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dc.date.accessioned2018-02-07T14:29:47Z
dc.date.available2018-02-07T14:29:47Z
dc.date.created2017-01-13T22:49:18Z
dc.date.issued2017
dc.identifier.citationKalanxhi, Ert Risberg, Karianne Barua, Imon Shoumitra Dueland, Svein Waagene, Stein Andersen, Solveig Norheim Pettersen, Solveig Lindvall, Jessica Margareta Redalen, Kathrine Røe Flatmark, Kjersti Ree, Anne Hansen . Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy. Cancer research and treatment : official journal of Korean Cancer Association. 2017, 49(2), 374-386
dc.identifier.urihttp://hdl.handle.net/10852/59925
dc.description.abstractPurpose When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser. Materials and Methods This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA. Results PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss. Conclusion The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.en_US
dc.languageEN
dc.language.isoenen_US
dc.publisherKorean Cancer Association
dc.rightsAttribution-NonCommercial 3.0 Unported
dc.rights.urihttps://creativecommons.org/licenses/by-nc/3.0/
dc.titleInduction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapyen_US
dc.typeJournal articleen_US
dc.creator.authorKalanxhi, Ert
dc.creator.authorRisberg, Karianne
dc.creator.authorBarua, Imon Shoumitra
dc.creator.authorDueland, Svein
dc.creator.authorWaagene, Stein
dc.creator.authorAndersen, Solveig Norheim
dc.creator.authorPettersen, Solveig
dc.creator.authorLindvall, Jessica Margareta
dc.creator.authorRedalen, Kathrine Røe
dc.creator.authorFlatmark, Kjersti
dc.creator.authorRee, Anne Hansen
cristin.unitcode185,53,82,10
cristin.unitnameAvdeling for klinisk molekylærbiologi
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1
dc.identifier.cristin1427191
dc.identifier.bibliographiccitationinfo:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Cancer research and treatment : official journal of Korean Cancer Association&rft.volume=49&rft.spage=374&rft.date=2017
dc.identifier.jtitleCancer research and treatment : official journal of Korean Cancer Association
dc.identifier.volume49
dc.identifier.issue2
dc.identifier.startpage374
dc.identifier.endpage386
dc.identifier.doihttp://dx.doi.org/10.4143/crt.2016.080
dc.identifier.urnURN:NBN:no-62613
dc.type.documentTidsskriftartikkelen_US
dc.type.peerreviewedPeer reviewed
dc.source.issn1598-2998
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/59925/1/Kalanxhi%2BCRT2016.pdf
dc.type.versionPublishedVersion
dc.relation.projectHSØ/2014012
dc.relation.projectHSØ/2012002
dc.relation.projectKF/2180105
dc.relation.projectHSØ/2013101


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