Preclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer.

2.50
Hdl Handle:
http://hdl.handle.net/10147/206374
Title:
Preclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer.
Authors:
Rajendran, Simon; O'Hanlon, Deirdre; Morrissey, David; O'Donovan, Tracey; O'Sullivan, Gerald C; Tangney, Mark
Affiliation:
Cork Cancer Research Centre, Mercy University Hospital and Leslie C Quick Jnr., Laboratory, University College Cork, Cork, Ireland.
Citation:
Exp Biol Med (Maywood). 2011 Apr 1;236(4):423-34. Epub 2011 Mar 28.
Journal:
Experimental biology and medicine (Maywood, N.J.)
Issue Date:
31-Jan-2012
URI:
http://hdl.handle.net/10147/206374
DOI:
10.1258/ebm.2011.010234
PubMed ID:
21444371
Abstract:
Preclinical results with various gene therapy strategies indicate significant potential for new cancer treatments. However, many therapeutics fail at clinical trial, often due to differences in tissue physiology between animal models and humans, and tumor phenotype variation. Clinical data relevant to treatment strategies may be generated prior to clinical trial through experimentation using intact patient tissue ex vivo. We developed a novel tumor slice model culture system that is universally applicable to gene delivery methods, using a realtime luminescence detection method to assess gene delivery. Methods investigated include viruses (adenovirus [Ad] and adeno-associated virus), lipofection, ultrasound (US), electroporation and naked DNA. Viability and tumor populations within the slices were well maintained for seven days, and gene delivery was qualitatively and quantitatively examinable for all vectors. Ad was the most efficient gene delivery vector with transduction efficiency >50%. US proved the optimal non-viral gene delivery method in human tumor slices. The nature of the ex vivo culture system permitted examination of specific elements. Parameters shown to diminish Ad gene delivery included blood, regions of low viability and secondary disease. US gene delivery was significantly reduced by blood and skin, while tissue hyperthermia improved gene delivery. US achieved improved efficacy for secondary disease. The ex vivo model was also suitable for examination of tissue-specific effects on vector expression, with Ad expression mediated by the CXCR4 promoter shown to provide a tumor selective advantage over the ubiquitously active cytomegalovirus promoter. In conclusion, this is the first study incorporating patient tissue models in comparing gene delivery from various vectors, providing knowledge on cell-type specificity and examining the crucial biological factors determining successful gene delivery. The results highlight the importance of in-depth preclinical assessment of novel therapeutics and may serve as a platform for further testing of current, novel gene delivery approaches.
Language:
eng
MeSH:
Aged; Breast Neoplasms/*therapy; Female; Humans; Infant, Newborn; Middle Aged; Oncolytic Virotherapy; Transfection/*methods
ISSN:
1535-3699 (Electronic); 1535-3699 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorRajendran, Simonen_GB
dc.contributor.authorO'Hanlon, Deirdreen_GB
dc.contributor.authorMorrissey, Daviden_GB
dc.contributor.authorO'Donovan, Traceyen_GB
dc.contributor.authorO'Sullivan, Gerald Cen_GB
dc.contributor.authorTangney, Marken_GB
dc.date.accessioned2012-01-31T16:40:04Z-
dc.date.available2012-01-31T16:40:04Z-
dc.date.issued2012-01-31T16:40:04Z-
dc.identifier.citationExp Biol Med (Maywood). 2011 Apr 1;236(4):423-34. Epub 2011 Mar 28.en_GB
dc.identifier.issn1535-3699 (Electronic)en_GB
dc.identifier.issn1535-3699 (Linking)en_GB
dc.identifier.pmid21444371en_GB
dc.identifier.doi10.1258/ebm.2011.010234en_GB
dc.identifier.urihttp://hdl.handle.net/10147/206374-
dc.description.abstractPreclinical results with various gene therapy strategies indicate significant potential for new cancer treatments. However, many therapeutics fail at clinical trial, often due to differences in tissue physiology between animal models and humans, and tumor phenotype variation. Clinical data relevant to treatment strategies may be generated prior to clinical trial through experimentation using intact patient tissue ex vivo. We developed a novel tumor slice model culture system that is universally applicable to gene delivery methods, using a realtime luminescence detection method to assess gene delivery. Methods investigated include viruses (adenovirus [Ad] and adeno-associated virus), lipofection, ultrasound (US), electroporation and naked DNA. Viability and tumor populations within the slices were well maintained for seven days, and gene delivery was qualitatively and quantitatively examinable for all vectors. Ad was the most efficient gene delivery vector with transduction efficiency >50%. US proved the optimal non-viral gene delivery method in human tumor slices. The nature of the ex vivo culture system permitted examination of specific elements. Parameters shown to diminish Ad gene delivery included blood, regions of low viability and secondary disease. US gene delivery was significantly reduced by blood and skin, while tissue hyperthermia improved gene delivery. US achieved improved efficacy for secondary disease. The ex vivo model was also suitable for examination of tissue-specific effects on vector expression, with Ad expression mediated by the CXCR4 promoter shown to provide a tumor selective advantage over the ubiquitously active cytomegalovirus promoter. In conclusion, this is the first study incorporating patient tissue models in comparing gene delivery from various vectors, providing knowledge on cell-type specificity and examining the crucial biological factors determining successful gene delivery. The results highlight the importance of in-depth preclinical assessment of novel therapeutics and may serve as a platform for further testing of current, novel gene delivery approaches.en_GB
dc.language.isoengen_GB
dc.subject.meshAgeden_GB
dc.subject.meshBreast Neoplasms/*therapyen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshHumansen_GB
dc.subject.meshInfant, Newbornen_GB
dc.subject.meshMiddle Ageden_GB
dc.subject.meshOncolytic Virotherapyen_GB
dc.subject.meshTransfection/*methodsen_GB
dc.titlePreclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer.en_GB
dc.contributor.departmentCork Cancer Research Centre, Mercy University Hospital and Leslie C Quick Jnr., Laboratory, University College Cork, Cork, Ireland.en_GB
dc.identifier.journalExperimental biology and medicine (Maywood, N.J.)en_GB
dc.description.provinceMunster-

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