Cyclooxygenase-2 and Colorectal Cancer
By Robert D. Lewis and David A. Corral, MD
In the early 1900s, it was discovered that two isoforms of the enzyme cyclooxygenase (COX) take part in the biologic conversion of arachidonic acid to prostaglandin. This important discovery eventually led to further studies that demonstrated a clear physiologic difference between COX-1 and COX-2, with different implications concerning the effects of COX-1 and COX-2 in different organs, tissues, and disease states.1
Research into COX-1 and COX-2 expression was performed using monoclonal antibodies and messenger RNA hybridization. It was discovered that COX-1 is constitutively expressed in all tissues producing prostaglandins which regulate several key physiologic functions. In stark contrast, COX-2 expression is almost undetectable in normal cells. However, during inflammation, COX-2 expression is increased in inflammatory cells (such as macrophages, etc.).3 These important results would seem to support the theory that COX-1 performs homeostatic functions in tissues, whereas COX-2 is generally an inducible enzyme that is responsive to inflammatory stimuli. The upshot of this theory is that it has lead to investigation to determine whether specific inhibition of COX-2 would result in the blockade of pain and inflammation without affecting the homeostatic function of COX-1.3 Additionally, this selective blockade of COX-2 would avoid the deleterious side effects associated with COX-1 inhibition produced by non-steroidal anti-inflammatory drugs (NSAIDs), namely gastrointestinal (GI) bleeding.
Results of clinical and pharmacologic studies support the evidence that COX-2 inhibition is sufficient to replicate the analgesic and anti-inflammatory effects seen with NSAIDs while limiting the GI side effects. Additionally, the recent success and popularity of the new COX-2 inhibitor drugs such as celecoxib (Celebrex) would seem to support this view as they have clear indications for treatment of rheumatoid and osteoarthritis.
COX-2’s complex array of physiologic roles has been recently discovered. It has been shown to play a role in prostaglandin production in the brain and kidney. There has also been recent speculation that it might have a direct role in Alzheimer’s disease as well as colorectal cancer.
COX-2 has a clear role in kidney function. Experiments by Harris in rats have shown that the kidney always exhibits low but measurable concentrations of COX-2 messenger RNA.1 Harris’ studies of the localized COX-2 expression to regions of the kidney mainly involved in sodium reabsorption and renin release which ultimately results in the release of aldosterone, thus promoting sodium reabsorption in the kidney. Additionally, COX-2 expression was observed in the macula densa and the loop of Henle. It must be understood that these observations made by Harris are animal experiments and have not been replicated in humans.
Laboratory Data
Animal experiments in rats have shown COX-2 to be constitutively expressed in the brain of developing rats. COX-2 is detectable in the hippocampus by postnatal day 5 and in the cortex by day 21.1 In adult rats, COX-2 expression has been shown to be regulated by physiologic synaptic activity. It has been shown in animals that a multitude of stimuli can upregulate COX-2 in the brain. It has been theorized in the past that Alzheimer’s disease involves stress to the brain, followed by activation of microglia that express COX-2 in a cerebral inflammatory process. This cascade, it has been hypothesized, ultimately leads to cell death and loss of memory.1 Of additional interest is the fact that NSAIDs have been shown in studies to retard the progress of Alzheimer’s disease. A study by Rich et al showed that patients with Alzheimer’s disease who took NSAIDs daily exhibited a slower disease progression than non-users.1 Thus, it can by hypothesized that the NSAID inhibition of COX-2 production might be slowing the disease progression leading to these positive results.
