Influence of 5-fluorouracil on colonic healing and expression of transforming growth factor-beta 1.

ABSTRACT

BACKGROUND: Administration of chemotherapeutic agents in the immediate postoperative period may have beneficial effects by decreasing local cancer recurrence rates, but this must be weighed against possible impairment of wound healing. Since local expression of transforming growth factor-beta1 (TGF-beta1) is normally upreglated following creation of experimental colonic anastomoses, this study examines the effects of 5-fluorouracil (5-FU) on colonic healing and on the local expression of TGF-beta1. MATERIALS AND METHODS: Forty-eight male Sprague-Dawley rats underwent transection of the descending colon with primary anastomosis and were then randomly assigned to receive either intraperitoneal 5-FU (20 mg/kg/day) or saline (SAL). On Postoperative Days (PODs) 3, 5, and 7, bursting pressure (BP, mm Hg) and bursting energy (BE, mm Hg xs) were determined in situ. Anastomotic and nonoperated segments of colon were harvested and analyzed using the semiquantitative reverse transcriptase-polymerase chain reaction to determine the relative expression of TGF-beta1 normalized to that of a constitutive gene. RESULTS: Progressive increases in BP and BE were observed in both the 5-FU and the SAL groups, across the time course examined. Overall, these measures were decreased in the 5-FU groups compared to SAL, significantly so on PODs 5 and 7; BP, 127.8 +/- 7.6 vs 161.1 +/- 7.2 and 139.9 +/- 10.9 vs 186.0 +/- 8.6; BE, 1093.6 +/- 190.0 vs 2207.9 +/- 308.2, and 1518.5 +/- 326.5 vs 3279.3 +/- 225.7, respectively. Anastomotic TGF-beta1 expression also increased progressively in both groups over the postoperative time course. Expression in the 5-FU group, however, was significantly decreased compared to that in the SAL group on POD 3; 0.42 +/- 0.05 vs 0.84 +/- 0.04. Interestingly, this preceded the reduction in BP and BE in the 5-FU group on PODs 5 and 7. TGF-beta1 expression in nonoperated colonic segments did not change during the time points studied or in response to 5-FU administration. CONCLUSIONS: Wound healing following a colonic anastomosis is associated with local increases in TGF-beta1 expression, which in turn is diminished by the administration of 5-FU. If this deleterious effect on wound healing could be counteracted, then chemotherapy administration in the immediate postoperative period may become safer.