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)

Recently, accumulated statistical data indicate the protective effect of caffeine consumption against several types of cancer diseases. There are also reports about protective effect of caffeine and other xanthines against tumors induced by polycyclic aromatic hydrocarbons. One of the explanations is based on biological activation of such carcinogens by cytochromes that are also known for metabolism of caffeine. However, there is also numerous data indicating reverse effect on cytotoxicity of anticancer drugs that inhibit the action of topoisomerase I (e.g. Camptothecin or Topotecan) and topoisomerase II inhibitors (e.g. Doxorubicin, Mitoxantrone or mAMSA). In this work we tested the hypothesis that the caffeine protective effect is the result of sequestering of aromatic mutagens by formation of stacking (pi-pi) complexes. As the models for the study we have chosen two well-known mutagens, that do not require metabolical activation: quinacrine mustard(QM, aromatic, heterocyclic nitrogen mustard) and mechlorethamine (NM2, aliphatic nitrogen mustard). The flow cytometry study of these agents' action on the cell cycle of HL-60 cells indicated that caffeine prevents the cytotoxic action of QM, but not that of NM2. The formations of stacking complexes of QM with caffeine were confirmed by light absorption, calorimetric measurements and by molecular modeling calculation. Using the statistical thermodynamics calculations we calculated the "neighborhood" association constant (K(AC)=59+/-2M(-1)) and enthalpy change (DeltaH(0')=-116cal mol(-1)); the favorable entropy change of complex formation (DeltaS(0')=7.72cal mol(-1)K(-1), due to release of several water molecules, associated with components in the process of complex formation). The Gibbs' free energy change of QM-CAF formation is DeltaG(0')=-2.41kcal mol(-1). We were unable to detect any interaction between NM2 and caffeine either by spectroscopic or calorimetric measurement. In order to establish, whether the intercalation of QM plays any role in cytotoxic effect we tested, as a control, non-alkylatiatig, but also intercalating QM derivative-quinacrine (Q). The later had no cytostatic effect on HL-60 cell even at there order of higher concentration than QM or NM2 but, similar to QM forms (which we demonstrated) stacking complexes with caffeine (K(AC)=75+/-3M(-1)). These results strongly indicate, that the attenuating effect of caffeine on cytotoxic or mutagenic effects of some mutagens, is not the results of metabolic processes in the cells, but simply the physicochemical process of sequestering of aromatic molecules (potential carcinogens or mutagens) by formation of stacking complexes with them. The caffeine may then act as the "interceptor" of potential carcinogens (especially in the upper part of digesting track where its concentration can reach the concentration of mM level). There is, however, no indication either in the literature or in our experiments that xanthines can reverse the damage to nucleic acids when the damage to DNA has already occurred.
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PMID:The modulation of the DNA-damaging effect of polycyclic aromatic agents by xanthines. Part I. Reduction of cytostatic effects of quinacrine mustard by caffeine. 1199 30

In order to elucidate the tumor-initiating potential of flumequine (FL) in the liver, male C3H mice were given dietary administration of 4000 ppm FL throughout the study or for 2 weeks at the initiation stage, and then received 2 intraperitoneal injections of D-galactosamine (Gal) at weeks 2 and 5, with or without 500 ppm phenobarbital (PB) in their drinking water for 13 weeks to provide tumor-promoting effects. Hepatocellular foci were observed in 2 out of 8 and 6 out of 7 animals in the FL/PB + Gal and FL/FL + Gal groups, respectively. In addition, in an alkaline single-cell gel electrophoresis (comet) assay that was performed using adult, infant, or partial hepatectomized male ddY mice to evaluate the potential of FL at 500 mg/kg or less, to act as a DNA damaging agent. FL induced dose-dependent DNA damage in the stomach, colon, and urinary bladder of adult mice at 3 h but not at 24 h after its administration. Similarly, DNA damage was noted in the regenerating liver and the livers of infant mice at the 3 h time point. Furthermore, in in vitro assays that were conducted to investigate the potential of FL to inhibit eukaryotic topoisomerase II, which is responsible for the double-strand DNA breakage reaction as well as bacterial gyrase, inhibitory effects of FL on topoisomerase II were high relative to the influence on bacterial gyrase. The results of our studies thus strongly suggest that FL has initiating potential in the livers of mice that is attributable to its induction of DNA strand breaks.
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PMID:Mechanistic study on flumequine hepatocarcinogenicity focusing on DNA damage in mice. 1237 80

Type IB topoisomerases cleave and rejoin DNA strands through a stable covalent DNA-(3'-phosphotyrosyl)-enzyme intermediate. The stability of the intermediate is a two-edged sword; it preserves genome integrity during supercoil relaxation, but it also reinforces the toxicity of drugs and lesions that interfere with the DNA rejoining step. Here, we identify a key determinant of the stability of the complex by showing that introduction of an Sp or Rp methylphosphonate linkage at the cleavage site transforms topoisomerase IB into a potent endonuclease. The nuclease reaction entails formation and surprisingly rapid hydrolysis of a covalent enzyme-DNA methylphosphonate intermediate. The approximately 30,000-fold acceleration in the rate of hydrolysis of a methylphosphonate versus phosphodiester suggests that repulsion of water by the DNA phosphate anion suppresses the latent nuclease function of topoisomerase IB. These findings expose an Achilles' heel of topoisomerases as guardians of the genome, and they have broad implications for understanding enzymatic phosphoryl transfer.
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PMID:Guarding the genome: electrostatic repulsion of water by DNA suppresses a potent nuclease activity of topoisomerase IB. 1288 5

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.
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PMID:PG490-88, a derivative of triptolide, causes tumor regression and sensitizes tumors to chemotherapy. 1455 4

Parent genistein and its new amine complexes with morpholine and piperazine were studied comparatively in the solid and liquid states by X-ray crystallography and 13C and 15N NMR spectroscopy. Biochanine A and its complexes were used as reference. Secondary deuterium isotope effects on 13C chemical shifts in solution were studied in parent isoflavones and their morpholine and piperazine complexes to aid in evaluation of the electronic distribution in both systems. In addition, to quantify the extent of proton transfer as well as to establish strong hydrogen bonding of the 7-OH group in a morpholine complex, proton transfer from the 7-OH group to the piperazine nitrogen atom was also confirmed by 13C NMR in the solid state and by X-ray studies. The effect of 7-OH deprotonation yields a high frequency shift of 7-8 ppm on the C-7 carbon atom of the piperazine complex whereas it is as large as 12 ppm in the morpholine complex in the solid. The former trend is confirmed from solution state concentration studies which also show that the isoflavones have a strong tendency to form complexes with bases. Depending on the pKa difference between the isoflavones and the base this leads either to proton transfer and ion-pair formation or, in the case of a larger pKa difference, to a hydrogen bonded ion pair. The concentration studies show formation of a 1:1 genistein-piperazine complex in DMSO. Addition of water leads to formation of solvent separated ions. The C-5 OH group is involved in strong intramolecular hydrogen bonding leading to a pseudo aromatic ring extending the aromatic part of the drug pharmacophore. The analysis also suggests the way that both the C-7 and C-4' hydroxyl group of genistein may participate in stabilising the ternary inhibitor complexes of tyrosine-specific kinases or DNA topoisomerase II.
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PMID:Solution and solid state 13C NMR and X-ray studies of genistein complexes with amines. Potential biological function of the C-7, C-5, and C4'-OH groups. 1459 21

We reported previously that sulfoquinovosyl diacylglycerol and sulfoquinovosyl monoacylglycerol (SQDG/SQMG) are potent inhibitors of mammalian DNA polymerases and DNA topoisomerase II, and can be potent immunosuppressive agents and anticancer chemotherapy agents [Matsumoto, Y., Sahara, H., Fujita T., Shimozawa, K., Takenouchi, M., Torigoe, T., Hanashima, S., Yamazaki, T., Takahashi, S., Sugawara, F., et al., An Immunosuppressive Effect by Synthetic Sulfonolipids Deduced from Sulfonoquinovosyl Diacylglycerols of Sea Urchin, Transplantation 74, 261-267 (2002); Sahara, H., Hanashima, S., Yamazaki, T., Takahashi, S., Sugawara, F., Ohtani, S., Ishikawa, M., Mizushina, Y., Ohta, K., Shimozawa, K., et al., Anti-tumor Effect of Chemically Synthesized Sulfolipids Based on Sea Urchin's Natural Sulfonoquinovosylmonoacylglycerols, Jpn. J. Cancer Res. 93, 85-92 (2002)]. In those experiments, the in vivo effectiveness greatly depended on the degree of water solubility of SQDG/SQMG. In the present work, we studied the emulsification of SQDG/SQMG in terms of their use in in vivo experiments. Lipid emulsions containing SQDG/SQMG (oil-in-water emulsions) in which the particle size was smaller than 100 nm were designed and synthesized, and then the biochemical modes of emulsified SQDG/SQMG were studied in comparison with those of SQDG/SQMG solubilized by DMSO. Emulsified SQDG/SQMG are also selective mammalian DNA polymerase inhibitors and potent antineoplastic agents but do not inhibit the DNA topoisomerase II activity. The growth inhibition effect of emulsified SQMG to NUGC-3 cancer cells was twofold stronger than DMSO-soluble SQMG (69 and 151 microM, respectively). From these results, the properties of lipid emulsions containing SQDG/SQMG and their possible use in in vivo experiments including clinical use are discussed.
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PMID:Inhibitory action of emulsified sulfoquinovosyl acylglycerol on mammalian DNA polymerases. 1466 72

The structure of the complex formed between 9-amino-[N-(2-dimethylamino)propyl]acridine-4-carboxamide and d(CGTACG)(2) has been refined to a resolution of 1.55 A. The complex crystallized in space group C222. An asymmetric unit comprises two strands of DNA, one disordered drug molecule, two cobalt(II) ions, two magnesium ions and 32 water molecules. The DNA helices stack in continuous columns, with their four central base pairs adopting a B-like motif. The terminal G.C base pairs engage in different interactions. At one end of the duplex there is a CpG dinucleotide overlap modified by ligand intercalation and terminal cytosine exchange between symmetry-related duplexes. An intercalation complex is formed involving four DNA duplexes, four disordered ligand molecules and two pairs of base tetrads. The other end of the DNA is frayed, with the terminal guanine lying in the minor groove of the next duplex in the column. The structure is stabilized by guanine N7-cobalt(II) coordination. The structure is compared with previously published isomorphous structures of d(CGTACG)(2) complexed with intercalators in the presence of cobalt and it is concluded that the formation of this crystal form is primarily determined by DNA-DNA interactions and packing forces, rather than by special interactions between the ligand and the DNA. Given the nature of the ligands found in these complexes, the relevance of the quadruplex structure to the biological activity of those agents, known to be topoisomerase poisons, is questioned.
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PMID:Structure of 9-amino-[N-(2-dimethylamino)propyl]acridine-4-carboxamide bound to d(CGTACG)(2): a comparison of structures of d(CGTACG)(2) complexed with intercalatorsin the presence of cobalt. 1510 27

In MAG-camptothecin (MAG-CPT), the topoisomerase inhibitor camptothecin is linked to a water-soluble polymer. Preclinical experiments showed enhanced antitumour efficacy and limited toxicity compared to camptothecin alone. Prior phase I trials guided the regimen used in this study. The objectives were to determine the maximum tolerated dose, dose-limiting toxicities, safety profile, and pharmacokinetics of weekly MAG-CPT. Patients with solid tumours received MAG-CPT intravenously administered weekly for 3 weeks in 4-week cycles. At the starting dose level (80 mg x m(-2) week(-1)), no dose-limiting toxicities occurred during the first cycle (n=3). Subsequently, three patients were enrolled at the second dose level (120 mg x m(-2) week(-1)). Two of three patients at the 80 mg x m(-2) week(-1) cohort developed haemorrhagic cystitis (grade 1/3 dysuria and grade 2/3 haematuria) during the second and third cycles. Next, the 80 mg x m(-2) week(-1) cohort was enlarged to a total of six patients. One other patient at this dose level experienced grade 1 haematuria. At 120 mg x m(-2) week(-1), grade 1 bladder toxicity occurred in two of three patients. Dose escalation was stopped at 120 mg x m(-2) week(-1). Cumulative bladder toxicity was dose-limiting toxicity at 80 mg x m(-2) week(-1). Pharmacokinetics revealed highly variable urinary camptothecin excretion, associated with bladder toxicity. Due to cumulative bladder toxicity, weekly MAG-CPT is not a suitable regimen for treatment of patients with solid tumours.
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PMID:A phase I study with MAG-camptothecin intravenously administered weekly for 3 weeks in a 4-week cycle in adult patients with solid tumours. 1515 Jun 11

Eight 4'-ester epipodophyllotoxin derivatives (9-16) were designed and synthesized with the aim to overcome drug-resistance and improve water-solubility simultaneously. These compounds were superior to etoposide (1) in causing cellular protein-linked DNA breaks and inhibiting KB and 1-resistant KB-7d cell replication. Compounds 9 and 10 showed significant inhibitory activity against DNA topoisomerase II in vitro. Compound 10 also exhibited an in vitro DNA cleavage pattern similar to that of GL-331 (5). A hypothetical model on the action mode of 1-analogues is proposed based on the results.
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PMID:Antitumor agents. Part 235: Novel 4'-ester etoposide analogues as potent DNA topoisomerase II inhibitors with improved therapeutic potential. 1515 5

In 1995, we discovered new antiherpetic antibiotics, called fattiviracins. The producing organism was classified as a strain belonging to Streptomyces microflavus. The strain produced at least 13 fattiviracin derivatives (FV-1 to FV-13). Fattiviracins were obtained as a white amorphous powder, and their molecular weights are in the range of 1400 to 1500. They are readily soluble in water, methanol, pyridine, and DMSO, but insoluble in other organic solvents. Fattiviracins have macrocyclic diesters formed by the binding of two trihydroxy fatty acids and two D-glucose residues in the molecule, and they can be divided into five families according to the length of the fatty acid moiety. Fattiviracins have potent activity against enveloped DNA viruses such as the herpes family, HSV-1, and VZV and enveloped RNA viruses such as influenza A and B viruses, and three strains of HIV-1, with EC(50) values on the order of a few micrograms per milliliter. The biosynthetic pathway of fattiviracins is also becoming clearer. Using bacitracin-resistant strains, enhanced and astringent production of fattiviracin was achieved. Fattiviracin FV-13, which has the longest fatty acid chains in the molecule, was dramatically enhanced by a C(55)-isoprenyl phosphate metabolism. In addition, we have screened various inhibitors of enzymes such as alkaline protease, glucosyltransferase, glucuronidase, phospholipase, deoxyribonuclease, DNA methyltransferase, and DNA topoisomerase. All the inhibitors we discovered are briefly summarized in this paper.
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PMID:[Metabolites produced by actinomycetes--antiviral antibiotics and enzyme inhibitors]. 1529 17


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