Skip to main content
SpringerLink
Log in

New targets for pyrimidine antimetabolites for the treatment of solid tumours

2: Deoxycytidine kinase

  • Published:
Pharmacy World and Science Aims and scope Submit manuscript

Abstract

Deoxycytidine kinase is an enzyme required for the activation of, for example, cytarabine, the most widely used agent for the chemotherapy of haematological malignancies. However, deoxycytidine kinase also plays an important role in the activation of several new agents used in the treatment of leukaemia, such as cladribine. Recently, a new cytidine analogue, gemcitabine, has shown impressive activity as a single agent against several solid malignancies (ovarian cancer, non-small cell lung cancer), demonstrating that in solid tumours deoxycytidine kinase can be an important target for the activation of antimetabolites. Studies on the regulation of deoxycytidine kinase have shown that the enzyme has a complicated regulation (feedback inhibition by the product and regulation by ribonucleotides). Modulation of deoxycytidine kinase activity has already been shown to be an effective way to improve the effect of cytarabine and will probably be a target for new therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Durham JP, Ives DH. Deoxycytidine kinase. I. Distribution in normal and neoplastic tissues and interrelationships of deoxycytidine and 1-β-D-arabinofuranosylcytosine phosphorylation. Mol Pharmacol 1969;5:358–75.

    PubMed  Google Scholar 

  2. Ho DHW. Distribution of kinase and deaminase of 1-β-Darabinofuranosylcytosine in tissues of man and mouse. Cancer Res 1973;33:2816–20.

    PubMed  Google Scholar 

  3. Arnér ESJ, Flygar M, Bohman C, Wallström B, Eriksson S. Deoxycytidine kinase is constitutively expressed in human lymphocytes: consequences for compartmentation effects, unscheduled DNA synthesis and viral replication in resting cells. Exp Cell Res 1988;178:335–42.

    PubMed  Google Scholar 

  4. Habteyesus A, Nordenskjöld A, Bohman C, Eriksson S. Deoxynucleoside phosphorylating enzymes in monkey and human tissues show great similarities, while mouse deoxycytidine kinase has a different substrate specificity. Biochem Pharmacol 1991;42:1829–36.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  6. Ruiz van Haperen VWT, Veerman G, Vermorken JB, Peters GJ. Deoxycytidine kinase and deoxycytidine deaminase activities in human tumour xenografts. Eur J Cancer 1993;29A:2132–7.

    PubMed  Google Scholar 

  7. Song JJ, Walker S, Chen E, Johnson II EE, Spychala J, Gribbin T, et al. Genomic structure and chromosomal localization of the human deoxycytidine kinase gene. Proc Natl Acad Sci USA 1993;90:431–4.

    PubMed  Google Scholar 

  8. Chottiner EG, Shewach DS, Datta NS, Ashcraft E, Gribbin D, Ginsburg D, et al. Cloning and expression of human deoxycytidine kinase cDNA. Proc Natl Acad Sci USA 1991;88:1531–5.

    PubMed  Google Scholar 

  9. Karlsson A, Herrström A, Eriksson S. Sequencing and expression of mouse and monkey deoxycytidine kinase [abstract]. Pharm World Sci 1993;15 Suppl F:F19.

    Google Scholar 

  10. Datta NS, Shewach DS, Hurley MC, Mitchell BS, Fox IH. Human T-lymphoblast deoxycytidine kinase: purification and properties. Biochemistry 1989;28:114–23.

    PubMed  Google Scholar 

  11. Chan TS, Lakhchaura BD, Hsu TF. Differences in deoxycytidine metabolism in mouse and rat. Biochem J 1983;210:367–71.

    PubMed  Google Scholar 

  12. Singhal RL, Yeh YA, Scekeres T, Weber G. Increased deoxycytidine kinase activity in cancer cells and inhibition by difluorodeoxycytidine. Oncol Res 1992;4:517–22.

