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Study on DNA Metabolizing Enzymes as Molecular Theraputic Targets in Renal Cell Carcinoma

Research Project

Project/Area Number 15390496
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Urology
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

MIZUTANI Yoichi  Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Associate Professor, 医学研究科, 助教授 (10243031)

Co-Investigator(Kenkyū-buntansha) KAWAUCHI Akihiro  Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Associate Professor, 医学研究科, 助教授 (90240952)
MIKI Tsuneharu  Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Professor, 医学研究科, 教授 (10243239)
浮村 理  京都府立医科大学, 医学研究科, 助手 (70275220)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥9,800,000 (Direct Cost: ¥9,800,000)
Fiscal Year 2004: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
KeywordsRCC / BT / DNA / DPD / TS / TK / OPRT / TP / PDECGF
Research Abstract

5-fluorouracil(5-FU) is an anticancer chemotherapeutic agent clinically used against various cancers including renal cell carcinoma(RCC). 5-FU inhibits thymidylate synthase(TS) and blocks DNA synthesis. TS is the key enzyme in the catalysis of the methylation from deoxyuridine monophosphate to deoxythymidine monophosphate in the DNA synthetic process. Little is known about the significance of TS in RCC. We investigated the activity of TS in 68 RCC samples and evaluated the association between the level of TS activity and the stage/grade of RCC. In addition, prognostic significance of TS activity in RCC was examined. The relationship between TS activity in primary cultured RCC cell lines and their sensitivity to 5-FU was also analyzed.
The level of TS activity in non-fixed fresh frozen RCC and normal kidney specimens was determined biochemically by the 5-fluoro-2'-deoxyuridine 5'-monophosphate binding assay. The sensitivity of primary cultured RCC cell lines to 5-FU was assessed by the m … More icroculture tetrazolium dye assay.
The activity of TS was approximately 5-fold higher in RCC compared to normal kidney. TS activity in T3/4 RCC was 2.5-fold higher than that in T1/2 RCC. TS activity in M1 RCC was 2.5-fold higher than that in M0 RCC. In addition, TS activity in Stage III/IV RCC was 3-fold higher than that in Stage I/II RCC. The levels of TS activity in Grade 3 RCC were 3-fold and 2-fold higher than that in Grade 1 and Grade 2 cancer, respectively. TS activity in clear cell RCC were 4-fold higher than that in papillary RCC. Patients with low TS activity had a longer disease-specific survival as compared to those with high activity in the 5-year follow-up. TS activity in primary cultured RCC cell lines positively correlated with their sensitivity to 5-FU.
The present study is the first study to demonstrate that TS activity in RCC was higher than that in normal kidney, and that the level of TS activity correlated with both the progression of the stage and the increase of the grade of RCC. In addition, higher TS activity in RCC predicted worse prognosis and higher sensitivity to 5-FU. These results suggest that the level of TS activity may be used as both a prognostic parameter and a predictive indicator for 5-FU efficacy in RCC, and that TS may be a molecular therapeutic target in RCC. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (27 results)

All 2005 2004 2003 Other

All Journal Article (19 results) Book (1 results) Publications (7 results)

  • [Journal Article] Downregulation of Smac/DIABLO expression in renal cell carcinoma and Its prognostic significance.2005

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      Journal of Clinical Oncology 23

      Pages: 448-454

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Prognostic significance of orotate phosphoribosyltransferase activity in bladder cancer.2004

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      Cancer 100

      Pages: 723-731

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significance of orotate phophorybosyltransferase activity in renal cell carcinoma.2004

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      Journal of Urology 171

      Pages: 605-610

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significance of orotate phophorybosyltransferase activity in renal cell carcinoma.2004

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      J.Urol 171

      Pages: 605-610

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Prognostic significance of orotate phosphoribosyltransferase activity in bladder cancer.2004

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      CANCER 100

      Pages: 723-731

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Prognostic significance of serum osteoprotegerin levels in patients With bladder cancer.2004

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      CANCER 101

      Pages: 1794-1802

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Significance of orotate phosphoribosyltransferase activity in renal cell carcinoma.2004

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      Journal of Urology 171

      Pages: 605-610

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Enhanced sensitivity of baldder cancer cells to cisplatin-mediated cytotoxicity and apootosis in vitro and in vivo by the selective cyclooxygenase-2 inhibitor JTE-552.2004

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      Journal of Urology 172

      Pages: 1474-1479

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Oncogenic role of NALP7 in testicular seminomas.2004

    • Author(s)
      Okada, K., Mizutani, Y.et al.
    • Journal Title

      Cancer Science 95

      Pages: 706-709

    • NAID

      10014260493

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Significance of thymidylate synthase activity in renal cell carcinoma.2003

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      Clinical Cancer Research 9

      Pages: 1453-1460

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The significance of thymidine phosphorylase/platelet-derived endothelial cell growth factor activity in renal cell carcinoma.2003

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      Cancer 98

      Pages: 730-736

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significance of dihydropyrimidine dehydrogenase activity in renal cell carcinoma.2003

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      European Journal of Cancer 39

      Pages: 541-547

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significance of thymidine kinase activity in renal cell carcinoma.2003

    • Author(s)
      Mizutani, Y. et al.
    • Journal Title

      Journal of Urology 169

      Pages: 706-709

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significance of Thymidylate synthase activity in renal cell carcinoma2003

    • Author(s)
      Mizutani Y., Wada H., Yoshida O., Fukushima M., Nomura M., Nakao M., Miki T.
    • Journal Title

      Clin.Cancer Res. 9

      Pages: 1453-1460

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The Significance of thymidine phosphorylase/platelet- derived endothelial cell growth factor activity in renal cell carcinoma.2003

    • Author(s)
      Mizutani Y., Wada H., Yoshida O., Fukushima M., Kawauchi A., Nakao M., Miki T.
    • Journal Title

      Cancer 98

      Pages: 730-736

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significance of dihydropyrimidine dehydrogenase activity in renal cell carcinoma.2003

    • Author(s)
      Mizutani Y., Wada H., Yoshida O., Fukushima M., Nakanishi H., Nakao M, Miki T.
    • Journal Title

      Eur.J.Cancer 39

      Pages: 541-547

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significance of thymidine kinase activity in renal cell carcinoma.2003

    • Author(s)
      Mizutani Y., Wada H., Yoshida O., Fukushima M., Nakao M., Miki T.
    • Journal Title

      J.Urol. 169

      Pages: 706-709

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significant antitumoral activity of cationic multilamellar liposomes containing human interferon-β gene against human renal cell carcinoma.2003

    • Author(s)
      Nakanishi H., Mizutani Y., Kawauchi A., Ukimura O., Shiraishi T., Hatano M., Mizuno M., Yoshida J., Miki T.
    • Journal Title

      Clin.Cancer Res. 9

      Pages: 1129-1135

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nonviral genetic transfer of Fas ligand induced significant growth suppression and apoptotic tumor cell death in prostate cancer in vivo.2003

    • Author(s)
      Nakanishi H., Mazda O., Satoh E., Asada H., Moriokam H., Kishida T., Nakao M., Mizutani Y., Kawauchi A., Kita M., Imanishi J., Miki T.
    • Journal Title

      Gene.Ther. 10

      Pages: 434-442

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] ASCO 2003 ハイライト2003

    • Author(s)
      水谷陽一
    • Total Pages
      4
    • Publisher
      株式会社ファーマインターナショナル
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Nakanishi, H. et al.: "Significant antitumoral activity of cationic multilamellar liposomes containing human interferon-Bgene against human renal cell carcinoma"Clinical Cancer Research. 9. 1129-1135 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizutani, Y. et al.: "Significance of thymidylate synthase activity in renal cell carcinoma"Clinical Cancer Research. 9. 1453-1460 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizutani, Y. et al.: "The significance of thymidine phosphorylase/platelet-derived endothelial cell growth factor activity in renal cell carcinoma"Cancer. 98. 730-736 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizutani, Y. et al.: "Significance of dihydropyrimidine dehydrogenase activity in renal cell carcinoma"European Journal of Cancer. 39. 541-547 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizutani, Y. et al.: "Significance of thymidine kinase activity in renal cell carcinoma"Journal of Urology. 169. 706-709 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakanishi, H. et al.: "Nonviral genetic transfer of Fas ligand induced significant growth suppression and apoptotic tumor cell death in prostate cancer in vivo"Gene Therapy. 10. 434-442 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 水谷陽一: "ASCO 2003 ハイライト"株式会社ファーマインターナショナル. 4 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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