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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human NK cells (with CD3-/56+ phenotype) acquired features characteristic of apoptosis after incubation with autologous monocytes, as revealed by apoptotic nuclear morphology, degradation of DNA into oligonucleosomal fragments, and reduced nuclear interchalation of propidium iodide. In contrast, T cells (CD3+/56-) remained non-apoptotic. The monocyte-induced apoptosis in NK cells was prevented by catalase, a scavenger of hydrogen peroxide; whereas superoxide dismutase (a scavenger of superoxide anion), hydroxyl radical scavengers such as mannitol and deferoxamine, or the hypochlorus acid scavenger taurine did not prevent apoptosis. Sodium azide, a myeloperoxidase inhibitor, substantially reduced the monocyte-induced apoptosis in NK cells. Exogenous hydrogen peroxide, at concentrations exceeding 1 microns, induced apoptosis in both NK and T cells. Apoptosis induced by hydrogen peroxide occurred independently of synthesis of protein or mRNA and was blocked by the endonuclease inhibitor aurin tricarboxylic acid. Furthermore, oxidatively induced apoptosis in NK cells was inhibited by herbimycin A, indicating that apoptosis was dependent on protein kinases. Two to five times more hydrogen peroxide was required to induce apoptosis in T cells compared with NK cells. Similarly, NK cells were considerably more susceptible to apoptosis induced by the topoisomerase II inhibitor etoposide or by gamma-irradiation than were T cells. We conclude that monocyte-derived reactive oxygen metabolites kill NK cells by apoptosis and that NK cells are unusually sensitive to oxidatively as well as non-oxidatively induced apoptosis.
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PMID:Induction of apoptosis in NK cells by monocyte-derived reactive oxygen metabolites. 859 91

There is compelling evidence for the central role of oxidative damage in the aging process and for the participation of reactive oxygen species in tumor initiation and promotion. Caloric restriction (CR) or energy restriction retards age-associated increases in mitochondrial free-radical production and reduces the accumulation of oxidatively damaged cell components. CR has also been shown to slow down age-related declines in various repair capabilities, including some types of DNA repair. It is proposed that inhibitors of mitochondrial electron transport and/or uncouplers of oxidative phosphorylation (rotenone, amytal, amiodarone, valinomycin, etc.), when used at extremely low doses, could mimic the effects of CR in model systems. The objective is to lower mitochondrial free-radical production by decreasing the fraction of electron carriers in the reduced state. In addition to a variety of other effects, CR has been shown to increase the rate of apoptosis, particularly in preneoplastic cells, and in general, to promote elevated levels of free glucocorticoids (GCs). GCs are known to induce tissue-specific apoptosis and to upregulate gap-junction-mediated intercellular communication (GJIC). Tumor promoters like phorbol esters have the opposite effect, in that they inhibit both the process of apoptosis and GJIC. The enzyme poly (ADP-ribose) polymerase (PARP) is thought to play a central role in apoptosis, in a manner that has been highly conserved in evolution. There is good evidence that the apoptosis-associated Ca/Mg-dependent DNA endonuclease is maintained in a latent form by being poly (ADP-ribosylated). Apoptosis would require the removal of this polymer from the endonuclease, and, most likely, its removal from topoisomerase II and histone H1 as well. The role of poly (ADP-ribose) in apoptosis, carcinogenesis, and aging could be studied by the use of modulators of PARP activity (3-aminobenzamide, 3-nitrosobenzamide, 1% ethanol, etc.), inhibitors of poly ADP-ribose) glycohydrolase activity (ethacridine, 43 degrees C, etc.), and inhibitors of the PARP-specific protease (interleukin-1 beta converting enzyme (ICE)-like protease). Also, it would be of interest to determine if CR can decrease the half-life of poly (ADP-ribose), upregulate GJIC, and modulate the activities of PARP, the glycohydrolase, and the PARP-specific protease, factors potentially important in these processes.
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PMID:The beneficial effects of dietary restriction: reduced oxidative damage and enhanced apoptosis. 865 88