    PubMed  Google Scholar 

  13. Madani S, Baillon J, Fries J, Belhadj O, Bettaieb A, Ben Hamida M, et al. Pyrimidine pathway enzymes in human tumours of brain and associated tissues: potentialities for the therapeutic use ofN-phosphonacetyl-L-aspartate and 1-β-Darabinofuranosylcytosine. Eur J Cancer Clin Oncol 1987;23:1485–90.

    PubMed  Google Scholar 

  14. Kawasaki H, Carrera CJ, Carson DA. Quantitative immunoassay of human deoxycytidine kinase in malignant cells. Anal Biochem 1992;207:193–6.

    PubMed  Google Scholar 

  15. Cory AH, Shibley IA, Chalovich JM, Cory JG. Deoxyguanosine-resistant leukaemia L1210 cells-loss of specific deoxyribonucleoside kinase activity. J Biol Chem 1993;268:405–9.

    PubMed  Google Scholar 

  16. Veerman G, Ruiz van Haperen VWT, Vermorken JB, Peters GJ. Regulation of deoxycytidine kinase (dCK) by CTP and UTP [abstract]. Pharm World Sci 1993;15 Suppl F:F29.

    Google Scholar 

  17. Bohman C, Eriksson S. Deoxycytidine kinase from human leukemic spleen: preparation and characterization of the homogenous enzyme. Biochemistry 1988;27:4258–65.

    PubMed  Google Scholar 

  18. Durham JP, Ives DH. Deoxycytidine kinase. II. Purification and general properties of the calf thymus enzyme. J Biol Chem 1970;245:2276–84.

    PubMed  Google Scholar 

  19. Sarup JC, Johnson, MA, Verhoef V, Fridland A. Regulation of purine deoxynucleoside phosphorylation by deoxycytidine kinase from human leukemic blast cells. Biochem Pharmacol 1989;38:2601–7.

    PubMed  Google Scholar 

  20. Eriksson S, Kierdaszuk B, Munch-Petersen B, Öberg B, Johansson NG. Comparison of the substrate specificity of human thymidine kinase 1 and 2 and deoxycytidine kinase toward antiviral and cytostatic nucleoside analogs. Biochem Biophys Res Commun 1991;176:586–92.

    PubMed  Google Scholar 

  21. Bohman C, Kierdaszuk B, Eriksson S. Negative cooperativity and different conformational states of human deoxycytidine kinase. In: Purification and characterization of human deoxycytidine kinase. Stockholm: Karolinska Institute, 1989:V.

    Google Scholar 

  22. Ives DH, Durham JP. Deoxycytidine kinase. III. Kinetics and allosteric regulation of the calf thymus enzyme. J Biol Chem 1970;245:2285–94.

    PubMed  Google Scholar 

  23. Datta NS, Shewach DS, Mitchell BS, Fox IH. Kinetic properties and inhibition of human T-lymphoblast deoxycytidine kinase. J Biol Chem 1989;264:9359–64.

    PubMed  Google Scholar 

  24. White JC, Hines LH. Role of uridine triphosphate in the phosphorylation of 1-β-D-arabinofuranosylcytosine by Ehrlich ascites tumour cells. Cancer Res 1987;47:1820–4.

    PubMed  Google Scholar 

  25. White JC, Capizzi RL. A critical role for uridine nucleotides in the regulation of deoxycytidine kinase and the concentration dependence of 1-β-D-arabinofuranosylcytosine phosphorylation in human leukaemia cells. Cancer Res 1991;51:2559–65.

    PubMed  Google Scholar 

  26. Shewach DS, Reynolds KK, Hertel LW. Nucleotide specificity of human deoxycytidine kinase. Mol Pharmacol 1992;42:518–24.

    PubMed  Google Scholar 

  27. Ruiz van Haperen VWT, Veerman G, Vermorken JB, Peters GJ. Interaction of metabolism of 2′,2′-difluorodeoxycytidine (gemcitabine, dFdC) with normal pyrimidine metabolism [abstract]. Proc Am Assoc Cancer Res 1992;33:Abstr 182.

  28. Kim M-Y, Ives DH. Human deoxycytidine kinase: kinetic mechanism and end product regulation. Biochemistry 1989;28:9043–7.

