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)

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

The activities of enzymes catalyzing the formation of nucleic acid precursors, nucleoside kinases, as well as of those involved in the degradation of nucleic acids, were studied in nuclei of the liver of healthy persons, human hepatomas and the liver of patients with cancer of gastrointestinal tract. The activities of thymydine kinase and uridine kinase in the human hepatoma nuclear sap were found to increase 40- to 50-fold and 120- to 150-fold, respectively, as compared to those in normal human liver. The activities of DNase and RNase in the fraction of chromatin protein of human hepatomas, on the contrary, decreased almost to zero. As to the liver of patients with cancer of gastrointestinal tract, drastic alterations in the activities of nucleoside kinases and nucleases in the direction characteristic of tumors themselves were observed. This phenomenon is regarded as a manifestation of the systemic effects of the tumor on the host.
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PMID:[Enzymes of anabolic and catabolic nucleic acid pathways in human hepatomas, in liver of healthy persons, and in liver of patients with cancer of gastrointestinal tract]. 19 26

Uridine kinase activities were found chiefly in the soluble fractions of rat tissues. In normal adults the activities ranged from 13 munits/g in skeletal muscle to 178 munits/g in colon. Enzyme activities in several rat neoplasms were significantly higher (e.g. in a fibrosarcoma, mammary carcinoma, renal carcinoma, pancreatic carcinoma and lymphocytic lymphoma, but not in a fast-growing Morris hepatoma). The activities were not related to tumour growth rates or sizes. In normal foetal liver, lung, brain, heart and kidney, uridine kinase concentrations equalled or exceeded those in the adult homologous tissue, but maximal activities in liver were reached 3--5 days post partum. In suckling rats the intestinal activity decreased substantially immediately after birth and normally did not rise again until late in the third postnatal week. Premature upsurges could be evoked by an injection of cortisol or by starvation of the pups overnight. Pancreatic activity was absent from 1-day-old rats, and only about 5% of the adult activity was reached by day 20; adult activities were attained rapidly after weaning. In pancreas, precocious formation or uridine kinase was elicited by overnight starvation of 2-week-old rats.
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PMID:Uridine kinase activities in developing, adult and neoplastic rat tissues. 22 27

The combination of 3 types of antipyrimidines was studied in AS-30D hepatoma cells in suspension culture and in the rat in vivo. Cellular UTP and CTP pools can be depleted most effectively by combining an inhibitor of de novo UMP synthesis with sugar analogs diverting UMP to UDP-sugar analogs. The following UMP-trapping sugar analogs were employed: D-galactosamine, D-galactosone, D-glucosone, and D-glucosamine. These D-galactose and D-glucose analogs intensified the depletion of UTP and CTP pools induced by the following inhibitors of de novo UMP synthesis: acivicin, PALA, lapachol, pyrazofurin, and 6-azauridine. The sugar analogs, in the absence of inhibitors of the de novo pathway, enhanced the rate of de novo UMP synthesis several-fold, as indicated by incorporation of 14CO2 into intermediates and products of the pathway and by the expansion of the acid-soluble uracil nucleotide pool. Reduction of UTP and CTP contents to less than 5 and 15% of control, respectively, by D-galactosamine and PALA resulted in a decrease of the rate of RNA synthesis to 19% of control as calculated from the changes in specific activities of [14C]CTP and of [14C]cytidine in RNA after labeling with [14C]uridine. Hepatoma cells released uridine and cytidine into the extracellular fluid. This release was reduced to one third in UTP-deficient cells, indicating that pyrimidine nucleoside excretion is regulated by pyrimidine nucleotide levels, possibly by UTP and CTP regulation of uridine kinase. Determination of the rates of de novo pyrimidine synthesis, of the formation of RNA pyrimidines, and of pyrimidine nucleoside excretion indicates that de novo synthesis provides only about 67% of the pyrimidines required for the consuming processes. The difference, as well as the dilution of labeled pyrimidine nucleotide pools under conditions of a blocked de novo pathway, suggests a considerable salvage of pyrimidine nucleosides derived from RNA. This salvage of pyrimidines may be intracellular and/or by an excretion and re-uptake process. Depletion of UTP and CTP pools, induced in hepatoma cells by D-galactosamine and 6-azauridine, leads to growth inhibition in suspension culture; this inhibition becomes irreversible in an increasing percentage of cells, killing all cells after 20 hr of UTP deficiency. The enhanced uptake of 5-fluorouridine by UTP-deficient cells was associated with an increase of FUMP incorporation into RNA up to 4-fold and with stronger inhibition of cell growth.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Uridylate-trapping sugar analogs in combination with inhibitors of uridylate synthesis de novo and 5-fluorouridine. 241 94

The changes in the biochemical parameters of peritoneal macrophages and their coupling to the secretory and phagocytic functions in CH3A mice during the growth of the reinoculated solid hepatoma 22a were studied. The DNA and RNA synthesis during the active tumour growth was more intense than that in resident macrophages. The activity of uridine kinase increased up to 156.0 +/- 12.0 nmol/hour/10(8) but was absent in resident macrophages. This was accompanied by a 7.2-fold increase of interleukin-1 synthesis as determined by the [3H]thymidine incorporation into thymocyte DNA in response to concanavalin A administration to C3H mice. Similar changes were observed in peptone-stimulated macrophages. A specific feature of macrophages from tumour-bearing mice was the impairment of activity of purine exchange enzymes and the efficiency of phagocytosis that were unobserved in peptone-stimulated macrophages. The activity of adenosine deaminase and purine nucleoside phosphorylase was inhibited as a result of their preincubation with zymosan, a phagocytosis-stimulating agent. This was accompanied by a significant decrease of the first chemiluminescence peak resulting from disturbances in Fc-reception. Macrophages of tumour-bearing animals possessed an increased 2.2-fold activity of membrane-bound AMP 5'-nucleotidase concomitant with the lack or decrease of the amplitude of the second chemiluminescence peak reflecting the disturbances in digestion resulting from phagocytosis.
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PMID:[Change in activity of enzymes for purine metabolism and RNA and DNA biosynthesis in macrophages, reflecting impairment of their functions in neoplastic growth]. 248 7

