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 activity of PIP kinase (1-phosphatidylinositol 4-phosphate 5-kinase; EC 2.7.1.68), the second ATP-utilizing enzyme of 1,4,5-trisphosphate and diacylglycerol biosynthesis, was determined in the rat in a spectrum of transplantable solid hepatomas of different growth rates and in normal tissues of high and low cell renewal rates. In a standard isotopic method developed for the assay, the enzyme activity was linear with time for 4 min and proportional with protein concentration over a range of 0.05 to 1 mg per 0.135-ml reaction mixture. The apparent Km for the substrate PIP (phosphatidylinositol 4-phosphate) and for ATP and Mg2+ in normal liver were 0.06, 0.5, and 4.2 mM, respectively, and in rapidly growing hepatoma 3924A, 0.08, 0.7, and 7.1 mM. The kinase activity in adult Wistar rat liver was 0.046 +/- 0.003 nmol/h/mg protein. In hepatomas of slow and intermediate growth rates, PIP kinase activity increased 3.3-9.7-fold, and in hepatoma 3924A, it was elevated 45-fold over that of normal liver. When hepatoma 3924A cells were plated and expressed their proliferative program, enzyme activity increased 4.3-fold in mid-log phase. To further clarify the linkage between PIP kinase activity and proliferation, enzyme activity was determined in rat organs of high and low cell renewal capacity. The PIP kinase activity in rat thymus, bone marrow, spleen, and testes was 5.4-, 6.3-, 4.8- and 4.3-fold higher, respectively, than in normal rat liver; in lung, brain, skeletal muscle, renal cortex, and heart, the activities were low. In all tissues examined, the activity of PIP kinase was 4.6 to 18% of that of phosphatidylinositol kinase. Since enzymes of crucial significance frequently have short half-lives, the decay rates of PIP kinase were examined in liver, bone marrow, and hepatoma 3924A in rats injected with cycloheximide, which inhibits protein biosynthesis. In cycloheximide-treated animals, PIP kinase had the shortest decay rate (t1/2 = 0.12 h) in comparison with eight enzymes of purine and pyrimidine biosynthesis of rat bone marrow (t1/2 = 0.6 to 4.3 h). In liver and solid hepatoma 3924A, the activity of PIP kinase was degraded less rapidly (t1/2 = 5 h). The relationship of PIP kinase activity with proliferation and transformation is apparent in the high activity in thymus, bone marrow, spleen, and testes and in the increased activities in the rat hepatomas of different growth rates. The coordinate increases in phosphatidylinositol and PIP kinase activities suggest that the capacity for signal transduction is heightened in cancer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:1-Phosphatidylinositol 4-phosphate 5-kinase (EC 2.7.1.68): a proliferation- and malignancy-linked signal transduction enzyme. 792 99

HOE-402 (4-amino-2-[4,4-dimethyl-2-oxo-1-imidazolidinyl]-pyrimidine-5-N- [trifluoromethylphenyl]-carboxamide-monohydrochloride) has been shown to exhibit hypolipidemic action in heterozygous Watanabe heritable hyperlipidemic rabbits. In all animals, elevated cholesterol levels were reduced to normal (from 3.0 to 1.5 mmol/L) after 3 weeks of HOE-402 treatment. This was due entirely to reduction of low density lipoprotein (LDL) cholesterol and was paralleled by accelerated removal of plasma 125I-LDL. This reduction of LDL levels was not found in homozygous LDL receptor-defective animals, emphasizing the necessity of a functional LDL receptor system for the hypolipidemic action. The effect of HOE-402 on LDL receptor activity in the cultured hepatoma cell line HepG2 was also determined. When cells were incubated with plasma from treated animals (containing cholesterol 1.5 mmol/L and HOE-402 80 ng/mL), high-affinity cell-surface binding sites for LDL were induced more than threefold, as shown by Scatchard analysis of cell-surface binding data. Induction of the LDL receptor was detectable after 6 hours and was 300% after 18 hours. This induction was specific for LDL, as 125I-transferrin and [59Fe]transferrin were internalized normally in HOE-402-treated cells. The increase of LDL receptor protein was related to induced LDL receptor mRNA levels (400%), as shown by quantification of Northern blotting experiments. These findings suggest that HOE-402 mediated its hypolipidemic action mainly via the LDL receptor pathway. It enhanced mRNA levels for LDL receptor, hence increasing its synthesis, which subsequently resulted in reduced plasma LDL levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hypolipidemic activity of HOE-402 is mediated by stimulation of the LDL receptor pathway. 831 2

