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)

Data about the changes of the cell nucleus structure at different levels of its organization are summarized in the review. The data about the change of the DNA break number during the cycle and in resting state are presented and the role of the changes of the repair efficiency in this process is discussed. The changes of the chromatin protein spectrum, the chromatin structure at nucleosomal and supranucleosomal levels, the DNA superhelicity, topoisomerase activity, nuclear matrix composition and structure are discussed as well. The nucleus structure during the S-phase and mitosis and the cycle-related changes of the chromatin structure in lower eukaryotes are reviewed separately.
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PMID:[The molecular organizational characteristics of the cell nucleus components at different phases of the mitotic cycle and in the resting state]. 129 55

Chemotherapy failure remains a significant medical problem in the treatment of neoplastic disease and is thought to be due to many different factors including membrane transport, p-glycoprotein in multidrug resistance, glutathione and its related enzymes, topoisomerase II and DNA repair. Glutathione is a major constituent of non-protein thiol and participates in detoxification of chemotherapy and radiation. Thus, glutathione concentration is correlated with sensitivity to alkylating agents and radiation, and increased in resistant cell lines. Buthionine sulfoximine (BSO) is an inhibitor of glutathione biosynthesis and may increase cytotoxicities of alkylating agents, including melphalan and cisplatin, and radiation in sensitive and resistant cell lines. We studied effects on cellular glutathione levels and cytotoxicities of cisplatin, carboplatin and radiation by BSO treatment in human stomach cancer cell line (SNU-1) and ovarian cancer cell line (OVCAR-3). The results were as follow: 1) After BSO treatment of 1 mM and 2 mM for 2 days, the intracellular thiol concentration was depleted to 75.7% and 76.2% in SNU-1, and 74.1% and 63.0% in OVCAR-3, respectively. 2) The intracellular thiol concentration in SNU-1 was depleted to 33.4% after BSO 2 mM for only 2 hours incubation and 71.5% after small amount of BSO (0.02 mM) for 2 days. 3) The recovery of intracellular thiol concentration required more than 3 days after BSO removal. 4) BSO inhibited partially the growth of SNU-1 and OVCAR-3. 5) The cytotoxicities of cisplatin and carboplatin were markedly enhanced both in SNU-1 and OVCAR-3 by BSO treatment. 6) The cytotoxicities of radiation was increased in OVCAR-3 and SNU-1 by BSO treatment. Therefore, it is concluded that BSO can deplete effectively the intracellular thiol concentration and enhance the cytotoxicities of cisplatin, carboplatin and radiation.
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PMID:Effects of buthionine sulfoximine treatment on cellular glutathione levels and cytotoxicities of cisplatin, carboplatin and radiation in human stomach and ovarian cancer cell lines. 130 72

Anilino analogues of amsacrine showed increased activity against amsacrine (AMSA)-resistant cell lines when compared with the parent compound, but the mechanisms of amsacrine resistance in these lines were unknown (Finlay, G. J., Baguley, B. C., Snow, K., and Judd, W., J. Natl. Cancer Inst., 82: 662-667, 1990). We tested the cytotoxic and DNA-cleaving activities of two amsacrine analogues which were derivatives of 9-anilinoacridine (1'-methylcarbamate and 1'-benzenesulfonamide) against an amsacrine-resistant human leukemia cell line (HL-60/AMSA) whose resistance is due to an amsacrine-resistant topoisomerase II. Neither agent could overcome the amsacrine resistance of HL-60/AMSA. Neither agent could induce HL-60/AMSA topoisomerase II-mediated cleavage of DNA in an isolated biochemical system, although at high concentrations the two analogues could inhibit HL-60/AMSA topoisomerase II-mediated DNA strand passage. Both analogues were at least as active, if not more active, than amsacrine against amsacrine-sensitive HL-60 and its topoisomerase II. Comparison of the cellular and biochemical results with those from computer simulation of the energy-minimized structures of amsacrine, its inactive isomer o-AMSA, and the two new active analogues suggests the following possibilities: (a) the positioning of the potential topoisomerase II-binding site (1'-anilino group) of the two new drugs resembles the positioning of this site in amsacrine; (b) the HL-60 topoisomerase II has a binding site which interacts with amsacrine and the two anilino analogues but not with o-AMSA, an analogue with altered positioning of the methoxy group; (c) the HL-60/AMSA topoisomerase II interacts with reduced affinity with amsacrine and the two anilino analogues, although HL-60/AMSA topoisomerase II still interacts with the structurally distinct topoisomerase II-reactive nonintercalator, etoposide; (d) because of their higher DNA binding affinity or the greater possible positions of their side groups in comparison to amsacrine, the two analogues can, at high concentrations, inhibit the strand-passing activity of HL-60/AMSA topoisomerase II.
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PMID:Relative activity of structural analogues of amsacrine against human leukemia cell lines containing amsacrine-sensitive or -resistant forms of topoisomerase II: use of computer simulations in new drug development. 130 24

