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Etude de l’effet sur la P‐glycoprotéine (ABCB1) de deux médicaments dirigés contre le récepteur de facteur de croissance épithélial (EGFR), le cétuximab et le lapatinib et conséquence sur la pharmacocinétique et l’efficacité anti‐tumorale de médicaments substrats de ABCB1

Abstract : P-glycoprotein (P-gp) is a membrane transporter and belongs to the ATP-binding cassette (ABC) transporter super family. P-gp decreases oral bioavailability of substrate drugs and can cause multidrug resistance in tumor cells by decreasing intracellular drug levels. P-gp is overexpressed in colorectal carcinoma naturally resistant to chemotherapy. The aim of our first study was to document the in vivo transport of everolimus (Afinitor®), a mTOR inhibitor, by P-gp. A significant increase of everolimus oral bioavaibility was observed in mdr1a-/1b- mice compared to the wild type. In addition, a significant increase of everolimus oral bioavaibility was showed in mice that received a lapatinib pre-treatment (a dual EGFR/HER2 tyrosine kinase inhibitor) compared to mice that received everolimus alone. These results were accompanied by a significant decrease of P-gp expression in duodenum segment in lapatinib pre-treated group as compared to control group. Finally, each drug given alone or in association showed a major antitumor activity in a xenograft model of human colorectal carcinoma with KRAS mutation. Our second study showed for the first time that cetuximab (Erbitux®), a monoclonal antibody directed towards EGFR, inhibits P-gp functionality in two cell lines overexpressing P-gp (IGROV-1 and HEK P-gp cells) independently of EGFR status and leads to significant increases of oral bioavailability and intratumoral concentration of SN-38, the active metabolite of irinotecan (Campto®) in mice bearing colorectal carcinoma xenograft. Cetuximab is used in combination with irinotecan in patients with metastatic colorectal cancer, initially refractory to irinotecan, our results may partly explain the reversion of resistance to irinotecan by inhibiting P-gp efflux by cetuximab. In conclusion, our results showed the interest to study the effect of recent anticancerous drugs on P-gp, including their ability to improve oral bioavailability of oral chemotherapy used.
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Céline Chu. Etude de l’effet sur la P‐glycoprotéine (ABCB1) de deux médicaments dirigés contre le récepteur de facteur de croissance épithélial (EGFR), le cétuximab et le lapatinib et conséquence sur la pharmacocinétique et l’efficacité anti‐tumorale de médicaments substrats de ABCB1. Médecine humaine et pathologie. Université Paris Sud - Paris XI, 2013. Français. ⟨NNT : 2013PA114806⟩. ⟨tel-00868797⟩

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