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)

Interferon-alpha (IFN-alpha) and other cytokines are able to interfere with hepatitis B virus (HBV) replication. However, a sustained antiviral effect is achieved only in 25% to 40% of the patients with chronic HBV infection and clearance of the virus rarely occurs, stressing the need for developing therapeutic alternatives. In this study the antiviral potential of a new recombinant interferon, IFN-omega was investigated. IFN-omega was assessed in comparison with IFN-alpha 2c, IFN-gamma, and TNF-alpha with respect to production of HBV proteins and DNA in HepG2.2.15 cells, a HBV-DNA transfected hepatoma cell line which produces infectious viral particles. Cells were seeded at different states of confluence (20%-90%) and treated with increasing concentrations of interferons (5 to 5,000 U/ml), TNF-alpha (5 to 500 ng/ml), or combinations of both for one to three days. IFN-omega reduced the production of HBsAg down to 59% of the untreated controls, which was comparable to the reduction obtained by treatment with IFN-alpha (60%), the standard interferon used for the treatment of chronic HBV infections. The strongest inhibition, however, was achieved by treatment with 500 ng/ml TNF-alpha (42%). Likewise, production of HBeAg and synthesis of HBV DNA were inhibited to similar degrees by the different interferons. In non-replicating high-density cultures only TNF-alpha was effective. IFN-omega is of similar antiviral potential as IFN-alpha in this in vitro experimental system.
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PMID:Antiviral potential of interferon-omega on hepatitis B virus replication in human hepatoma cells. 955 91

We investigated the therapeutic effects of ONO-4007, a novel synthetic lipid A derivative with low toxic activities, on transplanted hepatocellular carcinoma KDH-8 in WKAH rats. ONO-4007 brought about complete cures in about 60% of rats bearing tumor necrosis factor (TNF)-alpha-sensitive KDH-8 cells, whereas no complete cure was observed in rats bearing cKDH-8/11 which is identical to KDH-8 but a TNF-alpha-resistant cell line, KMT-17 and KEG-1. Then we examined the influence of rabbit anti-TNF-alpha antibody on the therapeutic effects of ONO-4007 against the TNF-alpha-sensitive KDH-8. The concomitant administration of the rabbit anti-TNF-alpha antibody completely abrogated the therapeutic effects of ONO-4007. On the other hand, rechallenged tumor cells of both KDH-8 and cKDH-8/11 were completely rejected in the rats cured of KDH-8 tumor, although no rejection of KEG-1 was observed. Moreover, Winn assay, i.e. the tumor cell neutralizing assay, indicated that CD4+ T cells were involved in the antigen-specific transplantation resistance. These findings suggest that antigen-specific T cell responses are involved in the complete cure of tumors after the treatment with ONO-4007, although its therapeutic effect is initiated by TNF-alpha.
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PMID:ONO-4007 induces specific anti-tumor immunity mediated by tumor necrosis factor-alpha. 962 38

Although treatment for hepatocellular carcinoma (HCC) has recently improved, most patients still relapse and die from this disease. The development of new therapeutic and preventive strategies for HCC is, therefore, required. A novel mutant protein (mutein) of human tumor necrosis factor alfa (TNF-alpha mutein F4614, 1SSSRGDSD... 29V ... 155L) was developed to decrease several adverse effects of TNF-alpha. F4614 is known to lack hypotensive effects of human TNF-alpha without losing its anti-tumor effect in mice transplanted with Meth-A sarcoma. Our study investigated the anti-tumor effects of F4614 against hepatoma cells in vitro and in vivo. F4614 significantly inhibited growth of all four tumor cells in vitro. A murine hepatoma cell line, MH134, when incubated in the presence of F4614, exhibited upregulation of surface major histocompatibility complex (MHC) class-I, intercellular adhesion molecule-1 (ICAM-1) and B7-1 molecules, and a decreased proportion of cells in the G2/M phase of the cell cycle. In addition, F4614 induced apoptosis in a significant number of MH134 cells. TNF-alpha and F4614 (5 microg/mouse daily for 5 days) showed similar anti-tumor activities in syngeneic MH134-bearing mice and heterogeneic PLC/PRF/5-bearing athymic nude mice. Intratumoral injection of F4614 or TNF-alpha was more effective than intravenous injection. Immunohistochemical analysis of the tumors treated by F4614 revealed that tumors were surrounded with a large number of Mac-1+ cells and a small number of CD4+ and CD8+ T cells; that suggests that intratumoral injection of F4614 elicited host immunoreactions. Thus, F4614 may be a new strategy for immunotherapy of HCC.
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PMID:A novel human tumor necrosis factor alfa mutein, F4614, inhibits in vitro and in vivo growth of murine and human hepatoma: implication for immunotherapy of human hepatocellular carcinoma. 965 97

