title: 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.affiliation: Department of Surgery, Jikei University School of Medicine, Tokyo, Japan. k-furukawa@jikei.ac.jp
authors.forename: Kenei
authors.initials: K
authors.lastname: Furukawa
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Haruki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Tomonori
authors.initials: T
authors.lastname: Iida
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiba
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uwagawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanaga
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001550:Benzamidines; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D001550:Benzamidines; D004791:Enzyme Inhibitors; D006146:Guanidines; D016328:NF-kappa B; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C032855:nafamostat