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:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroxyurea is a potent inhibitor of the enzyme ribonucleotide reductase. Due to its effects on cellular deoxyribonucleotide pools, hydroxyurea can modulate the activity of several pyrimidine and purine antimetabolites. As an inhibitor of DNA repair, it can potentially interact with DNA-damaging agents such as alkylating agents or inhibitors of topoisomerase II. Both cytokinetic and biochemical interactions occur between hydroxyurea and cytarabine (ara-C), which account for their synergistic cytotoxicity. Inhibition of ribonucleotide reductase by hydroxyurea depletes cellular deoxycytidine triphosphate pools, thereby enhancing ara-C uptake and phosphorylation to ara-C triphosphate. In a phase II clinical trial, the combination of hydroxyurea and ara-C produced a 43% response rate in patients with refractory malignant lymphoma. Studies in murine leukemia models have demonstrated therapeutic synergy when hydroxyurea is combined with fluoropyrimidines. High levels of deoxyuridine monophosphate that have been associated with resistance to 5-fluorouracil can be suppressed by hydroxyurea, leading to greater inhibition of thymidylate synthase. Despite the strong biochemical rationale for the use of hydroxyurea and 5-fluorouracil in combination, few clinical trials have been conducted thus far. Antimetabolites and topoisomerase II inhibitors have also been shown to be synergistic in vitro. Hydroxyurea has been shown to enhance the formation of DNA strand breaks produced by amsacrine and to produce synergistic cytotoxicity with etoposide. A phase I clinical trial of these drugs has demonstrated bone marrow suppression to be the major toxicity of the combination. In summary, hydroxyurea has been shown to undergo cytokinetic and biochemical interactions with a number of established antitumor agents. Clinical trials of hydroxyurea in combination with these agents have identified doses and schedules of administration that produce acceptable levels of clinical toxicity and appear feasible for further testing.
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PMID:Laboratory and clinical studies of biochemical modulation by hydroxyurea. 164 59

We have studied the effect of some specific enzyme inhibitors on DNA repair and replication after UV damage in Chinese hamster ovary cells. The DNA repair was studied at the level of the average, overall genome and also in the active dihydrofolate reductase gene. Replication was measured in the overall genome. We tested inhibitors of DNA polymerase alpha and delta (aphidicolin), of poly(ADPr) polymerase (3-aminobenzamide), of ribonucleotide reductase (hydroxyurea), of topoisomerase I (camptothecin), and of topoisomerase II (merbarone, VP-16). In addition, we tested the effect of the potential topoisomerase I activator, beta-lapachone. All of these compounds inhibited genome replication and all topoisomerase inhibitors affected the overall genome repair; beta-lapachone stimulated it. None of these compounds had any effect on the gene-specific repair.
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PMID:Effect of specific enzyme inhibitors on replication, total genome DNA repair and on gene-specific DNA repair after UV irradiation in CHO cells. 165 49

Detergent-soluble DNA is the fraction (2-4%) of DNA that is released into the supernate upon mild detergent lysis. It is nonmitochondrial in origin. It labels efficiently with deoxy[3H]ribonucleosides and the labeling is prevented by inhibitors of polymerase alpha and ribonucleotide reductase. In previous publications we have characterized detergent-soluble DNA from splenocytes of immunologically activated mice. In this publication we show that incorporation of [3H]thymidine into detergent-soluble DNA is prevented by pretreatment with novobiocin, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), and teniposide (VM26), three inhibitors of type II topoisomerases. Camptothecin, an inhibitor of type I topoisomerases, also reduces incorporation of [3H]thymidine but only to 50% of control levels. In addition to affecting incorporation of [3H]thymidine, preincubation with the topoisomerase II inhibitors m-AMSA and VM26 alters the amount of DNA recovered in the detergent-soluble fraction. At low concentrations of m-AMSA the amount of detergent-soluble DNA increases somewhat, whereas at higher drug concentrations a marked decrease is observed. Treatment with VM26 results in diminished amounts of DNA being released into the detergent-soluble fraction as well. However, maximal inhibition of detergent-soluble DNA release by VM26 requires the presence of camptothecin. Therefore, we suggest that topoisomerases play an important role in making a small part of lymphocyte chromatin detergent labile. Furthermore, these results are consistent with recent studies demonstrating a role for topoisomerases in yeast replication. Thus, the newly synthesized portion of detergent-soluble DNA may arise as DNA replication intermediates not yet stabilized into mature chromatin.
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PMID:Role for topoisomerases in the release of DNA into the detergent-soluble fraction of eukaryotic cells. 301 25

