A whole cord model for the identification of mechanisms for the antivascular effects of DMXAA

dc.contributor.authorMoses, Kiriana Mihien_NZ
dc.date.accessioned2007-05-24T18:23:18Z
dc.date.available2007-08-29T15:36:58Z
dc.date.issued2007en_NZ
dc.description.abstractEndothelial cells form the inner lining of a blood vessel and their structure and functional integrity are important in maintenance of the vessel wall and circulatory function. These cells play key roles in immune and inflammatory reactions by regulating lymphocyte and leukocyte movement into tissues; they are also main targets for antivascular agents in cancer therapy. Endothelial cell responses to different stimuli have been previously investigated using conventional approaches, 'HUVEC in vitro culture system'. In this study an ex vivo perfusion model was constructed and utilized using whole human umbilical cords, in attempts to replicate a more accurate in vivo microenvironment. Assessment of the proportion and duration of endothelial cell viability in the ex vivo model was undertaken using a MTT 3, (4,5-dimethylthiazol-2-yl) 2, 5-diphenyl-tetrazolium bromide viability assay. A time baseline was successfully established for all experimental perfusions. Endothelial cell immune response was assessed through intravenous perfusion of the endotoxin, Lipopolysaccharide (LPS). Gene expression profiles revealed a significant increase in expression levels of E-Selctin (E-Sel), Intracellular adhesion molecule (I-CAM) and Tissue Factor (TF) relative to the housekeeping gene Beta 2 Microglobulin. When LPS was administered in combination with Hypertonic Saline Solution (HSS), expression levels declined indicating HSS interferes with the activation pathway of LPS ultimately suppressing its effectiveness on endothelial cells. HSS impact was also recognized from perfusion experiments on resting endothelial cells. All identified genes were suppressed by HSS apart from inducible nitric oxide synthase (iNOS). As a potential target for antivascular agents, HUVEC were then stimulated with DMXAA and gene responses of Tumour Necrosis Factor-α (TNF-α) was analysed. DMXAA demonstrates excellent antivascular acivity in experimental tumours, so tumour conditioned media (TCM) was administered intravenously through umbilical cord segments to replicate a tumour microenvironment prior to DMXAA addition. When cells were stimulated with Tumour conditioned media then administered DMXAA, TNF-α expression was significantly upregulated; relative to the housekeeping gene Human Proteosome subunit Y, however, when the cells were exposed to tumour conditioned media in absence of DMXAA gene expression significantly decreased. Thus, the antitumour action of DMXAA is capable of inhibiting the gene response of TNF-α replicated in a tumour environment.en_NZ
dc.format.mimetypeapplication/pdf
dc.identifier.citationMoses, K. M. (2007). A whole cord model for the identification of mechanisms for the antivascular effects of DMXAA (Thesis, Master of Science (MSc)). The University of Waikato, Hamilton, New Zealand. Retrieved from https://hdl.handle.net/10289/2488en
dc.identifier.urihttps://hdl.handle.net/10289/2488
dc.language.isoen
dc.publisherThe University of Waikatoen_NZ
dc.rightsAll items in Research Commons are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectendothelial cellsen_NZ
dc.subjectHUVECen_NZ
dc.subjectDMXAAen_NZ
dc.titleA whole cord model for the identification of mechanisms for the antivascular effects of DMXAAen_NZ
dc.typeThesisen_NZ
pubs.place-of-publicationHamilton, New Zealanden_NZ
thesis.degree.disciplineScience and Engineeringen_NZ
thesis.degree.grantorUniversity of Waikatoen_NZ
thesis.degree.levelMasters
thesis.degree.nameMaster of Science (MSc)en_NZ
uow.date.accession2007-05-24T18:23:18Zen_NZ
uow.date.available2007-08-29T15:36:58Zen_NZ
uow.date.migrated2009-06-09T23:31:45Zen_NZ
uow.identifier.adthttp://adt.waikato.ac.nz/public/adt-uow20070524.182318en_NZ
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