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Etude épidémiologique et moléculaire des voies métaboliques associées au glutathion dans le cancer du sein

Abstract : Glutathione S-transferases (GST) and glutathione peroxidases, (GPX), together with glutathione reductase (GSSR) catalyse essential reactions for cell defence from toxic agents such as anticancer drugs and/or reactive oxygen species. With glutathione as the central component, this metabolic pathway is activated in most tumours and linked to resistant phenotype. Two approaches have been developed in this work. 1) An epidemiological study, on 41 patients, showed higher glutathione contents and an increase of the above-mentioned glutathione-dependent enzymes in the breast tumours, resulting in the improvement of the intracellular redox status. The numerous correlations between the components of the glutathione system observed only in non-cancerous breast suggest a highly coordinated and organised system that is disrupted in cancerous breast. The increased levels of GSH contents and its related enzymes activities are correlated with various prognostic factors linked to cell proliferation, suggesting the incidence of these inductions in resistance and tumour aggressiveness in breast cancer. 2) A molecular study was performed on human breast adenocarcinoma cell line MCF-7 sensitive or resistant to doxorubicin and/or vincristine. GST as well as GPX activities and expressions were increased according to cellular resistance levels, whereas GSSR and glutathione contents decreased. We focused on the one hand on the role of GPX, that we selectively induced with selenium, which nonetheless did not improve the antioxidative defence and, on the other hand, on GSTT2 subunit overexpressed in vincristine resistant cells and whose 5' regulatory gene region was isolated in order to further study its expression. Resistant phenotype could result from a concomitant variation of parai lei metabolic pathways, distinct from the early adaptive response to a defined cytotoxic agent.
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Submitted on : Thursday, March 29, 2018 - 10:47:03 AM
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Magali Perquin. Etude épidémiologique et moléculaire des voies métaboliques associées au glutathion dans le cancer du sein. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2000. Français. ⟨NNT : 2000NAN10301⟩. ⟨tel-01746892⟩



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