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

The ability of normal and malignant blood-borne cells to extravasate correlates with the activity of an endo-beta-D-glucuronidase (heparanase) which degrades heparan sulfate (HS) in the subendothelial extracellular matrix (ECM). The association of malignancy with different types of coagulopathies prompted us to study the effect of thrombin (EC 3.4.21.5), a serine protease elaborated during activation of the clotting cascade, on the ability of heparanase to degrade the ECM-HS. The circulating zymogen form of thrombin, prothrombin, was converted to proteolytically active thrombin during incubation with ECM. Thrombin generation by the ECM was time and dose dependent, reaching maximal conversion by 6 h incubation at 3 U/ml of prothrombin. Heparanase-mediated release of low Mr HS cleavage products from sulfate-labeled ECM was stimulated four- to sixfold in the presence of alpha-thrombin, but there was no effect on degradation of soluble HS. Similar results were obtained with heparanase preparations derived from mouse lymphoma and human hepatoma cell lines and from human placenta. Incubation of ECM with alpha-thrombin alone resulted in release of nearly intact high-Mr labeled proteoglycans. Thrombin stimulation of heparanase action was dose and time dependent, reaching a maximal value at 24 h incubation with 1 microM alpha-thrombin. The effect of modified thrombin preparations correlated with their proteolytic activity. Catalytically blocked preparations of thrombin (e.g., DIP-alpha-thrombin, MeSO2-alpha-thrombin) failed to facilitate heparanase action, while catalytically modified preparations (e.g., gamma-thrombin, NO2-alpha-thrombin) exerted only a slight enhancement. Antithrombin III (ATIII) and hirudin both inhibited thrombin-stimulated heparanase degradation of ECM-bound HS. Heparanase action was also facilitated by ECM-immobilized thrombin to an extent which was similar to that induced by soluble thrombin. This result implies that thrombin sequestered by the subendothelial ECM and protected from interaction with its natural inhibitor ATIII (Bar-Shavit et al., 1989, J. Clin. Invest. 84, 1096-1104) may participate locally in cellular invasion during tumor metastasis, inflammation, and autoimmunity.
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PMID:Thrombin enhances degradation of heparan sulfate in the extracellular matrix by tumor cell heparanase. 161 23

A 55-year-old man with a chief complaint of melena had diffusely infiltrated lymphoma from the rectum to the sigmoid colon and polyclonal hypergammaglobulinemia. Biopsy specimen obtained from the rectum revealed diffuse medium-sized lymphoma cell with plasmocytosis. Histochemical analysis with monoclonal antibodies indicated that the origin of the tumor cell to be T-lymphocyte. Chemotherapy with cyclophosphamide, vincristine and prednisolone (VEP regimen) was effective for mucosal bleeding of the colonic lesion and reduction of polyclonal hypergammaglobulinemia. Five yrs later he showed recurrence of the disease and elevation of serum alphafetoprotein, and died of pulmonary infections. Autopsy finding confirmed the diagnosis of malignant lymphoma of the colon and disclosed the association of hepatocellular carcinoma.
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PMID:Diffuse infiltrating T-cell lymphoma of the colon associated with polyclonal hypergammaglobulinemia and hepatocellular carcinoma: report of a case. 165 Aug 55

Viruses may contribute to the development of human tumors by different mechanisms: indirectly by inducing immunosuppression or by modifying the host cell genome without persistence of viral DNA; directly by inducing oncoproteins or by altering the expression of host cell proteins at the site of viral DNA integration. Human cancers associated with papillomavirus, hepatitis B virus, Epstein-Barr virus, and human T cell leukemia-lymphoma virus infections are responsible for approximately 15 percent of the worldwide cancer incidence. Cancer of the cervix and hepatocellular carcinoma account for about 80 percent of virus-linked cancers. Because experimental and epidemiologic data imply a causative role for viruses, particularly in cervical and liver cancer, viruses must be thought of as the second most important risk factor for cancer development in humans, exceeded only by tobacco consumption.
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PMID:Viruses in human cancers. 165 43

This review first considered some general problems in establishing causal links between a virus and a human cancer and offered some guidelines in the pursuit of this objective. Second, it reviewed the current causal associations for several candidate oncogenic viruses in relation to the tumors with which they are associated. These include Epstein-Barr virus in relation to Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, and non-Hodgkin's lymphoma; hepatitis B and C viruses in relation to hepatocellular carcinoma; human T-cell leukemia/lymphoma virus type 1 and atypical leukemia/lymphoma; and human papilloma viruses in relation to cervical carcinoma. For some, the causal relationship is strong: hepatitis B virus with hepatocellular carcinoma, and human T-cell leukemia/lymphoma virus with adult T-cell leukemia/lymphoma. For one, the causal relationship is moderate: Epstein-Barr virus with African Burkitt's lymphoma. For others it is incomplete or inconclusive: Epstein-Barr virus with Hodgkin's disease and non-Hodgkin's lymphoma, and hepatitis C virus with hepatocellular carcinoma. Current techniques do not permit an answer for some: human papilloma virus with cervical carcinoma.
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PMID:Viruses and cancer. Causal associations. 166 91

