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)

The requirement for rational drug design in the search for new agents that are active against parasitic protozoa prompted our in vitro studies with a group of 9-anilinoacridines. In vitro growth assays with Trypanosoma lewisi identified a series of C-1' alkylaminoacridines which possess previously unreported potent growth-inhibitory activities against T. lewisi at a concentration range of 0.1 to 1 microM. In contrast, several 9-anilinoacridines that possess acridine ring NH2 substituents at C-3 and C-6 were inactive against T. lewisi, but they possessed strong activity against Plasmodium falciparum at a concentration range of 0.1 to 2.8 microM. In mammalian cells, amsacrine [4'-(9-acridinylamino)methanesulfon-m-anisidide] inhibits DNA topoisomerase II; however, amsacrine was only weakly active against T. lewisi. Such differences in the patterns of susceptibility of mammalian cells, T. lewisi, and P. falciparum to these 9-anilinoacridines may reflect enzyme differences between different parasites and mammalian cells that can be exploited by further improvements in drug design.
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PMID:In vitro study of anticancer acridines as potential antitrypanosomal and antimalarial agents. 141 46

Fluoroquinolones are potent inhibitors of bacterial topoisomerase II (DNA gyrase). They can also inhibit eukaryotic topoisomerases, which could possibly lead to clastogenicity and/or cellular toxicity. Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the fluoroquinolones and the potential of these compounds to induce micronuclei, a genetic toxicity endpoint. In an effort to identify potent nontoxic quinolone antibacterials, we have examined the structural features of the fluoroquinolones associated with mammalian cell cytotoxicity. An investigation of a wide variety of substituents at the 1, 5, 7, and 8 positions of a quinolone nucleus was conducted. The results indicate that no one position has a controlling effect on the observed cytotoxicity. Instead, a combination of the various substituents contributes to the effects seen. Certain trends were apparent, such as the fact that compounds with pyrrolidines at the R-7 position were more cytotoxic than those with piperazines, and halogens at R-8 (X-position) were associated with more cytotoxicity relative to hydrogen. A general trend also existed between the cytotoxicity of the compounds and their Gram-positive antibacterial activity. A detailed comparison between the various groups and positional variations as they controlled the cytotoxicity and antibacterial activity is presented.
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PMID:Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity. 146 2

A series of mono- and dicationic derivatives of various di- and triazaphenanthrenes were synthesized and evaluated against both wild-type and amsacrine-resistant P388 leukemia in vitro. Monocationic derivatives of the fully-aromatic benzo[c][1,8]naphthyridine chromophore showed moderate and equal cytotoxicity in both cell lines, suggestive of efficacy against both the alpha and beta isozymes of mammalian DNA topoisomerase II. Derivatives of both the benzo[c][1,8]naphthyridine and benzo[c][1,8]naphthyridine-3(4H)-one chromophores also showed significant in vivo activity against wild-type P388 leukemia.
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PMID:Cytotoxic and DNA binding properties of aminoalkyl derivatives of di- and triazaphenanthrenes. 151 Jul 98

The cytotoxic activity of human recombinant tumor necrosis factor (rHuTNF) (from 0.01 to 10000 U/ml) was assayed on six human ovarian cancer cell lines and one human cervical carcinoma cell line using a crystal violet assay. rHuTNF was cytotoxic to four cell lines (A2780, A2774, SW626, PA1), while 3 cell lines (IGROV1, SKOV3, Me180) were marginally sensitive to its activity. However, under the same experimental conditions rHuTNF markedly enhanced the cytotoxicity of mitoxantrone, a chemotherapeutic drug targeted at DNA topoisomerase II, in six cell lines. The potentiation of mitoxantrone cytotoxicity was not caused by increased drug accumulation after rHuTNF treatment. No significant increase in cytotoxicity to Me180 cell line was seen when rHuTNF was added to mitoxantrone.
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PMID:Potentiation by tumor necrosis factor of mitoxantrone cytotoxicity to human ovarian cancer cell lines. 151 45

