T, Sasvari-Szekely M, Keszler G, Albertioni F, Eriksson S, Staub M. Treatment of normal and malignant cells with nucleoside analogues and etoposide enhances deoxycytidine kinase activity. Eur J Cancer 1999;35:1862–1867.PubMedCrossRefGoogle Scholar
  37. 37.
    Ooi K, Ohkube T, Higashigawa M, Kawasaki H, Sakurai M. Increased deoxycy-tidine kinase activity by etoposide in L1210 murine leukemic cells. Biol Pharm Bull 1996;19:1382–1383.PubMedGoogle Scholar
  38. 38.
    Staub M, CsapÓ Zs, Spasokoukotskaja T, Sasvà-Székely M. Deoxycytidine kinase can be also potentiated by the G-protein activator NaF in cells. Adv Exp Med Biol 1998;431:425–428.PubMedGoogle Scholar
  39. 39.
    Csapo Z, Sasvari-Szekely M, Spasokoukotskaja T, Staub M. Modulation of human deoxycytidine kinase activity as a response to cellular stress induced by NaF. Acta Biochim Pol 2001;48:251–256.PubMedGoogle Scholar
  40. 40.
    Csapo Zs, Keszler G, Safrany G, et al. Activation of deoxycytidine kinase by gamma-irradiation and inactivation by hyperosmotic shock in human lympho-cytes. Biochem Pharmacol 2003;65:2031–2039.PubMedCrossRefGoogle Scholar
  41. 41.
    Van den Neste E, Smal C, Delacauw A, et al. Activation of deoxycytidine kinase by UV-C irradiation in chronic lymphatic leukemia B-lymphocytes. Biochem Pharmacol 2003;65:573–580.CrossRefGoogle Scholar
  42. 42.
    Kreder CN, van Bree C, Peters GJ, Loves PJ, Haveman J. Enhanced levels of deoxycytidine kinase and thymidine kinase 1 and 2 after pulsed low dose rate irradiation as an adaptive response to radiation. Oncol Rep 2002;9:141–144.PubMedGoogle Scholar
  43. 43.
    Ohkubo T, Higashigava M, Kavasaki H, et al. Synergistic interaction between etopo-side and 1-β-arabinofuranosylcytosine. Adv Exp Med Biol 1989;253B:355–362.PubMedGoogle Scholar
  44. 44.
    Keszler G, Szikla K, Kazimierczuk Z, Spasokoukotskaja T, Sasvari-Szekely M, Staub M. Selective activation of deoxycytidine kinase by thymidine-5′-thiosul-phate and release by deoxycytidine in human lymphocytes. Biochem Pharmacol 2003;65:563–571.PubMedCrossRefGoogle Scholar
  45. 45.
    Hershfield MS, Mitchell BS. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleotide phosphorylase deficiency. In:Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. McGraw-Hill Health Professions, New York, NY, vol. 2. 1995:1725–1769.Google Scholar
  46. 46.
    Keszler G, Spasokoukotskaja T, Csapo Zs, Virga S, Staub M, Sasvari-Szekely M. Selective increase of dATP pools upon activation of deoxycytidine kinase in lym-phocytes: implications in apoptosis. Nucleosides Nucleotides Nucleic Acids 2004; 23:1335–1342.PubMedCrossRefGoogle Scholar
  47. 47.
    Genini D, Budihardjo L, Plunkett W, et al. Nucleotide requirements for the in vitro activation of the apoptosis protein-activating factor-1-mediated caspase pathway. J Biol Chem 2000;275:29–34.PubMedCrossRefGoogle Scholar
  48. 48.
    Oren M. Decision making by p53: life, death and cancer. Cell Death Differ 2003;10:431–442.PubMedCrossRefGoogle Scholar
  49. 49.
    Komarov PG, Komarova EA, Kondratov RV, et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 1999;285:1733–1737.PubMedCrossRefGoogle Scholar
  50. 50.
    Keszler G, Spasokoukotskaja T, Csapo Zs, et al. Activation of deoxycytidine kinase in lymphocytes is calcium dependent and involves a conformational change detectable by native immunostaining. Biochem Pharmacol 2004;67;947–955.PubMedCrossRefGoogle Scholar
  51. 51.
    Tamura RN, Cox GS. Effect of pyrimidine deoxynucleosides and sodium butirate on expression of the glycoprotein hormone a-subunit and placental alkaline phos-phatase in HeLa cells. Biochem Biophys Acta 1988;968:151–159.PubMedCrossRefGoogle Scholar
  52. 52.
    Achanta G, Pelicano H, Feng L, Plunkett W, Huang P. Interaction of p53 and DNA-PK in response to nucleoside analogues: potential roles as a sensor com-plex for DNA damage. Cancer Res 2001;61:8723–8729.PubMedGoogle Scholar
  53. 53.
    Yamaguchi T, Matsuda K, Sagiya Y, et al. p53R2-dependent pathway for DNA synthesis in p53 regulated cell cycle checkpoint. Cancer Res 2001;61:8256–8261.PubMedGoogle Scholar
  54. 54.
    Smal C, Vertommen D, Bertrand L, et al. Identification of in vivo phosphoryla-tion sites on human deoxycytidine kinase. Biol Chem 2006;281:4887–4893.Google Scholar
  55. 55.
    Tombal B, Denmeade SR, Gillis JM, Isaacs JT. A supramicromolar elevation of intracellular free calcium is consistently required to induce the execution phase of apoptosis. Cell Death Differ 2002;9:561–573.PubMedCrossRefGoogle Scholar
  56. 56.
    Dieter P, Fitzke E, Duyster J. B APTA induces a decrease of intracellular free cal-cium and a translocation and inactivation of protein kinase C in macrophages. Biol Chem Hoppe Seyler 1993;374:171–174.Google Scholar
  57. 57.
    Plunkett W, Gandhi V. Purine and pyrimidine nucleoside analogs. Cancer Chemother Biol Response Modif 2001;19:21–45.PubMedGoogle Scholar
  58. 58.
    Gumina G, Chong Y, Choo H, Song GY, Chu CK. L-Nucleosides: antiviral activ-ity and molecular mechanism. Curr Top Med Chem 2002;2:1065–1086.PubMedCrossRefGoogle Scholar
  59. 59.
    Chang CN, Skalski V, Zhou JH, Cheng YC. Biochemical pharmacology of (+)-and (−)-2′,3′-dideoxy-3′-thiacytidine as anti-hepatitis B virus agents. J Biol Chem 1992;267:22,414–22,420.PubMedGoogle Scholar
  60. 60.
    Maury G. The enantioselectivity of enzymes involved in current antiviral therapy using nucleoside analogues: a new strategy? Antivir Chem Chemother 2000;11:165–189.PubMedGoogle Scholar
  61. 61.
    Wang J, Choudhury D, Chattopadhyaya J, Eriksson S. Stereoisomeric selectivity of human deoxyribonucleoside kinases. Biochemistry 1999;38:16,993–16,999.PubMedCrossRefGoogle Scholar
  62. 62.
    Grove KL, Cheng YC. Uptake and metabolism of the new anticancer compound β-L-(−)-dioxolane-cytidine in human prostate carcinoma DU-145 cells. Cancer Res 1996;56:4187–4191.PubMedGoogle Scholar
  63. 63.
    Verri A, Focher F, Priori G, et al. Lack of enantiospecificity of human 2′-deoxy-cytidine kinase: relevance for the activation of β-L-deoxycytidine analogs as anti-neoplastic and antiviral agents. Mol Pharmacol 1997;51:132–138.PubMedGoogle Scholar
  64. 64.
    Liu SH, Grove KL, Cheng YC. Unique metabolism of a novel antiviral L-nucleoside analog, 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil: a substrate for both thymi-dine kinase and deoxycytidine kinase. Antimicrob Agents Chemother 1998;42:833–839.PubMedGoogle Scholar
  65. 65.
    Maltseva T, Usova E, Eriksson S, Milecki J, Foldesi A, Chattopadhayaya J. An NMR conformational study of the complex of 13C/2H double labeled 2′-deoxynu-cleoside and deoxycytidine kinase. J C S Perkin Trans 2000;2:199–2207.Google Scholar
  66. 66.
