Intestinal microflora and digestive toxicity of irinotecan in mice

Purpose: Delayed diarrhea is the most important side effect of irinotecan. The aim of this study was to investigate the role of intestinal microflora on the induction of systemic and intestinal toxicity and diarrhea, studying germ-free and holoxenic mice i.p. injected with irinotecan. Experimental Design: To evaluate the lethal dose, starting with 100 mg/kg/4 d, we treated the holoxenic mice with 100, 80, and 60 mg/kg/4 d and germ-free mice with 60, 80,100, and 150 mg/ kg/4 d. We recorded the percentage of dead animals, diarrhea, and the epithelial damage to the jejunum, ileum, cecum, and colon at optical and scanning electron microscopy. Results: Germ-free mice were more resistant to irinotecan than the holoxenic group. The lethal dose was between 60 and 80 mg of irinotecan for holoxenic mice and >= 150 mg for the germ-free. The intestinal damage score was higher in holoxenic than germ-free mice at 100 mg and equally diffuse in the small and large bowel. The damage in germ-free mice was less severe (8 of 40 samples) prevailing in the ileum. The differences were significant for all sites (jejunum, P < 0.001; ileum, P = 0.012; cecum, P = 0.001; colon, P < 0.001). No damage was found in germ-free mice at 60 mg. Diarrhea was present in all 100 and 80 mg holoxenic mice and in 19 of 20 cases at 60 mg whereas it was absent in 60 mg or sporadic in 80 and 100 mg germ-free mice. Conclusions: The intestinal microflora plays a key role in the intestinal toxicity of irinotecan.