Purpose: To evaluate and compare the influence of dietary elements on cancer progression, chemotherapy efficacy, and toxicity, particularly severe, late-onset diarrhea related to irinotecan (CPT-11) treatment. Experimental Design: We used laboratory rats fed a standardized basal diet,Ward colon tumor, and CPT-11therapy for the study of CPT-11^induced diarrhea. Dietary interventions were selected from nutrients already established to modify other forms of colitis and which have been hypothesized to mitigate chemotherapy-induced gastrointestinal injury (glutamine, n-3 fatty acids, prebiotic oligosaccharides). Animals adapted to test diets were treated with CPT-11at the maximum tolerated dose (125 mg/kg  3 days) and diarrhea was followed continuously for 1week.Results: The inclusion of n-3 fatty acids in the diet (5%, w/w of total fat) suppressed tumor growth and enhanced CPT-11's efficacy; this treatment did not affect the incidence or severity of diarrhea. By contrast, oral glutamine bolus (0.75 g/kg) administered prior to each CPT-11 treatment reduced the incidence of severe diarrhea (34.1 F 4.7% versus 53.8 F 4.2%, P < 0.005) and decreased the area under the curve of diarrhea score (16.5 F 1.0 versus 18.8 F 0.5, P < 0.05).Identical results were obtained with i.v. bolus glutamine administration. Glutamine treatment did not alter CPT-11's antitumor efficacy. The addition of prebiotic oligosaccharides to the diet (8%, w/w of diet) did not mitigate the severity of diarrhea, and it raised the activity of h-glucuronidase in cecal contents, a key bacterial enzyme mediating CPT-11^related intestinal toxicity. Conclusion: Our experiments suggest that glutamine and n-3 fatty acids might be potentially useful adjuncts to CPT-11treatment.