Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mortality in patients with advanced colorectal cancer(CRC) remains high. Epidemiologic studies show that individuals taking nonselective, nonsteroidal anti-inflammatory drugs, including aspirin, have a significant reduction in CRC mortality, compared with those not taking these agents. The recent characterization of cyclooxygenase- I and -2 (COX- I and COX-2) isoforms has led to an expanded understanding of how nonsteroidal anti-inflammatory drugs may help prevent polyp formation. Cyclooxygenase enzymes are required for the conversion of arachidonic acid to prostaglandins.COX-2 mediates the inflammatory effects of COX activity, is induced by a wide spectrum of growth factors and proinflammatory cytokines, and is overexpressed in numerous premalignant and malignant lesions, including CRC. Treatment with the selective COX-2 inhibitor celecoxib has shown promising results in the prevention of CRC, Numerous studies show that this COX-2 selective inhibitor is a potent suppressor of colon polyps both in animal models for familial adenomatous polyposis and in patients with this condition. This has led to the US Food and Drug Administration approval of celecoxib for the treatment of patients with familial adenomatous polyposis. The role of celecoxib in cancer treatment is still evolving. Recent studies have identified a potential benefit for adding celecoxib to standard CRC chemotherapy regimens to increase their efficacy and reduce their associated toxicity.
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PMID:COX-2 inhibition and colorectal cancer. 1525 26

In colorectal cancer, cyclooxygenase-2 (COX-2) overexpression in stromal cells induces angiogenesis through EP2 prostaglandin E2 receptor signaling. Cytoplasmic phospholipase A2 (PLA2) alpha preferentially hydrolyses arachidonic acid, which is the limiting substrate for prostaglandin production, from membrane phospholipids. We therefore investigated a possible relationship between cytoplasmic PLA2 and COX-2 overexpression in stromal cells, angiogenesis and microsatellite instability in 48 human colorectal adenocarcinomas. Cytoplasmic PLA2 and COX-2 expression in stromal cells and vascular endothelial growth factor (VEGF) expression in tumor cells were evaluated by immunohistochemistry. Microvessel density was assessed in 10 x 400 fields after CD31 staining. Microsatellite instability was evaluated by PCR and immunohistochemistry. A total of 16 tumors had microsatellite instability. We found an overexpression of cytoplasmic PLA2 in superficial stromal cells. These cells corresponded to fibroblasts and myofibroblasts. There was an association between the number of cytoplasmic PLA2 and COX-2-expressing cells (P=0.006). Cytoplasmic PLA2-positive stromal cells usually also expressed COX-2. A high number of cytoplasmic PLA2-positive stromal cells was correlated with a high microvessel density (P=0.002), a strong VEGF (P=0.01) and the absence of microsatellite instability (P=0.001). The coordinate overexpression of cytoplasmic PLA2 and COX-2 in stromal cells could lead to an important prostaglandin production. These results suggest that cytoplasmic PLA2 overexpression in these cells regulates COX-induced angiogenesis probably by providing arachidonic acid, which is the limiting factor for prostaglandin production. The lower number of cytoplasmic PLA2-positive stromal cells in carcinomas with microsatellite instability could be related to their lower microvessel density and VEGF expression.
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PMID:Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer. 1547 36

