Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Mechanisms of resistance to nucleoside analogue chemotherapy in mantle cell lymphoma: a molecular case study

Leukemia volume 16, pages 1886–1887 (2002)Cite this article

De novo and acquired drug resistance limit the effectiveness of nucleoside analogue chemotherapy, and the responsible molecular mechanisms are under intense study. Lack of intracellular drug accumulation is an important and commonly identified mechanism of anticancer nucleoside resistance (for review see Galmarini et al1). Intracellular nucleoside drug accumulation is determined by (1) cellular plasma membrane nucleoside transport capacity, and (2) the balance of catabolic and anabolic cytosolic enzyme activities. The major route of cellular entry is via the nucleoside transporters (NTs). Five NTs have been cloned in humans, including two equilibrative transporters (hENT1, hENT2) and three concentrative transporters (hCNT1, hCNT2, hCNT3). However, hENT1 appears to be the major determinant of nucleoside drug uptake. Once inside the cell, the key enzyme in the conversion of a nucleoside analogue to its cytotoxic nucleotide form is deoxycytidine kinase (dCK). In opposition to dCK are the 5′-nucleotidases, which cleave phosphate groups from the 5′-carbon group of nucleoside monophosphates. Although high 5′-nucleotidase activity is associated with drug resistance, the responsible 5′-nucleotidases are not completely defined. One leading candidate is CN-II; two other 5′-nucleotidases which have yet to be evaluated in this role are dNT-I and ectonucleotidase.

We report the case of a patient with mantle cell lymphoma/ leukemia who, as is typical for this disease, exhibited resistance to nucleoside chemotherapy. We demonstrated impaired nucleoside analogue accumulation and fludarabine resistance in this patient's circulating lymphoma cells, and performed molecular analyses to explore potential mechanisms of nucleoside analogue resistance in mantle cell neoplasia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Galmarini CM, Mackey JR, Dumontet C . Nucleoside analogues: mechanisms of drug resistance and reversal strategies Leukemia 2001 15: 875–890

    Article  CAS  Google Scholar 

  2. Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR, Cass CE . Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines Cancer Res 1998 58: 4349–4357

    CAS  PubMed  Google Scholar 

  3. Fink L, Seeger W, Ermert L, Hanze J, Stahl U, Grimminger F, Kummer W, Bohle RM . Real-time quantitative RT-PCR after laser-assisted cell picking Nat Med 1998 4: 1329–1333

    Article  CAS  Google Scholar 

  4. Griffiths M, Beaumont N, Yao SY, Sundaram M, Boumah CE, Davies A, Kwong FY, Coe I, Cass CE, Young JD, Baldwin SA . Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs Nat Med 1997 3: 89–93

    Article  CAS  Google Scholar 

  5. Coiffier B . Mantle cell lymphoma: new treatment possibilities. In: Schechter GP, Hoffmann R, Schrier SL (eds) American Society of Hematology Education Program American Society of Hematology: Washington DC 1999 329–334

    Google Scholar 

  6. Fisher RI . Mantle cell lymphoma: prognostic factors and treatment results. In: Schechter GP, Hoffmann R, Schrier SL (eds) American Society of Hematology Education Program American Society of Hematology: Washington DC 1999 325–328

    Google Scholar 

  7. Hofmann WK, de Vos S, Tsukasaki K, Wachsman W, Pinkus GS, Said JW, Koeffler HP . Altered apoptosis pathways in mantle cell lymphoma detected by oligonucleotide microarray Blood 2001 98: 787–794

    Article  CAS  Google Scholar 

  8. Borst P, Evers R, Kool M, Wijnholds J . A family of drug transporters: the multidrug resistance-associated proteins J Natl Cancer Inst 2000 92: 1295–1302

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C Santos for expert technical assistance and L Harris and M Shirton for assistance in manuscript preparation. This work was funded by the National Cancer Institute of Canada, the Canadian Institute of Health Research, the Research Initiatives Program of the Alberta Cancer Board, the Alberta Cancer Foundation, and the Alberta Heritage Foundation for Medical Research.

Author information

Authors and Affiliations

  1. Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada

    T Reiman, KA Graham, J Wong, AR Belch, R Coupland, J Young, CE Cass & JR Mackey

Authors
  1. T Reiman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. KA Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. AR Belch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Coupland
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. CE Cass
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. JR Mackey
    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

Reiman, T., Graham, K., Wong, J. et al. Mechanisms of resistance to nucleoside analogue chemotherapy in mantle cell lymphoma: a molecular case study. Leukemia 16, 1886–1887 (2002). https://doi.org/10.1038/sj.leu.2402579

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402579

This article is cited by

Search

Advanced search

Quick links