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)

Zajdela ascitic hepatoma cells are shown to take up pyrimidine bases at much lower rates than obtained in slices from normal rat liver. The rates of uptake of adenine and uridine by the Zajdela cells are, however, as high as in the slices. Like the slices, again, the Zajdela cells take up E. coli RNA and DNA at very low rates but, unlike the slices, thses cells degrade rapidly the RNA taken up. The Zajdela cells resemble parenchymal cell suspensions derived from normal rat liver in regard to the uptake of pyrimidine bases and the ability to degrade heterologous RNA.
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PMID:Uptake in vitro of nucleic acid precursors and nucleic acids by Zajdela ascitic hepatoma cells. 16 53

2-Amino-3-(hydroxynitrosoamino)propionic acid (alanosine), at a concentration as low as 2.7 muM, completely inhibits the incorporation of hypoxanthine into adenosine triphosphate by cultured Novikoff rat hepatoma cells. Alanosine inhibits the first step in the conversion of inosine monophosphate to adenosine monophosphate because inosine monophosphate, but not adenylosuccinate, accumulates in treated cells. However, the alanosine inhibition is not prevented by aspartic acid, even at a concentration of 1 mM. Alanosine treatment results in the inhibition of cell division, DNA synthesis, RNA and protein synthesis (in this order), and a depletion of the cells of adenosine triphosphate. Some of the cells accumulate in late G2 or M, but the remainder become arrested in other stages of the cell cycle. All effects are due to the inhibition of adenosine monophosphate synthesis and the consequent depletion of the adenosine triphosphate pool since they are completely prevented or reversed by addition of adenine, but not hypoxanthine, to the medium. Pyrimidine nucleotide synthesis is not significantly inhibited by alanosine, since the uridine triphosphate pool is not affected and uridine fails to reverse the cytotoxicity of alanosine. Alanosine also inhibits the transport of aspartic acid, but has a much lower affinity for this transport system than aspartic acid.
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PMID:Alanosine toxicity in Novikoff rat hepatoma cells due to inhibition of the conversion of inosine monophosphate to adenosine monophosphate. 17 7

Pyrimidine nucleoside monophosphate kinase [deoxycytidine monophosphate:adenosine triphosphate (dCMP:ATP) phosphotransferase. EC 2.7.4.14] has been purified from rat Novikoff ascites hepatoma and rat liver, each to a single major band appearing on sodium dodecyl sulfate polyacrylamide gel electrophoresis. Differences exist in regard to efficiency and regulation of enzymatic activities. The Km values of the tumor kinase for cytidine monophosphate (CMP) (0.0053 +/- 0.0008 MM) and dCMP (0.715 +/- 0.068 MM) are approximately one-fourth the Km values of the rat liver kinase, for CMP (0.030 +/- 0.007 MM) and dCMP (2.77 +/- 0.39 MM). The tumor dCMP kinase exhibits a lower Km for ATP (0.134 +/- 0.008 MM) than the rat liver kinase (0.68 +/- 0.09 mM). Moreover, the dCMP:CMP kinase activity ratio for the tumor enzyme is 1.12, while that for the rat liver enzyme is 0.45. The uridine monophosphate:CMP kinase activity ratio for the tumor enzyme is 1.93, while that for the rat liver enzyme is 2.68. Lower concentrations of dithiothreitol are required for 50% reactivation of the tumor dCMP kinase (1.00 mM) and CMP kinase (0.10 mM) than rat liver dCMP kinase (2.20 mM) and CMP kinase (0.57 mM). Thus, the kinase from Novikoff hepatoma exhibits properties of increased efficiency and relaxed regulation of activity which render it more suitable for a tumor, in which active DNA synthesis is ongoing.
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PMID:Differences between pyrimidine nucleoside monophosphate kinase from rat Novikoff ascites hepatoma and rat liver. 17 2

Pyrazofurin (PYF), a C-riboside, inhibited the replication of cultured Novikoff rat hepatoma cells, HeLa cells, and mouse L-cells at concentrations as low as 0.1 to 10 muM, but Novikoff cells were more sensitive than the cells of the other two cell lines. Inhibition of cell replication was completely prevented by the presence of 0.1 to 1 mM uridine in the medium, and partly by the presence of other pyrimidine, but not purine nucleosides. A 2- to 4-hr treatment of the cells with 10 muM PYF resulted in a 2-fold increase in the rate of incorporation of uridine into the acid-soluble pool and nucleic acids, while the rate of incorporation of adenosine into RNA was reduced about 85%. The incorporation of adenosine and deoxyuridine into DNA were reduced about 85 and 50%, respectively. The results are consistent with the view that PYF inhibits the de novo synthesis of pyrimidine nucleosides. The inhibition of cell replication seems to be due mainly to an inhibition of DNA rather than RNA synthesis, resulting from a rapid depletion of the pyrimidine deoxynucleotide pool, since addition of thymidine and deoxycytidine reversed the inhibition of DNA synthesis and cell replication by PYF. PYF must enter the cells to exert its toxicity since the toxicity of PYF was reduced 70 to 80% by the presence of 8 muM Persantin, a potent inhibitor of the facilitated and simple diffusion of various substrates, in the medium. If PYF is incorporated via normal nucleoside salvage pathways, its affinity for the nucleoside transport system(s) and kinases, must be low since, even at a concentration of 1 mM, it had only a slight effect on the initial rates of incorporation of various nucleosides into the nucleotide pool.
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PMID:Inhibition of de novo pyrimidine nucleotide and DNA synthesis and growth of cultured Novikoff rat hepatoma cells and other cell lines by pyrazofurin (NSC 143095). 18 63

