Balb/c mice as a preclinical model for raltitrexed-induced gastrointestinal toxicity

Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor used for the treatment of advanced colorectal cancer. RTX induces proliferating tissue toxicities that are largely confined to the intestine, with diarrhe a being a severe side effect in a small but significant minority of patient s. Similarly, weight loss and diarrhea were observed in BALB/c mice, and a maximum tolerated dose (MTD) was determined as approximately 5-10 mg/kg/day x 5 days. At an equivalent dose of 10 mg/kg/day x 5 days (d1-5), DBA2 mice lost considerably less weight, leading to a higher MTD (>500 mg/kg/day x 5 days), and there was no evidence of diarrhea, Histopathological consequenc es of damage, such as changes in small intestinal crypt architecture and vi llus atrophy induced by the 10-mg/kg/day dose, were greater and of longer d uration in BALB/c mice. A higher dose of RTX (100 mg/kg/day x 5) induced we ight loss and histopathological damage similar to that seen in BALB/c mice (10 mg/kg/day x 5) but was of later onset, nadir, and recovery. Small chang es to the colon were only observed in BALB/c mice. Pretreatment levels of p lasma thymidine, deoxyuridine (similar to 1 mu M), and folate (similar to 4 0 ng/ml) were similar in both mouse strains, A single injection of radiolab eled RTX (5 mg/kg/day) did not lead to any marked difference 24 h later in the total drug concentration and distribution of polyglutamates (comprising 70-80% of drug extracted) in the liver, kidney, and intestinal epithelium (large and small intestine) between the two mouse strains. Further studies used a RIA to measure RTX polyglutamate formation in tissues at various tim es and drug doses. This led to the conclusion that, although there was a hi gher accumulation of RTX in BALB/c small intestinal epithelium (days 4-6), it may be an effect secondary to another undetermined cause of increased dr ug sensitivity. This model represents a vehicle by which the etiology and t reatment of severe clinical toxicity induced by RTX may be evaluated.