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dc.contributor.advisorGlynn, Sharon
dc.contributor.advisorSullivan, Frank
dc.contributor.authorToner, Aidan
dc.date.accessioned2015-06-22T10:03:34Z
dc.date.issued2015-03-31
dc.identifier.urihttp://hdl.handle.net/10379/5019
dc.description.abstractProstate cancer remains a growing problem for the male population, globally. Though there have been clinical advances in recent years, there still remains a need to develop drugs that can slow or stop progression beyond the organ-confined phase to distal aggressive metastases. Using the NCI-60 drug screen panel, the novel compound, EL102, was identified as a potent cytotoxin from a large screen of small molecule inhibitors. Classified as a toluidine sulphonamide, EL102 had displayed strong anti-cancer potential in the range of cell types assayed. Among these cell lines were prostate cancer models, PC-3 and DU145. These cell lines, along with fellow prostate cancer in vitro models CWR22, 22Rv1 and LNCaP were investigated further for their response to EL102 treatment. A 50 % reduction in cell viability was observed upon EL102 treatment of the in vitro panel, at a dose range of 20 alpha 50 nM. When EL102 was administered to CWR22 murine xenograft models, in combination with clinically-used docetaxel, a significant reduction in the rate of tumour growth was observed when compared to mice treated with either drug alone. Importantly, body weights remained consistent between the treatment arms, suggesting doses were well-tolerated, within this cohort. These data suggest the suitability of EL102 as a companion treatment. Separately, this study has determined that EL102 is a microtubule destabiliser that induces apoptosis. A previous 3D-quantitative structure-activity relationship (QSAR) study of toluidine sulphonamides, predicted these compounds directly inhibit hypoxia inducible factor 1 alpha (HIF1alpha). The findings of this document support that prediction. Moreover, the current study has detailed a role for EL102 as an androgen receptor (AR) antagonist which gives credence to the rationale for use as an anti-prostate cancer therapy. In vitro investigations, detailed within this study, have also asserted that EL102 has the capacity to overcome acquired drug-resistance mechanisms associated with MDR1 and BCRP up-regulation. Overall, EL102 is a multimodal compound which serves to impede prostate cancer cell survival through direct inhibition of important cell survival cues.en_US
dc.subjectToneren_US
dc.subjectProstateen_US
dc.subjectChemotherapyen_US
dc.subjectNovelen_US
dc.subjectTherapeuticen_US
dc.subjectPreclinicalen_US
dc.subjectDrugen_US
dc.subjectCanceren_US
dc.subjectHIF1aen_US
dc.subjectHypoxiaen_US
dc.subjectToluidinesulfonamideen_US
dc.subjectProstaticen_US
dc.subjectMicrotubuleen_US
dc.subjectTaxaneen_US
dc.subjectARen_US
dc.subjectInhibitoren_US
dc.subjectDownregulateen_US
dc.subjectProstate canceren_US
dc.subjectToluidine sulphonamideen_US
dc.subjectDrug resistanceen_US
dc.subjectAndrogen receptoren_US
dc.subjectMedicineen_US
dc.titlePreclinical assessment of the novel compound EL102 in prostate canceren_US
dc.typeThesisen_US
dc.contributor.funderGalway University Foundation Ltd.en_US
dc.local.noteThis study is the first to show the effects of new drug, EL102. Experiments have shown EL102 is effective at killing prostate cancer cells, reducing tumour growth and survival, and also appears to improve the effects of a currently-used drug in the clinic, when they are used together.en_US
dc.description.embargo2017-05-29
dc.local.finalYesen_US
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