Effects of dexamethasone or celecoxib on biliary toxicity after hepatic arterial infusion of 5-fluorodeoxyuridine in a canine model.
Previous work has shown that in humans the dose-limiting toxicity for fluorodeoxyuridine [2-fluoro-5'-deoxyuridine (FdUrd)] when administered by hepatic arterial infusion is biliary sclerosis. The current study was undertaken to attempt to modify this toxicity in a canine model that has been demonstrated to closely mimic the clinical situation. Unlike previous studies using this model, in which animals were sacrificed after extensive fibrosis had already occurred, the current experiments were designed so that observations of pathology were made at an earlier time, when the initial inflammatory injury underlying the fibrotic process was still taking place. Implantable pumps were used to deliver FdUrd into the hepatic artery of animals at a rate of 0.3 mg/kg/day in the presence or absence of 10 mg/week dexamethasone or 100 mg/day of celecoxib for 35 days, at which time the animals were beginning to show signs of toxicity. After evaluation for radiological evidence of biliary obstruction, the animals were sacrificed and portions of their livers were processed for examination of microscopic pathology and 2-bromo-5'deoxyuridine labeling index. Dexamethasone treatment protected the animals from biliary sclerosis determined radiologically, further validating this model as being representative of the response in humans. Similarly the Cox-2 inhibitor, celecoxib, appeared to provide protection against radiological changes of biliary stricture, although possibly to a lesser degree than the resultant from dexamethasone. In addition, FdUrd treatment caused elevation of the DNA 2-bromo-5'deoxyuridine labeling index above control levels in biliary epithelial cells. Dexamethasone and celecoxib each significantly attenuated the FdUrd-induced elevation of DNA labeling index in biliary epithelium. These findings demonstrate the usefulness of this canine model for studying the mechanisms of drug-induced biliary sclerosis and reinforce the hypothesis that blocking inflammation may retard the progression of injury that eventually leads to fibrosis. This study suggests that clinical testing of celecoxib as a preventive for hepatic arterial-FdUrd induced biliary damage could prove valuable.
Ensminger
William
W
Departments of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0504, USA. ensminge@umich.edu
Knol
James
J
DeRemer
Susan
S
Wilkinson
Erby
E
Walker
Suzette
S
Williams
David
D
Maybaum
Jonathan
J
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D000068579:Celecoxib; D003907:Dexamethasone / Q000627:therapeutic use*; D004285:Dogs; D005467:Floxuridine / Q000008:administration & dosage / Q000633:toxicity*; D005704:Gallbladder / Q000187:drug effects / Q000473:pathology*; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D008111:Liver Function Tests; D023421:Models, Animal; D011720:Pyrazoles; D013449:Sulfonamides / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D013449:Sulfonamides; D005467:Floxuridine; D003907:Dexamethasone; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase; D000068579:Celecoxib; D001663:Bilirubin