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 preneoplastic rat liver nodules produced by 2-acetylaminofluorene, certain uridine diphosphate-glucuronyltransferase (UDP-GT) activities, which are ascribed to a distinct enzyme form, were selectively increased (5-fold). This enzyme form, operationally termed UDP-GT1, accepts 1-naphthol,4-methylumbelliferone, and 3-hydroxybenzo(a)pyrene as substrates and is chiefly inducible in liver by 3-methylcholanthrene-type inducers. Glucuronidation of other substrates (morphine, 4-hydroxybiphenyl, chloramphenicol, bilirubin, and estrone) was only slightly enhanced or decreased in nodular tissue. Differentially increased UDP-GT1 activities were also found in Morris hepatomas 9121 and 7777. Rabbit antibodies to rat liver UDP-GT1, purified from 3-methylcholanthrene-treated rats, demonstrated immunological similarity between the enzymes from liver, nodular tissue, and Morris hepatoma 9121. Rocket immunoelectrophoresis ascertained that enhanced enzyme activity in nodular tissue reflected an increased level of enzyme protein. Increased activity of UDP-GT1 together with decreased cytochrome P-450-dependent monooxygenase may contribute to the resistance of preneoplastic hepatocytes to the cytotoxic actions of chemical carcinogens.
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PMID:Increased uridine diphosphate-glucuronyltransferase activity in preneoplastic liver nodules and Morris hepatomas. 617 9

The mechanism of action on RNA synthesis of anticancer dibromo-dulcitol (DBD, NSC-104800) and dianhydro-dulcitol (DAD, or elsewhere dianhydrogalactitol, DAG, NSC-132313) was investigated. Rats, bearing Yoshida or Novikoff hepatoma ascites tumor cells sensitive to these drugs were treated with doses equivalent to half the LD50 value. Nucleolar RNA (noRNA) and nuclear RNA (nRNA) were pulse labelled with 3H-uridine, isolated and fractionated on sucrose density gradient. After 18 h treatment with either drug and after 3 h with DAD noRNA synthesis increased and the rate of ribosomal RNA (rRNA) precursor processing was enhanced. Investigation of low-molecular weight nRNAs (LMW nRNAs) (separated by polyacrylamide gel electrophoresis) showed increased synthesis and/or accumulation of RNA species (5S RNA, uridylic acid rich RNAs) related to rRNA synthesis. The tritium labelled drugs were bound to distinct fractions of nRNA, separated by sucrose density gradient ultracentrifugation, both in vivo and in vitro. This fact may be explained by the formation of intra-, or intermolecular crosslinking of pre-messenger RNA. The enhanced RNA synthesis might be interpreted as an alteration in the functions of nuclear proteins, involved in the regulation of gene transcription and processing of RNA precursors.
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PMID:The effect of dibromo-dulcitol and dianhydro-dulcitol (galactitol) on RNA synthesis in ascites tumor cells. 618 26

We have tried without success to eliminate M. orale from a human hepatoma line, PLC/PRF/5, using five different methods. We report here the successful elimination of the contamination by a modification of the technique of Marcus et al. [1] using 5-bromodeoxy-uridine (BrdU) instead of 5-bromo-uracil (5-BrUra) and light. We believe that this method may prove useful when rare and valuable cell lines carry the more common mycoplasma contaminant M. orale.
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PMID:Elimination of Mycoplasma orale from the human hepatoma cell line, PLC/PRF/5. 619 15

Theophylline, caffeine, isobutylmethylxanthine, papaverine, N6-cyclohexyladenosine, N6-allyl-N6-cyclohexyladenosine ( ACHA ) and N6-L-phenylisopropyladenosine (L-PIA) inhibited the transport of adenosine, uridine and hypoxanthine in Novikoff rat hepatoma cells. The IC50 values for the inhibition of uridine transport ranged from 5 microM for ACHA to 3200 microM for caffeine and were inversely proportional to the lipid solubility of the inhibitors. L-PIA and papaverine inhibited uridine influx in a non-competitive manner, having a greater influence on the Michaelis-Menten constant than on maximum velocity, just as observed previously for the inhibition of nucleoside transport by dipyridamole and hypoxanthine. [3H]L-PIA rapidly accumulated in Novikoff cells at 25 degrees to about five times higher levels than present extracellularly. The initial rates of L-PIA uptake were directly proportional to its extracellular concentration between 0.01 and 240 microM and not affected by structurally related analogs, methylxanthines, papaverine, dipyridamole, or 2 mM uridine, but were dependent on temperature. We conclude that L-PIA inhibits nucleoside transport in these cells without being significantly transported by the carrier, that it equilibrates rapidly across the plasma membrane without carrier mediation consistent with its lipophilicity, and that it accumulates concentratively in cells due to partitioning into membrane lipids and binding to intracellular components.
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PMID:Inhibition of the transport of adenosine, other nucleosides and hypoxanthine in novikoff rat hepatoma cells by methylxanthines, papaverine, N6-cyclohexyladenosine and N6-phenylisopropyladenosine. 620 40

1. An improvement of the chemotherapy of hepatocellular carcinoma with adriamycin or 5-fluorouracil and a reduction of side effects has been achieved by intra-arterial administration of the drugs. This treatment provides a somewhat extended survival but no cure. 2. The treatment of hepatocellular carcinoma in patients by reduction of an inactive precursor of a cytocidal alkylating agent by azoreductase of the tumor showed no therapeutic effect. 3. A selective hepatocellular uptake of drugs coupled to asialoglycoproteins has been described. An application of this concept for the chemotherapy of hepatocellular carcinoma seems doubtful since a loss of binding proteins for desialylated glycoproteins during experimental hepatocarcinogenesis has been demonstrated. 4. The increased uptake of 5-fluorouridine in hepatomas after induction of a tissue-specific depletion of uridine 5'-triphosphate and cytidine 5'-triphosphate provides an effective experimental chemotherapy with limited side effects. A clinical use of this new concept for the chemotherapy of hepatocellular carcinoma may serve as a useful approach.
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PMID:[Approaches to a selective chemotherapy of hepatocellular carcinoma (author's transl)]. 626 89

Uridine kinase (ATP: uridine-5-phosphotransferase, EC 2.7.1.48) was isolated from cytosol of rat Zajdela ascite hepatoma cells by fractionation with ammonium sulfate and gel-filtration on Sephadex G-200. The enzyme has a pH optimum of 7.2 - 7.8; Km for uridine is 4.8 . 10(-5) M, that for ATP - 1.9 . 10(-4) M. The optimal ratio of ATP of Mg2+ is 2.6. The enzyme activity is inhibited by end products of pyrimidine biosynthesis with Ki for CTP of 6.0 . 10(-4) M and for UTP of 1.2 . 10(-3) M. The Ki values for uridine competitive analogs, i. e. 6-azauridine, 5-bromuridine and 5-azacytidine are equal to 4.0 . 10(-4) M, 1.5 . 10(-3) M and 2.5 . 10(-3) M, respectively. Further purification of the enzyme on Sepharose 4B allowed to obtain the most active, although heterogeneous fractions purified 86-fold, with specific activity of 11.2 mkmole/hour per mg of protein. Using electrofocusing, uridine kinase was found to consist of two major and one minor active fractions with pH of 6.2, 6.7 and 6.35, respectively. Chromatography on DEAE-cellulose DE-32 resulted in two major active fractions of the enzyme, differing in thermal stability and inhibition by CTP. It may be concluded that Zajdela ascite hepatoma cells contain at least two isoforms of uridine kinase.
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PMID:[Isolation and properties or uridine kinase from Zajdela hepatoma cells]. 627 84

In a family of clonal lines derived from the Reuber H 35 rat hepatoma, four electrophoretically distinct molecular forms of uridine kinase (UK I, II, III, and IV) have been characterized. They are the same as those found in foetal rat liver. Different UK profiles occur in these cell lines, and no strict correlation could be established between the state of differentiation of the cells and the form of UK expressed. A clone of somatic hybrid cells between line p4 (form 1 only) and Fu5-5 (forms II, III, and IV) that does not express form I indicates that p4 cells may lack a factor controlling the polymerization of form I. This variety of clonal cell lines was used to study the uptake and phosphorylation of labeled uridine. The results suggest a relationship between the UK form present and the rate uridine phosphorylation by the intact cells.
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PMID:Uridine kinase molecular species and uridine uptake in some variants of rat hepatomas. 631 3

Nucleotide biosynthesis in Novikoff hepatoma cells is markedly altered by a variety of chemical mutagens, whether the mechanism of mutagenesis is by base substitution, covalent binding (adduct formation), intercalation, or cross-linking of DNA. The compounds investigated (N-methyl-N'-nitro-N-nitrosoguanidine, 4-nitroquinoline 1-oxide, 9-aminoacridine, and mitomycin C), at concentrations that cause some inhibition of RNA and DNA synthesis, bring about a large increase in the pool levels of all four nucleoside triphosphates. At the same time, reactions leading to the synthesis of CTP from exogenous uridine and GTP and ATP from exogenous hypoxanthine are severely inhibited. The formation of UTP from uridine and ATP from adenosine, by more direct phosphorylation reactions, appears relatively unaffected. The increase in nucleotide pool size cannot be accounted for by a corresponding increase in de novo purine and pyrimidine nucleotide synthesis, as experiments with labeled formate and aspartate show similar inhibitions by the mutagens. With the salvage precursors, [3H]uridine and [3H]hypoxanthine, the mutagens can produce a widely divergent reduction in the labeling of RNA-CMP versus RNA-UMP and of RNA-GMP versus RNA-AMP, mostly a result of these agents causing large differences in the specific activities of the respective triphosphate precursors. These observations suggest that, in addition to the reactions with DNA, nucleotide biosynthesis could be another important biochemical target of chemical mutagens.
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PMID:The effect of chemical mutagens on purine and pyrimidine nucleotide biosynthesis. 640 46

The role and behavior of the salvage enzymes in the biosynthesis of purines (adenine and hypoxanthine-guanine phosphoribosyltransferases) and pyrimidines (uridine-cytidine, deoxycytidine and thymidine kinases) were elucidated. In liver purine metabolism the transferase activities were orders of magnitude higher than the activities of the enzymes of de novo biosynthesis. In both purine and pyrimidine biosynthesis the activities of the enzymes of the de novo pathways were low (23 pmol to 70 nmol/hr/mg protein), whereas those of salvage synthetic pathways ranged from 0.8 to 1,470 nmol/hr/mg protein. In purine metabolism the salvage enzymes had markedly higher affinity to the shared substrate PRPP (4 to 40 microM) than the rate-limiting enzyme of de novo synthesis, amidophosphoribosyltransferase (900 microM). In rapidly growing hepatoma 3924A the activities of the enzymes of de novo purine biosynthesis increased, whereas those of the salvage pathway changed little. However, the activities of the enzymes of the salvage pathways remained much higher than those of the enzymes of de novo purine production. In pyrimidine production in the hepatomas the activities of both de novo and salvage enzymes markedly increased. However, the activities of the salvage enzymes far outstripped those of the enzymes of the de novo pathways. To inhibit the operation of the salvage pathways, the action of the transport inhibitor, dipyridamole, was examined. In tissue culture, dipyridamole inhibited the transport of purine and pyrimidine nucleosides with an IC50 of 10(-6) or 10(-7) M. As measured by colony-forming assay, dipyridamole killed hepatoma cells with an IC50 of 20 microM. Dipyridamole markedly depressed the pools of ATP, GTP, CTP and UTP; in combination chemotherapy with acivicin, an anti-glutamine agent, synergistic action was observed on the pools of nucleotides in hepatoma 3924A in vivo. These investigations emphasize the importance of the capacity to utilize precursors by the salvage enzymes and may explain, in part at least, the failure of inhibitors of the de novo pathways to yield lasting chemotherapeutic results. Combination chemotherapy of inhibitors of the de novo pathways with an inhibitor of the salvage pathways (dipyridamole) should impact on our understanding of the contribution of salvage pathways and provide a rational basis for successful combination chemotherapy of neoplastic diseases.
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PMID:Salvage capacity of hepatoma 3924A and action of dipyridamole. 644 95

Isoelectric focusing and studies with 1-(2'-deoxy-beta-D-glucopyranosyl)thymine (GPT), a specific inhibitor of uridine phosphorylase activity, were used to determine the substrate specificities of mammalian pyrimidine nucleoside phosphorylases and their cleavage of 5-fluoro-2'-deoxyuridine (FdUrd). Isoelectric focusing profiles for the cytosol fractions from Ehrlich ascites cells and from Novikoff hepatoma cells each consisted essentially of one peak of nucleoside phosphorylase activity [isoelectric points (pl) 5.4 and 5.8, respectively] that cleaved both uridine and thymidine (dThd), as well as FdUrd. By contrast, cytosol fractions from HeLa (S3) cells, mouse liver, and normal human leukocytes each exhibited a major peak of activity (pl 4.6, 6.5, and 4.9, respectively) that cleaved only dThd and FdUrd, while mouse liver exhibited a second peak (pl 5.2) that cleaved primarily uridine. To distinguish clearly between (a) uridine phosphorylases that cleave primarily uridine and that are inhibited by GPT and (b)dThd phosphorylases that cleave only deoxynucleosides and that are not inhibited by GPT, we propose the term "uridine-deoxyuridine phosphorylases" to define those pyrimidine nucleoside phosphorylases that cleave both uridine and dThd and that are inhibited by GPT. On the basis of this definition and studies with GPT in nonfocused cytosol preparations, we conclude that FdUrd is cleaved to 5-fluorouracil by uridine-deoxyuridine phosphorylase activity in Ehrlich ascites cells and in Novikoff hepatoma cells, and by dThd phosphorylases in mouse liver, in normal human leukocytes, and in HeLa (S3) cells.
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PMID:Specificity of pyrimidine nucleoside phosphorylases and the phosphorolysis of 5-fluoro-2'-deoxyuridine. 645 Dec 86


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