Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Mechanisms of Acquired ARA-C and DAC Resistance in Acute Myeloid Leukemia (AML): Development of a Model for the Study of Mutational Loss of Deoxycytidine Kinase (DCK) Activity

  • Conference paper
Acute Leukemias V

Part of the book series: Haematology and Blood Transfusion / Hämatologie und Bluttransfusion ((HAEMATOLOGY,volume 37))

  • 76 Accesses

Abstract

Complex and largely unknown mechanisms determine whether sufficient cyto-reduction occurs following chemotherapy for acute myeloid leukemia. The reasons for failure of induction treatment are related to patients’ age. With the current supportive care measures, it is uncommon for patients < 50 years of age to die from complications of the initial therapy; most of the 20% failure rate in this group is due to primary resistant leukemia. In contrast, in patients > 60 years the cause of the failure rate (50%), can be equally divided between resistant leukemia and death occuring during marrow aplasia, due to the complications of pancytopenia. However, during subsequent relapses the majority of patients fails to respond due to drug resistance, and this is one of the major obstacles for long term disease free survival [1–3].

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Peters WG, Willemze, R & Colly LP. (1988) Results of induction and consolidation treatment with intermediate and high-dose cytosine arabinoside and m-Amsa of patients with poor risk acute myelogenous leukemia. Eur J Haematol 40: 198–204.

    Article  PubMed  CAS  Google Scholar 

  2. Schiller G, Gajewski J, Nimer S, Territo M, Ho W, Lee M & Champlin R. (1992) A randomized study of intermediate versus conventional-dose cytarabine cytarabine as intensive induction for acute myelogenous leukaemia. Br J Haematol 81 (2): 170–177.

    Article  PubMed  CAS  Google Scholar 

  3. Wiernik PH, Banks PL, Case DC jr., Arlin ZA, Periman PO, Todd MB, Ritch PS, Enck RE & Weitberg AB. (1992) Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated addult patients with acute myeloid leukemia. Blood 79 (2): 313–319.

    Google Scholar 

  4. Debusscher L, Marie JP, Dochin P, Blanc GM, Arrigo C, Zittoun R & Stryckmans P. (1989) Phase I-III trial of 5-Aza-2′-deoxycytidine in adult patients with acute leukemia. Proceedings: 5-Aza-2′-deoxycy-tidine, preclinical and clinical studies. Symposium, Amsterdam

    Google Scholar 

  5. Richel DJ, Colly LP, Kluin-Nelemans JC & Willemze R. (1990) The antileukaemic activity of 5-Aza-2′-deoxycytidine (Aza-dC) in patients with relapsed and resistant leukaemia. Br J Cancer 58: 144–148.

    Google Scholar 

  6. Hall A, Cattan AR & Proctor SJ. (1989) Mechanisms of drug resistance in acute leukemia. Leukemia Res 13 (5): 351–356.

    Article  Google Scholar 

  7. Momparler RL, Onetto-Pothier N. (1989) In: D. Kessel, Ed. Drug resistance to cytosine arabinoside. Chapter 19; Resistance to antineoplastic drugs. CRC Press.

    Google Scholar 

  8. Reichard P. (1988) Interactions between deoxyri-bonucleotide and DNA synthesis. Annu Rev Biochem 57: 349–374.

    Article  PubMed  CAS  Google Scholar 

  9. Wasternack C. (1980) Degradation of pyrimidines and pyrimidine analogs: pathways and mutual influences. Pharmacol Ther 8 (3): 629–651.

    Article  Google Scholar 

  10. Munch-Petersen A. (1983) Metabolism of nucleotides,nucleosides and nucleobases in microorganisms. London: Academic Press Inc. Ltd.

    Google Scholar 

  11. Momparler RL & Fischer GA. (1976) Mammalian deoxynucleoside kinases. I. Deoxycytidine kinase: Purification properties and kinetic studies with cytosine arabinoside. J Biol Chem 243: 4298–4304.

    Google Scholar 

  12. Kierdaszuk B, Bohman C, Ullman B & Eriksson S. (1992) Substrate specificity of human deoxycytidine kinase toward antiviral 2′,3′-dideoxynucleoside analogs. Biochem Pharmacol 43: 197–206.

    Article  PubMed  CAS  Google Scholar 

  13. Eriksson S, Kierdaszuk B, Munch-Petersen B, Oberg B & Johansson NG. (1991) Comparison of the substrate specificities of human thymidine kinase 1 and 2 and deoxycytidine kinase towards antiviral and cytostatic nucleoside analogs. Biochem Biophys Res Comm 176(2): 586–592.

    Article  PubMed  CAS  Google Scholar 

  14. Habteyesus A, Nordenskjold A, Bohman C & Eriksson S. (1991) Deoxynucleoside phosphorylating enzymes in monkey and human tissues show great similarities, while mouse deoxycytidine kinase has a different substrate specificity. Biochem Pharmacol 42(9): 1829–1836.

    Article  PubMed  CAS  Google Scholar 

  15. Tanaka M & Yoshida S. (1982) Altered sensitivity to 1-ß-D-arabino-furanosylcytosine 5′-triphosphate of DNA polymerase from leukemic blasts of acute lymphoblastic leukemia. Cancer Res 42: 649–654.

    PubMed  CAS  Google Scholar 

  16. Zittoun J, Marquet J, David J-C, Maniey D & Zittoun R. (1989) A study of the mechanisms of cytotoxicity of Ara-C on three human leukemic cell lines. Cancer Chemother Pharmacol 24 (4): 251–255.

    Google Scholar 

  17. Major PP, Egan EM, Herrick DJ & Kufe DW. (1982) Effect of Ara-C incorporation on deoxyribonucleic acid synthesis in cells. Biochem Pharmacol 31 (18): 2937–2940.

    Article  PubMed  CAS  Google Scholar 

  18. Major P, Egan E, Bearsley G, Minden MD & Kufe D. (1982) Lethality of human myeloblasts correlates with the incorporation of Ara-C into DNA. Proc Natl Acad Sci USA. 78: 3235–3239.

    Article  Google Scholar 

  19. Gedik CM & Collins AR. (1991) The mode of action of l-ß-D-arabino-furanosylcytosine in inhibiting DNA repair; new evidence using a sensitive assay for repair DNA synthesis and ligation in permeable cells. Mutat Res 254 (3): 231–237.

    Article  PubMed  CAS  Google Scholar 

  20. Zittoun J, Marquet J & David J-C. (1991) Mechanism of inhibition of DNA ligase in Ara-C treated cells. Leukemia Res 15: 157–167.

    Article  CAS  Google Scholar 

  21. Bouchard J & Momparler RL. (1983) Incorporation of 5-Aza-2′-deoxy-cytidine triphosphate into DNA. Interactions with mammalian DNA polymerase and DNA methylase. Mol Pharmacol 24: 109–114.

    Google Scholar 

  22. Jones PA & Taylor SM. (1980) Cellular differentiation, cytidine analogs and DNA methylation. Cell 20: 85–93.

    Article  PubMed  CAS  Google Scholar 

  23. Santi DV, Garret CE & Barr PJ. (1983) On the mechanism of inhibition of DNA-cytosine methyltransferase by cytidine analogs. Cell 83: 9–10.

    Article  Google Scholar 

  24. Taylor SM. (1993) 5-Aza-2′-deoxycytidine: cell differentiation and DNA methylation. Leukemia 7 (suppl.): 3–8.

    PubMed  Google Scholar 

  25. Datta NS, Shewach DS, Hurley MC, Mitchell BS & Fox IF. (1989) Human T-lymphoblast deoxycytidine kinase: purification and properties. Biochemistry 28: 114–123.

    Article  PubMed  CAS  Google Scholar 

  26. Datta NS, Shewach DS, Mitchell BS & Fox IH. (1989) Kinetic properties and inhibition of human T-lymphoblast deoxycytidine kinase. J Biol Chem 264(16): 9359–9364.

    PubMed  CAS  Google Scholar 

  27. Bohman C & Eriksson S. (1988) Deoxycytidine kinase from human leukemic spleen: preparation and characterization of the homogenous enzyme. Biochemistry 27: 4258–4265.

    Article  PubMed  CAS  Google Scholar 

  28. 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: 481–492.

    Google Scholar 

  29. Kessel D. (1968) Properties of deoxycytidine kinase partially purified from L1210 cells. J Biol Chem 243: 4739.

    PubMed  CAS  Google Scholar 

  30. Singhal RL, Yeh YA, Szekeres T & Weber G. (1992) Increased deoxycytidine kinase activity in cancer cells and inhibition by difluorodeoxycytidine. Oncology Res 4: 517–522.

    CAS  Google Scholar 

  31. Momparler RL & Derse D. (1979) Kinetics of phosphorylation of 5-Aza-2′-deoxycytidine by deoxycytidine kinase. Biochem Pharmacol 28: 1443–1444.

    Article  PubMed  CAS  Google Scholar 

  32. Vesely J & Cihak A. (1980) 5-Aza-2′-deoxycytidine: Preclinical studies in mice. Neoplasma 27: 112–119.

    Google Scholar 

  33. Ives DH & Durham JP. (1970) Deoxycytidine kinase. III Kinetics and allosteric regulation. J Biol Chem 245: 2285–2294.

