Evaluation of 5-aminosalicylic acid (5-ASA) for cancer chemoprevention: lack of efficacy against nascent adenomatous polyps in the Apc(Min) mouse.
Recent experimental and epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the prevention of colorectal cancer. However, the toxicity associated with the long-term use of most classical NSAIDs has limited their usefulness for the purpose of cancer chemoprevention. Inflammatory bowel disease (IBD) patients, in particular, are sensitive to the adverse side effects of NSAIDs, and these patients also have an increased risk for the development of intestinal cancer. 5-Aminosalicylic acid (5-ASA) is an anti-inflammatory drug commonly used in the treatment of IBD and may provide protection against the development of colorectal cancer in these patients. To directly evaluate the ability of 5-ASA to suppress intestinal tumors, we studied several formulations of 5-ASA (free acid, sulfasalazine, and Pentasa) at multiple oral dosage levels [500, 2400, 4800, and 9600 parts/million (ppm)] in the adenomatous polyposis coli (Apc) mouse model of multiple intestinal neoplasia (Min). Although the ApcMin mouse is not a model of colitis-associated neoplasia, it is, nonetheless, a useful model for assessing the ability of anti-inflammatory agents to prevent tumor formation in a genetically preinitiated population of cells. We used a study design in which drug was provided ad libitum through the diet beginning at the time of weaning (28 days of age) until 100 days of age. We included 200 ppm of piroxicam and 160 ppm of sulindac as positive controls, and the negative control was AIN-93G diet alone. Treatment with either piroxicam or sulindac produced statistically significant reductions in intestinal tumor multiplicity (95% and 83% reductions in tumor number, respectively; P < 0.001 versus controls). By contrast, none of the 5-ASA drug formulations or dosage levels produced consistent dose-progressive changes in polyp number, distribution, or size, despite high luminal and serum concentrations of 5-ASA and its primary metabolite N-acetyl-5-ASA. Thus, 5-ASA does not seem to possess direct chemosuppressive activity against the development of nascent intestinal adenomas in the ApcMin mouse. However, because intestinal tumor development in the ApcMin mouse is driven by a germline mutation in the Apc gene rather than by chronic inflammation, we caution that these findings do not definitively exclude the possibility that 5-ASA may exert a chemopreventive effect in human IBD patients.
Ritland
S R
SR
Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Arizona 85259, USA.
Leighton
J A
JA
Hirsch
R E
RE
Morrow
J D
JD
Weaver
A L
AL
Gendler
S J
SJ
D018256:Adenomatous Polyps / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018890:Chemoprevention; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D005470:Fluorometry; D007414:Intestinal Neoplasms / Q000517:prevention & control*; D019804:Mesalamine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010894:Piroxicam / Q000494:pharmacology; D012460:Sulfasalazine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D004338:Drug Combinations; D010894:Piroxicam; D013467:Sulindac; D012460:Sulfasalazine; D019804:Mesalamine