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 effects of thymidine (TdR) co-administration on the cytotoxicity and incorporation of 5-fluorouracil (5-FU) into RNA of various tissues was studied in rats bearing an ascites hepatoma (AH 130). The role of pyrimidine degradation in determining the modulating effects of TdR on the formation of FU-RNA was studied in hepatocytes and AH 130 cells in vitro. TdR (500 mg/kg) potentiated the antitumour effect of 5-FU (150 mg/kg) and also increased host toxicity as judged by changes in body weight. TdR given alone did not significantly affect tumour growth and body weight gain. Examination of the effect of TdR on the incorporation of 5-FU into RNA revealed a differential modulation of RNA-directed toxicity in different tissues. Incorporation of 5-FU into RNA in tumour and bone marrow was increased 2- and 4-fold, respectively. In spleen and kidney the incorporation increased by approximately 50%, but the values did not reach statistical significance. In contrast, the incorporation into RNA of liver and intestinal mucosa was decreased to ca 35% of the control. TdR at concentrations of 40 microM-40 mM progressively inhibited the degradation of 5-FU and decreased the incorporation of 5-FU into RNA of hepatocytes in vitro. In AH 130 cells in vitro TdR did not significantly influence the metabolism of 5-FU and the incorporation into RNA. These results demonstrate that the enhanced incorporation of 5-FU into tumour RNA in vivo after pretreatment with TdR is related not to local effects on the tumour cells but rather to an increased bioavailability of the drug. Although co-administration of TdR did not selectively enhance the antitumour effect of 5-FU, a differential toxicity in host tissues was indicated by the modulated incorporation of 5-FU into RNA.
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PMID:Modulation of 5-fluorouracil metabolism by thymidine. In vivo and in vitro studies on RNA-directed effects in rat liver and hepatoma. 620 Nov 74

Activities of pyrimidine nucleoside phosphorylase in brain tumors were measured and their relationship to a clinical course of the patients was investigated. Pyrimidine nucleoside phosphorylase is said to exist more quantitatively in malignant tumors such as Sarcoma 180, Ehrlich ascites carcinoma, Walker 256, and hepatoma, and very little in normal tissues. In brain tumors the activities were measured by bioassay and compared to that of Sarcoma 180. When the activity of Sarcoma 180 was expressed to be 100%, those of brain tumors were as follows: ten cases of normal brain less than 8.5; six cases of glioblastoma 39.3 +/- 30.7; five cases of astrocytoma 22.0 +/- 13.8; five cases of meningioma 22.4 +/- 13.7; two cases of oligodendroglioma 8.1 and 11.3; two cases of sarcoma 94.3 and 145.4; chordoma 48.0; ependymoblastoma 3.7; plexus papilloma 22.5; parotid cancer 43.4; ten cases of metastatic brain tumors from lung cancer 61.5 +/- 41.6; two cases from breast cancer 28.0 and 68.8; that from thyroid cancer 10.0; that from gastric cancer 13.5; malignant melanoma 77.2. In 12 cases of gliomas (glioblastoma, astrocytoma, oligodendroglioma) the mean activity was highest in glioblastoma (39.3), followed by astrocytoma (22.0) and oligodendroglioma (9.7). The postoperative survival time became shorter in gliomas with the higher activities. In metastatic brain tumors from lung, breast, and gastric cancer, the average time from the diagnosis of primary cancer to brain metastasis was shorter in cases with high activities and longer in cases with low activities.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Activities of pyrimidine nucleoside phosphorylase in brain tumors and antitumor effect of 5'-DFUR]. 622 41

