Currently, DNA topoisomerase I (Topo I) inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors. In recent years, during our ongoing research on natural antitumor products, a collection of low cytotoxic or non-cytotoxic compounds with various structures were identified from marine invertebrates, plants, and their symbiotic microorganisms. In the present study, new Topo I inhibitors were discovered from low cytotoxic and non-cytotoxic natural products by virtual screening with docking simulations in combination with bioassay test. In total, eight potent Topo I inhibitors were found from 138 low cytotoxic or non-cytotoxic compounds from coral-derived fungi and plants. All of these Topo I inhibitors demonstrated activities against Topo I-mediated relaxation of supercoiled DNA
TY - JOUR. T1 - Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor. AU - Pastorino, Fabio. AU - Loi, Monica. AU - Sapra, Puja. AU - Becherini, Pamela. AU - Cilli, Michele. AU - Emionite, Laura. AU - Ribatti, Domenico. AU - Greenberger, Lee M.. AU - Horak, Ivan D.. AU - Ponzoni, Mirco. PY - 2010/10/1. Y1 - 2010/10/1. N2 - Purpose: Treatment of neuroblastoma is successful in less than half of patients with high-risk disease. The antitumor activity of a water soluble pegylated SN38 drug conjugate, EZN-2208, was compared with CPT-11 (a prodrug for SN38) in preclinical models of human neuroblastoma. Experimental Design: The in vitro cytotoxicity of EZN-2208 was tested by counting trypan blue dye-and Annexin V-positive cells, whereas its therapeutic efficacy was evaluated, in terms of survival, and antitumor and antiangiogenic activities, in s.c. luciferase-transfected, pseudometastatic, and orthotopic neuroblastoma ...
TY - JOUR. T1 - Determination of the glucuronide metabolites of the topoisomerase I inhibitors, 7-ethyl-10-hydroxy-camptothecin (SN-38) and NU-ICRF 505 by high performance liquid chromatography. AU - Cummings, J.. AU - Ethell, B T.. AU - Boyd, Gary. AU - Burchell, B.. AU - Smyth, J F.. AU - Jodrell, D I.. PY - 2002. Y1 - 2002. N2 - HPLC methods are presented for the determination of the topoisomerase I inhibitors 7-ethyl 10-hydroxycamptothecin (SN-38) and NU/ICRF 505, their chemical/enzymatic hydrolysis products and glucuronide metabolites in both aqueous media and biological specimens. Chromatographic conditions were optimised for baseline resolution of the water-soluble metabolites from their non-water soluble parent compounds while eetaining compatibility with both atmospheric pressure electrospray ionisation and electron impact ionisation mass spectrometric detection. Solid phase extraction sample preparation utilising a C2-bonded silica sorbent enabled simultaneous recovery of parent ...
We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38-a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a cancer targeting unit (biotin). Upon light activation in cancer cells, PT-1 interferes with DNA re-ligation, diminishes the expression of topoisomerase I, and enhances the expression of inter alia mitochondrial apoptotic genes, death receptors, and caspase enzymes, inducing DNA damage and eventually leading to apoptosis. In vitro andin vivo studies showed significant inhibition of cancer growth and the hybrid system PT-1 thus shows promise as a programmed photo-therapeutic ("phototheranostic").. ...
Cells maintain genomic stability by the coordination of DNA-damage repair and cell-cycle checkpoint control. In replicating cells, DNA damage usually activates intra-S-phase checkpoint controls, which are characterized by delayed S-phase progression and increased Rad53 phosphorylation. We show that in budding yeast, the intra-S-phase checkpoint controls, although functional, are not activated by the topoisomerase I inhibitor camptothecin (CPT). In a CPT-hypersensitive mutant strain that lacks the histone 2A (H2A) phosphatidylinositol-3-OH kinase (PI(3) K) motif at Ser 129 (h2a-s129a), the hypersensitivity was found to result from a failure to process full-length chromosomal DNA molecules during ongoing replication. H2A Ser 129 is not epistatic to the RAD24 and RAD9 checkpoint genes, suggesting a non-checkpoint role for the H2A PI(3) K site. These results suggest that H2A Ser 129 is an essential component for the efficient repair of DNA double-stranded breaks (DSBs) during replication in yeast, ...