Over the past 10 years, significant evidence has been accruing that shows a link between cyclooxygenase-2 and colorectal cancer/adenomas in humans. In 1994, Eberhart and colleagues conducted experiments measuring COX-1 and COX-2 messenger RNA levels isolated from human colorectal cancers and adenomas which they compared to normal mucosa. These results showed increased levels of COX-2 messenger RNA levels in 12 of 14 carcinomas, compared with normal mucosa.4 Additionally, this experiment also showed that COX-2 gene expression is low to undetectable in normal colorectal mucosa. Finally, in their study of colorectal adenomas, the precursor lesion to carcinoma, it was seen that many adenomas showed upregulation of COX-2 messenger RNA. It is imperative to note that the study showed equal expression of COX-1 in both normal and neoplastic colorectal tissue derived from humans.4
Other experiments by Fujita at the University at Tokyo took these previous findings a step further and sought to determine if there was a link between size/invasion of colorectal tumors in relation to levels of COX-2. The results of their experiment demonstrated that COX-2 levels are significantly higher in tumors with larger diameters and greater surface areas. Additionally, the COX-2 indices were also higher in tumors with deeper invasion.5 The experiment was not able to show any correlation between COX-2 levels and the presence of metastatic disease. These results would seem to imply that COX-2 levels increase during the progression of colorectal adenomas to carcinomas as most colorectal carcinomas are derived from smaller adenomas which progress in size, volume, and diameter.
An experiment in 1997 by Sheng et al set out to test the hypothesis that COX-2 is involved directly in intestinal tumor development. Sheng and colleagues were responding to studies which reported that daily NSAID intake decreased the risk of colorectal cancer by 40-50%. It was well known at this time that NSAIDs inhibited COX-1 and COX-2, but they wanted to directly link COX-2 inhibition with suppression of colorectal cancer.
Sheng et al addressed this issue by implanting human colorectal cancer cells (HCA-7) that constitutively expressed COX-2 in mice and measured the response to treatment with a highly selective COX-2 inhibitor SC-58125.2 Sheng et al also used a colon cancer cell line that lacked COX-2 expression to test drug selectivity. The results showed that treatment with the COX-2 inhibitor suppressed tumor growth by 85-90% in the cell line with high COX-2 expression, but had no effect on the cell line that lacked COX-2 expression.2 Thus, the results suggested that COX-2 inhibitor drugs, which are currently on the market for the treatment of inflammatory conditions, may in the future allow for progress in the treatment and even prevention of colorectal cancer.
Summary
The results of recent research concerning COX-2 shows that there is a direct link between COX-2 and colorectal cancer. The articles reviewed above would seem to support the theory that there is a direct link between COX-2 levels and the size, invasion, and growth of colorectal cancer. Additionally, the results of this research would seem to support the theory that the new COX-2 inhibitor drugs, such as celecoxib and rofecoxib (Vioxx), might have utility in the treatment and prevention of colorectal cancer as they work directly on an important factor potentially involved in progression and development, without causing the unwanted GI side effects seen with NSAIDs.
Recently, on Aug. 30, it was announced by the FDA that celecoxib a COX-2 inhibitor, will get priority review for the prevention of colorectal adenomatous polyps in patients with familial adenomatous polyposis (FAP). FAP is an uncommon hereditary condition which can cause hundreds of thousands of adenomatous polyps to develop in the rectum during adolescence and early childhood. Left untreated, virtually all patients will develop colon cancer by age 40-50. No drugs are currently approved for use in FAP. Hopefully, if the results are positive, testing of these drugs may be extended to prevention and treatment of non-hereditary colorectal cancer afflicting millions of Americans each year. The reviewed studies would seem to indicate a strong possibility that COX-2 inhibitors could be helpful not only in FAP but also in slowing and suppressing the growth of malignant carcinomas. (Robert D. Lewis is a medical student at the State University of New York at Buffalo School of Medicine.)
References
1. Lipsky PE. The clinical potential of cyclooxygenase-2-specific inhibitors. Amer J Med 1999;106:51-57.
2. Sheng HO, Shao JI, et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. Amer Soc for Clin Invest 1997;99:2254-2259.
3. Lipsky PE. Specific COX-2 inhibitors in arthritis, oncology, and beyond: Where is the science headed? J Rheumatol 1999;26:25-30.
4. Eberhart CH, Coffey RO, et al. Upregulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterol 1994;107:1183-1188.
5. Fujita TA, Matsui MI, et al. Size and invasion-dependent increase in cyclooxygenase-2 levels in human colorectal carcinomas. Can Res 1998;58:4823-4826.
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