Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CYP3A4, the predominant cytochrome P450 (CYP) expressed in human liver, contributes to the metabolism of approximately half the drugs in use today. In general, human-derived cell lines fail to express CYPs. It was previously shown that CYP3A4 mRNA and CYP3A immunoreactive protein are induced by 1alpha,25-dyhydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) in the human colon carcinoma cell line Caco-2. The aim of the present study was to examine whether 1alpha,25-(OH)(2)D(3) regulates CYP3A4 gene expression in HepG2 cells, a human hepatocarcinoma cell line. Treatment with 1alpha,25-(OH)(2)D(3) resulted in an induction of CYP3A4 mRNA and CYP3A4 immunoreactive protein, 1.5-fold and 4.0-fold respectively, when compared to control cultures, in a time-dependent fashion. These observations are in agreement with previous reports suggesting a role of 1alpha,25-(OH)(2)D(3) on CYP3A4 transcription regulation, and demonstrate that this hormone, as in Caco-2 cells, increase CYP3A4 levels in HepG2 cells. In conclusion, HepG2 cell cultures treated with 1alpha,25-(OH)(2)D(3), provides a useful model to study the function of CYP3A4 and its role in drug liver metabolism.
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PMID:Induction of CYP3A4 by 1alpha,25-dyhydroxyvitamin D3 in HepG2 cells. 1273 30

The enzyme gamma-glutamyltransferase (GGT) is frequently overexpressed in cancer cells and tissues and has significant utility as a cancer marker. Significant heterogeneity of the enzyme has been described due to both transcriptional and post-translational variations. For possible use in diagnosis and follow-up of patients with colorectal cancer, a search was performed for specific mRNA subtypes and glycan structures of the enzyme in liver metastases. We found no differences in the distribution of three GGT mRNA subtypes (fetal liver, HepG2, placenta) in metastatic tissue and normal liver tissue. Furthermore, the three subtypes were present in leukocytes isolated from both normal individuals and cancer patients. Two colon carcinoma cell lines (Colo 205 and HCC 2998) also displayed the three forms and no consistent changes in mRNA composition were noted after butyrate-induced differentiation of the cells. Thus, neither of the GGT mRNA subforms appear to be tumor-specific, although some qualitative and quantitative variations were noted. Two distinct glycosylation features were detected for GGT in metastatic tissue in contrast to normal liver GGT; an extreme sialic acid heterogeneity and a significant increase in beta1,6GlcNAc branching. The GGT glycans from the two colon carcinoma cell lines also possessed these features. As butyrate treatment of the cells resulted in an increased sialic acid content and a reduced beta1,6GlcNAc branching, the described carbohydrate structures appear to be part of a tumor-related pattern. We were, however, unable to identify such GGT isoforms in serum from patients with advanced colorectal cancer. This indicates that their usefulness in diagnostic use is doubtful.
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PMID:Heterogeneity in gamma-glutamyltransferase mRNA expression and glycan structures. Search for tumor-specific variants in human liver metastases and colon carcinoma cells. 1275 64

Cytochrome P450 (CYP) 1B1 is known to be induced by polycyclic aromatic hydrocarbons including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The constitutive and TCDD-inducible transcriptional expression of human CYP1B1 is known to be cell-specific. In order to identify the cis-elements that cell-specifically regulate the constitutive and TCDD-inducible transcription of CYP1B1, we constructed luciferase reporter plasmids containing a series of deletions of the XRE core sequence in the 5'-flanking region of the human CYP1B1 gene. Luciferase assays were performed with MCF-7 (breast carcinoma), HepG2 (hepatocellular carcinoma), LS-180 (colon carcinoma), and OMC-3 (ovarian carcinoma) cells. Although there were large differences in the relative luciferase activity and inducibility between these four cell lines, the contribution of each reporter construct was similar. Constitutive expression increased with the regulatory elements that are present at -910 to -852 and -1652 to -1243. Potential enhancer elements for TCDD-induction were located from -1022 to -852 including three XREs, XRE3 at -853, XRE4 at -940, and XRE5 at -989. Gel shift analyses revealed binding of the AhR/ARNT heterodimer to XRE2 at -834, XRE3 at -853, XRE6 at -1024, and XRE7 at -1490. In addition, the binding of a nuclear transcriptional factor, Sp1, near XRE2 and XRE8 was observed. It was suggested that mutual interaction of XRE2 and XRE3 is important for transcriptional regulation, and that the Sp1 binding to the Sp1-like motif (-824) enhances both the constitutive and inducible transcriptional activities of the human CYP1B1 gene.
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PMID:Critical enhancer region to which AhR/ARNT and Sp1 bind in the human CYP1B1 gene. 1280 9

