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 effect of bleomycin on [3H]thymidine 5'-triphosphate ([3H]TTP) incorporation into isolated sucrose nuclei from host liver and Morris hepatomas has been compared. Bleomycin stimulates [3H]TTP incorporation 13-fold in host liver and hepatoma 16 nuclei, 8-fold in hepatoma 7800 nuclei, and 3-fold in hepatoma 7777 nuclei. Differences in the nuclear membranes are not responsible for the different response of the nuclei. Nuclei, denuded of their membranes by Triton X-100 treatment, give similar results to sucrose nuclei. Analysis of DNA extracted from liver or hepatoma nuclei incubated with bleomycin indicates that bleomycin produces scissions in the nuclear DNA and that some repair synthesis takes place. Incubation of nuclei with 111indium-labeled bleomycin shows an equal binding capacity of liver and hepatoma nuclei for bleomycin. Bleomycin also stimulates incorporation of [3H]TTP in a system using chromatin or calf thymus DNA as primer. Host liver or hepatoma chromatin incubated with a DNA polymerase extracted from normal rat liver nuclei is stimulated approximately to the same extent by bleomycin. When DNA polymerase extracts from host liver and hepatoma nuclei are assayed with calf thymus DNA as primer, bleomycin has a greater stimulatory effect on [3H]TTP incorporation with host liver DNA polymerase than with hepatoma DNA polymerase in the system. We suggest that a defect in the repair system in hepatoma nuclei is responsible for the relatively lower response to bleomycin.
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PMID:Effect of bleomycin on [3H]Thymidine 5'-Triphosphate incorporation into host liver and hepatoma nuclei. 5 97

The addition of bleomycin to a nuclear incorporating system results in an increased incorporation of 3H-thymidine 5'-triphosphate (3H-TTP) into the DNA of liver and hepatoma nuclei. Bleomycin added to the nuclear incorporating system also produces scissions of DNA as determined by sucrose density gradient centrifugation of the extracted DNA. The action of bleomycin is dependent on the presence of sulfhydryl agents in the incubation mixture. Two compounds, N-ethyl maleimide and daunomycin, inhibit the bleomycin-induced incorporation of 3H-TTP preferentially. N-Ethyl maleimide inhibits bleomycin-induced activity in liver and hepatoma 7777 nuclei equally. Lower levels of daunomycin inhibit the bleomycin-induced activity in the hepatoma 7777 nuclei than are required to inhibit the activity in liver nuclei. The two compounds inhibit the bleomycin effect by different mechanisms. The addition of N-ethyl maleimide to bleomycin in the incubation system prevents bleomycin from causing breaks in the DNA. The addition of daunomycin, despite inhibition of bleomycin-induced 3H-TTP incorporation, does not affect the bleomycin-produced breaks in the DNA. N-Ethyl maleimide acts by binding to the DNA and by competing with a sulfhydryl agent for bleomycin-sensitive sites on the DNA. Daunomycin apparently inhibits a repair enzyme that is responsible for the increased incorporation following bleomycin treatment.
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PMID:Inhibition of bleomycin-induced [3H] thymidine 5'-triphosphate incorporation into liver and hepatoma nuclei by N-ethyl maleimide and daunomycin. 6 27

We investigated the effect of camptothecin and adriamycin on [3H]TTP incorporation and bleomycin-stimulated [3H]TTP incorporation in host liver and hepatoma nuclei of rats. Camptothecin neither stimulated nor inhibited incorporation in the regular nuclear incorporating system. Bleomycin stimulated incorporation to a much greater extent in host liver nuclei and slow-growing hepatomas than it did in the fast-growing hepatoma 7777. Addition of camptothecin to bleomycin stimulated incorporation of [3H]TTP even further. This camptothecin stimulation was slightly greater in hepatoma nuclei than it was in host liver nuclei. Adriamycin inhibited [3H]TTP incorporation in the regular system as well as the bleomycin-induced incorporation. Hepatoma nuclei were more sensitive to this inhibition than were host liver nuclei. Sucrose density gradients indicated that camptothecin caused DNA strand scissions in addition to those produced by bleomycin. Camptothecin alone produced some single-strand but no double-strand scissions. The action of bleomycin was dependent on sulfhydryl-reducing agents. Camptothecin could partially substitute for this requirement. Adriamycin did not produce DNA breaks as determined by neutral or alkaline sucrose density gradients. Despite complete inhibition of bleomycin-induced [3H]TTP incorporation, adriamycin did not prevent bleomycin-induced DNA breaks. The inhibitory effect of adriamycin might have been on the repair system.
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PMID:Effect of camptothecin and adriamycin on bleomycin-induced tritiated thymidine triphosphate incorporation in a rat nuclear system. 6 12

Six different tumor antibiotics have been investigated in a nuclear incorporating system for their ability to inhibit 3H-TTP incorporation. Both host liver nuclei and nuclei prepared from two different Morris hepatomas have been used in the investigation. Three of these anti-tumor agents inhibit 3H-TTP incorporation equally in host liver and hepatoma nuclei, two preferentially inhibit incorporation in hepatoma nuclei and one stimulates incorporation preferentially in host liver nuclei. The effects of these compounds on nuclear DNA has been analyzed on neutral and alkaline sucrose density gradients. The nuclear incorporation system appears to be useful as a screening test system for potential anti-tumor agents.
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PMID:The effect of several antitumor agents on 3H-TTP incorporation in host liver and hepatoma nuclei. 7 Jul 69

Incorporation of [3H]TTP into membrane-denuded nuclei and fractions of these nuclei from host liver and Morris hepatomas has been compared. Treatment of sucrose nuclei with Triton X-100 removed 95% of the phospholipids and 15 to 20% of the protein. These membrane-denuded nuclei remained physically stable. The Triton X-100-extracted nuclei incorporated label into their DNA in nuclear-incorporating system similar to sucrose nuclei with their membranes intact. Triton X-100-treated nuclei from hepatoma 7777 incorporated six times more label and those from hepatoma 7800 incorporated three times more label than Triton X-100-treated host liver nuclei. Nuclei from the three sources incorporated more label when exogenous DNA was added to the incubation system, but the difference in incorporation between the hepatoma nuclei and the host liver nuclei disappeared. When Triton X-100-treated nuclei, prepared from a tumor-bearing animal given injections of [3H]thymidine for 10 min were fractionated on sucrose gradients after disruption by high Mg2+ concentration, the fractions from hepatoma 7777 nuclei contained six times as much label as the host liver nuclear fractions. Nuclear fractions prepared from unabeled hepatomas or host livers had DNA polymerase activity. The activity, however, is the same in fractions prepared from hepatoma 7777 or host liver nuclei. It is suggested that the nuclear membrane does not play an important role in nuclear DNA synthesis. It is further suggested that the increased incorporation found with hepatoma nuclei is dependent on a physical or chemical arrangement of components within the nucleus and not solely on different enzyme levels.
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PMID:DNA synthesis in membrane-denuded nuclei and nuclear fractions from host liver and Morris hepatomas. 16 67

A serum protein present in normal rat serum and absent from the serum of hepatoma-bearing animals at advanced stages has a stimulatory effect on 3H-thymidine incorporation into hepatoma cells in suspension. Liver cells maintained in a similar suspension are not affected by the factor. The stimulation appears to be at the level of chromatin or DNA. Isolated membrane-denuded nuclei from Morris hepatoma 7777 incorporate more 3H-TTP when the factor is present in the incubation mixture. Nuclei from host liver are not stimulated. The factor also stimulates incorporation of 3H-TTP in a system using calf thymus DNA as primer and an extracted DNA polymerase. In this system incorporation is stimulated with DNA polymerase from both tissues, host liver and hepatoma 7777. It is concluded that the factor does not act on the DNA polymerase but on chromatin or DNA.
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PMID:Stimulatory effect of a serum factor on DNA synthesis in isolated hepatoma nuclei. 17 43

The activity of deoxycytidine kinase (EC 2.7.1.74), an important pyrimidine salvage enzyme, was elevated 5- to 30-fold in human ovarian carcinoma and OVCAR-5 cells, in human colon carcinoma and HT-29 cells, in rat hepatoma 3924A solid tumors and cells, and in rat sarcoma as compared with the respective control normal cells. There was an inverse relationship between cell doubling time and deoxycytidine kinase activity in 8 cancer cell lines, with rapidly growing HL-60 cells (20 hr) showing the highest, and slower-growing lung H69 cells (60 hr) the smallest, increase in enzyme activity. In time-sequence studies in human HL-60, OVCAR-5, PANC-1, and rat hepatoma 3924A cells, there was a significant rise in deoxycytidine kinase activity after 3-6 hr of seeding, with peak increases (3.5- to 4-fold) at 48-72 hr in the log phase in comparison with values of the respective plateau phase cells (96-144 hr). In extracts of various cancer cells, the high deoxycytidine kinase activity was competitively inhibited by difluorodeoxycytidine (DFDC), with Ki = 7 to 30 microM. The Km for deoxycytidine in various carcinoma cell lines ranged from 0.3 to 0.7 mM and addition of DFDC increased the apparent Km from 0.7 to 4 mM. Deoxycytidine kinase activity in human HL-60 cells was inhibited by the end product, dCTP, with IC50 = 3 microM; dCTP elevated the Km for deoxycytidine from 0.35 to 0.9 mM. dTTP reversed the inhibition by dCTP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased deoxycytidine kinase activity in cancer cells and inhibition by difluorodeoxycytidine. 129 79

The influence of orotic acid on the incorporation of precursors into nucleic acids was studied in mice and rats and in isolated cells. In vivo, orotate levels were modified by two diets which are known to increase the rate of pyrimidine nucleotide synthesis in rat liver. Of these diets, a 1% orotate diet had greater inhibitory effects than an arginine-deficient diet on the incorporation of [3H]orotate into RNA of mouse kidney than mouse liver. This contrasted with the situation in the rat where there was a greater effect in the liver than the kidney. The situation in the rat was more readily interpreted than in the mouse in terms of previously established effects of these diets on ribonucleotide pool sizes. However, studies using [3H]adenosine as a precursor for incorporation into RNA suggested that even in the mouse the effects of orotate were on pool sizes rather than an inhibitory effect on RNA synthesis. The incorporation of [3H]thymidine into DNA was inhibited by orotate to a similar degree in cultured HTC hepatoma cells and a line of rat liver epithelial cells. An effect on DNA synthesis rather than solely on pool sizes was suggested by the observation that the pool size of dTTP was not increased by 5 mM orotate under conditions in which there was a four-fold increase in the level of UTP in HTC cells. An inhibitory effect of orotate on DNA synthesis was further supported by an observation of decreased incorporation of [3H]deoxyadenosine into DNA and a lower rate of cellular proliferation.
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PMID:Inhibitory effects of orotate on precursor incorporation into nucleic acids. 169 33

Metabolism of arabinose 5-P, ribose 5-P and glucose 6-P in permeabilized and resealed Morris hepatoma 5123TC cells was investigated by measuring the contribution of these compounds to nucleic acid biosynthesis. The level of [14C]-arabinose (non-phosphorylated) incorporation into nucleic acids was slight, presumably due to the low activity of the transport system or the absence or low activity of a specific 'kinase' enzyme. The permeabilizing procedure involved the brief treatment of Morris hepatoma 5123TC cells with lysolecithin and resulted in a cell population which was permeable to charged compounds i.e. sugar phosphates and nucleotides, that otherwise could not cross the plasma membrane. The permeabilized (and resealed cells) retained normal cellular morphology and intactness of specific organelles as judged by the maintenance of functional properties. Following permeabilization, these cells resealed when transferred back to normal growth medium, and continued to divide and increase at the same rates as control non-permeabilized cell cultures. The permeabilized cells incorporated deoxyribonucleotides ([methyl -3H]-TTP) into DNA at a linear rate of 0.047 nmol per 10(7) cells min-1, representing 90-100 per cent of the DNA synthesis rate in vivo. The permeabilization technique, when coupled with procedures to establish cell synchrony, permitted the comparative estimate of the contributions of [14C]-labelled arabinose 5-P, ribose 5-P and glucose 6-P to RNA, DNA, amino acids, CO2, lactate and sugar mono- and bisphosphates. The percentage of [14C]-isotope incorporated into total nucleic acids by these three labelled sugar phosphates were 2.3, 4.9 and 6.3 respectively. Possible reasons for the lower incorporation of 14C from arabinose 5-P are given. The results are consistent with the proposal that arabinose 5-P, an intermediate of the L-type pentose pathway activity of 5123TC cells, was incorporated into nucleic acids by its interconversion with ribulose 5-P and ribose 5-P and thus into PRPP. This study represents the first report of sugar phosphate as opposed to free sugar metabolism by tumour cells in culture.
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PMID:Introduction and metabolism of pentose and hexose phosphates in permeabilized Morris hepatoma 5123TC cells. 244

1-(1,3-Dihydroxy-2-propoxymethyl)-5,6-tetramethylene-uracil (DHPTU) is a newly synthesized acyclonucleoside which shows cytostatic properties. It was tested in Syrian hamster 6 days after heterotransplantation of Kirkman-Robbins hepatoma. A reduction of tumour weight by 61% was found 48 h after its intraperitoneal (i.p.) administration in doses of 20 mg per kg of body weight. Inhibition of tumour growth is accompanied by a reduction of dThd, dGuo and dTMP kinase activities in tumour cytosol (by 91% and 74% and 55%, respectively) and decrease in contents of dTTP, dGTP and dATP (by 92%, 77% and 67%, respectively) in dNTP pool. DHPTU is not phosphorylated by any tumour dN kinases, but undergoes cleavage with TU release in reaction catalyzed by the tumour cell enzyme, competitively inhibited by FA. After [14C]DHPTU or [14C]TU had been given i.p. to the animals with the tumour, 90% of the subcellular fraction labelling fell into the nuclear fraction. However, if [14C]DHPTU was administered with FA and DCF, 27% of radioisotope was found in the nuclear fractions and 68% in cytosol. Since DCF which prevented FA deamination to FB (which is not an inhibitor of the mentioned enzyme) reduces DHPTU-induced changes in activity of dN kinases and dTMP kinase in hepatoma cells, the cytostatic activity of DHPTU seems to be connected to an enzyme which releases TU from DHPTU.
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PMID:Growth inhibition of Kirkman-Robbins hepatoma by 1-(1,3-dihydroxy-2-propoxymethyl)-5,6-tetramethyleneuracil and possible mechanism of its biological activity. 256 Oct 52


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