    PubMed  Google Scholar 

  29. Shewach DS, Reynolds KK, Hahn T. Apparent allosteric regulation of deoxycytidine kinase by UTP [abstract]. Proc Am Assoc Cancer Res 1993;34:Abstr 55.

  30. Heinemann V, Hertel LW, Grindey GB, Plunkett W. Comparison of the cellular pharmacokinetics and toxicity of 2′,2′-difluorodeoxycytidine and 1-β-D-arabinofuranosylcytosine. Cancer Res 1988;48:4024–31.

    PubMed  Google Scholar 

  31. Tseng W, Derse D, Cheng Y, Brockman RW, Bennett Jr LL,In vitro biological activity of 9-β-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. Mol Pharmacol 1982;21:474–7.

    PubMed  Google Scholar 

  32. Bouffard DY, Laliberté J, Momparler RL. Kinetic studies on 2′,2′-difluorodeoxycytidine (gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. Biochem Pharmacol 1993;45:1857–61.

    PubMed  Google Scholar 

  33. Stegmann APA, Honders MW, Kester MGD, Landegent JE, Willemze R. Role of deoxycytidine kinase in anin vitro model for ara-C and DAC resistance: substrate-enzyme interactions with deoxycytidine, 1-β-D-arabinofuranosylcytosine and 5-aza-2′-deoxycytidine. Leukaemia 1993;7:1005–11.

    Google Scholar 

  34. Bolwell BJ, Cassileth PA, Gale RP. High dose cytarabine: a review. Leukaemia 1988;2:253–60.

    Google Scholar 

  35. Momparler RL, Onetto-Pothier N. Drug resistance to cytosine arabinoside. In: Kessel D, editor. Resistance to antineoplastic drugs. Boca Raton: CRC Press, 1989:353–67.

    Google Scholar 

  36. Grant S. Biochemical modulation of cytosine arabinoside. Pharmacol Ther 1990;48:29–44.

    PubMed  Google Scholar 

  37. Paterson ARP, Kolassa N, Cass CE. Transport of nucleoside drugs in animal cells. Pharmacol Ther 1981;12:515–36.

    PubMed  Google Scholar 

  38. Sirotnak FM, Barrueco JR. Membrane transport and the antineoplastic action of nucleoside analogues. Cancer Metastasis Rev 1987;6:459–80.

    PubMed  Google Scholar 

  39. Townsend A, Cheng YC. Sequence specific effects of ara-5-aza-CTP and ara-CTP on DNA synthesis by purified human DNA polymerasesin vitro: visualisation of chain elongation on a defined template. Mol Pharmacol 1987;32:330–9.

    PubMed  Google Scholar 

  40. Gunji H, Kharbanda S, Kufe D. Induction of internucleosomal DNA fragmentation in human myeloid leukaemia cells by 1-β-D-arabinofuranosylcytosine. Cancer Res 1991;51:741–3.

    PubMed  Google Scholar 

  41. Kharbanda S, Huberman E, Kufe D. Activation of the jun-D gene during treatment of human myeloid leukaemia cells with 1-β-D-arabinofuranosylcytosine. Biochem Pharmacol 1993;45:2055–61.

    PubMed  Google Scholar 

  42. Karon M, Chirakawa S. The locus of 1-β-D-arabinofuranosylcytosine in the cell cycle. Cancer Res 1970;29:687–96.

    Google Scholar 

  43. Drenthe-Schonk A, Holdrinet R, Van Egmond J, Wessels H, Haanen C. Cytokinetic changes after cytosine arabinoside in acute myeloid leukaemia. Leukaemia Res 1981;5:89.

    Google Scholar 

  44. Richel DJ, Colly LP, Lurvink E, Willemze R. Comparison of the antileukemic activity of 5-aza-2′-deoxycytidine and arabinofuranosylcytosine in rats with myelocytic leukaemia. Br J Cancer 1988;58:730–3.

    PubMed  Google Scholar 

  45. Richel DJ, Colly LP, Lurvink E, Willemze R. Activity of 5-aza-2′-deoxycytidine in ara-C resistant and sensitive leukaemia. Contrib Oncology 1989;37:20–9.

