COMPUTERIZED QUANTITATION OF SYNERGISM AND ANTAGONISM OF TAXOL, TOPOTECAN, AND CISPLATIN AGAINST HUMAN TERATOCARCINOMA CELL-GROWTH - A RATIONAL APPROACH TO CLINICAL PROTOCOL DESIGN
COMPUTERIZED QUANTITATION OF SYNERGISM AND ANTAGONISM OF TAXOL, TOPOTECAN, AND CISPLATIN AGAINST HUMAN TERATOCARCINOMA CELL-GROWTH - A RATIONAL APPROACH TO CLINICAL PROTOCOL DESIGN
复制标题
DOI：
10.1093/jnci/86.20.1517
复制
发表时间：
1994-10-19
影响因子：
10.3
通讯作者：
BOSL, GJ
中科院分区：
文献类型：
--
作者：
CHOU, TC;MOTZER, RJ;BOSL, GJ
背景：基于顺铂的诱导化疗可能会达到完全缓解（即，在70%-80%的生殖细胞肿瘤患者中，治疗后无肿瘤迹象）。然而，只有少数一线治疗方案失败的患者通过挽救治疗方案治愈。目的：这些研究的目的是通过对两种有前景的新抗肿瘤药物（紫杉醇[Taxol]和拓扑替康）和三种更成熟的药物（顺铂、长春新碱和依托泊苷）进行体外定量评估，确定治疗生殖细胞肿瘤的新药物或新方案。这些药物单独使用或以两种或三种药物组合使用，并被选择，因为它们代表了五种不同的药物代谢机制。研究方法：采用基于Chou和Talalay提出的中位效应原理的组合指数-等值线图法进行计算机数据分析。选择这种方法是因为它考虑了每种药物和这些药物的组合的效力以及它们的剂量效应曲线的形状。结果如下：对顺铂耐药的畸胎瘤细胞（833 K/64 CP 10细胞）的生长的协同作用大于对亲本833 K细胞的生长。协同作用的程度依次为：顺铂+托泊替康大于或等于紫杉醇+顺铂+托泊替康>紫杉醇+托泊替康大于或等于紫杉醇+依托泊苷>紫杉醇+顺铂+依托泊苷>紫杉醇+顺铂，所有其他组合均显示接近累加效应或中度拮抗作用。顺铂+足叶乙甙>紫杉醇+长春新碱>紫杉醇+顺铂+长春新碱>顺铂+长春新碱。紫杉醇和顺铂联合应用对833 K/64 CP 10细胞有协同作用，对833 K细胞有中度拮抗作用。由于紫杉醇、顺铂和拓扑替康的组合以及这些药物的双组分组合（顺铂+拓扑替康和紫杉醇+拓扑替康）显示出比其他组合更强的协同作用，因此选择这三种药物使用该研究所开发的计算机软件程序进行详细的数据分析。结论和影响：我们的研究结果表明，作为协同作用的结果，当这些药物联合给药时，达到抗肿瘤作用所需的这些药物的剂量可能会减少2倍至8倍。目前的协同或拮抗作用的定量数据分析提供了一个合理设计的临床方案，联合化疗晚期生殖细胞肿瘤患者的基础。
Background: Cisplatin-based induction chemotherapy may achieve a complete response (i.e., no sign of tumor following treatment) in 70%-80% of patients with germ cell tumors. However, only a minority of patients in whom the first-line regimens fail are cured with the salvage regimens. Purpose: The aim of these studies was to identify new agents or new regimens for the treatment of germ cell tumors by carrying out quantitative assessment in vitro of two promising new antitumor agents (paclitaxel [Taxol] and topotecan) and three more established agents (cisplatin, vincristine, and etoposide). These agents were used singly or in two- and three-drug combinations and were selected because they represent five distinct categories of antineoplastic mechanisms. Methods: The combination index-isobologram method, which is based on the median-effect principle developed by Chou and Talalay, was used for computerized data analysis. This method was selected because it takes into account both the potencies of each drug and combinations of these drugs and the shapes of their dose-effect curves. Results: Synergism against the growth of teratocarcinoma cells resistant to cisplatin (833K/64CP10 cells) was greater than against the growth of parent 833K cells. The degrees of synergism were in the following order: cisplatin + topotecan greater than or equal to paclitaxel + cisplatin + topotecan > paclitaxel + topotecan greater than or equal to paclitaxel + etoposide > paclitaxel + cisplatin + etoposide > paclitaxel + cisplatin, All other combinations showed nearly additive effects or moderate antagonism. The degrees of antagonism were an follows: cisplatin + etoposide greater than or equal to paclitaxel + vincristine > paclitaxel + cisplatin + vincristine > cisplatin + vincristine. The combination of paclitaxel and cisplatin was synergistic against 833K/64CP10 cells and moderately antagonistic against 833K cells. Since the combination of paclitaxel, cisplatin, and topotecan and the two-component combinations of these drugs (cisplatin + topotecan and paclitaxel + topotecan) showed synergism stronger than that of other combinations, these three drugs were selected for illustrating detailed data analysis, using a computer software program developed in this institute. Conclusions and Implications: Our findings suggest that, as a result of synergy, the doses of these agents needed to achieve an antitumor effect may be reduced by twofold to eightfold when these agents are given in combination. The present quantitative data analyses for synergism or antagonism provide a basis for a rational design of clinical protocols for combination chemotherapy in patients with advanced germ cell tumors.