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)

Merkel cell carcinomas are rare and aggressive tumors about which the expression of cell cycle regulatory proteins are not well known. We evaluated the clinicopathologic features of Merkel cell carcinomas and examined the expression of the cell cycle regulatory markers p27 and S-phase kinase-associated protein 2 (Skp2) and the proliferation markers Ki-67 and DNA topoisomerase II alpha (topo II alpha) in a group of these tumors. Thirty-nine cases of Merkel cell carcinoma were studied, 19 from the Mayo Clinic, Rochester, MN, and 20 from the University of Torino, Torino, Italy. Although the University of Torino patients tended to be slightly older at time of surgery compared to the Mayo Clinic patients, no clinical, pathologic, or immunohistochemical feature was statistically significantly different between the two groups. Of the 39 patients, 20 were male and 19 were female. The age at surgery averaged 72 yr. Formalin-fixed paraffin-embedded archival tissues from the 39 Merkel cell carcinomas were analyzed by immunohistochemistry for p27, Skp2, Ki-67, and topo II alpha with the avidin-biotin peroxidase system. The distribution of immunoreactivity was analyzed by quantifying the percentage of positive nuclei, which was expressed as the labeling index. There was a statistically significant inverse relationship between p27 and Skp2 (p = 0.005). Most tumors with increased levels of Skp2 were associated with reduced p27, and tumors with high levels of p27 expression were associated with reduced levels of Skp2. These results suggest that Skp2 regulates p27 expression in Merkel cell carcinomas. Tumors showing increased Skp2 expression were not always correlated with increased proliferation as evaluated by Ki-67 and topo II alpha, suggesting that Skp2 may be involved in Merkel cell tumorigenesis, but that other factors may also influence cell proliferation in these tumors.
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PMID:Merkel cell carcinomas: expression of S-phase kinase-associated protein 2 (Skp2), p27, and proliferation markers. 1458 67

Benzene is an established human and animal carcinogen. While many of the key mechanisms underlying its carcinogenic effects remain unknown, there is increasing evidence that chromosomal alterations play an important role in the development of the induced leukemias. Inhibition of enzymes involved in DNA replication and maintenance such as topoisomerases by benzene metabolites represents a potential mechanism by which benzene may induce its chromosome-altering effects. Previous work from our laboratory and others has demonstrated that bioactivated benzene metabolites are capable of inhibiting topoisomerase II (topo II) in isolated enzyme and cell systems as well as in mice administered benzene in vivo. The current studies were designed to build upon this hypothesis, and show that in the presence of human myeloperoxidase and H2O2, hydroquinone can be activated to a potent topo II inhibitor. In the absence of dithiothreitol, partial inhibition can be seen at hydroquinone concentrations as low as 50 nM. The potential role of topo II inhibition in the development of benzene-induced leukemia is also discussed in the context of other known leukemia-inducing agents. Current evidence indicates that multiple mechanisms are likely to contribute to benzene-induced leukemias, and that inhibition of topo II could represent an important step in the development of certain leukemia subtypes.
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PMID:Topoisomerase II inhibition by myeloperoxidase-activated hydroquinone: a potential mechanism underlying the genotoxic and carcinogenic effects of benzene. 1593 18

We have recently reported on two cases of scleroderma patients with ANCA-associated vasculitis for the first time in Korea. In order to explore the nature of this disease combination, we pooled together all the previously known cases and statistically analyzed them. Out of the 50 selected cases, survival analysis was done for comparison of the scleroderma disease period and the clinical factors associated with ANCA-associated vasculitis (AAV). Kaplan-Meier analysis revealed that patients having anti-topoisomerase antibody (anti-Scl-70) and, probably, PR-3 ANCA are at a higher risk for developing AAV than patients without both anti-topoisomerase antibody and anti-centromere antibody (ACA), and patients with MPO-ANCA. Multivariate Cox regression analysis revealed having anti-topoisomerase antibody as a risk factor for developing AAV [OR 3.1 (95% CI 1.11-8.55), P=0.031]. We suggest that having anti-topoisomerase antibodies may play a role among scleroderma patients in developing AAV.
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PMID:Scleroderma associated with ANCA-associated vasculitis. 1603 90

Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Since we found that ellipticine also forms the cytochrome P450 (CYP)-mediated covalent DNA adducts, this anticancer drug is considered to function as a pro-drug, whose pharmacological efficiency and/or genotoxic side effects are dependent on its enzymatic activation in target tissues. Here, we demonstrate that ellipticine is also oxidized by peroxidases, which are abundantly expressed in several target tumor tissues. Lactoperoxidase, myeloperoxidase and horseradish peroxidase were used as models. Peroxidases in the presence of hydrogen peroxide oxidize ellipticine to an ellipticine dimer and N(2)-oxide of ellipticine as the major and minor metabolite, respectively. Inhibition of the peroxidase-mediated ellipticine oxidation by radical scavengers ascorbate, glutathione and NADH suggests a one-electron mechanism of the oxidation. The implication of the oxidation of ellipticine by peroxidases in its mechanism of action is discussed.
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PMID:Oxidation of an antitumor drug ellipticine by peroxidases. 1660 8

