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)

In an attempt to evaluate the relationship between circulating immune complexes (CIC) and alpha-fetoprotein (AFP), CIC and AFP were detected in 93 hepatitis B surface antigen-positive (HBsAg+) patients with hepatocellular carcinoma (HCC) and 54 healthy controls. The median level of 3% PEG (polyethylene glycol)-CIC and Clq-CIC were higher in patients than in controls (p less than 0.001). In patients with HCC, the prevalence of elevated 3% PEG-CIC, Clq-CIC, and AFT was 27.9%, 55.9%, and 77.4%, respectively. There was association between AFP and 3% PEG-CIC positivity (p less than 0.01). The median level of 3% PEG-CIC and Clq-CIC increased as AFP levels elevated (p less than 0.05), but decreased as AFP exceeded 1599 ng/ml (p less than 0.05). For adjusting the effect of impaired liver function on the level of CIC, multivariate analysis with stepwise logistic regression revealed that 3% PEG-CIC was associated, in a dose-related fashion, with an increased risk for developing HCC (odds ratio = 1.003, p less than 0.001). These results imply that elevation of 3% PEG-CIC may be related to tumor mass. Additionally, 3% PEG-CIC is a useful marker to monitor therapy with transcatheter arterial embolization in patients with HBsAg+ HCC.
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PMID:Elevation of circulating immune complexes and its relationship to alpha-fetoprotein levels in patients with hepatitis B surface antigen-positive hepatocellular carcinoma. 171 4

The EBV-hybridoma system will be, at present, the best method for rescuing low-frequency tumor-reactive B-cell clones in cancer patients to produce human monoclonal antibodies reactive with tumor-related antigens. To improve this system, we established a nobel fusion partner, 3HL3-6J(C5), which produced hybridomas efficiently (greater than 2 x 10(-5)) after fusion with EBV-transformed B cell lines. TAPC-301 and C5TK1, anti-SRBC IgM and anti-HBs IgG producer, respectively, which provided by Prof. Y. Ono, were used as standard EBV-transformed B cell lines. Their hybridomas were good antibody producers (greater than 10 micrograms/10(6) cells/24 hrs) and their cloning was relatively easy. The fusion rate was improved further when electrofusion was carried out instead of the conventional PEG fusion. Using PBL from a hepatoma patient, human monoclonal autoantibodies reactive with some cytoskeleton structure were easily produced by means of this system.
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PMID:[A strategy for the production of human monoclonal antibodies]. 285 41

The study was prompted by the apparent detection of insulin antibodies in a black patient with HCC and recurrent hypoglycemia who had never received insulin. It consisted of two parts. Initially the sera of 30 individuals (six normoglycemic HCC patients, three with HCC and recurrent hypoglycemia, 11 patients with noncancerous liver diseases, and 10 healthy black controls) were analyzed for the presence of insulin (and glucagon) antibodies by precipitating the bound, labeled hormone with ethanol and also by the technique of radioimmunoelectrophoresis. In the nine HCC patients, binding of 125I-insulin averaged 13% by ethanol separation and 0.018 mU/ml with radioimmunoelectrophoresis, levels that were similar to those of patients with noncancerous liver disease and significantly higher than those of the healthy controls. Mean binding of 125I-glucagon was 11% in HCC sera. Serum binding of labeled hormones correlated significantly with IgG concentrations in the patients. The second part of the study attempted to define the nature of insulin binding in HCC and other forms of liver disease. After confirmation of the increased serum binding of labeled insulin by another method of precipitation, PEG, an attempt was made to compete with the labeled insulin for its serum binding sites by adding a large amount of unlabeled insulin. This binding was not displaceable, however, and was therefore considered nonspecific. When the same procedures were repeated using normal serum to which increasing amounts of gamma globulin were added, the nonspecific binding of insulin increased in a linear fashion. Furthermore, a similar degree of high nonspecific insulin binding occurred in six patients with multiple myeloma and raised serum IgG concentrations. We therefore conclude that in the many clinical situations where hypergammaglobulinemia exists, false positive tests for the detection of antibodies against insulin (and probably other peptide hormones) will emerge unless appropriate methods are used to check for nonspecific peptide binding.
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PMID:Nonspecific blinding of insulin to gamma globulin in the serum of black patients with hepatocellular carcinoma and other forms of liver disease. 618 Jan 12

