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)

The metabolism of deoxycytidine (dCyd) and dCyd nucleotides in Yoshida ascites sarcoma (YS) cells and the host rat liver was investigated with reference to the increased excretion of urinary dCyd. Incorporation of [14C]orotic acid into the livers of rats at the fifth day after the transplantation of YS cells, the time when the amount of excretion of dCyd in urine was near maximal, was 2 times higher than that into the normal rat livers. After the injection of [14C]orotic acid, the ratio of the specific radioactivity of cytidylate to uridylate moieties of the host liver RNA was measured and found to be higher than that of normal rat liver RNA and to be similar to that of YS cell RNA. When [14C]orotic acid was injected into rats followed by the transplantation of YS cells, the radioactivities present in the livers disappeared more rapidly than those in the control rat livers. The activities of pyrimidine de novo synthesis enzymes, such as cytidine triphosphate synthetase (EC 6.3.4.2) and cytidine diphosphate reductase (EC 1.17.4.1), in YS were higher than those in both rat ascites hepatoma AH 7974 and Walker 256 carcinosarcoma, the transplantations of which did not induce increased excretion of dCyd into urine of the hosts. The activities of dCyd kinase (EC 2.7.1.10) and dCyd deaminase (EC 3.5.4.5) in YS cells were lower than those in the other two tumors investigated. The activities of cytidine triphosphate synthetase and cytidine diphosphate reductase in the livers of YS-bearing rats were elevated compared with those in the livers of rat ascites hepatoma AH 7974- or Walker 256 carcinosarcoma-bearing rats and normal rats, while the activities of dCyd kinase, 5'-nucleotidase (EC 3.1.3.5), and dCyd deaminase were similar between normal rat livers and tumor-bearing rat livers. These results suggest that the increased excretion of urinary dCyd in YS-bearing rats could be caused by both the stimulation of the synthesis of dCyd nucleotides and the low activity of dCyd deaminase in YS cells as well as in the host liver.
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PMID:Origin of increased deoxycytidine excretion into urine of rats bearing Yoshida ascites sarcoma. 672 78

In view of the increasing interest in low molecular weight ribonucleoprotein particles in exon-intron binding and cleavage reactions (Lerner, M. R., Boyle, J. A., Mount, S. M., Wolin, S. L., and Steitz, J. A. (1980) Nature 283, 220--224), the complementarity of the conserved regions to HnRNAs, or protein binding sites, or both, is of potential importance. U3A, U3B, and U3C are three RNA species localized to the nucleolus of Novikoff hepatoma cells. The nucleotide sequence of U3A RNA determined in this study was compared to that of U3B RNA (Reddy, R., Henning, D., and Busch, H. (1979) J. Biol. Chem. 254, 11097--11105). Both U3A and U3B RNAs contained 5' "caps" and were 216 nucleotides long. The nucleotide sequence 1 to 87 was identical in both U3A and U3B, but differences were found at 18 positions in the remainder of the sequence. Of these differences, 11 were single base replacements, two were dinucleotide replacement AU leads to GG at positions 93 to 94, UC leads to GG at positions 173 to 174, and one was a trinucleotide replacement, UCG leads to CUU at positions 179 to 181. Of the total 18 base replacements, 11 (61%) were purine leads to purine or pyrimidine leads to pyrimidine. Interestingly, two base insertions/deletions were found in each RNA when both RNA sequences were compared for maximum sequence similarity. These data establish that the heterogeneity of some low molecular weight nuclear and nucleolar RNA species resulted from a small number of mutations but much of the sequence was conserved.
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PMID:Substitutions, insertions, and deletions in two highly conserved U3 RNA species. 677 Dec 80

