Show simple item record

dc.contributor.advisorShnyder, Steven D.
dc.contributor.advisorLoadman, Paul
dc.contributor.advisorPatterson, Laurence H.
dc.contributor.advisorGill, Jason H.
dc.contributor.authorBin Saeedan, Abdulaziz S.A.*
dc.date.accessioned2017-12-05T15:23:44Z
dc.date.available2017-12-05T15:23:44Z
dc.date.issued2014
dc.identifier.urihttp://hdl.handle.net/10454/14070
dc.description.abstractNon-Small Cell Lung Cancer (NSCLC), which accounts for 80% of all lung cancer cases, is associated with resistance to chemotherapy and poor prognosis. Exploitation of NSCLC-upregulated pathways that can either be targeted by novel therapeutics or used to improve the tumour-delivery of current chemotherapeutics are required. Among the matrix metalloproteinases (MMPs) that are essential for tumour development, MMP10 is a potential candidate as a therapeutic target based on its expression and contribution to NSCLC development. This research aims to explore the expression and functions of MMP10 in the tumour microenvironment of NSCLC and evaluate the potential of MMP10 as a target for therapeutic intervention. Herein, MMP10 expression at gene and protein levels were analysed in a panel of NSCLC cell lines using RT-PCR and Western blotting analysis. To determine MMP10 functional relevance, an in vitro angiogenesis assay using cell conditioned media was carried out. To identify specific peptide sequences for the design of prodrugs rationalised to be MMP10 activated, in vitro substrate cleavage studies were performed using a mass spectrometry approach to differentiate between MMP10 and the structurally similar MMP3. This study demonstrates that MMP10 is highly expressed in NSCLC and that high levels of MMP10 are associated with induction of angiogenesis, a crucial process supporting tumour growth. In addition to the achievement of having been able to differentiate between closely similar MMP3 and MMP10 through carefully monitoring the hydrolysis rate of compound 444259 (a known MMP substrate), data generated herein provides the basis for further studies to exploit MMP10 as a prodrug-activator.en
dc.language.isoenen_US
dc.rights<a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>.eng
dc.subjectNon-small cell lung cancer (NSCLC); Matrix metalloproteinase-10 (MMP10); MMP3; Histone deacetylase-7; Metabolism; siRNA; Angiogenesis; Liquid chromatography coupled with mass spectrometry (LC-MS); Pharmacologyen_US
dc.titleThe role of MMP10 in non-small cell Lung cancer, and pharmacological evaluation of its potential as a target for therapeutic intervention. Investigation of the role of MMP10 in the tumour microenvironment of non-small cell lung cancer using gene, protein and mass spectrometry approaches to determine MMP10’s potential in drug development strategiesen_US
dc.type.qualificationleveldoctoralen_US
dc.publisher.institutionUniversity of Bradfordeng
dc.publisher.departmentInstitute of Cancer Therapeuticsen_US
dc.typeThesiseng
dc.type.qualificationnamePhDen_US
dc.date.awarded2014
dc.description.publicnotesFull text was made available at the end of the embargo period, 12th Dec 2019en
refterms.dateFOA2020-06-09T09:56:13Z


Item file(s)

Thumbnail
Name:
Abdulaziz thesis (corrections ...
Size:
3.721Mb
Format:
PDF
Description:
PhD Thesis

This item appears in the following Collection(s)

Show simple item record