Journal
MATHEMATICAL BIOSCIENCES AND ENGINEERING
Volume 16, Issue 6, Pages 6257-6273Publisher
AMER INST MATHEMATICAL SCIENCES-AIMS
DOI: 10.3934/mbe.2019312
Keywords
cancer; mathematical oncology; drug response; multiscale model; radiation; hypoxia; hypoxia-activated prodrugs
Categories
Funding
- ERC (ERC-ADG-2015) [694812 Hypoximmuno]
- Kankeronderzoekfonds Limburg from the Health Foundation Limburg
- Natural Sciences and Engineering Research Council of Canada (NSERC)
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Tumour hypoxia has been associated with increased resistance to various cancer treatments, particularly radiation therapy. Conversely, tumour hypoxia is a validated and ideal target for guided cancer drug delivery. For this reason, hypoxia-activated prodrugs (HAPs) have been developed, which remain inactive in the body until in the presence of tissue hypoxia, allowing for an activation tendency in hypoxic regions. We present here an experimentally motivated mathematical model predicting the effectiveness of HAPs in a variety of clinical settings. We first examined HAP effectiveness as a function of the amount of tumour hypoxia and showed that the drugs have a larger impact on tumours with high levels of hypoxia. We then combined HAP treatment with radiation to examine the effects of combination therapies. Our results showed radiation-HAP combination therapies to be more effective against highly hypoxic tumours. The analysis of combination therapies was extended to consider schedule sequencing of the combination treatments. These results suggested that administering HAPs before radiation was most effective in reducing total cell number. Finally, a sensitivity analysis of the drug-related parameters was done to examine the effect of drug diffusivity and enzyme abundance on the overall effectiveness of the drug. Altogether, the results highlight the importance of the knowledge of tumour hypoxia levels before administration of HAPs in order to ensure positive results.
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