Novel strategy for prevention of esophageal stricture after endoscopic surgery

Taro Mizutani, Akimitsu Tadauchi, Manabu Arinobe, Yuji Narita, Ryuji Kato, Yasumasa Niwa, Naoki Ohmiya, Akihiro Itoh, Yoshiki Hirooka, Hiroyuki Honda, Minoru Ueda, Hidemi Goto

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background/Aims: 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. Methodology: 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.

Original languageEnglish
Pages (from-to)1150-1156
Number of pages7
JournalHepato-gastroenterology
Volume57
Issue number102-103
Publication statusPublished - 01-09-2010
Externally publishedYes

Fingerprint

Esophageal Stenosis
Fluorouracil
Cicatrix
Canidae
Cell Proliferation
Liposomes
Skin
Injections
Vomiting
Fibroblasts
Dogs
Hypertrophic Cicatrix
Gastrointestinal Neoplasms
Drug Delivery Systems
Esophagus
Ulcer
Pathologic Constriction
Fibrosis
Collagen
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Mizutani, T., Tadauchi, A., Arinobe, M., Narita, Y., Kato, R., Niwa, Y., ... Goto, H. (2010). Novel strategy for prevention of esophageal stricture after endoscopic surgery. Hepato-gastroenterology, 57(102-103), 1150-1156.
Mizutani, Taro ; Tadauchi, Akimitsu ; Arinobe, Manabu ; Narita, Yuji ; Kato, Ryuji ; Niwa, Yasumasa ; Ohmiya, Naoki ; Itoh, Akihiro ; Hirooka, Yoshiki ; Honda, Hiroyuki ; Ueda, Minoru ; Goto, Hidemi. / Novel strategy for prevention of esophageal stricture after endoscopic surgery. In: Hepato-gastroenterology. 2010 ; Vol. 57, No. 102-103. pp. 1150-1156.
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abstract = "Background/Aims: 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. Methodology: 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.",
author = "Taro Mizutani and Akimitsu Tadauchi and Manabu Arinobe and Yuji Narita and Ryuji Kato and Yasumasa Niwa and Naoki Ohmiya and Akihiro Itoh and Yoshiki Hirooka and Hiroyuki Honda and Minoru Ueda and Hidemi Goto",
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Mizutani, T, Tadauchi, A, Arinobe, M, Narita, Y, Kato, R, Niwa, Y, Ohmiya, N, Itoh, A, Hirooka, Y, Honda, H, Ueda, M & Goto, H 2010, 'Novel strategy for prevention of esophageal stricture after endoscopic surgery', Hepato-gastroenterology, vol. 57, no. 102-103, pp. 1150-1156.

Novel strategy for prevention of esophageal stricture after endoscopic surgery. / Mizutani, Taro; Tadauchi, Akimitsu; Arinobe, Manabu; Narita, Yuji; Kato, Ryuji; Niwa, Yasumasa; Ohmiya, Naoki; Itoh, Akihiro; Hirooka, Yoshiki; Honda, Hiroyuki; Ueda, Minoru; Goto, Hidemi.

In: Hepato-gastroenterology, Vol. 57, No. 102-103, 01.09.2010, p. 1150-1156.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel strategy for prevention of esophageal stricture after endoscopic surgery

AU - Mizutani, Taro

AU - Tadauchi, Akimitsu

AU - Arinobe, Manabu

AU - Narita, Yuji

AU - Kato, Ryuji

AU - Niwa, Yasumasa

AU - Ohmiya, Naoki

AU - Itoh, Akihiro

AU - Hirooka, Yoshiki

AU - Honda, Hiroyuki

AU - Ueda, Minoru

AU - Goto, Hidemi

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Background/Aims: 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. Methodology: 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.

AB - Background/Aims: 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. Methodology: 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.

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Mizutani T, Tadauchi A, Arinobe M, Narita Y, Kato R, Niwa Y et al. Novel strategy for prevention of esophageal stricture after endoscopic surgery. Hepato-gastroenterology. 2010 Sep 1;57(102-103):1150-1156.