Azathioprine induction of tumors with microsatellite instability: risk evaluation using a mouse model.

Autor: Bodo S; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Svrcek M; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.; AP-HP, Hôpital Saint-Antoine, Service d'Anatomie Pathologique, F-75012 Paris, France., Sourrouille I; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Cuillières-Dartigues P; AP-HP, Institut Gustave Roussy, Service d'Anatomie Pathologique, F-94805 Villejuif, France., Ledent T; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Dumont S; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.; IFR 65, F-75012 Paris, France., Dinard L; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Lafitte P; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Capel C; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Collura A; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Buhard O; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Wanherdrick K; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Chalastanis A; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Penard-Lacronique V; INSERM, U985, Institut Gustave Roussy, F-94805 Villejuif, France., Fabiani B; AP-HP, Hôpital Saint-Antoine, Service d'Anatomie Pathologique, F-75012 Paris, France., Fléjou JF; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.; AP-HP, Hôpital Saint-Antoine, Service d'Anatomie Pathologique, F-75012 Paris, France., Brousse N; AP-HP, Hôpital Necker-Enfants Malades, Service d'Anatomie Pathologique, F-75015 Paris, France., Beaugerie L; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.; AP-HP, Hôpital Saint-Antoine, Service de Gastroentérologie, F-75012 Paris, France., Duval A; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France., Muleris M; INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2015 Sep 22; Vol. 6 (28), pp. 24969-77.
DOI: 10.18632/oncotarget.4638
Abstrakt: Mismatch-repair (MMR)-deficient cells show increased in vitro tolerance to thiopurines because they escape apoptosis resulting from MMR-dependent signaling of drug-induced DNA damage. Prolonged treatment with immunosuppressants including azathioprine (Aza), a thiopurine prodrug, has been suggested as a risk factor for the development of late onset leukemias/lymphomas displaying a microsatellite instability (MSI) phenotype, the hallmark of a defective MMR system. We performed a dose effect study in mice to investigate the development of MSI lymphomas associated with long term Aza treatment. Over two years, Aza was administered to mice that were wild type, null or heterozygous for the MMR gene Msh2. Ciclosporin A, an immunosuppressant with an MMR-independent signaling, was also administered to Msh2(wt) mice as controls. Survival, lymphoma incidence and MSI tumor phenotype were investigated. Msh2(+/-) mice were found more tolerant than Msh2(wt) mice to the cytotoxicity of Aza. In Msh2(+/-) mice, Aza induced a high incidence of MSI lymphomas in a dose-dependent manner. In Msh2(wt) mice, a substantial lifespan was only observed at the lowest Aza dose. It was associated with the development of lymphomas, one of which displayed the MSI phenotype, unlike the CsA-induced lymphomas. Our findings define Aza as a risk factor for an MSI-driven lymphomagenesis process.
Databáze: MEDLINE