Chronic gastrointestinal and liver infections account for a significant percentage of human cancer deaths. Rodent models help elucidate how infection can lead to malignancy. Helicobacter pylori, the leading cause of human gastric tumors, produces similar disease in Mongolian gerbils. H. pylori, H. felis, and H. hepaticus induce stomach, lower bowel, or liver tumors in susceptible wild-type and genetically engineered mice. Immune dysregulated mice recapitulate features of inflammatory bowel disease including colon carcinoma. Hepatitis B and C virus transgenic mice provide insights into viral hepatitis and hepatocellular carcinoma. Rodent models enhance our understanding of infectious cancer pathogenesis and suggest novel targets for intervention.
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PMID:Inflammation and Cancer. I. Rodent models of infectious gastrointestinal and liver cancer. 1476 34

One strategy for improving selectivity of gene therapy is the use of a replication-activated adenovirus vector that mediates transgene expression specifically in tumor cells through homologous recombination of viral genomes. In this study, we compared replication-activated adenovirus containing inverted repeats (Ad.IR-BG) with IR-deficient virus (Ad.BG) for selective gene expression in hepatocellular carcinoma and colon carcinoma metastases in the liver. We found that Ad.IR-BG conferred specific gene expression in both carcinoma cells, with minimal expression in hepatocytes and colon epithelial cells. This occurred through viral DNA recombination in Ad.IR-BG-infected tumor cells but not in normal cells. Hydroxyurea, which blocks DNA replication, inhibited DNA recombination and beta-gal expression in Ad.IR-BG-infected but not Ad.BG-infected tumor cells. Finally, systemic injection of Ad.IR-BG into tumor xenografts in nude mice significantly improved selectivity of gene expression in tumors with minimal expression in normal tissues. Viral DNA recombination, which was absent in normal liver, was detected in Ad.IR-BG-infected tumors but not in Ad.BG-infected tissue. These findings demonstrated that replication-activated adenovirus can mediate tumor-specific gene expression through viral DNA recombination, which is otherwise deficient in normal cells.
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PMID:Gene expression in intrahepatic tumors through DNA recombination by a replication-activated adenovirus vector. 1507 12

The content of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (Ca 19-9), carbohydrate antigen 15-3 (Ca 15-3) and the expression of LewisY related carbohydrate antigens in benign and malignant pleural effusion were determined. These included 35 malignant pleural effusions: 13 breast cancers, 12 lung cancers (6 squamous cell carcinomas, 5 adenocarcinomas and 1 microcytoma), 2 mesotheliomas, 1 epithelioma, 1 kidney cancer, 1 hepatocarcinoma, 1 colon carcinoma, 3 lymphomas, 1 osteosarcoma and 9 benign pleural effusions. We showed that pleural fluid content of CEA, Ca 19-9 and Ca 15-3 were higher in malignant than in benign effusions. However CEA levels in squamous lung cancers were very high in both serum and pleural fluids whereas its levels were only slightly above the cut-off in breast cancers and in lung adenocarcinomas. Serum and pleural fluid Ca 15-3 values were higher in breast and in lung cancers with the highest values in the patients with breast cancer. Furthermore, the LewisY related carbohydrate antigens, evaluated by the reactivity of the cell extracts to MAb B3, were expressed only in breast cancers. These data suggest that pleural fluid content of CEA, and Ca 15-3 associated with the immunoblotting of cell extracts with MAb B3 appear to be very useful to improve the diagnosis of malignant pleural effusions.
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PMID:New approaches in the diagnostic procedure of malignant pleural effusions. 1520 63

Three diterpenoid quinones (royleanone- SAR 3, horminone- SAR 26, and acetyl horminone- SAR 43) isolated from the roots of Salvia officinalis L. were tested for their cytotoxic and DNA-damaging activity in human colon carcinoma cells Caco-2 and human hepatoma cells HepG2 cultured in vitro. Cytotoxicity was measured by the trypan blue exclusion technique and induction of apoptosis was evaluated by flow immunofluorocytometry after 30-300 min. exposure of HepG2 and Caco-2 cells to diterpenoid quinones and following 24 hr post-incubation in the culture medium. Induction of DNA breaks was measured after 60 min. exposure of cells to different concentrations of the compounds studied by the alkaline elution of DNA and by the Comet assay. Though all the quinones tested decreased the viability of the cells studied proportionally to the concentration and to the time of treatment (cytotoxicity= 30-60%), the increased level of apoptotic nuclei comparable to the level of apoptotic nuclei induced by a topoisomerase I inhibitor was proved only in HepG2 cells treated with 1x10(-4) mol/l SAR 26 or SAR 43. Either no or marginal increase of the level of apoptotic nuclei was observed in SAR 3-treated HepG2 cells and in SAR 3-, SAR 26- or SAR 43-treated Caco-2 cells. All compounds tested induced creation of DNA strand breaks in both cell types at concentrations >1x10(-7)-1x10(-6) mol/l. The occurrence of DNA strand breaks at different pH values as well as the kinetics of DNA breaks rejoining were evaluated only in colonic cells Caco-2. The Comet assay processed in parallel at pH 13.0 and pH 12.1 showed that strand breaks detected in SARs-treated colonic Caco-2 cells originated from alkali-labile sites, as induced DNA lesions were converted to DNA strand breaks only under strong alkaline conditions. The kinetics of DNA rejoining revealed that SARs-induced DNA breaks were repaired very slowly.
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PMID:Cytotoxic and DNA-damaging effects of diterpenoid quinones from the roots of Salvia officinalis L. on colonic and hepatic human cells cultured in vitro. 1522

