Analysis of Thymidine phosphorylase- Uridine phosphorylase double knockout mice

2002 Fiscal Year Final Research Report Summary

• Project/Area Number: 13670149
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kagoshima University
• Principal Investigator: HARAGUCHI Misako Kagoshima University, Graduate School of Medical and Dental Science, Research Associated, 大学院・医歯学総合研究科, 助手 (10244229)
• Project Period (FY): 2001 – 2002
• Keywords: Thymidine phosphorylase

Research Abstract

Thymidine phosphorylase (TP) is an enzyme involved in the reversible conversion of thymidine to thymine. In cancer patients and tumor-bearing animals, plasma TP level is elevated, and its expression in various solid tumors is higher than in the adjacent non-neoplastic tissues. Both TP itself and the degradation product of thymidine, 2-deoxy-D-ribose, had chemotactic and angiogenic activities, and the enzymatic activity of TP was required for its angiogenic activity. TP was expressed mainly at the invasive edges of tumors and TP expression was associated with the extent of invasion of gastric and colorectal carcinoma.
TP expression was also elevated in chronically inflamed tissues. TNF alpha and IFN gamma are reported to induce TP expression. To confirm the physiological role of TP, we generated mice deficient in TP gene (TPKO). TPKO mice showed an increased resistance to infection by Listeria monocytogenes. Splenic and hepatic bacterial loads 3 days after inoculation were decreased about 1 logs in TPKO. TPKO mice displays increase Interferon gamma level in plasma whereas less level of IL-10. The liver cells and spleen cells were obtained from infected mice, and cultured. The IL-10 levels in the conditioned media of the cells from TPKO mice were significantly less than those from wild-type mice. IL-10 is known to be a potent anti-inflammatory cytokine, and is suggested to reduce the function of tumor infiltrating lymphocytes and contributes the tumor growth. Therefore, we tried to test the role of TP in the escape of tumors from immune systems. Age and sex matched mice (wild-type and TP-/-) were injected i.p. with 1x10^6 of EL-4 cells. Two week after the challenge with EL-4 cells, the increase in volumes of ascites and the growth of EL-4 cells are significantly less in TPKO mice than in wild-type mice. Thus, TP may allow the escape of tumors from immune destruction and contribute the tumor growth.

Research Products

• [Publications] Ikeda, -R;, Furukawa, -T;, Mitsuo, -R;, Noguchi, -T;, Kitazono, -M;, Okumura, -H;, Sumizawa, -T;, Haraguchi, -M;, Che, -X-F;, Uchimiya, -H;, Nakajima, -Y;, Ren, -X-Q;, Oiso, -S;, Inoue, -I;, Yamada, -K;, Akiyama,-S: "Thymidine phosphorylase inhibits apoptosis induced by cisplatin"Biochem-Biophys-Res-Commun.. 301 2. 358-363 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Haraguchi-M., Tsujimoto-H., Fukushima-M., Higuchi-I., Kuribayashi-H., Utsumi-H., Nakayama-A., Hashizume-Y., Hirato-J., Yoshida-H., Hara-H., Hamano-S., Kawaguchi-H., Furukawa-T., Miyazono-K., Ishikawa-F., Toyoshima-H., Kaname-T., Komatsu-M., Chen_Z.H., Gotanda-T., Tachiwada-T., Sumizawa-T., Miyadera-K., Osame-M., Yoshida-H., Noda-T., Yamada-Y., Akiyama-S.: "Targeted Deletion of both Thymidine Phosphorylase and Uridine Phosphorylase and consequent disorders in mice"Mol.Cell.Biol.. 22. 5212-5221 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Uchimiya-H., Furukawa-T., Okamoto-M., Nakajima-Y., Matsushita-S., Ikeda-R., Gotanda-T., Haraguchi-M., Sumizawa-T., Ono-M., Kuwano-M., Kanzaki-T., Akiyama-S.: "Suppression of thymidine phosphorylase-mediated angiogenesis and tumor growth by 2-deoxy-L-ribose"Cancer Res.. 62. 2834-2839 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ikeda-R, Furukawa-T., Kitazono-M., Ishitsuka-K., Okumura-H., Tani-A., Sumizawa-T., Haraguchi-M., Komatsu-M., Uchimiya-H., Ren-X.Q., Motoya-T., Yamada-K., Akiyama-S: "Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-d-ribose"Biochem.Biophys.Res.Commun.. 291. 806-812 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ikeda,-R, Furukawa,-T., Mitsuo,-R, Noguchi,-T, Kitazono,-M, Okumura,-H, Sumizawa,-T, Haraguchi,-M, Che,-X-F, Uchimiya, -H, Nakajima,-Y, Ren,-X-Q, Oiso,-S, Inoue,-I, Yamada,-K, Akiyama,-S: "Thymidine phosphorylase inhibits apoptosis induced by cisplatin"Biochem-Biophys-Res-Commun. 301(2). 358-363 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Haraguchi-M., Tsujimoto-H., Fukushima-M., Higuchi-I., Kuribayashi-H., Utsumi-H., Nakayama-A., Hashizume-Y., Hirato-J., Yoshida-H., Hara-H., Hamano-S., Kawaguchi-H, Furukawa-T., Miyazono-K., Ishikawa-F., Toyoshima-H., Kaname-T., Komatsu-M., Chen-Z.H., Gotanda-T., Tachiwada-T., Sumizawa-T., Miyadera-K., Osame-M., Yoshida-H., Noda-T., Yamada,-Y. & Akiyama-S: "Targeted Deletion of both Thymidine Phosphorylase and Uridine Phosphorylase and consequent disorders in mice"Mol. Cell. Biol.. 22. 5212-5221 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Uchimiya-H., Furukawa-T., Okamoto-M., Nakajima-Y., Matsushita-S., Ikeda-R., Gotanda-T., Haraguchi-M., Sumizawa-T., Ono-M., Kuwano-M., Kanzaki-T. & Akiyama-S: "Suppression of thymidine phosphorylase-mediated angiogenesis and tumor growth by 2-deoxy-L-ribose"Cancer Res.. 62. 2834-2839 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ikeda-R., Furukawa-T., Kitazono-M., Ishitsuka-K., Okumura-H., Tani-A., Sumizawa-T., Haraguchi-M., Komatsu-M., Uchimiya-H., Ren-X.Q., Motoya-T., Yamada-K. & Akiyama-S.: "Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-d-ribose"Biochem. Biophys. Res. Commun.. 291. 806-812 (2002)
  • Description: 「研究成果報告書概要(欧文)」より