Uridine kinase (ATP: uridine-5-phosphotransferase, EC 2.7.1.48) was isolated from cytosol of rat Zajdela ascite hepatoma cells by fractionation with ammonium sulfate and gel-filtration on Sephadex G-200. The enzyme has a pH optimum of 7.2 - 7.8; Km for uridine is 4.8 . 10(-5) M, that for ATP - 1.9 . 10(-4) M. The optimal ratio of ATP of Mg2+ is 2.6. The enzyme activity is inhibited by end products of pyrimidine biosynthesis with Ki for CTP of 6.0 . 10(-4) M and for UTP of 1.2 . 10(-3) M. The Ki values for uridine competitive analogs, i. e. 6-azauridine, 5-bromuridine and 5-azacytidine are equal to 4.0 . 10(-4) M, 1.5 . 10(-3) M and 2.5 . 10(-3) M, respectively. Further purification of the enzyme on Sepharose 4B allowed to obtain the most active, although heterogeneous fractions purified 86-fold, with specific activity of 11.2 mkmole/hour per mg of protein. Using electrofocusing, uridine kinase was found to consist of two major and one minor active fractions with pH of 6.2, 6.7 and 6.35, respectively. Chromatography on DEAE-cellulose DE-32 resulted in two major active fractions of the enzyme, differing in thermal stability and inhibition by CTP. It may be concluded that Zajdela ascite hepatoma cells contain at least two isoforms of uridine kinase.
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PMID:[Isolation and properties or uridine kinase from Zajdela hepatoma cells]. 627 84

Nucleotide biosynthesis in Novikoff hepatoma cells is markedly altered by a variety of chemical mutagens, whether the mechanism of mutagenesis is by base substitution, covalent binding (adduct formation), intercalation, or cross-linking of DNA. The compounds investigated (N-methyl-N'-nitro-N-nitrosoguanidine, 4-nitroquinoline 1-oxide, 9-aminoacridine, and mitomycin C), at concentrations that cause some inhibition of RNA and DNA synthesis, bring about a large increase in the pool levels of all four nucleoside triphosphates. At the same time, reactions leading to the synthesis of CTP from exogenous uridine and GTP and ATP from exogenous hypoxanthine are severely inhibited. The formation of UTP from uridine and ATP from adenosine, by more direct phosphorylation reactions, appears relatively unaffected. The increase in nucleotide pool size cannot be accounted for by a corresponding increase in de novo purine and pyrimidine nucleotide synthesis, as experiments with labeled formate and aspartate show similar inhibitions by the mutagens. With the salvage precursors, [3H]uridine and [3H]hypoxanthine, the mutagens can produce a widely divergent reduction in the labeling of RNA-CMP versus RNA-UMP and of RNA-GMP versus RNA-AMP, mostly a result of these agents causing large differences in the specific activities of the respective triphosphate precursors. These observations suggest that, in addition to the reactions with DNA, nucleotide biosynthesis could be another important biochemical target of chemical mutagens.
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PMID:The effect of chemical mutagens on purine and pyrimidine nucleotide biosynthesis. 640 46

The role and behavior of the salvage enzymes in the biosynthesis of purines (adenine and hypoxanthine-guanine phosphoribosyltransferases) and pyrimidines (uridine-cytidine, deoxycytidine and thymidine kinases) were elucidated. In liver purine metabolism the transferase activities were orders of magnitude higher than the activities of the enzymes of de novo biosynthesis. In both purine and pyrimidine biosynthesis the activities of the enzymes of the de novo pathways were low (23 pmol to 70 nmol/hr/mg protein), whereas those of salvage synthetic pathways ranged from 0.8 to 1,470 nmol/hr/mg protein. In purine metabolism the salvage enzymes had markedly higher affinity to the shared substrate PRPP (4 to 40 microM) than the rate-limiting enzyme of de novo synthesis, amidophosphoribosyltransferase (900 microM). In rapidly growing hepatoma 3924A the activities of the enzymes of de novo purine biosynthesis increased, whereas those of the salvage pathway changed little. However, the activities of the enzymes of the salvage pathways remained much higher than those of the enzymes of de novo purine production. In pyrimidine production in the hepatomas the activities of both de novo and salvage enzymes markedly increased. However, the activities of the salvage enzymes far outstripped those of the enzymes of the de novo pathways. To inhibit the operation of the salvage pathways, the action of the transport inhibitor, dipyridamole, was examined. In tissue culture, dipyridamole inhibited the transport of purine and pyrimidine nucleosides with an IC50 of 10(-6) or 10(-7) M. As measured by colony-forming assay, dipyridamole killed hepatoma cells with an IC50 of 20 microM. Dipyridamole markedly depressed the pools of ATP, GTP, CTP and UTP; in combination chemotherapy with acivicin, an anti-glutamine agent, synergistic action was observed on the pools of nucleotides in hepatoma 3924A in vivo. These investigations emphasize the importance of the capacity to utilize precursors by the salvage enzymes and may explain, in part at least, the failure of inhibitors of the de novo pathways to yield lasting chemotherapeutic results. Combination chemotherapy of inhibitors of the de novo pathways with an inhibitor of the salvage pathways (dipyridamole) should impact on our understanding of the contribution of salvage pathways and provide a rational basis for successful combination chemotherapy of neoplastic diseases.
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PMID:Salvage capacity of hepatoma 3924A and action of dipyridamole. 644 95

