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 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% 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 times and drug doses. This led to the conclusion that, although there was a higher accumulation of RTX in BALB/c small intestinal epithelium (days 4-6), it may be an effect secondary to another undetermined cause of increased drug sensitivity. This model represents a vehicle by which the etiology and treatment of severe clinical toxicity induced by RTX may be evaluated.
Clarke
S J
SJ
The CRC Centre for Cancer Therapeutics at the Institute of Cancer Research, Surrey, United Kingdom.
Farrugia
D C
DC
Aherne
G W
GW
Pritchard
D M
DM
Benstead
J
J
Jackman
A L
AL
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D003857:Deoxyuridine / Q000097:blood; D003967:Diarrhea / Q000139:chemically induced*; D004064:Digestive System / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005492:Folic Acid / Q000097:blood; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D007420:Intestine, Large / Q000187:drug effects / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011799:Quinazolines / Q000633:toxicity*; D013876:Thiophenes / Q000633:toxicity*; D013936:Thymidine / Q000097:blood; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D015431:Weight Loss / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; D013876:Thiophenes; D005492:Folic Acid; D013940:Thymidylate Synthase; C068874:raltitrexed; D013936:Thymidine; D003857:Deoxyuridine