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. 2005 Aug 19;95(11):851–857. doi: 10.1111/j.1349-7006.2004.tb02193.x

The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression

Shin‐ichi Akiyama 1,✉, Tatsuhiko Furukawa 1, Tomoyuki Sumizawa 1, Yuji Takebayashi 2, Yuichi Nakajima 1, Shunji Shimaoka 3, Misako Haraguchi 1
PMCID: PMC11159696  PMID: 15546501

Abstract

Thymidine phosphorylase (TP), an enzyme involved in pyrimidine metabolism, is identical with an angiogenic factor, platelet‐derived endothelial cell growth factor (PD‐ECGF). TP is overex‐pressed in various tumors and plays an important role in angiogenesis, tumor growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP. A novel, specific TP inhibitor, TPI, inhibits angiogenesis induced by overexpression of TP in KB/TP cells (human KB epidermoid carcinoma cells transfected with TP cDNA), as well as the growth and metastasis of KB/TP cells in vivo. 2‐Deoxy‐D‐ribose, the degradation product of thymidine generated by TP activity, has both angiogenic and chemotactic activity. Both 2‐deoxy‐D‐ribose and TP inhibit a hypoxia‐induced apoptotic pathway. These findings suggest that 2‐deoxy‐D‐ribose is a downstream mediator of TP function. 2‐Deoxy‐L‐ribose, a stereoisomer of 2‐deoxy‐D‐ribose, inhibits the promotion of angiogenesis, tumor growth and metastasis by TP. Although the mechanism of the action of 2‐deoxy‐D‐ribose is still unknown, 2‐deoxy‐L‐ribose may inhibit the physiological activities of 2‐deoxy‐D‐ribose, and consequently those of TP. Inhibition of TP activity and function appears to be a promising approach for the chemotherapy of various tumors.

References

  • 1. Iltzsch MH, Kouni MH, Cha S. Kinetic studies of thymidine phosphory‐lase from mouse liver. Biochemistry 1985; 19: 6799–807. [DOI] [PubMed] [Google Scholar]
  • 2. Friedkin M, Roberts D. The enzymatic synthesis of nucleosides. I. Thymidine phosphorylase in mammalian tissue. J Biol Chem 1954; 207: 245–56. [PubMed] [Google Scholar]
  • 3. Krenitsky TA, Koszalka GW, Tuttle JV. Purine nucleoside synthesis, an efficient method employing nucleoside phosphorylases. Biochemistry 1981; 20: 3615–21. [DOI] [PubMed] [Google Scholar]
  • 4. Zimmerman M, Seidenberg J. Deoxyribosyl transfer. Thymine phosphorylase and nucleosides deoxyribosyl transferase in normal and malignant tissues. J Biol Chem. 1964; 239: 2618–21. [PubMed] [Google Scholar]
  • 5. Gallo RC, Perry S, Breitman TR. The enzymatic mechanisms for deoxythy‐midine synthesis in human leukocytes. I. Substrate inhibition by thymine and activation by phosphate or arsenate. J Biol Chem. 1967; 242: 5059–68. [PubMed] [Google Scholar]
  • 6. Krenitsky TA. Pentosyl transfer mechanisms of the mammalian nucleoside phosphorylases. J Biol Chem. 1968; 243: 2871–5. [PubMed] [Google Scholar]
  • 7. Desgranges C, Razaka G, Rabaud M, Bricaud H. Catabolism of thymidine in human blood platelets: purification and properties of thymidine phosphorylase. Biochim. Biophys Acta 1981; 654: 211–8. [DOI] [PubMed] [Google Scholar]
  • 8. Furukawa T, Yoshimura A, Sumizawa T, Haraguchi M, Akiyama S, Fukui K, Ishizawa M, Yamada Y Angiogenic factor. Nature 1992; 356: 668. [DOI] [PubMed] [Google Scholar]
