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Potentialisation de la virothérapie anti-tumorale basée sur des adénovirus oncolytiques dans le traitement des cancers côliques et rénaux

Abstract : During this thesis, we investigated different strategies to increase the therapeutic effects of oncolytic adenovirus (CRAd) to fight several kinds of tumors.The first strategy seeks to evaluate in human colon carcinomas the association of a CRAd bearing Δ24 deletion in E1A with valproic acid (VPA), a histone deacetylase inhibitor. Interestingly, this combination led to a dramatic reduction of cell survival both in vitro and in vivo compared to single treatment with CRAd or VPA. This effect did not stem from a better CRAd replication and production in the presence of VPA. Inhibition of cell proliferation and a non-apoptotic cell death were shown to be two mechanisms mediating the effects of the combined treatment. Interestingly, whereas cells treated only with CRAd displayed a > 4N population and polyploidy, this phenotype was strongly increased in cells treated with both CRAd and VPA. In addition, the increase in polyploidy triggered by a combined treatment with CRAd and VPA was associated with the enhancement of H2AX phosphorylation (γH2AX), a hallmark of DNA damage. The second strategy developed aimed to find new entry pathways allowing CRAd to better infect and kill renal tumor cells, known to be refractory of Ad infection. We demonstrated that CRAd with capsid modified (Ad-HCKS-17-E1Δ24 and AdF3-E1Δ24), containing respectively a ligand CKS-17 in hexon or a fiber of serotype 3, were more efficient to infect different renal cell carcinomas in vitro compared to a CRAd with a wild type capsid. However, these capsid-modified oncolytic adenovirus provoked, neither increase of the infection level, nor a better efficacy of growth inhibition in renal tumor xenografts bearing by nude mice. Nevertheless, both types of modifications reduce Ad ability to transduce hepatocytes after intratumoral injection.
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Submitted on : Thursday, April 17, 2014 - 5:20:38 PM
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Christian Bressy. Potentialisation de la virothérapie anti-tumorale basée sur des adénovirus oncolytiques dans le traitement des cancers côliques et rénaux. Sciences agricoles. Université Paris Sud - Paris XI, 2013. Français. ⟨NNT : 2013PA11T020⟩. ⟨tel-00921952⟩

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