    Google Scholar 

  46. Pinto A, Zagonel V. 5-Aza-2′-deoxycytidine (decitabine) and 5-azacytidine in the treatment of acute myeloid leukemias and myelodysplastic syndromes: past, present and future trends. Leukaemia 1993;7 Suppl 1:51–60.

    Google Scholar 

  47. Santi DV, Garrett CE, Barr PJ. On the mechanism of inhibition of DNA-cytosine methyltransferase by cytidine analogs. Cell 1983;83:9–10.

    Google Scholar 

  48. Taylor SM. 5-Aza-2′deoxycytidine: cell differentiation and DNA methylation. Leukaemia 1993;7(Suppl 1):3–8.

    Google Scholar 

  49. Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, et al. Evaluation of the antitumour activity of gemcitabine (2′,2′-difluoro-2′-deoxycytidine). Cancer Res 1990;50:4417–22.

    PubMed  Google Scholar 

  50. Braakhuis BJM, Van Dongen GAMS, Vermorken JB, Snow GB. Preclinicalin vivo activity of 2′,2′-difluorodeoxycytidine (gemcitabine) against human head and neck cancer. Cancer Res 1991;51:211–4.

    PubMed  Google Scholar 

  51. Boven E, Schipper H, Erkelens CAM, Hatty SA, Pinedo HM. The influence of the schedule and the dose of gemcitabine on the anti-tumour efficacy in experimental human cancer. Br J Cancer 1993;68:52–6.

    PubMed  Google Scholar 

  52. Lund B, Kristjansen PEG, Hansen H. Clinical and preclinical activity of 2′,2′-difluorodeoxycytidine (gemcitabine). Cancer Treat Rev 1993;19:45–55.

    Google Scholar 

  53. Ruiz van Haperen VWT, Veerman G, Vermorken JB, Peters GJ. 2′,2′-difluorodeoxycytidine (gemcitabine) incorporation into DNA and RNA of tumour cell lines. Biochem Pharmacol 1993;46:762–6.

    PubMed  Google Scholar 

  54. Bhalla K, Holladay C, Lutzky J, Ibrado AM, Bullock G, Jasiok M, et al. Deoxycytidine protects normal bone marrow progenitors against ara-C and gemcitabine cytotoxicity without compromising their activity against cisplatin-resistant human ovarian cancer cells. Gynaecol Oncol 1992;45:32–9.

    Google Scholar 

  55. Heinemann V, Xu Y-Z, Chubb S, Sen A, Hertel LW, Grindey GB, et al. Inhibition of ribonucleotide reduction in CCRFCEM cells by 2′,2′-difluorodeoxycytidine. Mol Pharmacol 1990;38:567–72.

    PubMed  Google Scholar 

  56. Heinemann V, Xu Y-Z, Chubb S, Sen A, Hertel LW, Grindey GB, et al. Cellular elimination of 2′,2′-difluorodeoxycytidine 5′-triphosphate: a mechanism of self-potentiation. Cancer Res 1992;52:533–9.

    PubMed  Google Scholar 

  57. Plunkett W. Modulation of deoxycytidylate deaminase in intact human leukaemia cells. Biochem Pharmacol 1992;44:1819–27.

    PubMed  Google Scholar 

  58. Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2′,2′-difluorodeoxycytidine on DNA synthesis. Cancer Res 1991;51:6110–7.

    PubMed  Google Scholar 

  59. Verhoef V, Sarup J, Fridland A. Identification of the mechanism of activation of 9-β-D-arabinofuranosyladenine in human lymphoid cells using mutants deficient in nucleoside kinases. Cancer Res 1981;41:4478–83.

    PubMed  Google Scholar 

  60. Dow LW, Bell DE, Poulakos L, Fridland A. Differences in metabolism and cytotoxicity between 9-β-arabinofuranosyladenine and 9-β-arabinofuranosyl-2-fluoroadenine in human leukemic lymphoblasts. Cancer Res 1980;40:1405–10.

