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Gene Review

TYMP  -  thymidine phosphorylase

Homo sapiens

Synonyms: ECGF, ECGF1, Gliostatin, MEDPS1, MNGIE, ...
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Disease relevance of ECGF1

  • TS and TP both were of prognostic significance in these patients with colorectal cancer [1].
  • Significant correlation was seen between DPD and TP expression levels in both primary CRC (rs=0.38, p=0.03) and liver metastases (rs=0.72, p<0.0001) [2].
  • COX-2 is upregulated in endometrial cancer and facilitates tumor growth via angiogenesis produced in associated with VEGF and TP [3].
  • MCP-1 expression correlated significantly with VEGF but not PD-ECGF expression in gastric carcinomas [4].
  • The TP inhibitor significantly inhibited the angiogenesis induced by the serous adenocarcinoma cells [5].

High impact information on ECGF1

  • The mRNA levels of the A- and B-chains of PDGF in HUVE cells were analysed and shown to respond differently to the endothelial cell growth factor (ECGF) [6].
  • TP activity in leukocytes from MNGIE patients was less than 5 percent of controls, indicating that loss-of-function mutations in TP cause the disease [7].
  • Examination of 12 MNGIE probands revealed homozygous or compound-heterozygous mutations in the gene specifying thymidine phosphorylase (TP), located on chromosome 22q13.32-qter [7].
  • VEGFs are secreted proteins, in contrast to other endothelial cell mitogens such as acidic or basic fibroblast growth factors and platelet-derived endothelial cell growth factor [8].
  • This deficiency of TP leads to increased circulating levels of thymidine (deoxythymidine, dThd) and deoxyuridine (dUrd) and has been associated with multiple deletions and depletion of mitochondrial DNA (mtDNA) [9].

Chemical compound and disease context of ECGF1


Biological context of ECGF1


Anatomical context of ECGF1

  • In vivo angiogenesis in the ovarian cancer cells was evaluated by the dorsal air sac assay and revealed that SHIN-3 and HRA serous adenocarcinoma cells, which have high levels of TP expression, induced angiogenesis, while KK clear cell carcinoma cells with low TP expression, did not [5].
  • Moreover, the correlation between TS, DPD and TP expression and cytotoxicity of 5-fluorouracil was evaluated in Colo 320, HT-29, CaCo-2 and SW620 human CRC cell lines [17].
  • CONCLUSIONS: The present results demonstrated significant differences in DPD and TP gene expression between normal mucosa and tumour samples, while TSER*3G/3G and high-grade histology were associated with significant variation in TS gene expression in tumour samples [17].
  • METHODS: Immunostaining for PD-ECGF was performed on 96 colon cancer specimens, some of which were previously stained for VEGF and factor VIII, a marker that is specific for endothelial cells [18].
  • RESULTS: Immunohistochemical analysis demonstrated that PD-ECGF was expressed in infiltrating cells in most of the colon cancer specimens (80 [83%] of 96) but rarely in tumor epithelium (five [5%] of 96) [18].

Associations of ECGF1 with chemical compounds


Regulatory relationships of ECGF1

  • MAIN OUTCOME MEASURE(S): The secretion of VEGF in supernatant media and the numbers of cells expressing VEGF or TP [21].
  • Only five tumors failed to express TP but four of these expressed DPD, suggesting capecitabine resistance [20].
  • This significant association was observed also when PPAR gamma was expressed in the presence of PDECGF, which resulted, when considered alone, to an angiogenic factor typical of solid cancers and appeared related to poor prognosis [22].
  • This study demonstrates that IFN induces TP/PD-ECGF expression in vivo by regulation of the level of mRNA expression [23].
  • In the cellular level, TP and MT were scarcely co-expressed with AFP in either gastric cancer or xenograft series, using double immunostaining and serial sectioning techniques [24].

Other interactions of ECGF1

  • VEGF expression correlated significantly with TP immunostaining and Ki67 index [1].
  • Double staining demonstrated that infiltrating cells staining positive for both PD-ECGF and CD68 were more predominant than those staining positive for both PD-ECGF and CD3 [18].
  • IL-8 was expressed in two of five cultured cell lines, but neither PD-ECGF nor bFGF was detected [25].
  • Statistical analysis revealed that the proportions of MCP-1-positive myxoma and stromal cells, and TP-positive myxoma and stromal cells significantly correlated with increased microvessel count [26].
  • In this study, peripheral blood mononuclear cells were obtained from patients prior to and during treatment with IFN and FUra and analyzed for TP/PD-ECGF expression [23].

