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)

To examine the possibility of immunotherapy for activating liver-associated mononuclear cells (liver MNC) in hepatocellular carcinoma (HCC), we evaluated the cytotoxicity of liver MNC and peripheral blood mononuclear cells (PBMNC) in HCC patients and examined how they can be activated by cytokines and how this activation is modulated by reduction/oxidation. Cytotoxicity of liver MNC but not PBMNC in HCC patients was significantly decreased compared with that of controls, despite no alteration in the subpopulation of liver MNC between the two groups. We next measured intracellular glutathione (GSH), which is required for the enhancement of the cytotoxicity by interleukin-2 (IL-2). Intracellular GSH levels of liver MNC in HCC were significantly lower than that of controls. In vitro administration of N-acetylcysteine (NAC) not only restored intracellular GSH levels but also enhanced the IL-2-stimulated cytotoxicity of liver MNC in HCC patients. This suggests that intracellular GSH of liver MNC in HCC may participate in the modulation of cytotoxicity of liver MNC in vitro and that NAC may be effective as an adjunct to immunotherapy for HCC.
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PMID:Possible availability of N-acetylcysteine as an adjunct to cytokine therapy for hepatocellular carcinoma. 971 97

Gene therapy, using cytokine gene transduction, aims to increase the antigenicity of tumor cells, and to activate the immune effector cells, and thereby inducing tumor regression. With regards to in vitro sensitivity to peripheral blood monocytes and in vivo tumorigenic activity we compared the differences between parent hepatoma cell lines and interleukin-2 (IL-2) transduced hepatoma cell lines using N2A/IL-2 and LNC/IL-2 retrovirus. IL-2 secretion was 186 pg/10(6) cells/24 h in SK-Hep1 cell line and 147 pg/106 cells/24 h in Hep-3B cell line with N2A/IL-2 retroviral vector and was 55,000 pg/10(6) cells/24 h in Hep-3B cell line with LNC/IL-2 retroviral vector. in vitro sensitivity to peripheral blood monocytes was increased by 163.8-254% in IL-2 transduced hepatoma cell lines (Hep-3B/LNC/IL-2, Hep-G2/LNC/IL-2) compared to those of the parent cell lines. The tumor was formed in 1 of 3 BALB/c mice and all 3 nude mice with the injection of 1x107 cells. Simultaneous injection of 1x10(7) cells of the parent cell line (Hep-3B) into the right flank and IL-2 transduced cell line (Hep-3B/LNC/IL-2) into the left flank of the three BALB/c mice and of 5x10(5) cells for the three nude mice resulted in a complete regression of the IL-2 modified tumor cell line (Hep-3B/LNC/IL-2) in 3 weeks and the parent cell line (Hep-3B) in 5 weeks. After injection of 1x10(7) cells into five other nude mice, the tumor of the IL-2 transduced hepatoma cells (Hep-3B/LNC/IL-2) gradually disappeared, however, the tumor of the parent hepatoma cell line initially decreased and then gradually regrew 20 days later. In conclusion, IL-2 transduced hepatoma cell lines secreting IL-2 became more sensitive to peripheral blood monocytes. IL-2 secretion by LNC/IL-2 retrovirus from the hepatoma cell lines was more prominent compared with that by N2A/IL-2 retrovirus. IL-2 transduction into the hepatoma cells resulted in increased antigenicity to the tumors formed by IL-2 transduced hepatoma cell line and parent cell line, which leads the regression of the tumors. However, the higher the tumor burden, the less efficient tumor regression by IL-2 transduction into the hepatoma cell line in nude mice was observed.
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PMID:Effects of interleukin-2 transduction on the human hepatoma cell lines using retroviral vector. 986