  • 9. Miyadera K, Sumizawa T, Haraguchi M, Yoshida H, Konstanty W, Yamada Y, Akiyama S. Role of thymidine phosphorylase activity in the angiogenic effect of platelet derived endothelial cell growth factor/thymidine phosphorylase. Cancer Res 1995; 55: 1687–90. [PubMed] [Google Scholar]
  • 10. Takebayashi Y, Yamada K, Miyadera K, Sumizawa T, Furukawa T, Kinoshita F, Aoki D, Okumura H, Yamada Y, Akiyama S, Aikou T. The activity and expression of thymidine phosphorylase in human solid tumours. Eur Cancer 1996; 32A: 1227–32. [DOI] [PubMed] [Google Scholar]
  • 11. Haraguchi M, Miyadera K, Uemura K, Sumizawa T, Furukawa T, Yamada K, Akiyama S, Yamada Y. Angiogenic activity of enzymes. Nature 1994; 368: 198. [DOI] [PubMed] [Google Scholar]
  • 12. Ishikawa F, Miyazono K, Hellman U, Drexler H, Wernstedt C, Hagiwara K, Usuki K, Takaku F, Risau W, Heldin CH. Identification of angiogenic activity and the cloning and expression of platelet‐derived endothelial cell growth factor. Nature 1989; 338: 557–62. [DOI] [PubMed] [Google Scholar]
  • 13. Miyazono K, Okabe T, Urabe A, Takaku F, Heldin CH. Purification and properties of an endothelial cell growth factor from human platelets. J Biol Chem. 1987; 262: 4098–103. [PubMed] [Google Scholar]
  • 14. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3: 401–10. [DOI] [PubMed] [Google Scholar]
  • 15. Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors (Review). Nat Rev Cancer 2002: 2727–39. [DOI] [PubMed] [Google Scholar]
  • 16. Miyadera K, Dohmae N, Takio K, Sumizawa T, Haraguchi M, Furukawa T, Yamada Y, Akiyama S. Structural characterization of thymidine phosphorylase purified from human placenta. Biochem Biophys Res Commun 1995; 212: 1040–5. [DOI] [PubMed] [Google Scholar]
  • 17. Sumizawa T, Furukawa T, Haraguchi M, Yoshimura A, Takeyasu A, Ishizawa M, Yamada Y, Akiyama S. Thymidine phosphorylase activity associated with platelet‐derived endothelial cell growth factor. J Biochem (Tokyo) 1993; 114: 9–14. [DOI] [PubMed] [Google Scholar]
  • 18. Usuki K, Saras J, Waltenberger J, Miyazono K, Pierce G, Thomason A, Heldin CH. Platelet‐derived endothelial cell growth factor has thymidine phosphorylase activity. Biochem Biophys Res Commun 1992; 184: 1311–6. [DOI] [PubMed] [Google Scholar]
  • 19. Asai K, Nakanishi K, Isobe I, Eksioglu YZ, Hirano A, Kama K, Miyamoto T, Kato T. Neurotrophic action of gliostatin on cortical neurons. Identity of gliostatin and platelet‐derived endothelial cell growth factor J Biol Chem 1992; 267: 20311–6. [PubMed] [Google Scholar]
  • 20. Hirano T, Asai K, Matsukawa K, Kato T, Takeuchi M, Yonezawa M, Otsuka T, Matsui N. Establishment of an enzyme immunoassay system for gliostatin/platelet‐derived endothelial cell growth factor (PD‐ECGF). Biochim. Biophys Acta 1993; 1176: 299–304. [DOI] [PubMed] [Google Scholar]
  • 21. Moghaddam A, Zhang HT, Fan TP, Hu DE, Lees VC, Turley H, Fox SB, Gatter KC, Harris AL, Bicknell R. Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci USA 1995; 92: 998–1002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Miyadera K, Emura T, Suzuki N, Akiyama S, Fukushima M, Yamada Y. Novel functional antitumor nucleoside TAS‐102, combined from of F3Rhd and its modulator (2): inhibitory effect of TPI on tumor‐derived angiogenesis and metasis. Proc Am. Assoc Cancer Res 1998; 39: 609. [Google Scholar]
