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)

The initial rate of thymidine-(3)H incorporation into the acid-soluble pool by cultured Novikoff rat hepatoma cells was investigated as a function of the thymidine concentration in the medium. Below, but not above 2 microM, thymidine incorporation followed normal Michaelis-Menten kinetics at 22 degrees , 27 degrees , 32 degrees , and 37 degrees C with an apparent K(m) of 0.5 microM, and the V(max) values increased with an average Q(10) of 1.8 with an increase in temperature. The intracellular acid-soluble (3)H was associated solely with thymine nucleotides (mainly deoxythymidine triphosphate [dTTP]). Between 2 and 200 microM, on the other hand, the initial rate of thymidine incorporation increased linearly with an increase in thymidine concentration in the medium and was about the same at all four temperatures. Pretreatment of the cells with 40 or 100 microMp-chloromercuribenzoate for 15 min or heat-shock (49.5 degrees C, 5 min) markedly reduced the saturable component of uptake without affecting the unsaturable component or the phosphorylation of thymidine. The effect of p-chloromercuribenzoate was readily reversed by incubating the cells in the presence of dithiothreitol. Persantin and uridine competitively inhibited thymidine incorporation into the acid-soluble pool without inhibiting thymidine phosphorylation. At concentrations below 2 microM, thymidine incorporation into DNA also followed normal Michaelis-Menten kinetics and was inhibited in an apparently competitive manner by Persantin and uridine. The apparent K(m) and K(i) values were about the same as those for thymidine incorporation into the nucleotide pool. The over-all results indicate that uptake is the rate-limiting step in the incorporation of thymidine into the nucleotide pool as well as into DNA. The cells possess an excess of thymidine kinase, and thymidine is phosphorylated as rapidly as it enters the cells and is thereby trapped. At low concentrations, thymidine is taken up mainly by a transport reaction, whereas at concentrations above 2 microM simple diffusion becomes the principal mode of uptake. Evidence is presented that indicates that uridine and thymidine are transported by different systems. Upon inhibition of DNA synthesis, net thymidine incorporation into the acid-soluble pool ceased rapidly. Results from pulse-chase experiments indicate that a rapid turnover of dTTP to thymidine may be involved in limiting the level of thymine nucleotides in the cell.
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PMID:Thymidine transport by cultured Novikoff hepatoma cells and uptake by simple diffusion and relationship to incorporation into deoxyribonucleic acid. 434 49

Cytochalasin B competitively inhibits the transport of uridine and thymidine by Novikoff rat hepatoma cells growing in suspension culture with apparent K(i)'s of 2 and 6 microM, respectively, but has no effect on the intracellular phosphorylation of the nucleosides. Choline transport is not affected by cytochalasin B. Results from pulse-chase experiments indicate that cytochalasin B has no direct effect on the synthesis of RNA, DNA, or uridine diphosphate-sugars. The inhibition of uridine and thymidine incorporation into nucleic acids by cytochalasin B is solely the consequence of the inhibition of nucleoside transport.
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PMID:Cytochalasin B. VI. Competitive inhibition of nucleoside transport by cultured Novikoff rat hepatoma cells. 434 50

A clone of cells in which the regulation of purine metabolism is genetically altered was selected and isolated from chemically mutagenized HTC cells (a line of rat hepatoma cells in continuous culture). The clone, designated MAU V, was selected for increased ability to salvage exogenous purines by isolating it in medium containing methylmercaptopurine ribonucleoside, adenine, and uridine, in which medium wild-type cells cannot divide. We have characterized these cells as having an increased rate of de novo purine biosynthesis, apparently as the result of an altered phosphoribosylpyrophosphate (PRPP) synthetase. The altered enzyme has normal catalytic properties but an altered sensitivity to feedback inhibition by purine and pyrimidine nucleotides. The types of inhibitions (competitive and uncompetitive) exerted by AMP, ADP, and TDP on the wild-type enzyme have been maintained in the altered enzyme, but values for K(i) have been increased by factors of 10, 17.5, and 5, respectively. The specific catalytic activities of AMP: pyrophosphate phosphoribosyltransferase and IMP:pyrophosphate phosphoribosyltransferase are normal. The mutant cell may serve as a model for a specific human disease, one type of dominantly inherited overproduction hyperuricemia.
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PMID:Characterization of a feedback-resistant phosphoribosylpyrophosphate synthetase from cultured, mutagenized hepatoma cells that overproduce purines. 435 85