An array of novel 2-acyl-1,2-dihydroellipticines was prepared and evaluated for in vitro cytotoxicity in a variety of human cancer cell lines. The ellipticine analogs were also tested for inhibition of topoisomerase II in both decatenation and cleavable complex formation assays. Some of the new ellipticine derivatives were prepared by acylation of ellipticine with acid chlorides in tetrahydrofuran, followed by reduction of the intermediate 2-acylellipticinium ions with sodium cyanoborohydride. Others were synthesized by acylation of ellipticine with p-nitrophenyl chloroformate, reduction of the 2-acylellipticinium ion with sodium cyanoborohydride, and displacement of the p-nitrophenoxide anion with a variety of oxygen and nitrogen nucleophiles. The cytotoxicities of the new 2-acyl-1,2-dihydroellipticines varied widely, and correlated well with their topoisomerase II inhibitory activities.
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PMID:Synthesis of a series of cytotoxic 2-acyl-1,2-dihydroellipticines which inhibit topoisomerase II. 867 54

The thymine oxidative lesion-5-hydroxymethyluracil (HMUra)-was measured in urine collected from cancer patients. These patients all received chemotherapy using Adriamycin. Adriamycin (ADR) intercalates DNA coils and interferes with normal cell metabolism through diverse biochemical mechanisms that may explain its different actions. The anticancer action of ADR could derive from its interaction with topoisomerase II, resulting in DNA nicking followed by DNA fragmentation and apoptosis. Side effects of ADR-mainly its cardiotoxicity-may derive from the fact that ADR generates superoxide and hydroxyl radicals in two ways: redox-cycling and a Haber-Weiss type reaction due to Fe-ADR complexes. The oxygen free radicals, particularly .OH, are thought to be produced by ADR directly in genomic material and attack all its components. 5-Hydroxymethyluracil is a thymine lesion provoked by these attacks, and it has been proposed as a marker of DNA alterations. In this article, we report the results of a study involving 14 cancer patients treated with ADR. We found that urine HMUra is significantly increased by the anticancer therapy (HMUra (nmol/24 h): 74.4 9.46 vs. 96.3 8.74; p < .01), this increase reveals a higher risk of mutagenesis. Our study is the first to show an in vivo alteration of DNA by ADR. Results also show that thiobarbituric acid reactants increase significantly, and that the vitamin levels for retinol and alpha-tocopherol, which are antioxidant vitamins, are lower at the end of chemotherapy. We suggest to supplement these patients with vitamins A and E, and selenium to reduce the side effects of ADR.
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PMID:5-Hydroxymethyluracil excretion, plasma TBARS and plasma antioxidant vitamins in adriamycin-treated patients. 874 84

Several laboratories have recently demonstrated the feasibility of using radiation-induced DNA strand breaks (SBs) and DNA-protein cross-links (DPCs) to detect and quantify hypoxic cells in tumours and normal tissues. However, if radiation-induced SBs and DPCs are going to provide reasonable estimates of the hypoxic fraction or fractional hypoxic volume of tumours and normal tissues, their formation as a function of the oxygen concentration must be relatively independent of biological factors such as cell type, proliferative status or the composition and properties of proteins that are intimately associated with the DNA. In the present study, the shape of the oxygen dependence curves and the K(m) values for radiation-induced SBs and DPCs were measured by alkaline elution for two human leukaemia cell lines, CEM and CEM/VM-1, whose nuclear matrix-associated topoisomerase II varied substantially in quantity, activity and binding properties. The sigmoidal shape of the oxygen dependence curves, the K(m) for sB formation (approximately 0.027 mM), and the K(m) for DPC formation (approximately 0.064 mM) were identical for both of these human leukaemia cell lines. Consequently, the quantity and properties of topoisomerase II had no measurable influence on the oxygen-dependent formation of radiation-induced SBs and DPCs. These data suggest that varying levels of nuclear matrix-associated proteins and DNA binding proteins will not be a complicating factor when using radiation-induced SBs and DPCs for estimating the hypoxic fraction or fractional hypoxic volume of tumours and normal tissues.
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PMID:Influence of topoisomerase II on the formation of oxygen-dependent radiation-induced DNA damage. 876 79

