AnatomyOrganismsDiseasesChemicals and DrugsAnalytical, Diagnostic and Therapeutic Techniques and EquipmentPhenomena and ProcessesInformation Science
Topoisomerase I InhibitorsCamptothecinDNA Topoisomerases, Type ITopotecanTopoisomerase II InhibitorsDNA Topoisomerases, Type IIAntineoplastic Agents, PhytogenicTopoisomerase InhibitorsTeniposideIndenesEnzyme InhibitorsAntineoplastic AgentsDrug Screening Assays, AntitumorDNA CleavageDNA, SuperhelicalDNA DamageIntercalating AgentsEtoposideTumor Cells, CulturedAmsacrineDNAIsoquinolinesDNA Topoisomerase IVCell Line, TumorCarbazolesBenzodioxolesApoptosisDrug Administration ScheduleDrug Resistance, NeoplasmDose-Response Relationship, DrugNaphthyridinesCell SurvivalHT29 CellsDrug SynergismNeoplasmsPoly(ADP-ribose) PolymerasesCell CycleDNA ReplicationColonic NeoplasmsCarboxylesteraseInfusions, IntravenousInhibitory Concentration 50RotenoneMice, NudeDNA FragmentationDNA RepairDNA, NeoplasmDNA TopoisomerasesStructure-Activity RelationshipNovobiocinEllipticinesBase SequenceMolecular Sequence DataMolecular StructureXenograft Model Antitumor AssaysCarcinoma, Small CellCell LineTumor Suppressor Protein p53Cell DivisionTransplantation, HeterologousModels, MolecularDNA-Binding ProteinsNeutropeniaDrug ResistanceHistonesAntineoplastic Combined Chemotherapy ProtocolsMutationPlasmidsLung NeoplasmsNucleic Acid ConformationKineticsNeoplasm ProteinsAntigens, NeoplasmDNA, CatenatedRazoxaneLeukemia P388Substrate SpecificityHeLa CellsCatalysisCamptothecaBinding SitesAphidicolinElectron Transport Complex IKB CellsPodophyllotoxinEscherichia coliLeishmania donovaniOvarian NeoplasmsSaccharomyces cerevisiaeHL-60 CellsDNA Gyrase
IrinotecanTopotecanAnalogsAlkaloidPotent inhibitorsCamptothecaAntitumorInhibitSynthesisApoptosisEnzymeStabilizes the topoisomeraseTOP1ComplexesTumorsDerivativesInhibitsAnti-tumor activityTopological statePharmacologyEtoposideBreakageNucleic AciCancersCytotoxicityProteasomeLipophilicNuclearCovalentAnticancerKinaseCancerTDP1ActivitySensitivityDamageCellularVitroProteinsCells treatedMolecularCellGene
Irinotecan7
  • 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)
  • Strong CYP3A4 Inhibitors may increase the serum concentration of SN-38 (active metabolite for irinotecan products). (medscape.com)
  • Irinotecan HCl trihydrate is an antineoplastic agent of the topoisomerase I inhibitor class. (rxmed.com)
  • Irinotecan HCl is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata. (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 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)
  • DNA topoisomerase I inhibitors: camptothecin, irinotecan and topotecan 14. (present5.com)
Topotecan4
Analogs4
  • 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)
Alkaloid3
  • Semisynthetic derivative of camptothecin, an alkaloid extract from the Camptotheca acuminate tree. (medscape.com)
  • Camptothecin is an alkaloid compound used as an anti-cancer agent. (goldbio.com)
  • 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)
Potent inhibitors2
  • They are potent inhibitors on topoisomerase I and both have alkylsilyl groups in position 7 which make them lipophilic and more stable. (wikipedia.org)
  • Among immune cells, Foxp3 + regulatory T cells (Treg cells) are potent inhibitors of cancer immunity, and their presence within solid tumors is generally associated with a poor prognosis. (mdpi.com)
Camptotheca1
  • 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)
Antitumor1
  • TMPyP4 tosylate (TMP 1363) is a telomerase inhibitor with antitumor effects in osteosarcoma cell lines. (adooq.com)
Inhibit3
  • 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)
  • Agents that inhibit DNA repair: PARP inhibitors 15. (present5.com)
Synthesis1
Apoptosis3
  • Camptothecin, an inhibitor of nuclear topoisomerase, induces apoptosis in many types of cells. (enzolifesciences.com)
  • 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)
Enzyme4
  • Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. (rxmed.com)
  • Camptothecin has been shown to bind and stabilize a topoisomerase I-DNA complex in vitro , preventing the enzyme from reannealing DNA strands. (goldbio.com)
  • 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)
  • 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)
Stabilizes the topoisomerase2
  • 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)
TOP19
  • 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)
  • He discovered the indenoisoquinolines as novel Top1 inhibitors, which are in clinical development, and the mitochondrial topoisomerase gene, TOP1mt. (cancer.gov)
  • Three of his indenoisoquinoline TOP1 inhibitors are in Phase 1/2 clinical development (Thomas & Pommier, Clin Cancer Res 2019): LMP400 (Indotecan), LMP776 (Indimitecan) and LMP744. (cancer.gov)
  • 2020). Based on their promising clinical activity and their superior medicinal properties over the camptothecins, the indenoisoquinolines represent the first non-camptothecin TOP1 inhibitors for the treatment of cancers. (cancer.gov)
  • Recently, Dr. Pommier demonstrated that misincorporated ribonucleotides (the most frequent DNA alteration) trap topoisomerases, which convert them to toxic and mutagenic nicks by TOP1 (Kim et al. (cancer.gov)
  • 2018). While studying the tyrosyl-DNA-phosphodiesterase (TDP1 and TDP2) repair pathways for the excision of topoisomerases from DNA, Dr. Pommier revealed that TDP1 repairs a broad range of 3'-blocking lesions in addition to TOP1 (Murai et al. (cancer.gov)
  • 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)
  • The destruction of TOP1 was also prevented in cells treated with MG-132 and lactacystin, specific inhibitors of the 26S proteasome. (tmu.edu.tw)
Complexes2
  • Dr. Pommier conceptualized the "interfacial inhibitors" mechanism based on his finding that DNA topoisomerase inhibitors act by trapping topoisomerase-DNA complexes (Capranico et al. (cancer.gov)
  • J Med Chem 2005) and extended it to macromolecular complexes involving proteins and protein-RNA complexes beyond topoisomerases (Pommier et al. (cancer.gov)
Tumors3
  • 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)
  • We describe areas where major inroads were initially achieved by targeting angiogenesis and by unraveling pathways in the heterogeneous tumors of mesenchymal origin-spurred by the identification of c-Kit-activating mutations in GIST and the regressions that ensued when tumors harboring these mutations were exposed to the tyrosine kinase inhibitor imatinib (Gleevec). (cancernetwork.com)
  • Here, in Part I, we describe areas where major inroads were initially achieved by targeting angiogenesis (central to the biology of renal cell carcinoma and hepatocellular cancer) and by unraveling pathways in the heterogeneous tumors of mesenchymal origin-spurred by the identification of c-Kit-activating mutations in gastrointestinal stromal tumors (GIST) and the regressions that ensued when tumors harboring these mutations were exposed to the tyrosine kinase inhibitor imatinib (Gleevec). (cancernetwork.com)
Derivatives2
  • 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)
  • Title : "Sar of indenoisoquinoline derivatives as topoisomerase inhibitior" - A review. (kvmpharmacycollege.in)
Inhibits1
Anti-tumor activity1
  • 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)
Topological state2
  • 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)
  • 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)
Pharmacology1
  • He revealed the interfacial inhibition paradigm based on molecular mechanisms of topoisomerase inhibitors, and has championed its broad relevance for molecular pharmacology and drug discovery. (cancer.gov)
Etoposide1
  • We have shown that colorectal cancer cell lines defective in DNA MMR exhibit an increased sensitivity to both camptothecin, a topoisomerase I inhibitor, and etoposide, a topoisomerase II inhibitor. (aacrjournals.org)
Breakage1
  • 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)
Nucleic Aci1
