IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
MRP4 association with 5FU and gemcitabine resistance in pancreatic cance
Autor/es:
YANEFF A; CAROZZO A; DAVIO C; DI SIERVI N; MAY M; SAHORES A; GOMEZ N; SHAYO C
Lugar:
Mar del Plata
Reunión:
Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC). LXIV Reunión Anual Sociedad Argentina de Inmunología (SAI) y XLVIII Reunion Anual Sociedad Argentina de Farmacología Experimental (SAFE); 2016
Institución organizadora:
SAIC
Resumen:
Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal of human malignancies due to several factors: there are no early detection markers, has extensive local tumor invasion, early systemic dissemination, and extremely poor response to chemotherapy and radiation treatment. Gemcitabine (GEM) became the reference regimen for advanced pancreatic cancer after a randomized trial showed significant improvement in the median overall survival as compared with fluorouracil (5FU) administered as an intravenous bolus. This chemotherapy treatment reduces primary tumor burden, but patients have an overall survival not longer than six months. Our laboratory has validated a membrane transporter (MRP4) as a new therapeutic target in pancreatic cancer and its association with cAMP efflux. Both gene silencing (shRNA) and pharmacological inhibition (MK571) leads to lower tumorigenicity, malignancy and proliferation in PDAC models both on in vivo and in vitro assays. The hypothesis of our work is that 5FU and GEM cause an adaptation of the tumor, overexpressing MRP4, increasing their level of invasion and malignancy. We performed a kinetic cAMP transport assay to assess MRP4 activity in the presence of these two chemotherapeutic agents in PANC-1 cell line, concluding that they do not significantly affect the flow of cAMP. In proliferation concentration-response curves, neither MK571 nor MRP4 gene specific silencing modified 5FU or GEM sensitivity after 72 hours treatment. Interestingly, we observed an increase in MRP4 mRNA levels of up to six times (p