AbstractFeeding rats a semipurified diet containing casein as a protein source results in severe gastrointestinal (GI) toxicity when the chemotherapeutic drug methotrexate (MTX) is given. However, when soy concentrate protein is used in place of casein, rats are completely protected from toxicity. The purpose of this study was to determine whether soy protein was also protective against two other chemotherapeutic agents, 5‐fluorouracil (5‐FU) and cyclophosphamide (CY), which are routinely used in a multidrug regimen with MTX in a clinical setting. Three diets were tested; they consisted of a control complex diet (rat chow) and two semipurified diets containing casein or soy concentrate as the protein fraction given to non‐tumor‐bearing rats receiving a single injection of 5‐FU or CY at three different levels (Experiment I: 5‐FU: 100, 260, and 420 mg/kg; Experiment II: CY: 120, 180, and 240 mg/kg). Each diet was fed to seven rats for seven days before injection and seven days after injection. Food intake decreased at Day 3 in all groups receiving 5‐FU (35–90% reduction from preinjection level), with the greatest decrease associated with the group receiving the highest drug level. Animals fed the control diet ate consistently less than animals fed the other two diets regardless of the drug level. Intake was not significantly different between the casein and soy concentrate groups at any drug level. Animals gained weight on the low‐dose treatment regardless of diets. At 260 and 420 mg/kg 5‐FU, all diet groups lost weight, but the difference was significant only between the control and the two other diets (p<0.05). Diarrhea was absent in the casein diet groups, regardless of drug dose, and present in the other diet groups. Food intake decreased on Day 1 for all groups receiving CY. At any dose, the control diet group maintained a greater intake on Day 1 than the other two diet groups. The difference in intake was significant between the control and the two other diet groups at low dose, between the control and the casein diet groups at 180 mg/kg, and between the control and the soy concentrate diet groups at high dose (p<0.05). All animals lost weight regardless of diet and drug dose. A third experiment was conducted to evaluate histological damage to the intestine when these three diets were fed to animals injected with 420 mg/kg 5‐FU. This experiment was conducted in the same manner as Experiment I, except animals were sacrificed on Day 3 after injection to remove jejunal samples. Crypt necrosis and debris occurred in all groups receiving 5‐FU. Valus height was decreased in all groups, with a less reduction in the casein diet group, and the difference was significant with the 2 other diet groups (p<0.05). Results indicate that none of the three diets promoted significant protection against 5‐FU‐or CY‐induced toxicity.