Combining hypoxia-activated prodrugs and radiotherapy in silico: Impact of treatment scheduling and the intra-tumoural oxygen landscape
Combining hypoxia-activated prodrugs and radiotherapy in silico: Impact of treatment scheduling and the intra-tumoural oxygen landscape
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DOI：
10.1371/journal.pcbi.1008041
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发表时间：
2020-08-01
影响因子：
4.3
通讯作者：
Powathil, Gibin G.
中科院分区：
文献类型：
--
作者：
Hamis, Sara;Kohandel, Mohammad;Powathil, Gibin G.
缺氧激活的前药（HAP）提出了一个概念上优雅的方法，不仅克服，但更好的是，利用肿瘤内缺氧。尽管HAP在体外和体内都取得了成功，但在临床上还没有取得成功的结果。据推测，这种临床成功的缺乏可以部分地解释为确定哪些肿瘤适合HAP治疗的临床筛选选择不够严格。采用数学建模方法，我们研究了肿瘤特性和HAP辐射调度如何影响模拟肿瘤的治疗结果。以下关键结果在计算机上得到证实：（i）HAP和电离辐射（IR）单一疗法可能以不同的互补方式攻击肿瘤。（ii）HAP-IR调度可能影响治疗功效。（iii）HAP可用作IR治疗增强器。（iv）时空肿瘤内氧景观可能影响HAP功效。Ourin silicoframework是基于一个跨越三维空间的非格、混合、多尺度元胞自动机。肿瘤球体生长的数学模型由多细胞肿瘤球体（MCTS）数据参数化。
Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successfulin vitroandin 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 demonstratedin 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. Ourin silicoframework 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.