A mathematical model of combined therapies against cancer using viruses and inhibitors

作     者：TAO YouShan GUO Qian 

作者机构：Department of Applied MathematicsDong Hua UniversityShanghai 200051China Department of MathematicsShanghai Normal UniversityShanghai 200234China 

出 版 物：《Science China Mathematics》 (中国科学：数学（英文版）)

年 卷 期：2008年第51卷第12期

页      面：2315-2329页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China (Grant No. 10571023) 

主　　题：tumors oncolytic viruses MEK inhibitors mathematical modeling 35Q80 35R35 92A15 92C50 

摘      要：This paper deals with a procedure for combined therapies against cancer using oncolytic viruses and inhibitors. Replicating genetically modified adenoviruses infect cancer cells, reproduce inside them and eventually cause their death (lysis). As infected cells die, the viruses inside them are released and then proceed to infect other tumor cells. The successful entry of virus into cancer cells is related to the presence of the coxsackie-adenovirus receptor (CAR). Mitogen-activated protein kinase kinase (known as MEK) inhibitors can promote CAR expression, resulting in enhanced adenovirus entry into cancer cells. However, MEK inhibitors can also cause G1 cell-cycle arrest, inhibiting reproduction of the virus. To design an effective synergistic therapy, the promotion of virus infection must be optimally balanced with inhibition of virus production. We introduce a mathematical model to describe the effects of MEK inhibitors and viruses on tumor cells, and use it to explore the reduction of the tumor size that can be achieved by the combined therapies. Furthermore, we find an optimal dose of inhibitor: Poptimal = 1 - μ/δ for a certain initial density of cells (where μ is the removal rate of the dead cells and δ is the death rate of the infected cells). The optimal timing of MEK inhibitors is also numerically studied.