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

摘要

Author summary Studies in 3D cultures, notably multicellular tumour spheroids that mimic many features of solid tumours, have great potential for speeding up anticancer drug development. However the increased complexity of 3D cultures makes interpretation of experiments more difficult. We have developed a hybrid continuum/agent-based mathematical model, validated by experiments, to aid interpretation of spheroid experiments in developing drugs designed to eliminate radiation-resistant hypoxic cells. This model includes key features of the tumour microenvironment including oxygen and glucose transport and regions of hypoxia where the cells are resistant to radiation, but sensitive to hypoxia-activated prodrugs such as SN30000. This enables us to predict the growth and cell response in untreated spheroids and compare the results to spheroids treated with radiation and SN30000. We demonstrate good prediction of cellular responses in spheroids treated with radiation and SN30000 and good agreement with spheroid regrowth after treatment when additional effects of cellular growth delay are added. This demonstrates that the modelling approach has potential to improve interpretation of experimental investigations of drug and radiation combinations.