UMLS:C0009402 - FACTA Search

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Query: UMLS:C0009402 (colorectal cancer)
53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological, clinical and animal studies indicate non-steroidal anti-inflammatory drugs (NSAIDs) to be chemopreventive for colorectal cancer. The best established target for NSAIDs are the two isoforms of cyclooxygenase (COX), a key enzyme in the biosynthesis of prostaglandins. Recent investigations using human colorectal tumor cell lines have focused on the cellular and molecular mechanisms potentially underlying the chemopreventive effect of NSAIDs. These studies have used 'traditional' NSAIDs and their metabolites which either do not inhibit COX, are non-selective for the COX isoforms or selectively inhibit COX-1 over COX-2, and recently developed NSAIDs that are highly selective for COX-2. In vitro, apoptosis is the dominant anti-proliferative effect of each of these classes of NSAID and sensitivity to NSAID-induced apoptosis increases with the malignant potential of the tumor cells. Limited in vivo evidence backs up these findings. Cell cycle arrest also contributes to the in vitro growth inhibitory effect of traditional NSAIDs. The induction of apoptosis by NSAIDs may result from the inhibition of the COX isoforms but other as yet undefined paths to NSAID-induced apoptosis clearly exist. A member of each class of NSAID is under trial as a chemopreventive agent for colorectal cancer.
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PMID:Induced apoptosis in the prevention of colorectal cancer by non-steroidal anti-inflammatory drugs. 1463 39

Two isoforms of cyclooxygenase, COX-1 and COX-2, have been identified and shown to be involved in tumorigenesis. Although, overexpression of COX-2 in human cancers has been repeatedly reported, no data have hitherto been available for Thai patients. To cast light on the role(s) of COX enzymes in the development and progression of colorectal cancers and to determine the incidence of COX-2 overexpression, the expression levels of COX-1 and COX-2 proteins using Western blot analysis in tumor tissues and adjacent normal tissues obtained from 44 Thai patients with colorectal cancer. Compared with paired normal tissues, COX-2 was overexpressed in 13 of 44 colorectal tumor tissues (29.5%). Overall, COX-2 levels in colorectal tumor specimens were significantly correlated with histological differentiation, in particular in the tumors with poor differentiation (p<0.05). In addition, overexpression of COX-2 was found more frequently in colorectal tumors with lymphatic invasion, regional lymph node metastasis and larger size, although without statistical significance. In contrast to the relatively consistent alteration in COX-2 expression, the level of COX-1 expression was quite varied in tumor tissues. Forty-eight percent of colorectal tumors exhibited a decreased level of COX-1 in comparison to normal tissues and overexpressed in 23%. Thus both isoforms may both play roles in promoting tumorigenesis. However, there was no significant relationship between the alteration of COX-1 protein levels and any pathological features of tumors.
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PMID:Expression of cyclooxygenase-1 and -2 and clinicopathologic features of colorectal cancer in northern Thailand. 1507 4

Dietary heterocyclic aromatic amines (HCA) and polyunsaturated fatty acids (PUFA) are both believed to play a role in colon carcinogenesis, and are both substrate for the enzyme cyclooxygenase (COX). In HCA-7 cells, highly expressing isoform COX-2, we investigated the effects of PUFA on prostaglandin synthesis and DNA adduct formation by the HCA 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Furthermore, we studied the role of COX, COX-2 in particular, and cytochrome P4501A2 (CYP1A2) by using the enzyme inhibitors indomethacin (IM), NS-398, and phenethyl isothiocyanate (PEITC), respectively. COX-mediated formation of prostaglandin E2 (PGE2) from linoleic acid (LA) showed that HCA-7 cells can convert LA into arachidonic acid (AA). Alternatively, eicosapentaenoic acid (EPA) was found to compete with AA for COX. Strongly decreased PGE2 levels by addition of IM demonstrated involvement of COX in PUFA metabolism. Both IM and NS-398 inhibited adduct formation by HCA to nearly the same extent, indicating involvement of COX-2 rather than COX-1, while CYP1A2 activity in HCA-7 cells was demonstrated by addition of PEITC. Overall, inhibiting effects were stronger for PhIP than for IQ. HCA-DNA adduct formation was stimulated by addition of PUFA, although high PUFA concentrations partly reduced this stimulating effect. Finally, similar effects for n-3 and n-6 fatty acids suggested that adduct formation may not be the crucial mechanism behind the differential effects of PUFA on colon carcinogenesis that have been described. These results show that COX, and COX-2 in particular, can play a substantial role in HCA activation, especially in extrahepatic tissues like the colon. Furthermore, the obvious interactions between PUFA and HCA in COX-2 expressing cancer cells may be important in modulating colorectal cancer risk.
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PMID:Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. 1522 50