We tested an experimental approach in which the specialized enzymatic pattern characteristic of the tissue of origin of a tumor might be exploited to target and enhance drug selectivity. In the present work, the D-galactosamine-induced depletion of uridine 5'-triphosphate (primarily a hepatic event) was employed to enhance the growth inhibition caused by 3-deazauridine. As predicted, the drug effect was most pronounced in the slower growing, well differentiated hepatoma lines where the activities of certain hepatic metabolic pathways and enzymes, though decreased, were still operative. The interactions of D-galactosamine and cytosine arabinoside with 3-deazauridine were examined in vitro in four liver tumor cell lines and two nonhepatic lines. The effects of D-galactosamine and 3-deazauridine on the growth of the Morris hepatoma cell lines 3924A, 8999S,AND 8999R were strongly synergistic; on the Novikoff hepatoma and the nonhepatic cell lines they were only additive. The combination of 3-deazauridine with cytosine arabinoside gave approximately additive growth inhibition with all cell types, without selective toxicity towards the hepatocellular lines. Results of growth-inhibition studies with the combination of D-galactosamine and cytosine arabinoside and with combinations of all three agents are also presented. These results are analyzed in the context of the regulation of hepatic pyrimidine nucleotide metabolism and our design of enzyme pattern directed drug selectivity.
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PMID:Enzyme pattern-directed chemotherapy: synergistic interaction of 3-deazauridine with D-galactosamine. 18 52

A selective deficiency of uridine triphosphate (UTP) was induced in AS-30D rat ascites hepatoma cells by the synergistic action of D-galactosamine and 6-azauridine. The resistance of these hepatoma cells to low concentrations of D-galactosamine (less than 2 mM) was due to their active de novo pyrimidine synthesis which compensated the trapping of uridylate in the form of uridine diphosphate-amino sugars derived from D-galactosamine. The additional blockage of de novo pyrimidine synthesis led to noncompensated uridylate trapping with a UTP content of less than 0.05 mmole/kg of cell wet weight as compared to the control level of 0.66 mmole/kg. The induction of UTP deficiency by incubating the cells with low concentrations of D-galactosamine and 6-azauridine (0.5 mM each) was not accompanied by significant changes in the content of adenine and guanine nucleotides, uridine diphosphate glucose, and uridine diphosphate galactose. The depletion of UTP pools could be reversed within 10 min by the addition of uridine; orotate or uracil were completely ineffective in these hepatoma cells. A UTP content in the range of 0.1 to 0.4 mmole/kg, induced by either 6-azauridine or D-galactosamine, was associated with a reversible depression of cell growth in suspension culture. A UTP content below 0.05 mmole/kg led to irreversible growth inhibition and to necrocytosis in culture, as well as to a loss of transplantability in vivo. Uridine reversal studies indicated that the percentage of cells able to resume growth in culture decreased with an increasing time period of UTP deficiency. The deficiency period required for irreparable or lethal damage in these hepatoma cells ranged from 3 to 20 hr. The principle of noncompensated uridylate trapping can be extended to other inhibitors of nucleotide synthesis combined with various nucleotide-trapping sugar analogs. Noncompensated nucleotide trapping may be useful for an induction of selective nucleotide deficiencies in tumor cells.
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PMID:Uridine triphosphate deficiency, growth inhibition, and death in ascites hepatoma cells induced by a combination of pyrimidine biosynthesis inhibition with uridylate trapping. 18 18