Based on our earlier data on the enhancing effect of histamine on the action of interleukin-6 (IL-6), we have studied the molecular mechanisms of these interactions. The effect of histamine was investigated on the binding of 125I-IL-6 by B lymphoma cell line CESS, monocytoid cell line U937 and hepatoma cell line HepG2. Histamine increases the IL-6 binding by CESS cells and inhibits that by U937 and HepG2 cells. Using H1 receptor (cetirizin and loderix) and H2 receptor (cimetidine and ranitidine) specific antagonists, an H1-dependent stimulation of IL-6 binding by CESS cells was found. In contrast, down-regulation of IL-6 binding by histamine was clearly mediated through H2 receptors. On U937 cells, using a monoclonal antibody reacting with the 80 kd chain of the human IL-6 receptor, and H2-receptor mediated inhibition of IL-6 receptor expression was found by FACS analysis.
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PMID:Histamine influences the expression of the interleukin-6 receptor on human lymphoid, monocytoid and hepatoma cell lines. 168 Feb 74

Determination of the transient increase in plasma homocysteine following administration of excess methionine is an established procedure for the diagnosis of defects in homocysteine metabolism in patients. This so-called methionine loading test has been used for 25 years, but the knowledge of the response of various cell types to excess methionine is limited. In the present paper we investigated homocysteine export from various cell types cultured in the presence of increasing concentrations (15-1,000 microM) of methionine. For comparison of homocysteine export, the export rates per million cells were plotted versus cell density for proliferating cells, and versus time for quiescent cells. The homocysteine export from growing cells was greatest during early to mid-exponential growth phase, and then decreased as a function of cell density. The export rate was higher from phytohemagglutinin-stimulated than non-stimulated lymphocytes, and higher from proliferating than from quiescent fibroblasts. The hepatocytes showed highest export rate among the cell types investigated. The enhancement of homocysteine export by excess methionine ranged from no stimulation to marked enhancement, depending on cell type investigated, and three different response patterns could be distinguished: 1) quiescent fibroblasts and growing murine lymphoma cell showed no significant increase in homocysteine export following methionine loading; export from human lymphocytes was only slightly enhanced in the presence of excess methionine; 2) the homocysteine export from proliferating hepatoma cells and benign and transformed fibroblasts was stimulated three to eightfold by increasing the methionine concentration in the medium from 15 to 1,000 microM; and 3) the response to methionine loading was particularly increased (about 15-fold) in non-transformed primary hepatocytes in stationary culture. The results outline a potentially useful procedure for the comparison of homocysteine export during cell growth in the presence of various concentrations of methionine. The results are discussed in relation to the special feature of homocysteine metabolism in various cell types and tissues including liver, and to the possible source of plasma homocysteine following methionine loading in vivo.
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PMID:Homocysteine export from cells cultured in the presence of physiological or superfluous levels of methionine: methionine loading of non-transformed, transformed, proliferating, and quiescent cells in culture. 199 19

Five analogues of methotrextate (MTX), 10-deazaaminopterin (10-DAM), and 10-ethyl-10-deazaaminopterin (10-EDAM) in which the glutamate moiety was replaced by either a gamma-methyleneglutamate or beta-hydroxyglutamate were synthesized and evaluated for their antifolate activity. These analogous are 4-amino-4-deoxy-N10-methylpteroyl-beta-hydroxyglutamic acid (1), 4-amino-4-deoxy-10-deazapteroyl-beta-hydroxyglutamic acid (2), 4-amino-4-deoxy-N10-methylpteroyl-gamma-methyleneglutamic acid (3, MMTX), 4-amino-4-deoxy-10-deazapteroyl-gamma-methyleneglutamic acid (4, MDAM), and 4-amino-4-deoxy-10-ethyl-10-deazapteroyl-gamma-methyleneglutamic acid (5, MEDAM). None of these compounds were metabolized to the respective polyglutamate derivative as judged by their inability to serve as substrates for CCRF-CEM human leukemia cell folylpolyglutamate synthetase (FPGS) in vitro. All compounds inhibited recombinant human-dihydrofolate reductase (DHFR) at nearly equivalent magnitude as MTX. Growth-inhibition studies with H35 hepatoma, Manca human lymphoma, and CCRF-CEM human leukemia cells established greater cytotoxic effects with compounds 3-5 than with compounds 1 and 2. gamma-Methyleneglutamate derivatives 3-5 were transported to H35 hepatoma cells better than MTX or beta-hydroxyglutamate derivatives 1 and 2. Compound 3 was 2.5 times better than MTX in competing with folinic acid transport in H35 hepatoma cells. Compound 1 did not have a significant inhibitory effect on folinic acid transport even at 50 microM under identical conditions. The IC50 for compound 1 against H35-hepatoma cell growth was 8.5-fold higher than MTX. Compounds with the gamma-methyleneglutamate moiety (3-5) exhibited almost equal or lower IC50 values than MTX against the growth of CCRF-CEM human leukemia cells. These studies show that on continuous exposure, the non-polyglutamylatable inhibitors DHFR (3-5) can exhibit superior antifolate activity compared to the polyglutamylatable methotrexate, presumably due to their enhanced transport to these cell lines. Compounds 3-5 appear to be excellent models to study the role of polyglutamylation of antifolates in antitumor activity and host toxicity.
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PMID:Folate analogues. 34. Synthesis and antitumor activity of non-polyglutamylatable inhibitors of dihydrofolate reductase. 199 21

