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    Investigation of mechanisms of drug resistance in colorectal cancer: a proteomic and pharmacological study using newly developed drug-resistant human cell line subclones

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    PhD Thesis (13.22Mb)
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    Publication date
    2017
    Author
    Duran, M. Ortega
    Supervisor
    Shnyder, Steven D.
    Sutton, Chris W.
    Keyword
    Colorectal cancer; 5-Fluorouracil; Oxaliplatin; Irinotecan; Drug resistance; Proteomics; SILAC; Chemotherapy; Protein interactions; Chemosensitivity assays
    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    Faculty of Life Sciences
    Awarded
    2017
    
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    Abstract
    Despite therapeutic advances, colorectal cancer still has a 45% mortality rate, and one of the most crucial problems is the development of acquired resistance to treatment with anticancer drugs. Thus the aims of this project are to develop drug-resistant colon cancer cell lines in order to identify mechanisms of resistance for the most commonly drugs used in colorectal cancer: 5-fluorouracil, oxaliplatin, and irinotecan. Following evaluation of drug sensitivity to these agents in an initial panel of eight colorectal cancer cell lines, 3 lines (DLD-1, KM-12 and HT-29) were selected for the development of 5-FU (3 lines), oxaliplatin (2) and irinotecan (1) resistant sublines by continuous drug exposure, with resistance confirmed using the MTT assay. Consistently resistant sublines were subject to a „stable isotope labelling with amino acids in cell culture‟ (SILAC) approach and a MudPIT proteomics strategy, employing 2D LC and Orbitrap Fusion mass spectrometric analysis, to identify novel predictive biomarkers for resistance. An average of 3622 proteins was quantified for each resistant and parent cell line pair, with on average 60-70 proteins up-regulated and 60-70 down-regulated in the drug resistant sublines. The validity of this approach was further confirmed using immunodetection techniques. These studies have provided candidate proteins which can be assessed for their value as predictive biomarkers, or as therapeutic targets for the modulation of acquired drug resistance in colorectal cancer.
    URI
    http://hdl.handle.net/10454/15064
    Type
    Thesis
    Qualification name
    PhD
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    Theses

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