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Adverse Effects of the Antiangiogenic Agent Angiostatin on the Healing of Experimental Colonic Anastomoses

From the Department of Surgery (EATV, AV, JH, IHBR) and the Laboratory of Medical Oncology (EEV, MFG), University Medical Center Utrecht, The Netherlands; and the Department of Pathology (JMVG), Diakonessen Hospital, Utrecht, The Netherlands.

Correspondence: Address correspondence and reprint requests to: I. H. M. Borel Rinkes, MD, PhD, Department of Surgery (G04.228), University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands; Fax: 31-30-2505459; E-mail: i.h.m.borelrinkes{at}chir.azu.nl

Background: Antiangiogenic cancer therapy is likely to be administered long term for sustained suppression of tumor outgrowth. Surgeons will encounter more patients undergoing such therapy. Therefore, it is essential to know the effects of antiangiogenic agents on physiological angiogenesis, as occurs during the healing of colonic anastomoses.

Methods: Angiostatin was generated from human plasma and administered continuously. In 38 mice, the right colon was anastomosed after transection: group 1 (n = 13), anastomotic healing under angiostatin treatment from surgery until death (day 7); group 2 (n = 13), phosphate-buffered saline controls. For healing on discontinuation of treatment, group 3 (n = 6) received angiostatin treatment preceding surgery during 4 days; group 4 (n = 6) included controls. On day 7, all mice were inspected for signs of anastomotic leakage. Bursting pressure measurements were performed to test anastomotic strength. Neovascularization was assessed semiquantitatively by immunohistochemistry.

Results: Mice treated with angiostatin postoperatively showed significantly more signs of leakage, more adhesions, and peritonitis. One mouse died on day 5. Five mice had paralytical ileus. The bursting pressure in group 1 was 135 ± 20 mm Hg, versus 175 ± 12 mm Hg in group 2 (mean ± SEM). Significantly fewer new vessels were found surrounding the anastomosis in the treated group (6.6 ± .9) versus controls (16 ± 1.6). All controls, as well as those animals treated with angiostatin only until surgery (group 3), displayed normal healing and showed no signs of peritonitis or ileus.

Conclusions: Angiostatin impairs anastomotic healing in mice. However, on discontinuation of antiangiogenic therapy, normal anastomotic healing is promptly restored.

Key Words: Angiogenesis • Angiostatin • Colonic anastomoses • Wound healing

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