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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Abstract

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.

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