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)

Reuber (H35) hepatoma cells were grown in medium containing 10(-5)M bromodeoxyuridine (BrdU), which was incorporated into their DNA. Cell growth rate was unaffected by BrdU for the first two generations, after which it was reduced by about 50%. The effect of BrdU incorporation on the activities of several enzymes with rapid turnover rates was examined to test the hypothesis that the synthesis of such enzymes will be preferentially inhibited by BrdU. Tyrosine amino-transferase (TAT) activity decreased by 70% within two generations whereas thymidine kinase activity remained at control values. PEP carboxykinase activity was unchanged during the first generation in BrdU-containing medium but, during the second, its activity increased by at least 30%. Ornithine decarboxylase levels decreased by about 50% only after two generations in the presence of BrdU. There appeared to be no simple relationship between turnover rates and the effect of BrdU on enzyme activity. Incorporation of BrdU was found to inhibit the induction of both TAT and PEP carboxykinase by dexamethasone and to enhance the inhibition of cell growth by this steroid. These results are discussed with respect to possible mechanisms of gene expression and development in both normal and neoplastic cells.
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PMID:The diverse effects of 5'-bromodeoxyuridine on enzyme activities in cultured H35 hepatoma cells. 1 36

In tissue culture experiments, cells derived from glioma 26, a transplantable tumor of C57B1/6 mice, were sensitive to both floxuridine (5-fluorodeoxyuridine) and 5-fluorodeoxyuridine-5'-(5-iodo-3-indolyl)phosphate, an enzyme-mediated drug activated by 5'-nucleotide phosphodiesterase. When these compounds were tested on the tumor in animals at a level of 5 mg/kg for 5 days, tumor growth was inhibited approximately 20% by both compounds. When higher levels of 5-fluorodeoxyuridine, 100 mg/kg four times weekly throughout the lifespan of the mouse, were given, the tumor, although inhibited at first, developed resistance and continued to grow until it killed the animal. Phosphodiesterase levels in the tumor rose as the tumor grew. On the other hand, thymidine kinase levels dropped as anticipated from the known 5-fluorodeoxyuridine-resistant hepatoma tissue culture data. This enzyme pattern was maintained in transplantable mouse glioma lines established from the resistant tumors. One of these lines, tested at a level of 5 mg/kg for 5 days, showed no response to 5-fluorodeoxyuridine but was still sensitive to 5-fluorodeoxyuridine-5'-(5-iodo-3-indolyl) phosphate. These experiments, therefore, offer a model system and a rationale for the design and study of more compounds that could be activated by the enzyme phosphodiesterase. Such compounds might be used alternatively when resistance to 5-fluorodeoxyuridine develops, a common clinical experience in the use of this anticancer drug.
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PMID:5'-nucleotide phosphodiesterase activity of floxuridine-resistant mouse glioma. 17 49

A cytoplasmic form of thymidine kinase was detected in sera from rats bearing Morris hepatoma 7777. Polyacrylamide electrophoretic properties demonstrate similarity between the serum enzyme extracted from hepatoma tissue. This form of thymidine kinase has also been described in normal human fetal tissue and a variety of human tumor cells. The results suggest that serum isoenzymes of thymidine kinase may be a useful adjunctive test for the presence of certain types of malignant tumors.
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PMID:Tumor-associated thymidine kinase in the sera of rats with transplanted hepatomas. 17 42

Considerable thymidine kinase and pyrroline-5-carboxylate reductase activities were found in the plasma of rats bearing a transplanted lymphoma; neither activity was detected in plasma of hosts carrying hepatic, renal, mammary, or submaxillary gland tumors. All host livers exhibited signs of biochemical immaturity as indicated by the appropriate increases or decreases in the concentrations of the nine enzymes measured. The extent and time schedule of the changes in host liver varied with the enzyme and with the tumor that caused them. The hepatic concentrations of ornithine aminotransferase, arginase, pyrroline-5-carboxylate reductase, and glucokinase (all diminished), and of peptidyl proline hydroxylase and hexokinase (increased) were sensitive indicators of tumor growth in general. The concentration of ornithine aminotransferase decreased before the tumors became palpable. At more advanced stages, the high hepatic thymidine kinase activity distinguished the presence of hepatoma and lymphoma from those of all other equally fast-growing tumors. However, only in lymphoma-bearing rats did a fivefold elevation of hepatic thymidine kinase occur as early as 4 days after implantation. Additional observations on the lymphoma itself, on blood cells, and on the involuting thymus of normal rats indicate that the striking systemic effects of this tumor cannot be explained by a release of enzymes from the thymus or by the increased number of lymphoma cells present in blood or liver.
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PMID:The effect of lymphoma and other neoplasms on hepatic and plasma enzymes of the host rat. 18 34

