Assessment of the intestinal permeability after a gastrectomy and the oral administration of anticancer drugs in rats: Nitric oxide release in response to gut injury

• Published in: Surgery 2002, Vol.131 (1), p.S92-S97
• Main Authors: Nagahama, Shunichi, Korenaga, Daisuke, Honda, Masayuki, Inutsuka, Sadaaki, Sugimachi, Keizo
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Dextrans - pharmacokinetics; Fluorescein-5-isothiocyanate - analogs & derivatives; Fluorescein-5-isothiocyanate - pharmacokinetics; Gastrectomy; Gastroenterology. Liver. Pancreas. Abdomen; Intestinal Absorption - drug effects; Intestinal Mucosa - injuries; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Male; Medical sciences; Nitric Oxide - blood; Rats; Rats, Sprague-Dawley; Stomach, duodenum, intestine, rectum, anus; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Stress, Physiological - metabolism; Stress, Physiological - pathology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the digestive system; Tegafur - pharmacology; Tumors; Uracil - pharmacology
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1067/msy.2002.119310

Although intestinal permeability is known to increase in conditions of stress (such as endotoxemia, septic shock, and ischemia-reperfusion), the mechanism of gut barrier dysfunction during chemotherapy remains to be elucidated. We designed an experiment in which a gastrectomy and anticancer drugs were administered to rats to assess the extent of damage or an increase in permeability of the intestinal mucosa. The rats were separated into the following groups: group A, no operation without an anticancer drug (control rats); group B, a gastric operation; group C, chemotherapy; and group D, a gastric operation followed by chemotherapy. Six rats were placed in each group. The groups that were given the anticancer drug received 45 mg/kg for 7 and 14 days, respectively. Intestinal permeability was determined by an injection of fluorescein isothiocyanate-dextran (FITC-D) intravenously and the measurement of the amount of FITC-D leakage in the luminal lavage. The plasma nitric oxide concentrations were measured spectrophotometrically by the Griess reaction. The cell surface expression of CD44 in the rat small intestine was evaluated immunohistochemically. During the entire experimental period, the FITC-D levels in the anticancer drug that was administrated to rats (groups C and D) were significantly higher than the levels in groups A and B (P < .001). Similarly, the plasma nitric oxide concentration increased significantly not only in groups C and D but also in group B (P < .05). A linear regression analysis revealed a positive significant correlation between FITC-D and the plasma nitric oxide levels (r = 0.617; P < .001). When the anticancer drug was administered, the intestine histologically revealed so-called mucosal atrophy and a decreased expression of CD44 within the intestinal mucosa. The administration of anticancer drugs impairs the gut barrier function, possibly by reducing the cell-cell and cell-matrix interactions. This may contribute to the development of hyperpermeability that is induced by an overexpression of nitric oxide.