Evaluation of synergism by a novel three-dimensional model for the combined action of cisplatin and etoposide on the growth of a human small-cell lung-cancer cell line, SBC-3.
Although the combination of cisplatin and etoposide has been used as standard therapy for small-cell lung cancer, it is difficult to demonstrate combination effects between cisplatin and etoposide in vitro. We therefore adopted a 3-dimensional (3-D) model to analyze the combination effects of anticancer drugs, and compared the results of analysis by the new 3-D model with those obtained from traditional 2-D models for the cisplatin-etoposide combination. In this study, using a human small-cell lung-cancer cell line (SBC-3), 3-D model analysis clearly identified a relationship depending on the concentrations of both drugs, and demonstrated that peak synergy occurred at the higher concentrations of cisplatin and etoposide. Antagonistic interactions were noted with a nadir at low concentrations of etoposide and cisplatin. In contrast, 2-D models such as combination index and isobologam analysis fail to characterize the complex interactions between cisplatin and etoposide, since their joint effects are concentration-dependent. Combination index (CI) plots show that synergy is evident only for molar ratios of cisplatin: etoposide of 2:1 to 1:5. On isobologram analysis, synergy could be detected when great inhibitory effects on cell growth were present (high endpoint), but not with small inhibitory effects (lower endpoints). Thus, either synergy or antagonism may occur, but depend on the selection of variables, such as the molar ratios or the endpoints chosen for the experiments. This could explain the inconsistency in the in vitro combination effects reported to date. The 3-D model, which compensates for the above deficiencies of 2-D models, can facilitate rigorous analysis of drug interactions over the entire clinical dose range, using microcomputers and sophisticated graphics programs. This direct and pragmatic method offers investigators a practical new tool with which to analyze drug combinations for cancer chemotherapy.
Kanzawa
F
F
Pharmacology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. fkanzawa@gan2.ncc.go.jp
Nishio
K
K
Fukuoka
K
K
Fukuda
M
M
Kunimoto
T
T
Saijo
N
N
D000970:Antineoplastic Agents / Q000633:toxicity*; D018288:Carcinoma, Small Cell; D002455:Cell Division / Q000187:drug effects*; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004357:Drug Synergism; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006801:Humans; D008175:Lung Neoplasms; D008962:Models, Theoretical; D011336:Probability; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005047:Etoposide; D002945:Cisplatin