Nonsteroidal antiinflammatory drugs (NSAIDs) are postulated to protect against colorectal cancer and adenomas at least in part by a cyclooxygenase (COX-mediated mechanism. The results reported herein address the questions of what factors are associated with expression (relative messenger RNA levels) of COX-1 and COX-2 in colorectal adenomas and whether there is heterogeneity in the protective effect of NSAIDs by levels of COX expression. Paraffin-embedded tissue samples and data describing selected risk factors were obtained from cases enrolled in a case-control study of colorectal adenomatous polyps. RNA was isolated from paraffin-embedded specimens. Samples of complementary DNA were quantified using a fluorescence-based real-time detection method. We tested for differences in levels of COX expression among selected subgroups of cases using a standard Student t test. Odds ratios for the effects of NSAID variables were calculated using unconditional logistic regression in order to make use of all available data on COX expression. Results suggest that use of NSAIDs is associated with lower levels of COX-2 expression and that the protective effect of NSAIDs on polyp occurrence is stronger in the subgroup of cases with higher expression of COX-2 and a higher COX-2/COX-1 ratio. The results suggest that at least part of the protective effect of NSAIDs on the risk of colorectal adenoma involves a COX-mediated pathway.
Clin Colorectal Cancer 2005 Mar
PMID:A molecular/epidemiologic analysis of expression of cyclooxygenases 1 and 2, use of nonsteroidal antiinflammatory drugs, and risk of colorectal adenoma. 1580 32

Recently, cyclooxygenase-2 (COX-2) inhibitor therapy has emerged as a possible new approach to the prevention and treatment of colorectal cancer (CRC). The COX enzymes (COX-1 and COX-2) are key enzymes of prostaglandin (PG) biosynthesis and are overexpressed in approximately 80% of human CRCs. Presumably, bioactive lipid products of COX, such as PGE(2), are responsible for some of the pro-neoplastic effects mediated by this enzyme. The early effects of COX-2-derived PGE(2) are in part mediated by the epidermal growth factor receptor (EGFR). Selenomethionine decreases COX-2 protein and PGE(2) levels. Cetuximab is a chimeric IgG1 monoclonal antibody that binds to EGFR with high specificity thus blocking ligand-induced phosphorylation of EGFR. Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory CRC. We suggest that selenium supplementation by decreasing the COX-2 protein and PGE-2 levels in cancer cells may increase efficacy of cetuximab in advanced CRC patients.
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PMID:Selenium supplementation may increase the efficacy of cetuximab in metastatic colorectal cancer patients. 1582 8

Various biochemical, clinical and epidemiological studies have shown that aspirin (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) demonstrate antineoplastic properties, particularly in the gastrointestinal tract, inhibiting the proliferation of colorectal cancer cells. The mechanism of action may be prostaglandin mediated through inhibition of the COX enzymatic system. This includes two iso-enzymes, COX-I and COX-II, working in concert with the activation of apoptosis, activation of immune surveillance, inhibition of proliferation, and inhibition of carcinogen activation. 5-Fluorouracil (5-FU) has demonstrated activity against colorectal cancer, leading to apoptosis of neoplastic cells. We evaluated the effects of varying doses of ASA (0.5, 1, 1.5 mM), both as a single agent and in combination with 5-FU (50 microg) in HT-29, a colon adenocarcinoma cell line. Proliferation assays showed that aspirin at a concentration of 1 mM inhibits cell growth. Cells treated with ASA, both alone and in combination with 5-FU, demonstrated apoptotic activity with the up-regulation of Bax protein, which is consistent with 5-FU anticancer treatment. Furthermore, there was synergistic cell death with ASA and 5-FU. DNA fragmentation, TUNEL, and trypan blue exclusion methods indicated that a combination of ASA and 5-FU induces apoptosis in cells in a time- and concentration-dependent manner. This study serves to further elucidate the mechanism of action of ASA, and ASA in combination with 5-FU, in colorectal cancer as evidenced by its effect on the HT-29 cell line.
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PMID:Apoptosis induced by aspirin and 5-fluorouracil in human colonic adenocarcinoma cells. 1598 48

