Skip to main content

Advertisement

SpringerLink
Log in

In vitro cross-resistance to nucleoside analogues and inhibitors of topoisomerase 1 and 2 in acute myeloid leukemia

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Only about one third of all patients with acute myeloid leukemia (AML) will be cured by common chemotherapy regimens. Susceptibility towards chemotherapy either of the leukemic bulk or the leukemic stem cell is considered the major determining parameter for long-term outcome. The purpose of the present study was to investigate whether chemoresistance was correlated between different antileukemic drugs or not. We determined the lethal concentration of chemotherapy necessary to reduce viability of cells to 50% compared to untreated control (LC50) as a surrogate marker of chemotherapy susceptibility of six established chemotherapeutic agents [cytarabine (median 0.83 μg/ml), daunorubicine (0.09 μg/ml), idarubicine (0.03 μg/ml), mitoxantrone (0.05 μg/ml), etoposide (4.81 μg/ml), and topotecan (0.14 μg/ml)] in an overall number of 147 samples from consecutive patients with AML by WST-1 assay in vitro. We found that susceptibility to chemotherapy was significantly correlated between all six agents (all p values < 0.01). A homogenous response of the blast populations was significantly correlated to high chemoresistance. These data indicate that cross-resistance in AML against antileukemic drugs exists between agents with different modes of action and seems not to be mediated by drug-specific resistance mechanisms but rather by more generalized death-defying features of the affected cells (e.g., inhibited apoptosis).

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. SOFTmax PRO—User manual, 2.4 edn. Molecular Devices Corporation, Sunnyvale, California

  2. Andreeff M, Jiang S, Zhang X et al (1999) Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid. Leukemia 13:1881–1892

    Article  PubMed  CAS  Google Scholar 

  3. Braess J, Jahns-Streubel G, Schoch C et al (2001) Proliferative activity of leukaemic blasts and cytosine arabinoside pharmacodynamics are associated with cytogenetically defined prognostic subgroups in acute myeloid leukaemia. Br J Haematol 113:975–982

    Article  PubMed  CAS  Google Scholar 

  4. Braess J, Schneiderat P, Schoch C et al (2004) Functional analysis of apoptosis induction in acute myeloid leukaemia-relevance of karyotype and clinical treatment response. Br J Haematol 126:338–347

    Article  PubMed  Google Scholar 

  5. Braess J, Voss S, Jahns-Streubel G et al (2000) The pharmacodynamic basis for the increased antileukaemic efficacy of cytosine arabinoside-based treatment regimens in acute myeloid leukaemia with a high proliferative activity. Br J Haematol 110:170–179

    Article  PubMed  CAS  Google Scholar 

  6. Clark PI, Slevin ML (1987) The clinical pharmacology of etoposide and teniposide. Clin Pharmacokinet 12:223–252

    Article  PubMed  CAS  Google Scholar 

  7. Estey EH, Thall PF, Cortes JE et al (2001) Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. Blood 98:3575–3583

    Article  PubMed  CAS  Google Scholar 

  8. Fernandez V, Hartmann E, Ott G, Campo E, Rosenwald A (2005) Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. J Clin Oncol 23:6364–6369

    Article  PubMed  CAS  Google Scholar 

  9. Fonatsch C, Schaadt M, Kirchner H, Diehl V (1980) A possible correlation between the degree of karyotype aberrations and the rate of sister chromatid exchanges in lymphoma lines. Int J Cancer 26:749–756

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Ho AD, Brado B, Haas R, Hunstein W (1991) Etoposide in acute leukemia. Past experience and future perspectives. Cancer 67:281–284

    Article  PubMed  CAS  Google Scholar 

  12. Hortobagyi GN (1997) Anthracyclines in the treatment of cancer. An overview. Drugs 54:1–7

    Article  PubMed  CAS  Google Scholar 

  13. Hubeek I, Peters GJ, Broekhuizen R et al (2006) In vitro sensitivity and cross-resistance to deoxynucleoside analogs in childhood acute leukemia. Haematologica 91:17–23

    PubMed  CAS  Google Scholar 

  14. Konopleva M, Zhao S, Hu W et al (2002) The anti-apoptotic genes Bcl-X(L) and Bcl-2 are over-expressed and contribute to chemoresistance of non-proliferating leukaemic CD34+ cells. Br J Haematol 118:521–534

    Article  PubMed  CAS  Google Scholar 

  15. Larson RA, Daly KM, Choi KE, Han DS, Sinkule JA (1987) A clinical and pharmacokinetic study of mitoxantrone in acute nonlymphocytic leukemia. J Clin Oncol 5:391–397

    PubMed  CAS  Google Scholar 

  16. Levasseur LM, Slocum HK, Rustum YM, Greco WR (1998) Modeling of the time-dependency of in vitro drug cytotoxicity and resistance. Cancer Res 58:5749–5761

    PubMed  CAS  Google Scholar 

  17. Lowenberg B, Downing JR, Burnett A (1999) Acute myeloid leukemia. N Engl J Med 341:1051–1062

    Article  PubMed  CAS  Google Scholar 

  18. Norgaard JM, Bukh A, Langkjer ST et al (1998) MDR1 gene expression and drug resistance of AML cells. Br J Haematol 100:534–540

    Article  PubMed  CAS  Google Scholar 

  19. Osheroff N, Corbett AH, Robinson MJ (1994) Mechanism of action of topoisomerase II-targeted antineoplastic drugs. Adv Pharmacol 29B:105–126

    Article  PubMed  CAS  Google Scholar 

  20. Robert J, Rigal-Huguet F, Hurteloup P (1992) Comparative pharmacokinetic study of idarubicin and daunorubicin in leukemia patients. Hematol Oncol 10:111–116

    Article  PubMed  CAS  Google Scholar 

  21. Rowinsky EK, Adjei A, Donehower RC et al (1994) Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia. J Clin Oncol 12:2193–2203

    PubMed  CAS  Google Scholar 

  22. Schellens JH, Maliepaard M, Scheper RJ et al (2000) Transport of topoisomerase I inhibitors by the breast cancer resistance protein. Potential clinical implications. Ann N Y Acad Sci 922:188–194

    Article  PubMed  CAS  Google Scholar 

  23. Soni N, Meropol NJ, Pendyala L et al (1997) Phase I and pharmacokinetic study of etoposide phosphate by protracted venous infusion in patients with advanced cancer. J Clin Oncol 15:766–772

    PubMed  CAS  Google Scholar 

  24. Stollmann B, Fonatsch C, Havers W (1985) Persistent Epstein-Barr virus infection associated with monosomy 7 or chromosome 3 abnormality in childhood myeloproliferative disorders. Br J Haematol 60:183–196

    Article  PubMed  CAS  Google Scholar 

  25. Takashima Y, Matsuyama K (1987) Pharmacokinetic studies of intermediate- to high-dose 1-beta-D-arabinofuranosylcytosine in children with acute leukemia and lymphoma. J Clin Pharmacol 27:330–333

    PubMed  CAS  Google Scholar 

  26. Tamm I, Richter S, Oltersdorf D et al (2004) High expression levels of x-linked inhibitor of apoptosis protein and survivin correlate with poor overall survival in childhood de novo acute myeloid leukemia. Clin Cancer Res 10:3737–3744

    Article  PubMed  CAS  Google Scholar 

  27. Zhao S, Konopleva M, Cabreira-Hansen M et al (2004) Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias. Leukemia 18:267–275

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported in part by a grant of the Dr. Mildred Scheel Foundation for Cancer Research (Grant number W62/9/Hi3).

Author information

Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany

    Michael Fiegl, Inka Zimmermann, Isolde Lorenz, Wolfgang Hiddemann & Jan Braess

  2. Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital Grosshadern, Marchioninistr. 15, 81377, Munich, Germany

    Jan Braess

Authors
  1. Michael Fiegl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Inka Zimmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isolde Lorenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wolfgang Hiddemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jan Braess
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan Braess.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fiegl, M., Zimmermann, I., Lorenz, I. et al. In vitro cross-resistance to nucleoside analogues and inhibitors of topoisomerase 1 and 2 in acute myeloid leukemia. Ann Hematol 87, 27–33 (2008). https://doi.org/10.1007/s00277-007-0361-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-007-0361-z

Keywords

Search

Navigation