The National Cancer Institute estimates that over 150,000 new cases of colorectal cancer and 52,000 deaths will be reported in the United States in 2007, making it second to lung cancer in total deaths.1
Americans possess a one in eighteen lifetime risk of developing colorectal cancer.2
Five-year relative survival rates range from 9% for distally diagnosed CRC to 90% for localized CRC. This disparity drives public health efforts to increase early detection and to slow or prevent altogether the progression of colorectal carcinogenesis.
Inflammation is a known risk factor for colorectal cancer. Several inflammatory conditions predispose to colorectal cancer, such as ulcerative colitis3
and Crohn’s disease.4
Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, represent a potential means of decreasing inflammation in the colonic epithelium.5
There are two main subtypes of NSAIDs: nonselective and selective COX2 inhibitors. The COX2-selective drugs (coxibs) exhibit higher affinity for and therefore target the COX2 enzyme.5
NSAIDs have been successful in preventing colorectal neoplasia in high-risk populations, such as subjects with a prior diagnosis of CRC or colorectal adenoma. Recently, two randomized placebo-controlled trials (RCTs) showed aspirin to significantly reduce the risk of recurrent adenomatous polyps by 19% to 35%.6, 7
Two other RCTs showed a 33%-36% risk reduction for celecoxib and even greater reduction in the risk of advanced adenoma.8, 9
The magnitude of risk reduction from rofecoxib versus placebo was recently shown to be comparable to that of aspirin.10
However, rofecoxib is no longer commercially available due to concerns of cardiovascular toxicity.11-13
Gastrointestinal and cardiovascular toxicity from aspirin/NSAID and coxibs, respectively, have spurred research to identify genetic variations which might alter the risk-benefit trade-off of these drugs in clinically meaningful ways and allow tailoring of chemoprevention.5
NSAIDs inhibit the cyclooxygenase (COX) activity of COX enzymes (i.e., prostaglandin H synthases), which in turn decreases prostaglandin production.14 COX1
is constitutively expressed in many tissues and is linked to homeostatic functions, whereas COX2
is an inducible form involved in inflammatory and proliferative responses.15-17
Genetic variability in downstream enzymes in the prostaglandin or lipoxygenase pathway (which competes with the COX enzymes to metabolize arachidonic acid), may also play a role in colorectal cancer, because these may affect the overall availability and balance of inflammatory mediators in the body.
Recent interest has emerged in the role of ornithine decarboxylase (ODC) and NSAIDs in colorectal cancer. NSAIDs, including celecoxib, inhibit this enzyme.18
Whereas COX1 and COX2 mediate prostaglandin synthesis, ODC catalyzes the synthesis of polyamines, which are associated with carcinogenesis (increased cell division, up-regulation of genes involved in metastasis and tumor invasion, and down-regulation of apoptosis).19, 20
Increased intracellular polyamine concentrations are positively associated with risk of cancer19, 21
, including sporadic colorectal cancer22
, and are negatively associated with apoptotic activity and cell death.23
ODC is overexpressed in cancerous versus normal colon epithelium.19, 24-27
Thus, the chemopreventive properties of NSAIDs in colorectal cancer may stem in part from their activity on ODC-mediated polyamine synthesis.28-30
NSAIDs are primarily metabolized by two major classes of enzymes: the cytochrome P450 2C enzymes (CYP2C) and the UDP-glucuronosyltransferases (UGTs). The major metabolizers of NSAIDs are CYP2C931
, although other UGTs and CYPs may play minor roles. Both of these enzymes have common polymorphisms that are associated with less efficient drug metabolism. In CYP2C9
, two polymorphisms, Arg144Cys (also referred to as *2) and Ile359Leu (also referred to as *3) show markedly decreased warfarin metabolism compared to wild-type.33, 34
Similarly, there are two known variant alleles in UGT1A6
that have been associated with decreased enzyme activity; the first is characterized by amino-acid changes at amino acids 181 and 184 (Thr181Ala + Arg184Ser) and the second by Arg184Ser alone.35, 36
These known functional genetic polymorphisms may interact with NSAID use to affect risk of colorectal neoplasia.
Polymorphisms in COX1, COX2
, and ODC
appear to alter the risk of colorectal neoplasia.5, 37-43
Since genetic polymorphisms and NSAID use can each modify the risk for colorectal neoplasia, pharmacogenetic studies may help to identify the population for whom NSAIDs have the most favorable risk-benefit profile for colorectal adenoma prevention. Here, we review the potential interactions between NSAIDs and genetic polymorphisms in defining risk for colorectal neoplasia and discuss future considerations for research.