  • 23. Matsushita S, Nitanda T, Furukawa T, Sumizawa T, Tani A, Nishimoto K, Akiba S, Miyadera K, Fukushima M, Yamada Y, Yoshida H, Kanzaki T, Akiyama S. The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors. Cancer Res 1999; 59: 1911–6. [PubMed] [Google Scholar]
  • 24. Balzarini J, Gamboa AE, Esnouf R, Liekens S, Neyts J, de Clercq E, Camarasa MJ, Perez‐Perez MJ. 7‐Deazaxanthine, a novel prototype inhibitor of thymidine phosphorylase. FEBS Lett 1998; 438: 91–5. [DOI] [PubMed] [Google Scholar]
  • 25. Liekens S, Hernandez AI, Ribatti D, de Clercq E, Camarasa MJ, Perez‐Perez MJ, Balzarini J. The nucleoside derivative 5′‐O‐trityl‐inosine (KIN59) suppresses thymidine phosphorylase‐triggered angiogenesis via a noncom‐petitive mechanism of action. J Biol Chem 2004; 279: 29598–605. [DOI] [PubMed] [Google Scholar]
  • 26. Emura T, Murakami Y, Nakagawa F, Fukushima M, Kitazato K. A novel an‐timetabolite, TAS‐102 retains its effect on FU‐related resistant cancer cells. Int J Mol Med 2004; 13: 545–9. [PubMed] [Google Scholar]
  • 27. Norman RA, Barry ST, Bate M, Breed J, Colls JG, Ernill RJ, Luke RW, Minshull CA, McAlister MS, McCall EJ, McMiken HH, Paterson DS, Timms D, Tucker JA, Pauptit RA. Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor. Structure (Camb) 2004; 12: 75–84. [DOI] [PubMed] [Google Scholar]
  • 28. Kitazono M, Takebayashi Y, Ishitsuka K, Takao S, Tani A, Furukawa T, Miyadera K, Yamada Y, Aikou T, Akiyama S. Prevention of hypoxia‐in‐duced apoptosis by the angiogenic factor thymidine phosphorylase. Biochem Biophys Res Commun 1998; 253: 797–803. [DOI] [PubMed] [Google Scholar]
  • 29. Ikeda R, Furukawa T, Kitazono M, Ishitsuka K, Okumura H, Tani A, Sumizawa T, Haraguchi M, Komatsu M, Uchimiya H, Ren XQ, Motoya T, Yamada K, Akiyama S. Molecular basis for the inhibition of hypoxia‐in‐duced apoptosis by 2‐deoxy‐D‐ribose. Biochem Biophys Res Commun 2002; 291: 806–12. [DOI] [PubMed] [Google Scholar]
  • 30. Takebayashi Y, Akiyama S, Akiba S, Yamada K, Miyadera K, Sumizawa T, Yamada Y, Murata F, Aikou T. Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 1996; 88: 1110–7. [DOI] [PubMed] [Google Scholar]
  • 31. Imazono Y, Takebayashi Y, Nishiyama K, Akiba S, Miyadera K, Yamada Y, Akiyama S, Ohi Y. Correlation between thymidine phosphorylase expression and prognosis in human renal cell carcinoma. J Clin Oncol 1997; 15: 2570–8. [DOI] [PubMed] [Google Scholar]
  • 32. Mori S, Takao S, Ikeda R, Noma H, Mataki Y, Wang X, Akiyama S, Aikou T. Thymidine phosphorylase suppresses Fas‐induced apoptotic signal trans‐duction independent of its enzymatic activity. Biochem Biophys Res Com-mun 2002; 295: 300–5. [DOI] [PubMed] [Google Scholar]
  • 33. Ikeda R, Furukawa T, Mitsuo R, Noguchi T, Kitazono M, Okumura H, Sumizawa T, Haraguchi M, Che XF, Uchimiya H, Nakajima Y, Ren XQ, Oiso S, Inoue I, Yamada K, Akiyama S. Thymidine phosphorylase inhibits apoptosis induced by cisplatin. Biochem Biophys Res Commun 2003; 301: 358–63. [DOI] [PubMed] [Google Scholar]
  • 34. Brown NS, Bicknell R. Thymidine phosphorylase, 2‐deoxy‐D‐ribose and angiogenesis (Review). Biochem. J 1998; 334: 1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Brown NS, Jones A, Fujiyama C, Harris AL, Bicknell R. Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors. Cancer Res 2000; 60: 6298–302. [PubMed] [Google Scholar]
