GEMCITABINE ENHANCES THE EFFECT OF ADENOVIRUS-MEDIATED GENE THERAPY

Abstract

Backgrounds and Aims: Adenovirus-mediated gene therapy is a promising treatment for cancers, but its clinical efficacy is still low. So, more improved gene expression strategy is needed for gene therapy. Meanwhile, genotoxic stresses, such as those induced by chemotherapy, are known to enhance transgene expressions. Therefore, we investigated the effects of gemcitabine(GEM), now the first-line agent for treatment of pancreatic cancer, on the transgene expression of adenovirus vector. Methods: NK4 is an HGF-antagonist and inhibits invasion of cancer cells. In this study, we used Ad-NK4, which expresses NK4 under the control of CMV promoter. SUIT-2 cells were infected with Ad-NK4 and then treated with or without GEM for 24 hrs, and investigated the effects of GEM on Ad-NK4 by invasion assay. Results: The invasion of cancer cells was inhibited in a GEM-dose dependent manner (GEM 0, 1, 10, 100nM: 23, 27, 55, 79% inhibition on day3). Both of NK4 protein concentrations in supernatant of Ad-NK4 infected cells and of pcDNA transfected cells were increased in GEM-treated groups, and in vivo, NK4 expressions within subcutaneously implanted tumors in mice were increased in GEM-treated groups. Conclusion: These results indicate that GEM enhances the effects Ad-NK4 through GEM-enhanced CMV promoter. Combination of Ad-NK4 with GEM might be a new strategy for pancreatic cancer treatment.