Sulindac and other
NSAIDs have been widely studied as potential chemopreventive agents for
colon cancer. Short-term studies have shown
adenomatous polyps to regress in patients with
familial adenomatous polyposis (FAP). In this study the effect of
sulindac on
cancer as an endpoint was evaluated in ApcMin mice, a preclinical model of FAP with an Apc mutation in
codon 850 that leads to gastrointestinal
adenomas and
carcinomas. Three groups of mice were studied all of which were fed AIN-76A diet: one group was fed AIN-76A diet alone, a second group received
sulindac 200 p.p.m. premixed in the diet and a third group received
sulindac 180 p.p.m. added in
drinking water. ApcMin mice were killed 9 weeks after feeding was initiated. Mice receiving
sulindac developed fewer
tumors in the intestine overall; the major decrease in
tumor development after
sulindac was seen in the small intestine regardless of route of administration. In the large intestine, however,
sulindac significantly increased the incidence, multiplicity and volume of
tumors in the colon of ApcMin mice, a regional response to
sulindac differing from previous reports. Quantitative measurements of apoptosis, Bax and
Bcl-xL protein expression in the ApcMin mice revealed the ratio of Bax/Bcl-xL expression and apoptosis increased in the small intestine but decreased in the cecum, consistent with the regional
tumorigenesis observed after
sulindac. These findings thus suggest involvement of Bax and apoptosis in
tumors developing after
sulindac treatment in this mouse model.