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

Abstract

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

• Authors: Kenei Furukawa, Toya Ohashi, Koichiro Haruki, Yuki Fujiwara, Tomonori Iida, Hiroaki Shiba, Tadashi Uwagawa, Hiroshi Kobayashi, Katsuhiko Yanaga
• Journal: Cancer letters (Cancer Lett) Vol. 306 Issue 1 Pg. 92-8 (Jul 01 2011) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 21482023 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Benzamidines
• Enzyme Inhibitors
• Guanidines
• NF-kappa B
• Serine Proteinase Inhibitors
• Tumor Necrosis Factor-alpha
• nafamostat

Topics

• Adenoviridae (genetics)
• Animals
• Benzamidines
• Cell Cycle
• Cell Line, Tumor
• Cell Proliferation
• Enzyme Inhibitors (pharmacology)
• Gene Transfer Techniques
• Genetic Vectors
• Guanidines (pharmacology)
• Humans
• Male
• Mice
• Mice, Nude
• NF-kappa B (metabolism)
• Neoplasm Transplantation
• Pancreatic Neoplasms (genetics, metabolism)
• Serine Proteinase Inhibitors (pharmacology)
• Tumor Necrosis Factor-alpha (genetics)