Analytical, diagnostic and therapeutic context of ECGF1


  1. Prognostic role of thymidylate synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor, and proliferation markers in colorectal cancer. van Triest, B., Pinedo, H.M., Blaauwgeers, J.L., van Diest, P.J., Schoenmakers, P.S., Voorn, D.A., Smid, K., Hoekman, K., Hoitsma, H.F., Peters, G.J. Clin. Cancer Res. (2000) [Pubmed]
  2. 5-fluorouracil-related gene expression levels in primary colorectal cancer and corresponding liver metastasis. Kuramochi, H., Hayashi, K., Uchida, K., Miyakura, S., Shimizu, D., Vallbohmer, D., Park, S., Danenberg, K.D., Takasaki, K., Danenberg, P.V. Int. J. Cancer (2006) [Pubmed]
  3. Cyclooxygenase-2 expression in endometrial cancer: correlation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase. Fujiwaki, R., Iida, K., Kanasaki, H., Ozaki, T., Hata, K., Miyazaki, K. Hum. Pathol. (2002) [Pubmed]
  4. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas. Ohta, M., Kitadai, Y., Tanaka, S., Yoshihara, M., Yasui, W., Mukaida, N., Haruma, K., Chayama, K. Int. J. Oncol. (2003) [Pubmed]
  5. Thymidine phosphorylase-mediated angiogenesis regulated by thymidine phosphorylase inhibitor in human ovarian cancer cells in vivo. Tsukagoshi, S., Saga, Y., Suzuki, N., Fujioka, A., Nakagawa, F., Fukushima, M., Suzuki, M. Int. J. Oncol. (2003) [Pubmed]
  6. cDNA clones reveal differences between human glial and endothelial cell platelet-derived growth factor A-chains. Tong, B.D., Auer, D.E., Jaye, M., Kaplow, J.M., Ricca, G., McConathy, E., Drohan, W., Deuel, T.F. Nature (1987) [Pubmed]
  7. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Nishino, I., Spinazzola, A., Hirano, M. Science (1999) [Pubmed]
  8. Vascular endothelial growth factor is a secreted angiogenic mitogen. Leung, D.W., Cachianes, G., Kuang, W.J., Goeddel, D.V., Ferrara, N. Science (1989) [Pubmed]
  9. Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency. Nishigaki, Y., Martí, R., Copeland, W.C., Hirano, M. J. Clin. Invest. (2003) [Pubmed]
  10. The role of thymidylate synthase and dihydropyrimidine dehydrogenase in resistance to 5-fluorouracil in human lung cancer cells. Oguri, T., Achiwa, H., Bessho, Y., Muramatsu, H., Maeda, H., Niimi, T., Sato, S., Ueda, R. Lung Cancer (2005) [Pubmed]
  11. Phase II clinical trial of capecitabine in ovarian carcinoma recurrent 6-12 months after completion of primary chemotherapy, with exploratory TS, DPD, and TP correlates: a Gynecologic Oncology Group study. Garcia, A.A., Blessing, J.A., Lenz, H.J., Darcy, K.M., Mannel, R.S., Miller, D.S., Husseinzadeh, N. Gynecol. Oncol. (2005) [Pubmed]
  12. Effects of various steroids on platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA expression in uterine endometrial cancer cells. Aoki, I., Fujimoto, J., Tamaya, T. J. Steroid Biochem. Mol. Biol. (2003) [Pubmed]
  13. Increased muscle nucleoside levels associated with a novel frameshift mutation in the thymidine phosphorylase gene in a Spanish patient with MNGIE. Blazquez, A., Martín, M.A., Lara, M.C., Martí, R., Campos, Y., Cabello, A., Garesse, R., Bautista, J., Andreu, A.L., Arenas, J. Neuromuscul. Disord. (2005) [Pubmed]
  14. Regional localization of the human platelet-derived endothelial cell growth factor (ECGF1) gene to chromosome 22q13. Stenman, G., Sahlin, P., Dumanski, J.P., Hagiwara, K., Ishikawa, F., Miyazono, K., Collins, V.P., Heldin, C.H. Cytogenet. Cell Genet. (1992) [Pubmed]
