Tanaka Risa, Ariyama Hiroshi, Qin Baoli, Shibata Yoshihiro, Takii Yasushi, Kusaba Hitoshi, Baba Eishi, Mitsugi Kenji, Harada Mine, Nakano Shuji
First Department of Internal Medicin, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Oncol Rep. 2005 Sep;14(3):683-8.
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.
CPT - 11与奥沙利铂（一种对结肠癌具有强大抗肿瘤活性的新型铂衍生物）之间的相互作用尚未在胃癌细胞中得到确定。在本研究中，我们使用三种人胃癌细胞系（AZ - 521、MKN - 45和NUGC - 4），通过不同的暴露方案，研究了单独使用奥沙利铂或与CPT - 11的活性代谢产物SN - 38联合使用时的体外细胞毒性活性。通过WST - 1测定法确定细胞毒性。基于Chou和Talalay的中位效应原理，采用定量方法比较和评估了两种药物的不同治疗方案的协同性、相加性或拮抗性。通过流式细胞术评估细胞周期扰动。在24小时暴露中，同时给予奥沙利铂和SN - 38在AZ - 521和NUGC - 4细胞中显示出协同作用，在MKN - 45细胞中显示出相加作用。当先用奥沙利铂处理细胞然后再用SN - 38处理时，在所有细胞系中均观察到大于相加的效应，而在相反顺序处理时，仅在NUGC - 4细胞中观察到这种效应。在IC(50)水平的流式细胞术分析表明，在同时暴露时细胞凋亡最为显著，细胞在G(0)/G(1)期和S期均有积累。这些结果表明，SN - 38可能杀死从奥沙利铂产生的G(1)期阻滞中恢复并进入S期的细胞。同时给药在胃癌细胞系中似乎最具活性。这些结果可能为奥沙利铂和CPT - 11联合用于胃癌患者的临床试验提供重要信息。
