Effect of bevacizumab on postoperative adhesion formation in a rat uterine horn adhesion model and the correlation with vascular endothelial growth factor and Ki-67 immunopositivity

We investigated whether adhesion formation is prevented by the inhibition of angiogenesis in a rat uterine hornadhesion model. A single-dose of bevacizumab was effectivein preventing postoperativeintraperitoneal adhesionformation among 30 Wistar albino rats that underwent serosal injury by use of a standard technique afterlaparotomy with intraperitoneal bevacizumab. (Fertil Steril 2011;95:2638–41. 2011 by American Society forReproductive Medicine.)Key Words: Bevacizumab, experimental study, peritoneal adhesion, vascular endothelial growth factorThedevelopmentofperitonealadhesionsafterabdominalandpel-vicsurgeryleadstoclinicalproblems,includingintestinalobstruc-tion, chronic abdominal pain, infertility, and chronic pelvic pain(1). Studies have reported postoperative intra-abdominal adhesionsin 50% to 95% of women who undergo gynecologic surgery (2).The injuries have been attributed to various causes, including me-chanicaltrauma,ischemiaatsuturesites,ischemiacausedbyelec-trocautery, foreign bodies, tissue desiccation, and infection (3).Postoperative inflammation develops after tissue injury. Whenthe fibrin gel structure that is produced during wound healing isnot broken down by fibrinolytic activity, permanent fibrous tissueforms and adhesion develops (4). Vascular endothelial growthfactor (VEGF) expression increases during wound healing andangiogenesis, and is necessary for adhesion formation (5, 6).Adhesion formation may, therefore, be prevented by inhibitingangiogenic activity (7–9).Bevacizumab (Avastin; Genentech/Roche, San Francisco, CA)is a full-length recombinant humanized monoclonal antibody thatinhibits VEGF (10–12). Given the apparent close associationbetween VEGF and inflammation, bevacizumab inhibition ofVEGF might influence or possibly inhibit the inflammation andwound healing involved in postoperative adhesion formation.The antigen Ki-67 is a nuclear protein used as a marker of cellproliferation (13). Recent work has shown good correlation be-tweentheexpressionofKi-67andthenumberofmitoticcells(14).Our study was approved by the institutional review board of theAnkara Educating and Research Hospital in Ankara, Turkey, andwas performed at the hospital’s Animal Research Center(IP: 0378, tarih: 14.07.2010). The institutional review board’sguidelines for animal care and use were followed. Thirty mature,nonpregnant female Wistar albino rats (aged 10 to 12 weeks)were used as a model for experimental induction of postoperativeintra-abdominal and uterine horn adhesions. The rats were ran-domly divided into three groups before surgery, with 10 animalsin each group.The animals were anesthetized using ketamine hydrochloride(40 mg/kg intramuscularly) and xylazine (2 mg/kg intramuscu-larly). The adhesion model of Basbug et al. (15) was followed.A syringe of 1 mL of Ringer’s lactate (RL) containing 5 IU and7.5IUofbevacizumabwasinjectedintraperitoneallyintotheuter-inehorns(0.5mLintoeachuterinehorn)ofgroups1and2,respec-tively. Only 1 mL of RL was injected intraperitoneally into theuterine horn of the control group (16).The midline incision was closed within 10 minutes of the com-pletion of the procedure. One rat in the control group died duringthe study. After a 3-week recovery period, the rats were killed,and the adhesion areas were evaluated andgraded. Tissue samplesweretakenfromallserosalsurfaceswhereadhesionhaddeveloped.Ozlem Moraloglu, M.D.€