(1) Deoxycytidine kinase activity increased in a transformation- and progression-linked fashion in rat hepatomas of different proliferation rates. The activity also increased and was growth rate-linked in a series of tissue culture cell lines of human and animal tumors. (2) Deoxycytidine kinase activity was stringently linked with expression of the neoplastic proliferative program as it sharply increased in log phase in tissue culture cells of hepatoma 3924A and several human carcinoma strains. (3) Deoxycytidine kinase is subject to nutritional and hormonal regulation. On starvation the activity in liver decreased and on refeeding it returned to normal. Steroid hormone increased liver enzymic activity. Deoxycytidine kinase is substrate-inducible, since deoxycytidine injections in rat led to a 2- to 3-fold increase in hepatic enzyme activity. (4) Actinomycin or cycloheximide treatment blocked the increase in liver deoxycytidine kinase activity induced by steroid or deoxycytidine treatment. Therefore, it is assumed that the rise in deoxycytidine kinase activity requires new RNA and protein synthesis. (5) Cycloheximide treatment of rats carrying hepatomas yielded a t1/2 = 3.4 hr in the tumor for deoxycytidine kinase activity which was the shortest among the examined enzymes of purine and pyrimidine biosynthesis. (6) Actinomycin treatment of rats carrying hepatomas yielded a t1/2 of 5.8 hr for deoxycytidine kinase activity in the tumor which was one of the shortest in the examined enzymes of purine and pyrimidine biosynthesis. (7) Difluorodeoxycytidine (DFDC) is a competitive inhibitor (Ki = 7-28 microM) of deoxycytidine kinase from rat hepatoma and from human pancreatic carcinoma and ovarian carcinoma cells in culture.
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PMID:Regulation of deoxycytidine kinase activity and inhibition by DFDC. 835 16

Our earlier studies indicated that orotic acid, a precursor for pyrimidine nucleotide biosynthesis, exerts a promoting effect on rat hepatocarcinogenesis. The present study was designed to determine the optimum conditions of exposure to orotic acid required for promotion of hepatocarcinogenesis in the initiated rats. The first series of experiments was designed to determine the optimum dose of orotic acid needed to exert its liver tumor promoting effect. Accordingly male Fischer rats were given diethylnitrosamine (200 mg/kg, i.p.) or 0.9% NaCl. One week later carcinogen-injected rats were divided into six groups and fed either basal diet or the same diet containing 0.1, 0.5, 1, 2 or 4% orotic acid. Rats given 0.9% NaCl were fed 4% orotic acid. Two-thirds partial hepatectomy was performed on all animals 10 weeks after starting on their respective diets, and all groups were killed 3 weeks thereafter. Analysis of gamma-glutamyltransferase-positive foci and nodules revealed that 0.5-1% orotic acid in the diet is sufficient to exert a significant promoting effect on the selective growth of initiated hepatocytes, while higher concentrations of orotic acid were only marginally more effective. No gamma-glutamyltransferase-positive foci were observed in animals given 4% orotic acid diet following saline injection. Using 1% orotic acid as the promoting regimen, in the next series, the minimum exposure time required for dietary orotic acid to promote liver carcinogenesis was determined. Male Fischer 344 rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or 0.9% NaCl 18 h after 2/3 partial hepatectomy. After 1 week of recovery one group of rats was continued on a semisynthetic basal diet, while others were transferred to the same basal diet containing 1% orotic acid. Rats that were on the 1% orotic acid diet were progressively transferred to the basal diet after 5, 10, 20, 29 and 40 weeks of exposure. All rats were sacrificed 54 weeks after the beginning of the experiment. The results indicate that 100% of the initiated rats developed hepatic nodules whether or not they were exposed to an orotic acid-containing diet. However, the incidence of hepatocellular carcinoma was greatly increased in animals exposed to the orotic acid diet, with 42% incidence in initiated rats given orotic acid diet for 10 weeks and up to 75% in those exposed to this diet for 40 weeks. Further, promotion by orotic acid exhibited a high metastatic potential with 33-60% metastasis to the lungs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Studies on liver tumor promotion in the rat by orotic acid: dose and minimum exposure time required for dietary orotic acid to promote hepatocarcinogenesis. 840 98

The hepatic uptake of a hydrophilic, cationic linear peptide with renin inhibitory activity [5(4-amino-piperidyl-1-carbonyl)-L-2,6[3H]phenyl-alanyl-beta-alanyl-(4S- amino-3S-hydroxy-5-cyclohexyl)-pentan-carbonyl-L-isoleucyl-amin ome thyl-4-amino-2-methyl-pyrimidine-citrat] (code number EMD 56133; EMD, E. Merck, Darmstadt) was investigated in isolated rat hepatocytes. EMD 56133 was taken up by isolated rat liver cells in a time-, concentration-, energy- and temperature-dependent manner. The uptake was a combination of diffusion and a carrier-mediated process. EMD 56133 was accumulated 4.5-fold in liver cells. Eighty-three per cent of the accumulated peptide was found in the cytosol, not bound to membrane proteins. Seventeen per cent was associated with membrane proteins after cell fractionation and centrifugation at 100,000 g. The permeability coefficient of the non-saturable uptake of EMD 56133 was P = 1.973 x 10(-6) cm/sec. The kinetic constants for the carrier-mediated transport are Km = 92 microM and Vmax = 128 pmol/mg x min. Various substrate analogs inhibited the uptake of EMD 56133. AS-30D ascites hepatoma cells and Reuber hepatoma cells did not accumulate EMD 56133. The absence of oxygen or a decreased cellular ATP content blocked the hepatocellular uptake of the renin inhibitor. Temperatures above 20 degrees increased the transport; the activation energy was determined to be Aapp = 41 kJ/mol. The apparently active uptake of EMD 56133 was not sodium dependent. In contrast, the membrane potential might be a driving force for the transport of the positively charged EMD 56133.
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PMID:Hepatocellular uptake of peptides--I. Carrier-mediated uptake of hydrophilic linear peptides with renin inhibitory activity into isolated rat liver cells. 845 66

Newly synthesized allyloxymethyl purine and pyrimidine acyclonucleosides [Fig. 1, comp. 1-6] were tested in Syrian hamster, six days after heterotransplantations of Kirkman-Robbins hepatoma and compared with Th5, Th5P and PMT [Fig. 1, comp. 7-9]. 48 hours after intraperitoneal (i.p.) administration of AMT and Th5 in a dose of 80 mg per kg body weight, these compounds reduced tumor weight by 42%, while AMU (in the same dose) by 30%. The inhibition of tumor weight is accompanied by a decrease in dThd and dGuo kinase activities in tumor cytosol by AMU (36% and 33%, respectively) by AMT (59% and 53%, respectively) and by Th5 (58% and 55%, respectively). AMU, AMT and Th5 are phosphorylated in vivo by kinases present in cytosol of growing hepatoma to mono, di and triphosphates, but allyloxymethyl residue of AMU and AMT is first hydrated to hydroxypropoxymethyl residue, having CH2OH group. The lack of phosphorylation of PMT in vivo (having saturated propoxymethyl residue) and phosphorylation of Th5P (when used as a substrate for dNMP kinase) only to Th5 diphosphate suggested that AMU, AMT and Th5 triphosphates are responsible for the inhibition of dTMP and dGMP synthesis.
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PMID:The influence of alkoxymethyl purine and pyrimidine acyclonucleosides on growth inhibition of Kirkman-Robbins hepatoma and possible mechanism of their cytostatic activity. 872 Dec 15

After hepatectomy, purine and pyrimidine metabolism is a key process in synthesis of DNA and RNA and in energy metabolism. To supply nucleosides for salvage synthesis, nucleoside-nucleotide mixture solutions have been developed, and they have been found to improve protein metabolism and hepatic regeneration after partial hepatectomy in normal rats. However, the effect of the solution in cirrhotic liver, common in patients with hepatocellular carcinoma, has not been reported. The aim of this study was to evaluate the metabolic effect of the nucleoside-nucleotide mixture on cirrhotic rats after partial hepatectomy. Seventy percent partial hepatectomy was performed in thioacetamide-administered cirrhotic rats. The fractional protein synthetic rate, nitrogen balance, hepatic content of nucleic acid, and blood chemistry after the administration of the nucleoside-nucleotide mixture solution (OG-VI) with total parenteral nutrition was evaluated at 7 d after partial hepatectomy. OG-VI increased hepatic RNA level and hepatic fractional protein synthetic rate (p < 0.05). It is concluded that the nucleoside-nucleotide mixture solution is an effective nutritional supplement to the metabolism of cirrhotic rats after partial hepatectomy.
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PMID:Effect of a parenteral nucleoside-nucleotide mixture on hepatic metabolism in partially hepatectomized cirrhotic rats. 887 39

