Gastrointestinal
Effect of IGF-I on Healing of Colonic Anastomoses in Rats Under 5-FU Treatment

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Background

The aim of this experimental study was to investigate whether insulin-like growth factor I (IGF-I) can protect the colonic healing from the adverse effects of intraperitoneal administration of 5-fluorouracil (5-FU).

Materials and methods

Eighty male Wistar rats were randomized into four groups of 20 rats each. Immediately after anastomoses were performed, rats in the control group were injected with 1 mL/100 gr of intraperitoneal saline solution, which was repeated daily until killed. Rats in the 5-FU and IGF-I +5-FU groups received 5-FU in a dose of 20 mg/kg body weight intraperitoneally, from the day of operation until killed. Rats in the IGF-I and IGF-I +5-FU groups received IGF-I in a dose of 2 mg/kg body weight intraperitoneally, immediately after the colonic anastomosis was performed and on 2nd, 4th, and 6th postoperative day. Rats were sacrificed on the 7th postoperative day.

Results

The dehiscence rate in the 5-FU group was 30% and it was significantly higher compared with the control and the IGF-I group (P = 0.020 for both comparisons). However, in the IGF-I +5-FU group, the dehiscence rate decreased to 10%. The administration of IGF-I resulted in a significant rise of bursting pressure in the IGF-I +5-FU group compared with the 5-FU group (P < 0.001). There was no statistical difference in bursting pressure between the IGF-I +5-FU and control groups (P = 1.000). The hydroxyproline levels were higher in the IGF-I and the IGF-I +5-FU groups as a result of the stimulating act of IGF-I.

Conclusion

IGF-I, when given intraperitoneally, seems to mediate some of the adverse effects of 5-FU on the colonic healing in rats.

Introduction

Leaking colonic anastomoses are a major problem in colorectal surgery. They are responsible for numerous complications and as many as one-third of the postoperative deaths associated with colonic operations [1, 2, 3]. Clinically observed failure of anastomotic healing has been observed to increase hospital stay 2-fold and perioperative mortality 3-fold [4, 5, 6].

Moreover, it is well known that after colon resection for colonic cancer, the immediate postoperative intraperitoneal administration of 5-fluorouracil (5-FU) destroys the cancer cells that have been disseminated during operation and inhibits the micrometastases, which can later lead to recurrence [7, 8, 9, 10, 11]. However, previous experimental studies carried out in our laboratory, as well as those of other investigators, have shown that the immediate postoperative intraperitoneal administration of 5-FU has an adverse effect on the healing of colonic anastomoses [12, 13, 14, 15, 16, 17, 18].

The effects of growth hormone and growth factors on healing of bowel anastomoses are currently being evaluated in an attempt to identify agents that promote and improve the anastomotic healing progress. Insulin-like growth factor I (IGF-I) is a peptide hormone structurally related to insulin which has pleotrophic effects on cell growth and metabolism. This growth factor is synthesized by hepatocytes in response to growth hormone and has been shown to stimulate amino acid uptake, amino acid incorporation into liver and muscle proteins, and to decrease muscle protein degradation [19, 20].

The aim of this experimental study was to investigate whether the administration of IGF-I can protect the colonic healing from the adverse effects of immediate postoperative intraperitoneal administration of 5-FU, when injected intraperitoneally after colon resection.

Section snippets

Materials and Methods

Eighty male Wistar rats, weighing between 200 and 300 g, were used. Animals were housed individually and had unrestricted access to the standard laboratory diet and water pre- and postoperatively. The rats were weighed on the day of operation and when the animals were killed, and changes in weight were noted. Surgery was performed through a 3-cm midline incision under intraperitoneal thiopental anesthesia (40 mg/kg body weight). After resection of a 1-cm segment of the middle transverse colon,

Results

Mean body weight changed significantly in all groups (P < 0.05), except in the IGF-I +5-FU group (P = 0.181). The mean postoperative decrease of body weight was significantly higher in 5-FU group compared with the control group (P = 0.010, Fig. 1), the IGF-I (P < 0.001) and the IGF-I +5-FU group (P = 0.009). Also, the mean postoperative increase of body weight was significantly higher the IGF-I group compared with the control (P = 0.003) and the IGF-I +5-FU group (P = 0.006). There was no

Discussion

Dehiscence is much more common in colonic anastomoses compared with those in the small bowel [24]. Even though there have been significant advances in surgical techniques, leakage of the colonic anastomoses continues to be a significant cause of postoperative morbidity and mortality in patients undergoing colonic surgery [3, 5, 6]. The reported incidence of anastomotic leakage ranges from as low as 4% to as high as 30% [3, 4, 5, 6]. A variety of growth factors have been shown to enhance wound

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