The incorporation of uridine into the nucleotide pool of actinomycin-treated, mengovirus-infected Novikoff rat hepatoma cells in culture follows simple Michaelis-Menten kinetics, and the apparent V(max) and K(m) values are similar to those for uridine transport by uninfected cells. Incorporation of uridine into mengovirus-specific ribonucleic acid (RNA) also follows Michaelis-Menten kinetics, and the apparent K(m) (about 10 mum) is approximately the same as for uridine transport. Inhibition of uridine transport by the presence of adenosine, persantin, or phenethyl alcohol inhibits simultaneously and to the same extent the incorporation of uridine into the nucleotide pool and into viral RNA, without affecting viral RNA synthesis per se. Phenethyl alcohol, however, also inhibits virus maturation. The inhibition of uridine incorporation into the nucleotide pool and into viral RNA is of the simple competitive type, indicating that transport into the cells is the rate-limiting step in the incorporation of uridine into mengovirus RNA. The results also indicate that treatment with actinomycin D or mengovirus infection does not affect uridine transport.
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PMID:Transport as the rate-limiting step in the incorporation of uridine into mengovirus ribonucleic acid in Novikoff rat hepatoma cells. 554 26

The following evidence suggests that inhibition of hepatoma cell (HTC) growth by cyclic nucleotides is an adenosine-like effect that is greatly modified by the type and treatment of serum used in the culture medium and is probably not mediated by cyclic AMP-dependent protein kinase: 1) Heating serum reduces its phosphodiesterase content, thereby slowing metabolism of cyclic AMP and reducing the inhibition of HTC cell growth by cyclic AMP; 2) Using medium that contains phosphodiesterase but lacks adenosine deaminase causes adenosine to accumulate from cyclic AMP and increases the toxicity of cyclic AMP; 3) Uridine or cytidine reverses the growth inhibition caused by adenosine, 5'-AMP or cyclic AMP; 4) adenosine, 5'-AMP and N6-(delta 2-isopentenyl) adenosine are more toxic for HTC cells than is cyclic AMP, and N6,O2-dibutyryl cyclic AMP is not toxic; and 5) N6,O2'-dibutyryl cyclic AMP inhibits growth of Reuber H35 cells, but uridine prevents this inhibition of growth. We conclude that most, if not all, of the inhibitory effects of cyclic AMP and N6,O2'-dibutyryl cyclic AMP on HTc and Reuber H35 hepatoma cell growth are due to the generation of toxic metabolites.
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PMID:Inhibition of hepatoma cell growth by analogs of adenosine and cyclic AMP and the influence of enzymes in mammalian sera. 612 49

Insulin receptors and several biological effects of insulin were measured in H35 and HTC cells, two rat hepatoma lines in permanent cell culture that have been employed previously to study glucocorticoid action. In H35 cells, insulin at concentrations as low as 1 pM both enhanced tyrosine amino-transferase activity and stimulated [3H]uridine incorporation into RNA. In this cell line, the binding of approximately 10 molecules of insulin/cell was sufficient to elicit these two biological responses. In contrast, in HTC cells, much higher concentrations of insulin (3 nM or greater) were needed to stimulate both tyrosine aminotransferase activity and other biological functions. When insulin receptors were measured, both cell types had a major insulin-binding site with a Kd of approximately 20 nM. H35 cells, however, had approximately 6 times more receptors per cell than HTC cells. In both cell types, insulin degradation was minimal. These findings indicate that several biological functions in H35 cells are extremely sensitive to insulin in vitro. In contrast, HTC cells are much less sensitive to the hormone. This lack of sensitivity in HTC cells most likely reflects a decrease in the number of insulin receptors present. In addition, the very large differences in responsiveness suggest that postreceptor alterations are also operative.
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PMID:Insulin action in cultured HTC and H35 rat hepatoma cells: receptor binding and hormone sensitivity. 616 2

