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Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients

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Abstract

Purpose

The alkylating agent treosulfan exerts a high cytotoxic activity against various malignant cells. Due to limited non-hematological toxicity, treosulfan might be a promising compound in myeloablative therapy for hematopoietic transplantation in children. Since in vitro data regarding the activity of treosulfan against childhood leukemic cells are limited, we compared the effect of treosulfan and busulfan against pediatric leukemic and non-malignant cells.

Experimental design

Both agents were tested alone and in combination with fludarabine by means of the MTT and/or a five color-flow cytometric assay. Moreover, the induction of apoptosis by treosulfan was investigated via regulation of the proteinase caspase 3.

Results

Treosulfan was more active against leukemic cells of 20 children as well as against 3 leukemia-derived cell lines than busulfan, with increasing IC50 values from initial diagnosis to relapse. Overall purified stem cells were most sensitive, followed by CD56+CD3− NK and CD3+ T cells. The combination of treosulfan with fludarabine resulted in a synergistic effect against leukemic cells. In malignant cells, treosulfan induced rapid cell apoptosis measured by the activation of the centrally proteinase caspase 3.

Conclusion

Our results indicate that treosulfan has activity against pediatric leukemic cells, myeloablative potential and immunosuppressive properties suitable for conditioning regimen in childhood malignancies.

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Acknowledgments

This project was supported by “Hilfe für Krebskranke Kinder Frankfurt e.V.”, “Frankfurter Stiftung für Krebskranke Kinder” and medac GmbH, Hamburg. The authors thank Regine Quaritsch, Andrea Brinkmann, Carla Kramm, Stephanie Grohal and Frauke Röger for technical support.

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Authors and Affiliations

  1. Pediatric Hematology and Oncology, University Hospital, 60596, Frankfurt, Germany

    Doreen Munkelt, Ulrike Koehl, Stephan Kloess, Stefanie-Yvonne Zimmermann, Rabiá El Kalaäoui, Sibylle Wehner, Dirk Schwabe, Thomas Lehrnbecher, Thomas Klingebiel & Ruth Esser

  2. Pediatric Pneumology and Allergology, University Hospital, 60596, Frankfurt, Germany

    Ralf Schubert

  3. Department of Pharmaceutical Technology, J. W. Goethe University, Biozentrum Niederursel, 60438, Frankfurt, Germany

    Joerg Kreuter

  4. Pediatric Hematology and Oncology, Laboratory for Stem Cell Transplantation and Immunotherapy, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt, Germany

    Ulrike Koehl

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  1. Doreen Munkelt
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Correspondence to Ulrike Koehl.

Additional information

Doreen Munkelt and Ulrike Koehl have contributed equally to this work.

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Munkelt, D., Koehl, U., Kloess, S. et al. Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients. Cancer Chemother Pharmacol 62, 821–830 (2008). https://doi.org/10.1007/s00280-007-0669-3

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  • DOI: https://doi.org/10.1007/s00280-007-0669-3

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