Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity

M. De Bruin, T. Van Capel, K. Van Der Born, F. A. Kruyt, M. Fukushima, K. Hoekman, H. M. Pinedo, G. J. Peters

Research output: Contribution to journalArticle

Abstract

Platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (TP) catalyses the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose-1-phosphate and is involved in the metabolism of fluoropyrimidines. It can also activate 5′-deoxyfluorouridine (5′DFUR) and possibly 5-fluorouracil (5FU) and Ftorafur (Ft), but inactivates trifluorothymidine (TFT). We studied the contribution of TP activity to the sensitivity for these fluoropyrimidines by modulating its activity and/or expression level in colon and lung cancer cells using a specific inhibitor of TP (TPI) or by overproduction of TP via stable transfection of human TP. Expression was analysed using competitive template-RT-PCR (CT-RT-PCR), Western blot and an activity assay. TP activity ranged from nondetectable to 70678 pmol h-1 10-6 cells, in Colo320 and a TP overexpressing clone Colo320TPI, respectively. We found a good correlation between TP activity and mRNA expression (r = 0.964, P <0.01) in our cell panel. To determine the role of TP in the sensitivity to 5FU, 5′DFUR, Ft and TFT, cells were cultured with the various fluoropyrimidines with or without TPI and differences in IC50's were established. TPI modified 5′DFUR, increasing the IC50's 2.5- to 1396-fold in WiDR and Colo320TPI, respectively. 5-Fluorouracil could be modified by inhibiting TP but to a lesser extent than 5′DFUR: IC50's increased 1.9- to 14.7-fold for WiDR and Colo320TPI, respectively. There was no effect on TFT or Ft. There appears to be a threshold level of TP activity to influence the 5′DFUR and 5FU sensitivity, which is higher for 5FU. Even high levels of TP overexpression only had a moderate effect on 5FU sensitivity.

Original languageEnglish (US)
Pages (from-to)957-964
Number of pages8
JournalBritish Journal of Cancer
Volume88
Issue number6
DOIs
StatePublished - Mar 24 2003
Externally publishedYes

Keywords

  • 5′-deoxyfluorouridine
  • 5-fluorouracil
  • Ftorafur
  • Thymidine phosphorylase
  • Thymidine phosphorylase inhibitor
  • Trifluorothymidine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    De Bruin, M., Van Capel, T., Van Der Born, K., Kruyt, F. A., Fukushima, M., Hoekman, K., Pinedo, H. M., & Peters, G. J. (2003). Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity. British Journal of Cancer, 88(6), 957-964. https://doi.org/10.1038/sj.bjc.6600808