Role of hypoxia-activated prodrugs in combination with radiation therapy: An in silico approach

Cameron Meaney, Gibin G. Powathil*, Ala Yaromina, Ludwig J. Dubois, Philippe Lambin, Mohammad Kohandel

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)6257-6273
Number of pages17
JournalMathematical Biosciences and Engineering
Volume16
Issue number6
DOIs
Publication statusPublished - 2019

Keywords

  • cancer
  • mathematical oncology
  • drug response
  • multiscale model
  • radiation
  • hypoxia
  • hypoxia-activated prodrugs
  • TH-302
  • RADIOTHERAPY
  • CANCER
  • TUMORS
  • EVOFOSFAMIDE
  • MECHANISMS
  • REGIMENS

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