The use of NSAIDs or COX-2 inhibitors for chemoprevention of colorectal cancer has been suggested for patients at high risk for this disease. However, the gastrointestinal side effects of traditional NSAIDs which consist of bleeding and ulceration, and the cardiovascular effects of COX-2 inhibitors may limit their usefulness. In preclinical studies, our laboratory has shown that the addition of phosphatidylcholine (PC) to the NSAIDs aspirin (ASA) or ibuprofen (IBU) results in a NSAID-PC with fewer GI side effects and also maintained or enhanced analgesic, anti-pyretic and anti-inflammatory efficacy over the unmodified NSAID. Because NSAID-PCs have not been tested for anti-cancer activity, in the present study, ASA-PC and IBU-PC were tested on the SW-480 human colon cancer cell line. SW-480 cells were incubated in media containing 1-5 mM NSAID or NSAID-PC for 2 days. Measurements were made of cell number, cell proliferation (DNA synthesis), and manner of cell death (necrosis and apoptosis). ASA and IBU reduced cell number in a dose-dependent manner with IBU showing a greater potency than ASA. The association of PC to the NSAID resulted in greater reductions of cell number for both NSAIDs. Furthermore, the NSAID-PC formulation had significantly greater efficacy and potency to inhibit cellular DNA synthesis than the unmodified NSAID. PC alone at the doses and times used had no effect on cell number in this cell line, but did have a small effect to reduce DNA synthesis. None of the drugs had a clear effect on cell death by necrosis. Only IBU and IBU-PC caused cell death by apoptosis in SW-480 cells. We conclude that NSAID-PCs have activity to impede the growth of colon cancer cells in vitro, which is due, in major part, to a marked reduction in DNA synthetic activity of these cells. This growth inhibitory effect appears to be independent of COX-2 activity, since it is known that SW-480 cells do not have this inducible COX isoform. Due to its greater efficacy in this model system, IBU-PC should be further evaluated as a chemopreventive agent that is safer for the GI tract than unmodified NSAID.
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PMID:Phosphatidylcholine-associated nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit DNA synthesis and the growth of colon cancer cells in vitro. 1603 31

There is strong evidence for an important role for increased COX (cyclo-oxygenase)-2 expression and PG (prostaglandin) E2 production in colorectal tumorigenesis. PGE(2) acts through four E-prostanoid receptors (EP1-4). COX-2 has therefore become a target for the potential chemoprevention and therapy of colorectal cancer. However, any therapeutic/preventive strategy has the potential to have an impact on physiological processes and hence result in side effects. General COX (COX-1 and -2) inhibition by traditional NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin, although chemopreventive, has some side effects, as do some conventional COX-2-selective NSAIDs. As PGE2 is thought to be the major PG species responsible for promoting colorectal tumorigenesis, research is being directed to a number of protein targets downstream of COX-2 that might allow the selective inhibition of the tumour-promoting activities of PGE2, while minimizing the associated adverse events. The PGE synthases and E-prostanoid receptors (EP1-4) have therefore recently attracted considerable interest as potential novel targets for the prevention/therapy of colorectal cancer. Selective (and possibly combinatorial) inhibition of the synthesis and signalling of those PGs most highly associated with colorectal tumorigenesis may have some advantages over COX-2-selective inhibitors.
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PMID:Prospects in NSAID-derived chemoprevention of colorectal cancer. 1604 70

Epidemiologic and animal studies suggest that a high-fat diet containing mixed lipids promotes colorectal cancer, whereas fish oil lacks promoting effect. Although cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colon carcinogenesis, administration of high doses of these agents over time may induce side effects. Here, we compared the efficacy of moderately high and low doses of celecoxib administered in diets high in mixed lipids (HFML) or fish oil (HFFO) against azoxymethane-induced colon carcinogenesis in male F344 rats. One day after the last azoxymethane treatment (15 mg/kg body weight once weekly for 2 weeks), groups of rats were fed the HFML and HFFO diets containing 0, 250, 500, and 1,000 ppm celecoxib. Rats were killed 26 weeks later and colon tumors were subjected to histopathologic examination and analyzed for total COX and COX-2 synthetic activities and COX-2 expression. Rats fed the HFFO diet showed significantly lower colon tumor incidence and multiplicity compared with rats fed the HFML diet. Celecoxib at 250, 500, and 1,000 ppm in either diet significantly suppressed colon carcinogenesis. Inhibition of colon adenocarcinomas were more pronounced in animals given 250 ppm celecoxib in HFFO diet compared with 250 ppm celecoxib given in HFML diet, suggesting some synergism between omega-3 polyunsaturated fatty acids (PUFA) and celecoxib. Inhibition of colon tumors by celecoxib was associated with lower levels of COX-2 activity and expression in colon tumors. These studies support the use of low doses of celecoxib in omega-3 PUFA-rich diet as a promising approach for clinical trials.
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PMID:Prevention of colon cancer by low doses of celecoxib, a cyclooxygenase inhibitor, administered in diet rich in omega-3 polyunsaturated fatty acids. 1614 Sep 76