Angelman syndrome (AS) is a severe neurodevelopmental disorder lacking effective therapies. AS is caused by mutations in ubiquitin protein ligase E3A (UBE3A), which is genomically imprinted such that only the maternally inherited copy is expressed in neurons. We previously demonstrated that topoisomerase I (Top1) inhibitors could successfully reactivate the dormant paternal allele of Ube3a in neurons of a mouse model of AS. We also previously showed that one such Top1 inhibitor, topotecan, could unsilence paternal UBE3A in induced pluripotent stem cell-derived neurons from individuals with AS. Although topotecan has been well-studied and is FDA-approved for cancer therapy, its limited CNS bioavailability will likely restrict the therapeutic use of topotecan in AS. The goal of this study was to identify additional Top1 inhibitors with similar efficacy as topotecan, with the expectation that these could be tested in the future for safety and CNS bioavailability to assess their potential as AS therapeutics
LMP744 hydrochloride (MJ-III65 hydrochloride) is a DNA intercalator and Topoisomerase I (Top1) inhibitor with antitumor activity. - Mechanism of Action & Protocol.
What is the difference between Topoisomerase I and II? Topoisomerase I cuts one strand in double-stranded DNA while Topoisomerase, II cuts both strands in DNA
Research in our laboratory has focused on defining the mechanisms of drug resistance to inhibitors of mammalian DNA topoisomerase I, II alpha, and II beta. These enzymes are the targets of several commonly used anti-tumor agents, including etoposide, doxorubicin, mitoxantrone, topotecan and irinotecan. Recently, we have found that the trafficking of topoisomerase I and/or II to the cytoplasm is a mechanism of cellular drug resistance that can occur in the absence of drug exposure. Defining the nuclear export signal of topoisomerase II alpha is a current project in the laboratory. Our lab is also involved in several translational research studies, which aim to define the role of quantitative and qualitative alterations in topoisomerases in determining cellular sensitivity to topoisomerase inhibitors in vivo.. Thus, tumor biopsies from patients with multiple myeloma, AML, non-Hodgkins lymphoma, small cell lung cancer, rectal carcinoma, and malignant melanoma are currently being examined for this ...
TY - JOUR. T1 - Therapeutic targeting of CPT-11 induced diarrhea. T2 - a case for prophylaxis.. AU - Swami, Umang. AU - Goel, Sanjay. AU - Mani, Sridhar. PY - 2013/6. Y1 - 2013/6. N2 - CPT-11 (irinotecan), a DNA topoisomerase I inhibitor is one of the main treatments for colorectal cancer. The main dose limiting toxicities are neutropenia and late onset diarrhea. Though neutropenia is manageable, CPT-11 induced diarrhea is frequently severe, resulting in hospitalizations, dose reductions or omissions leading to ineffective treatment administration. Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT-11 induced late onset diarrhea. It is predicted that prophylaxis of CPT-11 induced diarrhea will reduce sub-therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates. This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity. ...
Tumor cells disseminate into compartments that are poorly accessible from circulation, which necessitates high doses of systemic chemotherapy. However, the effectiveness of many drugs, such as the potent topoisomerase I poison SN-38, is hampered by poor pharmacokinetics. To deliver SN-38 to lymphoma tumors in vivo, we took advantage of the fact that healthy lymphocytes can be programmed to phenocopy the biodistribution of the tumor cells. In a murine model of disseminated lymphoma, we expanded autologous polyclonal T cells ex vivo under conditions that retained homing receptors mirroring lymphoma cells, and functionalized these T cells to carry SN-38-loaded nanocapsules on their surfaces. Nanocapsule-functionalized T cells were resistant to SN-38 but mediated efficient killing of lymphoma cells in vitro. Upon adoptive transfer into tumor-bearing mice, these T cells served as active vectors to deliver the chemotherapeutic into tumor-bearing lymphoid organs. Cell-mediated delivery concentrated ...
Background nondestructive structural evaluation of the osteochondral unit is challenging. time and artifacts. An isovolumetric voxel shape allowed for multiplanar reconstructions. Within the osteochondral unit articular cartilage, cartilaginous restoration cells and bone marrow could clearly become distinguished from your subchondral bone plate and subarticular spongiosa. Specific alterations from the osteochondral device connected with cartilage fix such as consistent drill openings, subchondral bone tissue cysts, sclerosis from the subchondral bone tissue dish and of the subarticular spongiosa and intralesional osteophytes had been precisely discovered. Conclusions High res, nondestructive evaluation of the complete osteochondral device within a preclinical huge pet model thats sufficient for even more analyses can be done using MRI at 9.4?T. Specifically, 9.4?T is with the capacity of accurately depicting modifications from the subchondral bone tissue that are connected with osteochondral ...
The aim of this project is the development of Tyrosyl DNA phosphodiesterase (Tdp1) inhibitors in order to enhance the activity of DNA topoisomerase I inhibitors ...
Genz-644282, also known as SAR402674, is a non-camptothecin inhibitor of topoisomerase I with potential antineoplastic activity. Topoisomerase I inhibitor Genz-644282 binds to and inhibits the enzyme topoisomerase I, which may result in the inhibition of repair of single-strand DNA breaks, DNA replication, and tumor cell growth in susceptible tumor cell populations
Endonucleolytic processing of covalent protein-linked DNA double-strand breaks.: DNA double-strand breaks (DSBs) with protein covalently attached to 5 strand t
Clincally available camptothecin derivatives, though highly effective against a broad range tumors, are limited by their chemical instability, solubility, ABCG2-mediated efflux and reversibility of Top1-DNA complexes. Indenoisoquinolines were identified as topoisomerase I (Top1) inhibitors by the COMPARE analysis of the NCI drug screen database. Although structurally similar to camptothecin, idenoisoquinolines are chemically stable, able to overcome ABCG2 efflux while forming more persistent Top1-DNA complexes and maintaining potent antitumor activity. The potential for indenoisoquinoline derivatives as possible clinical agents is further aided by the synergistic effect observed between camptothecin and Chk1/2 inhibitors. Chk1/2 kinases regulate cell cycle, DNA damage response via ATM, ATR and DNA-PK, which are activated by genomic instability. Previous studies have shown Chk1/2 inhibitors, such as UCN-01, can potentiate camptothecin-mediated cytotoxicity in p53 mutant cells by eliminating the ...
This study examines the binding properties of a series of newly synthetized tacrine derivatives 1-4 and their anticancer effects. Spectroscopic techniques (UV-Vis, fluorescence spectroscopy, thermal denaturation, and linear spectropolarimetry) and viscometry were used to study DNA binding properties and to determine the types of DNA interaction with the studied derivatives. The binding constants for the complexes with DNA were obtained using UV-Vis spectroscopic titrations (K = 1.6 x 10(4)-4.0 x 10(5) M-1) and electrophoretic methods were used to determine the effect of the derivatives on topoisomerase I and II activity. Monotacrine derivative 1 showed evidence of topoisomerase I relaxation activity at a concentration of 30 x 10(-6) M, while bistacrine derivatives 2-4 produced a complete inhibition of topoisomerase I at a concentration of 5 x 10(-6) M. The biological activities of the derivatives were studied using MTT-assay and flow cytometric methods (detection of mitochondrial membrane ...
... , Authors: Jafar Sharif, Asami Tsuboi, Haruhiko Koseki. Published in: Atlas Genet Cytogenet Oncol Haematol.
Anticancer Drug Action Lab of Scott H. Kaufmann, M.D., Ph.D., at Mayo Clinic: Cellular Responses to DNA Damage Induced by Topoisomerase Poisons.
OConnell BC, Adamson B, Lydeard JR, Sowa ME, Ciccia A, Bredemeyer AL, et al. A genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability. Mol Cell. 2010 ;40(4):645-57. ...
Title: Transport Mechanism-Based Drug Molecular Design: Novel Camptothecin Analogues to Circumvent ABCG2-associated Drug Resistance of Human Tumor Cells. VOLUME: 12 ISSUE: 3. Author(s):Toshihisa Ishikawa, Yoji Ikegami, Kazumi Sano, Hiroshi Nakagawa and Seigo Sawada. Affiliation:Professor, Department ofBiomolecular Engineering, Graduate School of Bioscience and Biotechnology,Tokyo Institute of Technology, 4259-B-60 Nagatsuta, Midori-ku,Yokohama, 226-8501, Japan;. Keywords:ABCG2 gene, Camptothecin, antitumor, membrance vesicle, intracellular accumulation, drug development. Abstract: Acquired and intrinsic drug resistance in cancer is the major obstacle to long-term, sustained patient response to chemotherapy. Irinotecan (CPT-11) is a widely-used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I). However, overexpression of ABCG2 (BCRP/MXR/ABCP) reportedly confers cancer cells resistance to SN-38, the active form of CPT-11. To circumvent the ABCG2-associated drug resistance, ...
Manipulations of the DNA double helix during replication, transcription and other nucleic acid processing cause a change of DNA topology, which results in torsional stress. This stress is relaxed by DNA topoisomerases, a class of enzymes present in all domains of life. Negatively supercoiled DNA is relaxed by type IA topoisomerases that are widespread in bacteria, archaea and eukaryotes. In Escherichia coli there is conflicting data about viability of ΔtopA cells lacking topoisomerase I. In this study we sought to clarify whether E. coli cells lacking topoisomerase I are viable by using a plasmid-based lethality assay that allowed us to investigate the phenotype of ΔtopA cells without the presence of any compensatory mutations. Our results show that cells lacking topoisomerase I show an extreme growth defect and cannot be cultured without the accumulation of compensatory mutations. This growth defect can be partially suppressed by overexpression of topoisomerase III, the other type IA topoisomerase in
PLANT EXTRACTS AND TRADITIONAL MEDICINES HAVE LONG BEEN THOUGHT TO CONTAIN BIOACTIVE MOLECULES CAPABLE OF ELICITING A THERAPEUTIC RESPONSE. HOWEVER, THE POTENTIAL UTILITY OR MODE OF ACTION OF THESE NATURAL PRODUCTS HAS NOT BEEN EFFECTIVELY STUDIED IN WESTERN SCIENTIFIC RESEARCH. RECENT ADVANCES IN THE MOLECULAR UNDERSTANDING OF DRUG ACTION WILL BE EMPLOYED IN PHASE I IN AN EFFORT TO IDENTIFY AND FURTHER EVALUATE THE BIOACTIVITY OF NATURAL PRODUCTS. PLANT EXTRACTS AND TRADITIONAL MEDICINES WILL BE ANALYZED IN A HIGH-THROUGHPUT BIOCHEMICAL ASSAY FOR THEIR ABILITY TO INHIBIT TOPOISOMERASE ACTIVITY IN TRANSFORMED CELL LINES. BECAUSE TOPOISOMERASES HAVE BEEN IDENTIFIED AS THE PRIMARY TARGET OF SOME OF THE MOST POPULAR ANTINEOPLASTIC DRUGS CURRENTLY IN USE, THIS ASSAY WOULD IDENTIFY NATURAL PRODUCTSTHAT WOULD ULTIMATELY BE DEVELOPED INTO NOVEL ANTICANCER AGENTS. THE ABILITY OF LEAD COMPOUNDS TO INHIBIT TOPOISOMERASE ACTIVITY IN VITRO USING PURIFIED TOPOISOMERASE I AND II, AS WELL AS THEIR ABILITY TO ...