5-fluorouracil (5-FU), although a widely used chemotherapeutic agent, has a limited effect in the treatment of human solid tumors due to their resistance to the cytotoxic effects of 5-FU. Escherichia coli uracil phosphoribosyltransferase (UPRT) is a pyrimidine salvage enzyme that catalyzes the synthesis of UMP from uracil and 5-phosphoribosyl-alpha-1-diphosphate. The present study demonstrates that adenovirus-mediated transduction of E. coli UPRT gene results in marked sensitization of colon, gastric, liver, and pancreas cancer cell lines to low concentration of 5-FU in vitro. The in vitro bystander effect was observed when only 10% of the hepatoma Hep3B cells were infected with UPRT-expressing adenovirus. In addition, 5-FU treatment of human hepatoma or gastric cancer xenografts in nude mice transduced with UPRT was demonstrated to result in significant in vivo antitumor effects. The adenovirus vector transduction of the UPRT gene followed by 5-FU administration is representative of a new chemosensitization strategy for cancer gene therapy.
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PMID:Adenovirus-mediated transduction of Escherichia coli uracil phosphoribosyltransferase gene sensitizes cancer cells to low concentrations of 5-fluorouracil. 958 37

We have devised and evaluated a stable-isotopic method for measuring DNA synthesis rates. The probe is [1-13C]-glycine that is incorporated into purines via de novo biosynthesis. The human hepatoma cell line HEP G2 was grown in medium containing [1-13C]glycine, the cells were harvested at various times, and the DNA was extracted. Following hydrolysis to the nucleosides, a reversed-phase HPLC separation was used to provide separate peaks for deoxythymidine (dT), deoxyadenosine (dA), and deoxyguanosine (dG). The HPLC effluent was continuously fed into a chemical reaction interface and an isotope ratio mass spectrometer (HPLC/CRI/IRMS). The isotope ratio of the CO2 produced in the CRI was used to monitor for enrichment. The cells were grown continuously for 5 days in labeled medium and also in a 1-day pulse labeling experiment where the washout of label was observed for the subsequent 9 days. As predicted from the role of glycine in de novo purine biosynthesis, the isotope ratio of the pyrimidine dT did not change. However, for the two purines, dA and dG, the characteristic log growth behavior of the cells was observed in their 13C/12C ratios and good agreement in the doubling time was obtained for each type of experiment. Parallel experiments that measured the HEP G2 doubling time in culture using tritiated thymidine incorporation and direct cell counts were carried out compare to our new method with established ones. We believe that the use of [1-13C]-glycine and the HPLC/CRI/IRMS is a highly sensitive and selective approach that forms the basis of a method that can measure DNA synthesis rates using a nonradioactive, nontoxic tracer.
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PMID:Measuring DNA synthesis rates with [1-13C]glycine. 959 74

Pyrimidine nucleoside phosphorylase (PyNPase) is an enzyme which converts 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil (5-FU), and is induced by various cytokines in tumor cells. We evaluated a combination of 5'-DFUR and lentinan which is widely used as a biological response modifier (BRM), to verify antitumor effects, the induction of cytokines such as tumor necrosis factor (TNF)-alpha and latent transforming growth factor (TGF)-beta, and PyNPase activity against AH66 ascites hepatoma cells in rats. AH66 ascites hepatoma cells were subcutaneously injected into the backs of Donryu rats. Rats were randomly assigned to a group receiving either 5'-DFUR or lentinan alone, to a group receiving both 5'-DFUR and lentinan, or to a control group. 5'-DFUR was administered orally, and lentinan was administered intraperitoneally. The tumor size, PyNPase activity in the tumor and spleen, and TNF-alpha and TGF-beta in the tumor were examined. The results were as follows. a) Tumor growth was significantly (P < 0.05) inhibited in both the 5'-DFUR group and the 5'-DFUR + Lentinan group when compared to the control group. Tumor growth in the 5'-DFUR + Lentinan group was significantly (P < 0.01) inhibited compared to that in both the 5'-DFUR group and the Lentinan group. b) PyNPase activity in the tumor was significantly (P < 0.01) higher in each group than in the spleen. In the tumor, PyNPase activity was significantly (P < 0.01) higher in the Lentinan group compared to the control group. In the 5'-DFUR + Lentinan group PyNPase activity in the tumor was significantly (P < 0.01) lower compared to the Lentinan group. c) Levels of TNF-alpha and TGF-beta production in the tumor were significantly (P < 0.05) lower in the 5'-DFUR + Lentinan group compared to the control group. These findings suggested that PyNPase activity in the tumor was induced by lentinan but not so in the spleen, and lentinan increased the susceptibility of tumor cells to 5'-DFUR.
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PMID:Effects of 5'-DFUR and lentinan on cytokines and PyNPase against AH66 ascites hepatoma in rats. 1022 70


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