    PubMed  Google Scholar 

  61. Carson DA, Wasson DB, Kaye J, Ullman B, Martin Jr DW, Robins RK, et al. Deoxycytidine kinase mediated toxicity of deoxyadenosine analogs towards malignant human lymphoblastsin vitro and towards murine L1210 leukaemiain vivo. Proc Natl Acad Sci 1980;77:6865–9.

    PubMed  Google Scholar 

  62. Carson DA, Wasson DB, Taetle R, Yu A. Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood 1983;62:737.

    PubMed  Google Scholar 

  63. Ruiz van Haperen VWT, Veerman G, Eriksson S, Stegmann APA, Cloos J, Vermorken JB, et al. Development and characterization of AG6000, a gemcitabine (2′,2′-difluorodeoxycytidine) resistant human ovarian cancer cell line [abstract]. Proc Am Assoc Cancer Res 1993;34:307.

    Google Scholar 

  64. Piro LD, Carrera CJ, Beutler E, Carson DA. 2-Chlorodeoxyadenosine: an effective new agent for the treatment of chronic lymphocytic leukaemia. Blood 1988;72:1069–73.

    PubMed  Google Scholar 

  65. Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell leukaemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med 1990;322:1117–21.

    PubMed  Google Scholar 

  66. Cheson BD. The purine analogs — a therapeutic beauty contest. J Clin Oncol 1992;10:352–5.

    PubMed  Google Scholar 

  67. Robertson LE, Chubb S, Meyn RE, Story M, Ford R, Hittelman WN, et al. Induction of apoptotic cell death in chronic lymphocytic leukaemia by 2-chloro-2′-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine. Blood 1993;81:143–50.

    PubMed  Google Scholar 

  68. Keating MJ, Kantarjian H, O'Brien S, Koller C, Talpaz M, Schachner J, et al. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukaemia. J Clin Oncol 1991;9:44–9.

    PubMed  Google Scholar 

  69. Kristjansen PEG, Quistorff B, Spang-Thomsen M, Hansen HH. Cytostaticin vivo activity and pharmacokinetic analysis by19F-magnetic resonance spectroscopy (FMRS) of 2′,2′-difluorodeoxycytidine (dFdC, gemcitabine) in two small cell lung cancer (SCLC) xenografts [abstract]. Proc Am Assoc Cancer Res 1991;32:Abstr 2057.

  70. Edzes HT, Peters GJ, Noordhuis P, Vermorken JB. Determination of the antimetabolite gemcitabine (2′,2′-difluoro-2′-deoxycytidine) and of 2′,2′-difluoro-2′-deoxyuridine by19F nuclear magnetic resonance spectroscopy. Anal Biochem 1993;214:25–30.

    PubMed  Google Scholar 

  71. Van Groeningen CJ, Leyva A, O'Brien AMP, Gall HE, Pinedo HM. Phase I and pharmacokinetic study of 5-aza-2′-deoxycytidine (NSC 127716) in cancer patients. Cancer Res 1986;46:4831–6.

    PubMed  Google Scholar 

  72. Braakhuis BJM, Van Dongen GAMS, Van Walsum M, Leyva A, Snow GB. Preclinical antitumour activity of 5-aza-2′-deoxycytidine against human head and neck cancer xenografts. Invest New Drugs 1988;6:299–304.

    PubMed  Google Scholar 

  73. Heinemann V, Plunkett W. Inhibitory action of 2′,2′-difluorodeoxycytidine (dFdC) on cytidine 5′-triphosphate synthetase [abstract]. Ann Oncol 1992;3(Suppl 1):Abstr 510.

  74. Momparler RL, Bouffard DY, Momparler LF, Marquet J, Zittoun J, Marie J-P, et al. Enhancement of anti-neoplastic activity of cytosine arabinoside against human HL-60 myeloid leukemic cells by 3-deazauridine. Int J Cancer 1991;49:573–6.

    PubMed  Google Scholar 

  75. Schilsky RL, Ratain MJ, Vokes EE, Vogelzang NJ, Anderson J, Peterson BA. Laboratory and clinical studies of biochemical modulation by hydroxyurea. Semin Oncol 1992;19:84–9.

