Prospects in NSAID-derived chemoprevention of colorectal cancer.
There is strong evidence for an important role for increased COX (cyclo-oxygenase)-2 expression and PG (prostaglandin) E2 production in colorectal tumorigenesis. PGE(2) acts through four E-prostanoid receptors (EP1-4). COX-2 has therefore become a target for the potential chemoprevention and therapy of colorectal cancer. However, any therapeutic/preventive strategy has the potential to have an impact on physiological processes and hence result in side effects. General COX (COX-1 and -2) inhibition by traditional NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin, although chemopreventive, has some side effects, as do some conventional COX-2-selective NSAIDs. As PGE2 is thought to be the major PG species responsible for promoting colorectal tumorigenesis, research is being directed to a number of protein targets downstream of COX-2 that might allow the selective inhibition of the tumour-promoting activities of PGE2, while minimizing the associated adverse events. The PGE synthases and E-prostanoid receptors (EP1-4) have therefore recently attracted considerable interest as potential novel targets for the prevention/therapy of colorectal cancer. Selective (and possibly combinatorial) inhibition of the synthesis and signalling of those PGs most highly associated with colorectal tumorigenesis may have some advantages over COX-2-selective inhibitors.
Chell
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Cancer Research UK, Colorectal Tumour Biology Group, Department of Pathology and Microbiology, Bristol University, Bristol BS8 1TD, UK.
Patsos
H A
HA
Qualtrough
D
D
H-Zadeh
A M
AM
Hicks
D J
DJ
Kaidi
A
A
Witherden
I R
IR
Williams
A C
AC
Paraskeva
C
C
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D015994:Incidence; D008954:Models, Biological; D018078:Receptors, Prostaglandin E / Q000502:physiology; D058306:Receptors, Prostaglandin E, EP1 Subtype
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D016861:Cyclooxygenase Inhibitors; C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype