Editorial

 

Colorectal cancer and Coxibs

 

Colonoscopy is nowadays our most powerful tool for colorectal cancer (CRC) prevention (1). However, it has shortcomings such as its invasive nature and the high cost of screening policies based on this technique. As an alternative, the administration of agents able to prevent CRC from developing is under study. A number of epidemiological studies revealed a substantial decrease in CRC-related mortality in patients who were chronic users of aspirin or other non-selective NSAIDs (2,3). The NSAID sulindac reduces the number and size of adenomas in patients with familiar adenomatous polyposis (FAP), an inherited syndrome due to absence or inactivation of the APC tumor suppressor gene (4). Various NSAIDs have proven to be effective in the prevention of tumors using an experimental model -the MIN (multiple intestinal neoplasm) mouse, which bears a chemical mutation in the APC gene and develops multiple adenomas (5).

Non-selective NSAIDs inhibit the COX-2 isoform of the enzyme cyclo-oxygenase as well as the COX-1 isoform of this enzyme, which is expressed in a constitutive manner and plays an important role in the maintenance of physiologic mechanisms such as cytoprotection at the gastric mucosa. Selective COX-2 isoform inhibiting NSAIDs (which will be referred to as coxibs) may evade non-selective NSAID-induced adverse events, which are mainly gastrointestinal or renal in nature.

COX-2 is an enzyme inducible in various tissues by stimuli such as proinflammatory cytokines, growth factors, mitogens, and tumor promoters. Evidence exists that relates COX-2 expression to CRC. Patients with CRC exhibit an increased expression of COX-2 in their adenoma or adenocarcinoma tissue when compared to healthy colon tissue (6). Increased COX-2 levels and a normal COX-1 expression are seen both in APC^MIN mice adenomas (7) and in carcinogen-induced colon tumors in the rat (8). Tumors arising in the colon in an experimental ulcerative colitis model -interleukin-10 (-/-) mice- also overexpress COX-2 (9).

Of greater significance are intervention studies in APC ^∆179 knockout mice: both a COX-2 knockout mutation and the administration of a coxib reduce the development of intestinal adenomas in this experimental model (9). In a more recent study -also in APC ^∆179 mice- rofecoxib at doses equivalent to those used in humans showed a protective effect by inhibiting polyp development (10). A chemopreventive effect by celecoxib has been seen to reduce aberrant crypt foci and azoxymethane-induced colon cancer in rats (11).

NSAIDs seemingly exert their chemopreventive effect by mainly inhibiting COX-2, which would facilitate apoptosis in CRC cells. Intestinal epithelial cells modified for COX-2 overexpression are strongly resistant to apoptosis (12). Coxibs are capable of inducing apoptosis in cell lines from colon adenomas and cancer in humans (13). The mechanisms through which COX-2 inhibitors induce apoptosis are controversial. COX-2 inhibition decreases the synthesis of eicosanoids such as prostaglandins from arachidonic acid. Prostaglandins show a low proapoptotic effect, and hence coxib-induced PGE₂ decrease is seemingly not a major mechanism. Increased concentrations of arachidonic acid -not used in eicosanoid synthesis- activate sphingomyelinase, an enzyme that turns sphingomyelin into ceramide, in turn a potent apoptosis inductor (14). Arachidonic acid also disturbs mitochondrial permeability, which induces a release of cytochrome C and hence apoptosis (15). Coxib-induced, COX-independent proapoptotic mechanisms (such as an inhibition of proliferating factor NFκB or of growth promoting protein PPARδ) have also been described (16). Thus, NSAIDs seemingly exert their chemopreventive effect through mechanisms that are both COX-dependent and COX-independent.

Tumor angiogenesis is critical for tumor growth and spread. The chemopreventive effect of NSAIDs is partly exerted by inhibiting tumor angiogenesis. In COX-2-defficient mice a decrease in vascular endothelial growth factor, as well as a reduction in angiogenesis and tumor growth may be seen (17). COX-2 inhibitors also exert their antitumor effect through additional antiproliferative and antioxidative activity routes.

In this issue of Revista Española de Enfermedades Digestivas Noguera et al. (18) study the chemoprotective effect of rofecoxib and AAS in an experimental animal model. The particular attention paid to surface area and microscopic tumor percentage estimations is interesting, as these provide a better effect magnitude estimate than tumor counting alone. On the other hand, the use of rofecoxib in their study is to be highlighted, since it has been much less used than celecoxib in investigations despite its high specificity for COX-2. Consistently with this study and in a similar experimental model a coxib significantly reduced aberrant crypt foci in rats treated with 1-2 dimethylhydrazide (19).

In spite of all reported evidence there is still a long way to go for the establishment of valid strategies for CRC chemoprevention using coxibs except regarding celecoxib, which diminishes the number of polyps and induces polyp size regression in patients with FAP (in a blind controlled study), its use being accepted in this indication by the U.S. FDA (20). Many questions remain unanswered regarding sporadic CRC: the greatest experimental evidence for NSAIDs is based on the suppression of adenomas in FAP, experimental CRC models in animals are many and results depend upon the mouse strain used, and studies of cell lines from human colon cancer are hence thought to be of greater use. We need to wait for results from a number of ongoing phase-II and -III trials with AAS, sulindac, rofecoxib, celecoxib, and other NSAIDs in order to understand the potential toxic and beneficial effects of these drugs prior to their being indicated in CRC prevention. Studies are being performed using various tumor development stages: prevention of development, growth and invasion control, and response in already invasive cancer. Cost-benefit ratios should be assessed in these studies, and a recent investigation based on a Markov model found that the cost per life saved is higher for COX-2 chemoprevention versus colonoscopy screening (21). Lastly, the future of chemoprevention may lie in drug combinations (not only cyclo-oxygenase inhibitors but lipoxygenase inhibitors, conventional chemotherapeutic agents, etc.) synergically or additively exerting antitumor effects at various levels.

C. Taxonera and J. L. Mendoza

Unit of Inflammatory Bowel Disease. Service of Digestive Diseases.
Hospital Clínico San Carlos. Madrid. Spain

 

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