The cyclooxygenase (COX) enzymes (COX-1 and COX-2) are key enzymes of prostaglandin (PG) biosynthesis. Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of both COX-1 and COX-2. Selective COX-2 inhibitors have been developed that appear to have 50% less gastrointestinal toxicity than traditional nonselective NSAIDs. Experimental evidence suggests that the COX pathway is involved in tumor promotion. Evidence to support this comes from both clinical and laboratory findings suggesting that chronic NSAID use reduces the relative risk for developing colorectal cancer (CRC). Although the precise mechanism or mechanisms by which these drugs affect tumor progression is not completely understood, it is likely that part of their anti-tumor effect is due to inhibition of the COX- 2 enzyme. COX-2 levels are increased in CRC as well as in several other solid malignancies. COX-2-derived bioactive lipid products promote tumor-associated n eovascularization, inhibit cell death, and stimulate cell proliferation and motility. Additionally, treatment with COX-2-selective inhibitors reduces polyp burden in animal models of intestinal neoplasia and in humans with familial adenomatous polyposis (FAP). Ongoing human clinical trails are under way to test the efficacy of COX-2-selective inhibitors in a number of human cancers.
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PMID:Cyclooxygenase-2 and gastrointestinal cancer. 1528 21

Since the synthesis of salicylic acid, research into the synthesis of new nonsteroidal anti-inflammatory drugs (NSAIDs) has continued in two directions: drugs with higher anti-inflammatory activity and those causing less adverse side-effects. Several very potent classic, non-selective NSAIDs were already available in the 1970's, but problems with their toxicity, especially gastro- and nephrotoxicity, have remained unsolved. The discovery of two cyclooxygenase (COX) isoforms, COX-1 and COX-2, was a breakthrough that led to obtaining the so-called coxibs, which selectively inhibit COX-2. This property makes this kind of NSAID less gastrotoxic than classic, non-selective NSAIDs. Other strategies to reduce the toxic effects of NSAIDs were their applications as prodrugs or purified enantiomers. The latest are the synthesis of classic NSAIDs combined with a chemical group that serves as a nitric oxide donor or the synthesis of double cyclooxygenase/5-lipoxygenase inhibitors. Simple inhibition of prostaglandin (PG) synthesis cannot completely stop the inflammatory process. Therefore new agents are tested for their influence on many other elements of the mechanism of inflammation, e.g. the formation of inflammatory cytokines, free radicals and biogenic amines by the stimulated inflammatory cells. Such pleiotropic activity of an NSAID might increase its anti-inflammatory action.NSAIDs are widely used not only for their anti-inflammatory, but also analgesic, antipyretic, and (as in case of aspirin) anti-coagulating activity. Results of the latest studies suggest that NSAIDs prevent colorectal cancer and may protect against the development of Alzheimer's disease as well. Precise studies of NSAIDs' mechanism of action (e.g. research on the genetic conditions of NSAID metabolism, the discovery of COX-3, studies on microsomal PGE synthase or PG receptors) will probably enable the synthesis of other more selectively acting compounds.
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PMID:[Trends in nonsteroidal anti-inflammatory drug development and application]. 1557 51

Aspirin may reduce the risk of colorectal neoplasia at doses similar to those recommended for the prevention of cardiovascular disease. Thus, we aimed to address whether enhanced platelet activation, as assessed by the measurement of the urinary excretion of 11-dehydro-TXB(2) (a major enzymatic metabolite of TXB(2)), occurs in patients with colorectal cancer. In 10 patients with colorectal cancer, the urinary excretion of 11-dehydro-TXB(2) was significantly higher than in 10 controls, matched for sex, age and cardiovascular risk factors [1001(205-5571) versus 409(113-984) pg/mg creatinine, respectively, median (range), P<0.05]. The administration of aspirin 50 mg daily for 5 consecutive days to colorectal cancer patients caused a cumulative inhibition of platelet cyclooxygenase (COX)-1 activity either ex vivo, as assessed by the measurement of serum TXB(2) levels, or in vivo, as assessed by urinary 11-dehydro-TXB(2) excretion. In conclusion, enhanced platelet activation occurs in colorectal cancer patients. Permanent inactivation of platelet COX-1 by low-dose aspirin might restore anti-tumor reactivity.
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PMID:Platelet activation in patients with colorectal cancer. 1562 89

