Application of a new approach for the quantitation of drug synergism to the combination of cis-diamminedichloroplatinum and 1-beta-D-arabinofuranosylcytosine.
Application of a new approach for the quantitation of drug synergism to the combination of cis-diamminedichloroplatinum and 1-beta-D-arabinofuranosylcytosine.
复制标题
DOI：
--
复制
发表时间：
1990-09
期刊：
影响因子：
11.2
通讯作者：
William R. Greco;Hyoung Sook Park;Y. Rustum
中科院分区：
文献类型：
--
作者：
William R. Greco;Hyoung Sook Park;Y. Rustum
本报告描述了一种新方法（通用响应面方法）在药物相互作用定量评估中的应用，即确定协同作用、拮抗作用、加和性、增强作用、抑制作用和联合作用。本次介绍性应用的具体药物组合和实验生长系统是 1-β-D-阿拉伯呋喃糖基胞嘧啶 (ara-C) 和顺铂同时药物暴露（1、3、6、12 或 48 小时），在体外对抗 L1210 白血病。为了定量药物相互作用的类型和程度，使用非线性回归对每个单独实验的数据拟合模型，并估计参数（K. C. Syracuse 和 W. R. Greco, Proc. Biopharm. Sect. Am. Stat. Assoc., 127-132, 1986）。这些参数包括不存在药物时背景上的最大细胞密度、存在无限药物时的背景细胞密度、每种药物的 50% 抑制浓度和浓度效应斜率，以及协同-拮抗参数 α。正 alpha 表示协同作用，负 alpha 表示拮抗作用，零 alpha 表示加和作用。在两个单独的实验中，ara-C + 顺铂暴露 3 小时发现最大协同作用，α = 3.08 +/- 0.96 (SE) 和 2.44 +/- 0.70。原始数据和拟合曲线的四种不同图形表示提供了估计剂量反应表面与数据的拟合优度的视觉指示以及药物相互作用强度的视觉指示。通用响应面方法在数学上与传统等值线图方法一致，但更客观、更定量并且更容易自动化。虽然通用响应面方法是专门为体外癌症化疗应用而开发的，但应该证明它在药理学、毒理学、流行病学和生物医学科学领域是有用的。
This report describes the application of a new approach, the universal response surface approach, to the quantitative assessment of drug interaction, i.e., the determination of synergism, antagonism, additivity, potentiation, inhibition, and coalitive action. The specific drug combination and experimental growth system for this introductory application was that of 1-beta-D-arabinofuranosylcytosine (ara-C) and cisplatin with simultaneous drug exposure (1, 3, 6, 12, or 48 h) against L1210 leukemia in vitro. To quantitate the type and degree of drug interaction, a model was fitted using nonlinear regression to the data from each separate experiment, and parameters were estimated (K. C. Syracuse and W. R. Greco, Proc. Biopharm. Sect. Am. Stat. Assoc., 127-132, 1986). The parameters included the maximum cell density over background in absence of drug, the background cell density in presence of infinite drug, the 50% inhibitory concentrations and concentration-effect slopes for each drug, and a synergism-antagonism parameter, alpha. A positive alpha indicates synergism, a negative alpha, antagonism, and a zero alpha, additivity. Maximal synergy was found with a 3-h exposure of ara-C + cisplatin, with alpha = 3.08 +/- 0.96 (SE) and 2.44 +/- 0.70 in two separate experiments. Four different graphic representations of the raw data and fitted curves provide visual indications of goodness of fit of the estimated dose-response surface to the data and visual indications of the intensity of drug interaction. The universal response surface approach is mathematically consistent with the traditional isobologram approach but is more objective, is more quantitative, and is more easily automated. Although specifically developed for in vitro cancer chemotherapy applications, the universal response surface approach should prove to be useful in the fields of pharmacology, toxicology, epidemiology, and biomedical science in general.