Use of multicellular spheroids and agent-based modelling to optimise combination therapies with hypoxiaactivated prodrug SN30000

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dc.contributor.advisor Wilson, R en
dc.contributor.advisor Hicks, O en Mao, Xinjian en 2019-05-23T03:52:48Z en 2018 en
dc.identifier.uri en
dc.description.abstract Hypoxia-activated prodrugs (HAPs) selectively target hypoxic cells associated with resistance of tumours to radiotherapy/chemotherapy. Although HAPs potentiate radiotherapy/chemotherapy in preclinical models and have shown promise in some clinical trials, no HAP is approved for clinical use. Therefore new models are needed to explore the pharmacology of these prodrugs. The aim of this thesis is to extend understanding of HAPs and radiotherapy/chemotherapy combinations, using SN30000, a benzotriazine di-N-oxide, as a prototypical HAP by experimental and mathematical techniques using tumour spheroids that model important features of the tumour microenvironment. Testing combinations of SN30000 and chemotherapy drugs on HCT116 and SiHa spheroids demonstrated hypoxia- and schedule-dependent potentiation by SN30000 of spheroid growth inhibition by doxorubicin and gemcitabine. The schedule dependent SN30000/gemcitabine combination also provided a therapeutic gain in HCT116 xenografts, due to elimination of hypoxic cells that otherwise reoxygenated and repopulated the tumours after gemcitabine treatment alone. The study demonstrates the potential for HAPs to overcome this important mechanism of resistance to chemotherapy, and highlights the value of spheroid growth delay endpoints for investigating HAP/drug interactions. An initial mathematical agent-based model (ABM) with potential to improve the interpretation of drug and radiation interactions in spheroids by simulating individual cell fates, was parameterised by measuring glucose and SN30000 transport and oxygen metabolism in the HCT116 cell line. The ABM predicted growth and histological features of HCT116 spheroids, and cell killing after SN30000 and radiation, and indicated surprisingly limited SN30000 penetration. In this ABM where cells sit on a fixed lattice, the empirical relationships between cell fate and nutrients/drugs limited predictions of their combined effects and insight into drug/radiation interactions. A more mechanistic, novel ABM also predicted spheroid properties, in which cells are free to interact spatially and cell fate is mechanistically determined by production of ATP (survival) and anabolic intermediates (growth) by hypoxiamodulated metabolism of glucose and lactate. In addition the effect of radiation was mechanistically linked to the DNA damage response to simulate cell cycle delay, cell killing and cell growth inhibition. Although further development is needed, the ABM provides a flexible tool for dissecting interactions of HAPs with radiation and other cytotoxic drugs. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA99265150802602091 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.rights.uri en
dc.title Use of multicellular spheroids and agent-based modelling to optimise combination therapies with hypoxiaactivated prodrug SN30000 en
dc.type Thesis en Biomedical Science en The University of Auckland en Doctoral en PhD en
dc.rights.holder Copyright: The author en
dc.rights.accessrights en
pubs.elements-id 773007 en
pubs.record-created-at-source-date 2019-05-23 en

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