Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure to benzene, a human and animal carcinogen, results in the formation of structural chromosomal aberrations in the bone marrow and blood cells of animals and humans. The mechanisms underlying these clastogenic effects are unknown. Inhibition of enzymes involved in DNA replication and repair, such as topoisomerase enzymes, by the metabolites of benzene represents a potential mechanism for the formation of chromosomal aberrations. To test this hypothesis, the inhibitory effects of various phenolic and quinone metabolites of benzene on the activity of human topoisomerases I and II were studied in vitro. No inhibition of topoisomerase I was seen with any of the tested metabolites. Inhibitory effects on topoisomerase II were not observed for hydroquinone, phenol, 2,2'-biphenol, 4,4'-biphenol and catechol at concentrations as high as 500 microM. 1,4-Benzoquinone and 1,2,4-benzenetriol inhibited topoisomerase II at relatively high 500 and 250 microM concentrations, respectively. However following bioactivation using a peroxidase/H2O2 system, inhibitory effects were seen at concentrations as low as 50 microM for both phenol and 2,2'-biphenol and 10 microM for 4,4'-biphenol. The addition of reduced glutathione (GSH) to the 4,4'-biphenol and horseradish peroxidase reaction system protected topoisomerase II from inhibition suggesting that diphenoquinone or another oxidation product formed from 4,4'-biphenol might be the reactive species. These in vitro results indicate that inhibition of topoisomerase II may contribute to the clastogenic and carcinogenic effects of benzene. In addition, metabolites formed from these phenolic compounds appear to represent several new types of topoisomerase II-inhibiting compounds.
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PMID:Topoisomerase inhibition by phenolic metabolites: a potential mechanism for benzene's clastogenic effects. 758 26

1-Aryl 3-(2-chloroethyl) ureas (CEUs), a new class of potent antineoplastic agents, were recently developed in our laboratory. These compounds were designed from the aromatic moiety of chlorambucil and the unnitrosated pharmacophore of carmustine. In the present study we investigated the effect of the potent CEU derivative 4-tert-butyl-[3-(2-chloroethyl)ureido] benzene (tBCEU) on tumor cell lines selected for resistance to a wide range of anticancer drugs. The resistance mechanisms found in these cells included increased expression of P-glycoprotein, increased intracellular concentration of glutathione and/or glutathione-S-transferase activity, alteration of topoisomerase II, and increased DNA repair. Whereas the resistant cell lines were found to be highly resistant to a panel of clinically known anticancer drugs, tBCEU was found to be equally cytotoxic to both resistant and parental cells. The nitrobenzylpyridine assay indicated that tBCEU is a weaker alkylating agent than chlorambucil. This lack of cross-resistance in various resistant tumor cells suggests that tBCEU could be potentially useful in the treatment of cancers resistant to conventional anticancer drugs.
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PMID:Lack of cross-resistance to a new cytotoxic arylchloroethyl urea in various drug-resistant tumor cells. 813 59

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

Benzene is a clastogenic and carcinogenic agent that induces acute myelogenous leukemia in humans and multiple of tumors in animals. Previous research has indicated that benzene must first be metabolized to one or more bioactive species to exert its myelotoxic and genotoxic effects. To better understand the possible role of individual benzene metabolites in the leukemogenic process, as well as to further investigate inhibition of topoisomerase II by benzene metabolites, a series of known and putative benzene metabolites, phenol, 4,4'-biphenol, 2,2'-biphenol, hydroquinone, catechol, 1,2,4-benzenetriol, 1,4-benzoquinone, and trans-trans-muconaldehyde were tested for inhibitory effects in vitro on the human topoisomerase II enzyme. With minor modifications of the standard assay conditions, 1,4-benzoquinone and trans-trans-muconaldehyde were shown to be directly inhibitory, whereas all of the phenolic metabolites were shown to inhibit enzymatic activity following bioactivation using a peroxidase activation system. The majority of compounds tested inhibited topoisomerase II at concentrations at or below 10 microM. These results confirm and expand upon previous findings from our laboratory and indicate that many of the metabolites of benzene could potentially interfere with topoisomerase II. Since other inhibitors of topoisomerase II have been shown to induce leukemia in humans, inhibition of this enzyme by benzene metabolites may also play a role in the carcinogenic effects of benzene.
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PMID:Inhibition of human topoisomerase II in vitro by bioactive benzene metabolites. 911 13

Myelodysplastic syndromes (MDS) are a heterogeneous and common group of clonal hematological disorders characterized by cytopenias, dysplastic changes of hematopoietic cells, and a high rate of transformation into acute myeloblastic leukemia (AML). MDS provide a clinical model for studying the emergency and progression of malignancy. The initiating events leading to MDS remain almost unknown. Imbalance of proliferative and differentiating capabilities of progenitor hematopoietic cells along with abnormalities in the normal process of apoptosis are involved in both the pathogenesis of MDS and transformation into AML. Multiple genomic lesions, comprising oncogene activation and tumor-suppressor gene inactivation, are probably required. Alkylating agents, cytotoxic drugs targeting topoisomerase II and benzene are the only clear etiological factors identified. Advanced age and great prognostic variability, not explained by the FAB subtype, complicates the design and analysis of clinical trials and therapy-planning. The use of recently developed prognostic scores for selecting the best treatment according to the expected risk is encouraged. In most patients therapy is unsatisfactory. At present, bone marrow transplantation is considered as the only curative approach. A better knowledge of the pathobiology of MDS should be valuable to develop new, more rationale and effective therapies.
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PMID:Etiopathogeny, prognosis and therapy of myelodysplastic syndromes. 949 87

1,2-Naphthoquinones, such as beta-lapachone, 4-alkoxy-1,2-naphthoquinones, and tetrahydrofuran-1,2-naphthoquinones, react rapidly with 2-mercaptoethanol in benzene to give 1,4-, 1,2-, 1,3- and 1,6-Michael-type adducts that are formed by the addition of the thiol group to the quinone ring. Menadione (2-methyl-1,4-naphthoquinone) reacts with the thiol reagent very slowly under the same reaction conditions. Although the formation of the adducts can be followed by 1H-NMR, attempts to isolate the adducts failed due to their retroconversion to the starting products. On addition of a Lewis acid, however, the adducts undergo cyclization reactions that give stable derivatives that can be isolated and characterized. Determination of the structures of the derivatives allowed for the identification of the adducts from which they originated. Thus, beta-lapachone and 2,3-dinordunnione underwent 1,4- and 1,2-Michael type additions to the quinone ring, while 4-pentyloxy-1,2-naphthoquinone underwent two simultaneous Michael additions to the quinone ring of the naphthoquinone. Menadione underwent a single 1,3-addition. The alkylation rates of the thiol group of 2-mercaptoethanol by the naphthoquinones parallel the naphthoquinones efficiencies in inducing DNA cleavage through DNA-bound topoisomerase II. These results support our hypothesis that the cytotoxic effect of the naphthoquinones derive, at least in part, from their alkylation of exposed thiol residues on the topoisomerase II-DNA complex.
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PMID:Reaction of beta-lapachone and related naphthoquinones with 2-mercaptoethanol: a biomimetic model of topoisomerase II poisoning by quinones. 962 Apr 43

Increased levels of DNA-protein cross-links (DNAPC) have been observed in vitro and in vivo following treatment with a number of chemotherapeutic alkylating agents and topoisomerase II inhibitors, that is, agents that have also been associated with the development of bone marrow depression and acute myelogenous leukemia. The current studies were undertaken to examine the effect of benzene, a bone marrow toxin and human leukemogen, on DNAPC levels in mouse bone marrow cells. Using a K+/sodium dodecyl sulfate (SDS) precipitation assay for DNAPC determination, the results indicate increased DNA-protein cross-link levels in mouse bone marrow cells at 2 and 4 but not 8 h after a single ip injection of 440 mg/kg benzene. Following the administration of multiple hematotoxic benzene doses (440 or 880 mg/kg, 2x/d for 2 d), increases in DNA-protein cross-link levels were either slight or not present. These results suggest that DNAPC induced by benzene are neither cumulative nor persistent lesions. The toxicity of benzene is mediated by a number of number of ring-hydroxylated and ring-opened compounds; therefore the present studies also examined DNAPC levels in mice administered trans,trans-muconaldehyde (MUC), a ring-opened hematotoxic and genotoxic metabolite of benzene. No marked increases in DNAPC levels were observed in CD- mouse bone marrow cells 1-12 h following a single ip injection of 3 mg/kg muconaldehyde. It is possible that multiple doses of MUC are required to induce elevated DNAPC levels in bone marrow cells of mice, since multiple doses are required for MUC-induced hematotoxicity. Other reactive metabolites and/or an interaction of reactive intermediates may also be involved in DNAPC induced by benzene.
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PMID:DNA-protein cross-link levels in bone marrow cells of mice treated with benzene or trans,trans-muconaldehyde. 1009 61

The ability of two structurally different ruthenium complexes to interfere with the catalytic activity of topoisomerase II was studied to elucidate their molecular mechanism of action and relative antineoplastic activity. The first complex, [RuCl2(C6H6)(dmso)], could completely inhibit DNA relaxation activity of topoisomerase II and form a drug-induced cleavage complex. This strongly suggests that the drug interferes with topoisomerase II activity by cleavage complex formation. The bi-directional binding of [RuCl2(C6H6)(dmso)] to DNA and topoisomerase II was verified by immunoprecipitation experiments which confirmed the presence of DNA and ruthenium in the cleavage complex. The second complex, Ruthenium Salicylaldoxime, could not inhibit topoisomerase II relaxation activity appreciably and also could not induce cleavage complex formation, though its DNA-binding characteristics and antiproliferation activity were almost comparable to those of [RuCl2(C6H6)(dmso)]. The results suggest that the difference in ligands and their orientation around a metal atom may be responsible for topoisomerase II poisoning by the first complex and not by the second. A probable mechanism is proposed for [RuCl2(C6H6)(dmso)], where the ruthenium atom interacts with DNA and ligands of the metal atom form cross-links with topoisomerase II. This may facilitate the formation of a drug-induced cleavage complex.
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PMID:Inhibition of topoisomerase II catalytic activity by two ruthenium compounds: a ligand-dependent mode of action. 1019 57

NAD(P)H:quinone oxidoreductase (NQO1) converts benzene-derived quinones to less toxic hydroquinones and has been implicated in benzene-associated hematotoxicity. A point mutation in codon 187 (Pro to Ser) results in complete loss of enzyme activity in homozygous subjects, whereas those with 2 wild-type alleles have normal activity. The frequency of homozygosity for the mutant allele among Caucasians and African Americans is 4% to 5% but is higher in Hispanics and Asians. Using an unambiguous polymerase chain reaction (PCR) method, we assayed nonmalignant lymphoblastoid cell lines derived from 104 patients with myeloid leukemias; 56 had therapy-related acute myeloid leukemia (t-AML), 30 had a primary myelodysplastic syndrome (MDS), 9 had AML de novo, and 9 had chronic myelogenous leukemia (CML). All patients had their leukemia cells karyotyped. Eleven percent of the t-AML patients were homozygous and 41% were heterozygous for the NQO1 polymorphism; these proportions were significantly higher than those expected in a population of the same ethnic mix (P =.036). Of the 45 leukemia patients who had clonal abnormalities of chromosomes 5 and/or 7, 7 (16%) were homozygous for the inactivating polymorphism, 17 (38%) were heterozygous, and 21 (47%) had 2 wild-type alleles for NQO1. Thus, NQO1 mutations were significantly increased compared with the expected proportions: 5%, 34%, and 61%, respectively (P =.002). An abnormal chromosome no. 5 or 7 was observed in 7 of 8 (88%) homozygotes, 17 of 45 (38%) heterozygotes, and 21 of 51 (41%) patients with 2 wild-type alleles. Among 33 patients with balanced translocations [14 involving bands 11q23 or 21q22, 10 with inv(16) or t(15;17), and 9 with t(9;22)], there were no homozygotes, 15 (45%) heterozygotes, and 18 (55%) with 2 wild-type alleles. Whereas fewer than 3 homozygotes were expected among the 56 t-AML patients, 6 were observed; 19 heterozygotes were expected, but 23 were observed. The gene frequency for the inactivating polymorphism (0. 31) was increased approximately 1.4-fold among the 56 t-AML patients. This increase was observed within each of the following overlapping cohorts of t-AML patients: the 43 who had received an alkylating agent, the 27 who had received a topoisomerase II inhibitor, and the 37 who had received any radiotherapy. Thus, the frequency of an inactivating polymorphism in NQO1 appears to be increased in this cohort of myeloid leukemias, especially among those with t-AML or an abnormality of chromosomes 5 and/or 7. Homozygotes and heterozygotes (who are at risk for treatment-induced mutation or loss of the remaining wild-type allele in their hematopoietic stem cells) may be particularly vulnerable to leukemogenic changes induced by carcinogens.
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PMID:Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. 1039 48

We review the history of the toxicology of benzene and consider current exposure levels, the metabolism of benzene, reactions of the metabolites with biomolecules and possible mechanisms of carcinogenesis due to benzene. Epidemiological evidence indicates a relationship between exposure to benzene and the occurrence of acute non-lymphocytic leukaemia in humans. Working groups convened by IARC and other organizations have therefore judged that there is sufficient evidence for classifying benzene as a human carcinogen. Despite much research, including numerous studies in animals, the detailed mechanism of the carcinogenicity of benzene is unknown. The significant differences in the responses of rodents and humans to benzene are not understood. Benzene forms many metabolites, some of which are reactive towards biomolecules, but the metabolite(s) responsible for the induction of leukaemia is unknown. Candidate metabolites, either singly or in combination, include epoxides, oxepins, quinones and aldehydes, all of which are reactive towards proteins and DNA. Our studies on muconaldehydes and benzene oxide-oxepin are discussed in this context. The significance of DNA adduct formation in respect of human leukaemia is uncertain. The overall reactivity of benzene towards DNA has been shown to be very low in experimental animals, although dose-related reactivity of metabolites with DNA was observed. The lack of significant DNA reactivity is reflected in the lack of activity of benzene in short-term tests for genotoxicity; however, benzene causes oxidative stress, which can be detected as oxidative damage to DNA. Mechanisms other than DNA damage may play a role in benzene-related toxicity, e.g. reactions of benzene metabolites with essential enzymes such as topoisomerase II.
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PMID:Possible mechanisms of carcinogenesis after exposure to benzene. 1062 10


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