Tu1243 Risk Factors for Small Bowel Mucosal Breaks in Chronic Low-Dose Aspirin Users: Data From a Prospective Multicenter Capsule Endoscopy Registry

AIM: Gastrointestinal (GI) mucositis is a frequent complication of antineoplastic chemotherapy. Clinical practice guidelines recommend anti-acid secretory drugs such as H2-blockers for the prevention and treatment of GI mucositis. Recently, some of the newer H2-blockers (so-called second-generation antagonists) have been frequently used in Japan. These agents have a unique component structurally differing from conventional H2-blockers. Although clinical practices have improved the management of symptoms in patients with chemotherapy-induced mucositis, their effects on mucosal defense mechanisms remain poorly understood. We studied the effects of 5-fluorouracil (5-FU) and cisplatin on mucin, one of the principal defense factors of the GI mucosa, and evaluated the efficacy of two different types of H2-blockers against the mucositis. METHODS: 5-FU was administered orally to rats at a dose of 50 mg/kg once daily for 5 days. Cisplatin (6 mg/kg) was administered intravenously to rats. Using anti-mucin monoclonal antibodies, the immunoreactivity in different areas of the rats' GI tracts was compared, as well as the mucin content. Immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) or Ki-67 was used to determine whether or not the effects of anticancer agents on cell proliferation contributed to the changes in mucin. To evaluate the efficacy of H2-blockers, either famotidine (3 mg/kg) or lafutidine (30 mg/ kg) was given orally once daily. Famotidine is a well-known conventional H2-blocker, and lafutidine is a second-generation H2-blocker group, characterized by possessing a sixmembered aromatic ring. RESULTS: 1) 5-FU and cisplatin caused significant alterations of the immunoreactivity and content of mucin in the rat GI mucosa, especially in the jejunum and ileum. 2) The number of PCNA-positive cells strikingly decreased at day 1 after 5-FU withdrawal, but by day 7 had increased approximately 2-fold, compared with the control. 3) Body-weight decreased in the animals given 5-FU, but lafutidine inhibited 5-FU-induced body-weight loss. 4) Lafutidine, but not famotidine, caused the protective effects against 5FUor cisplatin-inducedmucosal injury and alleviation of the decreasedmucin accumulation. 5) Cisplatin decreased the expression of Ki-67-positive cells in the animals treated with or without lafutidine. CONCLUSION: Our study had two major findings. First, anticancer agents alter the mucus barrier function in the intestinal mucosa. Second, lafutidine effectively prevents chemotherapy-inducedmucositis by activating intestinal mucus cells. These findings suggest that alteration of the mucus barrier function is a cause of chemotherapy-induced mucositis. The appropriately manipulation of mucus cell function in the intestine could lead to more effective prevention of the mucositis.