An agent-based model for drug-radiation interactions in the tumour microenvironment: Hypoxia-activated prodrug SN30000 in multicellular tumour spheroids.

Show simple item record Mao, Xinjian en McManaway, Sarah en Jaiswal, Jagdish en Patel, Priyanka B en Wilson, William en Hicks, Kevin en Bogle, Miles en 2019-06-14T02:44:14Z en 2018-10-24 en
dc.identifier.citation PLoS computational biology 14(10):e1006469 24 Oct 2018 en
dc.identifier.issn 1553-734X en
dc.identifier.uri en
dc.description.abstract Multicellular tumour spheroids capture many characteristics of human tumour microenvironments, including hypoxia, and represent an experimentally tractable in vitro model for studying interactions between radiotherapy and anticancer drugs. However, interpreting spheroid data is challenging because of limited ability to observe cell fate within spheroids dynamically. To overcome this limitation, we have developed a hybrid continuum/agent-based model (ABM) for HCT116 tumour spheroids, parameterised using experimental models (monolayers and multilayers) in which reaction and diffusion can be measured directly. In the ABM, cell fate is simulated as a function of local oxygen, glucose and drug concentrations, determined by solving diffusion equations and intracellular reactions. The model is lattice-based, with cells occupying discrete locations on a 3D grid embedded within a coarser grid that encompasses the culture medium; separate solvers are employed for each grid. The generated concentration fields account for depletion in the medium and specify concentration-time profiles within the spheroid. Cell growth and survival are determined by intracellular oxygen and glucose concentrations, the latter based on direct measurement of glucose diffusion/reaction (in multilayers) for the first time. The ABM reproduces known features of spheroids including overall growth rate, its oxygen and glucose dependence, peripheral cell proliferation, central hypoxia and necrosis. We extended the ABM to describe in detail the hypoxia-dependent interaction between ionising radiation and a hypoxia-activated prodrug (SN30000), again using experimentally determined parameters; the model accurately simulated clonogenic cell killing in spheroids, while inclusion of reversible cell cycle delay was required to account for the marked spheroid growth delay after combined radiation and SN30000. This ABM of spheroid growth and response exemplifies the utility of integrating computational and experimental tools for investigating radiation/drug interactions, and highlights the critical importance of understanding oxygen, glucose and drug concentration gradients in interpreting activity of therapeutic agents in spheroid models. en
dc.format.medium Electronic-eCollection en
dc.language eng en
dc.relation.ispartofseries PLoS computational biology 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.subject HCT116 Cells en
dc.subject Humans en
dc.subject Triazines en
dc.subject Cyclic N-Oxides en
dc.subject Antineoplastic Agents en
dc.subject Prodrugs en
dc.subject Radiotherapy en
dc.subject Cell Hypoxia en
dc.subject Models, Biological en
dc.subject Tumor Microenvironment en
dc.title An agent-based model for drug-radiation interactions in the tumour microenvironment: Hypoxia-activated prodrug SN30000 in multicellular tumour spheroids. en
dc.type Journal Article en
dc.identifier.doi 10.1371/journal.pcbi.1006469 en
pubs.issue 10 en
pubs.begin-page e1006469 en
pubs.volume 14 en
dc.rights.holder Copyright: The authors en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.subtype Research Support, Non-U.S. Gov't en
pubs.subtype research-article en
pubs.subtype Journal Article en
pubs.elements-id 755695 en Bioengineering Institute en ABI Associates en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1553-7358 en
pubs.record-created-at-source-date 2018-10-26 en
pubs.dimensions-id 30356233 en

Files in this item

Find Full text

This item appears in the following Collection(s)

Show simple item record


Search ResearchSpace