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 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)].


CONCLUSIONS
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.
Kim
Sendia
S
Department of Surgery, Children's Hospital Boston Harvard Medical School, Boston, Massachusetts 02115, USA.
Lee
Sang
S
Greene
Arin K
AK
Arsenault
Danielle A
DA
Le
Hau
H
Meisel
Jonathan
J
Novak
Katherine
K
Flynn
Evelyn
E
Heymach
John V
JV
Puder
Mark
M
D034841:Abdominal Cavity; D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D004195:Disease Models, Animal; D007211:Indoles / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000008:administration & dosage*; D000077210:Sunitinib; D000267:Tissue Adhesions / Q000517:prevention & control*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib