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Development of molecular target medicine using ZD1839 in esophageal cancer

Research Project

Project/Area Number 16591346
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionIwate Medical University

Principal Investigator

IKEDA Kenichiro  Iwate Med. Univ., School of Med., Dept. of Surg., Associate Prof., 医学部, 助教授 (20254758)

Co-Investigator(Kenkyū-buntansha) MAESAWA Chihaya  Iwate Med. Univ., School of Med., Dept. of Pathol., Associate Prof., 医学部, 助教授 (10326647)
石田 薫  岩手医科大学, 医学部, 助教授 (70146041)
Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2006: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordshTERT / telomere / esophageal cancer / MAPK / ZD1839 / glioblastoma / molecular target medicine / telomerase / 食道癌 / 悪性膠芽腫瘍
Research Abstract

The selective epidermal growth factor receptor-tyrosine kinase-(EGFR, TK)-inhibitor, gefitinib, blocks several signal transduction pathways involved in tumor cell proliferation, anti-apoptosis and angiogenesis. We demonstrate for the first time that human telomerase reverse transcriptase (hTERT) is a molecular target of gefitinib through repression of the classical mitogen-activated protein kinase (MAPK)-Ets pathway. We used four human esophageal cancer cell lines (TE-1, TE-3, TE-4, and TE-5) that strongly express EGFR to evaluate the effects of gefitinib treatment on the phosphorylation status of EGFR/mitogen-activated protein kinase (MAPK), hTERT mRNA/protein expression, transcriptional activation of the hTERT gene promoter, and telomerase activity. Phosphorylation of EGFR tyrosine residues PY1086 and PY1173, and of ERK 1/2, as well as hTERT mRNA/protein expression were markedly repressed by gefitinib treatment. A reporter assay demonstrated that exposure to gefitinib markedly down-r … More egulated the transcriptional activity (0.28-to 0.45-fold decrease) of the Ets site of the hTERT core promoter. Telomerase activity was down-regulated by gefitinib treatment in a dose-dependent manner. The concentration necessary for 50% inhibition of telomerase activity (0.12-0.71 μM) was lower than that necessary for inhibition of growth (6.35-18.54 μM). Long-term and relatively low-dose exposure to gefitinib significantly (P< 0.01) increased the proportion of cells positive for β-galactosidase in 3 cell lines (TE-1, TE-4, and TE-5), but not in TE-3. The mean TRF lengths of the 3 susceptible cell lines, but not of TE-3, were reduced in comparison with those of no-treatment controls. These results suggest that gefitinib targets telomerase activity as an anti-cancer effect through inhibition of direct EGF-induced transcriptional activation of the hTERT gene. The ability of gefitinib to inhibit telomerase at low doses may provide an approach to avoid severe adverse effects such as pulmonary fibrosis. Less

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (52 results)

All 2007 2006 2005 2004

All Journal Article (52 results)

  • [Journal Article] Methylation status of the SOCS3 gene in human malignant melanomas.2007

    • Author(s)
      Tokita T, Maesawa C, Kimura T, et al.
    • Journal Title

      Int J Oncol 30

      Pages: 689-694

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Association of TNF-alpha gene promoter C-857T polymorphism with higher serum LDL cholesterol levels and carotid plaque formation in Japanese patients with type 2 diabetes.2007

    • Author(s)
      Yamashina M, Kaneko Y, Maesawa C, et al.
    • Journal Title

      Tohoku J Exp Med 211

      Pages: 251-258

    • NAID

      130004459548

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Methylation status of the SOCS3 gene in human malignant melanomas.2007

    • Author(s)
      Tokita T, Maesawa C, Kimura T et al.
    • Journal Title

      Int J Oncol 30

      Pages: 689-94

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Association of TNF-alpha gene promoter C-857T polymorphism with higher serum LDL cholesterol levels and carotid plaque formation in Japanese patients with type 2 diabetes.2007

    • Author(s)
      Yamashina M, Kaneko Y, Maesawa C et al.
    • Journal Title

      Tohoku J Exp Med 211

      Pages: 251-8

    • NAID

      130004459548

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Methylation status of the SOCS3 gene in human malignant melanomas.2007

    • Author(s)
      Tokita T, Maesawa C, Kimura T, Kotani K, Takahashi K, Akasaka T, Masuda T.
    • Journal Title

      Int J Oncol 30・3

      Pages: 689-94

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Coexistence of esophageal superficial carcinoma and multiple leiomyomas : A case report.2006

