Chou T C, Motzer R J, Tong Y, Bosl G J
Molecular Pharmacology and Therapeutics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
J Natl Cancer Inst. 1994 Oct 19;86(20):1517-24. doi: 10.1093/jnci/86.20.1517.
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 firstline regimens fail are cured with the salvage regimens.
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.
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.
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 > or = paclitaxel + cisplatin + topotecan > paclitaxel + topotecan > or = paclitaxel + etoposide > paclitaxel + cisplatin + etoposide > paclitaxel + cisplatin. All other combinations showed nearly additive effects or moderate antagonism. The degrees of antagonism were as follows: cisplatin + etoposide > or = paclitaxel + vincristine > paclitaxel + cisplatin + vincristine > cisplastin + 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.
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.
基于顺铂的诱导化疗可使70%-80%的生殖细胞肿瘤患者获得完全缓解（即治疗后无肿瘤迹象）。然而，一线治疗方案失败的患者中只有少数通过挽救方案治愈。
这些研究的目的是通过对两种有前景的新型抗肿瘤药物（紫杉醇和拓扑替康）以及三种更成熟的药物（顺铂、长春新碱和依托泊苷）进行体外定量评估，来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两药及三药联合使用，选择它们是因为它们代表了五类不同的抗肿瘤机制。
基于Chou和Talalay提出的中位效应原理的联合指数-等效线图法用于计算机数据分析。选择该方法是因为它既考虑了每种药物及其组合的效力，也考虑了它们剂量-效应曲线的形状。
对顺铂耐药的畸胎瘤细胞（833K/64CP10细胞）生长的协同作用大于对亲本833K细胞生长的协同作用。协同程度依次为：顺铂+拓扑替康≥紫杉醇+顺铂+拓扑替康＞紫杉醇+拓扑替康≥紫杉醇+依托泊苷＞紫杉醇+顺铂+依托泊苷＞紫杉醇+顺铂。所有其他组合显示出几乎相加的效应或中度拮抗作用。拮抗程度如下：顺铂+依托泊苷≥紫杉醇+长春新碱＞紫杉醇+顺铂+长春新碱＞顺铂+长春新碱。紫杉醇和顺铂的组合对833K/64CP10细胞具有协同作用，对833K细胞具有中度拮抗作用。由于紫杉醇、顺铂和拓扑替康的组合以及这些药物的两组分组合（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本研究所开发的计算机软件程序来说明详细的数据分析。
我们的研究结果表明，由于协同作用，这些药物联合使用时达到抗肿瘤效果所需的剂量可能会减少两倍至八倍。目前关于协同或拮抗作用的定量数据分析为晚期生殖细胞肿瘤患者联合化疗临床方案的合理设计提供了依据。
