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Physiological function of thymidine phosphorylase and the involvement of the enzyme in tumor growth

Research Project

Project/Area Number 10470043
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKagoshima University

Principal Investigator

AKIYAMA Shinichi  Kagoshima University, Faculty of Medicine, Professor, 医学部・腫瘍研究施設, 教授 (60117413)

Co-Investigator(Kenkyū-buntansha) TANI Ayako  Kagoshima University, Faculty of Medicine, Research Associate, 医学部・腫瘍研究施設, 助手 (70284867)
SUMIZAWA Tomiyuki  Kagoshima University, Faculty of Medicine, Research Associate, 医学部・腫瘍研究施設, 助手 (90206582)
FURUKAWA Tatsushiko  Kagoshima University, Faculty of Medicine, Research Associate, 医学部・腫瘍研究施設, 助手 (40219100)
小松 正治  鹿児島大学, 医学部・腫瘍研究施設, 講師 研究機関研究員
KOMATSU M  Kagoshima University, Faculty of Medicine, Instructor
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 1999: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 1998: ¥8,100,000 (Direct Cost: ¥8,100,000)
KeywordsThymidine phosphorylase / 2-deoxy-D-ribose / 2-deoxy-L-ribose / TPI / hypoxia / apotosis / metastasis / angiogenesis / PDーECGF / チミジン / 2-depxy-D-ribose / アポトーシス / TPI
Research Abstract

Thymidine phosphorylase (TP) is an enzyme involved in the reversible conversion of thymidine to thymine and is identical to an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), TP is expressed at higher levels in a wide variety of solid tumors than in the adjacent nonneoplastic tissues. KB/TP cells transfected with a PD-ECGF/TP cDNA were resistant to hypoxia-induced apoptosis. Among the degradation products of thymidine produced by PD-ECGF/TP, 2-deoxy-D-ribose partially prevented hypoxia-induced apoptosis, 2-Deoxy-L-ribose abrogated the effects of 2-deoxy-D-ribose. These findings suggested that TP can confer resistance to apoptosis induced by hypoxia and the degeadation products of thymidine are involved in this resistance.
In hypoxic condition, the level of HIF-1 α is elevated and the expression levels of Bcl-2 and Bcl-XL are lowered. 2-Deoxy-D-ribose inhibited the response of the cells to hypoxia. Patients with TP-positive colon and esophageal tumors have a … More poorer prognosis than those with TP-negative tumors. We have recently synthesized a new TP inhibitor (TPI), 5-chloro-6-[1-(2-iminopyrrolidinyl)methyl] uracil hydrochloride. We investigated the effect of TPI on angiogenesis in KB cells transfected with PD-ECGF cDNA, KB/TP, and a mock transfecta, KB/CV, using the mouse dorsal air sac assay model. We found that KB/TP cells had a higher angiogeneic ability than KB/CV cells and that TPI completely suppressed angiogenesis by KB/TP. Furthermore, at a dose of 50 mg/kg/day, TPI considerably decreased the growth rate of KB/TP cells xenografted into nude mice. Microvessel density in KB/TP tumors was higher than that in KB/CV tumors, and TPI did not significantly change the density in either of the tumors. The apoptotic index in KB/TP tumors was significantly lower than that in KB/CV tumors, and TPI significantly increased the apoptotic index in KB/TP tumors but not in KB/CV tumors. TPI inhibited the high chemotactic motility and basement membrane invasion of KB/TP cells. In nude mice, oral administration of TPI suppressed macroscopic liver metastases of highly metastasizing KB/TP cells. These findings demonstrate that TP plays a key role in invasiveness and metastasis of TP-expressing solid tumors, and TPI might be a novel anti-metastatic agent for blood-borne metastasis. Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (57 results)

All Other

All Publications (57 results)

  • [Publications] Takebayashi, Y.: "Thymidine phosphorylase in human esophageal squmous cell carcinoma"Cancer. 85. 282-289 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chu, X.-Y.: "Active efflux of CPT-11 and its metabolites in human KB-derived cell lines"J. Pharmacol. Exp. Ther.. 288. 753-741 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fukuiwa, T.: "Expression of thynidine phosphorylase and vascular endothelial cell growth factor in human head and neck squamous cell carcinoma and their different characteristics"Cancer. 85. 960-969 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fukuda, S.: "expression of vascular endothelial growth factor (VEGF) in testicular germ cell tumors as an indicator of metastatic disease"Cancer. 85. 1323-1330 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chen, Z.-S.: "An enhanced active efflux of CPT-11 and SN-38 in cisplatin-resistant human KB carcinoma cells"Cancer Lett.. 138. 13-22 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ueda, K.: "Differences in substrate specificity among GS-X pump family members: Comparison between MRP and a novel transporter expressed on a cisplatin-resistant cell line (KOP-4)"Jpn. J. Cancer Res.. 90. 439-447 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Matsushita, S.: "The effcts of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors"cancer Res.. 59. 1911-1961 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chen, Z. S.: "ATP-dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P"Mol. Pharmacol.. 55. 921-928 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kitazono, M.: "Multidrug resistance reversing agents on the transporting activity of human canalicular multispecific organic anion transporter (cMOAT)"Mol. Pharmacol.. 56. 1219-1228 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Aoki, S.: "Reversal of multidrug resistance in human carcinoma cell line by agosteroids, marine spongean sterols"Tetrahedron. 55. 13965-13972 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawabe, T.: "Enhanced transport of anticancer agents and leukotriene C4 by thehuman canalicular multispecific organic anion transporter"FEBS Lett.. 465. 327-331 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hasui, K.: "Immunohistochemical analysis of thymidine phosphorylase overexpression in malignant lymphomas (ML), especially in adult T-cell leukemia/lymphoma (ATLL)"Dendritic Cells. 9. 15-25 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] arima. J.: "Expression of thymidine phosphorylase as an indicator of poor prognosis in human transitional cell caecinoma"Cancer. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shimaoka, S.: "Role of thymidine phosphorylase expression in the invasion of gastric carcinomas"Cancer. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Komatsu, M.: "Copper transporting P-type ATPase (ATP7B) is associated with cisplatin resistance"Cancer Res.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takebayashi, Y., et al.: "Thymidine phosphorylase in human esophageal squamous cell carcinoma."Cancer. 85. 282-289 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chu, X.Y., et al Akiyama, S., and Sugiyama Y.: "Active efflux of CPT-11 and its metabolites in human KB-derived cell lines."J. Pharmacol. Exp. Ther.. 288. 753-741 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fukuiwa, T.,et al.: "Expression of thymidine phosphorylase and vascular endothelial cell growth factor in human head and neck squamous cell carcinoma and their different characteristics."Cancer. 85. 960-969 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fukuda, S., et al.: "Expression of vascular endothelial growth factor (VEGF) in testicular germ cell tumors as an indicator of metastatic disease."Cancer. 85. 1323-1330 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chen, Z.-S., et al.: "An enhanced active efflux of CPT-11 and SN-38 in cisplatin-resistant human KB carcinoma cells."Cancer Lett.. 138. 13-22 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ueda, K., et al.: "Differences in substrate specificity among GS-X pump family members: Comparison between MRP and a novel transporter expressed on a cisplatin-resistant cell line (KCP-4)"Jpn. J. Cancer Res.. 90. 439-447 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Matsushita, S., et al.: "The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors."Cancer Res.. 59. 1911-1961 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chen, Z.-S., et al.: "ATP-dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104."Mol. Pharmacol. 55. 921-928 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kitazono, M., et al.: "Multidrug resistance and the lung resistance-related protein in human colon carcinoma SW-620 cells."J. Natl. Cancer Inst.. 91. 1647-1653 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chen, Z.-S., et al.: "Effect of multidrug resistance reversing agents on the transporting activity of human canalicular multispecific organic anion transporter(cMOAT)"Mol. Pharmacol. 56. 1219-1228 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Aoki,S., et al.: "Reversal of multidrug resistance in human carcinoma cell line by agosterols, marine spongean sterols"Tetrahedron. 55. 13965-13972 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawabe, T., et al.: "Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter"FEBS Lett.. 465. 327-331 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hasui, K., et al.: "Immunohistochemical analysis of thymidine phosphorylase overexpression in malignant lymphomas (ML), especially in adult T-cell leukemia/lymphoma (ATLL)."Dendritic Cells. 