Suppression of intestinal polyps in Msh2-deficient and non-Msh2-deficient multiple intestinal neoplasia mice by a specific cyclooxygenase-2 inhibitorand by a dual cyclooxygenase-1/2 inhibitor

Epidemiological studies suggest that nonsteroidal anti-inflammatory agents decrease the risk of colorectal cancer. This is believed to be mediated, at least in part, by inhibition of cyclooxygenase (COX) activity. There are t wo COX isoenzymes, namely the constitutively expressed COX-1 and the induci ble COX-2. COX-2 is overexpressed in adenomas and colorectal cancers, and C OX-2-specific inhibitors have been shown to inhibit intestinal polyps in Ap c(Delta 716) mice more effectively than dual COX-1/COX-2 inhibitors such as sulindac. Various Ape knockout mice, including the multiple intestinal neo plasia (Min) mouse and the Apc(Delta 716) Mouse, are limited by their lack of large numbers of colonic adenomas and aberrant crypt foci, the putative precursors of large-bowel polyps and cancers. Our DNA mismatch-repair-defic ient Min mouse model (Apc+/-Msh2-/-) has genetic features of both familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, and mo st importantly, rapidly develops numerous small- and large-bowel adenomas, as well as colonic aberrant crypt foci. The purpose of this study was to de termine the effects of COX inhibitors on intestinal adenomas and colonic ab errant crypt foci in this accelerated polyposis, mismatch-repair-de ic ent in mouse model, in addition to a standard Min mouse model. Weanling Apc+/-M sh2-/- and Min mice were fed diets containing no drug, sulindac, or a speci fic COX-2 inhibitor (MF-tricyclic). Apc+/-Msh2-/- and Min mice were sacrifi ced after 4 weeks and 5 months on diet, respectively. Apc+/-Msh2-/- mice tr eated with MF-tricyclic had significantly fewer small-bowel polyps (mean +/ - SD, 178 +/- 29) compared with mice on sulindac (278 +/- 80), or control d iet (341 +/- 43; P < 0.001). There was no difference in numbers of large-bo wel polyps or aberrant crypt foci in mice in the three groups. MF-tricyclic was also effective in reducing both small- and large-bowel polyps in Min m ice. Western analysis demonstrated COX-2 expression in both large- and smal l-bowel polyps from mice of both genotypes. This study demonstrates that a specific COX-2 inhibitor is effective in preventing small-bowel polyps in m ismatch-repair-deficient Min mice and both small- and large-bowel polyps in standard Min mice. Therefore, specific COX-2 inhibitors may be useful as c hemopreventive and therapeutic agents in humans at risk for colorectal neop lasia.