Exposure of exponentially growing human promyelocytic of lymphocytic leukemic cells to the putative DNA topoisomerase II inhibitor fostriecin (FST), at a concentration of 1 microM, results in the suppression of their rate of progression through the S and G2 phases of the cell cycle. At concentrations between 5 microM and 0.5 mM, FST triggers endonucleolytic DNA degradation in human promyelocytic leukemia cells, resulting in apoptotic cell death; this effect is not selective for any particular phase of the cell cycle. Little or no apoptotic cell death is observed in lymphocytic leukemic cells at any FST concentration. Because FST, unlike other inhibitors of topoisomerase II, such as teniposide (TN) or amsacrine (m-AMSA), does not stabilize cleavable DNA-topoisomerase complexes, the observed differences between the effects of FST versus TN or m-AMSA on the cell cycle may provide clues regarding the role of such complexes in the kinetic effects of these inhibitors. The present results, therefore, are compared with our earlier data on the effects of TN and m-AMSA on the same cells. The only observed difference is the loss of cell cycle phase-specific triggering of DNA degradation by FST in human promyelocytic leukemia cells, compared to the S phase-specific effects of TN and m-AMSA. Therefore, stabilization of the DNA-topoisomerase cleavable complexes may be essential in the selectivity of cell kill during S phase. However, it appears that the presence of stabilized complexes is not essential to the suppression of cell progression through S or G2 or the induction of apoptotis or necrosis, in general, by topoisomerase II inhibitors.
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PMID:Cytostatic and cytotoxic effects of fostriecin on human promyelocytic HL-60 and lymphocytic MOLT-4 leukemic cells. 154 Sep 62

We have previously demonstrated in transient expression assay systems that a human multidrug resistance 1 (MDR1) promoter can be directly activated by cytotoxic anticancer agents. In this study, we examined whether the MDR1 promoter could be regulated in response to growth arrest induced by serum starvation. We have established human and rodent cell lines which stably expressed the chloramphenicol acetyltransferase (CAT) gene driven by various lengths of the MDR1, the viral thymidine kinase (TK) and the simian virus 40 (SV40) promoters. Serum starvation caused enhanced expression of CAT gene with MDR1 promoter, but not with two viral gene promoters in human cancer KB cells. Hydroxyurea activated the MDR1 promoter, but not TK and SV40 promoters. By contrast, the DNA topoisomerase II inhibitor, etoposide, equally activated the MDR1, TK and SV 40 promoters. Increased CAT gene expression by serum starvation was also specifically observed in stable transfectants of human adrenal SW-13 cell lines, but not in stable transfectants of mouse fibroblast NIH3T3 and adrenal Y-1 cell lines when the human MDR1 promoter-CAT was introduced. Etoposide, however, effectively induced CAT activity in both human and rodent cells. Assays with deletion constructs of the MDR1 promoter showed that serum starvation activated the MDR1 promoter carrying -258 approximately +121 base sequence of the promoter, but not -198 approximately +121 of the promoter. These results suggest that the expression of the MDR1 gene induced by serum starvation is regulated at the transcriptional level in a promoter sequence-specific manner in human cells.
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PMID:The human multidrug resistance 1 promoter has an element that responds to serum starvation. 155 May 97

Teniposide [4'-demethylepipophyllotoxin-4-(4,6-O-thenylidene-beta-D- glucopyranoside) (VM-26)] is a cancer chemotherapeutic drug with a high target specificity for DNA topoisomerase II. This agent induces repairable protein-bridged double-strand DNA breaks, which have been correlated with cytotoxicity, but high concentrations of VM-26 also induce irreversible DNA degradation and apoptotic cell death. It is not known whether this degradation occurs uniformly throughout the genome or in a gene-specific manner. To answer this question, DNA was isolated from HL-60 promyelocytic leukemia cells exposed to 5 microM VM-26 for varying periods of up to 12 h. Nucleosomal "ladders" on 2.0% agarose gels stained with ethidium bromide were detectable after 3 h of exposure, indicative of apoptosis. Gene-specific DNA degradation was investigated by Southern blot analysis. The genes for 18S rRNA and glucose-6-phosphate dehydrogenase were representatives of constitutively expressed (i.e., "housekeeping") genes. The proto-oncogenes c-myc, c-Ha-ras, and bcl-2 were examined as examples of other transcriptionally active genes, while transcriptionally inactive genes in HL-60 cells were studied by probing for the immunoglobulin heavy chain joining region and lambda light chain constant region genes. The rates of DNA degradation, and its extent after 12 h, were similar for all nuclear genes studied. However, there was striking resistance of mitochondrial DNA to endonucleolytic degradation. These data demonstrate that VM-26 can elicit a widespread degradative process which affects nuclear but not mitochondrial DNA.
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PMID:Teniposide induces nuclear but not mitochondrial DNA degradation. 159 97

