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)

We examined the antitumor effect of lipopolysaccharide extracted from Pantoea agglomerans, a Gram-negative bacterium, using intradermal administration on murine syngeneic tumors, Meth A fibrosarcoma, MH134 hepatoma and Lewis lung (LL) carcinoma. The latter two tumors are known to be relatively low in immunogenicity, highly metastatic and to have low sensitivity to biological response modifiers. Although the intradermal administration of LPSp had a significantly suppressive effect on the growth of all tumors, including seventy-five percent of complete regression of mice bearing Meth A tumor, no complete regression was observed in MH134 or LL tumors. In combination with cyclophosphamide given once prior to the administration of LPS, however, the antitumor effects by intradermal administration of LPS were significantly augmented and there was complete regression in all types of tumors. Pretreatment by anti-tumor necrosis factor antibody reduced the effect exerted by LPS, suggesting that induced tumor necrosis factor might have a crucial role. Toxicity of intradermal administration of LPS was 230-380 times less than that by the intravenous route. Thus clinical application of LPS administered intradermally in combination with chemotherapeutics such as cyclophosphamide appears promising in terms of its antitumor effect as well as toxicity.
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PMID:Anti-tumor effect of lipopolysaccharide by intradermal administration as a novel drug delivery system. 921 80

Previous studies have shown that the administration of concanavalin A (ConA) into mice induces immune-mediated liver injury, which can be largely abrogated by neutralizing tumor necrosis factor(TNF)alpha. Vesnarinone is an experimental drug which is known to inhibit TNF alpha release. Here we demonstrate that vesnarinone inhibits ConA-induced hepatic injury. In a dose-dependent manner, vesnarinone inhibits in several mouse strains the increase of serum aminotransferase concentrations. additional experiments show that vesnarinone inhibits ConA-mediated accumulation of DNA fragmentation in the liver. Furthermore, the drug significantly reduces the levels of circulating TNF alpha and interleukin-6 (IL-6). Vesnarinone does not modulate TNF alpha and IL-6 action on hepatic cells, as shown by its failure to reduce the cytokine specific-stimulation of acute phase plasma proteins in the rat hepatoma H-35 cell line. Neither vesnarinone nor anti-TNF alpha protect against direct liver injury induced by a sublethal dose of agonist anti-Fas (CD95) antibody. Taken together, these results suggest that vesnarinone blocks hepatic injury, in part by inhibiting the release of TNF alpha in vivo.
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PMID:Vesnarinone inhibits immune-mediated but not Fas (CD95) agonist-mediated hepatic injury. 922 79

There is now good evidence that cytokines contribute to the regulation of tumor growth. The cytokine-driven modulation of tumor growth was investigated during the progression of a hepatocellular carcinoma (HCC) in SV40 large T tumor antigen transgenic mice. In vivo, an increased rate of liver growth correlated with increased transforming growth factor (TGF)-beta 1 mRNA expression, while the greatest amounts of tumor necrosis factor (TNF)-alpha mRNA were detected earlier during tumor development. Conversely, no particular alteration of IL-1 alpha, IL-1 beta, IL-6, IL-2, IL-4 and IFN-gamma mRNA production could be reported. In vitro, hepatocyte-like tumor cell lines established at two stages, either before or after HCC differentiation, were characterized. The early-stage-derived cell line produced TNF-alpha mRNA, but had barely detectable expression of TGF-beta 1 mRNA, while later-stage-derived cell lines showed the reciprocal pattern. All cell lines displayed a lack of sensitivity to TNF-alpha, although some degree of sensitivity to TNF-alpha could be observed in the presence of actinomycin-D or after treatment with IFN-gamma. The early-stage-derived cell line was sensitive to the growth inhibitory effects of TGF-beta 1, but late-stage-derived tumor cell lines displayed a loss of sensitivity to TGF-beta 1 which correlated with the increased expression of TGF-beta 1 mRNA. Altogether, this suggests that tumor cells contribute to the discrete TNF-alpha and TGF-beta 1 expression patterns during HCC progression. This model of HCC could be of valuable interest to assess the impact of various immunotherapeutic strategies on modulation of tumor growth.
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PMID:Critical stages of tumor growth regulation in transgenic mice harboring a hepatocellular carcinoma revealed by distinct patterns of tumor necrosis factor-alpha and transforming growth factor-beta mRNA production. 935 45