IL-6 is a pleiotropic cytokine that modulates the diverse functions of hepatocytes such as acute phase responses and inflammation. When human hepatoma cells, Hep3B cells, were treated with IL-6, p140 was phosphorylated rapidly and reached its maximal rate at 1 min after treatment. Okadaic acid, an inhibitor of protein phosphatase 1 and 2A, affected IL-6-induced p140 phosphorylation. Interferon regulatory factor-1 (IRF-1) is a transcription factor on the enhancer of type I interferons, and its gene expression is induced by IL-6. When IRF-1 promoter-luciferase construct was transfected into Hep3B cells, okadaic acid increased IL-6- induced IRF-1 promoter activity. In addition, co-transfection of protein phosphatase 2A (PP2A) antisense constructs further increased IL-6-induced IRF-1 promoter activity, suggesting that PP2A is involved in IL-6 signaling. In addition, IL-6 directly induced the PP2A phosphorylation. PP2A phosphorylation was maximal at 1 min after IL-6 stimulation, but it was not induced by other inflammatory cytokines such as TNF-alpha or TGF-beta. Furthermore, IL-6 activated PP2A activity simultaneously. Taken together, these data indicate that IL-6 modulates the functions of PP2A which is involved in downstream events of IL-6 signaling in Hep3B.
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PMID:Roles of protein phosphatase 2A in IL-6 signal transduction in Hep3B cells. 965 61

The plasma level of erythropoietin (Epo) in anemic patients suffering from inflammation is often low in relation to the blood hemoglobin concentration. Various proinflammatory cytokines have been tested for their action on the synthesis of Epo. Interleukin 1 (IL-1) and tumor necrosis factor-alpha(TNF-alpha) suppress Epo gene expression in isolated perfused rat kidneys and in human hepatoma cell cultures. IL-6 inhibits in the kidney, and conflicting results have been reported for its effect on Epo synthesis in hepatic cells. Several other cytokines tested were without effect. Thus, mainly IL-1 and TNF-alpha seem to be responsible for the defect in Epo production in severe systemic and renal inflammatory diseases.
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PMID:Proinflammatory cytokines lowering erythropoietin production. 972 35

Human hepatocellular carcinoma is one of the most frequent malignant tumors. It may occur following exposure to various agents, including viruses and chemical carcinogens; however, the underlying mechanisms of the hepatocarcinogenesis are not known. The present study is the result of our search for genes which may be abundantly expressed in human primary liver carcinoma. One of these genes was found to encode the human hepatocyte growth factor-like protein (HGFLP), also known as macrophage-stimulating protein. HGFLP is structurally homologous to hepatocyte growth factor, a potent growth factor for liver. HGFLP mRNA was also found to be overexpressed in a hepatoblastoma sample and in a sample of subacute fulminant hepatic necrosis. In a study on the effects of cytokines on the expression of HGFLP, we found that IL-6 increased expression of HGFLP mRNA in Hep G2 cells, but IL-1alpha, IL-1beta and TNF-alpha had no effect. An increase in HGFLP could be the result of inflammation and/or tissue injury and its overexpression may prove to be useful as an indicator of hepatoma.
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PMID:Expression of the hepatocyte growth factor-like protein gene in human hepatocellular carcinoma and interleukin-6-induced increased expression in hepatoma cells. 1007 51

Postoperative infection is one of the main factors that affect mortality after hepatic resection, especially in patients with liver cirrhosis. In the pathogenesis of postoperative organ failures complicating endotoxemia or other surgical injuries, inflammatory cytokine has proved to play an important role. We herein report the changes in tumor necrosis factor-alpha, interleukin-1 beta, and granulocyte colony-stimulating factor in production from macrophages/monocytes stimulated with lipopolysaccharide (LPS) after hepatic resection of cirrhotic livers. Seven hepatocellular carcinoma patients with liver cirrhosis who were undergoing limited resection or segmental resection of the liver were examined. Peripheral blood monocytes were separated and incubated with 10 microg/ml LPS, and cytokine release was measured by ELISA before surgery as well as on Postoperative Days (PODs) 1, 3, 7, and 14. Preoperative cytokine production in cirrhotic patients was greater than cytokine production in noncirrhotic controls. Cytokine productivity increased after hepatic resection. TNF-alpha production was 1,846.6 +/- 882.6 pg/ml, 1,947.3 +/- 221.9 pg/ml, 2,486.9 +/- 519.7 pg/ml, and 1,640.2 +/- 416.0 pg/ml on PODs 1, 3, 7, and 14, respectively. The values on all PODs were significantly greater than the healthy control value, and the value on POD 7 was significantly greater than the preoperative value. Interleukin-1 beta and granulocyte colony-stimulating factor production values corroborated this result in general. In conclusion, macrophages/monocytes are primed in cirrhotic patients preoperatively, and they are supposed to carry greater cytokine producing abilities after hepatic resection. When endotoxin spills over in the blood or in the liver after hepatic resection, postoperative hepatic failure could develop as a result of hypercytokinemia.
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PMID:Inflammatory cytokine production enhancement in the presence of lipopolysaccharide after hepatic resection in cirrhotic patients. 1022 86

Pyrimidine nucleoside phosphorylase (PyNPase) is an enzyme which converts 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil (5-FU), and is induced by various cytokines in tumor cells. We evaluated a combination of 5'-DFUR and lentinan which is widely used as a biological response modifier (BRM), to verify antitumor effects, the induction of cytokines such as tumor necrosis factor (TNF)-alpha and latent transforming growth factor (TGF)-beta, and PyNPase activity against AH66 ascites hepatoma cells in rats. AH66 ascites hepatoma cells were subcutaneously injected into the backs of Donryu rats. Rats were randomly assigned to a group receiving either 5'-DFUR or lentinan alone, to a group receiving both 5'-DFUR and lentinan, or to a control group. 5'-DFUR was administered orally, and lentinan was administered intraperitoneally. The tumor size, PyNPase activity in the tumor and spleen, and TNF-alpha and TGF-beta in the tumor were examined. The results were as follows. a) Tumor growth was significantly (P < 0.05) inhibited in both the 5'-DFUR group and the 5'-DFUR + Lentinan group when compared to the control group. Tumor growth in the 5'-DFUR + Lentinan group was significantly (P < 0.01) inhibited compared to that in both the 5'-DFUR group and the Lentinan group. b) PyNPase activity in the tumor was significantly (P < 0.01) higher in each group than in the spleen. In the tumor, PyNPase activity was significantly (P < 0.01) higher in the Lentinan group compared to the control group. In the 5'-DFUR + Lentinan group PyNPase activity in the tumor was significantly (P < 0.01) lower compared to the Lentinan group. c) Levels of TNF-alpha and TGF-beta production in the tumor were significantly (P < 0.05) lower in the 5'-DFUR + Lentinan group compared to the control group. These findings suggested that PyNPase activity in the tumor was induced by lentinan but not so in the spleen, and lentinan increased the susceptibility of tumor cells to 5'-DFUR.
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PMID:Effects of 5'-DFUR and lentinan on cytokines and PyNPase against AH66 ascites hepatoma in rats. 1022 70

To investigate a new kind of anti-tumor immunological cells and improve surgical results of hepatocellular carcinoma by anti-recurrence application, we activated T cells isolated from tumor infiltrating lymphocytes by double stimulating signals: the one was autologus HCC cells which were treated with IFN-gamma and TNF-alpha for enhancing expression of MHC class I and presented tumor antigen, and the other was costimulation signals which was from ICAM-1 and B7 molecules expressed on treated HCC cells as well as CD28 mAbs. Activated T cells which bound to HCC cells were expanded selectively as tumor specific cytotoxic T lymphocytes (TS-CTLs), their cytotoxic activity in vitro and anti-tumor effects in vivo were observed. Our results suggested that TS-CTLs expressed high cytotoxicity against autologous HCC cells with MHC class I restriction manner. Adoptive TS-CTLs treatment could decrease serum AFP level, inhibit ascites formation and prolong survival in SCID mice bearing human HCC. In clinical trail of 12 cases of HCC, TS-CTLs treatment was able to delay tumor recurrence after HCC resection. Our data demonstrated that TS-CTLs as new immunological treatment modality, are of great value in further application of tumor comprehensive management.
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PMID:[Experimental and clinical research of cytolytic T lymphocytes specific for hepatocellular carcinoma]. 1037 86

The aim of the present study was the comparative analysis of morphological changes found in the lungs of Buffalo rats in the course of Morris hepatoma 5123 after i.t. treatment with recombinant human TNF-alpha (rhTNF-alpha) and its muteins. Modification of the native TNF-alpha molecule and synthesis of mutagenized analogues can prevent undesirable symptoms observed in the case of therapeutic administration of rhTNF-alpha. TNF-alpha has been shown to interact with two distinct membrane receptors (TNF-R): p55R and p75R. Mutagenized mutein V binds selectively with p55R. Mutein VI fails to recognize either TNF-R. The cytokines were applied in a dose of 10 micrograms protein in a cycle of 8 days. The control group consisted of tumor-bearing animals which were given PBS. Ultrastructural examinations were based on transmission electron microscope (TEM). Mutein VI-receiving animals showed enhanced changes of cytotoxic nature. Severe damage to endothelial cells (necrosis inclusive) was observed. Blood vascular lumen showed accumulation of neutrophils and monocytes. Features of enhanced activity of endothelial cells were noted. Focally, within pulmonary alveoli conglomerates of fibrin and fragments of damaged cells were found, with erythrocytes, neutrophils and macrophages in their vicinity. The epithelium of pulmonary alveoli showed signs of considerable damage, including necrosis. The lumen of pulmonary capillaries in rhTNF-alpha-treated animals showed a predominance of eosinophils and monocytic cells. Features of endothelial stimulation were observed, although without a tendency to form microthrombi. Much less pronounced changes both in the lung capillary bed and in the alveolar epithelial cells were noted in the mutein V-given animals. Our findings confirm the possibility of peripheral activation of cells involved in the cytokine-induced antitumor response. Mutein V with the smallest effect on the lung tissue rebuilding seems to be a rhTNF-alpha derivative which can delimit the undesirable symptoms in the course of antitumor therapy reduced to i.t. injections.
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PMID:Comparative studies on the ultrastructure of the rat lungs after intratumor treatment of Morris hepatoma with rhTNF-alpha and its muteins. 1045 12


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