基于数学建模和肿瘤细胞PK/PD研究中药逆转肿瘤多药耐药的体内外相关性

项目名称： 基于数学建模和肿瘤细胞PK/PD研究中药逆转肿瘤多药耐药的体内外相关性

项目编号： No.81473434

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 熊阳

作者单位： 浙江中医药大学

项目金额： 68万元

中文摘要： 逆转肿瘤多药耐药（MDR）是国内外医药界的重要课题。中药逆转肿瘤MDR效果较好且毒性低。但中药成分复杂，体内外药效评价很难建立有效关联，无法通过体外预测体内，目前基本依靠体内药效试验进行逆转剂筛选与评价，效率低成本高；且临床与化疗药物联合用药方案缺乏科学的理论指导。针对以上问题，根据D-荧光素钾和腔肠素在肿瘤细胞的外排动力学（PK）与ABC转运子药泵活性密切相关的理论支持，通过构建双萤光素酶报告基因系统，结合活体生物发光技术，以萤光素的肿瘤细胞PK作为联系纽带，采用典型相关分析方法对体内外PK参数的相关性进行整体性分析，然后通过基于遗传算法的非线性建模法，构建具有一定信度和效度的体内PK-PD函数模型，达到从体外萤光素PK仿真预测体内PK-PD的目的，体外高效率低成本的系统筛选和评价逆转MDR的中药，优化逆转剂与化疗药物的联合用药方案。该方法开启了抗肿瘤MDR中药逆转剂的研究新模式。

中文关键词： 中药逆转剂；肿瘤多药耐药；数学建模；肿瘤细胞药动/药效；体内外相关性

英文摘要： Reversing multidrug resistance (MDR) of tumor is an important topic at home and abroad. Traditional Chinese medicine（TCM）could be excellent MDR inhibitors as its good effect and low toxicity. But because of the complication of TCM components, the valid correlations could be hardly established between the in vitro and in vivo pharmacodynamic action(PD). Now the screening and evalution of TCM inhibitors mostly depends on pharmacodynamic trial in vivo, which is of high cost and low efficiency. More over, the usage of these TCM most rely on clinical experiences without scientific theory directing its combined use with chemotheropeutics. To solve these problems, based on the theory that the pharmacokinetics(PK) of D-luciferin potassium salt and coelenterazine in tumor cells are highly related with the drug pump activity of ATP-binding cassette transporters, dual-luciferase reporter assay system would be constructed combined with bioluminescence imaging technology to study PK in tumor cells of D-luciferin potassium salt and coelenterazine in vitro and in vivo. Then the PK of these two luciferases would be used as vinculum between in vitro and in vivo.The correlation of these PK parameters between in vivo and in vitro would be carried out integral analysis by canonical correlation analysis. Then nonlinear mathematical modeling method based on genetic algorithm would be selected to establishe the PK-PD model in vivo. Thus, with the correlations of PK in vitro and in vivo, the PK-PD in vivo could be predicted by PK in vitro. Using these models, systemic screening and evaluation of TCM inhibitors and optimization of its combinational usage with chemotherapeutics could be depend on in vitro trial to the maximum extent possible with high efficiency and low cost. This method would open a new mode to study TCM inhibitors reversing tumor MDR.

英文关键词： inhibitors of traditional Chinese medicine;multidrug-resistance;mathematical modeling;PK/PD of tumor cell;in vitro-in vivo correlations