Synergistic interaction between oxaliplatin and SN-38 in human gastric cancer cell lines in vitro.
The interaction between CPT-11 and oxaliplatin, a new platinum derivative that has a great antitumor activity against colon cancer, has not been determined in gastric cancer cells. In this study, we investigated in vitro cytotoxic activity of oxaliplatin alone or in combination with SN-38, an active metabolite of CPT-11, using different exposure schedules in three human gastric cancer cell lines (AZ-521, MKN-45, and NUGC-4). Cytotoxicity was determined by WST-1 assay. Different treatment schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation was evaluated by flow cytometry. In 24-h exposure, simultaneous administration of oxaliplatin and SN-38 showed a synergistic effect in AZ-521 and NUGC-4 cells, and an additive effect in MKN-45 cells. Greater than additive effects were observed in all of the cell lines when cells were treated with oxaliplatin followed by SN-38, whereas such effects were observed only in NUGC-4 cells in the reverse sequence. Flow cytometric analyses at IC(50) indicated that apoptosis was most prominent in simultaneous exposures with accumulation of cells in both G(0)/G(1) and S phases. These results suggest that SN-38 may kill the cells recovering from the G(1) block produced by oxaliplatin as they progress into the S phase. Simultaneous administration appears most active in gastric cancer cell lines. These results may provide important information for a clinical trial of oxaliplatin and CPT-11 combination for patients with gastric cancer.
Tanaka
Risa
R
First Department of Internal Medicin, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Ariyama
Hiroshi
H
Qin
Baoli
B
Shibata
Yoshihiro
Y
Takii
Yasushi
Y
Kusaba
Hitoshi
H
Baba
Eishi
E
Mitsugi
Kenji
K
Harada
Mine
M
Nakano
Shuji
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D013274:Stomach Neoplasms / Q000473:pathology / Q000503:physiopathology
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002166:Camptothecin