    • Author(s)
      Iwaya T, Maesawa C, Uesugi N, et al.
    • Journal Title

      World J Gastroenterol 12

      Pages: 4588-4592

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Aberrant maspin expression in human endometrial cancer.2006

    • Author(s)
      Murai S, Maesawa C, Masuda T. et al.
    • Journal Title

      Cancer Sci 97

      Pages: 883-888

    • NAID

      10018767453

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Interferon-gamma down-regulates expression of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats.2006

    • Author(s)
      Fujita T, Maesawa C, Oikawa K, et al.
    • Journal Title

      Int J Mol Med 17

      Pages: 605-616

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mutations of the epidermal growth factor receptor gene in gastrointestinal tract tumor cell lines.2006

    • Author(s)
      Kimura T, Maesawa C, Ikeda K, et al.
    • Journal Title

      Oncol Rep 15

      Pages: 1205-1210

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] True carcinosarcoma of the esophagus.2006

    • Author(s)
      Iwaya T, Maesawa C, Uesugi N, et al.
    • Journal Title

      Dis Esophagus 19

      Pages: 48-52

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Activated toll-like receptor 4 in monocytes is associated with heart failure after acute myocardial infarction.2006

    • Author(s)
      Satoh M, Shimoda Y, Maesawa C, et al.
    • Journal Title

      Int J Cardiol 109

      Pages: 226-234

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Coexistence of esophageal superficial carcinoma and multiple leiomyomas : A case report.2006

    • Author(s)
      Iwaya T, Maesawa C, Uesugi N et al.
    • Journal Title

      World J Gastroenterol 12

      Pages: 4588-92

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Aberrant maspin expression in human endometrial cancer.2006

    • Author(s)
      Murai S, Maesawa C, Masuda T et al.
    • Journal Title

      Cancer Sci 97

      Pages: 883-8

    • NAID

      10018767453

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Interferon-gamma down-regulates expression of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats.2006

    • Author(s)
      Fujita T, Maesawa C, Oikawa K et al.
    • Journal Title

      Int J Mol Med 17

      Pages: 605-16

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mutations of the epidermal growth factor receptor gene in gastrointestinal tract tumor cell lines.2006

    • Author(s)
      Kimura T, Maesawa C, Ikeda K et al.
    • Journal Title

      Oncol Rep 15

      Pages: 1205-10

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] True carcinosarcoma of the esophagus.2006

    • Author(s)
      Iwaya T, Maesawa C, Uesugi N et al.
    • Journal Title

      Dis Esophagus 19

      Pages: 48-52

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Activated toll-like receptor 4 in monocytes is associated with heart failure after acute myocaraial infarction.2006

    • Author(s)
      Satoh M, Shimoda Y, Maesawa C et al.
    • Journal Title

      Int J Cordial 109

      Pages: 226-34

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Interferon-gamma down-regulates expression of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats.2006

    • Author(s)
      Fujita T, Maesawa C, Oikawa K, Nitta H, Wakabayashi G, Masuda T.
    • Journal Title

      Int J Mol Med 17・4

      Pages: 605-16

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Coexistence of esophageal superficial carcinoma and multiple leiomyomas : A case report.2006

    • Author(s)
      Iwata T, Maesawa C, Uesugi N, Kimura T, Ikeda K, Kimura Y, Mitomo S, Ishida K, Sato N, Wakabayashi G.
    • Journal Title

      World J Gastroenterol 28・12

      Pages: 4588-92

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Aberrant maspin expression in human endometrial cancer.2006

    • Author(s)
      Murai S, Maesawa C, Masuda T, Sugiyama T.
    • Journal Title

      Cancer Sci 97・9

      Pages: 883-888

    • NAID

      10018767453

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Mutations of the epidermal growth factor receptor gene in gastrointestinal tract tumor cell lines.2006

    • Author(s)
      Kimura T, Maesawa C, Ikeda K, Wakabayashi G, Masuda T.
    • Journal Title

      Oncol Rep 15・5

      Pages: 1205-10

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Aberrant maspin expression in gallbladder epithelium is associated with intestinal metaplasia in patients with cholelithiasis.2006

    • Author(s)
      Maesawa C, Ogasawara S, Yashima-Abo A, Kimura T, Kotani K, Masuda S, Nagata Y, Iwaya T, Suzuki K, Oyake T, Akiyama Y, Kawamura H, Masuda T.
    • Journal Title

      J Clin Pathol 59(3)

      Pages: 328-330

    • Related Report
      2005 Annual Research Report
  • [Journal Article] True carcinosarcoma of the esophogus.2006