Independent hybrid clones resulted from the whole cell and microcell-mediated transfer of hamster or mouse fibroblast chromosomes into mouse hepatoma XXIIa cells. The fusion was promoted with PEG, ethidium bromide alone, or in combination with HAT and ouabain, was used for selecting the hybrids. Using indirect immunoautoradiography, three clones (one intra- and one interspecies microcellular; one interspecies, whole cell fusion) have been found to express their hepatic function to synthesize transferrin. The liver specific protein--albumin--was extinguished in all the hybrid combinations. Possible mechanisms of gene expression are discussed. The hybrids selected could be used for mapping chromosomes, coding proteins, as well as for studying regulation in the tandem of albumin and alpha-fetoprotein genes in the mouse genome. The microcell mediated chromosome transfer into differentiated cells has been used to construct original genetical combinations of regulatory and structural elements of the mouse genome.
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PMID:[Ability of the cells of intra- and interspecific hybrids of murine hepatoma XXIIa to synthesize the serum proteins albumin and transferrin]. 619 75

Human intraspecific hybrids were formed between tumor cells isolated from both primary and metastatic tumors and a tissue culture adapted cell line, D98OR, a HeLa derivative which is thioguanine and ouabain resistant. Five different tumor types in all were attempted: renal cell carcinoma, colon adenocarcinoma, melanoma, chrondrosarcoma, and hepatocarcinoma. The tumor tissue was either (1) immediately dissociated and fused, or (2) frozen and later thawed, dissociated, and fused. Two different PEG concentrations were used. The results reported here demonstrate that: (1) hybrid tumor cell lines can be made from several types of cancer, (2) unfrozen tumor tissue fused with D98OR by exposure to 50% PEG appears optimal, (3) chromosome loss, as determined by flow cytometry studies of hybrid DNA content, is minimal, and (4) hybrids have characteristics consistent with derivation from tumor cells rather than derivation from the nonmalignant cells of a tumor.
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PMID:Somatic cell hybridization of human tumor samples. 658 90

The efficacy of tumor therapy using polyethylene-glycol-modified interleukin-2 (PEG-IL-2), alone or in combination with cyclophosphamide, was studied in advanced metastatic disease in the guinea pig. Line 10 (L10) tumor cells appeared in the axillary lymph node only 7 days after intradermal tumor-cell inoculation, and lymph-node leukocytes were almost completely replaced by tumor cells on day 28. Local treatment of the intradermally growing L10 hepatocarcinoma in the guinea pig with a relatively low dose of PEG-IL-2 resulted in regression of the primary tumor and prevention of lymph-node metastases. Therapy was completely curative (4 out of 5 animals) when started on day 7 or 14 after tumor-cell inoculation. When started on day 21, therapy was effective in only some (2 out of 5 cured) of the treated animals. Anti-tumor effects against the primary tumor and against lymph-node metastases were observed only after intratumoral (i.t.) administration of PEG-IL-2. Injection of the agent into or near lymph-node metastases in the absence of the primary tumor had no curative effect. In PBS/BSA-treated control animals the primary tumor and metastases grew progressively. In the treatment of far advanced metastatic disease, the combination of i.t. administration of PEG-IL-2 and i.p. injection of cyclophosphamide (Cy) resulted in improved anti-tumoral effects (5/5 guinea pigs were cured) when compared with monotherapy using either agent (one and none out of 5 animals cured, respectively). PBS/BSA heated controls showed progressive tumor-growth. We conclude that large primary tumors and lymph-node metastases can be treated effectively with PEG-IL-2. The i.t. route of administration is of major importance in the treatment of metastases, since administration of PEG-IL-2 near or into the lymph node had no therapeutic effect. Combination of PEG-IL-2 therapy with systemic injections of Cy significantly improved the curative effects of the treatment of advanced metastatic cancer.
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PMID:PEG-IL-2 therapy of advanced cancer in the guinea pig. Impact of the primary tumor and beneficial effect of cyclophosphamide. 792 81

