Development of new gemcitabine that can overcome acquired gemicitabine resistancy

• Project/Area Number: 22591512
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Tohoku University
• Principal Investigator: SUNAMURA Makoto 東北大学, 大学院・医学系研究科, 非常勤講師 (10201584)
• Co-Investigator(Kenkyū-buntansha): HORII Akira 東北大学, 大学院・医学系研究科, 教授 (40249983)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 膵癌 / 薬剤耐性 / ジェムシタビン / 新規抗癌剤 / DCK / S100A4 / 膵がん / 新規抗がん剤

Research Abstract

Gemcitabine (GEM here-in after) is the best chemotherapeutic agent to patients with pancreatic cancer to date. However, patients often acquire resistance to GEM. In order to overcome this acquired chemo-resistance, we performed molecular analyses and identified DCK as the key molecule for acquired resistance; (1) high frequency of inactivating mutation in acquired cancer cells, (2) introduction of DCK to resistant cells recovered chemo-sensitivity to GEM, and (3) knockdown of DCK in parental cells acquired chemo-resistance. These results demonstrate that inactivating mutation of DCK is one of the key alterations for acquisition of GEM resistance.

Research Products

• [Journal Article] The expression of S100A4 in human pancreatic cancer is associated with invasion (2013)
  • Author(s): Tsukamoto N, Egawa S, Akada M, Abe K, Saiki Y, Kaneko N, Yokoyama S, Shima K, Yamamura A, Motoi F, Abe H, Hayashi H, Ishida K, Moriya T, Tabata T, Kondo E, Kanai N, Gu Z, Sunamura M, Unno M, Horii A.
  • Journal Title: Pancreas Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Crnogorac-Jurcevic T.S100P is a metastasis-associated gene that facilitates transendothelial migration of pancreatic cancer cells (2013)
  • Author(s): Barry S, Chelala C, Lines K, SunamuraM, Wang A, Marelli-Berg FM, Brennan C, Lemoine NR
  • Journal Title: Clin Exp Metastasis Volume: 30 Issue: 3 Pages: 251-264
  • DOI: 10.1007/s10585-012-9532-y
  • Peer Reviewed
• [Journal Article] The expression of S100A4 in human pancreatic cancer is associated with invasion (2013)
  • Author(s): Tsukamoto N, Egawa S, Akada M, Abe K, Saiki Y, Yamamura A, Motoi F, Abe H, Hayashi H, Ishida K, Moriya T, Gu Z, Sunamura M, Unno M, Horii A. et al.
  • Journal Title: Pancreas Volume: in press
  • Peer Reviewed
• [Journal Article] Flow patterns and preferred sites of intimal thickening in bypass-grafted arteries (2012)
  • Author(s): Sunamura M, Ishibashi H, Karino T.
  • Journal Title: Int Angiol Volume: 31 Pages: 187-197
  • Peer Reviewed
• [Journal Article] S100A4, frequently overexpressed in various human cancers, accelerates cell motility in pancreatic cancercells (2012)
  • Author(s): Sekine H, Chen N, Sato K, Saiki Y, Yoshino Y, Umetsu Y, Jin G, Nagase H, Gu Z, Fukushige S, Sunamura M, Horii A.
  • Journal Title: Biochem Biophys Res Commun Volume: 429 Issue: 3-4 Pages: 214-219
  • DOI: 10.1016/j.bbrc.2012.10.048
  • Peer Reviewed
• [Journal Article] miR-34a is downregulated in cis-diamminedichloroplatinum treated sinonasal squamous cell carcinoma patients with poor prognosis (2012)
  • Author(s): Ogawa T, Saiki Y, Shiga K, Chen N, Fukushige S, Sunamura M, Nagase H, Hashimoto S, Matsuura K, Saijo S, Kobayashi T, Horii A.
  • Journal Title: Cancer Sci Volume: 103 Issue: 9 Pages: 1737-1743
  • DOI: 10.1111/j.1349-7006.2012.02338.x
  • Peer Reviewed
• [Journal Article] Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in the patients with advanced pancreatic carcinoma (2012)
