Analysis of resistance mechanism of cell death in chemotherapy and monoclonal antibody therapy

• Project/Area Number: 17016077
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Japanese Foundation For Cancer Research
• Principal Investigator: HATAKE Kitohiko Japanese Foundation For Cancer Research, 癌化学療法センター臨床部, 部長 (80192699)
• Project Period (FY): 2005 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥46,200,000 (Direct Cost: ¥46,200,000); Fiscal Year 2009: ¥9,300,000 (Direct Cost: ¥9,300,000); Fiscal Year 2008: ¥9,300,000 (Direct Cost: ¥9,300,000); Fiscal Year 2007: ¥9,300,000 (Direct Cost: ¥9,300,000); Fiscal Year 2006: ¥9,300,000 (Direct Cost: ¥9,300,000); Fiscal Year 2005: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: 化学療法 / 抗体療法 / 耐性 / 細胞死 / 癌 / シグナル伝達 / 薬剤反応性 / 共焦点顕微鏡 / 抗癌剤

Research Abstract

I studied basic research in drug resistance mechanism as well as clinical samples analysis. Imatinib resistance, partly is explained by ABL mutation and autophagy pathway will be a next target. Rituximab resistance in CD20+ lymphoma is explained partly by CD20 mutation. I established bortezomib-resistant myeloma cell line.
We also established the assay system for ADCC and CDC.

Research Products

• [Journal Article] Dlk-1, a cell surface antigen on fetal hepatic stem/progenitor cells, is expressed in hepatocellular, colon, pancreas and breast carcinomas at a high frequency (2010)
  • Author(s): Yanai H, Nakamura K, Hijioka S, Kamei A, Ikari T, Ishikawa Y, Shinozaki E, Mizunuma N, Hatake K, Miyajima A.
  • Journal Title: J Biochem. (in press)
  • Peer Reviewed
• [Journal Article] Circulating tumor cells as a surrogate marker for determining Responseto chemotherapy in patients with advanced gastric cancer (2010)
  • Author(s): Matsusaka S, Chin K, Ogura M, Suenaga M, Shinozaki E, Mishima Y, Terui Y, Mizunuma N, Hatake K.
  • Journal Title: Cancer Sci. (in press)
  • Peer Reviewed
• [Journal Article] Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways (2010)
  • Author(s): Kobayashi T, Kuroda J, Ashihara E, Oomizu S, Terui Y, Taniyama A, Adachi S,Takagi T, Yamamoto M, Sasaki N, Horiike S, Hatake K, Yamauchi A, Hirashima M, Taniwaki M.
  • Journal Title: Leukemia. 24 Pages: 843-50
  • Peer Reviewed
• [Journal Article] Statin-independent prognosis of patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy (2009)
  • Author(s): Ennishi D, Asai H, Maeda Y, Shinagawa K, Ikeda K, Yokoyama M, Terui Y, Takeuchi K, Yoshino T, Matsuo K, Hatake K, Tanimoto M.
  • Journal Title: Ann Oncol. (in press)
  • Peer Reviewed
• [Journal Article] Functional in vivo optical imaging of tumor angiogenesis, growth, and metastasis prevented by administration of anti-human VEGF antibody in xenograft model of human fibrosarcoma HT1080 cells (2009)
  • Author(s): Hanyu A, Kojima K, Hatake K, Nomura K, Murayama H, Ishikawa Y, Miyata S, Ushijima M, Matsuura M, Ogata E, Miyazawa K, Imamura T.
  • Journal Title: Cancer Sci. 100 Pages: 2085-92
  • NAID: 10027196865
  • Peer Reviewed
• [Journal Article] Management of venous thromboembolism in colorectal cancer patients treated with bevacizumab (2009)
  • Author(s): Suenaga M, Mizunuma N, Kobayashi K, Shinozaki E, Matsusaka S, Chin K, Kuboki Y, Ichimura T, Ozaka M, Ogura M, Fujiwara Y, Matsueda K, Konishi F, Hatake K.
  • Journal Title: Med Oncol. (in press)
  • Peer Reviewed
• [Journal Article] Familial sideroblastic anemia associated with cardiac atrial septal defect. A (2009)
  • Author(s): Mori M, Nakamoto S, Akifuji Y, Tanaka T, Komatsu N, Hatake K, Ozawa K.
  • Journal Title: Am J Hematol. 84 Pages: 451-2
  • Peer Reviewed
• [Journal Article] An imaging-based rapid evaluation method for complement-dependent cytotoxicity discriminated clinical response to rituximab-containing chemotherapy (2009)
  • Author(s): ishima Y, Sugimura N, Matsumoto-Mishima Y, Terui Y, Takeuchi K, Asai S, Ennishi D, Asai H, Yokoyama M, Kojima K, Hatake K.
  • Journal Title: Clin Cancer Res. 15 Pages: 3624-32
  • Peer Reviewed
• [Journal Article] Identification of CD20 C-terminal deletion mutations associated with loss of CD20 expression in non-Hodgkin's lymphoma (2009)
  • Author(s): Terui Y, Mishima Y, Sugimura N, Kojima K, Sakurai T, Mishima Y, Kuniyoshi R, Taniyama A, Yokoyama M, Sakajiri S, Takeuchi K, Watanabe C, Takahashi S, Ito Y, Hatake K.
  • Journal Title: Clin Cancer Res. 15 Pages: 2523-30
  • Peer Reviewed
• [Journal Article] Breast Possible use of combination chemotherapy with mitomycin C and methotrexate for metastatic breast cancer pretreated with anthracycline and taxanes (2009)
  • Author(s): Tanabe M, Ito Y, Tokudome N, Sugihara T, Miura H, Takahashi S, Seto Y, Iwase T, Hatake K
  • Journal Title: Cancer. 16 Pages: 301-6
  • Peer Reviewed
• [Journal Article] Chemotherapy for small-bowel Adenocarcinoma at a single institution (2009)
  • Author(s): Suenaga M, Mizunuma N, Chin K, Matsusaka S, Shinozaki E, Oya M, Ueno M, Yamaguchi T, Muto T, Konishi F, Hatake K.
  • Journal Title: Surg Today. 39 Pages: 27-31
  • NAID: 10025130745
  • Peer Reviewed
• [Journal Article] An Imaging -Based Rapid Evaluation Method for Complement-Dependent Cytotoxicity Discriminated Clinical Response to Rituximab-Containing Chemotherapy. (2009)
  • Author(s): Mishima Y et al.
  • Journal Title: Clin Cancer Res. (印刷中)
  • Peer Reviewed
• [Journal Article] Identification of CD20 C-Terminal Deletion Mutations Associated with Loss of CD20 Expression in Non-Hodgkin's Lymphoma. (2009)
  • Author(s): Terui Y, et al.
  • Journal Title: Clin Cancer Res. 15(7) Pages: 2523-30
  • Peer Reviewed
• [Journal Article] Possible use of combination chemotherapy with mitomycin C and methotrexate for metastatic breast cancer pretreated with anthracycline and taxanes. (2009)
  • Author(s): Tanabe M, et al.
  • Journal Title: Breast Cancer. (印刷中)
  • Peer Reviewed
• [Journal Article] Efficacy of S-1 in heavily pretreated patients with metastatic breast cancer:cross-resistance to capecitabine. (2009)
  • Author(s): Ito Y,et al.
  • Journal Title: Breast Cancer 16(2) Pages: 126-31
  • Peer Reviewed
• [Journal Article] Chemotherapy for small-bowel Adenocarcinoma at a single in stitution. Surg Today. 2 (2009)
  • Author(s): Suenaga M, et al
  • Journal Title: Surg Today. 6(8) Pages: 27-31
  • Peer Reviewed
• [Journal Article] Soluble interleukin-2 receptor retains prognostic value in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP(RCHOP)therapy. (2009)
  • Author(s): Ennishi D, et al.
  • Journal Title: An Oncol 20(3) Pages: 526-33
  • Peer Reviewed
• [Journal Article] Predictive factors for efficacy of capecitabine in heavily pretreated patients with metastatic breast cancer. (2009)
  • Author(s): Osako T, et al.
