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

The acridine derivative m-AMCA (methyl-N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), a carbamate analogue of the topoisomerase II poison amsacrine, is distinguished by its high cytotoxicity against non-cycling tumour cells. We compared the response of cultured Lewis lung carcinoma cells to m-AMCA, amsacrine and the topoisomerase I poison camptothecin. The DNA polymerase inhibitor aphidicolin reversed the cytotoxicity of camptothecin fully, that of amsacrine partially, and that of m-AMCA minimally. The ability of m-AMCA to induce the enzyme poly(ADP-ribose)polymerase (PARP) was markedly lower than that of camptothecin or amsacrine. Cell cycle responses to m-AMCA and amsacrine were similar, with slowing of progress through S-phase and arrest in G2-phase. These cell cycle changes were also observed when plateau phase cultures were exposed to drug for 1 h, washed free of drug and cultured in fresh medium, with m-AMCA having a more pronounced effect than amsacrine and camptothecin having no effect. We also examined the role of p53 protein in the response using cultured human H460 cells. Both m-AMCA and amsacrine induced p53 protein expression in proliferating but not in non-proliferating H460 cells, and induced p21WAF1 regardless of proliferation status. Both induced G1-phase cell cycle arrest. It is suggested that two cytotoxicity mechanisms can be distinguished using these drugs. The first is specific for S-phase cells, is reversed by aphidicolin and induces PARP activity. The second is cell cycle non-specific, does not induce PARP and is unaffected by aphidicolin. Camptothecin activates only the first, m-AMCA primarily the second and amsacrine activates both.
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PMID:Cellular responses to methyl-N-[4-9-acridinylamino)-2-methoxyphenyl] carbamate hydrochloride, an analogue of amsacrine active against non-proliferating cells. 938 32

N-[(Trimethylamine-boryl-carbonyl]-L-tryptophan methyl ester and N[(trimethylamine-boryl)-carbonyl]-L-histidine methyl ester were obtained by synthesis using triphenyl-phosphine/carbon tetrachloride or dicyclohexyl-carbodiimide as coupling agents, respectively. Both agents reduced L1210 lymphoid leukemia DNA, RNA, and protein syntheses with the largest reductions occurring in DNA synthesis. Reductions in DNA synthesis appear to be mediated by inhibition of key enzyme activities (i.e., DNA polymerase a, IMP dehydrogenase, and PRPP amido transferase). These agents had little effect on in vitro L1210 DNA topoisomerase II activity at 100 microM but were able to cause synergistic increases in protein-linked DNA breaks when combined with etoposide (VP16). It was shown that these agents significantly reduced protein kinase C mediated phosphorylation of human topoisomerase II in vitro. Thus, inhibition of topoisomerase II phosphorylation may be a mechanism by which these agents and VP-16 are synergistic in causing protein-linked DNA breaks.
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PMID:Synthesis and antitumor activity of boronated dipeptides containing aromatic amino acids. 941 63

An ethanol extract of Psoralea corylifolia caused strong DNA polymerase inhibition in a whole cell bioassay specific for inhibitors of DNA replication enzymes. Bioassay-directed purification of the active compounds led to the isolation of the new compound corylifolin (1) and the known compound bakuchiol (2) as DNA polymerase inhibitors. On the basis of the structures of 1 and 2, resveratrol (3) was tested and found to be active as a DNA polymerase inhibitor in this bioassay. Neobavaisoflavone (4) was isolated as a DNA polymerase inhibitor, daidzein (5) as a DNA polymerase and topoisomerase II inhibitor, and bakuchicin (6) as a topoisomerase II inhibitor.
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PMID:DNA polymerase and topoisomerase II inhibitors from Psoralea corylifolia. 954 66

Positive results in the in vitro assay for chromosome aberrations sometimes occur with test chemicals that apparently do not react with DNA, being negative in tests for mutation in bacteria, for DNA strand breaks, and for covalent binding to DNA. These chromosome aberrations typically occur over a narrow concentration range at toxic doses, and with mitotic inhibition. Indirect mechanisms, including oxidative damage, cytotoxicity and inhibition of DNA synthesis induced by chemical exposure, may be involved. Understanding when such mechanisms are operating is important in evaluating potential mutagenic hazards, since the effects may occur only above a certain threshold dose. Here, we used two-parameter flow cytometry to assess DNA synthesis inhibition (uptake of bromodeoxyuridine [BrdUrd]) associated with the induction of aberrations in CHO cells by DNA-reactive and non-reactive chemicals, and to follow cell cycle progression. Aphidicolin (APC), a DNA polymerase inhibitor, induces aberrations without reacting with DNA; 50 microM APC suppressed BrdUrd uptake during a 3-h treatment to <10% of control levels. Several new drug candidates induced aberrations concomitant with marked reductions in cell counts at 20 h (to 50-60% of controls) and suppression of BrdUrd uptake (<15% of control). Several non-mutagenic chemicals and a metabolic poison, which induce DNA double strand breaks and chromosome aberrations at toxic dose levels, also suppressed DNA synthesis. In contrast, the alkylating agents 4-nitroquinoline-1-oxide, mitomycin C, methylnitrosourea, ethylnitrosourea, methylmethane sulfonate and ethylmethane sulfonate, and a topoisomerase II inhibitor, etoposide, produced many aberrations at concentrations that were less toxic (cell counts >/=73% of controls) and gave little inhibition of DNA synthesis during treatment (BrdUrd uptake >/=85% of controls), although cell cycle delay was seen following the 3-h treatment. Thus, inhibition of DNA synthesis at the time of treatment is supporting evidence for an indirect mechanism of aberrations, when there is no direct DNA reactivity.
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PMID:DNA synthesis inhibition as an indirect mechanism of chromosome aberrations: comparison of DNA-reactive and non-DNA-reactive clastogens. 968 28

