Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The COX expressions were evaluated separately in the epithelium and in the stroma of gallbladder cancer, chronic cholecystitis, xanthogranulomatous cholecystitis (XGC) and the normal gallbladder. In normal gallbladder COX-2 expression rate was significantly higher in the epithelium than in the stroma. The COX-2 expression rate in the epithelium of non-cancerous adjacent epithelium to cancerous lesion was significantly lower than those not only of cancer, but also chronic cholecystitis, XGC and normal gallbladder. In stroma, the COX-2 expression rate in cancer, chronic cholecystitis and XGC were significantly higher than that of the normal gallbladder. The rate in non-cancerous adjacent stroma to cancer is significantly lower than that of cancer and XGC. However, the difference of rate between of normal and of chronic cholecystitis was not significant. The COX-2 expression rates were significantly higher in both the epithelium and the stroma in the well and moderately differentiated cancer group than in the poorly and undifferentiated cancer group. Our results suggest that COX-2 expression in the gallbladder may be regulated by various factors and not directly related to carcinogenesis. The significance of its repression in the non-cancerous adjacent tissue to cancer lesion should be re-evaluated.
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PMID:Cyclooxygenase expression in the gallbladder. 1102 18

There is evidence from both genetic and pharmacologic studies to suggest that the cyclooxygenase-2 (COX-2) enzyme plays a causal role in the development of colorectal cancer. However, little is known about the identity or role of the eicosanoid receptor pathways activated by COX-derived prostaglandins (PG). We previously have reported that COX-2-derived prostacyclin promotes embryo implantation in the mouse uterus via activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) delta. In light of the recent finding that PPARdelta is a target of beta-catenin transactivation, it is important to determine whether this signaling pathway is operative during the development of colorectal cancer. Analysis of PPARdelta mRNA in matched normal and tumor samples revealed that expression of PPARdelta, similar to COX-2, is up-regulated in colorectal carcinomas. In situ hybridization studies demonstrate that PPARdelta is expressed in normal colon and localized to the epithelial cells at the very tips of the mucosal glands. In contrast, expression of PPARdelta mRNA in colorectal tumors was more widespread with increased levels in transformed epithelial cells. Analysis of PPARdelta and COX-2 mRNA in serial sections suggested they were colocalized to the same region within a tumor. Finally, transient transfection assays established that endogenously synthesized prostacyclin (PGI(2)) could serve as a ligand for PPARdelta. In addition, the stable PGI(2) analog, carbaprostacyclin, and a synthetic PPARdelta agonist induced transactivation of endogenous PPARdelta in human colon carcinoma cells. We conclude from these observations that PPARdelta, similar to COX-2, is aberrantly expressed in colorectal tumors and that endogenous PPARdelta is transcriptionally responsive to PGI(2). However, the functional consequence of PPARdelta activation in colon carcinogenesis still needs to be determined.
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PMID:Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. 1108 69

Cancer results from disturbances of cellular signal transduction and data processing at the genetic and epigenetic level. In the early phase of the disease these disturbances are mainly caused by environmental toxic agents, i.e. genotoxic and non-genotoxic carcinogens, whereas endogenous agents derived from dys-regulated metabolic reactions may take over this role at later stages, thereby leading to a state of 'genetic instability' and 'growth autonomy'. Among these metabolic reactions becoming dys-regulated in the course of tumorigenesis, eicosanoid biosynthesis from arachidonic acid seems to play a particular role. A steadily increasing body of evidence indicates a causal relationship between cancer development and an abnormal overexpression of eicosanoid-forming enzymes, i.e. cyclooxygenases and lipoxygenases, in a wide variety of human and animal tumors. This overexpression seems to result from disturbances of cellular signaling cascades such as the Ras-Raf-MAPkinase cascade due to oncogenic gene mutations. Presently, research is focussed on the proinflammatory enzyme cyclooxygenase-2 (COX-2) the pathological overexpression of which has been found to be related to key events of tumor promotion such as cellular hyperproliferation, inhibition of programmed cell death, and tumor angiogenesis. In the mouse skin model of multistage carcinogenesis COX-2-derived prostaglandin F(2alpha) has been indentified as an endogenous tumor promoter. Moreover, genotoxic byproducts of both cylooxygenase and lipoxygenase-catalyzed arachidonic acid metabolism (such as active oxygen species, free radicals etc.) are suspected to contribute to 'genetic instability' and thus to malignant progression of tumor cells. The enzymes of eicosanoid biosynthesis rank therefore among the most attractive targets for cancer chernoprevention. In fact, both nonsteroidal antiinflammatory drugs, i.e. non-specific COX inhibitors, and isozyme-specific COX-2 inhibitors have been shown to inhibit experimental and human cancer development, in the latter case in particular in the large bowel. Beside their role as indicators of neoplastic development eicosanoids may be also used as reporters of skin irritation. Based to this concept an in vitro test system for skin toxicity has been developed in which the release of arachidonic acid and interleukin-1alpha, i.e. two key mediators of acute inflammation, from a human keratinocyte cell line is measured. The excellent correlation found between this mediator release and the effects of various chemical irritants on human skin in vivo indicates that, in the near future, this and related methods may help to do without animal experiments in toxicological testing.
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PMID:A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism. 1109 Sep 44

