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Mitomycin-Induced Pulmonary Veno-Occlusive Disease: Evidence From Human Disease and Animal Models
Frédéric Perros1, Sven Günther1, Benoit Ranchoux1
1From Univ. Paris-Sud, Faculté de Médecine, Kremlin-Bicêtre, France (F.P., S.G., B.R., L.G., F.A., P.D., A.H., N.R., L.S., X.J., B.G., O.S., G.S., M.H., D.M.); AP-HP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France (F.P., S.G., B.R., L.G., F.A., A.H., L.S., X.J., B.G., O.S., G.S., M.H., D.M.); UMR_S 999, Univ. Paris-Sud, INSERM, Laboratoire d'Excellence (LabEx) en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (F.P., S.G., B.R., L.G., F.A., M-C.C., P.D., H.R., L.S., X.J., B.G., O.S., G.S., M.H., D.M.); Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France (M-C.C.); Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Canada (F.P.); Service de Pneumologie, CHU Mont-Godinne - Université Catholique de Louvain, Yvoir, Belgium (L.G.); AP-HP, Service de Pharmacie, Département Hospitalo-Universitaire (DHU) Thorax Innovation, Hôpital Antoine Béclère, Clamart, France (M-C.C.); Department of Pathology, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France (P.D.); and National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital, Lyon, France (V.C.).
Background:
Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD.
Methods And Results:
We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats.
Conclusions:
MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease.
Insights
Mitomycin-C (MMC) chemotherapy can cause pulmonary veno-occlusive disease (PVOD), a rare lung condition. Amifostine shows promise in preventing this serious side effect in rats.
Area of Science:
- Pulmonary Hypertension Research
- Oncology Drug Toxicity
Background:
- Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension.
- It is characterized by small pulmonary vein obstruction and has a poor prognosis.
- PVOD can be sporadic or heritable due to EIF2AK4 gene mutations; chemotherapy is a suspected risk factor.
Purpose of the Study:
- To investigate mitomycin-C (MMC) as an inducer of PVOD.
- To evaluate amifostine's potential to prevent MMC-induced PVOD.
Main Methods:
- Analysis of 7 human cases of PVOD linked to MMC therapy.
- Induction of PVOD in rats via intraperitoneal MMC administration.
- Assessment of pulmonary hypertension, vascular remodeling, GCN2 levels, and smad1/5/8 signaling in rats.
- Evaluation of amifostine's protective effect in the rat model.
Main Results:
- MMC therapy was identified as a potent inducer of PVOD in humans with anal cancer.
- The incidence of PVOD in anal cancer patients treated with MMC was significantly higher than in the general population.
- MMC induced PVOD in rats, characterized by pulmonary hypertension and vascular remodeling, with dose-dependent GCN2 depletion.
- Amifostine effectively prevented MMC-induced PVOD in the rat model.
Conclusions:
- Mitomycin-C (MMC) therapy is a significant cause of pulmonary veno-occlusive disease (PVOD) in humans and rats.
- Amifostine demonstrated preventive efficacy against MMC-induced PVOD in rats.
- Further clinical trials of amifostine for preventing MMC-induced PVOD in humans are warranted.
- The MMC-induced PVOD rat model offers a valuable platform for testing new therapies for this orphan disease.
