An integrated systems-based modelling framework for investigating the effect of anticancer drugs on solid tumours

摘要

Background. The effectiveness of clinical chemotherapy is dependent on the penetration ofanticancer agents in tumour tissues and the responsiveness of tumour cells towards exposureto administered drugs. Most blood-borne anticancer drugs gain their access to tumour cells bygoing through a series of physical and biological processes, including convection in thetumour vasculature, extravasation across the capillary wall, penetration through the tumourinterstitium and finally translocation inside tumour cells. However, these transport processesare often impaired by the abnormal tumour microenvironment (i.e. irregular tumourvasculature, elevated interstitial fluid pressure, and extracellular matrix composition),resulting in limited drug concentration available at the target site. Upon interaction with theirintracellular targets, anticancer drugs induce multiple cellular signalling pathways, throughwhich they exert therapeutic effects with apoptosis (programmed cell death) being of primaryinterest. The way by which cellular signalling functions is extremely complex as cellularpathways are carried out in a complex and interconnected network and usually display highlynon-linear input-output relationships. Given the complexities associated with drug transportin tumour tissues and intracellular signal transduction, understanding the effect of anticancerdrugs on solid tumours presents a highly challenging problem.Methods. In this study, an integrated systems-based modelling framework is developedwhich is capable of (ⅰ) capturing relevant biological processes and their interconnections, and(ⅱ) providing predictive and mechanistic insight into the effects of chemotherapeutic agents.As a first attempt, the model starts with basic descriptions of the essential elements with afocus on their integration in the system. The essential modules include drug transport,intracellular apoptosis signalling and tumour cell density dynamics.Drug transport in tumour tissue is described by a diffusion-convection-reaction equation, withdoxorubicin as the anti-cancer drug for modelling purpose. Velocity field is obtained by