Oxygenation and radiosensitization consequences of solid tumour perfusion
department or school: Medicine, Faculty of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Wadsworth, Brennan
issued: 2020-08-05T13:51:35Z
issued: 2020
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Solid tumours often develop regions that are poorly oxygenated (hypoxic). Hypoxic tumour cells are resistant to radiation and are associated with poor patient outcome. “Chronic hypoxia” develops where vascular density is insufficient, causing tumour cells beyond ~70-100 μm from blood vessels to receive little oxygen. “Transient hypoxia” occurs in solid tumours where fluctuating microregional perfusion exposes tumour cells to cycles of hypoxia and reoxygenation. The fundamental understanding of transient hypoxia in vivo is lacking, and there are no available strategies to eliminate transient hypoxia. This thesis hypothesizes that transiently hypoxic tumour cells are long-lived radiation resistant cells and that eliminating the development of transient hypoxia will improve tumour radiation response. This thesis first investigated the rate of hypoxic cell turnover in vivo. Exogenous hypoxia reporters were used to label hypoxic tumour cells, while loss of labelled cells over time indicated loss of hypoxic cells. The perfusion-modifying drug pentoxifylline was used to control which hypoxic populations were labelled and therefore which populations were lost over time. We find that transiently hypoxic tumour cells survive longer than neighbouring chronically hypoxic cells, further justifying transient hypoxia as an important therapeutic target. To better study tumour perfusion-modifying interventions, this thesis next validated 2-18F-fluoroethanol as a novel reporter of solid tumour perfusion compatible with positron emission tomography. We found 2-18F-fluoroethanol to effectively respond to established tumour perfusion-modifying interventions and applied 2-18F-fluoroethanol to characterize novel interventions aiming to modify tumour perfusion and transient hypoxia. This thesis then focused on the angiotensin II type 1 receptor blocker telmisartan. Telmisartan treatment reduced tumour collagen 1 content, increased and stabilized tumour perfusion, reduced the development of…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/75372
note: OXYGENATION AND RADIOSENSITIVITY CONSEQUENCES OF SOLID TUMOUR PERFUSION by Brennan Wadsworth B.Sc., University of Waterloo, 2014 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pathology and Laboratory Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2020 © Brennan Wadsworth, 2020 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Oxygenation and radiosensitivity consequences of solid tumour perfusion. submitted by Brennan Wadsworth in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pathology and Laboratory Medicine Examining Committee: Dr. Kevin L Bennewith, Associate Professor, Pathology and Laboratory Medicine Supervisor Dr. François Bénard, Professor, Radiology Supervisory Committee Member Dr. Andrew Minchinton, Associate Professor, Pathology and Laboratory Medicine University Examiner Dr. Christina Haston, Professor, Medical Physics University Examiner Additional Supervisory Committee Members: Dr. Calum MacAulay, Clinical Associate Professor, Pathology and Laboratory Medicine Supervisory Committee Member Dr. Pascal Bernatchez, Associate Professor, Pharmacology and Therapeutics Supervisory Committee Member iii Abstract Solid tumours often develop regions that are poorly oxygenated (hypoxic). Hypoxic tumour cells are resistant to radiation and are associated with poor patient outcome. “Chronic hypoxia” develops where vascular density is insufficient, causing tumour cells beyond ~70-100 μm from blood vessels to receive little oxygen. “Transient hypoxia” occurs in solid tumours where fluctuating microregional perfusion exposes tumour cells to cycles of hypoxia and reoxygenation. The fundamental understanding of transient hypoxia in vivo is lacking, and there are no available strategies to eliminate tr…
has type: Thesis/Dissertation
date issued: 2020-11
is shown at: 10.14288/1.0392640
language: eng
degree discipline: Pathology and Laboratory Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/75372