Surgery · 2018
EW-7197, an oral transforming growth factor β type I receptor kinase inhibitor, for preventing peritoneal adhesion formation in a rat model.
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Tsauo Jiaywei, Song Ho-Young, Choi Eun Young, Kim Dae-Kee, Kim Kun Yung, Park Jung-Hoon, Kim Min Tae, Yoon Sung Hwan, Lim Young Je
Аннотация
BACKGROUND: EW-7197 is an oral transforming growth factor β type I receptor kinase inhibitor currently undergoing phase I clinical trials for cancer treatment in the United States. This study evaluates whether EW-7197 prevents peritoneal adhesion formation in a rat model.
METHODS: Forty-eight female Wistar rats underwent peritoneal adhesion induction by the creation of peritoneal ischemic buttons and were randomly divided into 4 groups of 12 each. The control group received 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction. The 10 mg and 20 mg groups received 10 or 20 mg/kg EW-7197 phosphate dissolved in 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction. The rebound group received 20 mg/kg EW-7197 phosphate dissolved in 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction followed by 0.3 mL vehicle only by gavage once daily for an additional 21 days. After the respective treatments were completed, the animals were euthanized.
RESULTS: All rats survived until the end of the study without complications. EW-7197 reduced the incidence, quality, and tenacity of peritoneal adhesions in a dose-dependent manner. Fibrosis and collagen production were reduced in EW-7197-treated peritoneal ischemic buttons. Transforming growth factor β/Smad2/3 signaling and mesothelial-to-mesenchymal transition were inhibited in EW-7197-treated peritoneal ischemic buttons. Discontinuation of EW-7197 was not associated with rebound effects.
CONCLUSION: EW-7197 prevented peritoneal adhesion formation potentially via inhibition of transforming growth factor β1/Smad2/3-induced mesothelial-to-mesenchymal transition in a rat model.
METHODS: Forty-eight female Wistar rats underwent peritoneal adhesion induction by the creation of peritoneal ischemic buttons and were randomly divided into 4 groups of 12 each. The control group received 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction. The 10 mg and 20 mg groups received 10 or 20 mg/kg EW-7197 phosphate dissolved in 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction. The rebound group received 20 mg/kg EW-7197 phosphate dissolved in 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction followed by 0.3 mL vehicle only by gavage once daily for an additional 21 days. After the respective treatments were completed, the animals were euthanized.
RESULTS: All rats survived until the end of the study without complications. EW-7197 reduced the incidence, quality, and tenacity of peritoneal adhesions in a dose-dependent manner. Fibrosis and collagen production were reduced in EW-7197-treated peritoneal ischemic buttons. Transforming growth factor β/Smad2/3 signaling and mesothelial-to-mesenchymal transition were inhibited in EW-7197-treated peritoneal ischemic buttons. Discontinuation of EW-7197 was not associated with rebound effects.
CONCLUSION: EW-7197 prevented peritoneal adhesion formation potentially via inhibition of transforming growth factor β1/Smad2/3-induced mesothelial-to-mesenchymal transition in a rat model.
Предметные рубрики MeSH
Administration, OralAniline CompoundsAnimalsDisease Models, AnimalDrug Evaluation, PreclinicalEpithelial-Mesenchymal TransitionFemaleFibrosisHumansPeritoneal DiseasesPeritoneumPostoperative ComplicationsProtein Kinase InhibitorsRatsRats, WistarReceptor, Transforming Growth Factor-beta Type ISignal TransductionSurgical Procedures, OperativeTissue AdhesionsTreatment OutcomeTriazoles