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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological and laboratory studies suggest that nonsteroidal antiinflammatory drugs reduce the risk of colon cancer and that the inhibition of colon carcinogenesis is mediated through modulation of prostaglandin production by cyclooxygenase (COX) isozymes (COX-1 and -2). Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 activity could potentially serve as chemopreventive agents. Our recent study indicated that celecoxib (SC-58635), a specific COX-2 inhibitor, suppressed colonic aberrant crypt foci formation induced by azoxymethane in rats and led us to investigate more specifically the chemopreventive potential of this compound using colon tumors as end points. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or an experimental diet containing 1500 ppm celecoxib. Two weeks later, all animals except those in the saline-treated groups received s.c. injections of azoxymethane (15 mg/kg of body weight) once weekly for 2 weeks. All groups were kept on their regimen until the experiment was terminated, 50 weeks after carcinogen treatment. Colon tumors were evaluated histopathologically. Remarkably, dietary administration of celecoxib inhibited both incidence and multiplicity of colon tumors by about 93 and 97%, respectively. It also suppressed the overall colon tumor burden by more than 87%. The degree of tumor inhibition was more pronounced with celecoxib than it was with previously evaluated nonsteroidal anti-inflammatory drugs. The results of this study provide evidence, for the first time, that a specific COX-2 inhibitor, celecoxib, possesses strong chemopreventive activity against colon carcinogenesis.
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PMID:Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. 945 81

Nonsteroidal anti-inflammatory drugs (NSAIDs) suppress colon carcinogenesis in man and experimental animals. However, conventional NSAIDs inhibit both cyclooxygenase (COX) isoforms, COX-1 and COX-2, and cause gastrointestinal side-effects. Nimesulide, a selective inhibitor of COX-2, is much less ulcerogenic. We, therefore, examined its influence on the development of intestinal polyps in Min mice. Female Min mice at 4 weeks old were given 400 ppm nimesulide in their diet for 11 weeks. This treatment resulted in a significant reduction of the numbers of both small and large intestinal polyps, the total being 52% of that in untreated control Min mice. The size of the polyps in the nimesulide-treated group was also significantly decreased. The results suggest that nimesulide is a good candidate as a chemopreventive agent for human colon cancer with low toxicity.
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PMID:Suppression of intestinal polyp development by nimesulide, a selective cyclooxygenase-2 inhibitor, in Min mice. 947 26

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

Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.
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PMID:Cyclooxygenases 1 and 2. 959 50

Observational, clinical and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. Since toxicity and chemopreventive efficacy of selenium compounds depend to a large extent, on the form of selenium the development of efficacious organoselenium compounds with low toxicity is being pursued in our laboratory. We have assessed the chemopreventive properties of a newly synthesized organoselenium compound, benzyl selenocyanate glutathione conjugate (BSeSG), and of benzyl selenocyanate (BSC), as a positive control, using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) as a measure of efficacy. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 10 or 20 ppm BSeSG (1.7 and 3.4 ppm as Se, respectively), or 10 ppm BSC (4.1 ppm as Se). One week later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with AOM (15 mg/kg of body weight, once weekly for 2 weeks). All animals were sacrificed 7 weeks after the last AOM injection, and the ACF, levels of prostaglandin E2 (PGE2), cyclooxygenase protein expression (COX-1 and -2), and glutathione S-transferase type mu (GST-mu) were determined in the colon. As expected, dietary administration of BSC suppressed ACF development by about 37%. In rats administered 10 or 20 ppm BSeSG, the frequencies of AOM-induced colonic ACF were significantly decreased compared to those of rats given AOM and control diet by about 41% (P<0.01) and 61% (P<0.001), respectively. Administration of BSeSG inhibited PGE2 production (81-88% inhibition) via COX-2 synthesis in the colonic mucosa (18-60% inhibition). Also, BSeSG increased GST-mu protein activity in colonic mucosa (30-32% increase). These data suggest that a newly synthesized organoselenium compound, BSeSG might be a promising chemopreventive agent against colon carcinogenesis.
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PMID:Evaluation of benzyl selenocyanate glutathione conjugate for potential chemopreventive properties in colon carcinogenesis. 962

Aspirin decreases the risk of colorectal cancer, reportedly through suppression of cyclooxygenase (COX) activity. Using a rat model of colonic adenocarcinoma, we compared the chemopreventative effects of aspirin versus a nitric oxide-releasing derivative (NCX-4016) which does not inhibit COX. Beginning six weeks after intracolonic administration of trinitrobenzene sulfonic acid, the rats were given azoxymethane weekly (15 mg/kg i.p.) for 4 weeks. Over the same 4-week period, the rats were treated daily with vehicle, aspirin (10 mg/kg) or NCX-4016 (equimolar dose). Six weeks later, the number of aberrant crypt foci (an early preneoplastic lesion) were blindly counted by light microscopy. Effects of aspirin vs. NCX-4016 on COX-1 and COX-2 activity were compared, as was their analgesic activity. Rats receiving vehicle developed a mean of 856 +/- 260 aberrant crypt foci in the colon. Aspirin reduced the number of aberrant crypt foci by 64%, while NCX-4016 produced an 85% reduction. Aspirin, but not NCX-4016, markedly suppressed systemic COX-1 and COX-2 activity, and colonic prostaglandin synthesis. Despite not inhibiting COX, NCX-4016 exhibited comparable analgesic activity to aspirin. These results demonstrate that NCX-4016, a nitric oxide-releasing aspirin derivative, exhibited superior chemopreventative effects to aspirin in this model of colon cancer. This effect occurred independent of inhibition of COX-1 or COX-2.
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PMID:Cyclooxygenase-independent chemoprevention with an aspirin derivative in a rat model of colonic adenocarcinoma. 962 95