The nucleotide sequences of two major tRNALeu species (anticodon Mn-A-A)isolated from Morris hepatoma 5123D were determined by a combination of a newly developed thin-layer readout sequencing method [Gupta, R. C., & Randerath, K. (1979) Nucleic Acids Res. 6, 3443-3458] and additional 3H- and 32P-labeled derivative methods entailing chromatographic fingerprinting and base-specific enzymatic cleavages. The nucleotide sequence of the two hepatoma tRNAMm-A-ALeu species, one of which has U and the other of which has A in position 50 at the tip of the long extra arm, is pG-U-C-A-G-m2G-A-U-G-(m2)G-C-(ac4)C-G-A-G-U-G-G-D-C-psi-A-A-G-G-C-m22G-C-C-A-G-A--C-U-Mm-A-A-m1G*-psi-psi-C-U-G-G-L-(psi)U-C-C-G-U- or A-A-U-G-G-A-G-m5C-G-U-G-G-G-T-psi-C-G-m1A-A-U-C-C-C-A-C-U-U-C-U-G-A-C-A-C-C-AOH. These are the first leucine tRNA sequences from higher eukaryotes that have been determined. Noteworthy features of the mammalian leucine tRNAs are the presence of psi in the beta region of the D loop and the occurrence of three unknown hypermodified nucleosides (Mm, m1G*, and L) in positions 35, 38, and 45, respectively. m1G* was converted to m1G by treatment with alkali. Sequencing gels indicated that the parent base of the 2'-O-methylated nucleoside Mm may be a pyrimidine, probably a C derivative, as indicated by the chromatographic behavior of nucleotides containing Mm. The presence of a pyrimidine in the wobble position would be consistent with the antidodon sequence Mm-A-A and the leucine condons U-U-G and U-U-A. The occurrence of a hypermodified nucleoside, L, in the first position of the long extra arm appears unusual; thus far the only modified nucleoside found in this position is Um in eukaryotic serine tRNAs. Since all tRNAs with a long extra arm sequenced to date have a pyrimidine in this position, L is likely to be a pyrimidine, probably a U derivative, as inferred from chromatographic data.
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PMID:Isolation and sequence analysis of two major leucine transfer ribonucleic acids (anticodon Mm-A-A) from a rat tumor, Morris hepatoma 5123D. 677 43

The glutamine antagonist acivicin, L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, strongly reduced CTP and GTP contents in AS-30D rat hepatoma cells in suspension. UTP only dropped to 63% of the respective control after 4 hr; however, by combining acivicin with the uridylate-trapping sugar analogue D-galactosamine, a synergistic decrease in UTP contents to 7% of control was induced. Incorporation of 14CO2 into purine and pyrimidine nucleotides followed by radio-high performance liquid chromatography showed marked inhibition of purine and pyrimidine biosynthesis de novo; the latter was reduced to 35% of control. The inhibitory potency of acivicin on glutamine-dependent carbamoyl-phosphate synthetase and consequently on de novo uracil nucleotide formation was also reflected by the complete suppression of the D-galactosamine-induced rise in total uridylate. Induction of UTP deficiency by interference with the first and rate-limiting step in pyrimidine biosynthesis de novo together with a trapping of uridylate by D-galactosamine may provide a promising approach to the chemotherapy of hepatocellular carcinoma.
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PMID:Combined action of acivicin and D-galactosamine on pyrimidine nucleotide metabolism in hepatoma cells. 688 63

In rat livers and hepatomas, carbamoyl phosphate synthetase (glutamine-hydrolyzing) (EC 6.3.5.5) (synthetase II), the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, was separated from carbamoyl phosphate synthetase (ammonia) (EC 6.3.4.16) (synthetase I) ammonium sulfate and hydroxylapatite fractionations and gel filtration on Sephadex G-25. Both liver and hepatoma 3924A synthetase II activities were subject to feedback inhibition by UTP and to stimulation by 5-phosphoribosyl 1-pyrophosphate. UTP (0.5 mM) enhanced the apparent Km for MgATP from 2.3 to 7.6 mM, whereas 0.1 mM 5-phosphoribosyl 1-pyrophosphate reduced it to 0.5 mM. At 2 mM MgATP, 3 or 7 microM 5-phosphoribosyl 1-pyrophosphate yielded half-maximal activation (Ka) in the absence or presence of 0.5 mM UTP; UTP altered the stimulation kinetics from hyperbolic to sigmoidal. In the rat, synthetase II activities were highest in thymus, testis and spleen. In differentiating and regenerating rat livers, activities were 2.2- and 1.5-fold higher than in adult livers. In 17 hepatomas of different growth rates, synthetase II activity increased 1.3- to 9.5-fold over liver values; the rise correlated positively with tumor growth rates. Synthetase II activities also increased in a kidney tumor (5.0-fold) and in a sarcoma (18.1-fold) in the rat and in a human colon tumor (3.3-fold).
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PMID:Regulatory properties and behavior of activity of carbamoyl phosphate synthetase II (glutamine-hydrolyzing) in normal and proliferating tissues. 705 79