The C57BL/6 x C3H F1 (hereafter called B6C3F1) mouse is an important animal model for long-term carcinogenesis studies. Maintained under normal laboratory conditions, these mice develop various types of spontaneous tumors during their lifetime. Activated Ha-ras genes have been detected in 66% of spontaneous hepatocellular tumors in the B6C3F1 mouse [Reynolds et al., Science (Washington DC), 237:1309, 1988]. In this study 49 spontaneous non-liver tumors were investigated for oncogene activation by DNA transfection techniques. Of the 49 tumor DNAs analyzed, only 5 yielded multiple foci in the NIH 3T3 focus assay: 2 of 10 pulmonary adenocarcinomas; 0 of 25 lymphomas; 2 of 2 Harderian gland adenomas; 0 of 1 adenocarcinoma of the small intestine; 1 of 6 malignant skin tumors; 0 of 4 hemangiosarcomas; and 0 of 1 lung metastasis of a hepatocellular carcinoma. DNA from six lymphomas which were negative in the NIH 3T3 focus assay were further analyzed for transforming genes by the nude mouse tumorigenicity assay. One of the five lymphomas tested positive with this assay. Southern blot analysis identified five activated ras genes: H-ras in two Harderian gland adenomas; K-ras in one pulmonary adenocarcinoma and in one s.c. adenocarcinoma; and N-ras in one lymphoma. The mutations involved were CG to AT and AT to TA in codon 61 of the Ha-ras genes, GC to AT or TA in codon 12 of the K-ras genes, and a GC to AT mutation in codon 12 of the N-ras gene. Transformant DNA from a pulmonary adenocarcinoma which yielded multiple foci in the transfection assay did not hybridize to DNA probes specific for the K-, H-, and N-ras, raf, neu, and met genes. Thirteen additional tumor DNAs yielded a single focus in the NIH 3T3 transfection assay. The transformant DNAs retransmitted in a second cycle transfection assay. Rearranged and/or amplified raf genes were detected in six of the transformant DNAs. At present we do not know whether these activated raf genes were present in the original tumor DNA. The other seven transformant DNAs did not hybridize with any of the above mentioned specific DNA probes utilized in Southern blot analysis. Unlike liver tumors, the activation of ras protooncogenes is not a frequent event in the development of spontaneous non-liver tumors of the B6C3F1 mouse. The results from this study should aid in understanding the neoplastic development associated with exposure to chemical carcinogens in the B6C3F1 mouse.
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PMID:Activation of protooncogenes in spontaneously occurring non-liver tumors from C57BL/6 x C3H F1 mice. 199 58

Intrahepatic implants of M114 carcinoma in B6D2F1/J mice were treated by intraperitoneal injection of 30 mg sodium caprylate (octanoate), and implants of Nb2 lymphoma in Nb rats were treated with 300 mg tricaprylin orally. After 4-11 h extensive damage to tumor cells was evident microscopically whereas liver cells were unaffected. Tumors in mice treated once daily from the fourth to eighth day after implantation were obliterated. Subcutaneous implants of hepatoma Nb10L in Nb rats treated transdermally with a caprylic acid preparation underwent similar damage. Fatty acids can cause lysis of tumor cells with little damage to normal tissue in certain situations. This action is not related to mitotic activity and represents a novel mode of antitumor action.
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PMID:Oncolytic effects of fatty acids in mice and rats. 201 21

2,6-Dichlorobenzonitrile (Dichlobenil) is the active principle of a commercial herbicide that was previously shown to be carcinogenic for animals. Dichlobenil was administered to male Swiss albino mice in order to assess the possible oncogenic properties of the active principle alone. The substance at 2 ppm concentration was injected (0.0005 mg/injection) either by subcutaneous or intraperitoneal route to 2 randomized groups of 30 animals each every third day for 13 times. Dichlobenil induced a significant increase of malignant tumors (lymphoma, mesothelioma, hepatocellular carcinoma, and pulmonary alveologenic carcinoma) with respect to the controls (p less than 0.01 in both treated groups). As for tumor histotypes, only lymphoma incidence was significantly increased in the intraperitoneally treated animals (p less than 0.05). Dichlobenil can be suspected of being a possible carcinogen in Swiss mice but the mechanism of its action is not precisely known.
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PMID:A one-year carcinogenicity study with 2,6-dichlorobenzonitrile (Dichlobenil) in male Swiss mice: preliminary note. 204 73


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