Current Pharmaceutical Design - Volume 8, Issue 12, 2002

Early experiments performed during 1980s and 1990s using carcinogen-induced rat intestinal tumor models demonstrated the inhibitory effects of non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal tumorigenesis. Furthermore, epidemiological studies and clinical trials for familial adenomatous polyposis (FAP) patients supported the possibility that NSAIDs can be used as chemopreventive agents. The major target molecules of NSAIDs are cyclooxygenases (COX), which catalyze the rate-limiting step of prostaglandin biosynthesis. Two isoenzymes of COX have been identified, COX-1 and COX-2. Whereas COX-1 is expressed constitutively in most tissues and responsible for tissue homeostasis, COX-2 is inducible and plays an important role in inflammation and intestinal tumorigenesis. A genetic study using compound mutant mice of COX-2- / -, and ApcD716 which is a model for human familial adenomatous polyposis (FAP), directly demonstrated that induction of COX-2 is critical for intestinal polyp formation. Numerous studies have also demonstrated that COX-2 selective inhibitors suppress intestinal polyp formation in Apc gene-mutant mice, and xenografted cancer cell growths. In addition, stimulation of angiogenesis is one of the major effects by COX-2 expression that is induced in the polyp stromal cells. On the other hand, another study indicated that COX-1 also plays an important role in the early stage of intestinal tumorigenesis. These data from animal model studies should be helpful in understanding the in vivo mechanism(s) of tumor suppression by NSAIDs or COX-2 inhibitors. Here, we review the animal studies that have been published as of August 2001, and reported to suppress intestinal tumor growths by NSAIDs or COX-2 inhibitors.

Carcinogenesis results from the long-term accumulation of genetic and epigenetic aberrations at the molecular level, which are under constant selection pressure for growth advantage. Recognizing that cancer is the result of this long-term, multi-step process provides opportunities for molecularly targeted cancer prevention. Ideally, chemopreventive agents should be low in toxicity, morbidity, and cost. Several individual agents and agent combinations are currently under evaluation in the U.S. National Cancer Institute's (NCI) chemoprevention agent development program. Nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase (COX) -1 and -2 are among the most promising classes of agents for targeted molecular prevention.

Comparisons are made between the specific COX-2 inhibitors, celecoxib and rofecoxib, and acetaminophen. The specific COX-2 inhibitors are a significant advance in therapy because their antiinflammatory, analgesic and antipyretic activities are associated with a high degree of gastrointestinal safety. Acetaminophen is often not considered to be a potent inhibitor of COX-2 but it is a potent inhibitor of prostaglandin synthesis in intact cells after stimulation by cytokines. Its weak activity on the pathway of prostanoid synthesis involving COX-1 is shown by its weak anti-platelet activity and good gastrointestinal safety. The specific COX-2 inhibitors and acetaminophen are analgesic after dental surgery, orthopedic surgery and in osteoarthritis although acetaminophen appears to be a slightly weaker agent. The apparent analgesic activity of both the COX-2 inhibitors and acetaminophen may, in part, be due to their anti-inflammatory properties. Both groups of drugs also decrease the urinary excretion of prostacyclin metabolites consistent with inhibition of the systemic and renal activity of the COX-2 system. During repeated dosage with the specific COX-2 inhibitors, the 24 hour urinary excretion of sodium is only inhibited for the first day of treatment while the excretion of sodium is still decreased over the first 3 hours after the individual doses. Therapeutic doses of the COX-2 inhibitors and overdoses of acetaminophen have been associated with the development of occasional cases of acute renal failure. Acetaminophen also may decrease the excretion of sodium and the reason for its greater renal safety at therapeutic doses is unclear. Myocardial infarction has also been attributed to the specific COX-2 inhibitors from metaanalysis of large scale clinical trials and examination of reports of adverse drug reactions although this is still a topic of considerable discussion. No such associations have been made with acetaminophen, possibly because it is a weak inhibitor of COX-1 in platelets.

It appears that selective Cox-2 inhibitors do not affect the gastro duodenal mucosa whilst having antiinflammatory and analgesic efficacy similar to non-selective NSAIDs. Two broad categories of drugs are Cox-2 selective: coxibs and a number of pre-existing NSAIDs retrospectively found to have selectivity. Cox-2 inhibitors cause less dyspepsia than NSAIDs. They spare gastrointestinal mucosal generation of prostaglandins (PGs) and PGdependant bicarbonate secretion. Coxibs cause no acute mucosal injury in endoscopic studies and serendipitous Cox-2 inhibitors generally cause less acute injury than non -selective NSAIDs or placebo. Both celecoxib and rofecoxib have been associated with a substantial reduction in endoscopic ulcers compared to NSAID comparators. In the VIGOR study all upper GI events were reduced from 4.5 per 100 patient years to 2.1 per 100 patient years with supra-therapeutic doses of rofecoxib compared with naproxen. In the CLASS study, over a period of 3 days to 6 months, incidence of ulcer complications was 0.76% with celecoxib and 1.45% for ibuprofen or diclofenac. The less substantial reduction in events in the CLASS study compared with the VIGOR may be due, at least in part, to the fact that 21% of the patients were also on low dose aspirin. However it is premature to say that the benefit of Cox-2 inhibitors is lost in patients taking aspirin. There is continuing debate on the role of Cox-2 inhibitors in patients who have other risk factors for complicated ulcer disease e.g. patients who are elderly, on aspirin or corticosteroids, have a previous ulcer or have H. pylori infection.