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.

  • Letter to the Editor
  • Published:

Large interindividual differences in cellular sensitivity to calicheamicin may influence gemtuzumab ozogamicin response in acute myeloid leukemia

Leukemia volume 22, pages 2284–2285 (2008)Cite this article

Gemtuzumab ozogamicin (GO) is an immunoconjugate consisting of the cytotoxic drug calicheamicin linked to an anti-CD33 antibody. Walter and colleagues reported that CD33 expression and P-glycoprotein (P-gp) function predict clinical outcome in adults suffering from acute myeloid leukemia (AML) treated with GO.1 However, in leukemic samples from children, P-gp expression is infrequent. In a study designed to detect the clinical efficacy of P-gp inhibition, in pediatric AML, only 7 out of 447 (1.7%) children included expressed P-gp.2 Both CD33 expression and P-gp are involved in drug transport and determine the amount of calicheamicin that is available inside the leukemic cell to induce apoptosis. We hypothesized that in addition to the availability, the intrinsic calicheamicin sensitivity of leukemic cells might play a role in the clinical response to GO.

Therefore, we determined the in vitro sensitivity to unconjugated calicheamicin in 90 newly diagnosed and 32 (unpaired) relapsed pediatric AML samples using the 4 day MTT assay (concentration range 0.000004–0.4 μg/ml), as previously described in detail.3 The LC50 value, the drug concentration at which 50% of the cells are killed by the drug, is used as a measure of sensitivity. In addition to calicheamicin, a subset of samples was also tested for in vitro sensitivity to etoposide, cytarabine, daunorubicin, idarubicin, mitoxantrone, 6-thioguanine and L-asparaginase.

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

Relevant articles

Open Access articles citing this article.

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

Figure 1

References

  1. Walter RB, Gooley TA, van der Velden V, Loken MR, van Dongen JJ, Flowers DA et al. CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy. Blood 2007; 109: 4168–4170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Becton D, Dahl GV, Ravindranath Y, Chang MN, Behm FG, Raimondi SC et al. Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421. Blood 2006; 107: 1315–1324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Goemans BF, Zwaan CM, Harlow A, Loonen AH, Gibson BE, Hahlen K et al. In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets. Blood 2005; 106: 3532–3537.

    Article  CAS  PubMed  Google Scholar 

  4. Linenberger ML . CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leukemia 2005; 19: 176–182.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partially funded by ZonMW AGIKO Grant 920-03-374 (BFG). Calicheamicin was provided free of charge by Wyeth Pharmaceuticals. BFG performed the experiments, analyzed the data and wrote the paper; CMZ designed the research and wrote the paper; SJHV performed the experiments, analyzed the data and edited the paper; AHL performed the experiments and edited the paper; UC, KH, DR and BESG provided the leukemic samples and clinical data and edited the paper; JC analyzed the data and edited the paper; GJLK designed the research and edited the manuscript.

Author information

Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, VU university medical center, Amsterdam, The Netherlands

    B F Goemans, S J H Vijverberg, A H Loonen, J Cloos & G J L Kaspers

  2. Department of Pediatric Oncology/Hematology, Erasmus mc, Sophia Children's Hospital, Rotterdam, The Netherlands

    C M Zwaan & K Hählen

  3. AML-BFM Study Group, University of Muenster, Muenster, Germany

    U Creutzig & D Reinhardt

  4. DCOG, the Hague, The Netherlands

    K Hählen

  5. MRC Childhood Leukaemia Working Party, Glasgow, UK

    B E S Gibson

Authors
  1. B F Goemans
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C M Zwaan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S J H Vijverberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A H Loonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U Creutzig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Hählen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Reinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B E S Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Cloos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G J L Kaspers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B F Goemans.

Additional information

Conflict of interest

The authors state no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goemans, B., Zwaan, C., Vijverberg, S. et al. Large interindividual differences in cellular sensitivity to calicheamicin may influence gemtuzumab ozogamicin response in acute myeloid leukemia. Leukemia 22, 2284–2285 (2008). https://doi.org/10.1038/leu.2008.147

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.147

This article is cited by

Search

Advanced search

Quick links