The antitumor drug acivicin, L-(alphaS,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, in vivo irreversibly inactivated carbamoyl-phosphate synthetase II(glutamine-dependent)(EC 6.3.5.5), the first and rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, in transplantable rat hepatoma and host liver. With two injections of 0.5 mg acivicin per 100 g body weight to one group and two injections of 5 mg to another group, enzyme activity decreased to 20 and 1% in hepatoma and to 99 and 31% in liver respectively. Aspartate carbamoyltransferase (EC 2.1.3.2) activity was not affected. Acivicin in vitro selectively inactivated glutamine-dependent activity of the synthetase II from the hepatoma and liver, with an inactivation constant (Kinact) of 90 microM and a minimum inactivation half-time (T) of 0.7 min. The inactivation velocity with 10 microM acivicin was 5.0-fold stimulated by 2 mM MgATP and 18.4-fold by 2 mM MgATP plus 16.7 mM bicarbonate. MgATP at 0.5 mM caused half-maximum stimulation of the inactivation velocity. Under in vitro conditions, L-glutamine (1 mM) protected the enzyme from inactivation by 10 microM acivicin. The synthetase activity was protected in vitro by 6 mM concentrations for glycine (84%), L-glutamate (59%) and L-aspartate (51%) and by 0.5 mM UTP (35%) from inactivation by 20 microM acivicin. The results are compatible with the suggestion that acivicin is an active site-directed affinity analog of L-glutamine.
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PMID:In vivo inactivation by acivicin of carbamoyl-phosphate synthetase II in rat hepatoma. 708 74

d-Galactosone (d-lyxo-2-hexosulose) is phosphorylated and metabolized to the uridine diphosphate derivative in AS-30D hepatoma cells and rat liver. These reactions were catalysed in vitro by galactokinase and hexose-1-phosphate uridylyltransferase. Nucleotide analyses by high-performance liquid chromatography and enzymic assays revealed that this galactose analogue interferes with cellular pyrimidine nucleotide metabolism leading to a deficiency of UTP. [(14)C]Uridine labelling of hepatoma cells indicated a division of [(14)C]uridylate from UTP into UDP-galactosone; the latter was formed at a rate of more than 1.7mmolxh(-1)x(kg AS-30D or liver wet wt.)(-1). As a consequence of UTP deficiency, d-galactosone (1mmol/1 or 1mmol/kg body wt.) strongly enhanced the rate of pyrimidine synthesis de novo as evidenced by incorporation of (14)CO(2) into uridylate and by an expansion of the uridylate pool. This resulted in a doubling of the total acid-soluble uridylate pool within 70min in the hepatoma cells and within 110min in rat liver. Combined treatment of hepatoma cells with d-galactosone and N-(phosphonoacetyl)-l-aspartate, an inhibitor of aspartate carbamoyltransferase, prevented the expansion of the uridylate pool and led to a synergistic reduction of UTP to 10% of the content in control cells. Hepatic UTP deficiency was selective with respect to other nucleotide 5'-triphosphates but was associated with reduced contents of UDP-glucose, UDP-glucuronate, and UDP-N-acetylhexosamines. Isolation of the UDP derivative of d-galactosone revealed an extremely alkali-labile UDP-sugar, probably an isomerization product of UDP-galactosone, that was degraded by elimination of UDP with a half-life of 45min at pH7.5 and 37 degrees C. The instability of UDP-galactosone may contribute in vivo to limit the time period of severe uridine phosphate deficiency in addition to the compensatory role of pyrimidine synthesis de novo. During the initial time period, however, d-galactosone is effective as a powerful uridylate-trapping sugar analogue.
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PMID:Uridylate trapping, induction of UTP deficiency, and stimulation of pyrimidine synthesis de novo by D-galactosone. 712 88