In the third millennium, preventive medicine is becoming a cornerstone in our concept of health. Colorectal cancer (CRC) prevention, in particular, has become an important goal for health providers, physicians and the general public. CRC fits the criteria of a disease suitable for chemopreventive interventions. It is a prevalent disease that is associated with considerable mortality and morbidity rates, with more than 1,000,000 new cases and 500,000 deaths expected, worldwide, in 2004. CRC has a natural history of transition from precursor to malignant lesion that spans, on average, 15-20 years, providing a window of opportunity for effective interventions and prevention. A pre-malignant precursor lesion (i.e. adenoma) usually precedes cancer, and helps to identify a subset of the population that is at increased risk of harbouring and developing cancer. Science and technology have evolved to a point where we are able to use our knowledge of cancer biology to identify individuals at risk and interrupt the process of malignant transformation at the level of the pre-cancerous lesion. Recent progress in molecular biology and pharmacology enhances the likelihood that cancer prevention will increasingly rely on chemoprevention. Chemoprevention, a new emerging science, means the use of agents to inhibit, delay or reverse carcinogenesis. Recent observations suggest a number of potential targets for chemoprevention. Many agents have potential benefit but only modest chemopreventive efficacy in clinical trials. There is much evidence suggesting an inverse relationship between aspirin or non-steroidal anti-inflammatory drug (NSAID) consumption and CRC incidence and mortality. However, NSAID consumption is not problem-free; 1997 data show 107,000 hospitalisations and 16,500 deaths due to NSAID consumption in the U.S. alone. Therefore, although chemoprevention of CRC is already possible, drugs that have more acceptable side-effect profiles than the currently available NSAIDs are required. Cyclo-oxygenase (COX)-2-specific inhibitors, which have an improved safety profile compared to traditional NSAIDs that inhibit both the COX-1 and COX-2 enzymes, seem to be well-suited drug candidates for CRC prevention. The inhibition of the growth of pre-cancerous and cancerous cells without affecting normal cells is the ultimate aim of cancer treatment and is of particular importance in chemoprevention studies, which may be long term in nature, involving healthy subjects and minimal toxicity. Cancer prevention is certain to be a significant focus of research and intervention in the coming years, propelled by the realisation that we will be able to identify both individuals susceptible to specific cancers as well as the molecular targets that can alter or stop the carcinogenesis process. Pharmacology and genetics are collaborating to develop new chemoprevention agents designed to affect molecular targets linked to specific premalignant or predisposing conditions.
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PMID:Chemoprevention of colorectal cancer: ready for routine use? 1564 92

Although group VIA Ca2+-independent phospholipase A2beta (iPLA2beta) has been implicated in various cellular events, the functions of other iPLA2 isozymes remain largely elusive. In this study, we examined the cellular functions of group VIB iPLA2gamma. Lentiviral transfection of iPLA2gamma into HEK293 cells resulted in marked increases in spontaneous, stimulus-coupled, and cell death-associated release of arachidonic acid (AA), which was converted to prostaglandin E2 with preferred cyclooxygenase (COX)-1 coupling. Conversely, treatment of HEK293 cells with iPLA2gamma small interfering RNA significantly reduced AA release, indicating the participation of endogenous iPLA2gamma. iPLA2gamma protein appeared in multiple sizes according to cell types, and a 63-kDa form was localized mainly in peroxisomes. Electrospray ionization mass spectrometry of cellular phospholipids revealed that iPLA2gamma and other intracellular PLA2 enzymes acted on different phospholipid subclasses. Transfection of iPLA2gamma into HCA-7 cells also led to increased AA release and prostaglandin E2 synthesis via both COX-1 and COX-2, with a concomitant increase in cell growth. Immunohistochemistry of human colorectal cancer tissues showed elevated expression of iPLA2gamma in adenocarcinoma cells. These results collectively suggest distinct roles for iPLA2beta and iPLA2gamma in cellular homeostasis and signaling, a functional link between peroxisomal AA release and eicosanoid generation, and a potential contribution of iPLA2gamma to tumorigenesis.
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PMID:Group VIB Ca2+-independent phospholipase A2gamma promotes cellular membrane hydrolysis and prostaglandin production in a manner distinct from other intracellular phospholipases A2. 1569 10

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

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