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

---

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

We have used stopped-flow spectrophotometry and the sodium dodecyl sulfate sequestration technique to study the kinetics of dissociation of DNA complexes of the mixed topoisomerase I/II poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (termed DACA) and a range of related linear tricyclic carboxamides with neutral chromophores. Complexes of DACA and related acridine and phenazinecarboxamides bearing an N,N-dimethylaminoethyl side chain dissociate from calf thymus DNA by a kinetic pathway involving four discernible steps in a manner similar to complexes of N-[(2-dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (termed 9-amino-DACA). We infer from these findings that the side chains of DACA, its phenazine homologue, and 9-amino-DACA make comparable interactions with the DNA base pairs. In the case of 9-amino-DACA, a selective topoisomerase II poison, these are known, by crystallographic analysis, to involve hydrogen-bonding interactions between the protonated dimethylammonium group of the side chain and the O6/N7 atoms of guanine and to include a bridging water molecule hydrogen bonded to the carboxamide group and a phosphate oxygen. By contrast, we find that other linear tricyclic carboxamides with neutral chromophores which lack a peri nitrogen atom and are biologically inactive dissociate from DNA by a different mechanism in which it appears their side chains fail to interact with guanine. We conclude that the ability of the carboxamide group to lie preferentially in the plane of the chromophore, so facilitating the dimethylammonium-guanine hydrogen bond and ensuring maintenance of the water-bridged carboxamide-phosphate interaction, is a critical requirement for antitumor activity among ligands of the linear tricyclic carboxamide class. However, unlike the situation for 9-amino-DACA, for ligands with uncharged chromophores containing peri nitrogen atoms such as DACA, this outcome is possible with the 4-carboxamide group rotated cis or trans with respect to the ring nitrogen. This difference may have relevance to the ability of DACA to be a dual poison of both topoisomerases I and II.
...
PMID:Kinetic studies of the binding of acridinecarboxamide topoisomerase poisons to DNA: implications for mode of binding of ligands with uncharged chromophores. 1183 1

Several studies have shown that hexavalent chromium [Cr(VI)] induces apoptosis in a variety of in vitro test systems. We instilled intra-tracheally either saline or sodium dichromate (0.25 mg/kg body weight), for three consecutive days, to Sprague-Dawley rats. TUNEL analyses showed a marked increase of the apoptotic index in both bronchial epithelium and lung parenchyma of Cr(VI)-treated rats, but no effect was detected in their liver. In parallel, the expression of 13 out of 18 apoptosis-related genes, evaluated by cDNA array analysis, was significantly enhanced in rat lung. The overexpressed genes included c-Jun N-terminal kinases 1, 2 and 3, bcl-x, bcl-2-associated death promoter and bcl-2-related ovarian killer protein, caspases 1, 3 and 6, DNase I precursor, DNA topoisomerases I and II alpha, and poly(ADP-ribose) polymerase. The enhancement of p53 expression in the lung was borderline to statistical significance. Expressions of bcl-2, bax-alpha, mdm2 and DNA topoisomerase IIB were not enhanced to a significant extent in lung. No induction of gene expression was observed in rat liver. RT-PCR analyses confirmed that Cr(VI) enhances the expression of c-Jun N-terminal kinase 1, caspase 6, and DNase I precursor but not that of bcl-2 in lung, while none of these genes was overexpressed in the liver of Cr(VI)-treated rats. The lack of stimulation of apoptosis in the liver parallels the failure of Cr(VI) to produce genotoxic damage, as we previously observed under identical experimental conditions. These negative findings may be ascribed to reduction of Cr(VI) to Cr(III) when traveling from the respiratory tract to the liver. On the other hand, induction of apoptosis in the respiratory tract parallels the occurrence of genotoxic effects and oxidative DNA damage produced by Cr(VI) in the same tissue. As previously shown in another laboratory, Cr(VI) did not induce lung tumors after 30 months of administration of the same daily dose. Therefore, apoptosis is likely to provide a protective mechanism at a post-genotoxic stage of Cr(VI) carcinogenesis.
...
PMID:Induction of apoptosis in the lung but not in the liver of rats receiving intra-tracheal instillations of chromium(VI). 1196 Sep 10