The cytotoxicity of 6-thioguanine and 6-mercaptopurine to cultured lymphoblasts and fibroblasts was strongly antagonized by pretreatment of the cells with 100 microM adenosine. Administration of adenosine 2 hours after the antipurine agent did not cause antagonism. In two rat hepatoma cell lines, adenosine pretreatment did not protect cells from the antipurines. Treatment of lymphoblasts or fibroblasts with 100 microM adenosine gave increases up to 150% in cellular ATP and ADP and decreases greater than 80% in UTP and UDP. In the hepatoma lines, adenine nucleotides did not increase by greater than 45%, and uridine nucleotides did not decrease by greater than 40% following adenosine treatment. The selective protection of the normal cells from 6-thioguanine and 6-mercaptopurine was probably the consequence of phosphoribosylpyrophosphate (PRPP) depletion, since adenosine pretreatment decreased PRPP pools by greater than 90% in the normal cells but by only 30% in the malignant hepatoma cells. In the absence of PRPP the antipurines would not be metabolically activated. The selectivity of the adenosine and antipurine combinations was probably attributable to the low activity of adenosine kinase and high activities of adenosine deaminase and PRPP synthetase characteristic of malignant hepatomas.
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PMID:Biochemical approaches to enhancement of antitumor drug selectivity: selective protection of cells from 6-thioguanine and 6-mercaptopurine by adenosine. 616 56

To determine whether there are differences between the U1, U2, and U3 small nuclear RNA's of human cancer cells (HeLa cells) and human normal fibroblasts (IMR-90 cells), and between these uridine-rich small nuclear RNA's of human and Novikoff hepatoma cells, the cells were first incubated in Eagle's medium with [32P]Pi to label these RNA's uniformly. No differences were found between the RNase T1 fingerprints of the purified U1, U2, and U3 RNA's of HeLa cells and IMR-90 cells. The RNase T1 fingerprints of U1 RNA's from human tissues were very similar to that of the U1 RNA of Novikoff hepatoma cells. The RNase T1 fingerprints of U2 and U3 RNA's from human tissues had many similarities to those of Novikoff hepatoma cells, but a few differences were found, such as a point mutation of the U-U-Gp in the rat U2 RNA to A-U-Gp (U leads to A) in human U2 RNA. Unlike the three U3 RNA's of Novikoff hepatoma cells, U3 RNA from human tissues appears to be only one species. These results indicate that U1, U2, and U3 RNA's of human cancer cells are essentially the same as those of human normal cells. In addition, the uridine-rich small nuclear RNA's appear to be conserved through evolution.
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PMID:Comparison of RNase T1 fingerprints of U1, U2, and U3 small nuclear RNA's of HeLa cells, human normal fibroblasts, and Novikoff hepatoma cells. 616 60

Hepatoma tissue culture cells, grown in the presence of D-galactosamine and 6-azauridine, demonstrate a strong reduction of the intracellular UTP pool that can be replenished by formation of UTP from uridine and FUTP from 5-fluorouridine within 2 h. Concomitantly with the UTP deficiency, a decrease of dexamethasone-induced tyrosine aminotransferase activity occurs. 5-Fluorouridine, as compared to uridine, is even more efficient in restoring the activity of tyrosine aminotransferase. Treatment of the cells with D-galactosamine alone results in a minor lowering of UTP that is not followed by the inhibition of the enzyme induction. However, the administration of D-galactosamine, simultaneously or at any time up to 5 h before or after dexamethasone, leads to a 1.5- to 2-fold higher induction (superinduction) which appears 24 h later.
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PMID:Inhibition of tyrosine aminotransferase induction by UTP deficiency and its reversal by 5-fluorouridine in cultured hepatoma cells. 616 86

The rate of uptake of uridine into the acid-soluble fraction of Novikoff hepatoma cells is inhibited by low concentrations of the ionophores A23187 and gramicidin and other perturbants of intracellular cation levels. Inhibition of uridine uptake by A23187 is dependent on Ca2+ and is reduced by serum and high levels of Mg2+. The effectiveness of A23187 is dependent on the Ca2+/Mg2+ ratio rather than the absolute concentration of either ion. Inhibition of uridine uptake by gramicidin is not significantly affected by serum or divalent cations. Other effectors of monovalent cation flux such as ouabain and valinomycin also inhibit uridine uptake. These results indicate that net uptake of uridine may be influenced by intracellular levels of certain monovalent and divalent inorganic cations.
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PMID:Uridine uptake inhibition in Novikoff hepatoma cells by perturbants of intracellular Ca2+ and K+ levels. 616 98


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