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

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    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.
    Issue Date
    2011-04-01
    MeSH
    Aged
    Breast Neoplasms
    Female
    Humans
    Infant, Newborn
    Middle Aged
    Oncolytic Virotherapy
    Transfection
    
    Metadata
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    Citation
    Preclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer. 2011, 236 (4):423-34 Exp. Biol. Med. (Maywood)
    Journal
    Experimental biology and medicine (Maywood, N.J.)
    URI
    http://hdl.handle.net/10147/135646
    DOI
    10.1258/ebm.2011.010234
    PubMed ID
    21444371
    Additional Links
    http://www.ncbi.nlm.nih.gov/pubmed/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.
    Item Type
    Article
    Language
    en
    ISSN
    1535-3699
    ae974a485f413a2113503eed53cd6c53
    10.1258/ebm.2011.010234
    Scopus Count
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