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

We have produced a high-affinity chimeric anti-colorectal carcinoma antibody, ccM4, chimerized in both heavy and light chains by the construction of two expression vectors, the chimeric heavy-chain expression vector mpSV2neo-EP1-Vm4Cr1 and chimeric light-chain vector mpSV2gpt-EP1-VKCK. These vectors contained the neo or gpt gene as a selection marker, the murine immunoglobulin promoter and enhancer (EP1), the genomic DNA fragments of human immunoglobulin constant region (CK and C gamma 1), and murine cDNA fragments of VH and VK region amplified and cloned directly from the B72.3 hybridoma RNA by the polymer chain reaction technique. These two vector DNAs were sequentially transfected into the SP2/0Ag14 cell line. Transfectants were selected in media containing both G418 and mycophenolic acid. The ccM4 antibody was purified from transfectant supernatants with positive binding reactivity for the TAG72 antigen on a protein A column. We demonstrated that ccM4 antibody retained the same high binding reactivity for the TAG72 antigen as its counterpart, the high-affinity chimeric heavy-chain cB72.3m4 antibody. The ccM4 antibody bound specifically to human colon cancer cells, displayed biodistribution patterns similar to cB72.3m4 antibody, and mediated effective antibody-dependent cellular cytotoxicity to human OVCAR3 tumor cells. Therefore, the high-affinity chimeric ccM4 antibody should be useful in cancer immunotherapy.
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PMID:Construction and characterization of a high-affinity chimeric anti-colorectal carcinoma antibody ccM4. 147 71

Although the cyclooxygenase pathway of the arachidonic acid cascade has been suggested to play an important role in colon carcinogenesis, the molecular species of prostanoids and receptors involved have not been fully elucidated yet. We examined the development of aberrant crypt foci (ACFs), putative preneoplastic lesions of the colon, in two lines of knockout mice, each deficient in prostaglandin E receptors, EP1 and EP3, by treatment with the colon carcinogen, azoxymethane. Formation of ACFs was decreased only in the EP1-knockout mice to approximately 60% of the level in wild-type mice. Administration of 250, 500, or 1000 ppm of a novel selective EP1 antagonist, ONO-8711, in the diet to azoxymethane-treated C57BL/6J mice also resulted in a dose-dependent reduction of ACF formation. Moreover, when Min mice, having a nonsense mutation in the adenomatous polyposis coli gene, were given 500 ppm ONO-8711 in the diet, the number of intestinal polyps was significantly reduced to 57% of that in the basal diet group. These results strongly suggest that prostaglandin E2 contributes to colon carcinogenesis to some extent through its action at the EP1 receptor. Thus, EP1 antagonists may be good candidates as chemopreventive agents for colon cancer.
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PMID:Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. 1053 80

Several lines of evidence suggest that non-steroidal antiinflammatory drugs (NSAIDs) have anticarcinogenic effects. The causal relationship linking the preventive effect of NSAIDs on colon cancer and the inhibition of prostaglandin synthesis is questioned by the contrasting results obtained by many laboratories. The experiments reported in this paper demonstrate that prostaglandin E(2) (PGE(2)) did not stimulate the proliferation in HT-29 human colon adenocarcinoma cells under several experimental conditions. Moreover, PGE(2) and 17-phenyl trinor prostaglandin E(2) (a specific agonist of EP1 receptors) did not increase intracellular Ca(2+) concentration. Finally, PGE(2) did not affect the intracellular cAMP and did not reduce the isoproterenol dependent increase in cAMP. These results indicate that in HT-29 cells: (1) proliferation is not directly sensitive to PGE(2); and (2) PGE(2) does not stimulate a signal transduction pathway leading to intracellular increase in cAMP or Ca(2+) mobilization. Therefore, other cell lines should be used to assess the direct role played by prostanoids in promoting cell proliferation in colon cancer.
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PMID:Effect of prostaglandin E(2) on the proliferation, Ca(2+) mobilization and cAMP in HT-29 human colon adenocarcinoma cells. 1077 15