    PubMed  CAS  Google Scholar 

  34. Sarup JC & Fridland A. (1987) Identification of purine deoxynucleoside kinases from human leukemia cells: substrate activation by purine and pyrimidine deoxyribonucleosides. Biochemistry 26: 590–597.

    Article  PubMed  CAS  Google Scholar 

  35. Meyers MB & Kreis W. (1978) Comparison of the enzymatic activities of two deoxycytidine kinases purified from cells sensitive (P815) and resistant (P815/ara-C) to 1-ß-D-Arabinofuranosylcytosine. Cancer Res 38: 1105–1112.

    PubMed  CAS  Google Scholar 

  36. Kierdaszuk B, Rigler R & Eriksson S. (1993) Binding of substrates to human deoxycytidine kinase studied with ligand-dependant quenching of enzyme intrinsic fluorescence. Biochemistry 32: 699–707.

    Article  PubMed  CAS  Google Scholar 

  37. Kim M-Y & Ives DH. (1989) Human deoxycytidine kinase: kinetic mechanism and end product regulation. Biochemistry 28: 9043–9047.

    Article  PubMed  CAS  Google Scholar 

  38. Shewach DS, Reynolds KK, Hahn T. (1993) Apparent allosteric regulation of deoxycytidine kinase by UTP. Proc Am Assoc Canc Res 34: 10, abstract #55.

    Google Scholar 

  39. Shewach DS, Reynolds KK & Hertel L. (1992) Nucleotide specificity of human deoxycytidine kinase. Mol Pharmacol 42: 518–524.

    PubMed  CAS  Google Scholar 

  40. White JC & Capizzi RL. (1991) A critical role for uridine nucleotides in the regulation of deoxycytidine kinase and the concentration dependance of 1-ß-D-arabinofuranosylcytosine phosphorylation in human leukemia cells. Cancer Res 51: 2559–2565.

    PubMed  CAS  Google Scholar 

  41. Steuart CD & Burke PJ. (1971) Cytidine deaminase and the development of resistance to cytosine arabinoside. Nature New Biol 233: 109–113.

    Article  PubMed  CAS  Google Scholar 

  42. Harris AL, Grahame-Smith DG, Potter CG & Bunch C. (1981) Cytosine arabinoside deamination in human leukemic myeloblasts and resistance to cytosine arabinoside therapy. Clin Sci 60: 191–196.

    PubMed  CAS  Google Scholar 

  43. Momparler RL. (1968) Kinetic and template studies with cytosine arabinoside 5′-triphosphate and mamalian DNA polymerase. Mol Pharmacol 8: 362–367.

    Google Scholar 

  44. Chu Y & Fischer GA. (1965) Comparative studies of leukemic cells sensitive and resistant to cytosine arabinoside. Biochem Pharmacol 14: 333–341.

    Article  PubMed  CAS  Google Scholar 

  45. Stegmann, A.P.A., Honders, M.W., Kester, M.G.D., Landegent, J.E. and Willemze, R. Role of deoxycytidine kinase in an in vitro model for AraC- and DAC-resistance: substrate enzyme interactions with deoxycytidine, 1-ß-D-arabinofuranosylcytosine and 5-aza-2′-deoxycytidine. (1993) Leukemia 7(7), 1005–1011.

    PubMed  CAS  Google Scholar 

  46. Meyers MB & Kreis W. (1978) Structural comparison of deoxycytidine kinases purified from cells sensitive (P815) or resistant (P815/ara-C) to 1-ß-D-arabinofuranosylcytosine. Cancer Res 38: 1099–1104.

    PubMed  CAS  Google Scholar 

  47. Chottiner, E.G., Shewach, D.S., Datta, N.S., Ashcraft, E., Gribbin, D., Ginsburg, D., Fox, I.H. and Mitchell, B.S. (1991) Cloning and expression of human deoxycytidine kinase cDNA. PNAS 88: 1531–1535.

    Article  PubMed  CAS  Google Scholar 

  48. Song JJ, Walker S, Chen E, Johnson II EE, Spychala J, Gribbin T & Mitchell BS. (1993) Genomic structure and chromosomal localization of the human deoxycytidine kinase gene. PNAS 90: 431–434.

    Article  PubMed  CAS  Google Scholar 

  49. Stegmann APA, Honders MW, Bolk MWJ, Wessels J, Willemze R & Landegent J. (1993) Assignment of the human deoxycytidine kinase (DCK) gene to chromosome 4 band q13.3-q21.1. Genomics 17: 528–529.

    Article  PubMed  CAS  Google Scholar 

  50. Owens, J.K., Shewach, D.S., Ullman, B. and Mitchell, B.S. (1992). Resistance to 1-ß-D Arabino-furanosylcytosine in human T-lymphoblasts mediated by mutations within the deoxycytidine kinase gene. Cancer Res 52: 2389–2393.

    PubMed  CAS  Google Scholar 

  51. Martens ACM, Van Bekkum DW, Hagenbeek A. (1990) Review. The BN acute myelocytic leukemia (BNML) (A rat model for studying human acute myelocytic leukemia (AML)). Leukemia 4(4): 241–257.

    PubMed  CAS  Google Scholar 

  52. Bekkum DW van & Hagenbeek A. (1977) Relevance of the BN leukaemia as a model for human acute myeloid leukemia. Blood Cells 3: 565–579.

    Google Scholar 

  53. Hagenbeek A, Martens ACM & Colly LP. (1987) In vivo development of cytosine arabinoside resistance in the BN acute myelocytic leukemia. Semin Oncol 14: 202–206.

    PubMed  CAS  Google Scholar 

  54. Lacaze N, Gombaud-Saintonge G & Lanotte M. (1983) Conditions cotrolling long term proliferation of BN ratpromyelocytic leukemia in vitro: primary growth stimulation by microenvironment and establishment of an autonomous BN “leukemic stem cell line”. Leuk Res 7: 145–148.

    Article  PubMed  CAS  Google Scholar 

  55. Stegmann APA, Honders WM, Willemze R & Landegent J. Molecular cloning of rat deoxycytidine kinase (dck). Biochem Biophys Res Commun, submitted.

    Google Scholar 

  56. Stegmann APA, Honders WM, Willemze R & Landegent J. Mutations in the deoxycytidine kinase gene in acquired resistance to 1-ß-D-arabinofuranosylcytosine and 5-aza-2′-deoxycytidine in acute myeloid leukemia. 22nd Annual Meeting of the International Society for Experimental Hematology (ISEH), Rotterdam, The Netherlands, August 1993. Oral presentation.

    Google Scholar 

  57. Heinemann V, Hertel LW, Grindey GB & Plunkett W. (1988) Comparison of the cellular pharmacokinetics and cytotoxicity of 2′,2′-difluorodeoxycytidine and 1-ß-D-Arabinofuranosylcytosine. Cancer Res 48: 4024–4031.

    PubMed  CAS  Google Scholar 

  58. Starnes MC & Cheng Y-C. (1987) Cellular metabolism of 2′,3′-dideoxycytidine, a compound active against human immunodeficiency virus in vitro. J Biol Chem 262(3): 988–991.

    PubMed  CAS  Google Scholar 

  59. Beutler E. (1992) Cladribine (2-chlorodeoxyadenosine). Lancet 340: 952–956.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dept. of Experimental Hematology, University Hospital Leiden, 2300 RC, Leiden, The Netherlands

    A. P. A. Stegmann, M. W. Honders, J. E. Landegent & R. Willemze

Authors
  1. A. P. A. Stegmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. W. Honders
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. E. Landegent
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Willemze
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Internal Medicine, University of Göttingen, Robert-Koch-Strasse 40, 37075, Göttingen, Germany

    W. Hiddemann  & W. Plunkett  & 

  2. Department of Internal Medicine, University of Münster, Albert-Schweitzer-Strasse 33, 48145, Münster, Germany

    T. Büchner

  3. Department of Pediatric Oncology, University of Münster, Albert-Schweitzer-Strasse 33, 48145, Münster, Germany

    J. Ritter

  4. Department of Internal Medicine, MD Anderson Cancer Center, 1515 Holcombe Blvd., 77030, Houston, TX, USA

    B. Wörmann M.D., Ph.D.  & M. J. Keating M.D., B.S.  & 

  5. Koordinierungsstelle, Deutsche Krebsgesellschaft e.V., Thea-Bähnisch-Weg 12, 30657, Hannover, Germany

    U. Creutzig

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Stegmann, A.P.A., Honders, M.W., Landegent, J.E., Willemze, R. (1996). Mechanisms of Acquired ARA-C and DAC Resistance in Acute Myeloid Leukemia (AML): Development of a Model for the Study of Mutational Loss of Deoxycytidine Kinase (DCK) Activity. In: Hiddemann, W., et al. Acute Leukemias V. Haematology and Blood Transfusion / Hämatologie und Bluttransfusion, vol 37. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-78907-6_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-78907-6_14

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-78909-0

  • Online ISBN: 978-3-642-78907-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation