title: Iron Overload Exacerbates Busulfan-Melphalan Toxicity Through a Pharmacodynamic Interaction in Mice.
abstract: 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.
  
  
  
  We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice.
  
  
  
  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.
  
  
  
  Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.
authors.affiliation: UMR S-1185, Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris Saclay, F-94276, Le Kremlin Bicêtre, France.|Laboratoire de Génétique moléculaire, Pharmacogénétique et Hormonologie, Hôpital Universitaire de Bicêtre, Assistance Publique Hôpitaux de Paris, F-94275, Le Kremlin-Bicêtre, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bouligand
authors.affiliation: UMR S-1185, Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris Saclay, F-94276, Le Kremlin Bicêtre, France.|Laboratoire de Génétique moléculaire, Pharmacogénétique et Hormonologie, Hôpital Universitaire de Bicêtre, Assistance Publique Hôpitaux de Paris, F-94275, Le Kremlin-Bicêtre, France.|Service de Pharmacologie et d'Analyse du Médicament (SIPAM), Gustave Roussy Cancer Campus Grand Paris, Villejuif, 94805, France.
authors.forename: Clémentine
authors.initials: C
authors.lastname: Richard
authors.affiliation: Department of Paediatric Oncology, Gustave Roussy Cancer Campus Grand Paris, Institut Gustave Roussy, Villejuif, 94805, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau-Couanet
authors.affiliation: Integrated Biology Platform, Institut Gustave Roussy, Villejuif Cedex, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Orear
authors.affiliation: Service de Pharmacologie et d'Analyse du Médicament (SIPAM), Gustave Roussy Cancer Campus Grand Paris, Villejuif, 94805, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Mercier
authors.affiliation: Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Univ Paris-Sud, UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Centre National de la Recherche Scientifique (CNRS), UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Gustave Roussy Cancer Campus Grand Paris, UMR 8203, Villejuif, 94805, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Kessari
authors.affiliation: Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Univ Paris-Sud, UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Centre National de la Recherche Scientifique (CNRS), UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Gustave Roussy Cancer Campus Grand Paris, UMR 8203, Villejuif, 94805, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simonnard
authors.affiliation: Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Univ Paris-Sud, UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Centre National de la Recherche Scientifique (CNRS), UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Gustave Roussy Cancer Campus Grand Paris, UMR 8203, Villejuif, 94805, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Munier
authors.affiliation: Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Univ Paris-Sud, UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Centre National de la Recherche Scientifique (CNRS), UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Gustave Roussy Cancer Campus Grand Paris, UMR 8203, Villejuif, 94805, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Daudigeos-Dubus
authors.affiliation: UMR S-1185, Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris Saclay, F-94276, Le Kremlin Bicêtre, France.|Laboratoire de Génétique moléculaire, Pharmacogénétique et Hormonologie, Hôpital Universitaire de Bicêtre, Assistance Publique Hôpitaux de Paris, F-94275, Le Kremlin-Bicêtre, France.
authors.forename: Bassim
authors.initials: B
authors.lastname: Tou
authors.affiliation: Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Univ Paris-Sud, UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Centre National de la Recherche Scientifique (CNRS), UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Gustave Roussy Cancer Campus Grand Paris, UMR 8203, Villejuif, 94805, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.affiliation: Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Univ Paris-Sud, UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Centre National de la Recherche Scientifique (CNRS), UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Gustave Roussy Cancer Campus Grand Paris, UMR 8203, Villejuif, 94805, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Deroussent
authors.affiliation: Service de Pharmacologie et d'Analyse du Médicament (SIPAM), Gustave Roussy Cancer Campus Grand Paris, Villejuif, 94805, France. angelo.paci@gustaveroussy.fr.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Univ Paris-Sud, UMR 8203, Villejuif, 94805, France. angelo.paci@gustaveroussy.fr.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Centre National de la Recherche Scientifique (CNRS), UMR 8203, Villejuif, 94805, France. angelo.paci@gustaveroussy.fr.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Gustave Roussy Cancer Campus Grand Paris, UMR 8203, Villejuif, 94805, France. angelo.paci@gustaveroussy.fr.|Pharmacology and Drug Analysis Department, Vectorology and Therapeutic Treatments, UMR CNRS 8203, 114 rue Edouard Vaillant, 94800, Villejuif, France. angelo.paci@gustaveroussy.fr.
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.affiliation: Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Univ Paris-Sud, UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Centre National de la Recherche Scientifique (CNRS), UMR 8203, Villejuif, 94805, France.|Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Gustave Roussy Cancer Campus Grand Paris, UMR 8203, Villejuif, 94805, France.|Clinical Research Division, Institut Gustave Roussy, Villejuif Cedex, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000633:toxicity; D002066:Busulfan / Q000378:metabolism* / Q000633:toxicity*; D004347:Drug Interactions / Q000502:physiology; D019190:Iron Overload / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008558:Melphalan / Q000378:metabolism* / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan; D008558:Melphalan
keywords: Nrf2; bone marrow transplantation; drug interaction; glutathione; metabolism; mice; pharmacodynamic; pharmacokinetics; toxicity