Ex vivo culture of patient tissue and examination of gene delivery

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dc.contributor.advisor Tangney, Mark en
dc.contributor.author Rajendran, Simon
dc.date.accessioned 2015-08-13T11:58:43Z
dc.date.available 2015-08-13T11:58:43Z
dc.date.issued 2014
dc.date.submitted 2014
dc.identifier.citation Rajendran, S. 2014. Ex vivo culture of patient tissue and examination of gene delivery. PhD Thesis, University College Cork. en
dc.identifier.endpage 161
dc.identifier.uri http://hdl.handle.net/10468/1904
dc.description.abstract Gene therapy has emerged as a realistic prospect for the treatment of cancer due to its potential for selective tumour cell targeting. The greatest challenge gene delivery vectors face is the ability to safely and efficiently deliver genes into target cells. The overall objectives of this thesis are to evaluate the efficacy of various gene delivery methods in a clinically relevant tumour model and to also investigate potential strategies for tumour selective delivery. We began with the development of a tumour slice model system using patient waste tissue. This model involves the use of fresh human tumour tissue, cut into thin slices and maintained ex vivo and is universally applicable to gene delivery methods, using a real-time luminescence detection method to assess gene delivery. The nature of the ex vivo culture system permitted examination of specific physiological variables, the influence of intratumoural factors and tissue specific effects on vector expression. Adenoviral vectors under the control of the human CXCR4 promoter demonstrated a 'tumour on' and 'normal off' expression profile when compared with the ubiquitously active CMV promoter when tested in patient tumour tissue. In addition, we developed an ex vivo system of changing oxygenation using the hypoxia inducer, cobalt, to mimic the transient hypoxic conditions found in solid tumours. We found that Adenoviral transgene expression was robust in the cycling hypoxic conditions relevant to solid tumours and re-oxygenation of chronically hypoxic tissue enhanced transgene expression. Finally, we demonstrated an AAV-based tumour targeting strategy using a tumour-selective promoter allowing for the efficient targeting of AAV vectors to cancer cells and the sparing of normal tissue in both murine metastatic liver tumours models and patient tissue. The thesis highlights the importance of indepth preclinical assessment of novel therapeutics and may serve as a platform for further testing of novel gene delivery approaches. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2014, Simon Rajendran. en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Gene delivery en
dc.subject Cancer en
dc.subject Adenovirus en
dc.title Ex vivo culture of patient tissue and examination of gene delivery en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en
dc.check.info No embargo required en
dc.description.version Accepted Version
dc.description.status Not peer reviewed en
dc.internal.school Medicine en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
ucc.workflow.supervisor m.tangney@ucc.ie
dc.internal.conferring Autumn Conferring 2014


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© 2014, Simon Rajendran. Except where otherwise noted, this item's license is described as © 2014, Simon Rajendran.
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