高温腹腔内热化疗（HIPEC）中顺铂类药物丝裂霉素 C 和 5-FU 的温度依赖性在结直肠癌细胞系中的作用。

The Temperature-Dependent Effectiveness of Platinum-Based Drugs Mitomycin-C and 5-FU during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Cell Lines.

机构信息

Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers (UMC), University of Amsterdam, Cancer Center Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.

Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.

出版信息

Cells. 2020 Jul 25;9(8):1775. doi: 10.3390/cells9081775.

UNLABELLED

Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment with curative intent for peritoneal metastasis of colorectal cancer (CRC). Currently, there is no standardized HIPEC protocol: choice of drug, perfusate temperature, and duration of treatment vary per institute. We investigated the temperature-dependent effectiveness of drugs often used in HIPEC.

METHODS

The effect of temperature on drug uptake, DNA damage, apoptosis, cell cycle distribution, and cell growth were assessed using the temperature-dependent IC50 and Thermal Enhancement Ratio (TER) values of the chemotherapeutic drugs cisplatin, oxaliplatin, carboplatin, mitomycin-C (MMC), and 5-fluorouracil (5-FU) on 2D and 3D CRC cell cultures at clinically relevant hyperthermic conditions (38-43 °C/60 min).

RESULTS

Hyperthermia alone decreased cell viability and clonogenicity of all cell lines. Treatment with platinum-based drugs and MMC resulted in G2-arrest. Platinum-based drugs display a temperature-dependent synergy with heat, with increased drug uptake, DNA damage, and apoptosis at elevated temperatures. Apoptotic levels increased after treatment with MMC or 5-FU, without a synergy with heat.

CONCLUSION

Our in vitro results demonstrate that a 60-min exposure of platinum-based drugs and MMC are effective in treating 2D and 3D CRC cell cultures, where platinum-based drugs require hyperthermia (>41 °C) to augment effectivity, suggesting that they are, in principle, suitable for HIPEC.

未加标签

细胞减灭术（CRS）联合腹腔内热灌注化疗（HIPEC）是一种有治愈意图的结直肠癌（CRC）腹膜转移治疗方法。目前，尚无标准化的 HIPEC 方案：药物选择、灌注液温度和治疗持续时间因机构而异。我们研究了 HIPEC 中常用药物的温度依赖性疗效。

方法

使用温度依赖性 IC50 和热增强比（TER）值评估温度对药物摄取、DNA 损伤、细胞凋亡、细胞周期分布和细胞生长的影响，研究了化疗药物顺铂、奥沙利铂、卡铂、丝裂霉素-C（MMC）和 5-氟尿嘧啶（5-FU）在二维和三维 CRC 细胞培养物中的作用在临床相关的高热条件下（38-43°C/60 分钟）。