Colon cancer is second leading cause of
cancer-related deaths in Western countries. Diet and smoking, which contain aromatic and heterocyclic
amines, are major risk factors for
colon cancer.
Colorectal cancers have a natural history of long latency and therefore provide ample opportunities for effective
chemoprevention.
3,2'-Dimethyl-4-aminobiphenyl (DMABP) is an experimental aromatic
amine that causes
cancer in rat colon and serves as an experimental model for arylamine and heterocyclic
amine mutagens derived from diet and smoking. In this study, we investigated the effects of
celecoxib, a selective
cyclooxygenase-2 (COX-2) inhibitor on DMABP-induced
DNA adduct formation in rat liver and colon. Male F-344 rats (5-week old) were provided free access to modified AIN-76A rat chow containing 0 (control), 500, 1000, or 1500 ppm
celecoxib. Two weeks later, the rats received a
subcutaneous injection of 100mg/kg DMABP in
peanut oil. Two days after DMABP treatment, the rats were killed and DMABP-derived adducts were analyzed in colon and liver
DNA by
butanol extraction-mediated (32)P-postlabeling. Two major
DNA adducts, identified as dG-C8-DMABP and dG-N(2)-DMABP, were detected in liver and colon of rats treated with DMABP. These
DNA adducts were diminished approximately 35-40% with 500 ppm and 65-70% with 1,000 ppm
celecoxib. In the colon, no further decline in
DNA adducts was observed at 1500 ppm. The same DMABP-
DNA adducts also were detected in the liver and were also diminished by
celecoxib treatment. The reduction in DMABP-
DNA adduct levels in
celecoxib-treated animals provides further support for
celecoxib as a chemopreventive agent for
colorectal cancer.