The activation of carcinogenic aromatic and heterocyclic amines and benzo[a]pyrene-7,8-diol to intracellular electrophiles by prostaglandin H synthase (COX) is well documented for ovine sources of this enzyme. Here, the arachidonic acid-dependent activation of substrates by human (h)COX-1 and-2 is examined, utilizing recombinant enzymes. The COX-dependent activation of benzidine (BZ), 4-aminobiphenyl, (+)benzo[a]pyrene-7,8-diol, (+)benzo[a]pyrene-7,8-diol, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), and 4,4'-methylenebis(2-chloroaniline) (MOCA) is assessed by means of COX-catalyzed, covalent DNA binding. The hCOX isozymes activated all substrates tested, activation varied from barely detectable for IQ (0.76 and 1.52 pmol bound/mg DNA for COX-1 and -2, respectively) to a high of 65 and 117 pmol bound/mg DNA for COX-1 and -2, respectively, for the activation of MOCA. BZ, which is an excellent peroxidase substrate, did not exhibit high DNA binding levels in hCOX assays and this phenomenon was found to be due to high levels of binding to protein, which effectively competed with the DNA for binding in the assay. The demonstrated ability of the COX enzymes to activate a variety of environmental and dietary carcinogens indicates a potential role for COX in the activation pathway of aromatic and heterocyclic amines and polycyclic hydrocarbons at extra-hepatic sites during early or late stages of carcinogenesis.
Carcinogenesis 2001 Jan
PMID:Carcinogen substrate specificity of human COX-1 and COX-2. 1115 34

Exocrine ductal carcinoma of the pancreas has been associated with smoking, and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) causes this cancer type in laboratory rodents. Current knowledge on the growth regulation of this malignancy is extremely limited. Recent studies have shown overexpression of cyclooxygenase 2 (COX 2) and 5-lipoxygenase (5-lipox) in exocrine pancreatic carcinomas, suggesting a potential role of the arachidonic acid (AA) cascade in the regulation of this cancer type. In support of this interpretation, our data show high basal levels of AA release in two human cell lines derived from exocrine ductal pancreatic carcinomas. Both cell lines expressed m-RNA for beta2-adrenergic receptors and beta1-adrenergic receptors. Radio-receptor assays showed that beta2-adrenergic receptors predominated over beta1-adrenergic receptors. beta2-Adrenergic antagonist ICI118,551 significantly reduced basal AA release and DNA synthesis when the cells were maintained in complete medium. DNA synthesis of the cell line (Panc-1) with an activating point mutation in codon 12 of the ki-ras gene was significantly stimulated by NNK when cells were maintained in complete medium and this response was inhibited by the beta-blocker ICI118,551, the COX-inhibitor aspirin, or the 5-lipox-inhibitor MK-886. The cell line without ras mutations (BXPC-3) did not show a significant response to NNK in complete medium. When the assays were conducted in serum-free medium, both cell lines demonstrated increased DNA synthesis in response to NNK, an effect inhibited by the beta2-blocker, aspirin, or MK-886. Panc-1 cells were more sensitive to the stimulating effects of NNK and less responsive to the inhibitors than BXPC-3 cells. Our findings are in accord with a recent report which has identified NNK as a beta-adrenergic agonist and suggest beta-adrenergic, AA-dependent regulatory pathways in pancreatic cancer as a novel target for cancer intervention strategies.
Carcinogenesis 2001 Mar
PMID:Beta-adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas. 1123 89

