ORIGINAL ARTICLE
Antitumor Effect of Angiotensin II Type 1 Receptor Blocker Losartan for Orthotopic Rat Pancreatic Adenocarcinoma Songtae Kim, MD, Hideyoshi Toyokawa, MD, Jun Yamao, MD, Sohei Satoi, MD, Hiroaki Yanagimoto, MD, Tomohisa Yamamoto, MD, Satoshi Hirooka, MD, So Yamaki, MD, Kentaro Inoue, MD, Yoichi Matsui, MD, and A-Hon Kwon, MD
Objective: 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. Methods: 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. Results: Survival was significantly improved by treatment with gemcitabine (89.6 T 21.8 days) or losartan (76.9 T 18.7 days) alone compared with that in the control group (59.6 T 13.4 days; P G 0.05). Treatment with gemcitabine plus losartan further prolonged the survival time to 102.6 T 16.5 days compared with that in the control group (P G 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 G 0.05). Conclusions: 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. Key Words: angiotensin II type 1 receptor blocker, rat, pancreatic adenocarcinoma (Pancreas 2014;43: 886Y890)
A
denocarcinoma of the pancreas is associated with a poor prognosis and is often unresectable despite recent developments in surgical techniques, chemotherapy, irradiation, and immunotherapy. In most patients, the disease, when detected, is usually already well developed locally or has already metastasized. Thus, the overall 5-year survival rate of these patients is less than 5%,1 with a median survival after diagnosis of approximately 6 months. Chemotherapy with gemcitabine has been used for patients with pancreatic cancer since 1997, but the response rate is unsatisfactory at about 12% to 27%. Recently, several studies have investigated gemcitabine-based combination regimens to improve therapeutic efficacy. Erlotinib (an epidermal growth factor receptor inhibitor) combined with gemcitabine improved the overall survival and was approved for clinical use in the United States of America and in Europe.2 Meanwhile, a phase II study of S-1 in patients with metastatic pancreatic cancer yielded a good response rate of 37.5% and a median survival of 9.2 months.3 However, most of the studies to date have found limited benefits of the newer drugs on survival, partly because they are associated From the Department of Surgery, Kansai Medical University, Hirakata, Osaka, Japan. Received for publication May 22, 2013; accepted January 28, 2014. Reprints: Hideyoshi Toyokawa, MD, Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1191, Japan (e
Antitumor Effect of Angiotensin II Type 1 Receptor Blocker Losartan for Orthotopic Rat Pancreatic Adenocarcinoma Songtae Kim, MD, Hideyoshi Toyokawa, MD, Jun Yamao, MD, Sohei Satoi, MD, Hiroaki Yanagimoto, MD, Tomohisa Yamamoto, MD, Satoshi Hirooka, MD, So Yamaki, MD, Kentaro Inoue, MD, Yoichi Matsui, MD, and A-Hon Kwon, MD
Objective: 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. Methods: 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. Results: Survival was significantly improved by treatment with gemcitabine (89.6 T 21.8 days) or losartan (76.9 T 18.7 days) alone compared with that in the control group (59.6 T 13.4 days; P G 0.05). Treatment with gemcitabine plus losartan further prolonged the survival time to 102.6 T 16.5 days compared with that in the control group (P G 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 G 0.05). Conclusions: 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. Key Words: angiotensin II type 1 receptor blocker, rat, pancreatic adenocarcinoma (Pancreas 2014;43: 886Y890)
A
denocarcinoma of the pancreas is associated with a poor prognosis and is often unresectable despite recent developments in surgical techniques, chemotherapy, irradiation, and immunotherapy. In most patients, the disease, when detected, is usually already well developed locally or has already metastasized. Thus, the overall 5-year survival rate of these patients is less than 5%,1 with a median survival after diagnosis of approximately 6 months. Chemotherapy with gemcitabine has been used for patients with pancreatic cancer since 1997, but the response rate is unsatisfactory at about 12% to 27%. Recently, several studies have investigated gemcitabine-based combination regimens to improve therapeutic efficacy. Erlotinib (an epidermal growth factor receptor inhibitor) combined with gemcitabine improved the overall survival and was approved for clinical use in the United States of America and in Europe.2 Meanwhile, a phase II study of S-1 in patients with metastatic pancreatic cancer yielded a good response rate of 37.5% and a median survival of 9.2 months.3 However, most of the studies to date have found limited benefits of the newer drugs on survival, partly because they are associated From the Department of Surgery, Kansai Medical University, Hirakata, Osaka, Japan. Received for publication May 22, 2013; accepted January 28, 2014. Reprints: Hideyoshi Toyokawa, MD, Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1191, Japan (e
