Correlation of inhibition of colitis-associated dysplasia by celecoxib with degree of inflammation in the mouse model of DSS-induced colitis.
Authors: Renata A. Coudry, Harry S. Cooper, Monique Gary, Ronald A. Lubet, Wen-Chi L. Chang, Margie L. Clapper
Journal: Cancer Research (2004)

2368  While the ability of the cyclooxygenase 2 (COX-2) inhibitor celecoxib to inhibit the formation of sporadic and hereditary colon adenomas in humans has been well established, it remains unclear whether the chemopreventive activity of celecoxib is dependent on inflammation. The azoxymethane (AOM)/dextran-sulfate sodium (DSS) murine model of induced colitis represents a highly relevant system in which to assess both the anti-inflammatory and chemopreventive activity of agents against colitis-associated colorectal dysplasia. The goal of this study was to correlate tumor inhibition by celecoxib with degree of inflammation in colon tissues from Swiss Webster mice with AOM/DSS-induced colitis. Female Swiss Webster mice were injected i.p. with AOM (7.4 mg/kg) at 7 weeks of age. One week later, animals received either DSS and standard rodent chow (AOM/DSS, N = 29), no DSS and chow supplemented with 300 ppm celecoxib (AOM/Cel, N = 10), or DSS and chow supplemented with celecoxib (300 ppm) (AOM/DSS/Cel, N = 47). Celecoxib was administered from 8 weeks of age until the end of the experiment. DSS treatment began at 9 weeks of age and continued for three cycles. Each cycle consisted of 7 days of 4% DSS in the drinking water followed by 14 days of untreated water. For assessment of acute inflammation, 10 animals from each of the AOM/DSS and AOM/DSS/Cel groups were sacrificed 5 and 10 days following one cycle of DSS. Tumor incidence and chronic inflammation were assessed in the remaining animals at the time of sacrifice (18 weeks of age). Microscopically, no colon lesions were observed in animals receiving AOM/Cel. A 50% reduction in the multiplicity of total colonic dysplasias was observed among colitic animals administered celecoxib (mean ± SEM - AOM/DSS 16.0 ± 2.2, AOM/DSS/Cel 7.9 ± 1.5; p = 0.004). The incidence of dysplasias in the AOM/DSS/Cel group was decreased as compared to that of the AOM/DSS controls (72% and 100%, respectively). Celecoxib decreased the multiplicity of the dysplasia-associated lesion or mass (DALMs) (5.4-fold, AOM/DSS 6.0 ± 0.9, AOM/DSS/Cel 1.1 ± 0.5; p = 0.0002), while the flat lesions remained unaltered. The degree of inflammation in animals receiving DSS/AOM/Cel was more severe than that of control animals administered AOM/DSS alone (inflammatory scores 78.78 and 14.50, respectively, p = 0.00006). The acute inflammatory response observed in both the AOM/DSS and AOM/DSS/Cel groups 10 days following DSS administration was more severe than that observed 5 days after the same exposure. Animals receiving AOM/DSS/Cel exhibited a higher degree of inflammation and ulceration than those administered only AOM/DSS. The clinical significance of this elevation in inflammation remains to be determined. These data suggest that celecoxib prevents colitis-associated dysplasias in a manner that is independent of its anti-inflammatory activity. (Supported by N01 CN-05121).