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Impact de l'environnement chimique sur la prise en charge de molécules à visée anti-cancéreuse : effet du cadmium sur l'efficacité potentielle de la Phenstatine et de ses métabolites dans le traitement du cancer de la prostate

Abstract : Prostate cancer is ranked third among fatal cancers, after bronchial and colorectal cancers, with 150,000 deaths recorded in 2010. The design of new prostate cancer drugs should take into account : i) the metabolism which can alter the efficiency of an active compound in vivo, and ; ii) the individual differences in metabolism resulting from patients’ environments. Our study, in partnership with the HEI School of Lille, is concerned with Phenstatin (a compound in pre-clinical development) and its metabolites : indeed, promising therapeutic results have recently been obtained with taxanes in hormone-resistant prostate cancers which stabilize microtubules by inhibiting their depolymerization.The aim of this work was firstly to study the pharmacological effect of Phenstatin and its metabolites, obtained after biotransformation by human liver microsomes, on tubulin polymerization and the proliferation of human prostate cancer cells (PC3 cell line). Secondly, we attempted to determinate the CYPs responsible for the formation of the Phenstatin metabolites we have identified and quantified. Thirdly, we addressed the influence of environmental conditions, more specifically the presence of cadmium, on the metabolism of these novel compounds and their activity towards prostate cancer cells. In order to understand the response or non-response of different treatments, we determined expression profiles of genes involved in the metabolism of xenobiotics by using high throughput technology based on real time quantitative PCR (TaqmanTM Low Density Arrays). A study model was designed in order to show the effect of environmental factors on anticancer compounds’ efficiency. This model should subsequently be transposable to other agents involved in xenobiotic metabolism and reveal genetic or epigenetic mechanisms responsible for individuals’ responses to anticancer treatments.
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Delphine Le Broc. Impact de l'environnement chimique sur la prise en charge de molécules à visée anti-cancéreuse : effet du cadmium sur l'efficacité potentielle de la Phenstatine et de ses métabolites dans le traitement du cancer de la prostate. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2011. Français. ⟨NNT : 2011LIL2S038⟩. ⟨tel-00783929⟩

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