  • Journal Title: Cancer Chemother Pharmacol 63(5) Pages: 865-71
  • Peer Reviewed
• [Journal Article] Management of allergic reactions to oxaliplatin in colorectal cancer patients. (2008)
  • Author(s): Suenaga M, et al.
  • Journal Title: J Support Oncol. 6(8) Pages: 373-8
  • Peer Reviewed
• [Journal Article] Modified irinotecan plus bolus 5-fluorouracil/L-leucovorin for metastatic colorectal cancer at a single institution in Japan. (2008)
  • Author(s): Suenaga M, et al
  • Journal Title: J Gastroenterol. 43(11) Pages: 842-8
  • Peer Reviewed
• [Journal Article] Does rituximab really induce hepatitis C virus reactivation? (2008)
  • Author(s): Ennishi D, et al.
  • Journal Title: J Clin Oncol. 26(28)
  • Peer Reviewed
• [Journal Article] Autophagy and autophagic cell death are next targets for eilmination of the resistance to tyrosine kinase inhibitors. (2008)
  • Author(s): Mishima Y et al,
  • Journal Title: Cancer Sci. 99(11) Pages: 2200-8
  • Peer Reviewed
• [Journal Article] Trastuzumab and vinorlbine as first-line therapy for HER2-overxpressing metastatic breast cancer: multicenter phase II and pharmacokinetic study in Japan. (2008)
  • Author(s): Tokudome N, et al.
  • Journal Title: Anticancer Drugs. 19(7) Pages: 753-9
  • Peer Reviewed
• [Journal Article] CD5 expression is potentially predictive of poor outcome among biomarkers in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy. (2008)
  • Author(s): Ennishi D,et al.
  • Journal Title: Ann Oncol. 19(11) Pages: 1921-6
  • Peer Reviewed
• [Journal Article] Irinotecan plus cisplatin for therapy of small-cell carcinoma of the esophagus: report of 12 cases from single institution experience. (2008)
  • Author(s): Chin K, et al.
  • Journal Title: Jpn J Clin Oncol. 38(6) Pages: 426-31
  • Peer Reviewed
• [Journal Article] Serum level of macrophage colony-stimulating factor is increa sed in prostate cancer patients with bone metastasis. (2008)
  • Author(s): Ide H, et al.
  • Journal Title: Hum Cell. 21(1) Pages: 1-6
  • Peer Reviewed
• [Journal Article] Serum level of macrophage colony-stimulating factor is increased in prostate cancer patients with bone metastasis. (2008)
  • Author(s): Ide H, et. al.
  • Journal Title: Hum Cell. 21 Pages: 1-6
  • Peer Reviewed
• [Journal Article] Efficacy and safety of trastuzumab plus capecitabine in heavily pretreated patients with HER2-positive metastatic breast cancer. (2008)
  • Author(s): Osako T, et. al.
  • Journal Title: Am J Hematol. 83 Pages: 59-62
  • Peer Reviewed
• [Journal Article] Rituximab plus CHOP as an initial chemotherapy for patients with diss eminated MALT lymphoma. (2007)
  • Author(s): Ennishi D et. al
  • Journal Title: Leuk Lymphoma. 48 Pages: 2241-3
  • Peer Reviewed
• [Journal Article] Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer. (2007)
  • Author(s): Mitsuhashi J, et. al.
  • Journal Title: Hum Gene Ther. 18 Pages: 895-906
  • Peer Reviewed
• [Journal Article] Pilot study of MDR1 gene transfer into hematopoietic stem cells and chemoprotection in metastatic breast cancer patients. (2007)
  • Author(s): Takahashi S, et. al.
  • Journal Title: Cancer Sci. 98 Pages: 1609-16
  • Peer Reviewed
• [Journal Article] Phase II study of oxaliplatin in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines. (2007)
  • Author(s): Boku N, et. al.
  • Journal Title: Jpn J Clin Oncol. 37 Pages: 440-5
  • Peer Reviewed
• [Journal Article] Bone marrow-derived CXCR4+cells mobilized by macrophage colony-stimulating factor participate in the reduction of infarct area and improve ment of cardiac remodeling after myocardial infarction in mice. (2007)
  • Author(s): Morimoto H, et. al.
  • Journal Title: Am J Pathol. 171 Pages: 755-766
  • Peer Reviewed
• [Journal Article] Intermittent capecitabine monotherapy with lower dose intensity in heavily pretreated patients with metastatic breast cancer. (2007)
  • Author(s): Osako T, et. al.
  • Journal Title: Tumori. 93 Pages: 129-32
  • Peer Reviewed
• [Journal Article] Does lapatinib, a small-molecule tyrosine kinase inhibitor, constitute a breakthrough in the treatment of breast cancer? (2007)
  • Author(s): Ito Y, et. al.
  • Journal Title: Breast Cancer 14 Pages: 156-62
  • Peer Reviewed
• [Journal Article] Next generation molecular targeted agents for breast cancer: focus on EGFR and VEGFR pathways. (2007)
  • Author(s): Hatake K, et. al.
  • Journal Title: Breast Cancer 14 Pages: 132-49
  • NAID: 10019480566
  • Peer Reviewed
• [Journal Article] MEK-ERK is involved in SUMO-1 foci formation on apoptosis. (2007)
  • Author(s): Utsubo-Kuniyoshi R, et al.
  • Journal Title: Cancer Sci. 98・4 Pages: 569-576
• [Journal Article] Continuous treatment of bestatin induces anti-angiogenic property in endothelial cells. (2007)
  • Author(s): Mishima Y, et al.
  • Journal Title: Cancer Sci. 98・3 Pages: 364-372
• [Journal Article] INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system and cyclosporine A augments its in vivo activity. (2007)
  • Author(s): Yokota A, et al.
  • Journal Title: Blood. 109・1 Pages: 306-314
• [Journal Article] Differential Regulation of Eotaxin-1/CCL11 and Eotaxin-3/CCL26 Production by the TNF-alpha and IL-4 Stimulated Human Lung Fibroblast. (2006)
  • Author(s): Rokudai A, et al.
  • Journal Title: Biol Pharm Bull. 29・6 Pages: 1102-1109
• [Journal Article] Blockade of bulky lymphoma-associated CD55 expression by RNA interference overcomes resistance to complement-dependent cytotoxicity with rituximab. (2006)
  • Author(s): Terui Y, et al.
  • Journal Title: Cancer Sci. 97・1 Pages: 72-79
• [Journal Article] Blockade of bulky lymphoma-associated CD55 expression by RNA interference overcomes resistance to CDC with rituximab. (2006)
  • Author(s): Terui Y, Sakurai T, Mishima Y, Mishima Y, Sugimura N, Sasaoka C, Kojima K, Yokoyama M, Mizunuma N, Takahashi S, Ito Y, Hatake K
  • Journal Title: Cancer Science 97(1) Pages: 72-79
• [Journal Article] Differential Regulation of Eotaxin-1/CCL11 and Eotaxin-3/CCL26 Production by the TNF-a and IL-4 stimulated Human Lung Fibroblast. (2006)
  • Author(s): Rokudai A, Terui Y, Kuniyoshi R, Mishima Y, Mishima Y, Aizu-Yokota Y, Sonoda Y, Kasahara T, Hatake K
  • Journal Title: Biol.Pharm.Bull. 29(In press)
• [Journal Article] Gene therapy for breast cancer. -- Review of clinical gene therapy trials for breast cancer and MDR1 gene therapy trial in Cancer Institute Hospital. (2006)
  • Author(s): S Takahashi, Y Ito, K Hatake, Y Sugimoto
  • Journal Title: Breast Cancer 13(1) Pages: 8-15
  • NAID: 10017238537
• [Journal Article] Element array by scanning X-ray fluorescence microscopy after cis-diamminedichloro-platinum (II) treatment. (2005)
  • Author(s): Shimura M, Saito A, Matsuyama S, Sakuma T, Terui Y, Ueno K, Yumoto H, Yamauchi K, Yamamura K, Mimura H, Sano Y, Yabashi M, Tamasaku K, Nishio K, Nishino Y, Endo K, Hatake K, Mori Y, Ishizaka Y, Ishikawa T:
  • Journal Title: Cancer Res 65 Pages: 4998-5002
• [Journal Article] Increased incidence of interstitial pneumonia by CHOP combined with rituximab
  • Author(s): Ennishi D et. al
  • Journal Title: Int J Hematol. (in press)
  • Peer Reviewed
• [Presentation] Bevacizumab(Bev)/FOLFOX4併用療法の進行・再発結腸直腸癌に対する安全性と有効性 (2009)
  • Author(s): 末永光邦 他
  • Organizer: 日本臨床腫瘍学会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-03-20
• [Presentation] FOLFOX4+Bevacizumab(BV)の進行・再発結腸・直腸癌を対象とした安全性確認試験〜追跡調査 (2009)
  • Author(s): 仁科智裕 他
  • Organizer: 日本臨床腫瘍学会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-03-20
• [Presentation] リツキシマブ既治療再発・難治B・NHLに対するInotuzumab Ozogamic in(CMC・544)の国内第I相試験 (2009)
  • Author(s): 畠清彦 他
  • Organizer: 日本臨床腫瘍学会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-03-20
• [Presentation] EGFR標的療法の効果予測のための生細胞イメージング (2009)
  • Author(s): 三嶋雄二・照井康仁・松阪諭・國吉良子・三嶋裕子・高木浩一・畠清彦
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] リンパ系腫瘍におけるInsulin-like Growth Factor・1受容体の発現とその意義 (2008)
  • Author(s): 照井康仁 他
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] Establishment of an assay system for ADCC activity and search fbr factors that affect ADCC activity (2008)
  • Author(s): 三嶋雄二 他
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] Prediction of clinical response of rituximab containing chemotherapy using newly established live・cell-imaging procedure for estimating CDC susceptibility (2008)
  • Author(s): Mishima Y et.al
  • Organizer: EORTC-NCI-AACR Molecular Target and Cancer therapeutics
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 2008-10-21
• [Presentation] 治療前CDC感受性評価法の確立とrituximan治療効果予測における有用性 (2008)
  • Author(s): 三嶋雄二 他
  • Organizer: 日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-10
• [Presentation] CML、PH+陽性T-ALL細胞株におけるautophagyの役割 (2008)
  • Author(s): 三嶋裕子 他
  • Organizer: 日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-10
• [Presentation] ADCCアッセイシステムの確立とADCC抵抗性因子の探索 (2008)
  • Author(s): 三嶋雄二 他
  • Organizer: がん分子標的治療研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-06-27
• [Presentation] 膜蛋白質Diklの血液悪性腫瘍における高発現と正常造血における役割 (2008)
  • Author(s): 坂尻さくら 他
  • Organizer: がん分子標的治療研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-06-27
• [Presentation] 進行大腸癌に対する化学療法-特にbevacizumabのバイオマーカー (2008)
  • Author(s): 松阪諭 他
  • Organizer: がん分子標的治療研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-06-27
• [Patent(Industrial Property Rights)] 抗体医薬感受性検査方法 (2007)
  • Inventor(s): 杉村夏彦, 三嶋雄二, 畠清彦
  • Industrial Property Rights Holder: 財団法人癌研究会オリンパス株式会社
  • Filing Date: 2007-09-26
  • Overseas
• [Patent(Industrial Property Rights)] Fc受容体遺伝子導入NK細胞株、その作製方法、及びこれを用いた抗体依存性細胞障害のアッセイ方法 (2007)
  • Inventor(s): 杉村夏彦, 三嶋雄二, 畠清彦
  • Industrial Property Rights Holder: 財団法人癌研究会オリンパス株式会社
  • Industrial Property Number: 2007-254099
  • Filing Date: 2007-09-28
• [Patent(Industrial Property Rights)] 抗体医薬感受性検査方法 (2006)
  • Inventor(s): 杉村夏彦、三嶋雄二、照井康仁、畠清彦
  • Industrial Property Rights Holder: (財)癌研究会/オリンパス株式会社
  • Filing Date: 2006-09-26
• [Patent(Industrial Property Rights)] 抗体医薬感受性検査方法 (2006)
  • Inventor(s): 杉村夏彦, 三嶋雄二, 照井康仁, 畠清彦
  • Industrial Property Rights Holder: (財)癌研究会, オリンパス株式会社
  • Filing Date: 2006-09-26