Anatomical site-specific response to DNA damage is related to later tumor development in the rat azoxymethane colon carcinogenesis model

There is now general agreement that the etiology of proximal and distal col on cancers may differ, thus prompting renewed interest in understanding ana tomical site-specific molecular mechanisms of tumor development. Using a 2 X 2 X 2 factorial design with male Sprague-Dawley rats (corn oil, fish oil; pectin, cellulose; plus or minus azoxymethane injection) we found a greate r than 2-fold difference (P < 0.001) in tumor incidence proximally versus d istally (prox/dist ratio: corn oil, 2.25; fish oil, 2.61). The purpose of t he present study was to determine if the higher degree of proximal versus d istal tumors in our model system could be accounted for by differences betw een these two sites in initial DNA damage, response to that damage or an ef fect of diet at one site but not the other. DNA damage was assessed by quan titative inmumohistochemistry of O-6-methylguanine adducts; repair by measu rement of O-6-methylguanine-DNA alkyltransferase and removal was determined by measurement of targeted apoptosis. Although overall initial DNA damage was similar at both sites, in the distal colon there was a greater expressi on of repair protein (P < 0.001) and a greater degree of targeted apoptosis (P < 0.0001). There was also a reduction in DNA damage in the distal colon of rats consuming fish oil. Together, these results suggest that the lower tumor incidence in the distal colon may be a result of the capacity to dea l with initial DNA damage by the distal colon, as compared with the proxima l colon. Therefore, the determination of site-specific mechanisms in tumor development is important because distinct strategies may be required to pro tect against cancer at different sites.