Methoxypoly(ethylene glycol) (PEG) modification of Escherichia coli beta-glucuronidase (betaG) was examined as a method to improve the stability and pharmacokinetics of antibody-betaG conjugates for the targeted activation of glucuronide prodrugs at tumor cells. Introduction of 3 PEG molecules did not affect betaG activity whereas higher degrees of PEG modification produced progressively greater loss of enzymatic activity. The enzyme was found to be stable in serum regardless of PEG modification. PEG-modified betaG was coupled via a thioether bond to mAb RH1, an IgG2a antibody that binds to the surface of AS-30D hepatoma cells, to produce conjugates with 3 (RH1-betaG-3PEG), 5.2 (RH1-betaG-5PEG) or 9.8 (RH1-betaG-10PEG) PEG molecules per betaG with retention of 75%, 45% and 40% of the combined antigen-binding and enzymatic activity of the unmodified conjugate RH1-betaG. In contrast to the rapid serum clearance of RH1-betaG observed in mice, the PEG-modified conjugates displayed extended serum half-lives. RH1-betaG-3PEG and RH1-betaG-5PEG also exhibited reduced spleen uptake and greater tumor accumulation than RH1-betaG. BHAMG, the glucuronide prodrug of p-hydroxyaniline mustard (pHAM), was relatively nontoxic in vivo. Injection of 6 mg/kg or 12 mg/kg pHAM i.v. depressed white blood cell numbers by 46% and 71% whereas 80 mg/kg BHAMG reduced these levels by 22%. Although the tumor/blood ratio of RH1-betaG-5PEG was adversely affected by slow clearance from serum, combined therapy of small solid hepatoma tumors with this conjugate, followed 4 and 5 days later with i.v. injections of BHAMG, cured all of seven mice with severe combined immunodeficiency. Combined treatment with a control antibody-betaG conjugate and BHAMG delayed tumor growth and cured two of six mice while treatment with pHAM or BHAMG alone was ineffective.
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PMID:Poly(ethylene glycol) modification of beta-glucuronidase-antibody conjugates for solid-tumor therapy by targeted activation of glucuronide prodrugs. 929 32

To investigate the delivery of DNA into cells, lactose-poly(ethylene glycol)-grafted poly-L-lysine (Lac-PEG-PLL) polymers were synthesized as polymeric gene carriers. The new synthetic carriers, varying the substitution ratio of lactose-poly(ethylene glycol) (lactose-PEG), were characterized by NMR spectroscopy and size-exclusion chromatography. Electrophoretic mobility assay confirmed that the new gene carrier makes a complex with plasmid DNA. The attached poly(ethylene glycol) gives better solubility properties to gene/carrier complex. Transfection experiments showed that Lac-PEG-PLL efficiently delivers DNA to a hepatoma cell line in vitro; the best efficiency was achieved at a 1:3 weight ratio of DNA to carrier. As the lactose-PEG substitution content increased up to 30%, the transfection efficiency increased, which demonstrates that the lactose serves as a targeting moiety. No considerable cytotoxicity was observed due to Lac-PEG-PLL or its complex with DNA within the concentration range for this experiment. The use of chloroquine increased transfection efficiency that indicates the involvement of hydrolytic degradation of the system in lysosome. It is likely that plasmid DNA/Lac-PEG-PLL complexes enter the cells through a receptor-mediated endocytosis mechanism. These results show that Lac-PEG-PLL can form a complex with plasmid DNA and serve as an efficient gene delivery carrier with lower cytotoxicity compared to that of poly-L-lysine. Therefore, it is expected that our Lac-PEG-PLL carrier can be used as an in vivo gene delivery vector.
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PMID:Lactose-poly(ethylene glycol)-grafted poly-L-lysine as hepatoma cell-tapgeted gene carrier. 981 64