Vaccinia topoisomerase catalyzes DNA cleavage and rejoining via transesterification to pentapyrimidine recognition site 5'-(C/T)CCTT downward arrow in duplex DNA. The proposed reaction mechanism involves general-base catalysis of the attack by active site nucleophile Tyr-274 on the scissile phosphodiester and general-acid catalysis of the expulsion of the 5'-deoxyribose oxygen on the leaving DNA strand. The pKa values suggest histidine and cysteine side chains as candidates for the roles of proton acceptor and donor, respectively. To test this, we replaced each of the eight histidines and two cysteines of the vaccinia topoisomerase with alanine. Single mutants C100A and C211A and a double mutant C100A-C211A were fully active in DNA relaxation, indicating that a cysteine is not the general acid. Only one histidine mutation, H265A, affected enzyme activity. The rates of DNA relaxation, single-turnover strand cleavage, and single-turnover religation by H265A were 2 orders of magnitude lower than the wild-type rates. Yet the H265A mutation did not alter the dependence of the cleavage rate on pH, indicating that His-265 is not the general base. Replacing His-265 with glutamine or asparagine slowed DNA relaxation and single-turnover cleavage to about one-third of the wild-type rate. All three mutations, H265A, H265N, and H265Q, skewed the cleavage-religation equilibrium in favor of the covalently bound state. His-265 is strictly conserved in every member of the eukaryotic type I topoisomerase family.
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PMID:Histidine 265 is important for covalent catalysis by vaccinia topoisomerase and is conserved in all eukaryotic type I enzymes. 902 90

A conjugate molecule was synthesized by linking the DNA-intercalative antitumor drug 4'-(9-acridinylamino)methanesulfon-manisidide (mAMSA) via a 4-carboxamide side chain to a dipyrrolecarboxamide moiety structurally related to the minor groove-binding antibiotic netropsin. The molecule (netropsin/ mAMSA) behaves as a threading intercalator. Its netropsin-like tail becomes located in the minor groove of the double helix and serves to drive the hybrid molecule preferentially to AT-rich sites on various DNA fragments as revealed by DNase I footprinting. The hybrid retains the susceptibility to copper-dependent oxidation characteristic of the parent mAMSA moiety as well as its ability to generate oxygen radicals, which can mediate DNA damage, mainly at cytidine and guanosine nucleotides. It also retains the property of stimulating the formation of cleavable complexes with DNA in the presence of topoisomerase II, but its netropsin-like moiety confers little or no influence on the reaction with topoisomerase I. Although netropsin/mAMSA is less potent than mAMSA at producing cleavable complexes with topoisomerase II, it promotes the appearance of cleavage sites at much the same nucleotide sequences as does the parent compound. The dipyrrolecarboxamide tail is not silent, however, since it modifies the concentration-dependence of cleavable complex formation.
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PMID:Copper-dependent oxidative and topoisomerase II-mediated DNA cleavage by a netropsin/4'-(9-acridinylamino)methanesulfon-m-anisidide combilexin. 905

An overall hypothesis for benzene-induced leukemia is proposed. Key components of the hypothesis include a) activation of benzene in the liver to phenolic metabolites; b) transport of these metabolites to the bone marrow and conversion to semiquinone radicals and quinones via peroxidase enzymes; c) generation of active oxygen species via redox cycling; d) damage to tubulin, histone proteins, topoisomerase II, other DNA associated proteins, and DNA itself; and e) consequent damage including DNA strand breakage, mitotic recombination, chromosome translocations, and aneuploidy. If these effects take place in stem or early progenitor cells a leukemic clone with selective advantage to grow may arise, as a result of protooncogene activation, gene fusion, and suppressor gene inactivation. Epigenetic effects of benzene metabolites on the bone marrow stroma, and perhaps the stem cell itself, may then foster development and survival of the leukemic clone. Evidence for this hypothesis is mounting with the recent demonstration that benzene induces gene-duplicating mutations in human bone marrow and chromosome-specific aneuploidy and translocations in peripheral blood cells. If this hypothesis is correct, it also potentially implicates phenolic and quinonoid compounds in the induction of "spontaneous" leukemia in man.
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PMID:The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. 911 96

Histologic and biochemical studies were carried out to compare the protective activity of various bisdiketopiperazines against the cardiac and renal toxicity induced by doxorubicin in spontaneously hypertensive rats (SHR), a well-established animal model of this disorder, with: (1) the rates of hydrolysis of these agents to form the iron-chelating derivatives (which are considered to cause a decrease in the formation of reactive oxygen intermediates) and (2) the ability of these derivatives to bind iron. SHR were given 12 weekly injections of doxorubicin, 1 mg/kg i.v. either alone or 30 min after the administration of ICRF-154, ICRF-187, ICRF-192, ICRF-197, ICRF-198, ICRF-239 and ADR-559. Semiquantitative grading of the severity of the resulting cardiac and renal lesions showed that ICRF-187, ICRF-154 and ADR-559 were the most protective, whereas ICRF-197 and ICRF-239 provided intermediate degrees of protection, and ICRF-192 and ICRF-198 were not protective. Quantitative measurements in vitro revealed only relatively small differences in the rates of opening of the two diketopiperazine rings of the various agents to form the corresponding iron-chelating diacid diamide derivatives, and in the ability of these various derivatives to remove iron from the iron-doxorubicin complex. Such differences showed no relationship with cardioprotective activity. Some bisdiketopiperazines (including ICRF-154 and ICRF-187) with cardioprotective activity also are inhibitors of DNA topoisomerase II; however, the significance of this relationship remains uncertain, since ADR-925, the open-ring derivative of ICRF-187, does not inhibit DNA topoisomerase II.
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PMID:Comparison of the protective effects against chronic doxorubicin cardiotoxicity and the rates of iron (III) displacement reactions of ICRF-187 and other bisdiketopiperazines. 927 16

Treatment of U-937 promonocytic cells with the DNA topoisomerase II inhibitor etoposide rapidly caused death by apoptosis, as determined by changes in chromatin structure, production of DNA breaks, nucleosome-sized DNA degradation, decrease in mitochondrial membrane potential and phosphatidyl serine translocation in the plasma membrane, and at the same time induced intracellular acidification. Both the execution of the apoptotic process and the intracellular acidification were reduced by the addition of forskolin plus theophylline or other cAMP increasing agents. These agents also attenuated the induction of apoptosis by camptothecin, heat-shock, cadmium chloride and X-radiation. Although etoposide slightly increased the production of reactive oxygen intermediates, this increase was not prevented by forskolin plus theophylline, and the addition of antioxidant agents failed to inhibit apoptosis. Etoposide caused a great increase in NF-(kappa)B binding activity, which was not prevented by forskolin plus theophylline, while AP-1 binding was little affected by the topoisomerase inhibitor. The treatments did not significantly alter the levels of Bcl-2 and Bax. By contrast, the expression of c-myc, which was very high in untreated U-937 cells and only partially inhibited by etoposide, was rapidly and almost totally abolished by the cAMP increasing agents. Finally, it was observed that etoposide caused a transient dephosphorylation of retinoblastoma (Rb), which was associated with cleavage of poly(ADP-ribose) polymerase (PARP). Both Rb dephosphorylation and PARP cleavage were inhibited by forskolin plus theophylline. The inhibition of Rb (type I) phosphatase and ICE/CED-3-like protease activities, and the abrogation of c-myc expression, are mechanisms which could explain the anti-apoptotic action of cAMP increasing agents in myeloid cells.
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PMID:cAMP increasing agents attenuate the generation of apoptosis by etoposide in promonocytic leukemia cells. 945 37


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