Isoelectric focusing and studies with 1-(2'-deoxy-beta-D-glucopyranosyl)thymine (GPT), a specific inhibitor of uridine phosphorylase activity, were used to determine the substrate specificities of mammalian pyrimidine nucleoside phosphorylases and their cleavage of 5-fluoro-2'-deoxyuridine (FdUrd). Isoelectric focusing profiles for the cytosol fractions from Ehrlich ascites cells and from Novikoff hepatoma cells each consisted essentially of one peak of nucleoside phosphorylase activity [isoelectric points (pl) 5.4 and 5.8, respectively] that cleaved both uridine and thymidine (dThd), as well as FdUrd. By contrast, cytosol fractions from HeLa (S3) cells, mouse liver, and normal human leukocytes each exhibited a major peak of activity (pl 4.6, 6.5, and 4.9, respectively) that cleaved only dThd and FdUrd, while mouse liver exhibited a second peak (pl 5.2) that cleaved primarily uridine. To distinguish clearly between (a) uridine phosphorylases that cleave primarily uridine and that are inhibited by GPT and (b)dThd phosphorylases that cleave only deoxynucleosides and that are not inhibited by GPT, we propose the term "uridine-deoxyuridine phosphorylases" to define those pyrimidine nucleoside phosphorylases that cleave both uridine and dThd and that are inhibited by GPT. On the basis of this definition and studies with GPT in nonfocused cytosol preparations, we conclude that FdUrd is cleaved to 5-fluorouracil by uridine-deoxyuridine phosphorylase activity in Ehrlich ascites cells and in Novikoff hepatoma cells, and by dThd phosphorylases in mouse liver, in normal human leukocytes, and in HeLa (S3) cells.
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PMID:Specificity of pyrimidine nucleoside phosphorylases and the phosphorolysis of 5-fluoro-2'-deoxyuridine. 645 Dec 86

The levels of UMP synthase protein and mRNA are increased in rat hepatoma cells that have acquired resistance to pyrazofurin, a potent inhibitor of pyrimidine biosynthesis. A cDNA plasmid library was prepared from partially purified poly(A)+ mRNA isolated from the resistant cell line. Recombinant plasmids with inserts complementary to UMP synthase mRNA were selected by differential hybridization with cDNA prepared from wild type and resistant cell mRNA and analysis of hybrid-selected mRNA by in vitro translation reactions. One plasmid, pUMPS-2, contains a 850-base pair insert and was used to analyze UMP synthase gene sequences in the wild type and resistant cell lines. Blot hybridization of restricted genomic DNA demonstrated amplification of the UMP synthase gene in the resistant cells. The number of UMP synthase genes is increased 15-fold as determined by a modified dot hybridization procedure. Previous studies have shown that the resistant cells have a 16-fold increase in UMP synthase mRNA but a 40-fold increase in synthase activity (Suttle, D.P. (1983) J. Biol. Chem. 258, 7707-7713). To further investigate this discrepancy between the amount of increase in DNA and mRNA versus the increase in enzyme activity, we have determined the relative rate of synthesis and degradation of UMP synthase. The rate of synthesis was 13-fold faster in the resistant cells. The degradation rate was not significantly different between the two cell lines. These data indicate that gene amplification is the major factor contributing to the enzyme overproduction in the pyrazofurin-resistant cells.
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PMID:Amplification of the UMP synthase gene and enzyme overproduction in pyrazofurin-resistant rat hepatoma cells. Molecular cloning of a cDNA for UMP synthase. 654 85

In continuation of efforts to correlate the antitemplate activities of chemically modified polynucleotides with their base composition and structure, four synthetic copolymers, poly(A,C), poly(C,U), poly(A,C,U), and poly(A,C,G) were modified by thiolation of 2.6-4.8% of their pyrimidine bases. The resulting 5-mercaptoheteropolynucleotides and the previously described 5-mercapto-polycytidylate (MPC) and -polyuridylate (MPU) were tested in a comparative manner as inhibitors of the DNA polymerase-alpha from rat hepatoma. A wide scale of inhibitory potencies was obtained in the following (decreasing) order: MPU greater than M-poly(A,C,U) greater than M-poly(C,U) greater than MPC greater than M-poly(A,C) greater than or equal to M-poly(A,C,G). The sensitivity of the hepatoma DNA polymerase toward these antitemplates increased upon further purification of the enzyme through the DNA-agarose step. Partially thiolated DNA-isolates from rat hepatoma and calf thymus, respectively, showed significant inhibition of the hepatoma DNA polymerase, the thiolated hepatoma DNA being the more active inhibitor.
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PMID:Inhibition of DNA polymerase-alpha from rat hepatoma with a series of new synthetic polynucleotides. 661 28

A comparative study of some radiation effects on DNAs from mouse liver, Ehrlich ascites tumor and hepatoma 22A was made after X-irradiation of the 0.02% aerated solutions in 0.1 M NaCl. The electrophoretic and spectrophotometric methods were used to measure the radiation-chemical yields of single- and double-strand breaks, DNA secondary structure defects, a malonaldehyde analogue and pyrimidine hydroperoxides. DNA from tumors was found to be more affected by radiation than DNA from normal liver: this may be due to a higher degree of base damage (the yield of hydroperoxides) and to transformation of original secondary structure defects into single-strand breaks at low irradiation doses.
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PMID:[Analysis of radiation injuries of DNA from liver and transplanted tumors in vitro]. 665 40

Our earlier experiments revealed that orotic acid, a precursor for pyrimidine nucleotides, selectively stimulated the growth of carcinogen-modified liver cells to grow into enzyme-altered hepatocytes (Cancer Lett., 16: 191-196, 1982). The present study was designed to determine whether prolonged feeding of orotic acid will result in hepatocellular carcinoma in initiated rats. Accordingly, groups of rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or an equivalent volume of 0.9% sodium chloride solution 18 hr after two-thirds partial hepatectomy. After 1 week of recovery, they were continued on either the basal diet or the basal diet containing 1% orotic acid for 10 to 13 months. Some groups of rats, in addition, received a single necrogenic dose of CCl4 8 weeks following exposure to orotic acid diet. The results obtained indicated that 87.5% of initiated rats exposed to orotic acid developed hepatocellular carcinomas in 10 months and 100% in 13 months. Initiated rats exposed to orotic acid diet coupled with a single administration of CCl4 developed 100% hepatocellular carcinoma by 10 months. In contrast, the incidence of hepatocellular carcinoma in initiated rats fed basal diet alone for 13 months was 37.5%, while, in those that received CCl4 in addition, the incidence was 25% in 10 months. Interestingly, a significant number of liver cancers (29 to 36%) in the orotic acid-fed group metastasized to lungs, whereas none of the liver cancers in rats exposed to basal diet metastasized.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Promotion by orotic acid of liver carcinogenesis in rats initiated by 1,2-dimethylhydrazine. 671 5


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