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)

Several studies indicate that nonsteroidal anti-inflammatory drugs including indomethacin, aspirin, sulindac, and piroxicam reduce the risk of colon cancer. Furthermore, nonsteroidal anti-inflammatory drugs that inhibit the cyclooxygenase (COX) enzyme were shown to inhibit the development of colon cancer in animal models of carcinogenesis. Non-steroidal anti-inflammatory drugs inhibit the enzymatic activity of both the constitutive (COX-1) and inducible (COX-2) isoforms of COX enzyme. We have investigated the expression of COX-1 and COX-2 polypeptides in human colon cancer tissues using immunohistochemistry. Enhanced COX-2 expression was observed in colon cancer tissues from 15 subjects with clinically diagnosed colorectal cancer. Marked COX-2 expression was observed in cancer cells, inflammatory cells, vascular endothelium, and fibroblasts of the lesional tissues compared with the nonlesional and normal colon tissues. The extent and intensity of the immunoreactive COX-2 in cancer cells was much greater than that of the other cell types. In contrast, the expression of COX-1 polypeptide was weak in both normal and cancerous specimens. These data suggest that the enhanced expression of the COX-2 gene in colon cancer tissues may contribute to the enhanced synthesis of prostaglandin E2 by the colon cancer tissues. Enhanced expression of COX-2 may play a role in the pathogenesis of colon cancer. Furthermore, selective inhibition of COX-2 may prove to be more efficacious in the retardation of colon cancer development.
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PMID:Expression of cyclooxygenase-1 and -2 in human colorectal cancer. 764 Nov 94

Prostaglandin G/H synthase (PGHS), a key enzyme leading to the formation of prostaglandins, is the target of nonsteroidal antiinflammatory drugs. Two forms of the enzyme have been identified, PGHS-1 and PGHS-2. Epidemiological evidence has suggested that aspirin and other nonsteroidal antiinflammatory drugs may reduce the risk of colorectal cancer. We examined by immunoblot analyses the expression of human PGHS-1 and PGHS-2 protein in 25 matched colon cancer and nontumor tissues, 4 premalignant polyps, 5 control colon tissues from noncancer patients, and 3 matched normal and cancerous breast tissue samples. PGHS-1 was detected in all normal and tumor tissue. In contrast, PGHS-2 was not detected in 23 of 25 normal colon tissues but was detected in 19 of 25 colon tumors. PGHS-2 protein was not observed in four human premalignant polyp samples, control colon from noncancer patients, or matched normal or cancerous breast tissues. These results suggest that the beneficial effects of nonsteroidal antiinflammatory drugs in colon cancer may be mediated by inhibition of PGHS-2.
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PMID:Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. 778 Sep 68

Colorectal cancer is the second leading cause of death from cancer in the United States. Continuous use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the risk of colorectal cancer in humans by 40-50%. Patients with familial adenomatous polyposis who take NSAIDs, such as sulindac, undergo a regression of intestinal adenomas. Rodents exposed to carcinogens that cause colon cancer have a 50-60% reduction in the size and number of colonic tumors when treated continuously with NSAIDs. One common target for these drugs is prostaglandin endoperoxide synthase, also referred to as cyclooxygenase (COX). We and others have shown recently that COX-2 levels are increased dramatically in 85-90% of human colorectal adenocarcinomas and in 40-50% of colonic adenomas. We prepared intestinal epithelial cells that express the COX-2 gene permanently and found that they have altered adhesion properties and resist undergoing apoptosis. We report here that these cells also have a 3-fold increase in the duration of G1, lower levels of cyclin D1 protein, and a marked decrease in retinoblastoma kinase activity associated with cyclin-dependent kinase 4. The delay in G1 transit may relate to the resistance of these cells to undergo programmed cell death, which could affect their tumorigenic potential.
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PMID:G1 delay in cells overexpressing prostaglandin endoperoxide synthase-2. 863 Oct 5

Epidemiological and laboratory studies indicate an inverse relationship between the risk of colon cancer development and intake of nonsteroidal antiinflammatory agents, including aspirin. One of the mechanisms by which nonsteroidal antiinflammatory agents inhibit colon carcinogenesis is through the inhibition of prostaglandin production by cyclooxygenase isozymes (COX-1 and COX-2). Overexpression of COX-2 has been observed in colon tumors. Thus, selective inhibitors of COX-2 could potentially serve as chemopreventive agents. We have assessed the chemopreventive properties of SC-58635, a COX-2 inhibitor, and of sulindac, as a positive control, in a double-blind study, using azoxymethane-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 150 or 1500 ppm SC-58635, 320 ppm sulindac, or 1500 ppm placebo. Two weeks later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with azoxymethane (15 mg/kg of body weight, once weekly for 2 weeks). At 16 weeks of age, all rats were sacrificed and colons were evaluated for ACF. As expected, dietary administration of sulindac suppressed ACF development as such and reduced crypt multiplicity in terms of number of aberrant crypts/ focus. Administration of 1500 ppm SC-58635 inhibited total ACF induction and crypt multiplicity by about 40-49%. Our finding that SC-58635 significantly suppressed colonic ACF formation and crypt multiplicity strengthens the hypothesis that a selective COX-2 inhibitor possesses chemopreventive activity against colon carcinogenesis.
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PMID:Evaluation of cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis. 884 Sep 61

Nonsteroidal antiinflammatory drugs reduce the risk of colon cancer, possibly via cyclooxygenase (COX) inhibition. The growth factor-inducible COX-2, which is overexpressed in neoplastic colonic tissue, is an attractive target to mediate this effect. Herein we have exploited the ability of a human colon cancer cell line, HCA-7 Colony 29, to polarize when cultured on Transwell (Costar) filters to study COX-2 production and the vectorial release of prostaglandins (PGs). Administration of type alpha transforming growth factor to the basolateral compartment, in which the epidermal growth factor receptor (EGFR) resides, results in a marked induction of COX-2 immunoreactivity at the base of the cells and the unexpected appearance of COX-2 in the nucleus. The increase in COX-2 protein is associated with a dose- and time-dependent increase in PG levels in the basolateral, but not apical, medium. Amphiregulin is the most abundantly expressed EGFR ligand in these cells, and the protein is present at the basolateral surface. EGFR blockade reduces baseline COX-2 immunoreactivity, PG levels, and mitogenesis in a concentration-dependent manner. Two specific COX-2 inhibitors, SC-58125 and NS 398, also, in a dose-dependent manner, attenuate baseline and type alpha transforming growth factor-stimulated mitogenesis, although PG levels are decreased > 90% at all concentrations of inhibitor tested. These findings show that activation of the EGFR stimulates COX-2 production and its translocation to the nucleus, vectorial release of PGs, and mitogenesis in polarized HCA-7 Colony 29 cells.
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PMID:Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells. 901 40

Recent epidemiologic studies have shown a 40-50% reduction in mortality from colorectal cancer in individuals who take nonsteroidal antiinflammatory drugs on a regular basis compared with those not taking these agents. One property shared by all of these drugs is their ability to inhibit cyclooxygenase (COX), a key enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of COX have been characterized, COX-1 and COX-2. COX-2 is expressed at high levels in intestinal tumors in humans and rodents. Human colon cancer cells (Caco-2) were permanently transfected with a COX-2 expression vector or the identical vector lacking the COX-2 insert. The Caco-2 cells, which constitutively expressed COX-2, acquired increased invasiveness compared with the parental Caco-2 cells or the vector transfected control cells. Biochemical changes associated with this phenotypic change included activation of metalloproteinase-2 and increased RNA levels for the membrane-type metalloproteinase. Increased invasiveness and prostaglandin production were reversed by treatment with sulindac sulfide, a known COX inhibitor. These studies demonstrate that constitutive expression of COX-2 can lead to phenotypic changes that alter the metastatic potential of colorectal cancer cells.
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PMID:Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. 909 94

The accumulating evidence suggests that aspirin or other NSAIDs may prevent or inhibit the development of colon and perhaps other digestive tract cancers. Although the clinical, experimental, and epidemiologic evidence is promising, the hypothesis remains unproven except in the models of chemically induced colon cancer in rodents and adenomatous polyps in patients with FAP. Clinicians should await the results of randomized trials before using NSAIDs for cancer prevention or treatment. Recommendations are as follows: 1. Experimental studies should define the mechanism or mechanisms by which NSAIDs inhibit tumorigenesis in the rodent model. 2. Experimental and clinical studies should define the optimal drug, dosage, and treatment regimen. The new, selective COX-2 inhibitors should be studied for efficacy and toxicity. 3. Epidemiologic studies should continue to explore the issues of dosage, duration, drug, and toxicity. Because full-scale, randomized trials are feasible only for studying intermediate end points such as polyp recurrence or proliferative indices in high-risk populations, epidemiologic studies have an ongoing role. 4. Carefully designed randomized, clinical trials, now underway, are needed to test the efficacy of NSAIDs in inhibiting colorectal polyps or cancer in humans. 5. Better criteria are needed as to who should take aspirin and who should not.
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PMID:NSAID use and decreased risk of gastrointestinal cancers. 922 76