  • Nucleic Acids Res 2007) and he is a world leader for the discovery of TDP1 and TDP2 inhibitors (Marchand et al. (cancer.gov)
Cancers1
  • 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)
Cytotoxicity1
  • Because MMR is assumed to modulate cytotoxicity to various chemotherapeutic agents that act upon DNA, our objectives have been to define its possible involvement in the cytotoxicity of topoisomerase inhibitors. (aacrjournals.org)
Proteasome1
  • Proteasome inhibitors: bortezomib (Velcade) 13. (present5.com)
Lipophilic1
  • DESCRIPTION (provided by applicant): Based on the extensive data generated during the phase I portion of our studies, there is sufficient and compelling information to support the further development of the highly lipophilic and blood-stable topoisomerase inhibitor, DB-67. (elsevierpure.com)
Nuclear1
  • 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)
Covalent1
  • CPT binds to the topoisomerase I and DNA complex (the covalent complex) resulting in a ternary complex, and thereby stabilizing it. (wikipedia.org)
Anticancer3
  • Six of 23 species of Apocynaceae, Simaroubaceae and Magnoliaceae showed potential as anticancer agents, as DNA damag ing agent or Topoisomerase inhibitor. (stuartxchange.org)
  • 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)
  • Camptothecin and Nystatin were used as reference anticancer and antifungal agent. (stuartxchange.org)
Kinase1
  • The best known of all the early works studying concentration camp survivors is probably the article published by Eitinger.26 In selleck kinase inhibitor contrast to WWI, the course of symptoms over decades and their chronic nature were extensively studied in WWII survivors. (cxcrinhibitor.com)
Cancer4
  • 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)
  • Costunolide is an Inhibitor of human telomerase activity (IC50 = 65 μM in MCF-7 breast cancer cells). (adooq.com)
  • Dr. Pommier is a leader on DNA topoisomerase biology and biochemistry, and their cancer relevance. (cancer.gov)
  • 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)
TDP12
  • To understand the determinants of response to topoisomerase inhibitors, he is studying the repair pathway centered on tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2) and poly(ADP-ribose)polymerases (PARP). (cancer.gov)
  • Dr. Pommier reported the first TDP1 inhibitors (Antony et al. (cancer.gov)
Activity2
  • These groups are able to react with the DNA in the presence of topoisomerase I which leads to more tumor activity. (wikipedia.org)
  • Genz-644282 is a non-camptothecin inhibitor of topoisomerase I with potential antineoplastic activity. (adooq.com)
Sensitivity3
  • Sensitivity to these drugs cannot be predicted by measuring endogenous levels of topoisomerase I and II. (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)
  • 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)
Damage2
  • In parallel, Dr. Pommier has profoundly contributed to the elucidation of the repair pathways for topoisomerase-=induced DNA damage (Pommier et al. (cancer.gov)
  • He was the first to show that topoisomerases are trapped by DNA damage (by oxidative base lesions, base alkylation, DNA nicks) (Pourquier et al. (cancer.gov)
Cellular1
  • 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)
Vitro1
Proteins1
  • The 125- and 160-kDa proteins localized in the nucleolus and precisely within certain granules which are known to appear in the nucleolar area after camptothecin administration. (nih.gov)
Cells treated1
  • 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)
Molecular1
  • Scholars@Duke publication: Molecular cloning of a cDNA of a camptothecin-resistant human DNA topoisomerase I and identification of mutation sites. (duke.edu)
Cell1
  • cDNA clones of topoisomerase I were isolated from the CPT-resistant and the parental CPT-sensitive cell lines, respectively. (duke.edu)
Gene1
  • Dr. Pommier discovered the 6th vertebrate topoisomerase gene, TOP1MT (Zhang et al. (cancer.gov)