  15. Regulation of expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor in human colon carcinoma cells. Schwartz, E.L., Wan, E., Wang, F.S., Baptiste, N. Cancer Res. (1998) [Pubmed]
  16. The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells. Zhu, G.H., Lenzi, M., Schwartz, E.L. Oncogene (2002) [Pubmed]
  17. Thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer and normal mucosa in patients. Amatori, F., Di Paolo, A., Del Tacca, M., Fontanini, G., Vannozzi, F., Boldrini, L., Bocci, G., Lastella, M., Danesi, R. Pharmacogenet. Genomics (2006) [Pubmed]
  18. Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells. Takahashi, Y., Bucana, C.D., Liu, W., Yoneda, J., Kitadai, Y., Cleary, K.R., Ellis, L.M. J. Natl. Cancer Inst. (1996) [Pubmed]
  19. No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix. Kabuubi, P., Loncaster, J.A., Davidson, S.E., Hunter, R.D., Kobylecki, C., Stratford, I.J., West, C.M. Br. J. Cancer (2006) [Pubmed]
  20. Enzyme expression profiles suggest the novel tumor-activated fluoropyrimidine carbamate capecitabine (Xeloda) might be effective against papillary thyroid cancers of children and young adults. Patel, A., Pluim, T., Helms, A., Bauer, A., Tuttle, R.M., Francis, G.L. Cancer Chemother. Pharmacol. (2004) [Pubmed]
  21. Modulation of vascular endothelial growth factor and thymidine phosphorylase in normal human endometrial stromal cells. Abbas, M.M., Evans, J.J., Sykes, P.H., Benny, P.S. Fertil. Steril. (2004) [Pubmed]
  22. The role of peroxisome proliferator-activated receptor gamma in bladder cancer in relation to angiogenesis and progression. Possati, L., Rocchetti, R., Talevi, S., Beatrici, V., Margiotta, C., Ferrante, L., Calza, R., Sagrini, D., Ferri, A. Gen. Pharmacol. (2000) [Pubmed]
  23. Interferon induces thymidine phosphorylase/platelet-derived endothelial cell growth factor expression in vivo. Makower, D., Wadler, S., Haynes, H., Schwartz, E.L. Clin. Cancer Res. (1997) [Pubmed]
  24. Expression of chemoresistance-related proteins in alpha-fetoprotein-producing adenocarcinoma of the digestive organs. Kamoshida, S., Suzuki, M., Sakurai, Y., Ochiai, M., Kimura, F., Kuwao, S., Sakamoto, K., Sugimoto, Y., Fukushima, M., Tsutsumi, Y. Oncol. Rep. (2006) [Pubmed]
  25. Expression of angiogenesis factors in monolayer culture, multicellular spheroid and in vivo transplanted tumor by human ovarian cancer cell lines. Sonoda, T., Kobayashi, H., Kaku, T., Hirakawa, T., Nakano, H. Cancer Lett. (2003) [Pubmed]
  26. Significance of monocyte chemotactic protein-1 and thymidine phosphorylase in angiogenesis of human cardiac myxoma. Zhang, T., Koide, N., Wada, Y., Tsukioka, K., Takayama, K., Kono, T., Kitahara, H., Amano, J. Circ. J. (2003) [Pubmed]
  27. Cyclooxygenase-2 in human malignant fibrous histiocytoma: correlations with intratumoral microvessel density, expression of vascular endothelial growth factor and thymidine phosphorylase. Yamashita, H., Osaki, M., Ardyanto, T.D., Osaki, M., Yoshida, H., Ito, H. Int. J. Mol. Med. (2004) [Pubmed]
  28. combination of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) to improve angiogenic gene therapy. Bouïs, D., Boelens, M.C., Peters, E., Koolwijk, P., Stob, G., Kema, I.P., Klinkenberg, M., Mulder, N.H., Hospers, G.A. Angiogenesis (2003) [Pubmed]
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