Cyclooxygenase-2 (COX-2) is an inducible form of COX and is overexpressed in diverse tumors, raising the possibility of a role for COX-2 in carcinogenesis. In addition, COX-2 contributes to angiogenesis. The Epstein-Barr virus (EBV) oncoprotein, latent membrane protein 1 (LMP1), is detected in at least 70% of nasopharyngeal carcinoma (NPC) and all EBV-infected preinvasive nasopharyngeal lesions. We found that in specimens of LMP1-positive NPC, COX-2 is frequently expressed, whereas LMP1-negative NPC rarely express the enzyme. We next found that expression of LMP1 in EBV-negative nasopharyngeal epithelial cells induced COX-2 expression. Coexpression of IkappaBalpha(S32A/S36A), which is not phosphorylated and prevents NF-kappaB activation, with LMP1 showed that NF-kappaB is essential for induction of COX-2 by LMP1. We also demonstrate that NF-kappaB is involved in LMP1-induced cox-2 promoter activity with the use of reporter assays. Two major regions of LMP1, designated CTAR1 and CTAR2, are signal-transducing domains of LMP1. Constructs expressing either CTAR1 or CTAR2 induce COX-2 but to a lesser extent than wild-type LMP1, consistent with the ability of both regions to activate NF-kappaB. Furthermore, we demonstrate that LMP1-induced COX-2 is functional because LMP1 increased production of prostaglandin E(2) in a COX-2-dependent manner. Finally, we demonstrate that LMP1 increased production of vascular endothelial growth factor (VEGF). Treatment of LMP1-expressing cells with the COX-2-specific inhibitor (NS-398) dramatically decreased production of VEGF, suggesting that LMP1-induced VEGF production is mediated, at least in part, by COX-2. These results suggest that COX-2 induction by LMP1 may play a role in angiogenesis in NPC.
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PMID:Induction of cyclooxygenase-2 by Epstein-Barr virus latent membrane protein 1 is involved in vascular endothelial growth factor production in nasopharyngeal carcinoma cells. 1138 Nov 23

It is suggested that nonsteroidal antiinflammatory inhibitors alter the biology of colorectal carcinogenesis. Cyclooxygenase-2, one of target molecules of these drugs, is reported to be upregulated in cancer tissues. Cultured cells which were derived from intestinal epithelium and programmed to express COX-2 showed several phenotypic changes in favor of carcinogenesis, including resistance to apoptosis and enhancement of cell proliferation, angiogenesis, and invasion. Tumor growth implanted in COX-2 null mice was significantly attenuated, but not in COX-1 null or wild type mice, suggesting that COX-2 in stroma also has an important role in tumor growth. Moreover, PGE2, one of COX-2 metabolites, reversed these antitumor effects, indicating that inhibition of PGE2 production has a pivotal role in tumor suppression. However, NSAIDs show antitumor effects in cancer cells lacking COX-1 or COX-2 expression, and some derivatives lacking the ability to suppress COX activity show antitumor effects. These results suggest that COX independent pathway might be involved in antitumor effects of NSAIDs. For the development of novel and effective therapies, it is required to elucidate mechanisms underlying antitumor effects of NSAIDs.
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PMID:[COX-2 inhibitor and colon cancer]. 1172 71

Eicosanoids play an important role in numerous physiologic and pathophysiologic processes in the gastrointestinal tract, including maintenance of mucosal integrity, stimulation of mucus and electrolyte secretion, and inflammation. A rapidly growing body of evidence implicates COX-2 in colorectal carcinogenesis. COX-2 has been shown to alter cellular adhesion, apoptosis, and angiogenesis, contributing to its neoplastic potential. NSAIDs appear to attenuate this potential by mechanisms that are COX-2 dependent and independent. Several advances have been made in understanding the details of COX-2 regulation. The downstream effect of COX-2-dependent metabolites varies with the enzymatic machinery present in a particular cell, the level of COX activity, differences in location and types of prostaglandin receptors, and differences in signal transduction pathways. Further studies are needed to understand better these complex interactions, which may provide insight into the role of COX-2 in pathologic conditions, such as intestinal inflammation and colorectal cancer.
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PMID:Role of cyclooxygenase inhibitors for the prevention of colorectal cancer. 1176 29

Much has been learned about the role of NSAIDs as cancer preventives through epidemiologic and experimental studies. The pathways of carcinogenesis in the gastrointestinal tract are initiated by many different genetic, environmental, infective, and lifestyle factors. It is possible that the final common pathway of all these malignancies may have some common features. It is conceivable that head and neck, esophageal, gastric, and colorectal epithelial carcinogenesis all are influenced by or require COX-2 up-regulation as a step toward transformation. Intuitively, it is possible that selective COX-2 inhibitors may have a preventive role in all these epithelial malignancies. Today's challenge is to translate this information into clinical trials to define what role, if any, COX inhibition might play in the prevention of these malignancies.
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PMID:Prostaglandin inhibitors and the chemoprevention of noncolonic malignancy. 1176 39

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2), an inducible form of COX, represents a potential pharmacologic target to prevent cancer. Key data suggesting a causal relationship between increased COX-2 activity and carcinogenesis and possible mechanisms of action of COX-2 in this context will be discussed. The possibility that COX-2 represents a pharmacological target for preventing upper aerodigestive cancers (head and neck, lung) will be emphasized. Importantly, clinical trials have been initiated to assess the chemopreventive properties of selective COX-2 inhibitors.
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PMID:Inhibition of cyclooxygenase-2: an approach to preventing cancer of the upper aerodigestive tract. 1179 29


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