Human cells contain two topoisomerase II isozymes named topo II alpha and topo II beta. The complementary DNAs for both enzymes have been cloned. The topo II alpha and topo II beta complementary DNAs hybridized to unique sequences of human, rodent, and chicken DNAs in Southern blots. The human topo II alpha gene has previously been mapped to chromosome 17. We confirmed the chromosomal location of topo II alpha and mapped the topo II beta gene to chromosome 3. In addition, topo II beta exhibits genetic polymorphism as has been reported for topoisomerases I and II alpha.
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PMID:Topoisomerase II alpha and topoisomerase II beta genes: characterization and mapping to human chromosomes 17 and 3, respectively. 130 26

The effects of topoisomerases I and II on the replication of SV40 DNA were examined using an in vitro replication system of purified proteins that constitutes the monopolymerase system. In the presence of the two topoisomerases, two distinct nascent DNAs were formed. One product arising from the replication of the leading template strand was approximately half the size of the template DNA, whereas the other product derived from the lagging template strand consisted of short DNAs. These products were synthesized from both SV40 naked DNA and SV40 chromosomes. For the replication of SV40 naked DNA, either topoisomerase I or II maintained replication fork movement and supported complete leading strand synthesis. When SV40 chromosomes were replicated with the same proteins, reactions containing only topoisomerase I produced shorter leading strands. However, mature size DNA products accumulated in reactions supplemented with topoisomerase II, as well as in reactions containing only topoisomerase II. In the presence of crude extracts of HeLa cells, VP-16, a specific inhibitor of topoisomerase II, blocked elongation of the nascent DNA during the replication of SV40 chromosomes. These results indicate that topoisomerase II plays a crucial role as a swivelase in the late stage of SV40 chromosome replication in vitro.
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PMID:Topoisomerase II plays an essential role as a swivelase in the late stage of SV40 chromosome replication in vitro. 130 47

Eukaryotic topoisomerase II is capable of binding two separate nucleic acid helices prior to its DNA cleavage and strand passage events (Zechiedrich, E. L., and Osheroff, N (1990) EMBO J. 9, 4555-4562). Presumably, one of these helices represents the helix that the enzyme cleaves (i.e. cleavage helix), and the other represents the helix that it passes (i.e. passage helix) through the break in the nucleic acid backbone. To determine whether the passage helix is required for reaction steps that precede the enzyme's DNA strand passage event, interactions between Drosophila melanogaster topoisomerase II and a short double-stranded oligonucleotide were assessed. These studies employed a 40-mer that contained a specific recognition/cleavage site for the enzyme. The sigmoidal DNA concentration dependence that was observed for cleavage of the 40-mer indicated that topoisomerase II had to interact with more than a single oligonucleotide in order for cleavage to take place. Despite this requirement, results of enzyme DNA binding experiments indicated no binding cooperativity for the 40-mer. These findings strongly suggest a two-site model for topoisomerase II action in which the passage and the cleavage helices bind to the enzyme independently, but the passage helix must be present for efficient topoisomerase II-mediated DNA cleavage to occur.
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PMID:A role for the passage helix in the DNA cleavage reaction of eukaryotic topoisomerase II. A two-site model for enzyme-mediated DNA cleavage. 130 70

We have investigated the amount of DNA topoisomerase II and phosphorylation of the enzyme in Swiss 3T3 cells during the transition from cell quiescence to proliferation. A relatively high level of phosphorylation was observed with proliferating cells while no or a very low level of phosphorylation was observed with quiescent cells. Phosphoamino acid analysis of the phosphorylated topoisomerase II revealed that the phosphorylated aminoacyl residue was serine. When quiescent cells were stimulated to grow by the addition of serum, DNA synthesis began to increase at 9 h after serum addition, reaching a maximum at 15 h and then declining. The amount of topoisomerase II began to increase at 6 h and reached a maximum at 22-27 h, corresponding to the G2 phase. The phosphorylation of topoisomerase II measured by pulse-labeling gradually increased from 6 to 18 h and reached a maximum at 22 h when the amount of the enzyme was maximum. The level of phosphorylation measured by continuous-labeling increased gradually up to 12 h and markedly up to 28 h, and then declined. The increase in the rate of phosphorylation in the G2 phase was affected by inhibiting DNA synthesis, but the increase in the amount of the enzyme was not. Thus, it was suggested that the regulation of phosphorylation of topoisomerase II differs from that of the amount of the enzyme.
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PMID:Growth state and cell cycle dependent phosphorylation of DNA topoisomerase II in Swiss 3T3 cells. 131 36

