Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 1971, Vane showed that nonsteroid antiinflammatory drugs (NSAIDs) inhibited the biosynthesis of prostaglandins and proposed this as their mechanism of action. Much work around the world has followed. The aspirin-like drugs inhibit the binding of the prostaglandin substrate, arachidonic acid, to the active site of the enzyme. After characterization of the COX-1 enzyme in 1976, a second COX gene was discovered in 1991 encoding for the inducible COX-2. The constitutive isoform of COX, COX-1, has clear physiological functions. The inducible isoform, COX-2, is induced by pro-inflammatory stimuli in migratory cells and inflamed tissues. The range of activities of NSAIDs against COX-1 compared to COX-2 explains the variations in the side effects of NSAIDs at their antiinflammatory doses. Drugs which have the highest potency on COX-2 and less effect on COX-1 will have potent antiinflammatory activity with fewer side effects. All the results published so far support the hypothesis that the unwanted side effects of NSAIDs, such as damage to the gastric mucosa and kidneys, are due to their ability to inhibit COX-1, while their antiinflammatory (therapeutic effects) are due to inhibition of COX-2. Other roles for COX-2 inhibitors will surely be found in the next few years, for prostaglandin formation is under strong control in organs such as the kidney, lungs and uterus. COX-2 is also potently expressed in human colon cancer cells, and NSAIDs delay the progress of colon tumors possibly by causing apoptosis of the tumor cells. The risk of developing Alzheimer's disease, which may involve an inflammatory component, is lessened by chronic ingestion of NSAIDs. The new highly selective inhibitors of COX-2 will not only provide a means of delaying premature labor but will also lead to advances in cancer therapy and protection against Alzheimer's disease.
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PMID:Mechanism of action of antiinflammatory drugs. 956 41

Nonsteroidal anti-inflammatory drugs (NSAIDs) produce their therapeutic activities through inhibition of cyclooxygenase (COX), the enzyme that makes prostaglandins (PGs). They share, to a greater or lesser degree, the same side effects, including gastric and renal toxicity. Recent research has shown that there are at least two COX isoenzymes. COX-1 is constitutive and makes PGs that protect the stomach and kidney from damage. COX-2 is induced by inflammatory stimuli, such as cytokines, and produces PGs that contribute to the pain and swelling of inflammation. Thus, selective COX-2 inhibitors should be anti-inflammatory without side effects on the kidney and stomach. Of course, selective COX-2 inhibitors may have other side effects and perhaps other therapeutic potential. For instance, COX-2 (and not COX-1) is thought to be involved in ovulation and in labor. In addition, the well-known protective action of aspirin on colon cancer may be through an action on COX-2, which is expressed in this disease. Moreover, NSAIDs delay the progress of Alzheimer's disease. Thus, selective COX-2 inhibitors may demonstrate new important therapeutic benefits as anticancer agents, as well as in preventing premature labor and perhaps even retarding the progression of Alzheimer's disease.
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PMID:Anti-inflammatory drugs and their mechanism of action. 983 28

Since the synthesis of aspirin in 1897, aspirin-like or nonsteroidal antiinflammatory drugs (NSAIDs) have been the mainstay of therapy for rheumatoid arthritis. Although of diverse chemical structure, these drugs not only exhibit the same antipyretic, analgesic and antiinflammatory therapeutic actions, but they also manifest identical toxic actions on the gastric mucosa and the kidney. This indicated that a single pharmacological effect was responsible for the properties of NSAIDs, a theory that was confirmed by the epochal discovery by Vane in 1971, that inhibition of the enzyme-producing prostanoids (cyclooxygenase [COX]) produced both the therapeutic and side effects of aspirin-like drugs. However, at equivalent antiinflammatory doses, different NSAIDs exhibited different degrees of toxicity. The reason for this was resolved by the discovery that prostaglandins at sites of tissue damage were synthesized by an inducible COX (COX-2) formed by a gene distinct from that producing the constitutive enzyme (COX-1), responsible for the formation of prostaglandins that serve an essential physiological function. Modification of the structure of drugs showing a moderately selective effect on COX-2, and the elucidation of the crystal structure of both enzymes, has paved the way for the synthesis of NSAIDs that are highly selective for the inducible enzyme and which are, therefore, antiinflammatory without the typical side effects of the classical NSAIDs. The focus on COX-2 has also expanded our knowledge of the pathophysiological significance of prostanoids and raised the possibility of new uses for selective COX-2 inhibitors, for example, in colon cancer, premature labor and possibly Alzheimer's disease. However, the clinical effects of chronic administration of potent, selective COX-2 inhibitors must await the results of ongoing clinical trials.
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PMID:Nonsteroidal antiinflammatory agents. 1297 28

The introduction of celecoxib (Celebrex, Figure 1; GD Searle and Co) as the first cyclooxygenase (COX)2 selective inhibitor in the US and the expected introduction of rofecoxib (Vioxx; Merck and Co Inc) as the first COX2 inhibitor with an acute pain indication, has prompted interest in this class of drugs as a possible therapeutic improvement on dual COX1/COX2 inhibitor NSAIDs, currently on the market. Recognition that the COX-2 enzyme may have a broader role than pain and inflammation has led to studies investigating the efficacy of COX-2 inhibitors for Alzheimer's disease (AD), stroke, cardiovascular disease and colon cancer. Speakers at the second annual conference sponsored by IBC, addressed issues ranging from the basic concepts of COX2 specificity versus selectivity, pathways and regulatory factors related to COX2 expression, the principles underlying the possible broad implications of the COX2 mechanisms, as well as summaries of recently completed clinical trials supporting the clinical efficacy and safety of COX2 inhibitors in humans. The timeliness of this meeting is emphasized by the recent approval of rofecoxib by the FDA Arthritis Advisory panel and the initial reports in the media of toxicity attributed to celecoxib. Preclinical and limited clinical data presented suggest possible therapeutic roles for selective COX2 inhibitors in neurodegeneration due to both AD and stroke, the prevention and treatment of colon cancer, prevention of premature labor, as well as pain and inflammation.
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PMID:COX-2 inhibitors--IBC conference. 12-13 April 1999, Coronado, CA, USA. 1612 36