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)

Rats bearing Reuber H-35 or Novikoff hepatomas and mice bearing L1210 or L5178Y murine leukemias exhibited elevated serum levels of fetuin : N-acetylneuraminic acid transferase (EC 2.4.99.1) activity. The serum transferase activity could be correlated with the growth rate of the tumor; in animals bearing the more rapidly growing Novikoff hepatoma, activity was higher than in animals bearing the Reuber H-35 hepatoma. Higher transferase levels were also found in L1210 leukemic mice than in mice with the slightly slower growing L5178Y leukemia. Serum from rats bearing Reuber H-35 hepatoma and mice bearing L1210 murine leukemia had elevated levels of alpha- and beta-glucosidase (EC 3.2.1.20 and EC 3.2.1.21), alpha- and beta-galactosidase (EC 3.2.1.22 and (3.2.1.23), beta mannosidase (EC 3.2.1.25), alpha- and beta-fucosidase (EC 3.2.1.- and EC 3.2.1.38), beta-N-acetylglucosaminidase (EC 3.2.1.30) and acid phosphatase (EC 3.1.3.2); alpha-mannosidase (EC 3.2.1.24), beta-N-acetylgalactosaminidase (EC 3.2.2.-) and beta-xylosidase (EC 3.2.1.37) were not elevated. In animals bearing Reuber H-35 hepatoma, host liver levels of glycosidases, beta-glucuronidase (EC 3.2.1.31) and acid phosphatase were elevated over both the control and the hepatoma values. The data are interpreted to mean that the tumors or various host tissues release large quantities of enzymes into the serum and that enzyme levels in host organs may also be affected by the tumor.
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PMID:Serum and host liver activities of glycosidases and sialyltransferases in animals bearing transplantable tumors. 17 98

The ascites form of a chemically induced guinea pig hepatoma, line-10, was resistant to killing in vitro by xenogeneic antibody and guinea pig complement. Pretreatment of line-10 cells with certain proteolytic enzymes rendered tham susceptible to the killing action of antibody and guinea pig complement. The effects of enzyme pretreatment were dependent on enzyme concentration, temperature, and could be blocked by addition of competitive or non-competitive inhibitors. The effect of the enzyme treatment could reversed by incubating the treated cells at 37 degrees C (but not at 0 degrees C), in the absence of the enzyme. Effective enzymes included ficin, bromelain, pronase, elastase, papain, trypsin, collagenase, lipases type I and type VI, and the neuraminidase preparation isolated from Clostridium perfringens. The activity of the lipase preparations and the neuraminidase preparation isolated from Clostridium perfringens appeared to be caused by proteolytic enzyme contamination. Enzyme preparations that proved ineffecitve in rendering the line-10 cells sensitive to killing by antibody and guinea pig complement included DNase, RNase, beta-glucuronidase type 6A or type B10, hyaluronidase type V or type VI, and pectinesterase.
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PMID:Lysis of tumor cells by antibody and complement. VI. Enhanced killing of enzyme-pretreated tumor cells. 17 70

[G-3H]Dopamine (3,4-dihydroxyphenethylamine) metabolism in human skin fibroblasts and rat hepatoma cells in culture was determined by high-pressure liquid-chromatographic analysis of both cell extract and uptake medium. Conjugated metabolites were selectively hydrolysed by incubation with arylsulphatase or beta-glucuronidase before analysis. The principal metabolites of dopamine in fibroblast cells are 3-methoxytyramine 4-O-sulphate and 3-methoxytyramine. No significant differences, either in the amounts of these metabolites or in the amount of dopamine metabolism, were observed in fibroblasts from both normal and homocystinuric individuals. In rat hepatoma cells, the major metabolite of dopamine was 3-methoxytyramine 4- or 3-O-glucuronide; lower concentrations of dopamine 4- or 3-O-glucuronide, 4-hydroxy-3-methoxyphenylacetic acid, 3,4-dihydroxyphenylacetic acid and two unidentified glucuronide conjugates were also observed. Significant differences in the relative concentrations of these metabolites in cell and uptake medium were observed in both cell systems.
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PMID:Extensive conjugation of dopamine (3,4-dihydroxyphenethylamine) metabolites in cultured human skin fibroblasts and rat hepatoma cells. 56 77

An enzyme-linked immunosorbent assay (ELISA) was developed for human beta-glucuronidase, using a specific polyclonal antibody raised against the purified enzyme. beta-Glucuronidase from human liver consisted of three subunits with molecular mass of 76, 64 and 18 kDa. The assay offered a specific, sensitive and convenient means of measuring immunoreactive beta-glucuronidase in human sera. beta-Glucuronidase activity determined by the conventional method appeared to be extremely low, indicating that in human sera beta-glucuronidase exists in an enzymatically inactive form. The sensitivity of the assay permitted the detection of 1-100 ng of purified beta-glucuronidase. A mean serum level in normal subjects was 108 +/- 25 ng/ml (mean +/- S.D.). A high level of beta-glucuronidase was found in sera of patients with severe hepatocellular necrosis, including liver cirrhosis (152 +/- 130 ng/ml) and chronic active hepatitis (220 +/- 99 ng/ml), whereas no significant increase of the enzyme protein was observed in chronic persistent hepatitis (102 +/- 42 ng/ml). beta-Glucuronidase was also increased in sera of patients with primary hepatoma (156 +/- 125 ng/ml). The immunoreactive beta-glucuronidase determined in this assay was thought to be a supplementary serological indicator for hepatocellular necrosis.
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PMID:Serum immunoreactive beta-glucuronidase determined by an enzyme-linked immunosorbent assay in patients with hepatic diseases. 163 57

Cancer chemotherapy may be improved by increasing antineoplastic drug specificity for tumor cells. We have synthesized a glucuronide prodrug that can be enzymatically converted to an antineoplastic agent at tumor cells that are able to bind beta-glucuronidase-monoclonal antibody conjugates. The glucuronide prodrug BHAMG, the tetra-n-butyl ammonium salt of (p-di-2-chloroethylaminophenyl-beta-D-glucopyranoside) uronic acid, was 150 times less toxic than the parent drug, N,N-di-(2-chloroethyl)-4-hydroxyaniline, to HepG2 human hepatoma cells and over 1000-fold less toxic than the parent drug to AS-30D rat hepatoma cells in vitro. In the presence of beta-glucuronidase, BHAMG was activated and became as toxic as the parent drug N,N-di-(2-chloroethyl)4-hydroxyaniline. A conjugate (RH1-beta G) was formed by linking beta-glucuronidase to a monoclonal antibody which binds to an antigen expressed on the surface of AS-30D cells. The concentration of BHAMG causing 50% inhibition of AS-30D cellular protein synthesis was reduced over 1000-fold, from greater than 770 microM to less than 0.74 microM after these cells were preincubated with RH1-beta G. Specificity of BHAMG activation at antigen-positive cells was shown by monoclonal antibody RH1 blocking of RH1-beta G conversion of BHAMG to toxic drug and by the inability of BHAMG to be converted to active drug when antigen-negative control cells were preincubated with RH1-beta G. Our results show that the targeted-beta-glucuronidase activation of BHAMG can increase the specificity of chemotherapy for rat hepatoma in vitro and suggest that the targeted activation of glucuronide prodrugs may be useful for cancer therapy.
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PMID:Specific activation of glucuronide prodrugs by antibody-targeted enzyme conjugates for cancer therapy. 164 40

