title: Novel strategy for prevention of esophageal stricture after endoscopic surgery.
abstract: OBJECTIVE
  Recently, novel endoscopic surgery, including endoscopic submucosal dissection (ESD), was developed to resect a large superficial gastrointestinal cancer. However, circumferential endoscopic surgery in the esophagus can lead to esophageal stricture that affects the patient's quality of life. This major complication is caused by scar formation, and develops during the two weeks after endoscopic surgery. We hypothesized that local administration of a controlled release anti-scarring agent can prevent esophageal stricture after endoscopic surgery. The aims of this study were to develop an endoscopically injectable anti-scarring drug delivery system, and to verify the efficacy of our strategy to prevent esophageal stricture.
  
  
  METHODS
  We focused on 5-Fluorouracil (5-FU) as an anti-scarring agent, which has already been shown to be effective not only for treatment of cancers, but also for treatment of hypertrophic skin scars. 5-FU was encapsulated by liposome, and then mixed with injectable 2% atelocollagen (5FLC: 5FU-liposome-collagen) to achieve sustained release. An in vitro 5-FU releasing test from 5FLC was performed using high-performance liquid chromatography (HPLC). Inhibition of cell proliferation was investigated using normal human dermal fibroblast cells (NHDF) with 5FLC. In addition, a canine esophageal mucosal resection was carried out, and 5FLC was endoscopically injected into the ulcer immediately after the operation, and compared with a similar specimen injected with saline as a control.
  
  
  RESULTS
  5-FU was gradually released from 5FLC for more than 2 weeks in vitro. The solution of 5-FU released from 5FLC inhibited NHDF proliferation more effectively than 5-FU alone. In the canine model, no findings of stricture were observed in the 5FLC-treated dog at 4 weeks after the operation and no vomiting occurred. In contrast, marked esophageal strictures were observed with repeated vomiting in the control group. Submucosal fibrosis was markedly reduced histologically in the 5FLC-treated dog compared with the control.
  
  
  CONCLUSIONS
  5FLC showed sustained release of 5-FU and decreased cell proliferation in vitro. The clinically relevant canine model demonstrated that local endoscopic injection of 5FLC can prevent post-operative esophageal stricture. These results suggest that our strategy may be useful for preventing post-operative esophageal stricture.
authors.affiliation: Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Mizutani
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Tadauchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Arinobe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Narita
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kato
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Niwa
authors.forename: Naoki
authors.initials: N
authors.lastname: Ohmiya
authors.forename: Akihiro
authors.initials: A
authors.lastname: Itoh
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hirooka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Honda
authors.forename: Minoru
authors.initials: M
authors.lastname: Ueda
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002921:Cicatrix / Q000517:prevention & control*; D004285:Dogs; D016503:Drug Delivery Systems; D004940:Esophageal Stenosis / Q000517:prevention & control*; D004945:Esophagoscopy / Q000009:adverse effects*; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D008081:Liposomes
chemical_list: D008081:Liposomes; D005472:Fluorouracil