Arachidonic acid metabolism through
cyclooxygenase (COX) pathways leads to the generation of biologically active
eicosanoids.
Eicosanoid expression levels vary during development and progression of gastrointestinal (GI)
malignancies. COX-2 is the major COX-
isoform responsible for G.I.
cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic
NSAID use reduces the risk of
cancer development, while both incidence and risk of death due to G.I.
cancers were significantly reduced by daily
aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic
Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective
COX-2 inhibitors. However, chronic use of selective
COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while
NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in
cancer development/progression.
PGE(2), which binds to both EP and
PPAR receptors, is the major
prostanoid implicated in the
carcinogenesis of G.I.
cancers. The role of TXA(2) in G.I.
cancers has also been examined, although further studies are required to uncover its role in
carcinogenesis. Other
prostanoids investigated include
PGD(2) and its metabolite
15d-PGJ2,
PGF(1α) and PGI(2). Targeting these
prostanoids in G.I.
cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-
tumor reactivity. A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I.
cancers. In this review, we will discuss the role of the COX-derived
prostanoids in G.I.
cancer development and progression. Targeting these downstream
prostanoids for
chemoprevention and/or treatment of G.I.
cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field.