We investigated, in a cloned hamster tracheal epithelial cell line HTE-B, the effects of inhibitors of DNA topoisomerase, novobiocin and nalidixic acid; of DNA polymerase, 1-beta-arabinofuranosylcytosine (ara-C) and 2',3'-dideoxythymidine; of ribonucleotide reductase, hydroxyurea; and of poly(ADP-ribose)synthetase, 3-aminobenzamide, upon the removal of benzo[a]pyrene adducted to DNA [B[a]P--DNA]. A substantial reduction in the rate of removal of the polycyclic hydrocarbon-adducts occurred when nalidixic acid was added to the HTE-B cells that had been previously incubated with B[a]P for 8 h. Novobiocin produced a similar, but less marked, effect. The rate of disappearance of the individual B[a]P--DNA adducts was measured by analysis of the h.p.l.c. profiles. Of the 5 major adducts observed under the h.p.l.c. conditions, 4 were reduced in control cells to 30% of the original levels by 24 h after removal of the B[a]P from the medium; adduct 5 was almost completely removed. In the presence of nalidixic acid, during the 24 h repair period, only the removal of adduct 5 was unimpaired; the removal of the other 4 adducts was significantly retarded. On the other hand, 3-aminobenzamide addition did not affect the rate of removal of B[a]P--DNA adducts from the HTE-B cells. We employed the combinations of ara-C and dideoxythymidine or ara-C and hydroxyurea to allow the accumulation of single strand breaks after incubation of the HTE-B cells with B[a]P. These breaks were assayed by alkaline elution analysis. Inclusion of these inhibitors during the 2 h after removal of the B[a]P from the medium resulted in the accumulation of 4-5 single strand breaks/10(10) daltons of HTE-B DNA. This compares with a minimum estimate of the number of adducts removed during this period of 3 adducts/10(7) daltons. This discrepancy may indicate that the majority of lesions are not repaired by a pathway sensitive to polymerase inhibitors. In the presence of 3-aminobenzamide, we routinely observed a 10% increase in the alkaline elution of the DNA obtained from B[a]P-treated cells (1-2 breaks/10(10) daltons). Our results indicate that an excision repair process may be involved in the removal of at least some of the B[a]P-induced damage to DNA. However, the repair of the multiple adducts is complex and may involve pathways other than classical excision repair.
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PMID:The influence of inhibitors on the repair of benzo[a]pyrene-damaged DNA in hamster tracheal epithelial cells. 632 Oct 50

We have previously shown that a fraction from the nuclei of S phase (DNA-synthesizing) Chinese hamster embryo fibroblasts (CHEF/18 cells) can be obtained that has a number of the enzyme activities required for DNA biosynthesis, and can catalyse the incorporation of labelled precursors into DNA (refs 1-4, also see ref. 8). This fraction, which we have termed the 'replitase', contains spherical particles of diameter approximately 25 nm, apparently multienzyme complexes for de novo DNA biosynthesis. Here we present evidence for the functional association of one of the enzyme activities, thymidylate synthase, with several of the other enzyme activities. Hydroxyurea, novobiocin and aphidicolin, inhibitors of ribonucleotide reductase, topoisomerase and DNA polymerase alpha, respectively, all inhibit thymidylate synthase in intact S phase CHEF/18 cells, but not in their soluble extracts. We suggest that these results reflect allosteric interactions between the subunits of a multienzyme DNA-synthesizing complex, which can be modulated by the specific inhibitors of individual enzyme activities in intact cells.
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PMID:Inhibitor evidence for allosteric interaction in the replitase multienzyme complex. 640 86