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been used to treat human cancers in China since 1984. It was recently found to be capable of inducing apoptosis in human colon carcinoma, hepatoma and glioblastoma cells by way of an elusive mechanism. In this study, we demonstrated that NCTD also induces apoptosis in human oral cancer cell lines SAS (p53 wild-type phenotype) and Ca9-22 (p53 mutant) as evidenced by nuclear condensation, TUNEL labeling, DNA fragmentation and cleavage of PARP. Apoptosis induced by NCTD was both dose- and time-dependent. We found NCTD did not induce Fas and FasL, implying that it activated other apoptosis pathways. Our data showed that NCTD caused accumulation of cytosolic cytochrome c and activation of caspase-9, suggesting that apoptosis occurred via the mitochondria mediated pathway. NCTD enhanced the expression of Bax in SAS cells consistent with their p53 status. Moreover, we showed that NCTD downregulated the expression of Bcl-2 in Ca9-22 and Bcl-XL in SAS. Our results suggest that NCTD-induced apoptosis in oral cancer cells may be mediated by an increase in the ratios of proapoptotic to antiapoptotic proteins. Since oral cancer cells with mutant p53 or elevated Bcl-XL levels showed resistance to multiple chemotherapeutic agents, NCTD may overcome the chemoresistance of these cells and provide potential new avenues for treatment.
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PMID:Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. 1559 95

In the course of a clinical trial consisting of intratumoral injections of dendritic cells (DCs) transfected to produce interleukin-12, the use of (111)In-labeled tracing doses of DCs showed that most DCs remained inside tumor tissue, instead of migrating out. In search for factors that could explain this retention, it was found that tumors from patients suffering hepatocellular carcinoma, colorectal or pancreatic cancer were producing IL-8 and that this chemokine attracted monocyte-derived dendritic cells that uniformly express both IL-8 receptors CXCR1 and CXCR2. Accordingly, neutralizing antihuman IL-8 monoclonal antibodies blocked the chemotactic attraction of DCs by recombinant IL-8, as well as by the serum of the patients or culture supernatants of human colorectal carcinomas. In addition, tissue culture supernatants of colon carcinoma cells inhibited DC migration induced by MIP-3beta in an IL-8-dependent fashion. IL-8 production in malignant tissue and the responsiveness of DCs to IL-8 are a likely explanation of the clinical images, which suggest retention of DCs inside human malignant lesions. Impairment of DC migration toward lymphoid tissue could be involved in cancer immune evasion.
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PMID:Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8. 1580 Sep 14

Gastrointestinal (GI) malignancies are the most common types of human cancers. Despite the introduction of new cytotoxic drugs, a large proportion remains incurable. There is a great need to develop new complementary therapeutic modalities. Strategies exploiting targeted therapies are expanding. The focus of the present article is to review active specific immunotherapy (vaccination) in patients with GI malignancies. The review comprises a description of the immunogenicity of GI malignancies, various types of tumour antigens and mechanisms of action of cancer vaccines. Tumour escape from immune surveillance, vaccine strategies and adjuvants are also described. Clinical and immunological endpoints of cancer immunotherapy are outlined. Results of therapeutic vaccine trials published mainly during the last 5 years in PubMed enrolling a minimum of six patients with GI malignancies are included. Studies presented at the two last annual meetings of the American Society of Clinical Oncology are also covered. More than 2000 patients have been vaccinated with tumour antigens (self antigens). The procedure is safe and no autoimmune disorders have been observed after >4 years follow-up in a substantial number of patients. Humoral and cellular tumour antigen-specific immune responses were induced. A correlation between immune responses and prolonged overall survival was seen in several studies. The most encouraging results were noted in randomised controlled phase II/III trials including over 1300 colorectal carcinoma patients with minimal residual disease. A statistically significantly improved disease-free or overall survival was shown either in all vaccinated or in sub-groups of patients. Promising results were also reported in pancreatic and hepatocellular carcinoma. If the results of the randomised controlled trials hold true, active specific immunotherapy may provide a new promising targeted therapeutic approach in GI malignancies with minimal toxicity. Further enlarged randomised controlled studies are warranted to confirm the results, particularly in colon carcinoma with minimal residual disease.
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PMID:Therapeutic vaccination in patients with gastrointestinal malignancies. A review of immunological and clinical results. 1582 93


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