The Crithidia fasciculata KAP1 gene encodes a small basic protein (p21) associated with kinetoplast DNA. The p21 protein has a nine amino acid cleavable presequence closely related to those of several other proteins targeted to the kinetoplast and binds non-specifically to kinetoplast minicircle DNA. The p21 protein also has a calculated pI of 13 with two amino acids (lysine and alanine) accounting for more than 50% of the residues and with 25 out of 28 lysine residues contained in the C-terminal half of the protein. Immunolocalization of p21 shows that the protein is found exclusively in the kinetoplast with a localization distinctly different from the antipodal localization of kinetoplast DNA topoisomerase and DNA polymerase. The KAP11 gene is a single copy gene and the KAP1 mRNA is present at a constant level throughout the cell cycle. This highly basic protein may play a role in the condensation or segregation of the kinetoplast DNA.
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PMID:The Crithidia fasciculata KAP1 gene encodes a highly basic protein associated with kinetoplast DNA. 971 9

Previous work showed that the DNA double-strand cleaving agents bleomycin and neocarzinostatin were more mutagenic in plateau-phase than in log-phase cells. To determine whether topoisomerase II poisons that produce double-strand breaks by trapping of cleavable complexes would, likewise, induce mutations specific to plateau-phase cells, aprt mutations induced by amsacrine in both log-phase and plateau-phase CHO cells were analyzed. The maximum aprt mutant frequencies obtained were 7 x 10(-6) after treatment with 0.02 microM amsacrine in log phase and 27 x 10(-6) after treatment with 1 microM amsacrine in plateau phase, compared with a spontaneous frequency of < 1 x 10(-6). Base substitutions dominated the spectrum of mutations in log-phase cells, but were much less prevalent in plateau-phase cells. Both spectra also included small deletions, insertions and duplications, as well as few large-scale deletions or rearrangements. About 5% of the log-phase mutants and 16% of the plateau-phase mutants were +1 frameshifts, and all but one of these were targeted to potential free 3' termini of cleavable complexes, as determined by mapping of cleavage sites in DNA treated with topoisomerase II plus amsacrine in vitro. Thus, these insertions may arise from templated extension of the exposed 3' terminus by a DNA polymerase, followed by resealing of the strand, as shown previously for acridine-induced frameshifts in T4 phage.
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PMID:Enhanced amsacrine-induced mutagenesis in plateau-phase Chinese hamster ovary cells, with targeting of +1 frameshifts to free 3' ends of topoisomerase II cleavable complexes. 1044 82

Activation of the transcription factor NF-kappaB by extracellular signals involves its release from the inhibitor protein IkappaBalpha in the cytoplasm and subsequent nuclear translocation. NF-kappaB can also be activated by the anticancer agent camptothecin (CPT), which inhibits DNA topoisomerase (Topo) I activity and causes DNA double-strand breaks during DNA replication to induce S phase-dependent cytotoxicity. Here we show that CPT activates NF-kappaB by a mechanism that is dependent on initial nuclear DNA damage followed by cytoplasmic signaling events. NF-kappaB activation by CPT is dramatically diminished in cytoplasts and in CEM/C2 cells expressing a mutant Topo I protein that fails to bind CPT. This response is intensified in S phase cell populations and is prevented by the DNA polymerase inhibitor aphidicolin. In addition, CPT activation of NF-kappaB involves degradation of cytoplasmic IkappaBalpha by the ubiquitin-proteasome pathway in a manner that depends on the IkappaB kinase complex. Finally, inhibition of NF-kappaB activation augments CPT-induced apoptosis. These findings elucidate the progression of signaling events that initiates in the nucleus with CPT-Topo I interaction and continues in the cytoplasm resulting in degradation of IkappaBalpha and nuclear translocation of NF-kappaB to attenuate the apoptotic response.
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PMID:NF-kappaB activation by camptothecin. A linkage between nuclear DNA damage and cytoplasmic signaling events. 1073 98

Previous studies have demonstrated alkylating (melphalan) resistance in the B-CLL derived WSU-CLL cell line as compared to WIL2 B lymphocytic cells. Nuclear extracts from WSU-CLL cells demonstrate a highly significant increase in DNA topoisomerase II activity as compared to WIL2 cells. Western blot analysis showed the level of topoisomerase II proteins expressed in WSU-CLL cells to be increased as compared to WIL2 cells. WSU-CLL cells were 5.24-fold more sensitive than WIL2 cells to the cytotoxic effect of the topoisomerase II inhibitor doxorubicin. No difference in topoisomerase I activity or of the level of topoisomerase I protein expression was observed comparing the two cell lines. The sensitivity to the cytotoxic effects of topoisomerase I inhibitor, camptothecin, did not differ in WSU-CLL and WIL2 cell lines. Pre-incubation with doxorubicin significantly increased melphalan induced interstrand-DNA-crosslink formation and cytotoxicity in WSU-CLL cells as compared to WIL2 cells. The affinity of topoisomerase II for WSU-CLL UV-irradiated-crosslinked DNA was increased 2.84-fold as compared to that of WSU-CLL native DNA. The affinity of topoisomerase II for both UV-irradiated (crosslinked) and for native DNA was significantly decreased after doxorubicin-pretreatment. Measurement of DNA polymerase beta and DNA polymerase beta revealed significant elevations in DNA polymerase beta (58.82 +/- 3.67 units/mg protein in WSU-CLL cells, as compared to 27.82 +/- 4.39 units/mg protein in WIL 2 cells; p < 0.01) but not DNA polymerase beta (0.82 +/- 0.11 units/mg protein in WSU-CLL cells, compared to 0.74 +/- 0.09 units/mg protein in WIL2, p > 0.05). However, exposure to aphidicolin (an inhibitor of DNA polymerase a) failed to increase melphalan induced cytotoxicity suggesting that although DNA polymerase a activity was increased in WSU-CLL cells the mechanisms of resistance does not involve this specific DNA repair pathway. Elevated topoisomerase II activity and the increased affinity of topoisomerase II for crosslinked DNA in melphalan resistant cells appears to be the major factor responsible for alkylator resistance by changing DNA topology and thereby facilitating DNA repair.
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PMID:Alkylator resistance in human B lymphoid cell lines: (2). Increased levels of topoisomerase II expression and function in a melphalan-resistant B-CLL cell line. 1095 28

Bacteriophage T4 DNA replication proteins catalyze complete unidirectional replication of plasmids containing the T4 ori(uvsY) replication origin in vitro, beginning with a preformed R loop at the position of the origin R loop previously identified in vivo. T4 DNA polymerase, clamp, clamp loader, and 32 protein are needed for initial elongation of the RNA, which serves as the leading-strand primer. Normal replication is dependent on T4 41 helicase and 61 primase and is strongly stimulated by the 59 helicase loading protein. 59 protein slows replication without the helicase. As expected, leading-strand synthesis stalls prematurely in the absence of T4 DNA topoisomerase. A DNA unwinding element (DUE) is essential for replication, but the ori(uvsY) DUE can be replaced by other DUE sequences.
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PMID:Bacteriophage T4 proteins replicate plasmids with a preformed R loop at the T4 ori(uvsY) replication origin in vitro. 1117 9

Doxorubicin, a very potent and often used anti-cancer drug, has a wide spectrum of biological activity. Classic studies have demonstrated that doxorubicin and other members of the anthracycline family intercalate with DNA and partially uncoil the double-stranded helix. Doxorubicin has a high affinity for cell nuclei: as much as 60% of the total intracellular amount of doxorubicin is found in the nucleus. Once binding to DNA occurs, several consequences may ensue. The binding of anthracyclines to DNA inhibits DNA polymerase and nucleic acid synthesis. In addition, anthracyclines are known to stabilize the otherwise cleavable complex between DNA and homodimeric topoisomerase II enzyme subunits, resulting in the formation of protein-linked DNA double strand breaks. In tumor cells, these anthracycline-induced perturbations are believed to result in a final common pathway of endonucleolytic DNA fragmentation known as apoptosis. Because proliferation is an important determinant of tumor growth, interference with the genome is regarded as the primary cause of the anti-tumor action of doxorubicin. Intercalation with DNA may not be important in the cardiotoxicity associated with doxorubicin therapy (see next section), because cardiac cell proliferation in humans stops after 2 months of age. This review is focussed on the effects of doxorubicin on mechanical performance in skinned cardiac trabeculae after acute and chronic administration of doxorubicin. We look especially at the mechanical performance and the molecular changes observed and related to mechanical performance.
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PMID:Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review. 1124 45


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