    PubMed  Google Scholar 

  76. Plunkett W, Adams T, Keating M. Modulation of ara-CTP metabolism in leukaemia cells during high-dose ara-C (HD ara-C) therapy by thymidine and PALA [abstract]. Proc Am Soc Clin Oncol 1987;6:Abstr 115.

  77. Peters GJ, Noordhuis P, Kazemier KM, Kaspers GJ. Effect of N-(phosphon)-acetyl-L-aspartate (PALA) on cytotoxicity and metabolism of ara-C in acute myeloid (AML) and lymphoblastic leukemic (ALL) cells and cell lines [abstract]. Proc Am Assoc Cancer Res 1993;34:Abstr 1696.

  78. Plunkett W, Gandhi V. Cellular pharmacodynamics of anticancer drugs. Semin Oncol 1993;20:50–63.

    Google Scholar 

  79. Rustum YM, Raymakers RAP. 1-β-D-Arabinofuranosylcytosine in therapy of leukaemia — preclinical and clinical overview. Pharmacol Ther 1992;56:307–21.

    PubMed  Google Scholar 

  80. Tattersall MHN, Ganeshaguru K, Hoffbrand AV. Mechanisms of resistance of human acute leukaemia cells to cytosine arabinoside. Br J Haematol 1974;27:39–46.

    PubMed  Google Scholar 

  81. Hagenbeek A, Martens ACM, Colly LP.In vivo development of cytosine arabinoside resistance in the BN acute myelocytic leukaemia. Semin Oncol 1987;14:202–6.

    PubMed  Google Scholar 

  82. Momparler RL, Chu MY, Fischer GA. Studies on a new mechanism of resistance of L5178Y murine leukaemia cells to cytosine arabinoside. Biochim Biophys Acta 1968;161:481–93.

    PubMed  Google Scholar 

  83. Owens JK, Shewach DS, Ullman B, Mitchell BS. Resistance to 1-β-D-arabinofuranosylcytosine in human T-lymphoblasts mediated by mutations within the deoxycytidine kinase gene. Cancer Res 1992;52:2389–93.

    PubMed  Google Scholar 

  84. Stueart CD, Burke PJ. Cytidine deaminase and the development of resistance to cytosine arabinoside. Nature (New Biology) 1971;233:109.

    Google Scholar 

  85. De Saint Vincent BR, Buttin G. Studies on 1-β-D-arabinofuranosylcytosine-resistant mutants of Chinese hamster fibroblasts. III. Joint resistance to excess thymidine — a semidominant manifestation of deoxycytidine triphosphate pool expansion. Somat Cell Genet 1979;5:67.

    PubMed  Google Scholar 

  86. Meuth M, Trudel M, Siminovitch L. Selection of Chinese hamster cells auxotrophic for thymidine by 1-β-D-arabinofuranosylcytosine. Somat Cell Genet 1979;5:303.

    Google Scholar 

  87. Kreis W, Lesser M, Budman DR, Arlin Z, Deangelis L, Baskind P, et al. Phenotypic analysis of 1-beta-D-arabinofuranosylcytosine deamination in patients treated with high doses and correlation with response. Cancer Chemother Pharmacol 1992;30:126–30.

    PubMed  Google Scholar 

  88. Higashigawa M, Ido M, Nagao Y, Kuwabara H, Hori H, Ohkubo T, et al. Decreased DNA polymerase sensitivity to 1-β-D-arabinofuranosylcytosine 5′-triphosphate in P388 murine leukemic cells resistant to vincristine. Leukaemia Res 1991;15:675.

    Google Scholar 

  89. Wiley JS, Jones SP, Sawyer WH, Paterson ARP. Cytosine arabinoside influx and nucleoside transport sites in acute leukaemia. J Clin Invest 1982;69:479–89.

    PubMed  Google Scholar 

  90. Capizzi RL, Yang J, Rathmell JP, White JC, Cheng E, Cheng Y, et al. Dose-related pharmacologic effects of high-dose ara-C and its self-potentiation. Semin Oncol 1985;12(Suppl 3):65–75.