The antibacterial activities of the fluorinated 4-quinolones (e.g., ciprofloxacin) have been ascribed to a marked inhibition of bacterial DNA gyrase. In contrast, the influence on purified mammalian DNA enzymes, including topoisomerases, has been reported to be several orders of magnitude weaker, occurring at concentrations higher than 100 micrograms of ciprofloxacin per ml. In this study, using a nondenaturing filter elution method, a marked induction of double-strand DNA breaks in human lymphoblastoid cells exposed to 80 micrograms of ciprofloxacin per ml was seen. The proportion of single-strand versus double-strand DNA breaks was similar to that seen with the topoisomerase II inhibitory antitumor agent VP-16. The cellular recovery was more rapid after treatment with ciprofloxacin than after treatment with VP-16, displaying a normal elution profile within 15 min at 37 degrees C (60 min for VP-16). These data indicate that ciprofloxacin has an effect on intracellularly located topoisomerase II in humans.
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PMID:Ciprofloxacin-induced inhibition of topoisomerase II in human lymphoblastoid cells. 164 8

The cytotoxic effect of the 9-azaellipticine derivative pazelliptine in combination with gamma-ray irradiation was investigated using Chinese hamster V-79 cells in culture. gamma-ray irradiation and drug treatment (1-h drug exposure) were applied at 1-h intervals for partial DNA damage recovery in growth medium. Isobologram analysis of the clonogenic potential gave evidence of supraadditive interaction in the radiation----drug sequence with 10% survival as an endpoint. No synergistic potentiation was observed at higher survival or as pazelliptine was applied first. Pazelliptine abolished the low-dose shoulder characteristic of asynchronous cell response to gamma-rays. Although rejoining of radiation-induced DNA strand breaks was completed at the time of drug exposure, pazelliptine brought about a larger amount of DNA strand breaks in preirradiated than in nonirradiated cells. The time and dose dependencies of DNA strand break formation and repair with radiation and/or pazelliptine were analyzed by neutral and alkaline filter elution. Pazelliptine in the micromolar range showed the same pattern of double-stranded cleavable complex formation as expected of a DNA topoisomerase II-targeting agent. At a low concentration of pazelliptine, however, protein-concealed breaks were mostly in the form of single-stranded adducts. Such single-stranded complexes have been reported to occur with some topoisomerase II-targeting drugs; their properties are also reminiscent of those induced by the topoisomerase I poison, camptothecin. It is proposed that topoisomerase poisoning interacts with the repair of radiation-induced lesions.
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PMID:Additive and supraadditive interaction between ionizing radiation and pazelliptine, a DNA topoisomerase inhibitor, in Chinese hamster V-79 fibroblasts. 164 14

In this study, the effect of DNA single strand breaks (ssb) on the neutral (pH 9.6) filter elution of DNA from Chinese hamster ovary (CHO K1) cells containing DNA double strand breaks (dsb) was investigated. Protein associated ssb were induced by the inhibition of DNA topoisomerase I with camptothecin (cpt). Protein associated dsb were introduced by treating cells with the DNA topoisomerase II poison; etoposide (VP-16). Protein associated ssb and dsb were converted to ssb and dsb by proteinase K present in the lysis solution. In some experiments dsb were generated by the restriction endonuclease Pvu II. It was found that elution of DNA in the presence and absence of ssb was similar under neutral conditions. This finding is consistent with the view that the fast component of the bi-phasic repair kinetics observed in irradiated mammalian cells with the neutral filter elution technique is not attributable to the interference of ssb with the measurement of dsb, and thus suggests that the two components of repair observed with the neutral filter elution elution technique may represent two different types of dsb or modes of repair of dsb.
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PMID:Lack of interference of DNA single-strand breaks with the measurement of double-strand breaks in mammalian cells using the neutral filter elution assay. 164 64


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