Cyclooxygenase (COX)-2 has been suggested to play an important role in colon carcinogenesis. We found that the COX-2 selective inhibitor, nimesulide, reduces azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rats and colon carcinogenesis in mice, as well as formation of intestinal polyps in Min mice. Thus, selective inhibitors of COX-2, which catalyzes the synthesis of prostanoids, could be good candidates as chemopreventive agents against colon cancer. Examination of the effect of prostanoid receptor deficiency and a selective antagonist of prostanoid receptor on the development of AOM-induced ACF in mice revealed the involvement of the EP1 receptor. Moreover, a selective EP1 antagonist reduced the number of intestinal polyps in Min mice. These results suggest that PGE2 contributes to colon carcinogenesis through binding to the EP1 receptor. Nitric oxide synthase (NOS) is known to be overexpressed in colon cancers of humans and rats, and a NOS inhibitor, L-NG-nitroarginine methyl ester, was found to inhibit the development of AOM-induced ACF in rats. Thus, NOS including iNOS could also be a good target for chemoprevention of colon cancer, as in the COX-2 case.
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PMID:COX-2 and iNOS, good targets for chemoprevention of colon cancer. 1121 73

Arachidonic acid is metabolized to prostaglandin H(2) (PGH(2)) by cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role in intestinal polyposis. Among the metabolites of PGH(2), PGE(2) is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer. Here we show that homozygous deletion of the gene encoding a cell-surface receptor of PGE(2), EP2, causes decreases in number and size of intestinal polyps in Apc(Delta 716) mice (a mouse model for human familial adenomatous polyposis). This effect is similar to that of COX-2 gene disruption. We also show that COX-2 expression is boosted by PGE(2) through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE(2) receptors, EP1 or EP3, did not affect intestinal polyp formation in Apc(Delta 716) mice. We conclude that EP2 is the major receptor mediating the PGE2 signal generated by COX-2 upregulation in intestinal polyposis, and that increased cellular cAMP stimulates expression of more COX-2 and vascular endothelial growth factor in the polyp stroma.
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PMID:Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. 1153 9

Accumulating evidence indicates that COX-2 inhibitors are involved in colon and breast cancer development. Our previous studies indicated that nimesulide and celecoxib, selective COX-2 inhibitors, show inhibitory effects of intestinal carcinogenesis in azoxymethane-treated rats and mice and in Min mice models. We recently found that nimesulide suppressed PhIP-induced breast cancer in female SD rats in which COX-2 protein was overexpressed. These results led us to investigate the effects of prostaglandin E2 (PGE2) in the target tissues. PGE2 showed its biological activity through binding to its membrane receptors, EP(1 to approximately 4). We also investigated the effects of EP receptors on colon carcinogenesis. We used receptor knockout mice and selective receptor antagonists. Our results indicated that the EP1 receptor plays a pivotal role in colon carcinogenesis. Selective EP1 receptor antagonists may be a new class of chemopreventive agents against colon cancer.
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PMID:COX-2 and prostanoid receptors: good targets for chemoprevention. 1208 1

Nonsteroidal anti-inflammatory drugs (NSAIDs) can decrease the risk of colorectal cancer; however, it has not been established if this effect is solely through their ability to inhibit cyclooxygenase (COX). In this study the effects of indomethacin, a potent NSAID and nonselective COX inhibitor, was examined in LS174T human colon cancer cells. These cells were found to express EP2 prostanoid receptors, but not the EP1, EP3 or EP4 subtypes. Pretreatment of LS174T cells with indomethacin produced a complete inhibition of prostaglandin E(2) (PGE(2)) stimulated cyclic AMP (cAMP) formation in a dose dependent manner with an IC(50) of 21 microM. Interestingly, the inhibition of PGE(2)-stimulated cAMP formation by indomethacin was accompanied by a decrease in EP2 mRNA expression and by a decrease in the whole cell specific binding of [(3)H]PGE(2). Thus, treatment of LS174T cells with indomethacin causes a down regulation of EP2 prostanoid receptors expression that may be independent of COX inhibition.
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PMID:Indomethacin decreases EP2 prostanoid receptor expression in colon cancer cells. 1755 11