Uridine phosphorylase activity was detected in sonic extracts of six different mammalian cell lines and, in conjunction with uridine kinase, provides a route for the conversion of uracil to UMP via uridine. Uracil phosphoribosyl transferase activity was not detected in any of eight different mammalian cell lines. Uridine phosphorylase was purified 5,330-fold from Novikoff rat hepatoma cells by ammonium sulfate precipitation, DEAE-Sephadex chromatography, hydroxyapatite chromatography, and Sephadex G-200 fractionation. The molecular weight of the enzyme by gel filtration was approximately 45,000. The kinetics of the purified enzyme were analyzed with respect to all four substrates at saturating cosubstrate concentration, yielding the parameters KmUra = 360 microM, KmRib-1-P = 88 microM, KmUrd = 16 micron, and KmPi = 130 microM. However, in intact cells the phosphorolysis of uridine proceeded with an apparent Km of 231 microM. Novikoff cells treated with 0.5 mM inosine exhibited an increase in uracil uptake rate which was proportional to an observed increase in intracellular ribose-1-phosphate. Nevertheless, in cells whose de novo synthesis of pyrimidines was blocked by pyrazofurin or N-(phosphonacetyl)-L-aspartate ("PALA"), the uptake of uracil was insufficient to support proliferation, even when enhanced by inosine. These observations are consistent with the kinetic characteristics of the enzyme and provide evidence that the intracellular level of ribose-1-phosphate plays a rate-limiting role in the uptake of uracil mediated by uridine phosphorylase.
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PMID:Uridine phosphorylase from Novikoff rat hepatoma cells: purification, kinetic properties, and its role in uracil anabolism. 298 97

Two species of uridine kinase with molecular weights of approximately 120000 (I) and 30000 (II) have been identified in the rat liver system. Species I predominates in the 7-day postnatal and adult rat liver and increases in the regenerating remnant of the latter after partial hepatectomy; the concentration of species II is low in these tissues. Species I also predominates in the slow-growing hepatomas 5123D and 7800. In contrast, II is the predominant form in the foetal rat liver and accounts for 40% of the total activity in the rapidly growing Novikoff ascites hepatoma. In contrast to species II, which was stable, species I was inactivated by preincubation for 30min at 37 degrees C, before assay at 23 degrees C.
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PMID:Multiple forms of uridine kinase in normal and neoplastic rat liver. 433 62

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

The activity of uridine kinase (ATP: uridine 5'-phosphotransferase; EC 2.7.1.48), the rate-limiting enzyme of the UMP salvage pathway, was measured in human ovaries and ovarian carcinomas, in a spectrum of six rat hepatomas of different growth rates and in eleven normal rat tissues of high and low cell renewal rates. In a standard isotopic method developed for the 100,000 x g fraction, uridine kinase activity was linear for 20 min and proportional with protein concentration over a range of 0.1 to 0.8 mg per 0.1 ml reaction mixture. The apparent Kms for uridine, ATP and Mg++ in normal rat liver were 5.0, 3.4 and 1.5 mM and in the rapidly growing hepatoma 3924A, 0.8, 2.1 and 1.1 mM, respectively. In normal control ACl/N and Buffalo strain rat livers, kinase activity ranged from 159 to 180 nmol/h/mg protein. In hepatomas of slow and intermediate growth rates, kinase activity increased to 1.5- to 2.6-fold, and in hepatomas of rapid growth rates, to 5.1- to 5.8-fold over that of the relevant control, normal livers. When hepatoma 3924A tissue culture cells were plated and expressed their proliferative program, kinase activity increased to 2.1-fold in early log phase. To further clarify the linkage between uridine kinase and cell replicating capacity, the enzyme activity was measured in rat organs of high and low cell renewal. The kinase activity in liver of adult male Wistar rats was 176 +/- 6 nmol/h/mg protein. Activities in thymus, spleen and bone marrow were 4.7-, 2.1-, and 1.8-fold, respectively, of rat liver values; in adipose tissue, the activities were low. The decay rates of uridine kinase were examined in rats injected with a high dose of cycloheximide, which inhibits protein biosynthesis by 90%. The t(1/2) of the kinase in rat bone marrow was 0.64 h, in rat liver longer than 6 h. In human ovary and ovarian carcinoma, the apparent Kms for uridine were 11.5 and 0.5 mM, respectively. In human ovary (n = 3), kinase activity was 38 nmol/hr/mg protein; in ovarian carcinoma (n = 6), the activity increased to 5- to 13-fold over that in ovary. The positive linkage of uridine kinase activity with proliferation and transformation is apparent in human ovarian carcinomas and in rat hepatomas of different growth rates. Therefore, the increased uridine kinase activity should be an interesting target for anticancer chemotherapy.
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PMID:Increased uridine kinase (ATP: uridine 5'-phosphotransferase; EC 2.7.1.48) activity in human and rat tumors. 992 63


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