Azathioprine induction of tumors with microsatellite instability: risk evaluation using a mouse model
| Autor: | Sahra, Bodo, Magali, Svrcek, Isabelle, Sourrouille, Peggy, Cuillières-Dartigues, Tatiana, Ledent, Sylvie, Dumont, Laetitia, Dinard, Philippe, Lafitte, Camille, Capel, Ada, Collura, Olivier, Buhard, Kristell, Wanherdrick, Alexandra, Chalastanis, Virginie, Penard-Lacronique, Bettina, Fabiani, Jean-François, Fléjou, Nicole, Brousse, Laurent, Beaugerie, Alex, Duval, Martine, Muleris |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male congenital hereditary and neonatal diseases and abnormalities Time Factors Lymphoma Kaplan-Meier Estimate DNA Mismatch Repair Risk Assessment Young Adult thiopurine tolerance Risk Factors Azathioprine Animals Humans neoplasms Aged pharmacogenetics Mice Knockout Dose-Response Relationship Drug Middle Aged Inflammatory Bowel Diseases iatrogenic cancer Immunohistochemistry digestive system diseases Disease Models Animal MutS Homolog 2 Protein Phenotype Female microsatellite instability Immunosuppressive Agents Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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: | OpenAIRE |
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