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

Oncotarget
Sahra BodoMartine Muleris

Abstract

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 MS...Continue Reading

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Citations

Jul 6, 2019·Médecine sciences : M/S·Ada ColluraAlex Duval
Feb 23, 2020·Biochemistry. Biokhimii︠a︡·G A BelitskiyM G Yakubovskaya
Nov 18, 2018·Cancer Discovery·Giovanni GermanoAlberto Bardelli

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Methods Mentioned

BETA
genotyping
PCR
laser-capture microdissection
electrophoresis

Software Mentioned

GeneMapper
Graphpad Prism

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis