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Iron Overload Exacerbates Busulfan-Melphalan Toxicity Through a Pharmacodynamic Interaction in Mice

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Abstract

Purpose

Busulfan-melphalan high-dose chemotherapy followed by autologous stem cell transplantation is an essential consolidation treatment of high-risk neuroblastoma in children. Main treatment limitation is hepatic veno-occlusive disease, the most severe and frequent extra-hematological toxicity. This life threatening toxicity has been related to a drug interaction between busulfan and melphalan which might be increased by prior disturbance of iron homeostasis, i.e. an increased plasma ferritin level.

Methods

We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice.

Results

Iron excess dramatically increased the toxicity of melphalan or busulfan melphalan combination in mice but it did not modify the clearance of either busulfan or melphalan. We show that prior busulfan treatment impairs the clearance of melphalan. This clearance alteration was exacerbated in iron overloaded mice demonstrating a pharmacokinetic interaction. Additionally, iron overload increased melphalan toxicity without altering its pharmacokinetics, suggesting a pharmacodynamic interaction between iron and melphalan. Based on iron homeostasis disturbance, we postulated that prior induction of ferritin, through Nrf2 activation after oxidative stress, may be associated with the alteration of melphalan metabolism.

Conclusion

Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.

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Abbreviations

AUC:

Area under curve

BMT:

Bone marrow transplantation

BU:

Busulfan

HSCT:

Hematopoietic stem cell transplantation

HVOD:

Hepatic venooclusive disease

LOD:

Limit of detection

LOQ:

Limit of quantification

MEL:

Melphalan

QC:

Quality control

SFN:

Sulforaphane.

TTP:

Thiotepa

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ACKNOWLEDGMENTS AND DISCLOSURES

We thank all the staff of the animal unit at the Institute Gustave Roussy for their care of the animals. We are grateful to Irina Radu-Bouligand for editing the manuscript.

Author information

Authors and Affiliations

  1. UMR S-1185, Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris Saclay, F-94276, Le Kremlin Bicêtre, France

    Jérôme Bouligand, Clémentine Richard & Bassim Tou

  2. Laboratoire de Génétique moléculaire, Pharmacogénétique et Hormonologie, Hôpital Universitaire de Bicêtre, Assistance Publique Hôpitaux de Paris, F-94275, Le Kremlin-Bicêtre, France

    Jérôme Bouligand, Clémentine Richard & Bassim Tou

  3. Service de Pharmacologie et d’Analyse du Médicament (SIPAM), Gustave Roussy Cancer Campus Grand Paris, Villejuif, 94805, France

    Clémentine Richard, Lionel Mercier & Angelo Paci

  4. Department of Paediatric Oncology, Gustave Roussy Cancer Campus Grand Paris, Institut Gustave Roussy, Villejuif, 94805, France

    Dominique Valteau-Couanet

  5. Integrated Biology Platform, Institut Gustave Roussy, Villejuif Cedex, France

    Cedric Orear

  6. Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Univ Paris-Sud, UMR 8203, Villejuif, 94805, France

    Romain Kessari, Nicolas Simonnard, Fabienne Munier, Estelle Daudigeos-Dubus, Paule Opolon, Alain Deroussent, Angelo Paci & Gilles Vassal

  7. Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Centre National de la Recherche Scientifique (CNRS), UMR 8203, Villejuif, 94805, France

    Romain Kessari, Nicolas Simonnard, Fabienne Munier, Estelle Daudigeos-Dubus, Paule Opolon, Alain Deroussent, Angelo Paci & Gilles Vassal

  8. Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Gustave Roussy Cancer Campus Grand Paris, UMR 8203, Villejuif, 94805, France

    Romain Kessari, Nicolas Simonnard, Fabienne Munier, Estelle Daudigeos-Dubus, Paule Opolon, Alain Deroussent, Angelo Paci & Gilles Vassal

  9. Pharmacology and Drug Analysis Department, Vectorology and Therapeutic Treatments, UMR CNRS 8203, 114 rue Edouard Vaillant, 94800, Villejuif, France

    Angelo Paci

  10. Clinical Research Division, Institut Gustave Roussy, Villejuif Cedex, France

    Gilles Vassal

Authors
  1. Jérôme Bouligand
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  2. Clémentine Richard
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  3. Dominique Valteau-Couanet
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  4. Cedric Orear
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  5. Lionel Mercier
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  6. Romain Kessari
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  7. Nicolas Simonnard
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  8. Fabienne Munier
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  9. Estelle Daudigeos-Dubus
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  10. Bassim Tou
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  11. Paule Opolon
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  12. Alain Deroussent
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  13. Angelo Paci
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  14. Gilles Vassal
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Corresponding author

Correspondence to Angelo Paci.

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Bouligand, J., Richard, C., Valteau-Couanet, D. et al. Iron Overload Exacerbates Busulfan-Melphalan Toxicity Through a Pharmacodynamic Interaction in Mice. Pharm Res 33, 1913–1922 (2016). https://doi.org/10.1007/s11095-016-1927-z

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  • DOI: https://doi.org/10.1007/s11095-016-1927-z

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