    • Author(s)
      Iwaya T, Maesawa C, Uesugi N, Kimura T, Ogasawara S, Ikeda K, Kimura Y, Mitomo S, Ishida K, Sato N, Saito K, Masuda T.
    • Journal Title

      Dis Esophagus 19(1)

      Pages: 48-52

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone : a case report.2005

    • Author(s)
      Oikawa H, Maesawa C, Sato R, et al.
    • Journal Title

      World J Gastroenterol 11

      Pages: 5394-5397

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Distinguishing between proliferating nodal lymphoid blasts in chronic myelogenous leukemia and non-Hodgkin lymphoma : report of three cases and detection of a bcr/abl fusion signal by single-cell analysis.2005

    • Author(s)
      Yashima-Abo A, Satoh T, Maesawa C, et al.
    • Journal Title

      Pathol Int 55

      Pages: 273-279

    • NAID

      10016475387

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Gene expression profiles in human gastric cancer : expression of maspin correlates with lymph node metastasis.2005

    • Author(s)
      Terashima M, Maesawa C, Oyama K, et al.
    • Journal Title

      Br J Cancer 92

      Pages: 1130-1136

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Infrequent mutation of the human envoplakin gene is closely linked to the tylosis oesophageal cancer locus in sporadic oesophageal squamous cell carcinomas.2005

    • Author(s)
      Iwaya T, Maesawa C, Kimura T, et al.
    • Journal Title

      Oncol Rep 13

      Pages: 703-707

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expression of human telomerase reverse transcriptase splice variants is well correlated with low telomerase activity in osteosarcoma cell lines.2005

    • Author(s)
      Fujiwara-Akita H, Maesawa C, Honda T, et al.
    • Journal Title

      Int J Oncol 26

      Pages: 1009-1016

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Consensus JH gene probes with conjugated 3'-minor groove binder for monitoring minimal residual disease in acute lymphoblastic leukemia.2005

    • Author(s)
      Uchiyama M, Maesawa C, Yashima-Abo A, et al.
    • Journal Title

      J Mol Diagn 7

      Pages: 121-126

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Epigenetic status and aberrant expression of the maspin gene in human hepato-biliary tract carcinomas.2005

    • Author(s)
      Fujisawa K, Maesawa C, Sato R, et al.
    • Journal Title

      Lab Invest 85

      Pages: 214-224

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone : a case report.2005

    • Author(s)
      Oikawa H, Maesawa C, Sato R et al.
    • Journal Title

      World J Gastroenterol 11

      Pages: 5394-7

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Distinguishing between proliferating nodal lymphoid blasts in chronic myelogenous leukemia and non-Hodgkin lymphoma : report of three cases and detection of a bcr/abl fusion signal by single-cell analysis.2005

    • Author(s)
      Yashima-Abo A, Satoh T, Abo T et al.
    • Journal Title

      Pathol Int 55

      Pages: 273-9

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Gene expression profiles in human gastric cancer expression of maspin correlates with lymph node metastasis.2005

    • Author(s)
      Terashima M, Maesawa C, Oyama K et al.
    • Journal Title

      Br J Cancer 92

      Pages: 1130-6

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Infrequent mutation of the human envoplakin gene is closely finked to the tylosis oesophageal cancer locus in sporadic oesophaaeal squamous cell carcinomas.2005

    • Author(s)
      lwaya T, Maesawa C, Kimura T et al.
    • Journal Title

      Oncol Rep 13

      Pages: 703-7

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expression of human telomerase reverse transcriptase splice variants is well correlated with low telomerase activity in osteosarcoma cell lines.2005

    • Author(s)
      Fujiwara-Akita H, Maesawa C, Honda T et al.
    • Journal Title

      Int J Oncol 26

      Pages: 1009-16

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Consensus JH gene probes with conjugated 3'-minor groove binder for monitoring minimal residual disease in acute lvmphoblastic leukemia.2005

    • Author(s)
      Uchiyama M, Maesawa C, Yashima-Abo A et al.
    • Journal Title

      J Mol Diagn 7

      Pages: 121-6

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Epigenetic status and aberrant expression of the maspin gene in human hepato-biliary tract carcinomas.2005

    • Author(s)
      Fujisawa K, Maesawa C, Sato R et al.
    • Journal Title

      Lab Invest 85

      Pages: 214-24

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Group IIA-soluble phospholipase A2 levels in patients with infections after esophageal cancer surgery.2005

    • Author(s)
      Ogawa M, Sato N, Endo S et al.
    • Journal Title

      Surg Today 35

      Pages: 912-8

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mutations of the epidermal growth factor receptor gene in gastrointestinal tract tumor cell lines2005

    • Author(s)
      Kimura T, Maesawa C, Ikeda K, Wakabayashi G, Masuda T
    • Journal Title

      Oncol Rep (In press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Infrequent mutation of the human envoplakin gene is closely linked to the tylosis oesophageal cancer locus in sporadic oesophageal squamous cell carcinomas.2005

    • Author(s)
      Iwaya T, Maesawa C, Kimura T, Ogasawara S, Ikeda K, Kimura Y, Noda Y, Ishida K, Sato N, Saito K, Masuda T.
    • Journal Title

      Oncol Rep 13(4)

      Pages: 703-707

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Group IIA-soluble phospholipase A2 levels in patients with infections after esophageal cancer surgery.2005

    • Author(s)
      Ogawa M, Sato N, Endo S, Kojika M, Yaegashi Y, Kimura Y, Ikeda K, Iwaya T.
    • Journal Title

      Surg Today 35(11)

      Pages: 912-918

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Expression of human telomerase reverse transcriptase splice variants is well correlated with low telomerase activity in osteosarcoma cell lines.2005

    • Author(s)
      Fujiwara-Akita H, Maesawa C, Honda H, Kobayashi S, Masuda T
    • Journal Title

      Int J Oncol 26・4

      Pages: 1009-1016

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Acute renal failure due to leukemic cell infiltration followed by relapse at multiple extramedullary sites in a child with acute lymphoblastic leukemia.2004

    • Author(s)
      Sato A, Imaizumi M, Chikaoka S, et al.
    • Journal Title

      Leuk Lymphoma 45

      Pages: 825-828

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Prognostic significance of peritoneal minimal residual disease in gastric cancer detected by reverse transcription-polymerase chain reaction.2004

    • Author(s)
      Oyama K, Terashima M, Takagane A, et al.
    • Journal Title

      Br J Surg 91

      Pages: 435-443

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Short consensus probes with 3'-minor groove binder of the immunoglobulin heavy-chain gene for real-time quantitative PCR in B-cell non-Hodgkin lymphomas.2004

    • Author(s)
      Uchiyama M, Maesawa C, Yashima-Abo A, et al.
    • Journal Title

      Lab Invest 84

      Pages: 932-936

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Human PinX1, a potent telomerase inhibitor, is not involved in human gastrointestinal tract carcinoma.2004

    • Author(s)
      Akiyama Y, Maesawa C, Wada K, et al.
    • Journal Title

      Oncol Rep 11

      Pages: 871-874

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Group IIA-soluble phospholipase A2 levels in patients with infections after esophageal cancer surgery.2004

    • Author(s)
      Ogawa M, Sato N, Ikeda K, et al.
    • Journal Title

      Surg Today 35

      Pages: 912-918

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Acute renal failure due to leukemic cell infiltration followed by relapse at multiple extramedullary sites in a child with acute lvmDhoblastic leukemia..2004

    • Author(s)
      Sato A, Imaizumi M, Chikaoka S et al.
    • Journal Title

      Leuk Lymphoma 45

      Pages: 825-8

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Prognostic significance of peritoneal minimal residual disease in gastric cancer detected by reverse transcription-polymerase chain reaction.2004

    • Author(s)
      Oyama K, Terashima M, Takagane A et al.
    • Journal Title

      Br J Surg 91

      Pages: 435-43

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Short consensus probes with 3-minor groove binder of the immunoglobulin heavy-chain gene for real-time quantitative PCR in B-cell non-Hodgkin lymphomas.2004

    • Author(s)
      Uchiyama M, Maesawa C, Yashima-Abo A et al.
    • Journal Title

      Lab Invest 84

      Pages: 932-6

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Human PinXl, a potent telomerase inhibitor, is not involved in human gastrointestinal tract carcinoma.2004

    • Author(s)
      Akiyama Y, Maesawa C, Wada K et al.
    • Journal Title

      Oncol Rep 11

      Pages: 871-4

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Human PinXl, a potent telomerase inhibitor, is not involved in human gastrointestinal tract carcinoma2004

    • Author(s)
      Akiyama Y, Maesawa C, Wada K, Fujisawa K, Itabashi T, Noda Y, Honda T, Sato N, Ishida K, Takagane A, Saito K, Masuda T
    • Journal Title

      Oncol Rep 11・4

      Pages: 871-874

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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