COX-inhibitors promote nasal polyps or bronchial asthma in individuals susceptible to an alteration of the pattern of the eicosanoids, especially leukotrienes and prostaglandins. This is associated with an abnormal release of eicosanoids from white blood cells. Since COX-inhibitors also protect from colorectal cancer an analogous association may be suggested. The study was performed to detect abnormal patterns of eicosanoids in white blood cells of patients with intestinal cancer compared to healthy controls. Seventy patients with intestinal cancer (stomach = 5; colon = 25; sigma = 18; rectum = 22) were compared to 62 healthy controls. Blood leukocytes from patients in complete long-lasting remission were incubated with diluent, arachidonic acid or acetylsalicylic acid. The synthesis of prostaglandin E(2) and peptido-leukotrienes was quantified using competitive enzyme-immuno-assays and calculated for individual eicosanoid patterns. The mean basal and arachidonic- or acetylsalicylic acid-modulated PGE(2) synthesis in patients was significantly higher than in controls (4.8-fold, 9.4-fold, 3.7-fold, respectively) whereas pLT was generally less elevated. We conclude that the eicosanoid-pattern of white-blood-cells from patients with intestinal cancer differs significantly from that in healthy individuals. This abnormal cellular metabolism may contribute to the manifestation of cancer and help to detect individuals at risk.
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PMID:Abnormal eicosanoid-pattern of peripheral white-blood cells in gastro-intestinal cancer. 1624 93

Recent studies have suggested the inhibition of cyclooxygenase-2 (COX-2) as strategy to prevent colorectal cancer. In this study, the cytostatic and cytotoxic effects of different non-steroidal anti-inflammatory drugs (NSAIDs), all of them are reported COX inhibitors, were investigated in human skin melanoma A-375 cells. Using BrdU-cell proliferation assay, we showed that 50 and 100 microM of celecoxib (CEL) reduced proliferation of the melanoma cells at 72-h incubations by 34.0% and 82.7%, respectively. As determined by Toxilight-cytotoxicity assay, the drug was only toxic to the cancer cells at 100 microM. Indomethacin (IND) also inhibited the cell proliferation by about 40% at 240 and 480 pM and was only slightly toxic to the melanoma. Neither aspirin (ASP) nor piroxicam (PIR) exhibited cytostatic or cytotoxic effect on the cancer cells. Combinatory effects of the above NSAIDs with dietary docosahexaenoic acid (DHA) on inhibiting growth of the melanoma cells were further elucidated. Each of the NSAIDs, at doses 10-480 pM, was incubated simultaneously with the melanoma cells and 160 pM of DHA for 72 h. Results from MTT assay showed that both CEL and IND, starting from 20 microM. exhibited additive effects on the DHA-induced growth inhibition. ASP also enhanced the DHA-induced growth inhibition by 42.8% at 480 microM. To our surprise, although PRX did not suppress the melanoma growth, the drug at 40-240 microM enhanced the DHA-induced growth inhibition by 15.9-66.4%, respectively. Results from these studies suggest that the anticancer effects of NSAIDs may not be explained solely by their COX-inhibitory activities. Further studies are therefore required to understand their modes of action, before they could be used alone or in combinations with other agents for cancer chemoprevention.
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PMID:Cytostatic and cytotoxic effects of cyclooxygenase inhibitors and their synergy with docosahexaenoic acid on the growth of human skin melanoma A-375 cells. 1650 96


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