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 diarrhea being a severe side effect in a small but significant minority of patients. 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 (dl-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 consequences of damage, such as changes in small intestinal crypt architecture and villus atrophy induced by the 10-mg/kg/day dose, were greater and of longer duration in BALB/c mice. A higher dose of RTX (100 mg/kg/day x 5) induced weight 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 changes to the colon were only observed in BALB/c mice. Pretreatment levels of plasma thymidine, deoxyuridine (approximately 1 microM), and folate (approximately40 ng/ml) were similar in both mouse strains. A single injection of radiolabeled 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

作者：S J, Clarke；D C, Farrugia；G W, Aherne；D M, Pritchard；J, Benstead；A L, Jackman

来源：Clinical cancer research : an official journal of the American Association for Cancer Research 2000 年 6卷 1期