A novel, stable, biotin aldehyde derivative is reported in which the biotin moiety is N1,N3-protected by the allyloxycarbonyl group. The derivative is stable to sodium cyanoborohydride mediated reductive alkylation and is cleaved under mild Pd [0] catalysis. This novel biotin aldehyde should have wide application in avidin- and streptavidin-based detection systems and bioassays. The derivative is utilized in the synthesis of a biotinylated doxorubicin analogue that retains topoisomerase activity.
...
PMID:A stable bis-allyloxycarbonyl biotin aldehyde derivative for biotinylation via reductive alkylation: application to the synthesis of a biotinylated doxorubicin derivative. 1252 8

Treatment of solid tumors with combinations of chemotherapeutic agents has not led to significant increases in long-term survival. Recent studies support a role for inhibitors of checkpoint arrest as a means to enhance the cytotoxicity of chemotherapy. We have shown previously that triptolide (PG490), an oxygenated diterpene derived from a Chinese medicinal plant, induces apoptosis in cultured tumor cells and sensitizes tumor cells to topoisomerase inhibitors by blocking p53-mediated induction of p21. Here we extend our studies to a tumor xenograft model and evaluate the efficacy and safety of PG490-88 (14-succinyl triptolide sodium salt), a water-soluble prodrug of PG490. We also look at the combination of PG490 or PG490-88 with CPT-11, a topoisomerase I inhibitor, in cultured cells and in the tumor xenograft model. We show that PG490-88 is a safe and potent antitumor agent when used alone, causing tumor regression of lung and colon tumor xenografts. We also show that PG490-88 acts in synergy with CPT-11 to cause tumor regression. A phase I trial of PG490-88 for solid tumors began recently and safety and optimal dosing data should accrue within the next 12 months. Our findings that PG490-88 causes tumor regression and that it acts in synergy with DNA-damaging chemotherapeutic agents suggest a role as an antineoplastic agent and chemosensitizer for the treatment of patients with solid tumors.
...
PMID:PG490-88, a derivative of triptolide, causes tumor regression and sensitizes tumors to chemotherapy. 1455 4

Increased clinical applications of the anticancer drug etoposide (a non-intercalative epipodophyllotoxin derivative) and the frequent induction of a second malignancy, particularly leukaemia, in post-etoposide-treated cancer survivors warrant detailed genotoxicity testing of etoposide. The genotoxicity test results available on etoposide are either primarily in in vitro test systems or in lower organisms after treatment with unusually high doses, or after chronic exposures, having little extrapolative value to humans. Therefore, a cytogenetic risk assessment study on etoposide in mouse in vivo was undertaken after a low dose (in accordance with the human therapeutic dose) single exposure. The cytogenetic toxicity of etoposide was assessed from bone marrow of mouse at three separate endpoints: chromosomal aberration and mitotic index studies at 24 h post-treatment and the micronucleus test (MNT) at 30 h post-treatment. The flame drying technique using colchicine, hypotonic sodium citrate, methanol-glacial acetic acid and Giemsa was followed for the preparation of slides for the metaphase chromosomal aberration and mitotic index studies and a simple technique was followed for the MNT. Although induction of chromosomal aberrations, excluding gaps, per 100 metaphases by 10 and 15 mg kg(-1) etoposide was not significant statistically, 20 mg kg(-1) of etoposide induced a significantly higher number of chromosomal aberrations in female (P < or = 0.01) and male (P < or = 0.05) mice. There was no significant change in the induced percentages of dividing cells by any of the doses of etoposide tested. The micronucleus induction also was not significant statistically with the lowest dose but it was significant in female (P </= 0.01) and male (P </= 0.05) mice that received 15 mg kg(-1) etoposide and was highly significant (P </= 0.01) in both female and male mice that received 20 mg kg(-1) etoposide. The results indicated the clastogenic action of etoposide in mouse bone marrow after a single treatment with such low doses. However, the drug did not interfere with cell cycle progression. Although it is a DNA-non-intercalating agent, etoposide is known for its interference in the activity of DNA topoisomerase IIalpha enzyme, particularly in the proliferative cells where the concentration and activity of the enzyme are greater. This might be the reason for the induction of leukaemia in post-etoposide-treated cancer survivors. Therefore, it has become absolutely necessary to make etoposide target-specific, i.e. specific to the topoisomerase II enzymes of cancerous cells.
...
PMID:Cytogenetic risk assessment of etoposide from mouse bone marrow. 1505 6

Type II DNA topoisomerases catalyze changes in DNA topology and use nucleotide binding and hydrolysis to control conformational changes required for the enzyme reaction. We examined the ATP hydrolysis activity of a bisdioxopiperazine-resistant mutant of human topoisomerase II alpha with phenylalanine substituted for tyrosine at residue 50 in the ATP hydrolysis domain of the enzyme. This substitution reduced the DNA-dependent ATP hydrolysis activity of the mutant protein without affecting the relaxation activity of the enzyme. A similar but stronger effect was seen when the homologous mutation (Tyr28 --> Phe) was introduced in yeast Top2. The ATPase activities of human TOP2alpha(Tyr50 --> Phe) and yeast Top2(Tyr28 --> Phe) were resistant to both bisdioxopiperazines and the ATPase inhibitor sodium orthovanadate. Like bisdioxopiperazines, vanadate traps the enzyme in a salt-stable closed conformation termed the closed clamp, which can be detected in the presence of circular DNA substrates. Consistent with the vanadate-resistant ATPase activity, salt-stable closed clamps were not detected in reactions containing the yeast or human mutant protein, vanadate, and ATP. Similarly, ADP trapped wild-type topoisomerase II as a closed clamp, but could not trap either the human or yeast mutant enzymes. Our results demonstrate that bisdioxopiperazine-resistant mutants exhibit a difference in the stability of the closed clamp formed by the enzyme and that this difference in stability may lead to a loss of DNA-stimulated ATPase. We suggest that the DNA-stimulated ATPase of topoisomerase II is intimately connected with steps that occur while the N-terminal domain of the enzyme is dimerized.
...
PMID:Stability of the topoisomerase II closed clamp conformation may influence DNA-stimulated ATP hydrolysis. 1564 68

With the ultimate purpose of testing the hypothesis that, as shown in yeast mutants, any malfunction of DNA topoisomerase II might result in aberrant mitosis due to defective chromosome segregation, we have chosen three chemicals of different nature, recently reported to catalytically inhibit the enzyme. The endpoint selected to assess any negative effect on the ability of topoisomerase II to properly carry out decatenation of fully replicated chromosomes in the G2/M phase of the cell cycle was the presence of metaphases showing diplochromosomes as a result of endoreduplication, i.e. two successive rounds of DNA replication without intervening mitosis. The anti-topoisomerase drugs selected were the anthracycline antibiotic and antineoplastic agent aclarubicin, the respiratory venom sodium azide, and 9-aminoacridine, a chemical compound with planar topology capable of intercalation between DNA bases. Our results show that the three chemicals tested are able to induce endoreduplication to different degrees. These observations seem to lend support to the proposal that topoisomerase II plays a central role in chromosome segregation in mammalian cells.
...
PMID:Endoreduplication induced in cultured Chinese hamster cells by different anti-topoisomerase II chemicals. Evidence for the essential contribution of the enzyme to chromosome segregation. 1578 Dec 5

Leishmaniasis affects millions of people worldwide every year. Lack of effective vaccination, co-infection with other dreaded diseases like AIDS and generation of drug resistant strains demand immediate attention into this neglected area of research. The sodium m-arsenite (NaAsO2) resistant Leishmania donovani used in this study is resistant to 20 microM NaAsO2, which shows a 13-fold increase in resistance compared with wild type. Here we report that the arsenite resistant strain of L. donovani promastigotes shows cross-resistance to novobiocin, a catalytic inhibitor of topoisomerase II, with IC50 value of 320 microg ml-1 as compared with 242 microg ml-1 for wild type L. donovani. Leishmanicidal action of novobiocin induces dose- and time-dependent increase in cell death. Treatment with IC50 of novobiocin caused morphological and biochemical changes which lead to induction of cell death exhibiting characteristic features of metazoan apoptosis. Phosphatidylserine externalization, cytochrome C release to cytoplasm, activation of caspases, oligonucleosomal DNA fragmentation and in situ labelling of condensed and fragmented nuclei in both wild type and arsenite resistant L. donovani promastigotes strongly suggest the apoptosis-like mode of cell death. Cross-resistance to novobiocin in arsenite resistant strain has been correlated to over-expression of topoisomerase II and substantiated by differential inhibition of enzyme activity in wild type and arsenite resistant L. donovani.
...
PMID:Novobiocin induces apoptosis-like cell death in topoisomerase II over-expressing arsenite resistant Leishmania donovani. 1581 27

Microsporidia are a cause of emerging and opportunistic infections in humans and animals. Although two drugs are currently being used to treat microsporidiosis, concerns exist that albendazole is only selective for inhibiting some species of microsporidia that infect mammals, and fumagillin appears to have been found to be toxic. During a limited sequence survey of the Vittaforma corneae genome, a partial gene encoding for the ParC topoisomerase IV subunit was identified. The purpose of this set of studies was to determine if fluoroquinolones, which target topoisomerase IV, exert activity against Encephalitozoon intestinalis and V. corneae in vitro, and whether these compounds could prolong survival of V. corneae-infected athymic mice. Fifteen fluoroquinolones were tested. Of these, norfloxacin and ofloxacin inhibited E. intestinalis replication by more than 70% compared with non-treated control cultures, while gatifloxacin, lomefloxacin, moxifloxacin, and nalidixic acid (sodium salt) inhibited both E. intestinalis and V. corneae by at least 60% at concentrations not toxic to the host cells. These drugs were tested in vivo also, where gatifloxacin, lomefloxacin, norfloxacin, and ofloxacin prolonged survival of V. corneae-infected athymic mice (P < 0.05), whereas moxifloxacin and nalidixic acid failed to prolong survival. Therefore, these results support continued studies for evaluating the efficacy of the fluoroquinolones for treating microsporidiosis and for characterizing the target(s) of these fluoroquinolones in the microsporidia.
...
PMID:Antimicrosporidial activity of (fluoro)quinolones in vitro and in vivo. 1600 77

Different classes of topoisomerase (TOP) inhibitors and antitrypanosomatid agents exhibited variable efficacies against Leishmania donovani parasites and human mononuclear cells both at the level of DNA topoisomerase I (TOPI) catalytic activity and in cytotoxicity assays. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high efficacies against parasite and host enzymes as well as against parasite and mononuclear cells, but pentamidine showed around 2 orders of magnitude greater specificity for Leishmania TOPI and amastigote cells (P<0.05). The protoberberine coralyne and the flavonoid quercetin were highly potent, but non-selective, inhibitors in vitro, although the latter showed slight selectivity for parasite TOPI. Camptothecin was selective for mononuclear cells at both levels (P<0.05) and sodium stibogluconate was selective only at the enzyme level displaying 30-fold greater potency against parasite TOPI (P<0.05). These data suggest that at least part of pentamidines' leishmanicidal activity may be mediated through TOPI inhibition, and support the feasibility of exploiting differences between Leishmania and human TOPs to develop modified compounds with improved selectivity.
...
PMID:Leishmania donovani: differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays. 1629 47


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---