Impact of thymidine phosphorylase surexpression on fluoropyrimidine activity and on tumour angiogenesis.
Tumoral thymidine phosphorylase (TP) appears to play a dual role by being involved in neoangiogenesis and by activating 5FU prodrugs at the tumoral target site. The aim of the study was to investigate more thoroughly these potential physiological and pharmacological roles of TP. A rat carcinoma cell line (PROb) was transfected with TP/PD-ECGF in order to study the effect of the overexpression of this enzyme (1) on the sensitivity of cells to 5'DFUR and 5FU in vitro and (2) on tumour growth in vivo by using a syngenic tumour model in the BDIX rat (hepatic tumours, sub-cutaneous tumours). Cytotoxic effects of 5'DFUR, and to a lesser extent those of 5FU, were enhanced in TP clones as compared to control cells: there was a highly significant correlation between TP activity and in vitro sensitivity to 5'DFUR (r2= 0.91, P = 0.0002, n = 8) and, to a lesser extent, to 5FU (r2= 0.49, P = 0.053, n = 8). The impact of TP transfection on tumour growth was relatively modest and concerned only the initial stages of tumour expansion. Staining of TP tumours for endothelial (factor VIII) cells was always higher than controls. The staining ratio (TP/controls) tended to be reduced as tumours increased in size. The stability of TP expression was checked both in vitro (TP activity measurement) and in vivo (RT-PCR determinations) and there was no loss of TP expression over time which could be advanced to explain the progressive weakening of the impact of TP overexpression on both tumour growth and neoangiogenesis.
Marchetti
S
S
Centre Antoine Lacassagne, Nice, France.
Chazal
M
M
Dubreuil
A
A
Fischel
J L
JL
Etienne
M C
MC
Milano
G
G
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005467:Floxuridine / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D005562:Formazans; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010430:Pentosyltransferases / Q000378:metabolism; D057845:Pyrimidine Phosphorylases; D051381:Rats; D013778:Tetrazolium Salts; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000964:Antimetabolites, Antineoplastic; D005562:Formazans; D013778:Tetrazolium Salts; D005467:Floxuridine; C079782:MTT formazan; D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine