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)

Caffeine has been known to enhance lethal and chromosome damaging effects of chemical and physical mutagens. In spite of numerous investigations, the mechanism is not fully elucidated. In this paper, we describe that 1) post-treatment with camptothecin (CPT), a specific inhibitor of DNA topoisomerase (topo) I, enhances SCE-induction by ultraviolet light (UV), as post-UV caffeine treatment does, 2) the lethal effect of UV is also enhanced but to a lesser degree than by post-UV caffeine treatment, and 3) caffeine, like CPT, inhibits calf thymus topo I activity, as determined by relaxation of pBR322 supercoiled DNA. These results suggest that the mechanism(s) of lethal and SCE enhancement involves the ability of caffeine to inhibit topo I.
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PMID:A possible involvement of DNA topoisomerase I in "caffeine effect" after ultraviolet irradiation. 133 96

8-Methoxycaffeine (8-MOC) is a caffeine derivative, more potent than the parent compound, but very similar to caffeine in terms of induction of DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs) and DNA-protein crosslinks (DPCs). We have studied the capability of 8-MOC, caffeine and 8-chlorocaffeine (8-CC) of inducing SSBs, DSBs and DPCs, and we have compared 8-MOC with ellipticine, a typical inhibitor of DNA topoisomerase II. The DNA effects of 8-MOC appeared similar to those of ellipticine. In both cases SSBs, DSBs and DPCs were present in a similar ratio, and they were rapidly reversible after removal of the drug. The dose-response curve was bell-shaped for both compounds. In addition, 8-MOC, caffeine and 8-CC were capable of inhibiting DSBs induced by ellipticine. These results were obtained at the level of L1210 cell nuclei. In spite of these functional similarities, 8-MOC, caffeine and 8-CC were unable to stimulate the formation of a cleavable complex by purified L1210 topoisomerase II (p170 form) when SV40 DNA and human c-myc DNA were used as substrate. These methylated oxypurines could be active on a different form of topoisomerase II, or, alternatively, they could be active only in the natural chromatin 'milieu' within the nucleus.
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PMID:Production of protein-associated DNA breaks by 8-methoxycaffeine, caffeine and 8-chlorocaffeine in isolated nuclei from L1210 cells: comparison with those produced by topoisomerase II inhibitors. 165 26

Caffeine was found to inhibit both type I and type II topoisomerases in vivo as judged by its effects on replicating simian virus 40 (SV40) chromosomes. The study was facilitated by the use of a rapid filter assay for the detection and characterization of topoisomerase inhibitors. The assay, which requires neither purified enzymes nor substrates, was able to identify both antagonists and poisons of type I and type II topoisomerases.
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PMID:Rapid evaluation of topoisomerase inhibitors: caffeine inhibition of topoisomerases in vivo. 197 68

Using cultured V79 Chinese hamster cells, we found that novobiocin (or 2,4-dinitrophenol) can abrogate, almost completely, the cytotoxicity due to the topoisomerase II inhibitor amsacrine (mAMSA). V79 cells were sensitive to mAMSA killing at all stages in the cell cycle but mainly in S phase followed by late G1 phase; however, novo rescued cells of all ages. The properties of two kinds of radiation-sensitive Chinese hamster cells were also examined, i.e., the line of V79 cells that can be rescued by caffeine, designated S-10 (H. Utsumi and M.M. Elkind, Radiat. Res., 96: 348-358, 1983); and Chinese hamster ovary cells (P.A. Jeggo and L.M. Kemp, Mutat. Res., 112: 313-327, 1983) which are also sensitive to other DNA-damaging agents. As is the case for exposure to radiation, after mAMSA treatment caffeine rescued V79/S-10 cells. Although Jeggo's Chinese hamster ovary cells were more responsive to mAMSA, novo still abrogated mAMSA toxicity in the mutant cells as well as in the parental Chinese hamster ovary cells 2,4-Dinitrophenol acted similarly to novo with respect to mAMSA killing, but neither compound reduced the ATP content of V79 cells. We propose that one reason for the rescue from mAMSA killing of at least S-phase cells by novo or 2,4-dinitrophenol is their ability transiently to inhibit replicative DNA synthesis.
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PMID:Abrogation by novobiocin of cytotoxicity due to the topoisomerase II inhibitor amsacrine in Chinese hamster cells. 215 94

8-methoxycaffeine (8-MOC) is a caffeine derivative more potent than its parental compound in inducing chromosomal aberrations. 8-MOC has been postulated to produce chromosomal aberrations by DNA topoisomerase II inhibition. The effect of 8-MOC on nuclear DNA were studied by alkaline elution experiments and compared with those of Ellipticine and Adriamycin (ADR). Like Ellipticine and ADR, 8-MOC induced single strand breaks (SSBs), double strand breaks (DSBs), and DNA-protein cross-links (DPCs) in a bell-shaped manner with respect to drug concentration. As in the case of ADR and Ellipticine, 8-MOC induced equal SSB and DPC frequencies. These results could suggest that 8-MOC induces DNA breaks by interacting with DNA topoisomerase II or with a similar DNA metabolism enzyme.
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PMID:8-methoxycaffeine-induced protein-associated DNA breaks in isolated L1210 cell nuclei. 217 3

The polynucleotide length of single-stranded regions in double-stranded DNA may be determined by caffeine gradient elution from benzoylated DEAE-cellulose. On the basis of this principle, analysis has been made of sheared, deproteinized DNA isolated from synchronized lymphoblastoid cells. Two classes of single-stranded regions were detected. A minor fraction of replicating DNA contained single-stranded regions of 200 nucleotides, whilst the major structural discontinuity involved single-stranded regions of 1-4 kilobases. Newly incorporated [3H]thymidine was principally associated with the latter. Using a 'pulse-chase' protocol, the effect of certain cytotoxic drugs (and related compounds) on the proportion of replicating DNA exhibiting single-stranded character was assessed. The effects were variable. The proportion was increased by hydroxyurea and 3-aminobenzamide, but decreased by inhibitors of DNA polymerase and, to a greater extent, by inhibitors of topoisomerase. Caffeine gradient elution associated drug-induced changes with the radiolabelling of long single-stranded regions. The results are consistent with models of DNA replication involving DNA polymerization remote from replicating forks.
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PMID:Structural analysis of replicating DNA following exposure to cytotoxic drugs: implications for current models of DNA synthesis in mammalian cells. 231 56

The role of topoisomerase enzymes in the response of HeLa S3 cells to ionizing radiation was investigated. Exposure of cells to 100 Gy of X-radiation had no detectable effect either on the total cellular topoisomerase activity as measured by the relaxation of supercoiled plasmid DNA by cell sonicates or on the total cellular topoisomerase II activity as measured by plasmid DNA catenation. Total topoisomerase II activity remained constant for up to 90 min after cell irradiation. The effect of 2 drugs (caffeine and novobiocin) which inhibit topoisomerase II activity on the HeLa cell response to radiation was determined. Both drugs were found to inhibit topoisomerase II in vitro and to inhibit the recovery of nucleoid sedimentation in irradiated cells in vivo to the same extent. Topoisomerase II was inhibited by 50% by exposure to 10 mM caffeine and 0.79 mM novobiocin. At low concentrations neither drug affected the induction frequency, nor the rejoining rate, of DNA double-strand breaks. Caffeine (5 mM) inhibited the short-term recovery of cells from radiation while novobiocin (0.79 mM) had no detectable effect on the capacity of cells to recover from radiation exposure. The results indicate that topoisomerase II is not required for DNA double-strand break rejoining though it could be required for the recovery of DNA coiling in the irradiated cell. If topoisomerase II is involved at all in cell recovery from irradiation, this role does not apparently involve an ATP-dependent enzyme activity.
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PMID:Topoisomerase activity in irradiated mammalian cells. 253 62

The results presented here point to the difficulties that exist in connection with the identification of the molecular target of caffeine. Our data support the evidence that caffeine and caffeine derivatives cause DNA-protein cross-links (DPC) in whole mammalian cells or in isolated nuclei. These DPC have the same properties (saturability, reversibility and temperature-dependence) as those produced by an enzymatic inhibition. The experiments performed in reconstituted systems, in the presence of purified DNA topoisomerase II, do not support the original hypothesis that this enzyme might be a possible target for this class of drugs. We suggest the possibility that other DNA metabolism enzymes are involved in the biological effects of caffeine and caffeine derivatives. Further biochemical and molecular data are necessary to identify which of these enzymes is in fact affected.
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PMID:Biochemical and enzymatic aspects of caffeine and caffeine derivatives induced DNA strand breaks. 254 74

The frequency of sister chromatid exchanges (SCEs), both spontaneous and induced by UV-light, X-rays, mitomycin C and ethylmetansulphonate (EMS), has been investigated in cultured human peripheral blood lymphocytes. Besides, frequency of spontaneous and induced SCEs was studied under the action of the inhibitors of topoisomerase II, polymerase poly(ADP-ribose), and DNA repair, i. e. novobiocin, 3-metoxybenzamide, and caffeine, respectively. It is shown that the base-line SCEs in lymphocytes of the patient with xeroderma pigmentosum II (XP2LE) is dramatically higher compared to that in normal and pigmented xerodermoid cells (XP3LE). The above inhibitors of DNA synthesis and repair enhance the rate of spontaneous SCEs in normal, XP2LE and XP3LE cells. UV-, X-ray and chemical mutagens induced an increased frequency of SCEs in these cells. Simultaneous treatment with mutagenes and inhibitors of DNA synthesis and DNA repair enhanced the rate of SCEs in lymphocytes of healthy donors and in the XP3LE patient. The frequency of the XP2LE cells. Novobiocin, 3-MBA and caffeine significantly decreased the frequency of SCEs in mitomycin C- and EMS-treated XP2LE lymphocyte, which nevertheless was much higher than that in normal cells treated with the same agents.
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PMID:[Spontaneous and induced sister chromatid exchanges in the blood lymphocytes of healthy persons and of xeroderma pigmentosum patients exposed to the inhibitors of DNA repair and replication caffeine, 3-methoxybenzamide and novobiocin]. 308 51

This review is concerned with the influence of different classes of chemical agents on cellular repair of DNA damage induced by ionizing radiation. Single-strand break rejoining is little affected by inhibitors of DNA synthesis; however, such inhibitors do lead to a persistence of double-strand breaks in the DNA, and this correlates with an enhancement of chromosome aberrations and cell killing. Experiments with antagonists of topoisomerase II suggest an intriguing role for this DNA unwinding enzyme in double-strand break repair. Interference with poly(ADP-ribose) synthesis, by means of the inhibitor 3-aminobenzamide, does not have a clear-cut effect on recovery from ionizing radiation damage. Various substances (for example, caffeine and trypsin) affect DNA repair via a modulation of the cell cycle, altering the time available to the cell for repairing potentially lethal DNA damage before such damage is 'fixed' by the process of DNA replication. Finally, disturbing cellular energy metabolism, and depressing the level of ATP, can inhibit the repair of radiation damage.
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PMID:Cellular responses to ionizing radiation: effects of interrupting DNA repair with chemical agents. 329 8


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