5-aminosalicylic acid inhibits colitis-associated colorectal dysplasias in the mouse model of azoxymethane/dextran sulfate sodium-induced colitis.
BACKGROUND
The impact of the antiinflammatory agent 5-aminosalicylic acid (5-ASA) on the risk for colitis-associated colorectal cancer remains controversial. The chemopreventive activity of 5-ASA was evaluated in the Swiss Webster model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated neoplasia.


METHODS
Mice were injected with AOM (7.4 mg/kg i.p.) and randomized to receive either vehicle or 5-ASA (75, 150, and 225 mg/kg) for the remainder of the study. DSS treatment began at 9 weeks of age and continued for 3 cycles. At the time of sacrifice (18 weeks of age), the entire colon and rectum were processed for histopathologic examination.


RESULTS
An inverse trend was observed between dose and multiplicity of colonic dysplasias in all drug-treated groups (P = 0.03), with animals receiving 75 mg/kg 5-ASA exhibiting 56% of the number of dysplasias of the AOM/DSS controls (mean +/- SEM: 7.6 +/- 1.4 and 13.6 +/- 2.7, respectively). Administration of 75 mg/kg 5-ASA decreased both the mean multiplicity of flat dysplasias (1.8 +/- 0.4 for drug-treated versus 5.6 +/- 1.2 for AOM/DSS control) and the burden of polypoid dysplasias (tumor burden: 6.7 +/- 2.7 for drug-treated versus 14.9 +/- 3.9 units for AOM/DSS controls) significantly (P = 0.002 and 0.04, respectively). Inflammation was least severe in the 75 mg/kg group, which exhibited the fewest number of colorectal tumors.


CONCLUSIONS
These data suggest that low-dose 5-ASA may be efficacious in preventing colitis-associated dysplasias and provide strong support for optimizing this therapy for the prevention of colonic neoplasms in patients with ulcerative colitis.
Clapper
Margie L
ML
Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. margie.clapper@fccc.edu
Gary
Monique A
MA
Coudry
Renata A
RA
Litwin
Samuel
S
Chang
Wen-Chi L
WC
Devarajan
Karthik
K
Lubet
Ronald A
RA
Cooper
Harry S
HS
D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D003092:Colitis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D015179:Colorectal Neoplasms / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000302:isolation & purification; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019804:Mesalamine / Q000494:pharmacology*; D051379:Mice; D011897:Random Allocation
D019804:Mesalamine; D016264:Dextran Sulfate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D001397:Azoxymethane