Execution of apoptotic program in mitochondria is associated with accumulation of cardiolipin peroxidation products required for the release of proapoptotic factors into the cytosol. This suggests that lipid antioxidants capable of inhibiting cardiolipin peroxidation may act as antiapoptotic agents. Etoposide, a widely used antitumor drug and a topoisomerase II inhibitor, is a prototypical inducer of apoptosis and, at the same time, an effective lipid radical scavenger and lipid antioxidant. Here, we demonstrate that cardiolipin oxidation during apoptosis is realized not via a random cardiolipin peroxidation mechanism but rather proceeds as a result of peroxidase reaction in a tight cytochrome c/cardiolipin complex that restrains interactions of etoposide with radical intermediates generated in the course of the reaction. Using low-temperature and ambient-temperature electron paramagnetic resonance spectroscopy of H(2)O(2)-induced protein-derived (tyrosyl) radicals and etoposide phenoxyl radicals, respectively, we established that cardiolipin peroxidation and etoposide oxidation by cytochrome c/cardiolipin complex takes place predominantly on protein-derived radicals of cytochrome c. We further show that etoposide can inhibit cytochrome c-catalyzed oxidation of cardiolipin competing with it as a peroxidase substrate. Peroxidase reaction of cytochrome c/cardiolipin complexes causes cross-linking and oligomerization of cytochrome c. With nonoxidizable tetraoleoyl-cardiolipin, the cross-linking occurs via dityrosine formation, whereas bifunctional lipid oxidation products generated from tetralinoleoyl-cardiolipin participate in the production of high molecular weight protein aggregates. Protein aggregation is effectively inhibited by etoposide. The inhibition of cardiolipin peroxidation by etoposide, however, is realized at far higher concentrations than those at which it induces apoptotic cell death. Thus, oxidation of cardiolipin by the cytochrome c/cardiolipin peroxidase complex, which is essential for apoptosis, is not inhibited by proapoptotic concentrations of the drug.
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PMID:Mechanisms of cardiolipin oxidation by cytochrome c: relevance to pro- and antiapoptotic functions of etoposide. 1669 Jul 82

Ellipticine is a potent antineoplastic agent exhibiting the multimodal mechanism of its action. This article reviews the mechanisms of predominant pharmacological and cytotoxic effects of ellipticine and shows the results of our laboratories indicating a novel mechanism of its action. The prevalent mechanisms of ellipticine antitumor, mutagenic and cytotoxic activities were suggested to be intercalation into DNA and inhibition of DNA topoisomerase II activity. We demonstrated a new mode of ellipticine action, formation of covalent DNA adducts mediated by its oxidation with cytochromes P450 (CYP) and peroxidases. The article reports the molecular mechanism of ellipticine oxidation by CYPs and identifies human and rat CYPs responsible for ellipticine metabolic activation and detoxication. It also presents a role of peroxidases (i.e. myeloperoxidase, cyclooxygenases, lactoperoxidase) in ellipticine oxidation leading to ellipticine-DNA adducts. The 9-hydroxy- and 7-hydroxyellipticine metabolites formed by CYPs and the major product of ellipticine oxidation by peroxidases, the dimer, in which the two ellipticine skeletons are connected via N(6) of the pyrrole ring of one ellipticine molecule and C9 in the second one, are the detoxication metabolites. On the contrary, 13-hydroxy- and 12-hydroxyellipticine, produced by ellipticine oxidation with CYPs, the latter one formed also spontaneously from another CYP- and peroxidase-mediated metabolite, ellipticine N(2)-oxide, are metabolites responsible for formation of two ellipticine-derived deoxyguanosine adducts in DNA. The results reviewed here allow us to propose species, two carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating two major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.
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PMID:Molecular mechanisms of antineoplastic action of an anticancer drug ellipticine. 1693 98

Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation, inhibition of topoisomerase II and cytochrome P450-mediated formation of covalent DNA adducts. This is the first report on the molecular mechanism of ellipticine oxidation by peroxidases (human myeloperoxidase, human and ovine cyclooxygenases, bovine lactoperoxidase, horseradish peroxidase) to species forming ellipticine-DNA adducts. Using NMR spectroscopy, the structures of 2 ellipticine metabolites were identified; the major product is the ellipticine dimer, in which the 2 ellipticine skeletons are connected via N(6) of the pyrrole ring of one ellipticine molecule and C9 in the second one. The minor metabolite is ellipticine N(2)-oxide. Using (32)P-postlabeling and [(3)H]-labeled ellipticine, we showed that ellipticine binds covalently to DNA after its activation by peroxidases. The DNA adduct pattern induced by ellipticine consisted of a cluster of up to 4 adducts. The 2 adducts are indistinguishable from the 2 major adducts generated between deoxyguanosine in DNA and either 13-hydroxy- or 12-hydroxyellipticine or in rats treated with ellipticine, or if ellipticine was activated with human hepatic and renal microsomes. The results presented here are the first characterization of the peroxidase-mediated oxidative metabolites of ellipticine and we have proposed species, 2 carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating 2 major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.
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PMID:Mammalian peroxidases activate anticancer drug ellipticine to intermediates forming deoxyguanosine adducts in DNA identical to those found in vivo and generated from 12-hydroxyellipticine and 13-hydroxyellipticine. 1706 55

Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts mediated by cytochromes P450 and peroxidases. Here, the molecular mechanism of DNA-mediated ellipticine action in human neuroblastoma IMR-32, UKF-NB-3 and UKF-NB-4 cancer cell lines was investigated. Treatment of neuroblastoma cells with ellipticine resulted in apoptosis induction, which was verified by the appearance of DNA fragmentation, and in inhibition of cell growth. These effects were associated with formation of two covalent ellipticine-derived DNA adducts, identical to those formed by the cytochrome P450- and peroxidase-mediated ellipticine metabolites, 13-hydroxy- and 12-hydroxyellipticine. The expression of these enzymes at mRNA and protein levels and their ability to generate ellipticine-DNA adducts in neuroblastoma cells were proven, using the real-time polymerase chain reaction, Western blotting analyses and by analyzing ellipticine-DNA adducts in incubations of this drug with neuroblastoma S9 fractions, enzyme cofactors and DNA. The levels of DNA adducts correlated with toxicity of ellipticine to IMR-32 and UKF-NB-4 cells, but not with that to UKF-NB-3 cells. In addition, hypoxic cell culture conditions resulted in a decrease in ellipticine toxicity to IMR-32 and UKF-NB-4 cells and this correlated with lower levels of DNA adducts. Both these cell lines accumulated in S phase, suggesting that ellipticine-DNA adducts interfere with DNA replication. The results demonstrate that among the multiple modes of ellipticine antitumor action, formation of covalent DNA adducts by ellipticine is the predominant mechanism of cytotoxicity to IMR-32 and UKF-NB-4 neuroblastoma cells.
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PMID:The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells. 1942 84

Therapy-related myeloid neoplasms (t-MN) include acute myeloid leukemias and myelodysplastic syndromes arising in patients who have been treated with chemotherapy, radiation therapy, immunosuppressive agents or after documented exposure to environmental carcinogen. t-MN are defined according to the primary treatment and the corresponding genetic and molecular lesions. Chromosome(s) 7 and/or 5 monosomies or deletions are typical of alkylating agent-induced AML, while balanced translocations involving chromosome bands 11q23 and 21q22 are associated to preceeding therapy with DNA-topoisomerase II inhibitors. Antimetabolites, and in particular the immunosuppressive agents azathioprine and fludarabine, have also been recently associated to t-MN. Leukemias developing after benzene exposure are similar to t-MN and are characterized by chromosomal aberrations, which have been also observed among otherwise healthy benzene-exposed workers. Individual predisposing factors, including polymorphisms of detoxification and DNA-repair enzymes have been identified. Two genetic variants in key metabolizing enzymes, myeloperoxidase and NAD(P)H:quinone oxidoreductase, have been shown to influence susceptibility to benzene hematotoxicity. Combination of polymorphisms impairing detoxification and DNA repair may significantly increase therapy-related myeloid neoplasm risk. Among hematological malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased t-MN risk, particularly when receiving MOPP-based and escalated-BEACOPP regimens, and when alkylators are combined to radiotherapy. Patients with lymphoma are at highest risk if total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation. The addition of granulocyte-colony stimulating factor (G-CSF) and radiotherapy plays a significant role in t-MN following treatment of childhood acute lymphoblastic leukemia. In solid tumors, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of t-MN.
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PMID:Incidence and susceptibility to therapy-related myeloid neoplasms. 2002 17

We describe here a new case of therapy-related acute leukemia with t(1;21)(p36;q22). A 25-year-old man was admitted because of anemia and thrombocytopenia. Four years before, he had received combination chemotherapy including etoposide for seminoma. Bone marrow was hypercellular, with 49% myeloperoxidase (MPO) staining-negative blasts. Chromosome analysis showed 46,XY,t(1;21)(p36.3;q22)[11]/49,sl,+8,+16,+20[9]. Fluorescence in situ hybridization demonstrated that RUNX1 signals at 21q22 were split onto the der(1)t(1;21) and der(21)t(1;21). Immunophenotypic analyses revealed that blasts were positive for CD19, CD79a, and cytCD22, as well as MPO, CD13, and CD33, fulfilling the diagnostic criteria of mixed phenotype acute leukemia, B/myeloid. The patient died of disease progression after 10 months. Thus, acute leukemia with t(1;21) and RUNX1 rearrangement could be associated with B/myeloid mixed phenotype as well as previous topoisomerase II inhibitor therapy and poor prognoses.
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PMID:Therapy-related, mixed phenotype acute leukemia with t(1;21)(p36;q22) and RUNX1 rearrangement. 2068 97


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