It has been proposed that cyclooxygenase (COX)-1 and COX-2 subserve different physiologic functions largely because of the striking differences in their tissue expression and regulation. COX-1 displays the characteristics of a "housekeeping" gene and is constitutively expressed in almost all tissues. COX-1 appears to be responsible for the production of prostaglandins (PG) that are important for homeostatic functions, such as maintaining the integrity of the gastric mucosa, mediating normal platelet function, and regulating renal blood flow. In sharp contrast, COX-2 is the product of an "immediate-early" gene that is rapidly inducible and tightly regulated. Under basal conditions, COX-2 expression is highly restricted; however, COX-2 is dramatically upregulated during inflammation. For example, synovial tissues in patients with rheumatoid arthritis (RA) express increased levels of COX-2. In animal models of inflammatory arthritis, COX-2 increases in parallel with PG production and clinical inflammation. In vitro experiments have revealed increased COX-2 expression after stimulation with proinflammatory cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), in many cell types, including synoviocytes, endothelial cells, chondrocytes, osteoblasts, and monocytes/macrophages. Another distinguishing characteristic of COX-2 is decreased expression in response to glucocorticoids. COX-2 is also increased in some types of human cancers, particularly colon cancer. Mechanisms underlying the association between COX-2 overexpression and tumorigenic potential may include resistance to apoptosis, or programmed cell death. Upregulated COX-2 expression undoubtedly plays a role in pathologic processes characterized by increased local PG production. One would predict, based on current information regarding the differential tissue expression of COX-1 and COX-2, that highly selective inhibitors of COX-2 will provide effective antiinflammatory activity with marked reduction in toxicity.
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PMID:COX-1 and COX-2 tissue expression: implications and predictions. 924 46

Several epidemiological and experimental studies have indicated a strong relationship between different types of dietary fats and risk of colon cancer. However, the modulating effects of these nutritional factors at the molecular level are not fully elucidated. It has been documented that the modulation of tumorigenesis is associated with changes in the levels of prostaglandins production. To provide an understanding of the mechanism(s) of dietary fat-induced modulation of colon tumor development, we have analyzed the expression of cyclooxygenase (COX), an enzyme that catalyzes the metabolism of omega-3 and omega-6 polyunsaturated fatty acids in a critical step in prostaglandin biosynthesis. Male F344 rats were fed the semipurified AIN-76A diet containing low-fat corn oil and were s.c. injected azoxymethane (AOM) dissolved in normal saline at a dose rate of 15 mg/kg of body weight, once weekly, for 2 weeks. Vehicle controls received s.c. equal volumes of normal saline. One day after the second AOM or saline injection, rats intended to receive experimental diets were provided high-fat corn oil (HFCO) or high-fat fish oil (HFFO) mixed in semipurified AIN-76A diet, and the remaining rats continued to receive the low-fat corn oil diet. Animals were sacrificed 1, 12, or 36 weeks after the last AOM or saline injection, and their colonic mucosa, as well as the grossly visible colon tumors from rats sacrificed 36 weeks after the last AOM injection, were analyzed for the expression levels of COX-1 and COX-2. The results indicate that AOM induced increasingly high levels of COX-2 expression with advancing stages of colon tumorigenesis. HFCO further enhanced the AOM-induced COX-2 expression. In contrast, HFFO ingestion resulted in a significant decrease in COX-2 expression both in the colonic mucosa and in tumors. These results correlate with increased incidence and multiplicity of grossly visible colon tumors in AOM-treated animals that were fed the HFCO diet versus decreased tumor incidence and lower tumor multiplicity in animals that were fed the HFFO diet. No significant differences were observed in expression levels of COX-1. The data suggest that HFCO may promote colon tumorigenesis by up-regulating the COX-2 expression, whereas HFFO may exert its antitumor effect by inhibiting the COX-2 expression.
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PMID:Dietary fat and colon cancer: modulation of cyclooxygenase-2 by types and amount of dietary fat during the postinitiation stage of colon carcinogenesis. 927 14

Previously, we have shown that forced expression of prostaglandin endoperoxide synthase-2 [also called cyclooxygenase (COX) 2] leads to inhibition of programmed cell death in intestinal epithelial cells. More recently, we have demonstrated that growth of human colonic cancer xenografts is inhibited by treatment with a highly selective COX-2 inhibitor in tumors that express COX-2 (HCA-7) but not in those that lack COX-2 expression (HCT-116). To explore the biochemical mechanisms involved in these effects, we have evaluated the role of COX-2-derived eicosanoid products on programmed cell death in human colon cancer cells. Here we report that PGE2 treatment of human colon cancer cells leads to increased clonogenicity of HCA-7, but not HCT-116 cells. Treatment with a highly selective COX-2 inhibitor (SC-58125) decreases colony formation in monolayer culture and this growth inhibition was reversed by treatment with PGE2. Additionally, PGE2 inhibits programmed cell death caused by SC-58125 and induces Bcl-2 expression, but did not affect Bcl-x or Bax expression in human colon cancer (HCA-7) cells. Therefore, decreased cell death caused by PGE2 would enhance the tumorigenic potential of intestinal epithelial cells. Thus, these results may help to explain a component of the mechanism by which COX inhibitors prevent colorectal cancer in humans.
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PMID:Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. 944 18


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