1. A systematic study is reported on the control of 1-phosphatidylinositol 4-kinase (PI kinase) and PI 4-phosphate 5-kinase (PIP kinase), enzymes of the phosphatidylinositol phosphorylation pathway which leads to the production of second messengers. IP3 and DAG. In liver of normal male, adult, fed Wistar rats the steady state activity of PI kinase was 0.5 +/- 0.01 and that of PIP kinase was 0.046 +/- 0.003 nmol/hr/mg protein. The concentration of IP3 was 1.8 +/- 0.1 pmol/mg protein. 2. That the two kinases have short half-lives was observed in starvation. where in the rat liver or bone marrow activities rapidly decreased and on refeeding were restored in a day. Injection to rats of the protein synthetic inhibitor, cycloheximide, yielded t1/2 = 80 min for the two enzymes in bone marrow and t1/2 = 80 min in liver. 3. Linkage of the signal transduction enzymes with proliferation was shown by the high activities as compared to liver of these enzymes in rat organs of high cell renewal capacity, e.g., thymus, bone marrow, spleen and testes. 4. Linkage with malignant proliferation was indicated by the observation that in rat hepatomas the enzyme activities increased 5- to 9-fold and were highest in rapidly growing hepatoma 3924A (29- and 45-fold). 5. In human primary ovarian carcinoma PI and PIP kinase activities were elevated 4.4 and 2.9-fold, respectively, and in OVCAR-5 cells, 32- and 11-fold, respectively. Similar increases were observed in MDA-MB-435 human breast carcinoma cells in comparison with normal breast parenchymal cells. 6. The linkage of signal transduction enzyme activities with malignant proliferation was also observed in experiments when human breast carcinoma cells were plated in flasks and expressed their proliferative capacity in the log phase. PI and PIP kinase activities steadily and coordinately increased to a peak 11-fold rise in mid-log phase. In late log and plateau phases the kinase activities gradually declined to the starting level. Similar observations were made for the two enzymes in human ovarian carcinoma OVCAR-5 cells and in rat hepatoma 3924A cells in tissue culture. 7. In animals injected with cycloheximide the bone marrow PI and PIP kinase activities exhibited t1/2 = 0.12 hr, the shortest decay rate in comparison with 8 enzymes of purine and pyrimidine biosynthesis with t1/2 = 0.6 to 4.3 hr. 8. Injection of tiazofurin decreased PI and PIP kinase activities in the bone marrow with t1/2 = 82 and 78 min, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of signal transduction. 757 37

The aminopyrimidopyrimidine nucleoside 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (APP), which was previously shown to possess experimental antitumor and antiviral activity, was metabolized within WI-L2 human lymphoblastoid cells to a derivative identified as the beta-D-ribonucleotide (APP-MP). In a subline of WI-L2 cells deficient in adenosine kinase, this metabolite was not formed and APP was not cytotoxic, suggesting that APP is converted by adenosine kinase to its 5'-monophosphate. Because no evidence of di- or triphosphates was seen, the monophosphate appeared to be the active species. Treatment of WI-L2 or L1210 cells with APP (10 microM) for 30 min caused extensive depletion of both purine and pyrimidine ribonucleotides. Purine and pyrimidine deoxyribonucleotides were also depleted. Cells were not protected from the cytotoxicity of APP by hypoxanthine plus uridine, but uridine plus adenosine plus 2-deoxycoformycin gave considerable protection. This result was consistent with APP-MP acting as an inhibitor of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase, a hypothesis that was confirmed by preparing PRPP synthetase from Novikoff hepatoma cells; APP-MP was a noncompetitive inhibitor, with a Ki of 0.43 mM. APP-MP was found to accumulate in APP-treated cells to a concentration of almost 3 mM. The relevance of PRPP synthetase inhibition to the cytotoxic mechanism of APP is indicated by the fact that depletion of the PRPP pool was seen as early as 15 min after treatment, before any change was apparent in cellular levels of ATP or UTP. DNA synthesis was markedly suppressed within 30 min of APP treatment of WI-L2 cells, and a lesser degree of inhibition of RNA synthesis was apparent after 45 min.
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PMID:Inhibition of 5-phosphoribosyl-1-pyrophosphate synthetase by the monophosphate metabolite of 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine: a novel mechanism for antitumor activity. 768 45

The mouse alcohol dehydrogenase gene Adh-1 contains an unusually long alternating purine-pyrimidine sequence within its first intron. This alternating sequence differs in length between strains that differ in the extent of Adh-1 expression, and it has been suggested that it plays a role in gene expression. We demonstrate that this alternating sequence can form Z-DNA in vitro. The alternating sequence can act as a positive regulatory element in transient transfection assays in hepatoma cell lines, but not in CV-1 (monkey kidney) cells, suggesting that it can act as a tissue-specific regulatory element. Nuclear run-on experiments showed that the differential expression of Adh-1 from high- and low-activity strains is, however, controlled at the post-transcription level.
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PMID:Structure and function of a long alternating purine-pyrimidine sequence in the mouse alcohol dehydrogenase Adh-1 gene. 784 Jun 44

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