Open AccessCombining hypoxia-activated prodrugs and radiotherapy in silico: Impact of treatment scheduling and the intra-tumoural oxygen landscape
Author(s) -
Sara Hamis,
Mohammad Kohandel,
Ludwig Dubois,
Ala Yaromina,
Gibin Powathil
Publication year - 2020
Publication title -
plos computational biology/plos computational biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.628
H-Index - 182
eISSN - 1553-7358
pISSN - 1553-734X
DOI - 10.1371/journal.pcbi.1008041
Subject(s) - in silico , hypoxia (environmental) , prodrug , in vivo , computer science , radiation therapy , multicellular organism , exploit , scheduling (production processes) , oxygen , chemistry , biology , medicine , pharmacology , cell , mathematical optimization , biochemistry , surgery , microbiology and biotechnology , organic chemistry , mathematics , gene , computer security
Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successful in vitro and in vivo , HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments. Taking a mathematical modelling approach, we investigate how tumour properties and HAP-radiation scheduling influence treatment outcomes in simulated tumours. The following key results are demonstrated in silico : (i) HAP and ionising radiation (IR) monotherapies may attack tumours in dissimilar, and complementary, ways. (ii) HAP-IR scheduling may impact treatment efficacy. (iii) HAPs may function as IR treatment intensifiers. (iv) The spatio-temporal intra-tumoural oxygen landscape may impact HAP efficacy. Our in silico framework is based on an on-lattice, hybrid, multiscale cellular automaton spanning three spatial dimensions. The mathematical model for tumour spheroid growth is parameterised by multicellular tumour spheroid (MCTS) data.