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

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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 Colo320TP1, respectively. We found a good correlation between TP activity and mRNA expression (r=0.964, P50's were established. TPI modified 5′DFUR, increasing the IC50's 2.5- to 1396-fold in WiDR and Colo320TP1, 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 Colo320TP1, 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.

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