RaymondN. DuBois,2Jinyi Shao,MasahikoTsujii, HongmiaoSheng,andR. DanielBeauchamp

Colorectal cancer is the secondleading causeof death from cancer in the UnitedStates.Continuoususeof aspirinandothernonsteroidal anti inflammatorydrugs (NSAIDs) has been shownto reducethe risk of colorectal cancer in humansby 40—50%. Patientswith familial adenom atous polyposis who take NSAIDs, such as sulindac, undergo a regression of intestinaladenomas. Rodentsexposedto carcinogens that causecolon cancerhavea 50—60%reduction in thesizeand number ofcolonic tumors when treated continuously with NSAIDs. One common target for these drugs is prostaglandin endoperoxide synthase,also referred to as cy clooxygenase (COX). We and others have shown recently that COX-2 levelsare increaseddramaticallyin 85—90% of humancolorectaladeno carcinomasand in 40—50%of colonicadenomas. We preparedIntestinal epithelialcellsthat expressthe COX-2 genepermanentlyand foundthat theyhavealteredadhesionpropertiesandresistundergoIngapoptosis. We report here that these cells also have a 3-fold increase in the duration of G1, lower levelsof cyclin Dl protein, and a marked decreasein retino blastoma kinase activity associatedwith cyclin-dependentkinase 4. The delayin G1 transitmay relateto the resistanceof thesecellsto undergo programmed cell death, which could affect their tumorigenic potential.