New therapeutic target for human cholangiocarcinoma: systemic analysis of drug sensitivity and drug resistance for predicting the efficacy of adjuvant gemcitabine-based chemotherapy

• Project/Area Number: 24592028
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Hiroshima University
• Principal Investigator: MURAKAMI Yoshiaki 広島大学, 医歯薬保健学研究院, 准教授 (10263683)
• Co-Investigator(Kenkyū-buntansha): 上村 健一郎 広島大学, 医歯薬保健学研究院, 講師 (60379873)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 胆道癌 / 抗癌剤代謝関連酵素 / Gemcitabine / S1 / 個別化治療 / 胆管癌 / 抗癌剤感受性 / 抗癌剤耐性 / 薬剤代謝タンパク / 5-FU / 胆道外科学 / 化学療法

Outline of Final Research Achievements

This study aims to assess hENT1 abundance and RRM1 expression in 127 patients with cholangiocarcinoma underwent adjuvant gemcitabine-based chemotherapy after resection. A RT-PCR and immunohistochemical assay were applied. Relationships between clinicopathologic factors, and disease-free and overall survival (DFS and OS) were evaluated.
High intratumoural hENT1 and RRM1 expression levels were observed in 86 (68%) and 67 (53%) patients by immunohistochemical assay. Linear correlation was observed between expression using immuhohistochemical assay and PCR assay (R=0.898; P<0.01). Concurrent high hENT1 and low RRM1 expression was a powerful independent predictor of prolonged DFS (P<0.001) and OS (P=0.001). We concluded that concurrent analysis of hENT1 and RRM1 expression may increase the predictive value of these biomarkers for survival of advanced cholangiocarcinoma patients treated with adjuvant gemcitabine-based chemotherapy.

Research Products

• [Journal Article] Elevated perioperative serum CA 19-9 levels are independent predictors of poor survival in patients with resectable cholangiocarcinoma. (2014)
  • Author(s): Kondo N, Murakami Y, Uemura K, Sudo T, Hashimoto Y, Sasaki H, Sueda T
  • Journal Title: J Surg Oncol Volume: 110 Pages: 422-429
  • Peer Reviewed
• [Journal Article] Perineural invasion in extrahepatic cholangiocarcinoma: prognostic impact and treatment strategies. (2013)
  • Author(s): Murakami Y, Uemura K, Sudo T, Hashimoto Y, Kondo N, Nakagawa N, Muto T, Sasaki H, Urabe K, Sueda T.
  • Journal Title: J Gastrointest Surg Volume: 17(8) Pages: 1429-1439
  • Peer Reviewed
• [Journal Article] Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection. (2013)
  • Author(s): Nakagawa N, Murakami Y, Uemura K, Sudo T, Hashimoto Y, Kondo N, Sueda T.
  • Journal Title: Surgery Volume: 153(4) Pages: 565-575
  • Peer Reviewed
• [Journal Article] Early initiation of adjuvant chemotherapy improves survival of patients with pancreatic carcinoma after surgical resection. (2013)
  • Author(s): Murakami Y, Uemura K, Sudo T, Hashimoto Y, Kondo N, Nakagawa N, Sasaki H, Sueda T.
  • Journal Title: Cancer Chemother Pharmacol. Volume: 71(2) Pages: 419-429
  • Peer Reviewed
• [Journal Article] 胆管癌の個別化治療 腫瘍内gemcitabineおよびS-1代謝関連酵素発現検索による術後補助化学療法の感受性予測 (2013)
  • Author(s): 村上 義昭, 上村 健一郎, 首藤 毅, 橋本 泰司, 近藤 成, 小林 弘典, 中川 直哉, 佐々木 勇人, 武藤 毅, 浦部 和秀, 岡田 健司郎, 末田 泰二郎
  • Journal Title: 胆と膵 Volume: 34巻2号 Pages: 155-164
• [Journal Article] Human equilibrative nucleoside transporter 1 expression predicts survival of advanced cholangiocarcinoma patients treated with gemcitabine-based adjuvant chemotherapy after surgical resection. (2012)
  • Author(s): Kobayashi H, Murakami Y, Uemura K, Sudo T, Hashimoto Y, Kondo N, Sueda T.
  • Journal Title: Ann Surg Volume: 256(2) Issue: 2 Pages: 288-296
  • DOI: 10.1097/sla.0b013e3182536a42
  • Peer Reviewed
• [Journal Article] Adjuvant chemotherapy with gemcitabine and S-1 after surgical resection for advanced biliary carcinoma: outcomes and prognostic factors. (2012)
  • Author(s): Murakami Y, Uemura K, Sudo T, Hashimoto Y, Nakashima A, Sakabe R, Kobayashi H, Kondo N, Nakagawa N, Sueda T.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 19(4) Issue: 4 Pages: 306-313
  • DOI: 10.1007/s00534-011-0498-y
  • NAID: 10030950515
  • Peer Reviewed
• [Presentation] 膵癌・胆管癌に対する術後補助療法の個別化に向けたGemcitabine効果予測因子としてのhENT1/RRM1発現の検討 (2014)
  • Author(s): 近藤 成, 村上 義昭, 上村 健一郎, 首藤 毅, 橋本 泰司, 佐々木 勇人, 大塚 裕之, 末田 泰二郎
  • Organizer: 日本消化器外科学会総会 69回
  • Place of Presentation: 福島
  • Year and Date: 2014-07-16 – 2014-07-18
• [Presentation] 進行胆嚢癌に対する治療戦略 進行胆嚢癌に対する外科治療戦略 術後補助化学療法の意義 (2013)
  • Author(s): 首藤毅
  • Organizer: 日本臨床外科学会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] 進行胆管癌のhENT1発現とgemcitabineを用いた術後補助化学療法による治療効果の相関についての検討 (2012)
  • Author(s): 小林 弘典, 村上 義昭, 上村 健一郎, 首藤 毅, 橋本 泰司, 中島 亨, 近藤 成, 坂部 龍太郎, 中川 直哉
  • Organizer: 第24回日本肝胆膵外科学会
  • Place of Presentation: 大阪
• [Presentation] 胆管癌におけるTS、DPD、OPRT発現とS-1/GEM併用術後補助化学療法による治療効果の相関についての検討 (2012)
  • Author(s): 小林 弘典, 村上 義昭, 上村 健一郎, 首藤 毅, 橋本 泰司, 中島 亨, 近藤 成, 坂部 龍太郎, 中川 直哉, 大毛 宏喜, 末田 泰二郎
  • Organizer: 第74回日本臨床外科学会総会
  • Place of Presentation: 東京
• [Presentation] 胆管癌におけるTS、DPD、OPRT発現とS-1治療効果の相関についての検討 (2012)
  • Author(s): 小林 弘典, 村上 義昭, 上村 健一郎, 首藤 毅, 橋本 泰司, 中島 亨, 大毛 宏喜, 湯浅 吉夫, 加藤 楽, 近藤 成, 坂部 龍太郎, 檜山 英三, 末田 泰二郎
  • Organizer: 第112回日本外科学会定期学術集会
  • Place of Presentation: 千葉