To further explore whether BRCA1 enrichment and its associated exclusion of 53BP1 from the IRIF core correlates with inhibition of 53BP1-dependent repair at DSB sites during S phase, we analysed cells recovering from acute treatment with camptothecin (CPT), a topoisomerase I inhibitor that induces DSBs in S phase when replication forks encounter trapped Top1-DNA cleavage complexes (Pommier et al., 2003). In BRCA1-deficient cells, CPT-induced chromosomal aberrations are 53BP1 dependent; indicating BRCA1 normally counteracts 53BP1-mediated repair activities in this context (Bunting et al., 2010). Consistent with this notion, CPT-induced foci closely resembled S-phase IRIF by 3D-SIM, with BRCA1 and 53BP1 adopting equivalent focal positions (Fig. 4C). The repair of DSBs by HR in S phase also relies on CtIP-mediated DNA-end resection (Sartori et al., 2007). Consistent with a model in which the focus core corresponds to sites of HR in S-phase cells, 3D-SIM analysis of CtIP localisation in irradiated ...
Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients Huali Wu,1 Ramesh K Ramanathan,2 Beth A Zamboni,3 Sandra Strychor,4 Suresh Ramalingam,5 Robert P Edwards,4 David M Friedland,4 Ronald G Stoller,4 Chandra P Belani,4 Lauren J Maruca,4 Yung-Jue Bang,6 William C Zamboni11UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA; 2Translational Research Division, The Translational Genomics Research Institute, Scottsdale, AZ, USA; 3Department of Mathematics, Carlow University, Pittsburgh, PA, USA; 4School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 5Winship Cancer Institute, Emory University, Atlanta, GA, USA; 6College of Medicine, Seoul National University, Seoul, KoreaAbstract: S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD)
There are no specific protocols for Recombinant human Topoisomerase I protein (ab3808). Please download our general protocols booklet
Buy our Recombinant Human Topoisomerase I (mutated Y723) protein. Ab82093 is a full length protein produced in Baculovirus and has been validated in SDS-PAGE…
Camptothecin analogues showing more potent anti-tumor activity than a naturally occurring alkaloid camptothecin, which also exhibit an immunosuppressive activity, in which the 1-ethyl of camptothecin is replaced by various members of substitutents such as alkyls (except ethyl), alkenyls, alkynyls, aralkyls or aryloylalkyls; being produced from readily accessible starting materials on totally synthetic method newly developed by the present inventor.
DNA topoisomerase I (EC 5.99.1.2) [1,2,3,4] is one of the two types of enzyme that catalyze the interconversion of topological DNA isomers. Type I topoisomerases act by catalyzing the transient breakage of DNA, one strand at a time, and the subsequent rejoining of the strands. When a prokaryotic type I topoisomerase breaks a DNA backbone bond, it simultaneously forms a protein-DNA link where the hydroxyl group of a tyrosine residue is joined to a 5-phosphate on DNA, at one end of the enzyme-severed DNA strand. Prokaryotic organisms, such as Escherichia coli, have two type I topoisomerase isozymes: topoisomerase I (gene topA) and topoisomerase III (gene topB). Eukaroytes also contain homologs of prokaryotic topoisomerase III. There are a number of conserved residues in the region around the active site tyrosine; we used this region as a signature pattern. Last update: December 2004 / Pattern and text revised. ...