To explore the role of cyclooxygenase (COX) in endothelial cell migration and angiogenesis, we have used two in vitro model systems involving coculture of endothelial cells with colon carcinoma cells. COX-2-overexpressing cells produce prostaglandins, proangiogenic factors, and stimulate both endothelial migration and tube formation, while control cells have little activity. The effect is inhibited by antibodies to combinations of angiogenic factors, by NS-398 (a selective COX-2 inhibitor), and by aspirin. NS-398 does not inhibit production of angiogenic factors or angiogenesis induced by COX-2-negative cells. Treatment of endothelial cells with aspirin or a COX-1 antisense oligonucleotide inhibits COX-1 activity/expression and suppresses tube formation. Cyclooxygenase regulates colon carcinoma-induced angiogenesis by two mechanisms: COX-2 can modulate production of angiogenic factors by colon cancer cells, while COX-1 regulates angiogenesis in endothelial cells.
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PMID:Cyclooxygenase regulates angiogenesis induced by colon cancer cells. 963 Feb 16

In this review, COX-1 and COX-2 proteins have been shown to be homologous in protein structure and ability to synthesize PG, but they have been also shown to be induced differently. COX-1 mRNA and protein have been shown to be induced slowly in intestinal crypt cells in response to irradiation and suggested to be important for crypt cell survival. Therefore, the cox-1 gene is suggested to be a delayed response gene in some systems. However, in cox-1 gene knockout animals there are no pathological gastric and intestinal findings. Although the precise roles of COX-1 in epithelial proliferation and differentiation in the gastrointestinal tract are not yet known, it apparently acts as a constitutive PG producer, thereby protecting the mucosa. On the other hand, COX-2 mRNA and protein have been shown to be induced rapidly in inflammatory sites of the stomach and colon. Thus, COX-2-derived PG presumably plays a role in the repair process of gastritis, ulcers, and colitis. Furthermore, loss of apc gene function probably induces COX-2 mRNA in gastrointestinal mucosa. Thus, high expression levels of COX-2 may lead to phenotypic changes in both intestinal epithelial cells and colon cancer cells.
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PMID:Roles of COX-1 and COX-2 in gastrointestinal pathophysiology. 977 24

All of the selective COX-2 inhibitors described to date inhibit the isoform by binding tightly but noncovalently at the substrate binding site. Recently, we reported the first account of selective covalent modification of COX-2 by a novel inactivator, 2-acetoxyphenyl hept-2-ynyl sulfide (70) (Science 1998, 280, 1268-1270). Compound 70 selectively inactivates COX-2 by acetylating the same serine residue that aspirin acetylates. This paper describes the extensive structure-activity relationship (SAR) studies on the initial lead compound 2-acetoxyphenyl methyl sulfide (36) that led to the discovery of 70. Extension of the S-alkyl chain in 36 with higher alkyl homologues led to significant increases in inhibitory potency. The heptyl chain in 2-acetoxyphenyl heptyl sulfide (46) was optimum for COX-2 inhibitory potency, and introduction of a triple bond in the heptyl chain (compound 70) led to further increments in potency and selectivity. The alkynyl analogues were more potent and selective COX-2 inhibitors than the corresponding alkyl homologues. Sulfides were more potent and selective COX-2 inhibitors than the corresponding sulfoxides or sulfones or other heteroatom-containing compounds. In addition to inhibiting purified COX-2, 36, 46, and 70 also inhibited COX-2 activity in murine macrophages. Analogue 36 which displayed moderate potency and selectivity against purified human COX-2 was a potent inhibitor of COX-2 activity in the mouse macrophages. Tryptic digestion and peptide mapping of COX-2 reacted with [1-14C-acetyl]-36 indicated that selective COX-2 inhibition by 36 also resulted in the acetylation of Ser516. That COX-2 inhibition by aspirin resulted from the acetylation of Ser516 was confirmed by tryptic digestion and peptide mapping of COX-2 labeled with [1-14C-acetyl]salicyclic acid. The efficacy of the sulfides in inhibiting COX-2 activity in inflammatory cells, our recent results on the selectivity of 70 in attenuating growth of COX-2-expressing colon cancer cells, and its selectivity for inhibition of COX-2 over COX-1 in vivo indicate that this novel class of covalent modifiers may serve as potential therapeutic agents in inflammatory and proliferative disorders.
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PMID:Covalent modification of cyclooxygenase-2 (COX-2) by 2-acetoxyphenyl alkyl sulfides, a new class of selective COX-2 inactivators. 982 50

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


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