title: Inhibition of nuclear factor kappa-B enhances the antitumor effect of combination treatment with tumor necrosis factor-alpha gene therapy and gemcitabine for pancreatic cancer in mice.
abstract: BACKGROUND
  Combination therapy with tumor necrosis factor-alpha (TNF-α) gene delivery and gemcitabine is a new therapeutic approach for pancreatic cancer. However, the efficacy of both TNF-α and gemcitabine is suppressed due to activation of nuclear factor-kappa B (NF-κB). We hypothesized that nafamostat mesilate (FUT175), an NF-κB inhibitor, enhances the antitumor effect of combination treatment with an adenoviral vector-expressing TNF-α (AxCAhTNF-α) and gemcitabine for pancreatic cancer in mice.
  
  
  METHODS
  In vitro, we assessed that FUT175 inhibited both TNF-α- and gemcitabine-induced NF-κB activation and enhanced apoptosis in human pancreatic cancer cell lines (MIAPaCa-2 and AsPC-1). In vivo, we established a xenograft pancreatic cancer model in mice by subcutaneous injection of MIAPaCa-2 and AsPC-1. The animals were treated with AxCAhTNF-α intratumorally and gemcitabine intraperitoneally once a week (combination group) or AxCAhTNF-α intratumorally and gemcitabine intraperitoneally once a week as well as FUT175 intraperitoneally 3 times a week (triple combination group).
  
  
  RESULTS
  In vitro, FUT175 inhibited both TNF-α- and gemcitabine-induced NF-κB activation and enhanced induction of apoptosis. In the triple combination group, tumor growth in vivo was significantly slower and there were more apoptotic cells than in the combination group (p < 0.05).
  
  
  CONCLUSIONS
  Inhibition of NF-κB by FUT175 enhances the antitumor effect of combined TNF-α gene therapy and gemcitabine for pancreatic cancer.
authors.affiliation: Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan. sheetan@jikei.ac.jp
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiba
authors.forename: Ryota
authors.initials: R
authors.lastname: Iwase
authors.forename: Koichiro
authors.initials: K
authors.lastname: Haruki
authors.forename: Kenei
authors.initials: K
authors.lastname: Furukawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uwagawa
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Misawa
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanaga
mesh_terms: D000256:Adenoviridae; D000704:Analysis of Variance; D000818:Animals; D001550:Benzamidines; D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D001550:Benzamidines; D006146:Guanidines; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; C032855:nafamostat; D000093542:Gemcitabine