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Implication des mécanismes de réparation de l'ADN dans la résistance des glioblastomes à la chimiothérapie : De l'identification de gènes candidats in silico à leur validation préclinique

Abstract : Gliomas are common malignant tumors of the central nervous system whom oligodendrogliomas and glioblastomas are the major subtypes. Among them, oligodendrogliomas are distinguished by their remarkable sensitivity to chemotherapy, responding dramatically to treatment, contrasting with resistance of glioblastomas. Anaplastic oligodendrogliomas have loss of chromosomal arms 1p and 19q. This genetic alteration is statistically significantly associated with both chemosensitivity and longer recurrence-free survival after chemotherapy. We hypothesized that there are some resistance genes on this area, responsible for chemo-resistance of glioblastomas. Among them we focused on DNA-repair genes because they correct chemotherapy-induced adducts on DNA. We screened these genes with an in vitro chemosensitivity test that we developped, and identified 4 of them as involved in resistance of glioma cells to cisplatin : ercc1, ercc2, mutyh and pnkp. These results were confirmed with the gold standard chemotherapy drug : temozolomide. Expression of these genes were measured in resistant and sensitive human tumors, and the first 3 genes are overexpressed in glioblastomas. Thus, these genes can be considered as innovant targets of a chemo-sensitizing treatment. We entered a pre-clinical trial, financed by LNCC, to test this treatment on mice. We developped sub-cutaneous and intra-cerebral human xenografts of glioma on mice and treated them with siRNA directed to target genes, and with temozolomide. This treatment increased the tumor chemo-sensitivity, reducing tumoral volume. Our preclinical results confirmed both our in vitro data and the potentiality to chemosensitize glioblastoma using siRNA.
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https://tel.archives-ouvertes.fr/tel-00563481
Contributor : Sandra Boccard <>
Submitted on : Saturday, February 5, 2011 - 11:25:26 PM
Last modification on : Friday, November 6, 2020 - 4:06:53 AM
Long-term archiving on: : Friday, May 6, 2011 - 2:36:12 AM

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  • HAL Id : tel-00563481, version 1

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UJF | U836 | UGA

Citation

Sandra Boccard. Implication des mécanismes de réparation de l'ADN dans la résistance des glioblastomes à la chimiothérapie : De l'identification de gènes candidats in silico à leur validation préclinique. Biochimie [q-bio.BM]. Université Joseph-Fourier - Grenoble I, 2008. Français. ⟨tel-00563481⟩

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