Previous studies suggest that the core protein of hepatitis C virus (HCV) has a pleiotropic function in the replication cycle of the virus. To understand the role of this protein in HCV pathogenesis, we used a yeast two-hybrid protein interaction cloning system to search for cellular proteins physically interacting with the HCV core protein. One such cellular gene was isolated and characterized as the gene encoding the lymphotoxin-beta receptor (LT-betaR). In vitro binding analysis demonstrated that the HCV core protein binds to the C-terminal 98 amino acids within the intracellular domain of the LT-betaR that is involved in signal transduction, although the binding affinity of the full-length HCV core protein was weaker than that of its C-terminally truncated form. Our results also indicated that the N-terminal 40-amino-acid segment of the HCV core protein was sufficient for interaction with LT-betaR and that the core protein could form complexes with the oligomeric form of the intracellular domain of LT-betaR, which is a prerequisite for downstream signaling of this receptor. Similar to other members of the tumor necrosis factor (TNF) receptor superfamily, LT-betaR is involved in the cytotoxic effect of the signaling pathway, and thus we have elucidated the biological consequence of interaction between the HCV core protein and LT-betaR. Our results indicated that in the presence of the synergizing agent gamma interferon, the HCV core protein enhances the cytotoxic effects of recombinant forms of LT-betaR ligand in HeLa cells but not in hepatoma cells. Furthermore, this enhancement of the cytolytic activity was cytokine specific, since in the presence of cycloheximide, the expression of the HCV core protein did not elicit an increase in the cytolytic activity of TNF in both HeLa and hepatoma cells. In summary, the HCV core protein can associate with LT-betaR, and this protein-protein interaction has a modulatory effect on the signaling pathway of LT-betaR in certain cell types. Given the known roles of LT-betaR/LT-alpha1,beta2 receptor-ligand interactions in the normal development of peripheral lymphoid organs and in triggering cytolytic activity and NF-kappaB activation in certain cell types, our finding implies that the HCV core protein may aggravate these biological functions of LT-betaR, resulting in pathogenesis in HCV-infected cells.
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PMID:Direct interaction of hepatitis C virus core protein with the cellular lymphotoxin-beta receptor modulates the signal pathway of the lymphotoxin-beta receptor. 937 2

The possibility that serum ferritin is a secreted protein and an acute phase reactant regulated by inflammatory hormones and iron was examined in a hepatic cell line that secretes plasma proteins. Differentiated rat hepatoma cells released albumin and ferritin into the medium, as determined by rocket immunoelectrophoresis and isolation of ferritin by standard procedures plus immunoaffinity chromatography, following labeling with radioactive amino acid. Administration of interleukin-1-beta (IL-1) or tumor necrosis factor-alpha (TNF) doubled the amounts of ferritin released into the medium over 24 and 48 hours. Together, the cytokines had more than an additive effect. Albumin secretion was diminished by IL-1, but not TNF. Iron, administered as an iron dextran complex or as a 1:1 chelate with nitrilotriacetate (Fe-NTA), also enhanced ferritin release, but had no effect on albumin. Intracellular ferritin concentrations did not change significantly with cytokine treatment, but increased in response to iron. With or without treatments, release of ferritin and albumin from cells into the medium was inhibited by brefeldin A, an inhibitor of Golgi function. The effect of each of the cytokines and of iron on ferritin and albumin was also blocked by dichlorofuranosylbenzimidazole (DRB), an inhibitor of transcription. The stimulatory effect of Fe-NTA on ferritin secretion was diminished by TNF, and this was partially counteracted by IL-1, indicating additional regulatory complexity. These results show for the first time that hepatic cells secrete ferritin, that this ferritin secretion is regulated by iron and inflammatory cytokines, and that the mechanisms of regulation differ from those for intracellular ferritin. The results would explain why serum ferritin increases in inflammation or when iron flux is enhanced.
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PMID:Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. 938 17

Spermidine/spermine N1-acetyltransferase (cSAT), a key enzyme in polyamine degradation, is induced by various hepatotoxins and liver tumor promoters. In this paper we demonstrate that physiological factors, such as cytokines, control cSAT expression in HepG2 human hepatocarcinoma cells. Hepatocyte growth factor (HGF) induced the cSAT mRNA precursor (3.5 kb) at 4 h. The mature form of mRNA (1.3 kb) increased 6-8-fold between 8 and 10 h, and remained elevated until 18 h. An increase in cSAT activity (2-fold) and high levels of N1-acetylspermidine were observed concomitantly. Interleukin-1 beta (IL-1 beta) enhanced cSAT expression (both mRNA and enzyme activity) similar to HGF, while tumor necrosis factor-alpha (TNF-alpha) was less effective. This system also provides a useful means for examining the involvement of negative and positive changes of polyamines in the induction of cSAT and c-jun, a gene that participates in the control of cSAT expression. alpha-Difluoromethylornithine (DFMO) pretreatment, by lowering putrescine and spermidine in HGF- or IL-1 beta-treated cells, prevented the induction of cSAT. This effect was reversed by exogenous putrescine or spermidine. IL-1 beta induced c-jun mRNA more than HGF. DFMO prevented almost completely the enhancement of c-jun mRNA expression by IL-1 beta, and this effect was reversed by exogenous putrescine or spermidine. Therefore, we suggest that cSAT and c-jun expression is specifically regulated by polyamine-mediated mechanisms in IL-1 beta treated HepG2 cells. Since cSAT is inducibile by cytokines that control tumor metabolism and growth as well as tumor-host interaction, we hypothesize an involvement of cSAT in hepatoma growth.
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PMID:Regulation of spermidine/spermine N1-acetyltransferase expression by cytokines and polyamines in human hepatocarcinoma cells (HepG2). 939 63