This study explores the use of a liver-specific albumin promoter and a tumor-specific alpha-fetoprotein (AFP) enhancer to achieve the regulated expression of the cytokine interleukin-2/interferon alpha2b (IL-2/IFNalpha2b) fused gene for treatment of hepatocellular carcinoma (HCC). The human AFP enhancer (E(AFP)) and albumin promoter (P(ALB)) were amplified from human chromosome DNA by the polymerase chain reaction. A recombinant retrovirus was constructed including, as a selectable marker, the neoR gene and the IL-2/IFNalpha2b fused gene controlled by E(AFP)-P(ALB). The liver-targeted expression pattern of the IL-2/IFNalpha2b fused gene was observed when this product was tested in the culture medium of the infected cells (IL-2 activity was 850 IU/10(6) cells, IFNalpha activity was 320 IU/10(6) cells). Moreover, The growth of the IL-2/IFNalpha2b-fused-gene-infected HCC cells, SMMC7721, was clearly suppressed by the second week after innoculation of nude mice compared to the control SMMC7721 cells infected with LXSN and untreated SMMC7721 cells (0.5 +/- 0.1 cm versus 1.4 +/- 0.2 cm and 1.6 +/- 0.2 cm, P < 0.05). The results showed that the combined transcriptional regulatory sequences of E(AFP)-P(ALB) could control the targeted expression of cytokine genes in AFP-positive human HCC cells, and the expression level of the IL-2/IFNalpha2b fused gene was positively correlated to the level of AFP expression in the infected cells. The IL-2/IFNalpha2b fused protein that was expressed has the functions of both IL-2 and IFNalpha. Therefore, this study illustrates the superiority of using transcriptionally targeted recombinant retrovirus vectors in cytokine-based gene therapy.
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PMID:The targeted expression of the human interleukin-2/interferon alpha2b fused gene in alpha-fetoprotein-expressing hepatocellular carcinoma cells. 1019 Mar 13

Differential cDNA displays between hepatocellular carcinoma and adjacent non-malignant tissues have previously detected a PCR product, hIRH (human intercrine reduced in hepatomas), equivalent to SDF1alpha/PBSF whose mRNA was lost from human hepatocellular carcinoma and other malignant and pre-malignant samples and malignant cell lines. There are no reports to date of the mRNA status of the receptor for hIRH/SDF1alpha/PBSF, CXCR4 in malignant tissues. We report here that there is a reduction in the mRNA expression of CXCR4 in hepatocellular carcinoma as estimated by Northern blot and RT-PCR and compared to the adjacent non-malignant tissue. The average (mean SD) tumor/normal ratio for CXCR4 mRNA expression, determined by RT-PCR, was 0.65 0.36 in 10 pairs of hepatocellular carcinomas. There was no consistent loss of CXCR4 mRNA expression in a range of malignant cell lines. The 3'-non-coding region of hIRH, had typical early response gene element sequences. Despite the presence of these 3'-elements there was no induction of hIRH gene expression in human lung carcinoma A549 cells by tumor necrosis factor alpha, interleukin-2, lipopolysaccharide or phorbol myristic acetate, nor in human melanoma cell line SB-2 by uv irradiation, under conditions which induced the homologue CXC intercrine IL-8 expression. Furthermore, there was no induction of hIRH gene expression, but rather a suppression, upon serum or cytokine addition to serum-deprived fibroblast cell lines, to an in vitro mouse bone marrow preparation, and to monocytic cell line THP-1.
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PMID:Reduced expression of the CXCR4 receptor mRNA in hepatocellular carcinoma and lack of inducibility of its ligand alpha-chemokine hIRH/SDF1alpha/PBSF in vitro. 1020 Mar 43

Receptor-mediated gene delivery is an attractive method for gene transfer in vitro and shows promise for in vivo gene therapy applications. In the current study, we have selected the cytokine interleukin-2 (IL-2) gene to explore the feasibility of receptor-mediated gene transfer into human hepatocellular carcinoma HepG2 cells, using Epstein-Barr virus (EBV)-based vectors. We have developed a targeted DNA delivery system for the treatment of liver cancer by gene therapy. This system utilizes the hepatocyte-specific asialoglycoprotein receptor, which is uniquely expressed on liver cell membranes but not present on other cell types. Galactosylated histone, a ligand to the asialoglycoprotein receptors, was synthesized, and a new EBV-based expression vector bearing the human IL-2 cDNA was constructed and conjugated to the ligand through ionic interactions. The ligand/IL-2 DNA complex was able to bind specifically to cell-surface receptors on the target cell and, when incubated with HepG2 cells, resulted in elevated levels of IL-2 gene expression. These results indicate that therapeutic genes like IL-2 in ligand/DNA complex can be transferred into hepatoma cells via the hepatocyte receptor. This study constitutes an encouraging first step in the assessment of receptor-mediated gene transfer as a technique for gene therapy in liver cancer.
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PMID:Receptor-mediated interleukin-2 gene transfer into human hepatoma cells. 1034 Dec 90

Dietary supplementation with glutamine (Gln), arginine (Arg) or ornithine 2-oxoglutarate (alpha-ketoglutarate; OKG) has attracted recent attention for the potential to improve anti-cancer immune function. However, since these compounds have not been compared systematically in an internally controlled study, their relative efficacy is difficult to estimate. Buffalo rats were fed on nutritionally complete semi-purified diets supplemented with Gln, Arg or OKG for 14 days after implantation of the Morris hepatoma 7777 (n>/=7 per diet). The control diet was made isonitrogenous and isoenergetic by addition of a mixture of non-essential amino acids. After 14 days, peritoneal macrophages and splenocytes were isolated to determine cell phenotypes, macrophage cytostatic activity and natural killer (NK) cell cytotoxicity, as well as nitric oxide (NO) and cytokine production. Diet had no effect on tumour weight (1.6+/-0.2 g; n=59). However, rats fed OKG had increased macrophage cytostatic activity and NK cell cytotoxicity (P<0.05). Although enhanced killing ability by NK cells was associated with higher splenocyte NO production (P<0.04), increased cytotoxicity was not inhibited by a specific inhibitor of inducible NO synthase. The proportion of interleukin-2-receptor-positive T cells after stimulation increased in rats fed OKG (P<0.05); however, cytokine production was not affected by diet. None of OKG, Gln or Arg altered tumour growth compared with a control mixture of non-essential amino acids. These results suggest no net advantage for anti-cancer immunity, but do not preclude benefits in immune responses to disease recurrence or metastasis, therapy or secondary infection.
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PMID:Amino acid nutrition and immune function in tumour-bearing rats: a comparison of glutamine-, arginine- and ornithine 2-oxoglutarate-supplemented diets. 1058 93

Utility of the alpha-fetoprotein (afp) promoter for gene therapy against hepatocellular carcinoma (HCC) is limited because of the weak promoter activity. To circumvent this, the 5.1-kb 5;-flanking sequence of the human afp gene including the entire enhancer and silencer regions as well as the promoter region was employed for achieving strong, HCC-selective transgene expression. To thoroughly inhibit the promoter activity of the 5;-flanking sequence of the human afp gene, the afp 5;-flanking region was inserted downstream of the human interleukin-2 (il-2) gene controlled by the simian-virus-40 (SV40) early promoter. il-2-production ability of HCC cells transduced with the construct was significantly enhanced compared with that transduced with the same construct lacking the afp 5;-flanking region. Importantly, il-2 production of non-HCC cells was substantially inhibited by the addition of the afp 5;-flanking region to the construct. When the afp 5;-flanking region was inserted downstream of the human tumor-necrosis-factor-alpha (tnf-alpha) gene controlled by the retrovirus long-terminal-repeat (LTR) enhancer/promoter, tnf-alpha production ability of HCC cells was significantly enhanced and that of non-HCC cells was significantly suppressed compared with that transduced with the same construct lacking the afp 5;-flanking region. Our results indicated that the afp 5;-flanking region gave the enhanced HCC-selective activity to the non-tissue specific SV40 early promoter and LTR enhancer/promoter. It is essential for successful gene therapy to induce strong, target-cell-selective transgene expression. This novel strategy, therefore, may contribute to the establishment of HCC-selective cancer gene therapy.
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PMID:A novel approach for inducing enhanced and selective transgene expression in hepatocellular-carcinoma cells. 1086 83

The roles of lymphoid elements and apoptosis-related proteins in the development of extremely large hepatomas were studied in rats. Hepatoma cells were inoculated subcutaneously into 6-week-old rats, and 4 months later the quantities of T and B cells, macrophages, and cells positive for Fas, Fas ligand (FasL) and interleukin-2 (IL-2) were immunochemically evaluated in tumors. Grafting of hepatoma cells caused the development of giant tumors that could reach one-third of the rat's body weight. Within the hepatomas, almost all CD8(+) T cells were destroyed as they passed from the tumoral stroma into the parenchyma and came in contact with tumor epithelial cells. This could be the consequence of IL-2 production, since about 90% of tumor cells were CD25(+). The tumoral mass increased despite the significant increase in tumor necrosis. Cells with Ki67 or in mitosis, and cells positive for Fas and FasL were found only among tumor epithelial cells that were necrotic and never among viable cells. We suggest that progress in tumorigenesis is facilitated by inhibition of T helper cells, and the extensive death of T killer cells is caused by the high levels of the tumor produced IL-2.
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PMID:Tumor-induced insufficiency in T cell activity and hyperproduction of interleukin-2 in rat giant hepatomas. 1117 6

A full-length, PRL-inducible complementary DNA (cDNA) encoding a novel, nuclear-targeted carboxypeptidase D isoform (designated CPD-N) was identified in the rat PRL-dependent Nb2-11C and PRL-independent Nb2-Sp lymphoma cell lines by differential display. The CPD-N cDNA (3751 bp) has 99% (3582/3583) homology with rat carboxypeptidase D (CPD; 4377 bp). In comparison to the rat CPD cDNA (ORF of 4134 bp; 180-kDa protein), CPD-N was shorter by approximately 600 bases but contained 148 unique bases at the 5'-end to give an ORF of 3399 bp. RT-PCR with primers specific to the 5'-end of CPD-N or to CPD showed that the CPD-N transcript was expressed in the Nb2-11C and Nb2-Sp cells but was not detected in rat brain or lung. Conversely, the CPD transcript was expressed in rat brain but was not detected in the two Nb2 cell lines. CPD-N expression (7.5-kb messenger RNA) was stimulated by PRL (10 ng/ml) and/or by interleukin-2 (24 U/ml) in Nb2-11C and Nb2-Sp cells. Most rat tissues expressed multiple CPD transcripts (7.5, 4.1, and 2 kb). Curiously, CPD transcripts were low or undetectable in male rat liver but readily detected in female liver, suggesting that sex-specific hormone levels may regulate its expression. Indeed, CPD expression in the PRL-responsive HepG2 hepatoma and MCF-7 breast cancer cell lines was low in control cells but was markedly stimulated by PRL after 3 h. Consistent with the shorter ORF of CPD-N, Western analysis detected proteins of smaller molecular sizes of 160 kDa (abundant) and 117 kDa (weak) in the Nb2-11C cells. The Nb2-Sp cells expressed a single and abundant 117-kDa protein, implicating differential protein processing in the two cell lines. Rat CPD has been reported to colocalize with the trans-Golgi network marker TGN38. Subcellular fractionation showed predominant nuclear localization of CPD-N and trace amounts were detected in the 100,000 x g microsomal fraction after PRL treatment (4 h); in contrast, TGN38 was found only in the microsomal fraction at this time. In cells treated with PRL for 24 h, immunofluorescent confocal microscopy showed nuclear and cytoplasmic distribution of CPD-N. Cytoplasmic CPD-N colocalized with TGN-38 whereas nuclear CPD-N had a mesh-like distribution and colocalized with nuclear lamin B.
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PMID:Identification and nuclear localization of a novel prolactin and cytokine-responsive carboxypeptidase D. 1118 55

The effect of extremely large hepatomas on splenic lymphoid elements and apoptosis-related proteins in rats were studied. Hepatoma cells were inoculated subcutaneously into 6-week-old rats, and 4 months later the quantities of T and B cells, macrophages, and cells positive for Fas, Fas ligand (FasL) and interleukin-2 (IL-2) were immunohistochemically evaluated in spleens. Grafting of hepatoma cells caused hyperplasia of the spleen and development of giant tumors that could reach one-third of the rat's body weight. A 7-fold increase in the weight of the spleen was mainly due to proliferation of B lymphocytes and macrophages in the red pulp, while the relative quantity of CD4+ and CD8+ T cells decreased. Extremely small amount of Fas+ and FasL+ lymphocytes were present in the marginal zone, the follicles, red pulp, and occasionally in the PALS. All the splenic zones were abundant with IL-2+ cells, while macrophages and siderophages were present mainly in the red pulp and in the marginal zone of the white pulp. We suggest that all these changes are compensatory processes of the host's lymphatic system.
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PMID:Effect of giant hepatomas on lymphocyte production and secretion of apoptosis-related proteins in the rat spleen. 1141 Jul 74


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