Uridine kinase, the rate-limiting enzyme in the activation (phosphorylation) of uridine and the corresponding chemotherapeutic analogues, is present as two isoenzymes localized exclusively in the cytosol of rapidly growing neoplasms, including the S-37 sarcoma, EL-4 leukaemia, HeLa cells (a human carcinoma) and the Novikoff hepatoma. The activities of the isolated isoenzymes are markedly decreased when the concentrations of ATP, phosphate or Mg2+ that are optimum in vitro are replaced by concentrations of ATP, phosphate or Mg2+ that are optimum in vitro are replaced by concentrations approximating to those found in vivo. Further, comparisons of the Km values of isolated uridine kinases with those for cellular uptake of pyrimidine nucleosides and their rate of intracellular phosphorylation suggest that nucleoside-transport systems play a rate-limiting role in nucleoside analogue activation and consequently that it is impossible to estimate the Km of uridine kinase in the intact cell. During the development of tumour-cell resistance to 5-fluorouracil or 5-fluorouridine in vivo there was an early differential increase in the activity of a low-affinity (high-Km) uridine kinase isoenzyme, as measured in cell extracts, and a 7-fold increase in the Km values for the uptake of both uridine and 5-fluorouridine into the intact resistant cells.
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PMID:Uridine kinase activities and pyrimidine nucleoside phosphorylation in fluoropyrimidine-sensitive and -resistant cell lines of the Novikoff hepatoma. 19 85

Antitumor activity of 1-(gamma-chloropropyl)-2-chloromethylpiperidine hydrobromide (CAP-2) was studied in vivo and in vitro, using various rat ascites hepatoma cell lines. Among eight ascites hepatoma cell lines, AH-13 was extremely sensitive both to in vivo antitumor and to in vitro lethal action of the agent, whereas AH-44 was resistant in both cases. The sensitivity of ascites hepatoma cell lines to CAP-2, nitrogen mustard N-oxide, 4-nitroquinoline 1-oxide, and ultraviolet ray in vitro was widely different but their relative sensitivities were very similar against these agents. For all the agents, AH-13 was inactivated very rapidly and AH-109A moderately, whereas AH-44 was relatively resistant. These results indicate that the sensitivity of the cells to CAP-2 may be closely related to their repair-capability of damaged DNA. Similar experiments using various DNA repair-deficient mutants of Escherichia coli B strain demonstrated that the repair-deficient mutants were several times more sensitive to CAP-2 than the wild type strain. From these results, it may be concluded that CAP-2 induces DNA lesions repairable by the same repair mechanisms that work on pyrimidine dimers.
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PMID:Suggestive evidence for relationship between sensitivity and repair capability in rat ascites hepatoma cells treated with the antitumor agent, 1-(gamma-chloropropyl)-2-chloromethylpiperidine hydrobromide. 19 69

Studies were performed to test the applicability of the molecular correlation concept developed in chemically induced transplantable rat hepatomas to virally induced transplantable hepatoma in chicken. In a comparison of the activities of carbohydrate, purine, and pyrimidine key enzymes in rat and chicken hepatomas, similar patterns were observed in rodent and avian tumors. These results show that the enzymatic imbalance elucidated in chemically induced rat hepatomas is applicable to the virus-induced hepatoma in chicken, independent of the nature of the carcinogenic agent and the species.
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PMID:Biochemical behavior of MC-29 virus-induced transplantable chicken hepatoma. 22 6

The zero-trans uptake of purines and pyrimidines was measured in suspensions of Novikoff rat hepatoma, mouse L, P388 mouse leukemia, and Chinese hamster ovary cells by a rapid kinetic technique which allows the determination of uptake time points in intervals as short as 1.5 s. Kinetic parameters for purine/pyrimidine transport were determined by measuring substrate influx into cells in which substrate conversion to nucleotides was negligible either due to lack of the appropriate enzymes or to depletion of the cells of ATP (5'-phosphoribosylpyrophosphate), and by computer fitting exact, integrated rate equations derived for various carrier-mediated transport models directly to zero-trans influx data. The results indicate that different carriers function in the transport of hypoxanthine/guanine, adenine, and uracil with substrate:carrier association constants (K) at 24 degrees C of 300 to 400 muM, 2 to 3 mM, and about 14 mM, respectively, for Novikoff cells. K and Vmax for hypoxanthine transport by L and P388 cells are similar to those for Novikoff cells, but the transport capacity of Chinese hamster ovary cells is much lower and K = 1500 muM. All transport systems are completely symmetrical. Hypoxanthine transport is so rapid that an intracellular concentration of free hypoxanthine (90%) close to that in the medium is attained within 20 to 50 s of incubation at 24 degrees C, at least at extracellular concentrations below K. In cells in which conversion to nucleotides is not blocked free hypoxanthine accumulates intracellularly to steady state levels with equal rapidity and thereafter the rate of hypoxanthine uptake into total cell material is strictly a function of the rate of phosphoribosylation. The low Km systems for hypoxanthine (1 to 9 muM) and adenine (0.2 to 40 muM) uptake detected previously in many types of cells reflect the substrate saturation of the respective phosphoribosyltransferases rather than of the transport system.
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PMID:Purine and pyrimidine transport and phosphoribosylation and their interaction in overall uptake by cultured mammalian cells. A re-evaluation. 42 88


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