title: Chemotherapy-induced pulmonary hypertension: role of alkylating agents.
abstract: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Ranchoux
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), the Reference Center for Severe Pulmonary Hypertension, Pneumology and Respiratory Intensive Care Service, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Sven
authors.initials: S
authors.lastname: Günther
authors.affiliation: Respiratory Division, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Rozenn
authors.initials: R
authors.lastname: Quarck
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; AP-HP, Pharmacy Service, Département Hospitalo-Universitaire Thorax Innovation, Hôpital Antoine Béclère, Clamart, France.
authors.forename: Marie-Camille
authors.initials: MC
authors.lastname: Chaumais
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Pathology Service, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Antigny
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France.
authors.forename: Sébastien J
authors.initials: SJ
authors.lastname: Dumas
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Pathology Service, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Raymond
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), the Reference Center for Severe Pulmonary Hypertension, Pneumology and Respiratory Intensive Care Service, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Edmund
authors.initials: E
authors.lastname: Lau
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), the Reference Center for Severe Pulmonary Hypertension, Pneumology and Respiratory Intensive Care Service, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Savale
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), the Reference Center for Severe Pulmonary Hypertension, Pneumology and Respiratory Intensive Care Service, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jaïs
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), the Reference Center for Severe Pulmonary Hypertension, Pneumology and Respiratory Intensive Care Service, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sitbon
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), the Reference Center for Severe Pulmonary Hypertension, Pneumology and Respiratory Intensive Care Service, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: Department of Pediatrics, University of Colorado at Denver, Aurora, Colorado.
authors.forename: Kurt
authors.initials: K
authors.lastname: Stenmark
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cohen-Kaminsky
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), the Reference Center for Severe Pulmonary Hypertension, Pneumology and Respiratory Intensive Care Service, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), the Reference Center for Severe Pulmonary Hypertension, Pneumology and Respiratory Intensive Care Service, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.affiliation: Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France. Electronic address: frederic.perros@inserm.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D011667:Pulmonary Veins / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011817:Rabbits; D051381:Rats
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide