UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Accumulation of Ca2+ (+ phosphate) by respiring mitochondria from Ehrlich ascites or AS30-D hepatoma tumor cells inhibits subsequent phosphorylating respiration in response to ADP. The respiratory chain is still functional since a proton-conducting uncoupler produces a normal stimulation of electron transport. The inhibition of phosphorylating respiration is caused by intramitochondrial Ca2+ (+ phosphate). ATP + Mg2+ together, but not singly, prevents the inhibitory action of Ca2+. Neither AMP, GTP, GDP, nor any other nucleoside 5'-triphosphate or 5'-diphosphate could replace ATP in this effect. Phosphorylating respiration on NAD(NADP)-linked substrates was much more susceptible to the inhibitory effect of intramitochondrial Ca2+ than succinate-linked respiration. Significant inhibition of oxidative phosphorylation is given by the endogenous Ca2+ present in freshly isolated tumor mitochondria. The phosphorylating respiration of permeabilized Ehrlich ascites tumor cells is also inhibited by Ca2+ accumulated by the mitochondria in situ. Possible causes of the Ca2+-induced inhibition of oxidative phosphorylation are considered.
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PMID:Inhibition of oxidative phosphorylation in ascites tumor mitochondria and cells by intramitochondrial Ca2+. 676 37

Eukaryotic initiation factor 2 (eIF-2) preparations from mid-log and plateau-phase Yoshida ascites hepatoma AH 130 cells, from the liver of Yoshida ascites tumor-bearing rats and from 4-dimethylaminoazobenzene (DAB)-induced liver tumor tissue were assayed for ternary complex formation with 3H-met-tRNAf and GTP on nitrocellulose filters. The eIF-2 factor was extracted from postnuclear homogenate supernatants by high-salt wash and purified by ion exchange chromatography on DEAE-cellulose and phosphocellulose. The results here reported demonstrate changes of 3H-met-tRNAf X eIF-2 X GTP ternary complex formation under the conditions studied. Higher rates of ternary complex formation are present in control rat liver and in DAB-induced liver tumor tissue. The liver of Yoshida ascites tumor-bearing rats and the Yoshida ascites hepatoma cells show reduced rates of ternary complex formation, that are mostly evident at the plateau-phase of the intraperitoneal ascites cell growth. The present observations may be attributable to changes in the growing conditions of plateau-phase ascites cells, with accumulation in Gl phase, affecting the ability of eIF-2 to enter in the sequential assembly of the eukaryotic protein synthesis initiation complex.
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PMID:eIF-2 initiation factor activity in Yoshida ascites hepatoma AH 130 cells and in 4-dimethylaminoazobenzene-induced liver tumor tissue during growth. 681 8

As demonstrated by a simple procedure based on indirect immunoprecipitation, proteins retained on heparin-Sepharose 4B from postmitochondrial supernatants of rat liver and Zajdela hepatoma catalyse the translation of rabbit serum albumin mRNA in the presence of ribosomal subunits from rat liver, Zajdela hepatoma or rabbit reticulocytes. The albumin synthesis shows an optimum at 1.5 mM MgCl2 and 25 mM KCl and requires ATP and GTP. It is significantly stimulated by tRNA and proceeds for more than 2 h, suggesting a high rate of reinitiation. At the optimum ribosomes:mRNA ratio of 13:1, the immunoprecipitable radioactivity exceeds 15-20-times the blank values. Fluorography of polyacrylamide slabs after electrophoresis of immunoprecipitates revealed the presence of only complete full-size serum albumin without any smaller peptides resulting from premature terminations of polypeptide chains, demonstrating faithful translation. In stained gels only, both heavy and light chains of immunoglobulin G were found, indicating that the assay procedure is highly specific and reliable. The fractionated heterologous protein-synthesizing system described in this paper may be generally useful for studies on the synthesis of specific proteins and factors affecting their rates since, unlike comparable translation assays, a precise calculation of the balance of newly synthesized proteins is possible.
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PMID:Biosynthesis of rabbit serum albumin in a heterologous fractionated subcellular system. 683 51

The glutamine antagonist acivicin, L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, strongly reduced CTP and GTP contents in AS-30D rat hepatoma cells in suspension. UTP only dropped to 63% of the respective control after 4 hr; however, by combining acivicin with the uridylate-trapping sugar analogue D-galactosamine, a synergistic decrease in UTP contents to 7% of control was induced. Incorporation of 14CO2 into purine and pyrimidine nucleotides followed by radio-high performance liquid chromatography showed marked inhibition of purine and pyrimidine biosynthesis de novo; the latter was reduced to 35% of control. The inhibitory potency of acivicin on glutamine-dependent carbamoyl-phosphate synthetase and consequently on de novo uracil nucleotide formation was also reflected by the complete suppression of the D-galactosamine-induced rise in total uridylate. Induction of UTP deficiency by interference with the first and rate-limiting step in pyrimidine biosynthesis de novo together with a trapping of uridylate by D-galactosamine may provide a promising approach to the chemotherapy of hepatocellular carcinoma.
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PMID:Combined action of acivicin and D-galactosamine on pyrimidine nucleotide metabolism in hepatoma cells. 688 63

A single injection of the anti-glutamine drug, acivicin (NSC 163501), in tumor-bearing rats in 30 min decreased the activities of amidophosphoribosyltransferase, carbamoyl-phosphate synthetase II and CTP synthetase to 56, 50, and 7% of those of the controls. By 1 hr the activities were down to 32, 13 and 3% and they remained low for 12 hr, after which they slowly returned towards normal range in 72 hr. The decline of the activity of CTP synthetase (a loss of 80% in 10 min) was the most rapid, and the activity only returned to 60% of the controls by 3 days after the acivicin injection. In the hepatoma the concentrations of ATP and UTP changed little, but those of GTP and CTP rapidly decreased, reaching at the lowest point 32 and 2%, respectively, of control values 2 hr after acivicin; concentrations started to rise at 12 hr, reaching normal levels by 48 hr. The drop in enzyme activities preceded the decline in the pools of GTP and CTP. The behavior of enzyme activities and nucleotide concentrations in the host liver had a pattern similar to that in the hepatoma; however, the changes were less extensive than those in the tumor. The differential response between tumor and liver is attributed, in part at least, to the tissue L-glutamine concentration which in the hepatoma (0.5 mM) was 9 times lower than in the liver (4.5mM). The selectivity of acivicin action in inhibiting glutamine-utilizing enzymes is also demonstrated by the lack of effect on aspartate carbamoyltransferase, an enzymic activity which resides in the same complex as that of carbamoyl-phosphate synthetase II. The rapid decline in the activities of glutamine-utilizing enzymes is attributed to an inactivation of the enzymes by acivicin which functions as an active sitedirected affinity analog of L-glutamine. The rapid modulation of the enzymic phenotype and ribonucleotide concentrations by acivicin provides a useful tool for elucidating the role of enzymic and nucleotide imbalance in the commitment of cancer cells to replication and in the targeting of anticancer chemotherapy.
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PMID:Rapid in vivo inactivation by acivicin of CTP synthetase, carbamoyl-phosphate synthetase II, and amidophosphoribosyltransferase in hepatoma. 707 46

The antiglutamine agent acivicin, L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, inhibited the growth of hepatoma 3924A cells in culture. After 7 days of incubation with the drug, an LC50 of 1.4 microM was observed by determination of colony forming ability. A combination of cytidine (1 mM), deoxycytidine (10 microM) and guanosine (10 microM) completely protected the hepatoma cells against the cytotoxic action of acivicin, but each nucleoside by itself had no effect. Acivicin (0.1 mM) inhibited the incorporation of uridine and thymidine into macromolecules, but not that of leucine. Acivicin depressed the pools of CTP, GTP, dCTP, dGTP and dTTP to 46, 62, 40, 64 and 53%, respectively, but it increased UTP level to 152% of the values of untreated cancer cells. The activity of a highly purified CTP synthetase (EC 6.3.4.2) from rat liver and hepatoma 3924A was inhibited by acivicin. The inhibition was competitive with respect to L-glutamine, and the Ki values with liver and hepatoma enzymes, determined by Dixon and reciprocal plots, were 1.1 and 3.6 microM respectively. The hydroxy analog of acivicin was also a competitive inhibitor, but it was less effective than acivicin, with a Ki value of 1.8 mM for the hepatoma enzyme. Our observations on the impact of acivicin on the behavior of pools of ribonucleotides and deoxyribonucleotides and the competitive inhibition of purified CTP synthetase from hepatoma cells suggest that a major mechanism of action for this drug is the inhibition of CTP synthetase and GMP synthetase (EC 6.3.5.2).
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PMID:Biochemical pharmacology of acivicin in rat hepatoma cells. 715 Mar 66

6-Mercaptopurine and 6-thioguanine strongly inhibited the zero-trans entry of hypoxanthine into Novikoff rat hepatoma cells which lacked hypoxanthine/guanine phosphoribosyltransferase, whereas 8-azaguanine had no significant effect. 6-Mercaptopurine was transported by the hypoxanthine carrier with about the same efficiency as its natural substrates (Michaelis-Menten constant = 372 +/- 23 microM; maximum velocity = 30 +/- 0.7 pmol/microl cell H2O per s). 8-Azaguanine entry into the cells, on the other hand, showed no sign of saturability and was not significantly affected by substrates of the hypoxanthine/guanine carrier. The rate of entry of 8-azaguanine at 10-100 microM amounted to only about 5% of that of hypoxanthine transport and was related to its lipid solubility in the same manner as observed for various substances whose permeation through the plasma membrane is believed to be non-mediated. Only the non-ionized form of 8-azaguanine (pKa = 6.6) permeated the cell membrane. Studies with wild type Novikoff cells showed that permeation into the cell was the main rate-determining step in the conversion of extracellular 8-azaguanine to intracellular aza-GTP and its incorporation into nucleic acids. In contrast, 6-mercaptopurine was rapidly transported into cells and phosphoribosylated; the main rate-determining step in its incorporation into nucleic acids was the further conversion of 6-mercaptopurine riboside 5'-monophosphate.
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PMID:Facilitated transport of 6-mercaptopurine and 6-thioguanine and non-mediated permeation of 8-azaguanine in Novikoff rat hepatoma cells and relationship to intracellular phosphoribosylation. 719 51

A cyclic-nucleotide independent heparin-sensitive nuclear protein kinase (NII) from the Morris hepatoma 3924A has been purified by a combination of ion exchange and affinity chromatographic procedures and velocity gradient centrifugation. The purified kinase had a molecular weight of 140,000 as determined by gel filtration. Two polypeptides (Mr = 42,000 and 25,600) were present in the purified preparation in approximately equimolar concentrations. The protein kinase employed Mg2+ and Co2+ as divalent ion and preferred the nonhistone proteins, casein or phosvitin, as protein acceptors. In the presence of Mg2+, it utilized both ATP and GTP as substrates and transferred the terminal nucleotide phosphate to serine and threonine residues of the protein acceptor. Phosphorylation of casein was stimulated by polyamines, particularly spermine. This polyamine preferentially enhanced phosphate transfer to threonine. The enzyme was inhibited by several compounds including heparin, the o-n-octyloxime of rifamycin (AF/013), 3'-dATP, o-phenanthroline, polynucleotides, and ADP. Of these inhibitors, heparin was the most potent and completely abolished kinase activity at a concentration of 0.1 micrograms/ml. The kinase could be autophosphorylated by incubation with Mg2+ and [gamma-32P]ATP; under these conditions phosphorylation was confined to the polypeptide of Mr = 24,600 and was completely inhibited by heparin. Based on the unique properties of NII protein kinase (ability to use GTP, stimulation by spermine, sensitivity to heparin), a selective assay was developed which could measure NII activity in the presence of other nuclear kinases. Under the optimal assay conditions, the nuclear extract of hepatoma 3924A was found to contain at least five times more NII kinase activity than that of normal adult liver. Analysis of extensively purified preparations from the two sources confirmed these results. After purification 11 times more NII protein kinase activity was obtained from hepatoma 3924A than from liver. Although hepatoma and liver protein kinases exhibited many common properties, they displayed distinct nucleotide saturation kinetics. The apparent Km for ATP was 10 microM for hepatoma protein kinase and 24 microM for the liver enzyme.
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PMID:A heparin-sensitive nuclear protein kinase. Purification, properties, and increased activity in rat hepatoma relative to liver. 725 4

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