Show simple item record

dc.contributor.authorRamirez, Y.P.*
dc.contributor.authorMladek, A.C.*
dc.contributor.authorPhillips, Roger M.*
dc.contributor.authorGynther, M.*
dc.contributor.authorRautio, J.*
dc.contributor.authorRoss, A.H.*
dc.contributor.authorWheelhouse, Richard T.*
dc.contributor.authorSakaria, J.N.*
dc.date.accessioned2015-06-05T14:08:58Z
dc.date.available2015-06-05T14:08:58Z
dc.date.issued2015-01
dc.identifier.citationRamirez YP, Mladek AC, Phillips RM, Gynther M, Rautio J, Ross AH, Wheelhouse RT and Sakaria JN (2015) Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth. Molecular Cancer Therapeutics. 14(1):111-119.en_US
dc.identifier.urihttp://hdl.handle.net/10454/7235
dc.descriptionYesen_US
dc.description.abstractThe cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multiforme (GBM) cell lines and primary culture models are reported. Dose–response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repopulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR functions. DP68-induced interstrand DNA cross-links were demonstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell–cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced antiglioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collectively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DNA.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttp://dx.doi.org/10.1158/1535-7163.MCT-14-0113en_US
dc.rights(c) 2015 American Association for Cancer Research. Full-text reproduced in accordance with the publisher's self-archiving policy.en_US
dc.subjectTemozolomide analogues; TMZ; DP86; Glioblastoma multiforme; GBMen_US
dc.titleEvaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowthen_US
dc.status.refereedYesen_US
dc.date.Accepted2014-10-18
dc.typeArticleen_US
dc.date.EndofEmbargo2016-02-01
dc.type.versionAccepted Manuscripten_US
dc.description.publicnotesThe full-text of this article was released for public view at the end of the publisher embargo on 2 Feb 2016.en_US
refterms.dateFOA2018-07-25T11:30:09Z


Item file(s)

Thumbnail
Name:
wheelhouse_evaluation_of_novel ...
Size:
8.761Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record