Inhibition of Intra-Abdominal Adhesion Formation With the Angiogenesis Inhibitor Sunitinib Sendia Kim, M.D.,* Sang Lee, M.D.,* Arin K. Greene, M.D., MM.Sc.,† Danielle A. Arsenault, B.S.,* Hau Le, M.D.,* Jonathan Meisel, M.D.,* Katherine Novak, B.S.,* Evelyn Flynn, M.A.,* John V. Heymach, M.D., Ph.D.,* , ‡ and Mark Puder, M.D., Ph.D.* ,1 *Department of Surgery; †Department of Plastic Surgery; and ‡Vascular Biology Program; Children’s Hospital Boston Harvard Medical School, Boston, Massachusetts Submitted for publication July 3, 2007 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 inpa- tient 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 postop- erative abdominal adhesions by VEGFR-2 inhibition. Methods. The cecum of 37 mice were abraded to pro- mote adhesion formation and a silicone patch was su- tured to the abdominal wall. The mice were random- ized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. Af- ter 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then re- peated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib. Results. All 19 control mice developed intra- abdominal 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. © 2008 Elsevier Inc. All rights reserved. Key Words: sunitinib; adhesions; VEGF; angiogenesis INTRODUCTION Intra-abdominal adhesions, or abnormal scarring in the abdomen, cause complications such as postopera- tive pain, bowel obstruction, and infertility. It is esti- mated that following an intra-abdominal procedure, adhesions may occur in up to 90% of patients, although not all adhesions have clinical sequelae [1]. Adhesions are the major cause of intestinal obstruction, which can lead to prolonged hospital stay, additional abdominal surgery, and even death. Adhesions also increase the morbidity of future intra-abdominal procedures be- cause they increase risk of blood loss and iatrogenic injury to bowel and other organs. In the United States, the annual cost of complications from adhesions is $1 billion and accounts for 846,000 inpatient care days per year [2]. Adhesion prevention would decrease morbid- ity and reduce health care costs across a broad range of medical disciplines [3]. Adhesions result from peritoneal trauma causing two adjacent deperitonealized surfaces to develop a fibrin matrix [4]. This fibrin matrix is initially domi- nated by the presence of polymononuclear lympho- cytes, in a setting of large fibrin strands with few fibroblasts. Tissue injury, causing vascular disruption and subsequent ischemia, prevents fibrinolysis. Mac- rophages become the predominant cell in the fibrin matrix. After 7 days, this matrix is replaced by fibro- blasts and collagen and vascular channels become lined with endothelial cells [5]. Ultimately, the adhe- sion becomes a fibrous band. Various agents have been used to inhibit intra- abdominal adhesions, including anti-inflammatory agents, fibrinolytics, and physical barriers [6, 7]. Several investigators also have implicated mediators of angiogenesis in the formation of adhesions [8, 9]. Vascular endothelial growth factor (VEGF), fibro- blast growth factor (FGF), and transforming growth factor beta (TGF) are up-regulated during adhesion formation [10 –12]. 1 To whom correspondence and reprint requests should be ad- dressed at Department of Surgery, Children’s Hospital Boston Har- vard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA 02115. E-mail: mark.puder@childrens.harvard.edu Journal of Surgical Research 149, 115–119 (2008) doi:10.1016/j.jss.2007.10.010 115 0022-4804/08 $34.00 © 2008 Elsevier Inc. All rights reserved.