ONO-4007 is a new synthetic lipid A analog with low endotoxic activities. We previously found that ONO-4007 induced the production of tumor necrosis factor (TNF)-alpha in rat hepatoma KDH-8 tumor tissues and brought about the regression of transplanted KDH-8 cells. By contrast, ONO-4007 did not induce TNF-alpha production in spleens and sera 90 min after treatment. In the present study we attempted to elucidate how ONO-4007 induces TNF-alpha production in tumor tissues locally. We found that extracellular matrix including gelatin, fibronectin and Matrigel did not induce TNF-alpha production in splenocytes treated with ONO-4007 in vitro. However, splenocytes co-cultured with cKDH-8/11 tumor cells in the presence of ONO-4007 produced more TNF-alpha than splenocytes cultured by themselves in the presence of ONO-4007. The stimulation of cKDH-8/11 cells in the presence of ONO-4007 for splenocytes to produce TNF-alpha depended on the type of contact between the cells. The cKDH-8/11 cells fixed in formalin were not able to induce TNF-alpha production of splenocytes even in the presence of ONO-4007. However, syngeneic fibrosarcoma cell line KMT-17/A3, allogeneic hepatocellular carcinoma cell line LDH and rat lung endotherial cell line RLE induced TNF-alpha production in splenocytes, but their stimulation was weaker than that of cKDH-8/11. The soluble form of the cKDH-8/11 cell membrane did not stimulate splenocytes to produce TNF-alpha in the presence of ONO-4007. cKDH-8/11 cells did not stimulate the splenocytes devoid of macrophages to produce TNF-alpha in the presence of ONO-4007.
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PMID:The mechanism of locally enhanced production of tumor necrosis factor-alpha in tumor tissues by the administration of a new synthetic lipid A analog, ONO-4007, in hepatoma-bearing rats. 940 16

ONO-4007 is a new synthetic lipid A derivative with low endotoxic activities. ONO-4007 was effective against KDH-8, a tumor necrosis factor (TNF)-sensitive rat hepatoma cell line, but neither effective against KMT-17, a TNF-resistant rat fibrosarcoma cell line, nor SST-2, a TNF-resistant rat mammary adenocarcinoma cell line. We have established two sublines from KDH-8 to further examine the therapeutic mechanisms of ONO-4007 in vivo: TNF-sensitive KDH-8/YK and TNF-resistant cKDH-8/11. The two sublines equally proliferated in vitro. Multiple systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after tumor implantation. Although treatment with ONO-4007 had no effect on the growth of cKDH-8/11 in WKAH rats in vivo, 60% of KDH-8/YK-bearing rats treated with ONO-4007 survived. The administration of ONO-4007 brought about significant therapeutic effects on KDH-8/YK-bearing rats but not on cKDH-8/11-bearing rats. These results suggest that ONO-4007 is therapeutically useful for the treatment of TNF-alpha-sensitive tumors.
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PMID:Therapeutic effects of a new synthetic lipid A analog, ONO-4007, on rat hepatoma KDH-8 depend on tumor necrosis factor-sensitivity of the tumor cells. 940 18

It has been hypothesized that increased production of tumor necrosis factor-alpha (TNF-alpha) plays a role in causing the insulin resistance associated with obesity. Obesity with insulin resistance is associated with increased production of TNF-alpha by fat cells. Exposure of 3T3-L1 adipocytes to TNF-alpha for 3-4 days makes them insulin resistant. TNF-alpha has also been reported to rapidly (15-60 min) cause insulin resistance, with a decrease in insulin-stimulated tyrosine phosphorylation, in a number of cultured cell lines. Because skeletal muscle is the major tissue responsible for insulin-stimulated glucose disposal, we performed the present study to determine if acute exposure to TNF-alpha causes insulin resistance in muscle. We found that exposure of soleus muscles to 6 nmol/l TNF-alpha for 45 min in vitro had no inhibitory effect on insulin-stimulated tyrosine phosphorylation of the insulin receptor or insulin receptor substrate 1 (IRS-1) or on phosphatidylinositol 3-kinase association with IRS-1. Incubation of epitrochlearis and soleus muscles with 6 nmol/l TNF-alpha for 45 min or 4 h had no effect on insulin-stimulated 2-deoxyglucose (2-DG) uptake. Treatment of epitrochlearis muscles with 2 nmol/l TNF-alpha for 8 h also had no effect on insulin-stimulated 2-DG uptake. We conclude that in contrast to Fao hepatoma cells and 3T3-L1 fibroblasts, skeletal muscle does not become insulin resistant in response to short-term exposure to TNF-alpha.
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PMID:Short-term exposure to tumor necrosis factor-alpha does not affect insulin-stimulated glucose uptake in skeletal muscle. 958 42

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


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