Liposome uptake by HepG2 human hepatoma cells was investigated in comparison with the uptake by J774 murine macrophage-like cells. HepG2 cells accumulated liposomes (egg yolk phosphatidylcholine (EPC)/Chol; 75/25, diameter 0.2 micron) at 37 degrees C comparably to J774 macrophage-like cells. Confocal microscopic observations revealed that J774 cells internalized EPC/Chol liposomes efficiently but HepG2 cells kept most of the liposomes bound on their plasma membrane surfaces. Poly(ethylene glycol) (PEG)-coated liposomes (0.2 micron) containing poly(ethylene glycol) cholesteryl ether (PEG-Chol) avoided cellular uptake at 37 degrees C by either cell line. In both cell lines, binding of PEG-coated liposomes was lower than that of EPC/Chol liposomes when incubation was carried out at 4 degrees C. To analyze the binding process at 37 degrees C, surface-bound liposomes were removed from the cells by pronase treatment. A reduction of the amount of bound-liposomes on cell surfaces was observed in the case of PEG-coated liposomes. Therefore, PEG-coating reduces direct binding of liposomes to the cell surfaces. The presence of apolipoprotein E (apoE) increased the uptake to EPC/Chol liposomes via its receptor in both cell lines. In contrast, cellular uptake of PEG-coated liposomes was not enhanced by treatment with apoE. Therefore, while apoE-mediated liposome uptake occurs in the case of EPC/Chol liposomes, it does not occur for PEG-coated liposomes; PEG-coating also inhibits protein-mediated binding to the cells. These results further imply that elusion from liver clearance of PEG-coated liposomes is not only due to the reduction of uptake by Kupffer cells but also by hepatocytes when liposomes are small enough to go through the fenestrates of the endothelial lining.
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PMID:Poly(ethylene glycol) derivative of cholesterol reduces binding step of liposome uptake by murine macrophage-like cell line J774 and human hepatoma cell line HepG2. 988 Sep 10

RHI-betaG-PEG, formed by linking poly(ethylene glycol)-modified beta-glucuronidase to Mab RH1, was employed to examine bystander killing of antigen-negative N1S1 rat hepatoma cells by activation of a glucuronide prodrug (BHAMG) of p-hydroxyaniline mustard (pHAM) at antigen-positive AS-30D rat hepatoma cells. Sequential treatment of cells with 10 microg ml(-1) RH1-betaG-PEG and 20 microM BHAMG was not toxic to N1S1 cells but killed 99% of AS-30D cells. Over 98% of N1S1 cells, however, were killed in mixed populations containing as few as 2% AS-30D cells after identical treatment, demonstrating an in vitro bystander effect. Subcutaneous injection of AS-30D and N1S1 cells in BALB/c nu/nu mice produced solid tumours containing both cells. Uptake of radiolabelled RH1-betaG-PEG in solid AS-30D and mixed AS-30D/N1S1 tumours was 11.6 and 9.3 times greater than a control antibody conjugate 120 h after i.v. injection. Intravenous treatment with RH1-betaG-PEG and BHAMG cured seven of seven nude mice bearing solid s.c. AS-30D tumours and significantly delayed, compared with control conjugate and prodrug treatment, the growth of mixed N1S1/AS-30D tumours with one cure, showing that targeted activation of BHAMG kills bystander tumour cells in vivo.
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PMID:Bystander killing of tumour cells by antibody-targeted enzymatic activation of a glucuronide prodrug. 1018 79


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