3119

The aim of this work was to improve the cytotoxic and radiosensitizing effects of gemcitabine using a gene-directed enzyme prodrug therapy approach. Murine Gl261, rat C6 and human U373 glioma cell lines were transduced with an adenoviral vector encoding the human deoxycytidine kinase gene (Ad-HudCK). Deoxycytidine kinase activity was determined by an enzymatic assay. Intracranial tumors were established in C57BL/6 mice and Wistar rats by stereotactic implantation of either wild-type or Ad-HudCK transduced Gl261 and C6 glioma cells, respectively. In vitro growing cells and established tumors were treated with gemcitabine and irradiation either alone or in combination. Pronounced differences were found in basal dCK activities and gemcitabine sensitivity in the different glioma cell lines. Deoxycytidine kinase overexpression substantially increased both the toxic and radiosensitizing effect of gemcitabine in each cell line, but the enhancement rate of the treatment combinations varied: it was mild in the Gl261 cells and much stronger in the C6 and U373 cells. In vivo experiments showed a mild

radiosensitizing effect of dCK overexpression both in the Gl261 and C6
 >animal models. The combination of dCK overexpression, gemcitabine
 >treatment and irradiation led to significant improvement in the survival
 >rate of C6 bearing rats (66% survival). Overexpression of the dCK gene
 >could improve the cytotoxic and radiosensitizing effect of gemcitabine
 >both under in vitro and in vivo conditions in a tumor-specific manner.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA