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)

We report a case of hepatocellular carcinoma (HCC) treated successfully by transarterial chemoembolization (TACE) followed by combination therapy of 5-fluorouracil (5-FU) and pegylated interferon-alpha (PEG-IFN-alpha). In the present case, the patient had massive and advanced HCC with a diameter of over 8 cm located in segment 7 (S7) of the liver. Furthermore, the tumor invaded into the major branch of the portal vein (Vp3). After TACE, combined administration of 5-FU and PEG-IFN-alpha was performed for 5 mo. HCC was totally eradicated and the serum levels of tumor markers were markedly decreased by the treatment. Although it has been reported that the combined use of conventional IFN-alpha and 5-FU showed striking effects on HCC in some cases, this case may suggest the more promising effect of PEG-IFN-alpha with a long-lasting effect, in the combined use with 5-FU for the treatment of massive advanced HCC.
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PMID:Successful treatment of advanced hepatocellular carcinoma by combined administration of 5-fluorouracil and pegylated interferon-alpha. 1614 57

The asialoglycoprotein receptor (ASGP-R) on the hepatocyte membrane is a specific targeting marker for gene and drug delivery. Polyethylenimine (PEI) is a polycationic nonviral vector that is used for gene transfer. We have synthesized galactosylated polyethylenimine-graft-poly(ethylene glycol) (GPP) for performing gene delivery to the hepatocytes. The present study reports on the in vitro and in vivo data that was achieved in hepatoma bearing transgenic mice. The cytotoxicity was decreased with the increasing PEG content. The particle size of the complex was increased with the increasing PEG at an N/P ratio of 3.0, while the zeta potentials were decreased. The (99m)Tc labeled complexes were transfected into HepG2 and HeLa cells, while the GFP reporter genes were mainly expressed in the HepG2 cells. The in vivo data was achieved in ALB/c-Ha-ras transgenic mice. (99m)Tc labeled GPP(50)/DNA was injected into the mice via the tail vein, and the gamma images were acquired at 5, 15 and 30 min. The (99m)Tc labeled complexes were mainly localized in the heart and liver, and they were excreted through the kidneys. The GFP gene was mainly expressed in the proliferating cells at the tumor periphery. This result was confirmed by PCNA staining. The GPP(50)/DNA complexes were bound to ASGP-R of the proliferating hepatocytes in vitro and in vivo. The present results demonstrate the feasibility of nonviral gene transfer using galactosylated PEI-PEG in vivo.
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PMID:Asialoglycoprotein receptor targeted gene delivery using galactosylated polyethylenimine-graft-poly(ethylene glycol): in vitro and in vivo studies. 1625 76

Cirrhosis is the result of chronic inflammation and of the progressive increase of fibrosis. In France, hepatitis C infection is the second cause of cirrhosis after alcohol abuse. The other causes of cirrhosis are: hepatitis B infection, genetic haemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, drug-induced cirrhosis, secondary biliary cirrhosis, Wilson's disease and al-antitrypsin deficiency. Etiological treatment is based upon: abstinence in case of alcoholic cirrhosis, the combination of pegylated interferon alpha (PEG IFN) with ribavirin in case of C viral cirrhosis, the PEG IFN and the nucleoside analogs in case of B viral cause; corticosteroids and immunosuppressive drugs in case of autoimmune cirrhosis; venesections in case of genetic haemochromatosis and stopping the drug in case of drug-induced cirrhosis. The complications of cirrhosis such as ascites, oesophageal varices, bleeding, hepatic encephalopathy and hepatocellular carcinoma mainly explain the high rate of morbidity and mortality. Liver transplantation is the established therapy for decompensated liver disease of any etiology significantly changed the outcome of patients with advanced cirrhosis.
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PMID:[Liver cirrhosis in adults: etiology and specific treatments]. 1625 95

In order to obtain an HCC-selective drug delivery system, a novel functional lipid, which is cleaved by the protease activity of matrix metalloproteinase-2 (MMP-2), was developed. The amino group of dioleoylphosphatidylethanolamine (DOPE) was conjugated with PEGylated MMP-2 substrate peptide (Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln), and MMP-2-cleavable PEG-Peptide-DOPE (PEG-PD) was synthesized. When PEG-PD was incorporated in galactosylated liposomes (Gal-PEG-PD-liposomes), we expected that Gal-PEG-PD-liposomes would not be taken up by normal hepatocytes due to the steric hindrance effect, but would be activated around HCC cells by secreted MMPs. In the pretreatment by hMMP2 (1, 5, and 10mug/ml), an hMMP2 concentration-dependent higher uptake of Gal-PEG-PD-liposomes was observed in HepG2 cells, suggesting PEG-PD cleavage. In the presence of an excess of galactose, the uptake of Gal-PEG-PD-liposomes with hMMP2 was significantly inhibited, suggesting asialoglycoprotein receptor-mediated uptake of Gal-PEG-PD-liposomes following the PEG-PD cleavage. Pretreatment of Gal-PEG-PD-liposomes with the conditioned medium of B16BL6, which contained secreted MMPs, enhanced the binding to HepG2 cells, as in the case of hMMP-2 treatment. Moreover, the cytotoxicity of N(4)-octadecyl-1-beta-d-arabinofuranosylcytosine (NOAC) incorporated Gal-PEG-PD-liposomes was enhanced by hMMPs (5mug/ml) and its cytotoxicity was significantly reduced by the presence of an excess of galactose in HepG2 cells. In conclusion, Gal-PEG-PD-liposomes were successfully developed for novel HCC-selective targeting.
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PMID:Novel PEG-matrix metalloproteinase-2 cleavable peptide-lipid containing galactosylated liposomes for hepatocellular carcinoma-selective targeting. 1648 46

Pheonix is developing ADI-PEG-20, a PEGylated arginine deiminase for the potential treatment of hepatocellular carcinoma, for which the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products have granted the drug Orphan Drug status, and melanoma, for which the FDA has also awarded ADI-PEG-20 Orphan Drug status. ADI-PEG-20 is also being investigated for the potential treatment of influenza virus infection and hepatitis C virus infection.
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PMID:Drug evaluation: ADI-PEG-20--a PEGylated arginine deiminase for arginine-auxotrophic cancers. 1677 44

HCV infection is one of the leading causes of chronic liver disease worldwide,and it results in cirrhosis, liver failure, and HCC. As a result, hepatitis C cirrhosis has become the principal indication for liver transplantation. Ironically,HCV infection can be cured with available antiviral therapies, but only a minority of infected persons has ever been treated. The current standard of therapy isa combination of PEG-IFNalpha and ribavirin, which produces high rates of SVRs(absence of detectable HCV RNA at least 24 weeks after cessation of therapy):42% to 56% in genotype 1 and 75% to 84% in genotypes 2 and 3. Recent reports indicate that the less frequent genotypes 4, 5, and 6 also are responsive to combination therapy. Recommendations for treatment of conventional and special patient populations were reviewed in detail. Newer therapeutics that are entering clinical trials provide hope that SVRs may be possible in patients who are difficult to treat and in nonresponders to current therapy.
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PMID:Treatment of hepatitis C infection. 1688 75

Peptides in bee venom (PBV) have attracted considerable attention for anti-cancer therapy. In this study, sterically stabilized liposomal PBV (PBV-SL) was prepared using Soybean phosphatidylcholine, cholesterol, and the cholesterol derivatives of PEG with terminal COOH groups. The humanized anti-hepatoma disulfide-stabilized Fv (hdsFv25) was coupled to sterically stabilized liposomes. The hdsFv25-immunoliposome has strong affinity and specificity to SMMC-7721 cells in vitro. PBV-loaded sterically stabilized liposomes modified with the hdsFv25 can kill SMMC-7721 cells in vitro with higher efficiency than non-targeted liposomes. These results demonstrate that this strategy should also be applicable to immunotherapy for other cancers.
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PMID:Preparation and targeted delivery of immunoliposomes bearing poly(ethylene glycol)-coupled humanized anti-hepatoma disulfide-stabilized Fv (hdsFv25) in vitro. 1696 11

CS (chitosan) has emerged as a promising non-viral vector for gene delivery because of its ability to form complexes with pDNA (plasmid DNA) and enhance its transport across cellular membranes through endocytosis. Complexes of CS and pDNA may improve transfection efficiency; however, they are not capable of sustained DNA release and prolonging gene transfer. In order to achieve prolonged delivery of CS-DNA complexes, we prepared CS NP (nanoparticle) and CS-DNA complexes. alpha-Methoxy-omega-succinimidylpoly(ethylene glycol) was then conjugated to the surface of CS-DNA complexes using an active ester scheme; finally, the potential of PEGylation [poly(ethylene glycol)ylation] of CS NP as a non-viral gene-delivery vector to transfer exogenous genes in vitro and in vivo were examined. Electrophoretic analysis suggested that CS NPs could protect the DNA from nuclease degradation. The pDNA carried by CS NPs could enter and be expressed in HepG2 cells. However, the transfection efficiency was very low and the highest dose of DNA transferred was 1.6 microg. The transfection activities of CS-DNA-PEG were preserved and a higher dose (2.4 microg) of pDNA was transferred. This indicated that the transfection efficiency of the PEGylated complexes had been improved. In vivo experiments also showed that CS-DNA-PEG complexes mediated higher gene expression in tissues than did CS-DNA complexes, and that gene expression in tumours induced by CS-DNA-PEG complexes was the highest of all. These results suggested that PEGylation of CS-DNA complexes improves non-viral gene delivery in vitro or in vivo and has the potential to deliver therapeutic genes directly into hepatoma tissues.
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PMID:A novel PEGylation of chitosan nanoparticles for gene delivery. 1714 12

Persistent infection with hepatitis C virus (HCV) is a major cause of liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Here we report that inhibition of heat shock protein 90 (Hsp90) is highly effective in suppressing HCV genome replication. In HCV replicon cells, HCV replication was reduced by Hsp90 inhibitors and by knockdown of endogenous Hsp90 expression mediated by small-interfering RNA (siRNA). The suppression of HCV replication by an Hsp90 inhibitor was prevented by transfection with Hsp90 expression vector. We also tested the anti-HCV effect of Hsp90 inhibition in HCV-infected chimeric mice with humanized liver. Combined administration of an Hsp90 inhibitor and polyethylene glycol-conjugated interferon (PEG-IFN) was more effective in reducing HCV genome RNA levels in serum than was PEG-IFN monotherapy. These results suggest that inhibition of Hsp90 could provide a new therapeutic approach to HCV infection.
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PMID:Hsp90 inhibitors suppress HCV replication in replicon cells and humanized liver mice. 1719 31

This study communicates the molecular design, preparation, and biological application of novel symmetric amphiphilic polycationic dendritic poly(L-lysine)-b-poly(L-lactide)-b-dendritic poly(L-lysine) D2-LLA15-D2 bearing two two-generation poly(L-lysine) PLL dendrons D2 and a central hydrophobic biodegradable poly(L-lactide) block LLA15. First, an amino-protected precursor of L1-OH was designed and synthesized and was further employed to prepare L1-LLA15 with an organic 4-(dimethylamino)-pyridine-mediated living-ring-opening polymerization of l-lactide. Subsequently, the hydroxy end-capped L1-LLA15 was coupled to synthesize a new triblock L1-LLA15-L1 with two one-generation amino-protected PLL dendrons L1. Furthermore, with a repeated trifluoroacetic-acid-mediated amino deprotection-protection cycle, new amphiphilic triblock D2-LLA15-D2 was successfully prepared. By means of NMR, mass spectrometry, and gel permeation chromatography, these synthetic precursors and final amphiphilic product were characterized to bear well-defined triblock structures. In addition, this synthesized amphiphilic triblock polycationic macromolecule was applied as a new polycationic plasmid DNA carrier, and its DNA binding affinity was examined via an agarose electrophoresis and a fluorescence titration assay along with two important references of hydrophilic dendritic D2-HEX-D2 and double-hydrophilic D2-PEG-4K-D2 bearing the same two D2 dendrons; much enhanced DNA binding affinity was interestingly revealed for the new amphiphilic structural D2-LLA15-D2. Moreover, the assembled polyplex microparticles of plasmid DNA/polycationic carrier were further analyzed by dynamic light scattering and transmission electron microscopy, indicating their averaged nanoparticle size around 150-200 nm. As for the cytotoxicity of the new D2-LLA15-D2, MTT assays were conducted with a human hepatocellular carcinoma cell line (SMMC-7721), indicating a very low cytotoxicity as compared with commercial linear PLL-23K and PEI-2K, and a DNase I degradation of the assembled polyplex particles was also done in the HBS buffer solution to evaluate their stabilities. Finally, employing the new amphiphilic D2-LLA15-D2 as gene carrier, in vitro gene transfection experiments were conducted with the SMMC-7721 cell line, indicating a transfection efficiency increase of at least 10 times higher than that of the naked plasmid DNA under a N/P charge ratio of 10. Therefore, these interesting results may provide a new possible way to construct efficient polycationic macromolecular gene carriers with low toxicity and less expensive low-generation PLL dendrons.
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PMID:Novel symmetric amphiphilic dendritic poly(L-lysine)-b-poly(L-lactide)-b-dendritic poly(L-lysine) with high plasmid DNA binding affinity as a biodegradable gene carrier. 1745 96


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