Effect of BSO on the Toxicity of the Camptothecins. To assess the contribution of GSH in the sensitivity to the camptothecins, cells were pretreated with BSO before the cytotoxicity assays. BSO is an inhibitor of γ-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis (23). Treatment of MCF-7 and MDA-MB-231 cells for 24 h with 50 μm BSO led to a reduction in GSH levels of at least 75% in the cell lines tested (Table 1) without affecting cell growth. Pretreatment with BSO also resulted in lower IC50 values for each of the analogues tested in all of the cell lines (Table 1). GSH depletion had the greatest effect on CMMDC, the alkylating camptothecin analogue.. Effect of BSO on the Formation of topo I-DNA Complexes. To determine whether GSH depletion directly affected the stabilization of the camptothecin-topo I cleavage complex, the levels of camptothecin-induced DPCs were measured in control cells and in cells pretreated with BSO. These DPCs correspond to topo I cleavage ...
This project is supported by the Canadian Institutes of Health Research (award #111062), Alberta Innovates - Health Solutions, and by The Metabolomics Innovation Centre (TMIC), a nationally-funded research and core facility that supports a wide range of cutting-edge metabolomic studies. TMIC is funded by Genome Alberta, Genome British Columbia, and Genome Canada, a not-for-profit organization that is leading Canadas national genomics strategy with funding from the federal government. Maintenance, support, and commercial licensing is provided by OMx Personal Health Analytics, Inc. Designed by Educe Design & Innovation Inc. ...
Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis ...
Similar reductions of bss recovery time are observed by feeding two other phytochemicals that are potent top1 inhibitors, apigenin and kaempferol (26). Electrophysiological recordings corroborate these behavioral results. CPT treatment causes a modest increase in seizure threshold. Synaptic failure time is greatly decreased (25, 26). Taken together, the findings using top1 inhibitors show general consistency among the findings (25, 26). All three inhibitors, CPT, apigenin, and kaempferol, have similar results. Essential functions of DNA topoisomerase I in Drosophila melanogaster. Dev Biol 2000;222:27-40. Champoux JJ. DNA topoisomerases: Structure, function and mechanism. Annu Rev Biochem 2001;70:369-413. Boege F, Straub T, Kehr A, Boesenberg C, Christiansen K, Anderson A, Jacob F, Kohrle J. Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I. J Biol Chem 1996;271: 2262-2270. Pommier Y, Pourquier P, Fan Y, Strumberg D. Mechanism of action of ...
The lack of effective treatment modalities is a major problem in pancreatic cancer (PCa), a devastating malignancy that is nearly universally driven by the "undruggable" KRAS and TP53 cancer genes. Poor tumor tissue penetration is the major source of resistance in pancreatic cancer where chemotherapy is the mainstay of treatment. In this study we exploited the selective tumor-targeting properties of the heat shock 90 protein inhibitors as the vehicle for drug delivery to pancreatic tumor tissues. STA-12-8666 is a novel esterase-cleavable conjugate of an HSP90i and a topoisomerase I inhibitor, SN-38. STA-12-8666 selectively binds activated HSP90 and releases its cytotoxic payload resulting in drug accumulation in pancreatic cancer cells in vivo. We investigated the preclinical activity of STA-12-8666 in patient derived xenograft and genetic models of pancreatic cancer.Treatment with STA-12-8666 of the KPC mice (knock-in alleles of LSL-KrasG12D, Tp53fl/fl and Pdx1-Cre transgene) at the advanced ...
Your Search Returned No Results.. Sorry. There is currently no product that acts on isoform Topoisomerase together.. Please try each isoform separately.. ...
Topoisomerase I (Top1) is an established molecular target for anti‐cancer therapeutics. Top1 inhibitors function by trapping the catalytic intermediate of Top1 covalently attached to the DNA substrate, termed the Top1 covalent complex (Top1cc). We have developed and validated an immunoassay to measure Top1cc directly, in support of Phase 0 clinical trials for experimental Top1 inhibiting drugs. A simple Top1cc isolation step which separates Top1cc from free Top1 is followed by a quantitative infrared immunoblotting detection technique. Recombinant Top1 is used as the standard for quantification. The assay was used to measure Top1cc in cell lines that exhibit varied growth inhibitory responsiveness to topotecan (A375, HCT‐116, HT‐29 and SKMEL28). Cells were treated with single doses of Top1 inhibitors, topotecan and indenoisoquinoline and Top1cc levels were found to be dose dependent with a maximal response at/or before 30 min to 1h of exposure. To establish fitness‐for‐purpose for ...
