Optimización del sistema tet-on para regular la expresión de inteleucina-12 en el hígado y su aplicación al tratamiento de tumores hepáticos

Résumé

TITULO: OPTIMIZACIÓN DEL SISTEMA TET-ON PARA REGULAR LA EXPRESIÓN DE INTERLEUCINA-12 EN EL HÍGADO Y SU APLICACIÓN AL TRATAMIENTO DE TUMORES HEPÁTICOS RESUMEN: Optimization of the Tet-on system to regulate interleukin-12 expression in the liver for the treatment of hepatic tumors Maider zabala Uqalde Faculty of Science, university of Navarra (spain) 2005 Hepatocellular carcinoma (HCC) is a prevalent form of cancer, which lacks of curative treatment in most patients. For that reason there is an urgent need for new and efficient treatments. One experimental approach consists on interleukin-12 (iL-12)-based gene therapy. This cytokine has a potent antitumoral activity but it can be toxic at high doses. in order to minimize its side effects we have generated a plasmid vector able to direct expression of murine IL-12 in a liver-specific and doxycycline (Dox)-inducible manner. The plasmid was transferred to the liver by the hydrodynamics-based procedure and the antitumor efficacy of IL-12 was evaluated in two animal models: (i) metástasis of colon cancer to the liver and (ii) HCC developed in transgenic mice. In the first case 100% of animáis showed complete tumor regression after 10 days of mlL-12 expression. Transgenic PK/c-myc mice over-express c-myc in the liver and develop tumors in 6-8 months that resemble human HCC in terms of biology and gene expression profile. After several rounds of mlL-12 induction during 168 days, we observed an inhibition of tumor growth and survival of 40% of treated mice. These data showed the great potential of IL-12 for the treatment of metastatic and primary liver cancer, we have also aimed at improving the non-invasive detection of HCC using the PK/c-myc mice and different PET tracers. We found that combination of 18FDG and 11c-choline analysis allowed detection of up to 78% of tumor lesions