Inhibition of intra-abdominal adhesion formation with the angiogenesis inhibitor sunitinib

Objective. To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions. Background. In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition. Methods. The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib. Results. All 19 control mice developed intraabdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0-5.0; range 0-8.0)] than the control group [5.0 (IQR 3.0-8.0; range 2.0-10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0-3.0; range 0-7) and control 6.0 (IQR 3.0-7.0; range 0-12) (P = 0.049)]. Conclusion. Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR,2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures. (c) 2008 Elsevier Inc. All rights reserved.