    Prota A, Vogt J, Pilger B, et al. Kinetics and crystal structure of the wild-type and the engineered Y101F mutant of Herpes simplex virus type 1 thymidine kinase inter-acting with (North)-methanocarba-thymidine. Biochemistry 2000;39:9597–9603.PubMedCrossRefGoogle Scholar
  67. 67.
    Chottiner EG, Shewach DS, Datta NS, et al. Cloning and expression of human deoxycytidine kinase cDNA. Proc Natl Acad Sci USA 1991;88:1531–1535.PubMedCrossRefGoogle Scholar
  68. 68.
    Johansson K, Ramaswamy S, Ljungcrantz C, et al. Structural basis for substrate specificities of cellular deoxyribonucleoside kinases [erratum in: Nat Struct Biol 2001;8:818-819]. Nat Struct Biol 2001;8:616–620.PubMedCrossRefGoogle Scholar
  69. 69.
    Sabini E, Ort S, Monnerjahn C, Konrad M, Lavie A. Structure of human dCK suggests strategies to improve anticancer and antiviral therapy. Nat Struct Biol 2003; 10:513–519.PubMedCrossRefGoogle Scholar
  70. 70.
    Knecht W, Sandrini MP, Johansson K, Eklund H, Munch-Petersen B, Piskur J. A few amino acid substitutions can convert deoxyribonucleoside kinase specificity from pyrimidines to purines. EMBO J 2002;21:1873–1880.PubMedCrossRefGoogle Scholar
  71. 71.
    Ives DH, Durham JP. Deoxycytidine kinase. 3. Kinetics and allosteric regulation of the calf thymus enzyme. J Biol Chem 1970;245:2285–2294.PubMedGoogle Scholar
  72. 72.
    Kierdaszuk B, Rigler R, Eriksson S. Binding of substrates to human deoxycyti-dine kinase studied with ligand-dependent quenching of enzyme intrinsic fluores-cence. Biochemistry 1993;32:699–707.PubMedCrossRefGoogle Scholar
  73. 73.
    Hughes TL, Hahn TM, Reynolds KK, Shewach DS. Kinetic analysis of human deoxycytidine kinase with the true phosphate donor uridine triphosphate. Biochemistry 1997;36:7540–7547.PubMedCrossRefGoogle Scholar
  74. 74.
    Turk B, Awad R, Usova EV, Bj I, Eriksson S. A pre-steady state kinetic analy-sis of substrate binding to human recombinant deoxycytidine kinase: a model for nucleoside kinases. Biochemistry 1999;38:8555–8561.PubMedCrossRefGoogle Scholar
  75. 75.
    Mani RS, Usova EV, Eriksson S, Cass CE. Hydrodynamic and spectroscopic studies of substrate binding to human recombinant deoxycytidine kinase. Nucleosides Nucleotides Nucleic Acids 2003;22:175–192.PubMedCrossRefGoogle Scholar
  76. 76.
    Ikeda S, Chakravarty R, Ives DH. Multisubstrate analogs for deoxynucleoside kinases. Triphosphate end products and synthetic bisubstrate analogs exhibit identical modes of binding and are useful probes for distinguishing kinetic mech-anisms. J Biol Chem 1986;261:15,836–15,843.PubMedGoogle Scholar
  77. 77.
    Mikkelsen NE, Johansson K, Karlsson A, et al. Structural basis for feedback inhi-bition of the deoxyribonucleoside salvage pathway: studies of the Drosophila deoxyribonucleoside kinase. Biochemistry 2003;42:5706–5712.PubMedCrossRefGoogle Scholar
  78. 78.
    Krawiec K, Kierdaszuk B, Shugar D. Inorganic tripolyphosphate (PPP(i)) as a phosphate donor for human deoxyribonucleoside kinases. Biochem Biophys Res Commun 2003;301:192–197.PubMedCrossRefGoogle Scholar
  79. 79.
    Usova EV, Eriksson S. Identification of residues involved in the substrate speci-ficity of human and murine dCK. Biochem Pharmacol 2002;64:1559–1567.PubMedCrossRefGoogle Scholar
  80. 80.
    Ruiz van Haperen VW, Veerman G, Eriksson S, et al. Development and molec-ular characterization of a 2′,2′-difluorodeoxycytidine-resistant variant of the human ovarian carcinoma cell line A2780. Cancer Res 1994;54:4138–4143.Google Scholar
  81. 81.