    Google Scholar 

  91. Peters WG, Colly LP, Willemze R. High-dose cytosine arabinoside: pharmacological and clinical aspects. Blut 1988;56:1–11.

    PubMed  Google Scholar 

  92. Chan TCK. Augmentation of 1-β-D-arabinofuranosylcytosine cytotoxicity in human tumour cells by inhibiting drug efflux. Cancer Res 1989;49:2565–660.

    Google Scholar 

  93. Bhalla K, Nayak R, Grant S. Isolation and characterization of a deoxycytidine kinase-deficient human promyelocytic leukemic cell line highly resistant to 1-β-D-arabinofuranosylcytosine. Cancer Res 1984;44:5029–37.

    PubMed  Google Scholar 

  94. Kufe D, Springs D, Egan M, Munroe D. Relationships among ara-CTP pools, formation of (ara-C)DNA and cytotoxicity of human leukemic cells. Blood 1984;64:54–8.

    PubMed  Google Scholar 

  95. Flasshove M, Tirier C, Heit W, Ayscue L, Mitchell B, Seeber S, et al. Analysis of the deoxycytidine kinase gene in patients with acute myeloid leukaemia and resistance to cytosine arabinoside [abstract]. Proc Am Assoc Cancer Res 1993;34: Abstr 146.

  96. Fridland A, Verhoef V. Mechanism for ara-CTP catabolism in human leukemic cells and effect of deaminase inhibitors on this process. Semin Oncol 1987;14 Suppl 1:262–8.

    PubMed  Google Scholar 

  97. Plunkett W, Hug V, Keating MJ, Chubb S. Quantitation of 1-β-D-arabinofuranosylcytosine 5′-triphosphate in the leukemic cells from bone marrow and peripheral blood of patients receiving 1-β-D-arabinofuranosylcytosine therapy. Cancer Res 1980;40:588–91.

    PubMed  Google Scholar 

  98. Rustum YM, Preisler HD. Correlation between leukemic cell retention of 1-β-D-arabinofuranosylcytosine 5′-triphosphate and response to therapy. Cancer Res 1979;39:42–9.

    PubMed  Google Scholar 

  99. Colly LP, Richel DJ, Arentsen-Honders MW, Starrenburg CWJ, Edelbroek PM, Willemze R. A simplified assay for measurement of cytosine arabinoside incorporation into DNA in ara-C sensitive and resistant leukemic cells. Cancer Chemother Pharmacol 1990;27:151–6.

    PubMed  Google Scholar 

  100. Rustum YM, Danhauser L, Luccioni C, Au JLS. Determinants of response to antimetabolites and their modulation by purine and pyrimidine metabolites. Cancer Treat Rep 1981;65:73–82.

    Google Scholar 

  101. Preisler HD, Rustum Y, Proire RL. Relationship between leukemic cell retention of cytosine arabinoside triphosphate and the duration of remission in patients with acute nonlymphocytic leukaemia. Eur J Cancer Clin Oncol 1985;21:23–30.

    PubMed  Google Scholar 

  102. Kemena A, Gandhi V, Shewach DS, Meating MJ, Plunkett W. Inhibition of fludarabine metabolism by arabinosylcytosine during therapy. Cancer Chemother Pharmacol 1992;31:193–9.

    PubMed  Google Scholar 

  103. Gandhi V, Estey E, Keating MJ, Plunkett W. Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukaemia during therapy. J Clin Oncol 1993;11:116–24.

    PubMed  Google Scholar 

  104. Balzarini J. Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives. Pharm World Sci 1994;16:113–26.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Free University Hospital, P.O.Box 7057, 1007, MB Amsterdam, the Netherlands

    Veronique W. T. Ruiz van Haperen & Godefridus J. Peters

Authors
  1. Veronique W. T. Ruiz van Haperen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Godefridus J. Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruiz van Haperen, V.W.T., Peters, G.J. New targets for pyrimidine antimetabolites for the treatment of solid tumours. Pharm World Sci 16, 104–112 (1994). https://doi.org/10.1007/BF01880661

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01880661

Keywords

Search

Navigation