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)

A major glycoprotein of the plasma membranes of AH-66 hepatoma ascites cells was isolated in essentially pure form and in milligram amounts. The plasma membranes were solubilized with a solution containing both 0.3 M lithium diiodosalycylate and 0.2% cetylpyridinium chloride, and further extracted with 50% phenol, followed by gel filtration on Sepharose 6B in the presence of 0.1% Ammonyx-LO at pH 8.0. The apparent molecular weight of the purified glycoprotein was estimated to be 165 000 in 5.6% polyacrylamide gels, of which 54% was carbohydrate and 46% was protein. The chemical composition of the glycoprotein resembles glycophorin A from human erythrocyte membranes in that it has a high content of N-acetylgalactosamine, N-acetylglucosamine, galactose and sialic acid and a particularly large proportion of serine, threonine, aspartic acid and glutamic acid.
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PMID:Isolation and partial characterization of the major glycoprotein from the plasma membranes of AH-66 hepatoma cells. 46 37

A protein induced by vitamin K absence or antagonist II, PIVKA-II is synthesized in the liver and possesses a structure similar to prothrombin except that ten glutamic acid residues in amino-terminal Gla domain are not completely gamma-carboxylated and are functionally inactive. This protein can be detected in the plasma of patients with hepatocellular carcinoma (HCC) and used as a new tumor marker. To analyze the mechanism of PIVKA-II production in HCC tissue, the prothrombin gene of PIVKA-II-secreting HCC cell lines was sequenced to detect the mutation in the Gla domain and carboxylase recognition site of leader sequence located on exons I and II that may cause the inhibition of carboxylation. Exons I and II and donor and acceptor site of intron I of the prothrombin gene in two HCC cell lines, PLC/PRF/5 and huH-2, were analyzed by polymerase chain reaction (PCR), and the product was sequenced directly. In addition, RNA samples of these cell lines were used for complementary DNA synthesis, followed by PCR and sequencing. The nucleotide sequences of the Gla domain in both HCC cell lines were conserved. One nucleotide change was detected at nt.554 (adenine to guanine), but this did not influence the amino acid sequence. Splicing sites between exons I and II, the leader sequence of the precursor prothrombin, and protease target sites also were conserved as the reported prothrombin gene, and mutations reported for other des-gamma-carboxy coagulation factors were not detected. These results also were confirmed by DNA analysis of seven human fresh-frozen samples (three PIVKA-II-positive HCC samples and four control specimens). The mechanism of PIVKA-II production in HCC is still unclear, but it is not caused by mutation in the prothrombin gene.
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PMID:Nucleotide sequence of prothrombin gene in abnormal prothrombin-producing hepatocellular carcinoma cell lines. 130 75

Biochemical and biological studies have been carried out with 2-desamino-2-methylaminopterin (dmAMT), which inhibits tumor cell growth in culture but is only a weak inhibitor of dihydrofolate reductase (DHFR). Since it was possible that the species responsible for growth inhibition are polyglutamylated metabolites, the di-, tri-, and tetraglutamates of dmAMT were synthesized and tested as inhibitors of purified recombinant human DHFR, murine L1210 leukemia thymidylate synthase (TS), chicken liver glycinamide ribonucleotide formyltransferase (GARFT), and murine L1210 leukemia aminoimidazolecarboxamide ribonucleotide formyltransferase (AICARFT). The compounds with three and four gamma-glutamyl residues were found to bind two orders of magnitude better than dmAMT itself to DHFR, TS, and AICARFT, with 50% inhibitory concentration values in the 200 to 300 nM range against all three enzymes. In contrast, at a concentration of 10 microM, dmAMT polyglutamates had no appreciable effect on GARFT activity. These findings support the hypothesis that dmAMT requires intracellular polyglutamylation for activity and indicate that replacement of the 2-amino group by 2-methyl is as acceptable a structural modification in antifolates targeted against DHFR as it is in antifolates targeted against TS. In growth assays against methotrexate (MTX)-sensitive H35 rat hepatoma cells and MTX-resistant H35 sublines with a transport defect, dmAMT was highly cross-resistant with MTX, but not with the TS inhibitors N10-propargyl-5,8-dideazafolic acid and N-(5-[N-(3,4-dihydro-2-methyl-4-ox-oquinazolin-6-yl)-N- methylamino]thenoyl)-L-glutamic acid, implicating DHFR rather than TS as the principal target for dmAMT polyglutamates in intact cells. On the other hand, an H35 subline resistant to 2'-deoxy-5-fluorouridine by virtue of increased TS activity was highly cross-resistant to N10-propargyl-5,8-dideazafolic acid and not cross-resistant to MTX, but showed partial cross-resistance to dmAMT. Both thymidine and hypoxanthine were required to protect H35 cells treated with concentrations of dmAMT and MTX that inhibited growth by greater than 90% relative to unprotected controls. In contrast, N10-propargyl-5,8-dideazafolic acid and N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)-N-methylamino] thenoyl)- L-glutamic acid required only thymidine for protection. Like MTX, therefore, dmAMT appears to inhibit purine as well as pyrimidine de novo synthesis, and its effect on cell growth probably reflects the ability of dmAMT polyglutamates to not only block dihydrofolate reduction but also interfere with other steps of folate metabolism, either directly or indirectly via alteration of reduced folate pools.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical and biological studies on 2-desamino-2-methylaminopterin, an antifolate the polyglutamates of which are more potent than the monoglutamate against three key enzymes of folate metabolism. 131 37

Contents of 22 amino acids in hepatoma with surrounding and distant liver parenchyma resected from 10 pathologically proven patients were determined using high performance liquid chromatography. Analysis of the results showed that the contents of total amino acids and essential amino acids in hepatoma tissues were much higher than those in the surrounding and distant liver parenchyma. The contents of 11 amino acids, including glutamic acid, asparagine, glutamine, serine, histidine, arginine, tryptophan, methionine, leucine, isoleucine and lysine were higher than those in the surrounding and/or distant liver parenchyma. There was no statistically significant difference of amino acid contents between the surrounding and distant liver parenchyma. Most amino acid contents which increased in hepatoma tissues were positively correlated with tumor volume and/or serum gamma-glutamyl transpeptidase activity. These results suggested that hepatoma tissues can selectively take up the necessary amino acids which fail to be produced by the cancer tissues as raw material for synthesis of protein. The faster the hepatoma grows, the greater the need for amino acidosis. This study may be helpful to the application of imbalanced amino acid for correction of metabolic disturbances in hepatoma patients.
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PMID:[Changes in amino acid contents in hepatocellular carcinoma tissues]. 257 11

In order to increase the selective localization of anti-cancer drugs to the target tumor cells, polyclonal or monoclonal anti alpha-fetoprotein antibody (aAFP) was conjugated with anti-cancer drugs such as daunomycin (DM), adriamycin (AM) and mitomycin C (MMC) by chemical modification. Dextran (Dex) or poly L-glutamic acid (PLGA) was used to bind aAFP with DM (AM) as an intermediate drug carrier. For the conjugation of aAFP with MMC, a direct binding method through the aziridine ring of the activated MMC derivative or an indirect binding method through serum albumin as an intermediate drug carrier was employed. These conjugates caused greater inhibition of both in vitro and in vivo tumor growth of AFP-producing target tumor cells than did a mixture of aAFP and anti-cancer drugs or a simular conjugate of these drugs with normal horse immunoglobulin. AFP has high affinity to unsaturated fatty acids (UFA) such as arachidonic acid (C20:4) and so on. The antitumor effect of UFA-DM conjugate was also assessed using AFP-producing rat ascites hepatoma cells. It was found that UFA-DM conjugated showed highly selective cytocidal effects against the hepatoma cells.
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PMID:[Chemical modification of anti-cancer drugs to increase their affinity to tumor antigens]. 258 Apr 85

The presence and location of cytochrome P-450 in Donryu rat hepatocyte culture lines, Ac2F cells and 3 other cell lines were assessed by indirect immunofluorescence examination using anti-cytochrome P-450 monoclonal antibodies. Ac2F cells and other hepatocyte cell lines were selectively stained at their nuclear envelope, but not the cytoplasm, with a monoclonal antibody selective to a high-spin form of cytochrome P-448 (P-448H), although this monoclonal antibody stained primary cultured normal rat hepatocytes at both cellular components and did not stain hepatoma cells of 2 transplantation lines. The results of unscheduled DNA synthesis assay with Ac2F cells using several carcinogenic aromatic amines (4-aminoazobenzene derivatives and amino acid pyrolysis products) suggested that this nuclear envelope-associated cytochrome P-450 activates a restricted portion of these aromatic amines, i.e., a tryptophan pyrolysis component and a glutamic acid pyrolysis component. These results indicate that rat hepatocyte culture lines lack (or contain a reduced amount of) the cytoplasmic cytochrome P-450 but maintain a characteristic type of cytochrome P-450, probably a kind of cytochrome P-448H in their nuclear envelope, and this may be involved in oxidative metabolism of a restricted portion of aromatic amines.
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PMID:Immunochemically detected nuclear envelope-associated cytochrome P-450 component(s) in rat hepatocyte culture lines. 311 63

The effect of heparin, a polyanionic glycosaminoglycan known to alter the function of many proteins, on insulin binding and bioactivity was studied. Cultured human lymphocytes (IM-9) were incubated with varying concentrations of heparin, then extensively washed, and 125I-labeled insulin binding was measured. Heparin at concentrations used clinically for anticoagulation (1-50 U/ml) inhibited binding in a dose-dependent manner; 50% inhibition of binding occurred with 5-10 U/ml. Scatchard analysis indicated that the decrease in binding was due to a decrease in both the affinity and the apparent number of available insulin receptors. The effect occurred within 10 min at 22 degrees C and persisted even after the cells were extensively washed. Inhibition of insulin binding also occurred when cells were preincubated with heparinized plasma or heparinized serum but not when cells were incubated with normal serum or plasma from blood anticoagulated with EDTA. By contrast, other polyanions and polycations, e.g., poly-L-glutamic acid, poly-L-lysine, succinylated poly-L-lysine, and histone, did not inhibit binding. Heparin also inhibited insulin binding in Epstein-Barr (EB) virus-transformed lymphocytes but had no effect on insulin binding to isolated adipocytes, human erythrocytes, or intact hepatoma cells. When isolated adipocytes were incubated with heparin, there was a dose-dependent inhibition of insulin-stimulated glucose oxidation and, to a lesser extent, of basal glucose oxidation. Although heparin has no effect on insulin binding to intact hepatoma cells, heparin inhibited both insulin binding and insulin-stimulated autophosphorylation in receptors solubilized from these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of heparin on insulin binding and biological activity. 354 43

A 125-kilodalton (kDa) phosphoprotein was isolated from nucleoli of Novikoff hepatoma cells in the presence of various inhibitors of proteases, alkaline phosphatase, and RNase. This protein was the most highly phosphorylated protein found thus far in the nucleolus. The half-life of [32P]phosphate in the 125-kDa phosphoprotein was approximately 60 min. Amino acid analysis of the protein showed it had a high serine content (15.5 mol %), a high glutamine plus glutamic acid content (15.5 mol %), and a high lysine content (10.3 mol %). Phosphoserine was the only phosphorylated amino acid identified. After alkaline hydrolysis of the 32P-labeled protein, ribonucleotides were found which accounted for approximately 8.5% of the [32P]phosphate. After cytidine 3',5'-[32P]diphosphate ([32P]pCp) labeling by RNA ligase, several oligoribonucleotide sequences were purified including GGGCOH and GGGGCOH. The binding of oligonucleotides to peptides was stable under denaturing fractionation conditions including 6 M urea treatment and incubation at 100 degrees C for 10 min in sodium dodecyl sulfate and beta-mercaptoethanol. Furthermore, when nucleotide-peptide complex was treated with ribonuclease T2 followed by snake venom phosphodiesterase, the junctional nucleotide pCp was released. These results suggest that one or more ribonucleotides are covalently bound to the 125-kDa phosphoprotein.
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PMID:Isolation and characterization of a 125-kilodalton rapidly labeled nucleolar phosphoprotein. 408 83

In studies on antitumor antibody-cytotoxic drug conjugates as potential antitumor agents with improved tumor specificity, daunorubicin [(DM) daunomycin] was conjugated with an affinity-purified horse antibody to rat alpha-fetoprotein (AFP) with a novel derivative of poly-L-glutamic acid (PLGA) as the intermediate drug carrier. A single masked thiol group first was introduced by PLGA, and the thiol group was generated from it after the linking of DM to PLGA at the carboxyl groups of PLGA. The thiol group was used selectively for binding PLGA-DM to antibody that had been modified so as to have the maleimide groups. The conjugates (DM:PLGA:immunoglobulin molar ratio, 19.6:2.8:1 or 11.8:1.1:1) were more potent than DM in in vitro cytotoxicity against the AFP-producing rat ascites hepatoma cell line AH66. In therapeutic experiments, the conjugates were more efficacious in prolonging the lives of AH66 hepatoma-bearing DONRYU rats than DM, antibody, a mixture of DM and antibody, or a conjugate similarly prepared with normal horse immunoglobulin.
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PMID:An anti-alpha-fetoprotein antibody-daunorubicin conjugate with a novel poly-L-glutamic acid derivative as intermediate drug carrier. 620 72

In studies on antitumor antibody-cytotoxic drug conjugates as potential antitumor agents with improved tumor specificity, daunomycin (DM) was first linked to a poly-L-glutamic acid (PLGA) derivative having a single masked thiol group. At the thiol group, DM-linked PLGA was bound to horse anti-rat alpha-fetoprotein (AFP) antibody. The anti-AFP antibody-PLGA-DM conjugate (anti-AFP conjugate, DM/PLGA/Ig molar binding ratio, 7.5/1.2/1.0) retained most of the antigen-binding activity of the parent antibody and was more potent than either unconjugated DM, a conjugate similarity prepared with normal horse immunoglobulin (normal conjugate), or an unconjugated mixture of anti-AFP antibody and DM in an in vitro cytotoxicity assay against the AFP-producing rat ascites hepatoma cell line AH66. Anti-AFP conjugate tended to be less cytotoxic than DM against the AFP-nonproducing rat ascites hepatoma AH272 cells, and in this case there was no difference between the cytotoxicities of anti-AFP conjugate and of normal conjugate.
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PMID:A novel method of conjugation of daunomycin with antibody with a poly-L-glutamic acid derivative as intermediate drug carrier. An anti-alpha-fetoprotein antibody-daunomycin conjugate. 620 94


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