Many antitumor agents and antibiotics affect cells by interacting with type II topoisomerases, stabilizing a covalent enzyme-DNA complex. A pathway of recombination can apparently repair this DNA damage. In this study, transposon mutagenesis was used to identify possible components of the repair pathway in bacteriophage T4. Substantial increases in sensitivity to the antitumor agent m-AMSA [4'-(9-acridinylamino)methanesulfon-m-anisidide] were found with transposon insertion mutations that inactivate any of six T4-encoded proteins: UvsY (DNA synaptase accessory protein), UvsW (unknown function), Rnh (RNase H and 5' to 3' DNA exonuclease), alpha-gt (alpha-glucosyl transferase), gp47.1 (uncharacterized), and NrdB (beta subunit of ribonucleotide reductase). The role of the rnh gene in drug sensitivity was further characterized. First, an in-frame rnh deletion mutation was constructed and analyzed, providing evidence that the absence of Rnh protein causes hypersensitivity to m-AMSA. Second, the m-AMSA sensitivity of the rnh-deletion mutant was shown to require a drug-sensitive T4 topoisomerase. Third, analysis of double mutants suggested that uvsW and rnh mutations impair a common step in the recombinational repair pathway for m-AMSA-induced damage. Finally, the rnh-deletion mutant was found to be hypersensitive to UV, implicating Rnh in recombinational repair of UV-induced damage.
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PMID:Bacteriophage T4 mutants hypersensitive to an antitumor agent that induces topoisomerase-DNA cleavage complexes. 880 83

The purpose of this review is to summarize information published since 1990 on DNA replication, recombination and repair of vaccinia virus, a poxvirus. Temperature-sensitive mutations reveal four essential genes related to viral DNA replication: the E9L DNA polymerase, B1R protein kinase, D5R protein, and D4R uracil DNA glycosylase. Other proteins are likely to be also involved in viral DNA replication: the H6R DNA topoisomerase, I3L single stranded-DNA binding protein, H5R virosome-associated protein, and A50R DNA ligase. In addition, several viral-encoded proteins do regulate the level of the deoxyribonucleoside triphosphate pool: the J2R thymidine kinase, A48R thymidylate kinase, 14L and F4L subunits of ribonucleotide reductase, and F2L dUTPase. Despite the apparent simplicity of the mechanism of vaccinia virus DNA replication, several important questions related to the three Rs remain unsolved.
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PMID:Vaccinia virus DNA replication: a short review. 882 74

The Herpesviridae comprise a large class of animal viruses of considerable public health importance. Of the Herpesviridae, replication of herpes simplex virustype-1 (HSV-1) has been the most extensively studied. The linear 152-kbp HSV-1 genome contains three origins of DNA replication and approximately 75 open-reading frames. Of these frames, seven encode proteins that are required for originspecific DNA replication. These proteins include a processive heterodimeric DNA polymerase, a single-strand DNA-binding protein, a heterotrimeric primosome with 5'-3' DNA helicase and primase activities, and an origin-binding protein with 3'-5' DNA helicase activity. HSV-1 also encodes a set of enzymes involved in nucleotide metabolism that are not required for viral replication in cultured cells. These enzymes include a deoxyuridine triphosphatase, a ribonucleotide reductase, a thymidine kinase, an alkaline endo-exonuclease, and a uracil-DNA glycosylase. Host enzymes, notably DNA polymerase alpha-primase, DNA ligase I, and topoisomerase II, are probably also required. Following circularization of the linear viral genome, DNA replication very likely proceeds in two phases: an initial phase of theta replication, initiated at one or more of the origins, followed by a rolling-circle mode of replication. The latter generates concatemers that are cleaved and packaged into infectious viral particles. The rolling-circle phase of HSV-1 DNA replication has been reconstituted in vitro by a complex containing several of the HSV-1 encoded DNA replication enzymes. Reconstitution of the theta phase has thus far eluded workers in the field and remains a challenge for the future.
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PMID:Herpes simplex virus DNA replication. 924 11

