title: Combination paclitaxel and inhibitor of nuclear factor κB activation improves therapeutic outcome for model mice with peritoneal dissemination of pancreatic cancer.
abstract: OBJECTIVE
  Paclitaxel (PTX) is a useful treatment for peritoneal dissemination of malignant tumors. However, chemoresistance due to PTX-induced nuclear factor κB (NF-κB) activation is an important cause of suboptimal therapeutic effect. We previously reported nafamostat mesilate (FUT175) inhibits NF-κB activation and promotes apoptosis in pancreatic cancer. We hypothesized that addition of FUT175 to PTX may enhance the antitumor effect in peritoneal dissemination of pancreatic cancer.
  
  
  METHODS
  In vitro, we assessed NF-κB activity and apoptosis by the combination of FUT175 and PTX using human pancreatic cancer cell line (AsPc-1). In vivo, we established peritoneal dissemination in nude mice by intraperitoneal injection of AsPc-1 cells. The animals were treated with intraperitoneal injection thrice a week of FUT175, once a week of PTX, or a combination of thrice a week of FUT175 and once a week of PTX (combination group).
  
  
  RESULTS
  In the combination groups, PTX-induced NF-κB activation was inhibited, and apoptosis was enhanced in comparison with other groups both in vitro and in vivo. In the combination group, tumor growth, serum tumor marker, and survival rate were significantly better than those in other groups (P < 0.05).
  
  
  CONCLUSIONS
  Combination chemotherapy using PTX with FUT175 exerts an antitumor effect for peritoneal dissemination of pancreatic cancer.
authors.affiliation: Department of Surgery, Institute of DNA Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan. sheetan@jikei.ac.jp
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Kenei
authors.initials: K
authors.lastname: Furukawa
authors.forename: Yohta
authors.initials: Y
authors.lastname: Shimada
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: 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: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001550:Benzamidines; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010537:Peritoneum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000972:Antineoplastic Agents, Phytogenic; D001550:Benzamidines; D006146:Guanidines; D016328:NF-kappa B; D053181:Caspase 8; D017239:Paclitaxel; C032855:nafamostat