beta-Glucuronidase, a lysosomal hydrolase, was purified from human liver tissue, and an enzyme-linked immunosorbent assay was developed using specific antibody against the enzyme. Using the assay procedure, the serum immunoreactive beta-glucuronidase (beta-glucuronidase) was determined in 190 patients with various liver diseases and in 53 healthy controls to examine whether or not the serum level of beta-glucuronidase would successfully reflect the degree of histological hepatic cell necrosis. beta-Glucuronidase was also determined at regular intervals in 28 patients with chronic hepatitis to investigate the clinical usefulness of serial measurement of the enzyme to predict the histological progression of hepatitis. These 28 patients could be subdivided into three groups, "continuously low type", "labile type" and "elevated type" according to the profiles of fluctuation of serum beta-glucuronidase values. Serum beta-glucuronidase was significantly increased in patients with hepatoma, liver cirrhosis and chronic active hepatitis compared with normal controls. There was significant positive correlation between the beta-glucuronidase and the degree of hepatic cell necrosis determined by histological observation, on the other hand, there was no statistical correlation between the transaminase activities and the degree of hepatic cell necrosis. It was confirmed in immunohistochemical study that the increased beta-glucuronidase in serum has been released from necrotic hepatic cells into blood stream. It was speculated that the elevation of serum transaminase activities had resulted from the alteration in the membrane permeability of hepatic cells rather than from hepatocellular necrosis. Histological progression of hepatitis was found in 8 of 10 patients (80%) of "labile" and "elevated type", while it was found only 3 of 18 patients (16.7%) of "continuously low type". These results suggested that the serial measurement of beta-glucuronidase could be used for an indicator to predict the histological progression of hepatitis.
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PMID:[Measurement of serum immunoreactive beta-glucuronidase: a possible serological marker for histological hepatic cell necrosis and to predict the histological progression of hepatitis]. 165 3

A monoclonal antibody (2C5) raised against rat liver lysosomal membranes was used to identify a 78-kD glycoprotein that is present in the membranes of both endosomes and lysosomes and, therefore, is designated endolyn-78. In cultures of rat hepatoma (Fu5C8) and kidney cells (NRK), this glycoprotein could not be labeled with [35S]methionine or with [32P]inorganic phosphate but was easily labeled with [35S]cysteine and [3H]mannose. Pulse-chase experiments and determinations of endoglycosidase H (endo H) sensitivity showed that endolyn-78 is derived from a precursor of Mr 58-62 kD that is processed to the mature form with a t1/2 of 15-30 min. The protein has a 22-kD polypeptide backbone that is detected after a brief pulse in tunicamycin-treated cells. During a chase in the presence of the drug, this is converted into an O-glycosylated product of 46 kD that despite the absence of N-linked oligosaccharides is effectively transferred to lysosomes. This demonstrates that the delivery of endolyn-78 to this organelle is not mediated by the mannose-6-phosphate receptor (MPR). Immunocytochemical experiments showed that endolyn-78 is present in the limiting membranes and the interior membranous structures of morphologically identifiable secondary lysosomes that contain the lysosomal hydrolase beta-glucuronidase, lack the MPR, and could not be labeled with alpha-2-macroglobulin at 18.5 degrees C, a temperature which prevents appearance of endocytosed markers in lysosomes. Endolyn-78 was present at low levels in the plasma membrane and in peripheral tubular endosomes, but was prominent in morphologically diverse components of the endosomal compartment (vacuolar endosomes and various types of multivesicular bodies) which acquired alpha-2-macroglobulin at 18.5 degrees C, and frequently contained substantial levels of the MPR and variable levels of beta-glucuronidase. On the other hand, the MPR was very rarely found in endolyn-containing structures that were not labeled with alpha-2-macroglobulin at the low temperature. Thus, the process of lysosomal maturation appears to involve the progressive delivery of lysosomal enzymes to various types of endosomes that may have already received some of the lysosomal membrane proteins. Although endolyn-78 would be one of the proteins added early to endosomes, other lysosomal membrane proteins may be added only to multivesicular endosomes that represent very advanced stages of maturation.
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PMID:Endolyn-78, a membrane glycoprotein present in morphologically diverse components of the endosomal and lysosomal compartments: implications for lysosome biogenesis. 265 37

beta-Glucuronidases purified from human hepatoma and from normal liver could serve as a substrate for a cAMP-dependent protein kinase. The rate of phosphorylation reaction of the hepatoma beta-glucuronidase was rapid, whereas that of the normal liver beta-glucuronidase was slow and much lower. Stoichiometry of phosphorylation was 4.3 and 0.46 mol of phosphate/mol of the beta-glucuronidase from the hepatoma and normal liver, respectively. Tryptic peptide mapping of 32P-labeled beta-glucuronidase from hepatoma identified two distinct phosphopeptides (X and Y). The peptide from hepatoma hydrolase was phosphorylated predominantly at the X, while the peptide Y was the major phosphopeptide in the hydrolase of normal liver. Analysis of phosphoamino acids revealed two sites, phosphoserine and phosphothreonine. beta-Glucuronidase from hepatoma consisted of a major subunit with molecular mass of 64,000 (64 kDa) and a minor subunit with 76 kDa, whereas the hydrolase from normal liver had almost exclusively 64 kDa subunit. 32P-labeled beta-glucuronidase indicated that the 64 kDa subunit was phosphorylated both in hepatoma and normal liver beta-glucuronidases.
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PMID:Phosphorylation of beta-glucuronidases from human normal liver and hepatoma by cAMP-dependent protein kinase. 283 20

beta-Glucuronidase purified from human hepatocellular carcinoma consisted of a major subunit with molecular weight of 64,000 (64K-Da) and a minor 76K-Da subunit, whereas the hydrolase from normal liver had almost exclusively 64K-Da subunit. beta-Glucuronidase from the hepatoma and normal liver could serve as a substrate for a cAMP-dependent protein kinase. The rate of phosphorylation reaction of the hepatoma beta-glucuronidase was rapid, whereas that of the normal liver beta-glucuronidase was slow and much lower. Stoichiometry of beta-glucuronidase was 4.3 mol and 0.46 mol of phosphate per mol of the beta-glucuronidase from the hepatoma and normal liver, respectively. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of 32P-labeled beta-glucuronidase indicated that the 64K-dalton subunit was phosphorylated both in hepatoma and normal liver beta-glucuronidase. Tryptic peptide mapping of 32P-labeled beta-glucuronidase from hepatoma identified two distinct phosphopeptides (X and Y). The peptide from hepatoma hydrolase was phosphorylated predominantly at the X, while the peptide Y was the major phosphopeptide in the hydrolase of normal liver. Two-dimensional analysis of phosphoamino acids revealed two sites, phosphoserine and phosphothreonine.
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PMID:[Cancer-associated alterations of human hepatocellular carcinoma beta-glucuronidase--study on phosphorylation by 3', 5'-cyclic AMP dependent-protein kinase]. 283 6

We have cloned and sequenced the full-length cDNA for the human cation-independent mannose 6-phosphate receptor from four overlapping clones. The 9104-nucleotide sequence contains 7473 nucleotides which encode a protein of 2491 amino acids. The amino acid sequence includes a putative signal sequence of 40 amino acids, an extracytoplasmic domain consisting of 15 homologous repeat sequences of 134-167 amino acids, a transmembrane region of 23 amino acids, and a cytoplasmic domain of 164 amino acids. The predicted molecular size is greater than 270 kDa. Repeats 7-15 of the extracytoplasmic domain of the human receptor are highly homologous with the sequence recently reported for the partial cDNA for the bovine receptor (Lobel, P., Dahms, N. M., Breitmeyer, J., Chirgwin, J. M., and Kornfeld, S. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 2233-2237). The nucleotide sequence for the full-length cDNA and the deduced amino acid sequence for the cation-independent mannose 6-phosphate receptor, which are reported here, are strikingly similar (99.8% identical at the nucleotide level and 99.4% identical at the amino acid level) to those recently reported for the human insulin-like growth factor II receptor from HepG2 hepatoma cells (Morgan, D. O., Edman, J.D., Standring, D. N., Fried, V. A., Smith, M. C., Roth, R. A., and Rutter, W. J. (1987) Nature 329, 301-307). These findings support the suggestion that the cation-independent mannose 6-phosphate receptor for lysosomal enzymes is a multifunctional binding protein which is identical with the insulin-like growth factor II receptor. A cDNA construct containing the full coding sequence for the cation-independent mannose 6-phosphate receptor in the expression vector pSVL was used to transfect COS cells. Expression of the cDNA in transfected COS cells produced a cell-surface protein which co-migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with authentic human receptor, bound to an affinity column and was specifically eluted with mannose 6-phosphate, mediated cell-surface binding and endocytosis of beta-glucuronidase, and targeted the endocytosed enzyme to lysosomes.
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PMID:The human cation-independent mannose 6-phosphate receptor. Cloning and sequence of the full-length cDNA and expression of functional receptor in COS cells. 296 3


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