Prevention of Cancer in the Upper Gastrointestinal Tract with COX-Inhibition. Still an Option?

Epidemiological studies have shown that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction of gastrointestinal cancer risk. Since up-regulation of COX-2 has been reported in different stages of the esophageal and gastric carcinogenic sequence, the cyclooxygenase-2 selective inhibitors (COXIBs) were considered a good alternative to traditional NSAIDs since they cause less injury to the gastrointestinal mucosa. However, recent chemoprevention trial data reporting an increased risk of cardiovascular events have raised serious concerns on the safety of COXIBs in chemoprevention strategies. Moreover, low expression of COX-2 has been reported in a subset of gastrointestinal cancers due to COX-2 methylation, indicating that these patients could be less responsive to treatment by specific COX-2 inhibitors. Furthermore, the COX-1 isoform may have a potential role in the angiogenic process associated with esophageal adenocarcinoma, which suggests that inhibition of COX-1 may be another effective therapeutic target in upper gastrointestinal cancer. Finally, lipoxygenase-derived products may be increased following COX-inhibition due to shunting of the arachidonic acid metabolism. Specifically, the 5-LOX pathway seems to be relevant in gastrointestinal cancer development. Taken together, these data indicate that a re-evaluation of potential chemoprevention strategies for cancers of the upper gastrointestinal tract needs to be considered.