N1-S1/FdUrd Novikoff hepatoma cells, which lack thymidine kinase activity, are resistant to 5-fluorouracil (FUra) as well as 5-fluorodeoxyuridine (FdUrd), suggesting that the pathway, FUra leads to FdUrd leads to FdUMP, is utilized for the conversion of FUra to FdUMP. However, the inhibition of thymidylate synthetase activity, the presumed target of FdUMP, by 1 X 10(-4) M FUra in intact N1-S1 Novikoff hepatoma cells, which have significant levels of thymidine kinase activity, is completely eliminated by 5 X 10(-4) M hydroxyurea, which is a potent inhibitor of ribonucleotide reductase. These results imply that the formation of ribonucleotides and does not involve thymidine kinase. This apparent dichotomy can be explained by the fact that, in addition to the well known lack of thymidine kinase activity, [14C]FUra conversion to ribonucleotides is greatly depressed in the N1-S1/FdUrd cells. Hence, the formation of FdUMP from FUra in Novikoff hepatoma cells apparently proceeds primarily via the intermediate formation of ribonucleotides. The decreased conversion of FUra to ribonucleotides in N1-S1/FdUrd cells decreases not only the ability of the analog to inhibit DNA synthesis, but also its effect on RNA metabolism. FUra, at a concentration of 1 X 10(-5) M, inhibits rRNA maturation in N1-S1 cells, but not in N1-S1/FdUrd cells. Since N1-S1/FdUrd cells are completely resistant to 1 X 10(-5) M FUra, whereas N1-S1 cells are completely inhibited by 1 X 10(-5) M FUra, even in the presence of 1 X 10(-4) M thymidine, the effects of FUra on RNA metabolism appear to contribute significantly to the cytotoxicity of the analog at higher drug concentrations.
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PMID:Metabolism of 5-fluorouracil in sensitive and resistant Novikoff hepatoma cells. 19 Feb 17

Fractions of heavy and light mitochondria are isolated from homogenates of homologous rat tissues (intact liver, regenerating liver within 24 hours after hepatectomy and 27 hepatoma) by means of differential centrifugation. It is found that tumour mitochondria have higher heterogeneity and lower buyoant density than mitochondria from normal hepatocytes. The activity of two enzymes of DNA precursors synthesis (ribonucleotide reductase and thymidine kinase) in subcellular fractions is demonstrated to correlate with the tissue growth rate. A single injection of cyclic AMP into hepatectomised rats resulted in the retardation of the regeneration process, and the activity of both enzymes reached its normal level in all the fractions studied after 24 hours after the operation. Thymidine kinase and ribonucleotide reductase are located mainly in the mitochondrial matrix, however, pronounced enzyme activity is observed also in membrane fractions. The activity of the enzymes in the fraction of external mitochondria membranes in rapidly growing tissues is 2--3 times as high as in the same fraction from normal rat liver.
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PMID:[Mitochondrial thymidine kinase and ribonucleotide reductase from rat liver and rat hepatoma 27]. 19 36

