• Yuki Fujiwara, Hiroaki Shiba, Ryota Iwase, Koichiro Haruki, Kenei Furukawa, Tadashi Uwagawa, Takeyuki Misawa, Toya Ohashi, and Katsuhiko Yanaga.
• Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan. sheetan@jikei.ac.jp
• J. Am. Coll. Surg. 2013 Feb 1; 216 (2): 32032.e3320-32.e3.

BackgroundCombination 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.Study DesignIn 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).ResultsIn 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).ConclusionsInhibition of NF-κB by FUT175 enhances the antitumor effect of combined TNF-α gene therapy and gemcitabine for pancreatic cancer.Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

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