UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A study on the oncolytic activity of the L-cysteine derivative L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride (NSC 303861), revealed that the drug caused complete regression of the MX-1 human mammary tumor xenograft. The compound also exhibited moderate antitumor activity against murine leukemia P388 (T/C value of 169% at a daily dose of 400 mg/kg) and against M5076 sarcoma (T/C value of 135% at a daily dose of 600 mg/kg). The drug was inactive against B16 melanoma, Lewis lung, colon 38 and CD8F1 mammary carcinomas. The compound exhibited significant cytotoxicity against hepatoma 3924A cells in culture (LC50 = 6 microM). Studies on the mechanism of action revealed that the cytotoxicity of the drug could be partially abrogated by protecting hepatoma 3924A cells in culture with L-glutamine. At 6 h after injection of the compound (400 mg/kg) into rats bearing hepatoma 3924A, the pools of L-glutamine and L-glutamate in the tumor decreased to 33% and 71%, respectively, of control levels; the drug selectively inhibited the activities of L-glutamine-requiring enzymes of purine nucleotide biosynthesis, amidophosphoribosyltransferase, FGAM synthase, and GMP synthase, to 21%, 1%, and 69%, respectively, without significantly altering the activities of pyrimidine biosynthetic enzymes, carbamoylphosphate synthase II and CTP synthase. Measurement of the nucleotide concentrations further corroborated the actions of the drug on the purine nucleotide biosynthetic enzyme activities. Drug injection (400 mg/kg) in the hepatoma 3924A-bearing rats reduced the concentrations of IMP in the tumor to 52%, those of total adenylates to 52%, those of total guanylates to 57%, and those of NAD to 73%, without significantly perturbing the pyrimidine nucleotide pools. Studies on the mechanism of action of the L-cysteine derivative suggested that the compound behaved as an L-glutamine antagonist, selectively acting on the enzymes of purine nucleotide biosynthesis.
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PMID:Oncolytic activity and mechanism of action of a novel L-cysteine derivative, L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride. 234 42

The pattern of purine and pyrimidine derivatives was studied in the erythrocytes of C3HA and ICR mice during Hepatoma 22 and Ehrlich ascites tumor cell growth. Concentrations of purine nucleotides, nucleosides and nucleobases of host erythrocytes were changed after the implantation of the tumors. The host erythrocytes markedly concentrated adenine and guanine nucleotides both during logarithmic and plateau phase of tumor growth (5th and 11-12th days after inoculation of the tumor). The contents of nucleosides and nucleobases in the red blood cells were decreased during the logarithmic growth phase but restored within the plateau phase.
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PMID:Metabolism of purine and pyrimidine compounds in erythrocytes of tumor-bearing mice. 238 97

Six cell lines differing in histological origin were studied regarding the growth inhibitory effect of fluoropyrimidines in relation to their metabolism. The human colon carcinoma cell line WiDr was most sensitive to 5-fluorouracil (FUra) (50% growth inhibitory concentration, 0.7 microM) and to its analogue 5'deoxy-5-fluorouridine (5'dFUR) (50% growth inhibitory concentration, 18 microM). The murine B16 melanoma cell line was moderately sensitive to FUra but least sensitive to 5'dFUR. The 50% growth inhibitory concentration values in the human melanoma cell lines IGR3 and M5, the transformed human intestine cell line intestine 407 and the rat hepatoma cell line H35 varied for FUra between 1.7 and 5.0 microM, and for 5'dFUR between 54 and 160 microM. Several enzymes from pyrimidine metabolism responsible for FUra metabolism were measured with FUra as a substrate. The activity of uridine phosphorylase, which catalyzes the conversion of 5'dFUR to FUra, was lowest in B16 cells correlating with the low sensitivity to 5'dFUR. When adenosine 5'-triphosphate was included in the reaction mixture for uridine phosphorylase, FUra was rapidly channeled into FUra nucleotides via its nucleoside. The rate of channeling appeared to correlate with the nucleoside phosphorylase activity in the various cell lines. In several cell lines activities of nucleotide-degrading enzymes were rather high and interfered with the measurement of orotate phosphoribosyl transferase (OPRT) with FUra as substrate. Addition of the phosphatase inhibitor glycerol-2-phosphate partly prevented breakdown of the newly formed 5-fluorouridine 5'-monophosphate and enabled measurement of OPRT. The WiDr cell line had a relatively high OPRT activity which could explain its sensitivity to FUra. The activity of thymidylate synthase was measured at a suboptimal concentration of 1 microM and at the optimal concentration of 10 microM deoxyuridine 5'-phosphate. With all cell lines the ratio between the activities at 10 and 1 microM was between 2.3 and 3.6. The activity of thymidylate synthase was lowest in WiDr and IGR3 cells and 3-4 times higher in M5 and Intestine 407 cells. The inhibition of 0.01 microM 5-fluorodeoxyuridine 5'-monophosphate was 80-90% at 1 microM deoxyuridine 5'-phosphate and 50-70% at 10 microM deoxyuridine 5'-phosphate with all cell lines. At 0.1 microM 5-fluorodeoxyuridine 5'-monophosphate enzyme activity was inhibited by 95-100%. The incorporation of FUra into RNA was relatively low in IGR3 cells and 3-5 times higher in all other cell lines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sensitivity of human, murine, and rat cells to 5-fluorouracil and 5'-deoxy-5-fluorouridine in relation to drug-metabolizing enzymes. 241 45

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 binding of the 14C-labelled-ethylene and -pyrimidine moieties of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) to the biological macromolecules was studied with the AH-130 hepatoma-bearing rats, suspension of AH-130 cells, and isolated nucleic acids and proteins. In all systems examined, a significant level of the binding of the [14C]ethylene of ACNU to nucleic acids, probably due to alkylation, was observed. In contrast, the extent of the binding of the [14C]-pyrimidine was negligible. When a compound lacking the 4-amino group of ACNU (deamino-ACNU) was used for the binding study, relatively higher binding of this compound than that of ACNU to [14C]lysine was observed. It was revealed, therefore, that the low binding of ACNU to proteins could be due to instantaneous depletion of an isocyanate-intermediate, according to the formation of an intramolecularly carbamoylated product with the amino-group on the pyrimidine ring of ACNU molecule during incubation. This could be the molecular basis for the low carbamoylating activity of ACNU in vivo and in vitro, and the antitumor action of ACNU would be dependent on its alkylating activity only.
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PMID:Interaction of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitroso urea hydrochloride with nucleic acids and proteins. 241 82

We have characterized the 5' and 3' regions of the human albumin gene with respect to nucleotide sequences, mRNA transcription initiation and polyadenylation. There are at least two transcription initiation sites and two polyadenylation sites in the human albumin gene. The multiple transcription initiation sites are utilized almost equally. The two polyadenylation sites are used differentially, with the site proximal to the protein termination codon dominating. The "TATA" and the "CCAAT" boxes are present at about 30 and 90 nucleotides upstream of the putative cap sites. About 250 nucleotides immediately 5' to the transcription initiation sites are highly conserved among the human, rat, and chicken. Within the 1-kilobase pair 5' flanking region of the human albumin gene there are 8- and 35-base pair alternating purine/pyrimidine sequences, primarily consisting of dG and dT, and three nucleotide segments exhibiting homology to the proposed progesterone receptor-binding site. In these and other characteristics, the 5' flanking region of the human albumin gene is distinct from the corresponding region of the human alpha-fetoprotein gene. Each of the two polyadenylation sites of the human albumin gene is preceded by a AATAAA hexamer. In addition, the first polyadenylation site has several conserved sequences believed to play a role in the 3'-end formation. The second polyadenylation site lacks these signals which may explain why it is used less frequently. In spite of these differences the two polyadenylation sites show a high overall sequence similarity, suggesting that they arose by duplication. There is no major difference between the normal liver and hepatoma cells in the relative utilization of multiple sites for transcriptional initiation and polyadenylation of the human albumin gene, suggesting that the albumin mRNA polymorphism has no direct relevance to hepatocarcinogenesis.
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PMID:The human albumin gene. Characterization of the 5' and 3' flanking regions and the polymorphic gene transcripts. 241 29