Although it has been shown previously that the depletion of cellular thiols increases doxorubicin cytotoxicity, the mechanism of sensitization is not clear. To study this question, the effect of D,L-buthionine-S,R-sulfoximine (BSO) on doxorubicin cytotoxicity and the stabilization of DNA-topoisomerase II complexes (cleavable complexes) was investigated in V79 cells. Incubations with BSO (10 mM) were for 5 hr beginning 4 hr prior to doxorubicin exposure since a 4 hr incubation with 10 mM BSO is known to decrease glutathione levels below 5% of control V79 cells. These BSO pre-treatment increased doxorubicin cytotoxicity. At doxorubicin concentrations of 5 micrograms/ml, BSO resulted in an 8-10 fold decrease in surviving cells, compared to cells exposed to doxorubicin alone. It was determined that BSO pre-treatments did not affect the accumulation of doxorubicin into the cell, the rate of cleavable complex stabilization by doxorubicin, or the rate of dissociation of stabilized cleavable complexes. These data suggest that BSO-induced doxorubicin sensitization occurs at a step following the stabilization of cleavable complexes or by an independent mechanism.
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PMID:Interaction of buthionine sulfoximine and the stabilization of DNA-topoisomerase II complexes by doxorubicin. 131 Apr 96

We demonstrated previously that human cytomegalovirus (CMV) infections could enhance the expression of cellular topoisomerase II and this enzyme activity is essential for CMV to replicate in vitro (Benson and Huang, 1988; Benson and Huang, 1990). In this study, we further show that in addition to m-AMSA and VM26 which we had previously reported, a widely used and clinically available drug, etoposide (VP-16 or VePesid) can irreversibly inhibit CMV replication at the drug concentration (2.5 micrograms/ml) greatly below toxic levels to stationary phase cells. Growing cells were more sensitive to etoposide than stationary phase cells and slight growth inhibition occurred at 2.5 micrograms/ml level. This inhibitor does not prevent the expression of CMV immediate-early and early genes, but can inhibit viral DNA and late viral-proteins synthesis. Because of their irreversible inhibitory effects and approval usage in clinical oncology, it is suggested that this group of compounds, particularly etoposide (VP-16), can be used to control life-threatening CMV infections, such as CMV pneumonitis and CMV retinitis, in cancer and immunocompromised patients or patients with AIDS.
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PMID:Irreversible inhibition of human cytomegalovirus replication by topoisomerase II inhibitor, etoposide: a new strategy for the treatment of human cytomegalovirus infection. 131 May 81

A carcinogen-transformed rat hepatoma cell line (Reuber H-35) was utilized as a model system for investigation of the biochemical factors which may limit the effectiveness of chemotherapy in intrinsically resistant tumors such as hepatocellular carcinoma. Northern blotting demonstrated expression of mRNA coding for the P-170 membrane-glycoprotein associated with the multi-drug resistance phenotype, while Western blotting identified the P-170 glycoprotein in the hepatoma cell membrane. Consistent with these observations, tumor cell sensitivity to the vinca alkaloids, vincristine and vinblastine, to the anthracycline antibiotics, Adriamycin and daunorubicin, and to the demethylepipodophyllotoxin derivative, VM-26, was enhanced by continuous incubation in the presence of the calcium channel antagonist, verapamil. Verapamil produced a minimal change in cell sensitivity to the demethylepipodophyllotoxin derivative, VP-16, and to the aminoacridine, m-AMSA. Relatively high detoxification potential via the glutathione metabolic pathway was also observed in the hepatoma cell. The capacity of topoisomerase II in nuclear extracts from the hepatoma cell to mediate cleavable complex formation stimulated by VM-26, VP-16 and m-AMSA appeared to be at least comparable to, if not greater than that from drug-sensitive HL-60 cells, suggesting that drug resistance may not occur at the level of this enzyme. Consistent with findings in a number of tumor cell lines resistant to antineoplastic drugs, the antiproliferative activity of the topoisomerase II inhibitors VM-26, VP-16 and m-AMSA appeared to be dissociable from the induction of DNA strand breaks, suggesting that such lesions in DNA may fail to fully account for the antiproliferative activity of these agents in the hepatoma cell.
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PMID:Components of intrinsic drug resistance in the rat hepatoma. 131 Aug 53


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