利与害之间的细微界限：高热对不同胃肠道癌细胞中顺铂细胞毒性的相加作用。

Narrow line between benefit and harm: Additivity of hyperthermia to cisplatin cytotoxicity in different gastrointestinal cancer cells.

机构信息

Department of Surgery, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania.

Department of Obstetrics and Gynecology, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania.

出版信息

World J Gastroenterol. 2018 Mar 14;24(10):1072-1083. doi: 10.3748/wjg.v24.i10.1072.

AIM

To investigate the response to hyperthermia and chemotherapy, analyzing apoptosis, cytotoxicity, and cisplatin concentration in different digestive system cancer cells.

METHODS

AGS (gastric cancer cell line), Caco-2 (colon cancer cell line) and T3M4 (pancreatic cancer cell line) were treated by cisplatin and different temperature setting (37 °C to 45 °C) either in isolation, or in combination. Treatment lasted for one hour. 48 h after the treatment viability was evaluated by MTT, cell apoptosis by Annexin V-PE and 7ADD flow cytometry. Intracellular cisplatin concentration was measured immediately after the treatment, using mass spectrometry. Isobologram analysis was performed to evaluate the mathematical combined effect of temperature and cisplatin.

RESULTS

AGS cells were the most sensitive to isolated application of hyperthermia. Hyperthermia, in addition to cisplatin treatment, did not provoke a synergistic effect at intervals from 37 °C to 41 °C in neither cancer cell line. However, a temperature of 43 °C enhanced cisplatin cytotoxicity for Caco-2 cells. Moreover, isobologram analysis revealed mathematical antagonistic effects of cisplatin and temperature combined treatment in AGS cells; variations between synergistic, additive, and antagonistic effects in Caco-2 cells; and additive and antagonistic effects in T3M4 cells. Combined treatment enhanced initiation of cell apoptosis in AGS, Caco-2, and T3M4 cells by 61%, 20%, and 19% respectively. The increase of intracellular cisplatin concentration was observed at 43 °C by 30%, 20%, and 18% in AGS, Caco-2, and T3M4 cells, respectively.

CONCLUSION

In addition to cisplatin, hyperthermia up to 43 °C does not affect the viability of cancer cells in a synergistic manner.

目的

研究不同消化系统癌细胞对热疗和化疗的反应，分析细胞凋亡、细胞毒性和顺铂浓度。

方法

AGS（胃癌细胞系）、Caco-2（结肠癌细胞系）和 T3M4（胰腺癌细胞系）分别用顺铂和不同温度（37°C 至 45°C）处理，或单独处理，或联合处理。治疗持续 1 小时。处理后 48 小时，通过 MTT 评估细胞活力，通过 Annexin V-PE 和 7ADD 流式细胞术评估细胞凋亡。用质谱法立即测量处理后细胞内顺铂浓度。采用棋盘分析评估温度和顺铂联合应用的数学联合效应。

结果

AGS 细胞对单独应用热疗最敏感。在间隔 37°C 至 41°C 的情况下，除顺铂处理外，热疗对两种癌细胞系均未引起协同作用。然而，43°C 的温度增强了 Caco-2 细胞中顺铂的细胞毒性。此外，棋盘分析显示顺铂和温度联合处理在 AGS 细胞中具有数学拮抗作用；在 Caco-2 细胞中观察到协同、相加和拮抗作用的变化；在 T3M4 细胞中观察到相加和拮抗作用。联合处理分别使 AGS、Caco-2 和 T3M4 细胞中细胞凋亡的起始增加了 61%、20%和 19%。在 AGS、Caco-2 和 T3M4 细胞中，分别观察到 43°C 时细胞内顺铂浓度增加了 30%、20%和 18%。