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

Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print Cited Medium: Print ISSN: 0007-0920 (Print) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE

Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
Original Publication: London, Lewis.

Antimetabolites/*pharmacology ; Antimetabolites, Antineoplastic/*pharmacology ; Colonic Neoplasms/*pathology ; Fluorouracil/*pharmacology ; Lung Neoplasms/*pathology ; Tegafur/*pharmacology ; Thymidine Phosphorylase/*pharmacology ; Trifluridine/*pharmacology; Gene Expression Regulation ; Humans ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured

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, 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 IC(50)'s were established. TPI modified 5'DFUR, increasing the IC(50)'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: IC(50)'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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0 (Antimetabolites)
0 (Antimetabolites, Antineoplastic)
1548R74NSZ (Tegafur)
EC 2.4.2.4 (Thymidine Phosphorylase)
RMW9V5RW38 (Trifluridine)
U3P01618RT (Fluorouracil)

Date Created: 20030320 Date Completed: 20030505 Latest Revision: 20220317

20231215

PMC2377090

10.1038/sj.bjc.6600808

12644837