  • Author(s): Kimura Y, et al
  • Journal Title: Pancreas Volume: 41 Issue: 2 Pages: 195-205
  • DOI: 10.1097/mpa.0b013e31822398c6
  • Peer Reviewed
• [Journal Article] DCK is frequently inactivated in acquired gemcitabine-resistant human cancer cells (2012)
  • Author(s): Yuriko Saiki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: (in press) Issue: 1 Pages: 98-104
  • DOI: 10.1016/j.bbrc.2012.03.122
  • Peer Reviewed
• [Journal Article] 膵癌の疫学 (2012)
  • Author(s): 砂村眞琴、河地茂行、島津元秀
  • Journal Title: 臨床外科 Volume: 67 Pages: 214-221
• [Journal Article] Flow patterns and preferred sites of intimal thickening in bypass-grafted arteries (2012)
  • Author(s): Sunamura M., et al
  • Journal Title: Int.Angiol. Volume: 31 Pages: 187-197
  • Peer Reviewed
• [Journal Article] A human head and neck squamous cell carcinoma cell line with acquired cis-diamminedichloroplatinum-resist ance shows remarkable upregulation of BRCA1 and hypersensitivity to taxane (2011)
  • Author(s): Saiki Y, Ogawa T, Shiga K, Sunamura M, Kobayashi T, Horii A.
  • Journal Title: Int J Otolaryngol Volume: 2011 Pages: 521852-521852
  • DOI: 10.1155/2011/521852
  • Peer Reviewed
• [Journal Article] Identification of epigenetically silenced genes in human pancreatic cancer by a novel method "microarray coupled with methyl-CpG targeted transcriptional activation" (MeTA-array) (2011)
  • Author(s): Hideyuki Shimizu
  • Journal Title: Biochem Biophys Res Commun Volume: 411 Issue: 1 Pages: 162-167
  • DOI: 10.1016/j.bbrc.2011.06.121
  • Peer Reviewed
• [Journal Article] Adjuvant chemotherapy with fluorouracil plus folinic acid vsgemcitabine following pancreatic cancer resection: a randomized controlled trial (2010)
  • Author(s): Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Olah A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Buchler MW, European Study Group for Pancreatic Cancer (Sunamura M 他 259 名)
  • Journal Title: JAMA Volume: 304 Issue: 10 Pages: 1073-1081
  • DOI: 10.1001/jama.2010.1275
  • Peer Reviewed
• [Journal Article] lockade of delta-like ligand 4 signaling inhibits both growth and angiogenesis of pancreatic cancer (2010)
  • Author(s): Oishi H, Sunamura M. Egawa S, Motoi F, Unno M, Furukawa T, Habib NA, Yagita H
  • Journal Title: Pancreas Volume: 39 Issue: 6 Pages: 897-903
  • DOI: 10.1097/mpa.0b013e3181ce7185
  • Peer Reviewed
• [Journal Article] Upregulation of IGF2 (insulin-like growth factor 2) is associated with an acquired resistance for cis-diamminedichloroplatinum in human head and neck squamous cell carcinoma (2010)
  • Author(s): Ogawa T, Ogawa K, Shiga K, Furukawa T, Nagase H, Hashimoto S, Kobayashi T, Horii A.
  • Journal Title: Eur Arch Otorhinolaryngol Volume: 267 Issue: 10 Pages: 1599-1606
  • DOI: 10.1007/s00405-010-1257-4
  • Peer Reviewed
• [Journal Article] 膵臓癌の診療-基礎から臨床へ- (2010)
  • Author(s): 堀井明
  • Journal Title: 日本医事新報 Volume: 4491 Pages: 38-42
• [Journal Article] Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection : a randomized controlled trial. (2010)
  • Author(s): Neoptolemos JP, Sunamura M, et. al.
  • Journal Title: JAMA Volume: 304 Pages: 1073-1081
  • Peer Reviewed
• [Journal Article] Blockade of delta-like ligand 4 signaling inhibits both growth and angjogenesis of pancreatic cancer. (2010)
  • Author(s): Oishi H, Sunamura M, et. al.
  • Journal Title: Pancreas Volume: 39 Pages: 897-903
  • Peer Reviewed
• [Journal Article] Upregulation of IGF2 (insulin-like growth factor 2) is associated with an acquired resistance for cis-diamminedichloroplatinum in human head and neck squamous cell carcinoma. (2010)
  • Author(s): Ogawa T, Horii A, et. al.
  • Journal Title: Eur Arch Otorhinolaryngol Volume: 267 Pages: 1599-1606
  • Peer Reviewed
• [Presentation] 唾液バイオマーカーによる膵癌診断と切除症例における動態 (2013)
  • Author(s): 高野公徳、砂村眞琴、阿部雄太、梅田純子、糸井隆夫、土岐真朗、粕谷和彦、佐藤公、板倉淳、曽我朋義、杉本昌弘、千葉斉一、河地茂行、島津元秀
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: 福岡
• [Presentation] 唾液による膵癌診断法の開発 (2012)
  • Author(s): 梅田純子、糸井隆夫、砂村眞琴
  • Organizer: 第54回日本消化器病学会大会
  • Place of Presentation: 神戸
• [Presentation] 唾液を用いたメタボローム解析による膵癌診断法の開発 (2012)
  • Author(s): 砂村眞琴、糸井隆夫、梅田純子、土岐真朗、板倉淳、佐藤公、粕谷和彦、阿部雄太、高野公徳、杉本昌弘、曽我朋義、島津元秀
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] ゲムシタビン耐性ヒト癌細胞株におけるdeosycytidine kinaseの不活化 (2012)
  • Author(s): 斎木由利子、吉野優樹、福重真一、砂村眞琴、石田晶玄、元井冬彦、江川新一、海野倫明、堀井明
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] メタボロミクス解析を応用した膵癌診断法の開発 (2012)
  • Author(s): 砂村眞琴、阿部雄太、高野公徳、糸井隆夫、梅田純子、杉本昌弘、島津元秀
  • Organizer: 第67回日本消化器外科学会総会
  • Place of Presentation: 富山
• [Presentation] 唾液メタボローム解析を用いた膵癌診断法の開発 (2012)
  • Author(s): 糸井隆夫、砂村眞琴、土岐真朗、梅田純子、祖父尼淳、糸川文英、土屋貴愛、森安史典、阿部雄太、高野公徳、中村健二、板倉淳、佐藤公、杉本昌弘、曽我朋義、粕谷和彦、島津元秀
  • Organizer: 第43回日本膵臓学会大会
  • Place of Presentation: 山形
• [Presentation] 新しい膵癌バイオマーカーの探索-メタボローム解析の検討から- (2012)
  • Author(s): 梅田純子、糸井隆夫、祖父尼淳、糸川文英、土屋貴愛、栗原俊夫、石井健太郎、辻修二郎、池内信人、田中麗奈、殿塚亮祐、森安史典、曽我朋義、杉本昌弘、砂村眞琴
  • Organizer: 第43回日本膵臓学会大会
  • Place of Presentation: 山形
• [Presentation] ゲムシタビン耐性膵癌細胞株におけるゲムシタビン代謝の解析 (2011)
  • Author(s): 齋木由利子、江川新一、砂村眞琴、海野倫明、堀井明
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] NOG-EGFPマウス異種移植モデルを用いた高精度な癌細胞sampling systemの構築を目指して (2011)
  • Author(s): 嶋健太郎、水間正道、大村範幸、林洋毅、中川圭、岡田恭穂、北村洋、元井冬彦、力山敏樹、片寄友、江川新一、石井直人、堀井明、海野倫明
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 膵癌のGemcitabine耐性機構の解明 (2011)
  • Author(s): 齋木由利子、江川新一、海野倫明、砂村眞琴、堀井明
  • Organizer: 第42回日本膵臓学会大会
  • Place of Presentation: 弘前
• [Presentation] ゲムシタビン耐性膵癌細胞株におけるゲムシタビン代謝の解析 (2011)
  • Author(s): 齋木由利子、江川新一、砂村眞琴、海野倫明、堀井明
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] S100A4 regulates tumor growth, motility, and invasion in pancreatic cancer (2010)
  • Author(s): Sekine H, Tabata T, Tsukamoto N, Chen N, Sato K, Umetsu Y, Nakamura K, Kim G, Yamamura A, Yoshino Y, Fukushige S, Sunamura M, Horii A.
  • Organizer: アメリカ人類遺伝学会
  • Place of Presentation: アメリカ合衆国ワシン トン市
• [Presentation] Microarray analyses of mRNA and miRNA associated with an acquired resistance for cis-diamminedichloroplatinum inhuman head and neck squamous cell carcinoma (2010)
  • Author(s): Ogawa T, Ogawa K, Shiga K, Furukawa T, Hashimoto S, Kobayashi T, Horii A.
  • Organizer: International Federation of Head and Neck Oncologic Societies総会
  • Place of Presentation: 韓国ソウル市
• [Presentation] Microarray analyses of mRNA and miRNA associated with an acquired resistance for cis-diamminedichloroplatinum in human head and neck squamous cell carcinoma. (2010)
  • Author(s): Ogawa T, Horii A, et. al.
  • Organizer: International Federation of Head and Neck Oncologic Societies総会
  • Place of Presentation: 韓国ソウル市
• [Presentation] S100A4 regulates tumor growth, motility, and invasion in pancreatic cancer. (2010)
  • Author(s): Sekine, Sunamura M, Horii A, et. al.
  • Organizer: アメリカ人類遺伝学会
  • Place of Presentation: アメリカ合衆国ワシントン市