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Each of these structures contained unresolvable portions of the protein in the connector region (Pro635-Phe640). Moreover, the reconstituted enzyme has altered kinetics and is not sensitive to camptothecin in a plasmid relaxation assay (35). Hence, the structures reported here are the first structures of a fully active human TOP-I in covalent complex with DNA in the absence and presence of bound drug. (C) Comparison of the 22mer duplex oligonucleotides of the drug-bound (blue) and nondrug-bound (yellow). Arg364 makes a hydrogen bond contact with N3 of adenosine at position -1 of the uncleaved strand (-1A). Lys532 makes a hydrogen bond with the oxygen of thymidine at position -1 (-1T). Lys374 and the main chain nitrogens of 362 and 363 make hydrogen bond contacts Chapter 2 / Topoisomerase-DNA-Drug X-Ray Structure 27 with the nonbridging phosphodiester of the uncleaved strand (0P). Consistent with the observed drug-binding mode, mutations at position Arg364 (14) would be expected to destabilize ...
Even though current therapy is capable of inducing remissions in 60-80% of adults with acute leukemia (1,2), the vast majority of patients are not cured (3, 4, 5). This is particularly true for the...
The D2 sequence of the helix differs only at the thermophile valin was replaced for isoleucine in the mesophile. Both models of the mesophilic Doxorubicin Topoisomerase inhibitor and thermophilic D helices of the D1 and D2 proteins were placed in the..
WebMD provides common contraindications for Topotecan Oral. Find out what health conditions may be a health risk when taken with Topotecan Oral
Professional guide for Topotecan. Includes: pharmacology, pharmacokinetics, contraindications, interactions, adverse reactions and more.
Topotecan HClは一種のトポイソメラーゼI阻害剤ですが、無細胞試験でMCF-7 Luc細胞とDU-145 Luc細胞に作用する時のIC50値が13nMと2nMにそれぞれ分かれます。
TY - JOUR. T1 - Structural basis for suppression of hypernegative DNA supercoiling by E. coli topoisomerase I. AU - Tan, Kemin. AU - Zhou, Qingxuan. AU - Cheng, Bokun. AU - Zhang, Zhongtao. AU - Joachimiak, Andrzej. AU - Tse-Dinh, Yuk Ching. PY - 2015/12. Y1 - 2015/12. N2 - Escherichia coli topoisomerase I has an essential function in preventing hypernegative supercoiling of DNA. A full length structure of E. coli topoisomerase I reported here shows how the C-terminal domains bind single-stranded DNA (ssDNA) to recognize the accumulation of negative supercoils in duplex DNA. These C-terminal domains of E. coli topoisomerase I are known to interact with RNA polymerase, and two flexible linkers within the C-terminal domains may assist in the movement of the ssDNA for the rapid removal of transcription driven negative supercoils. The structure has also unveiled for the first time how the 4-Cys zinc ribbon domain and zinc ribbon-like domain bind ssDNA with primarily-stacking interactions. This novel ...
A16 Benzimidazoles are important compounds because of their antibacterial, antifungal, antimicrobial, antiprotozoal and antihelmintic activities. Some benzimidazole derivatives also interfere with the reactions of DNA topoisomerases, the enzymes functioning at almost all stages of the cell cycle. In this study, nine 1H-benzimidazole derivatives with substituents at positions 2- and 5- were synthesized and the structure of the compounds were elucidated by instrumental methods. The characterized compounds were screened to identify if they interfere with mammalian type I DNA topoisomerase activity via in vitro supercoil relaxation assays. Selected compounds were subjected to cytostatic assays using HeLa (cervix adenocarcinoma), MCF7 (breast adenocarcinoma) and A431 (skin epidermoid carcinoma) cells. Our results showed that 5-chloro-2-(2-hydroxyphenyl)-1H-benzimidazole exerted the most profound topoisomerase I inhibition and cytotoxicity. ...