Accumulating evidence indicates that elevated levels of prostaglandin E(2) (PGE(2)) can increase intestinal epithelial cell proliferation, and thus play a role in colorectal tumorigenesis. PGE(2) exerts its effects through four G-protein-coupled PGE receptor (EP) subtypes, named the EP1, EP2, EP3, and EP4. Increased phosphorylation of extracellular regulated kinases (ERK1/2) is required for PGE(2) to stimulate cell proliferation of human colon cancer cells. However, the EP receptor(s) that are involved in this process remain unknown. We provide evidence that L-161,982, a selective EP4 receptor antagonist, completely blocks PGE(2)-induced ERK phosphorylation and cell proliferation of HCA-7 cells. In order to identify downstream target genes of ERK1/2 signaling, we found that PGE(2) induces expression of early growth response gene-1 (EGR-1) downstream of ERK1/2 and regulates its expression at the level of transcription. PGE(2) treatment induces phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133 residue and CRE-mediated luciferase activity in HCA-7 cells. Studies with dominant-negative CREB mutant (ACREB) provide clear evidence for the involvement of CREB in PGE(2) driven egr-1 transcription in HCA-7 cells. In conclusion, this study reveals that egr-1 is a target gene of PGE(2) in HCA-7 cells and is regulated via the newly identified EP4/ERK/CREB pathway. Finally our results support the notion that antagonizing EP4 receptors may provide a novel therapeutic approach to the treatment of colon cancer.
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PMID:The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells. 1763 Dec 91

Cyclooxygenase enzymes play an important role in carcinogenesis, and increased expression of cyclooxygenase enzymes has been reported in cancers arising at a number of different sites. Most, if not all of these actions are thought to be mediated by prostaglandin E2 (PGE2). The actions of PGE2 are mediated via four main prostanoid receptors, designated EP1, EP2, EP3 and EP4, based on their different pharmacological properties and secondary messenger pathways. Recently, expression of EP1 has been reported in rat mammary gland and the inhibition of this receptor has been documented to have chemopreventive effect in this animal model. EP1 has also been shown to decrease the incidence of colon cancer in mouse models. In this study, we analysed the expression of EP1 in normal and malignant breast tissues. Expression of EP1 was analysed in breast (benign and cancer) cell lines by reverse-transcriptase polymerase chain reaction and by western blot analyses. Expression was also analysed by immunohistochemistry in normal breast tissues and in 89 cases of breast cancer. Semiquantitative analysis of the staining was performed. The data were compared with and correlated with other prognostic factors like tumour size, tumour grade, lymph node status, oestrogen receptor, progesterone receptor (PR), HER2/neu and cyclooxygenase-2. EP1 expression was demonstrated in human breast cancer by immunohistochemistry. Expression of EP1 was seen both in the cytoplasm and/or in the nuclear membrane in majority of cases. Nuclear EP1 expression correlated with PR (P=0.032) and inversely with node positivity (P=0.025). However, EP1 expression did not correlate with expression of cyclooxygenase-2 (P=0.059). Expression of EP1 is frequently seen in human breast cancers. Nuclear expression of EP1 correlates with good prognosis markers like node negative status and PR expression.
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PMID:Prostanoid receptor EP1 expression in breast cancer. 1790 15

Fas ligand (FasL/CD95L) is a member of the tumour necrosis factor superfamily that triggers apoptosis following crosslinking of the Fas receptor. Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E(2) (PGE(2)), plays a role in the upregulation of FasL expression in colon cancer. Suppression of either COX-2 or COX-1 by RNA interference in HCA-7 and HT29 colon tumour cells reduced FasL expression at both the mRNA and protein level. Conversely, stimulation with PGE(2) increased FasL expression and these cells showed increased cytotoxicity against Fas-sensitive Jurkat T cells. Prostaglandin E(2)-induced FasL expression was mediated by signalling via the EP1 receptor. Moreover, immunohistochemical analysis using serial sections of human colon adenocarcinomas revealed a strong positive correlation between COX-2 and FasL (r=0.722; P<0.0001) expression, and between EP1 receptor and FasL (r=0.740; P<0.0001) expression, in the tumour cells. Thus, these findings indicate that PGE(2) positively regulates FasL expression in colon tumour cells, adding another pro-neoplastic activity to PGE(2).
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PMID:Prostaglandin E2 stimulates Fas ligand expression via the EP1 receptor in colon cancer cells. 1864 68


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