  • 36. Nakajima Y, Gotanda T, Uchimiya H, Furukawa T, Haraguchi M, Ikeda R, Sumizawa T, Yoshida H, Akiyama S. Inhibition of metastasis of tumor cells overexpressing thymidine phosphorylase by 2‐deoxy‐L‐ribose. Cancer Res 2004; 64: 1794–801. [DOI] [PubMed] [Google Scholar]
  • 37. Hotchkiss KA, Ashton AW, Schwartz EL. Thymidine phosphorylase and 2‐deoxyribose stimulate human endothelial cell migration by specific activation of the integrins alpha 5 beta 1 and alpha V beta 3. J Biol Chem. 2003; 278: 19272–9. [DOI] [PubMed] [Google Scholar]
  • 38. Seeliger H, Guba M, Koehl GE, Doenecke A, Steinbauer M, Bruns CJ, Wagner C, Frank E, Jauch KW, Geissler EK. Blockage of 2‐deoxy‐D‐ribose‐induced angiogenesis with rapamycin counteracts a thymidine phosphory‐lase‐based escape mechanism available for colon cancer under 5‐fluorouracil therapy. Clin Cancer Res 2004; 10: 1843–52. [DOI] [PubMed] [Google Scholar]
  • 39. Xia H, Nho RS, Kahm J, Kleidon J, Henke CA. Focal adhesion kinase is upstream of phosphatidylinositol 3‐kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem. 2004; 279: 33024–34. [DOI] [PubMed] [Google Scholar]
  • 40. Haraguchi M, Tsujimoto H, Fukushima M, Higuchi I, Kuribayashi H, Utsumi H, Nakayama A, Hashizume Y, Hirato J, Yoshida H, Kara H, Hamano S, Kawaguchi H, Furukawa T, Miyazono K, Ishikawa F, Toyoshima H, Kaname T, Komatsu M, Chen ZS, 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 2002; 22: 5212–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999; 283: 689–92. [DOI] [PubMed] [Google Scholar]
  • 42. Yoshimura A, Kuwazuru Y, Furukawa T, Yoshida H, Yamada K, Akiyama S. Purification and tissue distribution of human thymidine phosphorylase; high expression in lymphocytes, reticulocytes and tumors. Biochim. Biophys Acta 1990; 1034: 107–13. [DOI] [PubMed] [Google Scholar]
  • 43. Takahashi Y, Bucana CD, Liu W, Yoneda J, Kitadai Y, Cleary KR, Ellis LM. Platelet‐derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells. J Natl Cancer Inst 1996; 88: 1146–51. [DOI] [PubMed] [Google Scholar]
  • 44. Shimaoka S, Matsushita S, Nitanda T, Matsuda A, Nioh T, Suenaga T, Nishimata Y, Akiba S, Akiyama S, Nishimata H. The role of thymidine phosphorylase expression in the invasiveness of gastric carcinoma. Cancer 2000; 88: 2220–7. [PubMed] [Google Scholar]
  • 45. Eda H, Fujimoto K, Watanabe S, Ura M, Hino A, Tanaka Y, Wada K, Ishitsuka H. Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5′‐deoxy‐5‐fluorouridine. Cancer ChemotherPharmacol 1993; 32: 333–8. [DOI] [PubMed] [Google Scholar]
  • 46. Goto H, Kohno K, Sone S, Akiyama S, Kuwano M, Ono M. Interferon gamma‐dependent induction of thymidine phosphorylase/platelet‐derived endothelial growth factor through gamma‐activated sequence‐like element in human macrophages. Cancer Res 2001; 61: 469–73. [PubMed] [Google Scholar]
  • 47. Takao S, Akiyama SI, Nakajo A, Yoh H, Kitazono M, Natsugoe S, Miyadera K, Fukushima M, Yamada Y, Aikou T. Suppression of metastasis by thymidine phosphorylase inhibitor. Cancer Res 2000; 60: 5345–8. [PubMed] [Google Scholar]
  • 48. 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 2002; 62: 2834–9. [PubMed] [Google Scholar]
  • 49. Takao S, Takebayashi Y, Che X, Shinchi H, Natsugoe S, Miyadera K, Yamada Y, Akiyama S, Aikou T. Expression of thymidine phosphorylase is associated with a poor prognosis in patients with ductal adenocarcinoma of the pancreas. Clin Cancer Res 1998; 4: 1619–24. [PubMed] [Google Scholar]
