Adverse effects of the antiangiogenic agent angiostatin on the healing of experimental colonic anastomoses.
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.
te Velde
Elisabeth A
EA
Department of Surgery, University Medical Center Utrecht, The Netherlands.
Voest
Emile E
EE
van Gorp
Joost M
JM
Verheem
Andrë
A
Hagendoorn
Jeroen
J
Gebbink
Martijn F
MF
Borel Rinkes
Inne H
IH
D000714:Anastomosis, Surgical; D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D003106:Colon / Q000473:pathology / Q000601:surgery*; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000009:adverse effects*; D010958:Plasminogen / Q000009:adverse effects*; D011897:Random Allocation; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries / Q000473:pathology
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen