Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adriamycin, daunomycin, acridylmethanesulfonanilide, and alkoxybenzophenanthridine alkaloids (coralyne acetosulfate, fagaronine chloride, and nitidine chloride) inhibit template-directed nucleic acid polymerizing enzyme activities like reverse transcriptase, DNA polymerase, and RNA polymerase. Enzyme reactions with poly(dA-dT), poly(rA)-oligo(dT) and poly(dA)-oligo(dT) are more strongly inhibited by the drugs than those with poly(dC)-poly(dG) and poly(rC)-oligo(dG). These results suggest that the antitumor drugs inhibit nucleic acid polymerases by a specific interaction with A:T base pairs of the templates.
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PMID:Base specificity in the inhibition of oncornavirus reverse transcriptase and cellular nucleic acid polymerases by antitumor drugs. 8 41

The histology, ultrastructure, and nuclear RNA polymerase activity are described in a murine primitive neuroectodermal tumor derived by serial transplantation from a tumor originally induced with methylcholanthrene and classified as an ependymoblastoma. The light microscope and ultrastructural studies show that this tumor does not contain the distinguishing morphological features of differentiated ependymal cells which are also commonly seen in human ependymomas. One outstanding feature is the size and number of the nucleoli. The mean number of nucleoli/nucleus is 4 which is two to four times that of the normal neuroglial cell. The nucleolar diameter is about twice that found in normal neuroglial cells. The nucleolar diameter is about twice that found in normal neuroglial cells. The nuclear RNA synthesizing activity is the highest of the chemically induced animal tumors we have studied. The alpha amanitin inhibition is the lowest seen in any of these tumors which suggests that RNA polymerases inhibited by alpha amanitin contribute less to the total nuclear RNA synthesis. Adriamycin significantly inhibits the nuclear RNA polymerase activity of this tumor.
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PMID:Methylcholanthrene induced murine primitive neuroectodermal tumor: ultrastructure and nuclear RNA polymerase activity. 73 55

The effect of adriamycin on DNA, RNA, and protein synthesis was investigated in cell-free systems and intact cells. In studies with purified mammalian cell enzymes, adriamycin produced a greater inhibition of DNA-dependent DNA polymerase than of RNA polymerase. The extent of inhibition of both these enzymes was decreased by increasing the concentration of the DNA template in the reaction mixture. In studies with isolated nuclei, adriamycin was also a more potent inhibitor of DNA synthesis than RNA synthesis. However, with intact cells, adriamycin inhibited both DNA and RNA synthesis to about the same extent. The inhibition produced by adriamycin on RNA synthesis in intact cells was greater than that observed in the cell-free systems. Adriamycin inhibited protein synthesis in a cell-free system consisting of polyribosomes, transfer RNA, and enzymes but did not inhibit protein synthesis in intact cells. These differences in the pattern of inhibition may be due to biotransformation of the drug and/or preferential binding to chromosomal DNA in the intact cell.
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PMID:Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. 127 99

CI-937 and CI-942 belong to a new class of DNA complexers, the anthra[1,9-cd]pyrazol-6(2H)-ones (anthrapyrazoles), and are being further developed as antitumor drugs based on their curative properties against murine solid tumour models. The biochemical effects of these agents were studied in L1210 leukemia in relation to other clinically used intercalators. After a 1-hr exposure, CI-937 and CI-942 reduced the cloning efficiency of L1210 cells by 50% at 3.0 X 10(-8) and 1.5 X 10(-7) M respectively. Based on an ethidium displacement assay, these drugs bound strongly to DNA, reducing the fluorescence of an ethidium-DNA complex by 50% at concentrations of 23 and 33 nM for CI-937 and CI-942 respectively. This was comparable to mitoxantrone at 15 nM, but much more potent than Amsacrine which required over 1.3 microM. A distinct property of the anthrapyrazoles was a much more potent inhibitory effect on whole cell DNA synthesis than on RNA synthesis. After L1210 cells were exposed to drug for 2 hr the concentration needed to inhibit DNA synthesis by 50% was 0.33 and 0.57 microM for CI-937 and CI-942, respectively, whereas 2.0 and 11.3 microM were required to inhibit RNA synthesis by the same extent. This was in contrast to Adriamycin and mitoxantrone which inhibited both activities equally at similar concentrations. It was apparent that the inhibition of these processes was not due to substrate depletion since intracellular ribonucleoside and deoxyribonucleoside triphosphates either remained constant or were elevated after a 2-hr exposure to 1 or 10 microM drug. A similar discriminatory effect was observed on DNA and RNA polymerase in permeabilized cells, and the inhibition of nucleic acid synthesis in this system could be reversed by exogenously added DNA. Since the high incidence of cardiotoxicity associated with the administration of anthracyclines has been related to the formation of reactive oxygen species, the ability of the anthrapyrazoles to augment superoxide dismutase sensitive oxygen consumption was observed in a rat liver microsomal system. CI-937 and CI-942 induced 5- and 10-fold less oxygen consumption than Adriamycin, producing rates of 12.4, 24.2 and 138.9 nmoles/min/mg microsomal protein, respectively, at a drug concentration of 0.5 mM.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vitro DNA strand scission and inhibition of nucleic acid synthesis in L1210 leukemia cells by a new class of DNA complexers, the anthra[1,9-cd]pyrazol-6(2H)-ones (anthrapyrazoles). 241 61

Transcription by RNA polymerase II occurs after formation of a transcription complex. This complex is assembled in stages by the interaction of transcription factors with the template and/or with each other. We report on the ability of six drugs to inhibit the assembly of the RNA polymerase II transcription complex. Assembly of the complex on the adenovirus major late promoter requires several transcription factors. The normal assembly process requires that the DNA first interact with TFIIA, then with TFIID, and finally with at least four additional transcription factors (one of which is RNA polymerase II). We observed that streptolydigin (10 micrograms/ml) inhibits association of ILA and IID, and at higher concentrations (100 micrograms/ml) inhibits that IIA/IID complex from binding to DNA. Streptovaricin (100 micrograms/ml) appears to inhibit the IIA/IID interaction with DNA and prevents reinitiation (at 500 micrograms/ml). Adriamycin (1 microgram/ml) inhibits the interaction of TFIID with the IIA/DNA complex and inhibits an additional event immediately prior to, or during, elongation. Daunorubicin may be an elongation inhibitor. Heparin at 10 micrograms/ml inhibits further assembly after the IIA/IID/DNA complex has formed, and at 100 micrograms/ml also inhibits a late event in the assembly process and blocks reinitiation. Rifamycin AF/013 (100 micrograms/ml) inhibits the early events necessary to form the IIA/IID/DNA complex and (at 10 micrograms/ml) an assembly event following formation of the IIA/IID/DNA complex. Therefore, these compounds should be useful as probes for further examination of the assembly process.
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PMID:Drug inhibitors of RNA polymerase II transcription. 257 59

We investigated the effects of six drugs on an RNA polymerase III in vitro transcription system. Adriamycin, daunorubicin, heparin, rifamycin AF/013, streptolydigin, and streptovaricin all inhibit RNA synthesis from a tRNA gene or the adenovirus 2 (AD2) VA1 RNA gene. The completed RNA polymerase III transcription complex is formed by the sequential, ordered addition of protein factors. Although both genes reportedly use the same transcription fractions for in vitro RNA synthesis, some of these drugs interfere differentially with these genes. A drug concentration that inhibits transcription from one gene may not inhibit transcription from the other gene. Adriamycin seems to block transcription if added between the binding of the individual transcription fractions. Daunorubicin appears to inhibit VA transcription only if added prior to both transcription fractions, but inhibits tRNA synthesis before and during transcription factor binding. Heparin blocks both genes between factors binding to DNA and after factor binding. Rifamycin blocks VA synthesis more effectively than tRNA synthesis. Streptolydigin blocks transcription of both genes. Streptovaricin probably blocks transcription by inhibiting early transcription complex assembly events. These drugs appear useful as appropriate probes to investigate transcription complexes since several discriminate between complexes formed on different genes during the assembly process.
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PMID:Effects of antibiotics on RNA polymerase III transcription. 290 35

The new Adriamycin (ADR) analogue, 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin (CMA), is the most potent anthracycline yet developed. The cellular pharmacology of CMA and 3'-(4-morpholinyl)-3'-deaminoadriamycin (MA), and their 5-imino derivatives, ICMA and IMA, were compared with ADR in a human colon carcinoma (HT-29) cell line in vitro. In a soft agar clonogenic assay, the order of antitumor activity was CMA greater than ICMA greater than ADR greater than MA greater than IMA, for both 2- and 24-h drug exposure periods, indicating a requirement for the cyanide group and an intact quinone ring for the potent antitumor effect of CMA. The cellular uptake of CMA was 2-fold less than that of MA, although, consistent with its greater nuclear binding, the degree of efflux of CMA was less than that of MA. The order of cytotoxicity of the analogues correlated approximately with their effects on cellular DNA synthesis, indicating that this feature may contribute to the antitumor effect. Using isolated nuclei, the order of inhibition of DNA transcription by the analogues was CMA greater than MA greater than ADR, which was similar to their nuclear affinities, suggesting that their effects on cellular nucleic acid synthesis were due to a direct interaction of drug with DNA. However, CMA did not appear to differ from the other drugs in its base specificity as all the analogues preferentially inhibited Escherichia coli RNA polymerase activity directed by poly(dAdT).poly(dAdT) compared to poly(dGdC).poly(dGdC).
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PMID:Cellular pharmacology of 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin and structural analogues in human colon carcinoma HT-29 cells in vitro. 330 Sep 58

A new indolocarbazole antitumor agent, NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H- indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione], enhanced the DNA cleavage catalyzed by HeLa S3 topoisomerase I at 0.01 microM but not the cleavage by topoisomerase II at 300 microM. It also caused single-strand DNA breakage in intact cells at 0.08 microM and more. Unlike the known topoisomerase I inhibitor camptothecin, NB-506 intercalated with DNA. However, the binding affinity to DNA and the inhibition against DNA polymerase alpha and RNA polymerase II were marginal compared with those of Adriamycin or actinomycin D. NB-506 inhibited the growth of various tumor cell lines at two micromoles or less, and its cytotoxicity was found to be cell line selective. This selective cytotoxicity of NB-506 was not fully explained by the differences in topoisomerase I activity in these cell lines, but there was some relationship between the amount of NB-506 accumulated in these cell lines and its cytotoxicity toward them. In conclusion, NB-506 is a potent topoisomerase I poison, acting selectively on tumor cell lines accumulating NB-506.
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PMID:Novel antitumor indolocarbazole compound 6-N-formylamino-12,13-dihydro-1,11- dihydroxy-13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4- c]carbazole-5,7(6H)-dione (NB-506): induction of topoisomerase I-mediated DNA cleavage and mechanisms of cell line-selective cytotoxicity. 788 28

Adriamycin is known to specifically induce DNA interstrand cross-links at 5'-GC sequences. Because 5'-GC sequences are a predominant feature of 5'-untranslated regions (transcription factor-binding sites, promoter, and enhancer regions), it is likely that adriamycin adducts at GC sites would affect the binding of DNA-interacting proteins. Two model systems were chosen for the analysis: the octamer-binding proteins Oct-1, N-Oct-3 and N-Oct-5, which bind to ATGCAAAT and TAATGARAT recognition sites, and Escherichia coli RNA polymerase binding to the lac UV5 promoter. Electrophoretic mobility shift studies showed that adriamycin adducts at GC sites inhibited the binding of octamer proteins to their consensus motifs at drug levels as low as 1 micoM, but no effect was observed with a control sequence lacking a GC site. Adriamycin adducts at GC sites also inhibited the binding of RNA polymerase to the lac UV5 promoter. Adriamycin may therefore function by down-regulating the expression of specific genes by means of inactivation of short but critical motifs containing one or more GC sites.
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PMID:Adriamycin-induced DNA adducts inhibit the DNA interactions of transcription factors and RNA polymerase. 862 97

The transcriptional mechanism of Borna disease virus (BDV) has been poorly understood. We have analyzed transcription of the virus upon various stimuli in Madin-Darby canine kidney cells which were persistently infected by BDV (MDCK/BDV). Treatment with actinomycin D (ActD) increased the level of BDV RNA, shifting the size of RNA from 1.9 kb to 2.3 kb beginning 5 hr after the treatment. To understand the mechanism of this unique modulation of BDV RNA, we conducted several experiments. The RNA increase occurred at the stage in which synthesis of cellular intrinsic mRNA was intact, suggesting BDV does not compete with cellular transcriptional machinery for intrinsic RNA polymerase II. The BDV transcription was also enhanced by cycloheximide treatment, indicating that newly synthesized viral or cellular proteins are not necessary for viral transcription. However, a shift in the RNA size was not observed for cycloheximide-induced BDV RNA. The increase in viral transcription persisted during the cellular apoptotic process consequent to p53 gene accumulation beginning 1 hr after ActD treatment. Caspase inhibitors Z-VAD and DEVD-CHO repressed the apoptotic process but failed to block the increase in BDV transcription. In addition, adenovirus-mediated transduction of wild-type p53 did not alter the BDV transcription, indicating that the increase in BDV transcription was independent of the p53-mediated apoptotic process. Other various stimuli that evoke cellular signal transductions failed to alter BDV transcription. Agents inhibitory to topoisomerase except adriamycin failed to enhance BDV transcription, indicating that the increase in BDV transcription is not mediated by an inhibitory action to the topoisomerase II of ActD. Adriamycin showed an increase and size-shift of BDV RNA similar to ActD. These results suggest that intercalation of the viral genome itself with ActD is related to the stabilization of viral RNA and alteration of RNA size rather than secondary host cell changes.
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PMID:The mechanism of actinomycin D-mediated increase of Borna disease virus (BDV) RNA in cells persistently infected by BDV. 1098 33


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