The promoter region for transcription of the 3.6-kilobase mRNA of hepatitis B virus was identified by the chloramphenicol acetyltransferase assay by using HuH-7 hepatoma cells and was found to function directly in virus production by way of the transient expression system of HBV. The 5'-upstream sequence from nucleotides 1573 to 1657 (the transcription start site) was indispensable for promoter function, while the AT-rich sequence (from nucleotides 1581 to 1604) containing a directly repeated sequence TGTT connecting the same flanking sequence PyAAAGAC (where Py is a pyrimidine) at both sides was an essential element within this promoter region. A specific cellular factor which interacted with the essential element was detected in the HuH-7 cell extract. A similar binding factor was also observed in HepG2 and huH2-2 hepatoma cells. This factor may thus be responsible for regulating 3.6-kilobase mRNA, pregenome RNA transcription, or both.
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PMID:Identification of a promoter region for 3.6-kilobase mRNA of hepatitis B virus and specific cellular binding protein. 254 3

Inhibition of colony formation in cultured hepatocellular carcinoma cells of the rat was used to test the efficacy of inhibitors of de novo pyrimidine biosynthesis as potential anticancer drugs. N-(phosphonacetyl)-L-aspartic acid (PALA) (10 and 100 micrograms/ml) and 5-aza-5,6-dihydroorotic acid (DHOX) (100 micrograms/ml) inhibited the formation of colonies and these inhibitions were completely reversed by inclusion of 0.1 mM uridine, the end product of de novo pyrimidine biosynthesis, in the culture medium. With some lots of fetal bovine serum where PALA and DHOX had little effect on inhibiting colony formation, addition of 0.1 mM cytidine restored the inhibitory characteristics of PALA and, to some extent, DHOX. The results demonstrate that cytidine levels modulate the inhibitions of hepatoma colony formation by both PALA and DHOX and that co-administration of these drugs together with cytidine provides a simple expedient to increase drug efficacy.
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PMID:Pyrimidine nucleosides enhance the efficacy of inhibitors of pyrimidine biosynthesis in cultured hepatocellular carcinoma cells. 334 91

Carbamoyl-phosphate synthase II (glutamine-hydrolyzing) (EC 6.3.5.5) (synthase II) is the first and rate-limiting enzyme in the de novo UTP biosynthetic pathway. Leucine pulse-labeling in the rat demonstrated that in the rapidly proliferating hepatoma 3924A the ratio of radioactivity of synthase II to that of total cytosolic protein was 168.2 +/- 11.0 (SE) X 10(-3). This synthetic rate for the tumor enzyme was 9.7-fold higher than that for the liver synthase II, 17.4 +/- 4.0 X 10(-3). Since the degradation rate for hepatoma 3924A enzyme (t1/2 = 65.5 h) was similar to the rate for liver synthase II (t1/2 = 69.3 h), the increase in tumor synthase II activity and amount was due primarily to an elevation in enzyme synthesis in the presence of an unaltered catabolic rate. The results indicate that the reprogramming of gene expression in the hepatoma entails an increased production rate of the rate-limiting enzyme of UTP synthesis. This increase in the activity, concentration, and synthesis of tumor synthase II should provide a heightened capacity for the de novo pyrimidine biosynthetic pathway, thus conferring a selective advantage to the cancer cells.
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PMID:Increased synthesis of carbamoyl-phosphate synthase II (EC 6.3.5.5) in hepatoma 3924A. 351 20

A high-pressure liquid chromatographic method was developed which achieved a separation and quantitation of 20 biologically important nucleosides and bases. The concentrations of pyrimidine nucleosides and bases, namely deoxycytidine, cytosine, cytidine, uracil, and uridine (22.6, 10.1, 5.2, 2.9, and 2.4 nmol/ml, respectively) were high in plasma, whereas purine nucleosides and bases were present in concentrations less than 2.5 nmol/ml. In erythrocytes, the pools of xanthine, hypoxanthine, and xanthosine were 32-, 27-, and 22-fold larger, respectively, whereas cytidine, uridine, and deoxycytidine were only 21, 12, and 5% of plasma concentrations. The results suggest a compartmental system for transport of some of the purine and pyrimidine nucleosides and bases in the whole blood. Studies on the effect of ischemia on nucleoside and base pools in rat liver indicated marked increases within 30 s in the concentrations of adenine, adenosine, inosine, hypoxanthine, uridine, and xanthine, whereas in hepatoma the effects were less pronounced. By 2 and 5 min ischemia these perturbations were most marked in both liver and hepatoma. These results indicate a need for rapid freeze-clamp preparation of tissue samples to obtain precise and repeatable results in the determination of tissue nucleoside and nucleobase concentrations.
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PMID:Effect of ischemia on nucleosides and bases in rat liver and hepatoma 3924A. 358 Oct 61

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