9. 15-25 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ogawa, K., et al.: "Clinicopathological and prognostic significance of thymidine phosphorylase expression in gastric carcinoma."Aniticancer Res.. 19. 4363-4367 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Arima, J., et al.: "Expression of thymidine phosphorylase as an indicator of poor prognosis in human transitional cell carcinoma."Cancer. 88. 1131-1138 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Komatsu, M., et al.: "Copper transporting P-type ATPase (ATP7B) is associated with cisplatin resistance."Cancer Res.. 60. 312-1316 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ren X-Q. ,et al: "Functional comparison between YCF1 and MRP1 expressed in Sf21 insect cells."Biochem. Biophys. Res. Commun.. 270. 608-615 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shimaoka, S., et al.: "Role of thymidine phosphorylase expression in the invasion of gastric carcinomas."Cancer. 88. 2220-2227 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takabayashi,Y.,: "Thymidine phosphorylase in human esophageal squamous cell carcinoma."Cancer. 85. 282-289 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Chu,X.-Y.,: "Active efflux of CPT-11 and its metabolites in human KB-derived cell lines."J.Pharmacol.Exp.Ther.,. 288. 753-741 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fukuiwa,T.,: "Expression of thymidine phosphorylase and vascular endothelial cell growth factor in human head and neck squamous cell carcinoma and their different characteristids."Cancer. 85. 960-969 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fukuda,S.,: "Expression of vascular endothelial growth factor (VEGF) in testicular germ cell tumors as an indicator of metastatic disease."Cancer. 85. 1323-1330 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Chen,Z.-S.,: "An enhanced active efflux of CPT-11 and SN-38 in cisplatin-resistant human KB carcinoma cells."Cencer Lett.,. 138. 13-22 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ueda,K.,: "Differences in substrate specificity among GS-X,pump family.members:Comparison between MRP and a novel transporter expressed on a cisplatin-resistant cell line(KOP-4)"Jpn.J.Cancer Res.,. 90. 439-447 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Matsushita,S.,: "The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors."Cancer Res.,. 59. 1911-1961 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Chen,Z.S.,: "ATP-dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P."Mol.Pharmacol.. 55. 921-928 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kitazono,M.,: "Multidrug resistance and the lung resistance-related protein in human colon carcinoma SW-620 cells."J.Natl.Cancer Inst.,. 91. 1647-1653 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Chen,Z-S.,: "Effect of multidrug resistance reversing agents on the teansporting activity of human canalicular multispecific organic anino transporter (cMOAT)."Mol.Pharmacol.,. 56. 1219-1228 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Aoki,S.,: "Reversal of multidrug resistance in human carcinoma cell line by agosterols,marine spongean sterols."Tetrahedron,. 55. 13965-13972 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kawabe,T.,: "Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter."FEBS Lett.,. 465. 327-331 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Dendritic Cells: "Immunohistochemical analysis of thymidine phosphorylase overexpression in malignant lymphomas (ML),especially in adult T-cell leukemia/lymphoma (ATLL)."Hasui,K.,. 9. 15-25 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Arima,J.,: "Expression of thymidine phosphorylase as an indicator of poor prognosis in human transitional cell carcinoma."Cancer. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Shimaoka,S.,: "Role of thymidine phosphorylase expression in the invasion of gastric carcinomas."Cancer. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Komatsu,M.,: "Copper transporting P-type ATPase (ATP7B) is associated with cisplatin resistance."Cancer Res.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Takao,S.,: "Expression of thymidine phosphorylase is associated with a poor prognosis in patients with ductal adenocarinoma of the pancreas." Clin.Cancer Res.,. 4. 1619-1642 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Chu,X-Y.,: "Active efflux of CPT-11 and its metabolites in human KB-derived cell lines." J.Pharmacol.Exp.Ther.253. 797-803 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takebayashi,Y.,: "Thymidine phosphorylase in human esophageal squamous cell carcinoma." Cancer. 85. 282-296 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fukuiwa,T.,: "Expression of thymidine phosphorylase and vascular endothelial cell growth factor in human head and neck squamous cell carcinoma,as a prognostic factor." Cancer. 85. 960-969 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fukuda,S.,: "Expression of vascular endothelial growth factor(VEGF)in testicular germ cell tumors as an indicator of metastatic disease" Cancer. (in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] Matsushita,S.: "The effect of a thimidine phosporylase inhibitor on angiogenesis and apoptosis in tumors." Cancer Res.(in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] 秋山伸一: "血管新生の最前線(共著)" 羊土社, 174 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 秋山伸一: "臨床腫瘍学(共著)" 癌と科学療法, 印刷中 (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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