Kim Songtae, Toyokawa Hideyoshi, Yamao Jun, Satoi Sohei, Yanagimoto Hiroaki, Yamamoto Tomohisa, Hirooka Satoshi, Yamaki So, Inoue Kentaro, Matsui Yoichi, Kwon A-Hon
From the Department of Surgery, Kansai Medical University, Hirakata, Osaka, Japan.
Pancreas. 2014 Aug;43(6):886-90. doi: 10.1097/MPA.0000000000000125.
The aim of this study was to investigate the synergistic inhibitory effects of gemcitabine and losartan, angiotensin II type 1 (AT1) receptor blockers, on an orthotopic rat pancreatic cancer model.
The rat orthotopic pancreatic cancer model was prepared using DSL-6A/C cells, a rat ductal pancreatic adenocarcinoma cell line. The rats were treated with gemcitabine alone (100 mg/kg per week), losartan alone (100 mg/kg per day), or gemcitabine plus losartan.
Survival was significantly improved by treatment with gemcitabine (89.6 ± 21.8 days) or losartan (76.9 ± 18.7 days) alone compared with that in the control group (59.6 ± 13.4 days; P < 0.05). Treatment with gemcitabine plus losartan further prolonged the survival time to 102.6 ± 16.5 days compared with that in the control group (P < 0.0001). Gemcitabine or losartan significantly and dose-dependently reduced the proliferation of DSL-6A/C cells in vitro. Both drugs inhibited pancreatic vascular endothelial growth factor expression compared with that in the control group (P < 0.05).
The results of this study indicate that combined treatment with gemcitabine and losartan significantly improved the survival of rats with orthotopic pancreatic cancer by inhibiting vascular endothelial growth factor synthesis and suppressing cancer cell proliferation via AT1 receptor blockade. Thus, an AT1 receptor blocker in combination with gemcitabine might improve the clinical outcomes of patients with advanced pancreatic cancer.
本研究旨在探讨吉西他滨与1型血管紧张素II（AT1）受体阻滞剂氯沙坦对大鼠原位胰腺癌模型的协同抑制作用。
采用大鼠胰腺导管腺癌细胞系DSL-6A/C细胞制备大鼠原位胰腺癌模型。大鼠分别接受单独吉西他滨（每周100mg/kg）、单独氯沙坦（每日100mg/kg）或吉西他滨加氯沙坦治疗。
与对照组（59.6±13.4天）相比，单独使用吉西他滨（89.6±21.8天）或氯沙坦（76.9±18.7天）治疗可显著提高生存率（P<0.05）。与对照组相比，吉西他滨加氯沙坦治疗进一步将生存时间延长至102.6±16.5天（P<0.0001）。吉西他滨或氯沙坦在体外显著且剂量依赖性地降低了DSL-6A/C细胞的增殖。与对照组相比，两种药物均抑制胰腺血管内皮生长因子的表达（P<0.05）。
本研究结果表明，吉西他滨与氯沙坦联合治疗通过抑制血管内皮生长因子合成和通过AT1受体阻断抑制癌细胞增殖，显著提高了原位胰腺癌大鼠的生存率。因此，AT1受体阻滞剂与吉西他滨联合使用可能会改善晚期胰腺癌患者的临床疗效。