  • 50. O'Brien T, Cranston D, Fuggle S, Bicknell R, Harris AL. Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res 1995; 55: 510–3. [PubMed] [Google Scholar]
  • 51. Jones A, Fujiyama C, Turner K, Cranston D, Williams K, Stratford I, Bicknell R, Harris AL. In vitro model of human bladder cancer invasion. J Urol 2002; 167: 1482–6. [PubMed] [Google Scholar]
  • 52. Patterson AV, Zhang H, Moghaddam A, Bicknell R, Talbot DC, Stratford IJ, Harris AL. Increased sensitivity to the prodrug 5′‐deoxy‐5‐fluorouridine and modulation of 5‐fluoro‐2′‐deoxyuridine sensitivity in MCF‐7 cells trans‐fected with thymidine phosphorylase. Br J Cancer 1995; 72: 669–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Haraguchi M, Furukawa T, Sumizawa T, Akiyama S. Sensitivity of human KB cells expressing platelet‐derived endothelial cell growth factor to pyrimi‐dine antimetabolites. Cancer Res 1993; 53: 5680–2. [PubMed] [Google Scholar]
  • 54. Evrard A, Cuq P, Robert B, Vian L, Pelegrin A, Cano JP. Enhancement of 5‐fluorouracil cytotoxicity by human thymidine‐phosphorylase expression in cancer cells: in vitro and in vivo study. Int J Cancer 1999; 80: 465–70. [DOI] [PubMed] [Google Scholar]
  • 55. Kanyama H, Tomita N, Yamano T, Miyoshi Y, Ohue M, Fujiwara Y, Sekimoto M, Sakita I, Tamaki Y, Monden M. Enhancement of the anti‐tumor effect of 5′‐deoxy‐5‐fluorouridine by transfection of thymidine phosphorylase gene into human colon cancer cells. Jpn J Cancer Res 1999; 90: 454–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Terashima M, Fujiwara H, Takagane A, Abe K, Araya M, Irinoda T, Yonezawa H, Nakaya T, Oyama K, Takahashi M, Saito K. Role of thymidine phosphorylase and dihydropyrimidine dehydrogenase in tumour progression and sensitivity to doxifluridine in gastric cancer patients. Eur J Cancer 2002; 38: 2375–81. [DOI] [PubMed] [Google Scholar]
  • 57. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H. Induction of thymidine phosphorylase activity and enhancement of capecitab‐ine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 1998; 4: 1013–9. [PubMed] [Google Scholar]
  • 58. Endo M, Shinbori N, Fukase Y, Sawada N, Ishikawa T, Ishitsuka H, Tanaka Y. Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5′‐deoxy‐5‐fluorouridine by cyclophosphamide in mammary tumor models. Int J Cancer 1999; 83: 127–34. [DOI] [PubMed] [Google Scholar]
  • 59. Hofheinz RD, Weisser A, Wilier A, Hehlmann R, Hochhaus A. Treatment of a patient with advanced esophageal cancer with a combination of mitomycin C and capecitabine: activation of the thymidine phosphorylase as active principle? Onkologie 2003; 26: 161–4. [DOI] [PubMed] [Google Scholar]
  • 60. Sawada N, Ishikawa T, Sekiguchi F, Tanaka Y, Ishitsuka H. X‐ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 1999; 5: 2948–53. [PubMed] [Google Scholar]
  • 61. Park YH, Ryoo BY, Choi SJ, Kim HT. A phase II study of capecitabine and docetaxel combination chemotherapy in patients with advanced gastric cancer. Br] Cancer 2004; 90: 1329–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Maher JF, Villalona‐Calero MA. Taxanes and capecitabine in combination: rationale and clinical results. Clin. Breast Cancer 2002; 2: 287–93. [DOI] [PubMed] [Google Scholar]

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