COMPUTERIZED QUANTITATION OF SYNERGISM AND ANTAGONISM OF TAXOL, TOPOTECAN, AND CISPLATIN AGAINST HUMAN TERATOCARCINOMA CELL-GROWTH - A RATIONAL APPROACH TO CLINICAL PROTOCOL DESIGN

Background: Cisplatin-based induction chemotherapy may achieve a compl ete response (i.e., no sign of tumor following treatment) in 70%-80% o f patients with germ cell tumors. However, only a minority of patients in whom the first-line regimens fail are cured with the salvage regim ens. Purpose: The aim of these studies was to identify new agents or n ew regimens for the treatment of germ cell tumors by carrying out quan titative assessment in vitro of two promising new antitumor agents (pa clitaxel [Taxol] and topotecan) and three more established agents (cis platin, vincristine, and etoposide). These agents were used singly or in two- and three-drug combinations and were selected because they rep resent five distinct categories of antineoplastic mechanisms. Methods: The combination index-isobologram method, which is based on the media n-effect principle developed by Chou and Talalay, was used for compute rized data analysis. This method was selected because it takes into ac count 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/64CP 10 cells) was greater than against the growth of parent 833K cells. Th e degrees of synergism were in the following order: cisplatin + topote can greater than or equal to paclitaxel + cisplatin + topotecan > pacl itaxel + topotecan greater than or equal to paclitaxel + etoposide > p aclitaxel + cisplatin + etoposide > paclitaxel + cisplatin, All other combinations showed nearly additive effects or moderate antagonism. Th e degrees of antagonism were an follows: cisplatin + etoposide greater than or equal to paclitaxel + vincristine > paclitaxel + cisplatin vincristine > cisplatin + vincristine. The combination of paclitaxel a nd 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 d rugs (cisplatin + topotecan and paclitaxel + topotecan) showed synergi sm stronger than that of other combinations, these three drugs were se lected for illustrating detailed data analysis, using a computer softw are 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 twofol d to eightfold when these agents are given in combination. The present quantitative data analyses for synergism or antagonism provide a basi s for a rational design of clinical protocols for combination chemothe rapy in patients with advanced germ cell tumors.