Incorporation of thymidine into Novikoff rat hepatoma cells was analyzed with a rapid sampling technique which allowed collection of 12 time points in 20 sec. Transport was a rapid, saturable, nonconcentrative process with a Km of about 85 micrometer. The intracellular thymidine pool was also rapidly labeled in cells which phosphorylated thymidine, that a group translocation process involving thymidine kinase can be ruled out. Under all conditions examined, phosphorylation, not the transport, of thymidine was the rate-determining step in its incorporation into the acid-soluble pool. Estimation of transport rates from total incorporation into cells which phosphorylate the substrate is invalid in this cell system and must be questioned in all instances.
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PMID:Relationship between thymidine transport and phosphorylation in Novikoff rat hepatoma cells as analyzed by a rapid sampling technique. 20 8

Isoenzyme composition of thymidine kinase was studied in submitochondrial fractions of liver tissue with various proliferative activity (intact, regenerating livers and Zhaidel ascites hepatoma) using polyacrylamide gel disc electrophoresis. Three zones, corresponding to proteins with Rf 0.1-0.2 (I), Rf 0.5-0.55 (II) and Rf 0.85-0.87 (III) and exhibiting thymidine kinase activity, were found in fractions of cytoplasmic and mitochondrial matrix proteins from resting and proliferating rat liver tissues. In fractions of outer and inner mitochondrial membranes three zones of the enzymatic activity were also observed but two of them did not coincide in the Rf value with the thymidine kinase isoenzymes from cytoplasmic fraction and mitochondrial matrix: I Rf 0.1-0.16, II Rf 0.35-0.4 and III Rf 0.62-0.68. Redistribution of the enzymatic activity between thymidine kinase isozymes occurred in conversion of liver tissue from the resting state to increased proliferation. In these cases slowly migrating enzymatic fraction (Rf 0.1-0.2) was activated in mitochondrial matrix and membranes; formation of TMP, catalyzed by isozymes with fast mobility (Rf 0.5-0.55 in matrix and Rf 0.62-0.68 in membrane fractions of mitochondria), which are typical for intact liver tissue, was decreased, respectively.
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PMID:[Mitochondrial thymidine kinase isoenzymes from normal and proliferating rat liver tissues]. 47 80

Thymidine kinase activity in the lymphoid organs of healthy and tumor-bearing chickens was studied after hydrocortisone or dexamethasone treatment. Glucocorticoid hormones (10 mg/100 g body wt) administered twice in 48 hours resulted in an 80% decrease in thymidine kinase activity in the thymuses of healthy chickens, whereas birds with transplantable MC 29 chicken hepatoma failed to respond to the hormones. In the bursae of Fabricius of healthy or tumor-bearing chickens, thymidine kinase activity did not change considerably after administration of hydrocortisone or dexamethasone. The steroid-binding capacity in cellfree systems prepared from thymuses of tumor-bearing birds was significantly decreased. Thus the difference in steroid-binding capacity between thymuses of healthy and tumor-bearing chickens correlated well with, and could account for, the failure of hydrocortisone and dexamethasone to reduce the thymidine kinase level in tumor-bearing birds.
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PMID:Analysis of thymidine kinase activity and glucocorticoid-binding capacity in the thymuses of healthy and tumor-bearing chickens. 90 99

Incubation of cultured Novikoff rat hepatoma and mouse L cells in a glucose-free basal medium containing 5 mM KCN and 5 mM iodoacetate for about 10 minutes resulted in a complete depletion of the cells of ATP. ATP-depleted wild type cells or thymidine kinase-deficient sublines of Novikoff or L cells took up thymidine rapidly from the medium without concentrating it intracellularly, and exhibited countertransport of thymidine. Thus uptake was by facilitated diffusion. This transport system differs from the substrate-specific, low-Km (0.5 muM] thymidine transport system previously described for various types of cultured cells in that it exhibits an at least 100-fold higher Km and transports equally well various ribo- and deoxyribonucleosides. The results suggest that the rate-limiting step in thymidine incorporation into the nucleotide pool by wild type cells is phosphorylation rather than transport, or that the cells possess two transport systems, a facilitated diffusion system with low substrate specificity and a second system which involves substrate phosphorylation by thymidine kinase.
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PMID:Transport and countertransport of thymidine in ATP depleted and thymidine kinase-deficient Novikoff rat hepatoma and mouse L cells: evidence of a high Km facilitated diffusion system with wide nucleoside specificity. 95 73


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