Show simple item record

dc.contributor.authorDillon, MT
dc.contributor.authorBarker, HE
dc.contributor.authorPedersen, M
dc.contributor.authorHafsi, H
dc.contributor.authorBhide, SA
dc.contributor.authorNewbold, KL
dc.contributor.authorNutting, CM
dc.contributor.authorMcLaughlin, M
dc.contributor.authorHarrington, KJ
dc.date.accessioned2016-12-19T15:05:25Z
dc.date.issued2017-01-01
dc.identifier.citationMolecular cancer therapeutics, 2017, 16 (1), pp. 25 - 34
dc.identifier.issn1535-7163
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/341
dc.identifier.eissn1538-8514
dc.identifier.doi10.1158/1535-7163.mct-16-0239
dc.description.abstractAZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found in vitro growth inhibitory activity of this ATRi in a panel of human cancer cell lines. We demonstrated radiosensitization by AZD6738 to single radiation fractions in multiple cancer cell lines independent of both p53 and BRCA2 status by the clonogenic assay. Radiosensitization by AZD6738 to clinically relevant doses of fractionated radiation was demonstrated in vitro using a 3D tumor spheroid model and, in vivo, AZD6738 radiosensitized by abrogating the radiation-induced G2 cell-cycle checkpoint and inhibiting homologous recombination. Mitosis with damaged DNA resulted in mitotic catastrophe as measured by micronucleus formation by live-cell fluorescent-ubiquitination cell-cycle imaging of cell-cycle progression and nuclear morphology. Induction of micronuclei was significantly more prominent for AZD6738 compared with inhibition of the downstream kinase CHK1 alone at isoeffective doses. Micronuclei were characterized as acentric chromosomal fragments, which displayed characteristics of increased DNA damage and cell-cycle dyssynchrony when compared with the primary nucleus. Mol Cancer Ther; 16(1); 25-34. ©2016 AACR.
dc.formatPrint-Electronic
dc.format.extent25 - 34
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.subjectCell Line, Tumor
dc.subjectMicronuclei, Chromosome-Defective
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectDNA Damage
dc.subjectDisease Models, Animal
dc.subjectSulfoxides
dc.subjectPyrimidines
dc.subjectProtein Kinase Inhibitors
dc.subjectRadiation-Sensitizing Agents
dc.subjectTumor Burden
dc.subjectXenograft Model Antitumor Assays
dc.subjectInhibitory Concentration 50
dc.subjectRadiation, Ionizing
dc.subjectRadiation Tolerance
dc.subjectTumor Suppressor Protein p53
dc.subjectHomologous Recombination
dc.subjectG2 Phase Cell Cycle Checkpoints
dc.titleRadiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei.
dc.typeJournal Article
dcterms.dateAccepted2016-11-01
rioxxterms.versionofrecord10.1158/1535-7163.mct-16-0239
rioxxterms.licenseref.startdate2017-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cancer therapeutics
pubs.issue1
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume16
pubs.embargo.termsNo embargo
icr.researchteamTargeted Therapy
dc.contributor.icrauthorDillon, Magnus
dc.contributor.icrauthorBhide, Shreerang
dc.contributor.icrauthorMcLaughlin, Martin
dc.contributor.icrauthorHarrington, Kevin


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record