The expression of seven enzymes involved in the biosynthesis of DNA was measured in HL-60 promyelocytic leukemia cells treated with dimethylsulfoxide (DMSO) or all-trans retinoic acid (RA) to gain information on their role in the termination of proliferation in cells undergoing granulocytic differentiation. The steady-state levels of the mRNAs for topoisomerase I, topoisomerase II. DNA polymerase-alpha, thymidylate synthase, thymidine kinase and hypoxanthine-guanine phosphoribosyltransferase progressively declined from day 3 to day 7 of exposure to the polar solvent or the retinoid suggesting that the expression of these enzymes is coordinately regulated. In contrast, a pronounced difference between the two inducers of differentiation occurred in the expression of the mRNA of the M2 subunit of ribonucleotide reductase, with DMSO causing virtually complete inhibition of the expression of the M2 subunit of the enzyme from day 5 through day 7, with no change in the steady-state levels of the mRNA being produced by retinoic acid. Measurement of the enzymatic activities of two of these catalysts, thymidylate synthase and thymidine kinase, in cells exposed to the two inducers of maturation corroborated the findings at the level of the mRNAs, with corresponding decreases in the activity of these enzymes. The findings collectively demonstrate that the down-regulation of the expression of a relatively wide variety of enzymes involved in DNA replication occurs as late events in the granulocytic differentiation of HL-60 cells, ensuring that cellular replication cannot occur in terminally differentiated cells.
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PMID:Regulation of the expression of enzymes involved in the replication of DNA in chemically-induced granulocytic differentiation of HL-60 leukemia cells. 968 95

The expression of a number of housekeeping enzymes of DNA biosynthesis was measured in HL-60 promyelocytic leukemia cells undergoing monocytic/macrophagic differentiation following treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) or 1alpha,25-dihydroxyvitamin D3 (vitamin D3). Progressive decreases in the steady-state levels of the mRNAs for thymidylate synthase, topoisomerase II, and hypoxanthine guanine phosphoribosyltransferase occurred following exposure to TPA or vitamin D3. In contrast, the steady-state levels of the mRNAs for thymidine kinase, topoisomerase I, and DNA polymerase-alpha did not decrease until days 3-5 of treatment with vitamin D3 and then progressively declined thereafter. The mRNAs for thymidine kinase and topoisomerase I decreased slightly and the mRNA for DNA polymerase-alpha by 30-40%, and then remained constant between days 1 to 3 of treatment with the phorbol ester. The M2 subunit of ribonucleotide reductase exhibited an even greater difference, with no change in the steady-state concentration of mRNA over 3 days of exposure to TPA or vitamin D3. On days 5-7 of treatment with vitamin D3, essentially complete loss of the expression of the mRNA for the M2 subunit of ribonucleotide reductase occurred. Measurement of the enzymatic activities of thymidylate synthase and thymidine kinase in cells exposed to either of the inducers of maturation corroborated the findings at the level of the mRNAs, with corresponding decreases in the activity of these enzymes. The results indicate that the down-regulation of the expression of housekeeping enzymes of DNA replication occurs as late events in HL-60 cells undergoing monocytic/macrophagic differentiation, implying that the decreases in their gene expression are the result of the termination of proliferation rather than an initiating event in the cessation of DNA biosynthesis.
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PMID:Regulation of the expression of enzymes involved in the replication of DNA in chemically induced monocytic/macrophagic differentiation of HL-60 leukemia cells. 968 96


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