姜黄素与阿霉素联用体外抗肿瘤作用的参数法和反应曲面法分析_吕映华

姜黄素与阿霉素联用体外抗肿瘤作用的参数法和反应曲面法分析吕映华, 杨娟, 陈君超, 李禄金, 刘红霞, 郑青山*

(上海中医药大学药物临床研究中心、计算药物学实验室, 上海 201203)

摘要: 对姜黄素 (Cur) 与阿霉素 (ADM) 体外抗肿瘤的相互作用进行全面定量评价, 为寻找药物最优组合提供更多信息。按照析因设计和数据类型, 选择两种相互作用分析模型(参数法和反应曲面法), 利用计算机模拟手段, 对不同剂量的Cur与ADM联用的体外抗肿瘤作用进行全面的定性和定量评价, 反映剂量变化的相互作用动态结果, 寻找最优组合和配比。结果提示, 与单用相比, ADM与Cur固定配比 (1∶3) 联用时, 量效关系变陡且左移。即当ADM (0.693～2.132 μmol·L−1) 与Cur (2.047～6.304 μmol·L−1) 按固定配比 (1∶3) 联用时, 可对K562细胞体外杀伤作用呈现协同性作用; 在同一配比, 在ADM大于2.132 μmol·L−1与Cur大于6.304 μmol·L−1时, 实测效应与期望效应趋同, 表现为相加性相互作用。反应曲面法分析得出理论上最佳组方为Cur 18.50 μmol·L−1和ADM 3.89 μmol·L−1, 配比为5∶1, 理论上达到最优药效。本研究表明, 析因设计类数据, 需要多种方法结合, 方能提供更丰富、更合理的结果, 有利于组方的定量设计, 阐明相互作用性质与程度。

关键词: 药物相互作用; 参数法; 反应曲面; 协同; 拮抗; 计算机模拟; 姜黄素; 阿霉素

中图分类号: R969.2 文献标识码:A 文章编号: 0513-4870 (2010) 08-1039-04

In vitro pharmacodynamic interactions of antitumor effect

of the combination of adriamycin and curcumin evaluated

by the parameter method and the response surface LÜ Ying-hua, YANG Juan, CHEN Jun-chao, LI Lu-jin, LIU Hong-xia, ZHENG Qing-shan*

(Laboratory of Pharmacometrics, Center for Drug Clinical Research, Shanghai University of Chinese Medicine,

201203 Shanghai, China)

Abstract: The paper aimed to find the optimal combination and evaluation of the interactions of antitumor effect of the curcumin (Cur) and adriamycin (ADM) in vitro.According to the factorial design and data characteristics, the parameter method combined with the response surface approach were used to analyze the pharmacodynamic interactions of in vitro antitumor effects of the combination of Cur and ADM at different dosages. The results showed that the dose-effect relationship of the combination with the ratio of ADM-Cur 1∶3 showed significant differences in comparison with either used alone. The dose-effect curve was shift left in combination. The combination of adriamycin (ADM, 0.693−2.132 μmol·L−1) and curcumin (Cur, 2.047−

6.304 μmol·L−1) with a fixed ratio (1∶3) showed a synergism. With increasing doses of the combination, there

is an additive effect. Computer simulation showed a trend of decreasing difference between the observed and expected effects with the dose increasing in Cur from 6.304 to 16.0 μmol·L−1 and ADM from 2.132 to 5.3 μmol·L−1. The response surface analysis showed the optimal combination to be Cur 18.50 μmol·L−1 and ADM

3.89 μmol·L−1 with a ratio of 5∶1. This study suggests that the parameter method combined with the response

surface analysis provides richer and more reasonable information, and is helpful for quantitative design of drug

收稿日期: 2010-01-20.

基金项目: 国家科技支撑计划项目 (2008BAI51B03, 2009ZX09502-021); 上海市教委项目(J50303, 2008GSP19-5, szy08058); 上海市高校中医内科学E-研究院资助项目 (E03008).

*通讯作者 Tel: 86-21-51323006, Fax: 86-21-51322750, E-mail: zhengqscn@