This study showed that in adult [9C11] and [12C17], continues to be instructive in identifying the sensory particularly, motor, and integrative the different parts of the neural control systems for feeding. can be found for the feasible modulation from the crop muscle tissue activity even though the crop is the major storage site for carbohydrates consumed by adult flies [36]. is usually a well-known model organism, increasingly used in translational neuroscience and behavioral research [37,38]. Given the current interest around the gut-brain axis as a primary subject in the start of neurodegenerative disorders, such as Parkinsons disease [39,40], it was evident that we needed to determine the possible modulatory effect of serotonin on crop contraction rate because in mammals it is known to modulate hypothalamic receptors, which control the size of carbohydrate-rich meals [41] and other aspects of ingestive behavior [42]. Thus, possesses a complex serotonergic system featuring all major genes ...
Zechiedrich and Osheroff (1990) were the first to visualize the preferential binding of eukaryotic type I topoisomerase at intramolecular crossovers. The present study of vaccinia virus topoisomerase confirms their findings regarding the formation of DNA loops by type IB enzymes. We suggest that the loops arise through protein-protein‐mediated DNA synapsis rather than through bivalent DNA binding of a single topoisomerase monomer.. Zechiedrich and Osheroff focused on DNA molecules containing what appeared to be a single protein complex at DNA nodes. These structures were prevalent at a 3:1 molar ratio of calf thymus topoisomerase I to plasmid DNA. As pointed out by Wang (1996), an inherent problem in microscopic analysis is that one cannot gauge the number of topoisomerase monomers within the seemingly discrete protein blobs. Therefore, it is unclear if the protein‐bound nodes are formed because one topoisomerase monomer simultaneously engages two DNA duplexes or because two (or more) ...
As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of …
Sikder, Devanjan and Unniraman, Shyam and Bhaduri, Tisha and Nagaraja, Valakunja (2001) Functional Cooperation Between Topoisomerase I and Single Strand DNA-binding Protein. In: Journal of Molecular Biology, 306 . pp. 669-679. Bhaduri, Tisha and Basak, Shashwati and Sikder, Devanjan and Nagaraja, Valakunja (2000) Inhibition of Mycobacterium smegmatis topoisomerase I by specific oligonucleotides. In: FEBS Letters, 486 (2). pp. 126-130. Bhaduri, Tisha and Baguis, Tapan Kumar and Sikder, Devanjan and Nagaraja, Valakunja (1998) DNA Topoisomerase I from Mycobacterium smegmatis - An Enzyme with Distinct Features. In: The Journal of Biological Chemistry, 273 (22). pp. 13925-13935. Bhaduri, Tisha and Nagaraja, V (1994) DNA topoisomerase I from Mycobacterium smegmatis. In: Indian Journal of Biochemistry & Biophysics, 31 . pp. 339-343. ...
T antigen is the only viral protein involved in SV40 DNA replication. It has two critical functions: one is to recognize the viral origin specifically, and the second is to separate the DNA strands at the origin and at replication forks. The first function takes place through its DNA-binding domain (2, 35, 49). Upon binding of ATP (5, 8, 17), T antigen assembles on the origin to form a double-hexamer structure (11, 27, 30, 36). This double-hexamer structure is the helicase that unwinds DNA (53, 54,61). Eventually, topo I is needed to release the torsion created by the progressing replication fork. At the same time, topoisomerase activity must be controlled according to the pace of the helicase to prevent too much or too little nicking, which might interfere with efficient replication. Although how helicase and topoisomerase activities are coordinated during DNA replication is still unclear, recent evidence (25, 26, 50, 51, 57) points to the likelihood that T antigen and topo I function together ...