• The SN-38 metabolite is approximately 1 000 times more potent than irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. (rxmed.com)
  • Genz-644282 is a non-camptothecin inhibitor of topoisomerase I with potential antineoplastic activity. (adooq.com)
  • However, WS cells have been reported to show abnormal sensitivity to the drug camptothecin (an inhibitor of topoisomerase type I). A rapid assay for this sensitivity would be a useful marker of loss of wrn function. (brighton.ac.uk)
  • Camptothecin (CPT), a plant alkaloid with antitumor activity, is a specific inhibitor of eukaryotic DNA topoisomerase I. We have previously isolated and characterized a CPT-resistant topoisomerase I isolated from a CPT-resistant human leukemia cell line, CPT-K5. (duke.edu)
  • Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. (usuhs.edu)
  • Semisynthetic derivative of camptothecin, an alkaloid extract from the Camptotheca acuminate tree. (medscape.com)
  • Irinotecan HCl is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata. (rxmed.com)
  • Camptothecin is an alkaloid compound used as an anti-cancer agent. (goldbio.com)
  • In addition to its role in these fundamental processes, the biological importance of eukaryotic DNA topoisomerase I is underscored by its identification as the target of the antitumor alkaloid camptothecin. (northwestern.edu)
  • TOP1 is the molecular target of camptothecin and related drugs such as irinotecan and SN38 (irinotecan's active metabolite). (hal.science)
  • Several derivatives of camptothecin, such as irinotecan and topotecan, have been developed and approved for the treatment of various cancers, including colorectal, lung, and ovarian cancers. (selfgrowth.com)
  • Irinotecan HCl trihydrate is an antineoplastic agent of the topoisomerase I inhibitor class. (rxmed.com)
  • Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks. (rxmed.com)
  • The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. (usuhs.edu)
  • The activity of the fluoroindenoisoquinolines was mostly correlated with camptothecin derivatives and the parent indenoisoquinolines, consistent with TOP1 targeting. (usuhs.edu)
  • ABSTRACT: BACKGROUND: Topoisomerase I (TOP1) is a nuclear enzyme that catalyzes the relaxation of supercoiled DNA during DNA replication and transcription. (hal.science)
  • Topoisomerase I (TOP1) relaxes superhelical DNA through a breakage/rejoining reaction in which the active site tyrosine links covalently to a 3' phosphate at the break site as a transient intermediate. (tmu.edu.tw)
  • Camptothecin (CPT) induces down-regulation of topoisomerase I (TOP1) via an ubiquitin/26S proteasome pathway. (tmu.edu.tw)
  • CPT blocks a DNA enzyme called topoisomerase 1 (Top1). (nih.gov)
  • Camptothecin analogs as potent inhibitors of topoisomerase I . (U.S. Patent No. 5106742 ). (rti.org)
  • A method for synthesizing camptothecin and camptothecin analogs using a novel hydroxyl-containing tricyclic intermediate and the camptothecin analogs produced by the process. (rti.org)
  • The camptothecin analogs are effective inhibitors of topoisomerase I and show anti-leukemic and anti-tumor activity. (rti.org)
  • The antitumor drug camptothecin (CPT) and its analogs inhibit the rejoining step of the breakage/rejoining reaction, which traps the enzyme in covalent linkage with DNA (the cleavable complex). (tmu.edu.tw)
  • Its planar structure is thought to be one of the most important factors in topoisomerase inhibition. (wikipedia.org)
  • Thus, when topoisomerase I inhibition occurs with agents such as SN-38 in cell lines, the cells compensate by increasing expression of topoisomerase II and vice versa. (cancernetwork.com)
  • 3] This antagonism might be related to topoisomerase I inhibition of DNA synthesis, which is required for the cytotoxic effect of topoisomerase II-induced cleavable complexes. (cancernetwork.com)
  • Tests of the growth inhibition potential of MEC in seven human tumor cell lines showed that the compound was approximately 2-18-fold more cytotoxic than lurtotecan, topotecan, and 7-ethyl-10-hydroxy-20(S)-camptothecin (SN-38). (eur.nl)
  • Camptothecin has been found to inhibit an enzyme called topoisomerase I, which plays a critical role in DNA replication and repair. (selfgrowth.com)
  • Camptothecin (Camptotheca acuminata), (GoldBio Catalog # C-705) has also been produced by endosymbiotic fungi present in Camptotheca acuminata, which is a tree predominantly found in southern China. (goldbio.com)
  • The open ring form is inactive and it must therefore be closed to inhibit topoisomerase I. The closed form is favored in acidic condition, as it is in many cancer cells microenvironment. (wikipedia.org)
  • Topoisomerase inhibitors inhibit cell growth and proliferation. (medscape.com)
  • However, it has low solubility and adverse effects have been reported when used therapeutically, so synthetic and medicinal chemists have developed numerous syntheses of camptothecin and various derivatives to increase the benefits of the chemical, with good results. (wikipedia.org)
  • Camptothecin (CPT) analogues and derivatives serve as a novel class of effective anticancer agents that exert their action against DNA topoisomerase I. This paper presents procedures for the rapid, high frequency regeneration of a camptothecin producing plant, Ophiorrhiza prostrata D. Don from leaf and internode explants via shoot organogenesis. (ejbiotechnology.info)
  • The D-ring interacts with the +1 cytosine on non-cleaved strand and stabilizes the topoisomerase I-DNA covalent complex by forming hydrogen bond. (wikipedia.org)
  • SN-38 binds to and stabilizes the topoisomerase I-DNA complex and prevents the relegation of DNA after it has been cleaved by topoisomerase I, inhibiting DNA replication. (medscape.com)
  • The bipartite DNA-binding regions of the 26 kDa fragment may enable eukaryotic DNA topoisomerase I to adapt to sequence-dependent structural variations in its DNA substrates. (northwestern.edu)
  • Topoisomerases are nuclear enzymes that modify the topological state of DNA and participate in fundamental metabolic processes such as replication, transcription, repair, recombination, and chromosome segregation (1) . (aacrjournals.org)
  • Background: Type I DNA topoisomerases, divided mechanistically into two subfamilies, are ubiquitous enzymes that participate in replication and transcription. (northwestern.edu)
  • DNA topoisomerases regulate the topological state of DNA, relaxing DNA supercoils and resolving catenanes and knots that result from biologic processes, such as transcription and replication. (bvsalud.org)
  • Human topoisomerase 1B regulates the topological state of supercoiled DNA enabling all fundamental cell processes. (mdpi.com)
  • They are potent inhibitors on topoisomerase I and both have alkylsilyl groups in position 7 which make them lipophilic and more stable. (wikipedia.org)
  • Interestingly, our observations provide the rationale for the better responsiveness of MSI+ tumors to CPT-11, a camptothecin derivative, which we have observed in patients with metastatic colorectal cancers. (aacrjournals.org)
  • To date, studies of this important problem have been focused on topoisomerases, which are a specialized class of enzymes that can resolve superhelical tension. (mpg.de)
  • DNA topoisomerase II (TOP2) enzymes achieve this by binding DNA and introducing an enzyme-bridged DNA double-strand break (DSB) where each protomer of the dimeric enzyme is covalently attached to the 5' end of the cleaved DNA via an active site tyrosine phosphodiester linkage. (bvsalud.org)
  • In this study we focused our attention on the behavior of four nuclear matrix proteins during the various stages of apoptosis in the HL-60 cell line exposed to the DNA topoisomerase I inhibitor, camptothecin. (nih.gov)
  • While the antibody to the nucleolar isoform of DNA topoisomerase II gave a fluorescent pattern that was well-maintained until the late phases of apoptosis, the other three nuclear antigens showed marked modifications in their distribution. (nih.gov)
  • Camptothecin, an inhibitor of nuclear topoisomerase, induces apoptosis in many types of cells. (enzolifesciences.com)
  • These groups are able to react with the DNA in the presence of topoisomerase I which leads to more tumor activity. (wikipedia.org)
  • Zymeworks camptothecin payload is specifically designed for antibody-drug conjugate (ADC) use, and is paired with established linker and conjugation technologies that provide a good balance of stability, safety, and anti-tumor activity. (zymeworks.com)
  • It was identified that the nuclear division cycle 80, cyclin B2 and topoisomerase 2‑α may serve important roles in adrenocortical tumor development. (cancerindex.org)
  • Nuclear magnetic resonance data indicate that cleavage of the piperazino moiety occurred at the N-C bond of the B-ring, yielding 7-methyl-10,11-ethylenedioxy-20(S)-camptothecin (MEC). (eur.nl)
  • CPT binds to the topoisomerase I and DNA complex (the covalent complex) resulting in a ternary complex, and thereby stabilizing it. (wikipedia.org)
  • This enzyme, which is the unique molecular target of the natural anticancer compound camptothecin, acts by nicking one DNA strand and forming a transient protein-DNA covalent complex. (mdpi.com)
  • With the addition of granulocytecolony-stimulating factor (G-CSF [Neupogen]) to the regimen,patients received epirubicin at clinically relevant doses after dose-escalation.Results of the topoisomerase activity will be reported with thefinal results of this phase I study. (cancernetwork.com)
