Combination treatment using adenovirus vector-mediated tumor necrosis factor-alpha gene transfer and a NF-κB inhibitor for pancreatic cancer in mice

Gene therapy using an adenoviral vector expressing tumor necrosis factor-alpha (TNF-alpha) is a new therapeutic approach for pancreatic cancer. However, the efficacy of TNF-alpha is limited, because it activates nuclear factor-kappa B (NF-kappa B). We investigated the combined use of AxCAhTNF-alpha, adenoviral vector-expressing human TNF-alpha, and nafamostat mesilate, a serine-protease inhibitor, a NF-kappa B inhibitor, using pancreatic cancer in mice. In vitro, nafamostat mesilate inhibited TNF-alpha-induced NF-kappa B activation and enhanced TNF-alpha-induced apoptosis in human cancer cell line (MIAPaCa-2). In vivo, we assessed combination treatment of AxCAhTNF-alpha and nafamostat mesilate using xenograft models in nude mice by subcutaneous injection of MIAPaCa-2. When the implanted tumor size reached 8.0 mm, TNF-alpha group (n = 12), was injected AxCAhTNF-alpha intra-tumorally once a week, while combination group (n = 12), was injected AxCAhTNF-alpha intra-tumorally once a week and nafamostat mesilate intraperitoneally thrice a week. In combination group, tumor growth was significantly slower, and the number of apoptosis cells was significantly greater than those in AxCAhTNF-alpha group (p < 0.05). In conclusion, adenovirus vector-mediated TNF-alpha gene therapy combined with nafamostat mesilate was effective for pancreatic cancer in mice. (C) 2011 Elsevier Ireland Ltd. All rights reserved.