    Owens JK, Shewach DS, Ullman B, Mitchell BS. Resistance to 1-β-D-arabinofu-ranosylcytosine in human T-lymphoblasts mediated by mutations within the deoxycytidine kinase gene. Cancer Res 1992;52:2389–2393.PubMedGoogle Scholar
  82. 82.
    Dumontet C, Fabianowska-Majewska K, Mantincic D, et al. Related common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562. Br J Haematol 1999; 106:78–85.PubMedCrossRefGoogle Scholar
  83. 83.
    Lotfi K, Månsson E, Spasokoukotskaja T, et al. Biochemical pharmacology and resistance to 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine, a novel analogue of cladrabine in human leukemic cells. Clin Cancer Res 1999;5:2438–2444.PubMedGoogle Scholar
  84. 84.
    Mansson E, Spasokoukotskaj a T, Sallstrom J, Eriksson S, Albertioni F. Molecular and biochemical mechanisms of fludarabine and cladribine resistance in a human promyelocytic cell line. Cancer Res 1999;59:5956–5963.PubMedGoogle Scholar
  85. 85.
    Mansson E, Flordal E, Liliemark J, et al. Down-regulation of deoxycytidine kinase in human leukemic cell lines resistant to cladribine and clofarabine and increased ribonucleotide reductase activity contributes to fludarabine resistance. Biochem Pharmacol 2003;65:237–247.PubMedCrossRefGoogle Scholar
  86. 86.
    Flasshove M, Strumberg D, Ayscue L, et al. Structural analysis of the deoxycyti-dine kinase gene in patients with acute myeloid leukemia and resistance to cyto-sine arabinoside. Leukemia 1994;8:780–785.PubMedGoogle Scholar
  87. 87.
    Veuger M, Honders M, Landegent J, Willemze R, Barge R. High incidence of alternatively spliced forms of deoxycytidine kinase. Blood 2000;96:1517–1524.PubMedGoogle Scholar
  88. 88.
    Kawasaki H, Caricia CJ, Carson DA. Quantitative immunoassay of human deoxycytidine kinase in malignant cell. Anal Biochem 1992;207:193–196.PubMedCrossRefGoogle Scholar
  89. 89.
    Leiby JM, Snider KM, Kraut EH, Metz EN, Malspeis L, Grever MR. Phase II trial of 9-β-D-arabinofuranosyl-2-fluoroadenine 5′-monophosphate in non-Hodgkin’s lymphoma: prospective comparison of response with deoxycytidine kinase activity. Cancer Res 1987;47:2719–2722.PubMedGoogle Scholar
  90. 90.
    Abertioni F, Lindemalm S, Reichlova V, et al. Pharmacokinetics of cladribine in plasma and its 5′-mono and triphosphate in leucemic cells in patients with chronic lymphocytic leukemia. Clin Cancer Res 1998;4:653–658.Google Scholar
  91. 91.
    Galmarini CM, Thomas X, Graham K, et al. Deoxycytidine kinase and cN-II nucleotidase expression in blast cells predict survival in acute myeloid leukaemia patients treated with cytarabine. Br J Haematol 2003; 122:53–60.PubMedCrossRefGoogle Scholar
  92. 92.
    Hapke DM, Stegmann APA, Mitchell BS. Retroviral transfer of deoxycytidine kinase into tumor cells lines enhances nucleoside toxicity. Cancer Res 1996;56:2343–2347.PubMedGoogle Scholar
  93. 93.
    Keszler G, Virga Sz, Spasokuokotskaja T, Bauer PI, Sasvari-Székely M, Staub M. Activation of deoxycytidine kinase by deoxyadenosine: implication in deoxyadenosine mediated cytotoxicity. Arch Biochem Biophys 2005;436:69–77.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Maria Staub
    • 1
  • Staffan Eriksson
    • 2
  1. 1.Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Faculty of MedicineSemmelweis UniversityBudapestHungary
  2. 2.Department of Molecular BiosciencesThe Swedish University of Agricultural Sciences, The Biomedical CenterUppsalaSweden

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