  • These findings have major implications for development of anti-WRN agents that may be useful in sensitising tumour cells to clinically relevant topoisomerase inhibitors. (brighton.ac.uk)
  • Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. (rxmed.com)
  • In cell lines, the cytotoxic effect of topoisomerase I and II is scheduledependent. (cancernetwork.com)
  • The best anticancer extracts were bark extracts of Funtumia elastic, Kibatalia arborea, and Michelia champaca that showed bioactivity on Saccharomyces cereviceae strain 1140 (Topoisomerase I inhibitor) with IC12 values at 1590.78, 1657.67, 3424.54 µg/mL, respectively and bioactivity on Saccharomyces cereviceae strain 1353 (Topoisomerase II inhibitor) with IC12 values at 353.42, 931.39, 2124.42 µg/mL, respectively. (stuartxchange.org)
  • Results The three-dimensional structure of a 26 kDa fragment (residues 135 to about 363) of Saccharomyces cerevisiae DNA topoisomerase I has been determined at 1.9 å resolution. (northwestern.edu)
  • The resistance index (greater than 125) of the CPT-K5 fusion topoisomerase I is similar to that of the native CPT-K5 topoisomerase I. These results indicate that either or both of the two amino acid changes identified in the mutant enzyme is responsible for the resistance to CPT. (duke.edu)
  • New Topoisomerase I mutations are associated with resistance to camptothecin. (hal.science)
  • Sensitivity to these drugs cannot be predicted by measuring endogenous levels of topoisomerase I and II. (aacrjournals.org)
  • Our results also indicate that neither p53 status, nor cell cycle alterations correlate with the sensitivity of colorectal cancer cells to topoisomerase inhibitors. (aacrjournals.org)
  • At the cellular level, WRN loss results in rapid replicative senescence, chromosomal instability and sensitivity to various DNA damaging agents including the topoisomerase inhibitor, camptothecin (CPT). (brighton.ac.uk)
  • Genotoxicity of Inhibitors of DNA Topoisomerases I (Camptothecin) and II (m-AMSA) In vivo and In vitro. (epa.gov)
  • Camptothecin has been shown to bind and stabilize a topoisomerase I-DNA complex in vitro , preventing the enzyme from reannealing DNA strands. (goldbio.com)
  • Such WS-like phenotypes are observed despite very limited decreases in total WRN protein, suggesting that levels of WRN protein are rate-limiting for the cellular response to camptothecin. (brighton.ac.uk)
  • It acts throughout the entire cell cycle and by direct intercalating into DNA triggers DNA breakage by topoisomerase II, causing subsequent cytocydal activity. (medscape.com)
  • Results of the topoisomerase activity will be reported with the final results of this phase I study. (cancernetwork.com)
  • The interaction of human topoisomerase 1B and dimethylmyricacene, a compound prepared semisynthetically from myricanol extracted from Myrica cerifera root bark, was investigated using enzymatic activity assays and molecular docking procedures. (mdpi.com)
  • We are excited to present at this year's 5th Meridian Clinical Trials conference and share perspectives on developing new therapies in various disease areas to improve the lives of patients and to demonstrate AR-67's therapeutic potential in reGBM, as well as in other difficult-to-treat cancers for which Camptothecins are administered in combination therapies," said Tina Runk, EVP of Clinical Operations, Co-Founder, and Director of Vivacitas. (globenewswire.com)
  • Six of 23 species of Apocynaceae, Simaroubaceae and Magnoliaceae showed potential as anticancer agents, as DNA damag ing agent or Topoisomerase inhibitor. (stuartxchange.org)
  • Using this assay, we have found that a significantly increased level of strand breaks can be demonstrated in WS cells treated with camptothecin compared with normal controls. (brighton.ac.uk)
  • Studies of these factors have proven tremendously fruitful yielding several classes of potent antibiotics and anticancer drugs (e.g. ciprofloxacin and camptothecin). (mpg.de)
  • Indeed, this property of topoisomerase has been exploited in cancer therapy in the form of topoisomerase poisons which block the religation stage of the reaction cycle, leading to an accumulation of topoisomerase-DNA adducts. (bvsalud.org)
  • By looking at the expression of genes known to be turned on during viral infection, they observed that one chemical, camptothecin (CPT), reduced virus-induced gene activation. (nih.gov)
  • This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. (cancerindex.org)
  • cDNA clones of topoisomerase I were isolated from the CPT-resistant and the parental CPT-sensitive cell lines, respectively. (duke.edu)