Thymidine phosphorylase activity and prodrug effects in a three-dimensional model of angiogenesis: implications for the treatment of ovarian cancer.
Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is associated with angiogenesis and the progression of human ovarian cancer. The enzyme converts thymidine to thymine and 2'-deoxyribose-1-phosphate and can also metabolize the prodrug 5'-deoxy-5-fluorouridine (Furtulon) to 5-fluorouracil and 5'-deoxy-D-ribose-1-phosphate. The aim of this study was to obtain information about the activities of Furtulon in an established three-dimensional model of angiogenesis. The plan was to study partial and complete effects of Furtulon (in the absence and presence of PD-ECGF/TP or ovarian cancer cyst fluids) on the formation and destruction of microvessels from cultured segments of rat aorta in serum-free media. The endpoint was the number and form of microvessels compared with controls after 4, 7, 11, and 14 (and sometimes 17) days in culture. Furtulon (10 micromol/L) gradually reduced the size and number of microvessels over 17 days of culture (100 micromol/L significantly reduced the number by day 4). PD-ECGF/TP (10 ng/ml) and ovarian cancer cyst fluids (2% in medium, v/v) stimulated the production of microvessels. The culture of explants with Furtulon and PD-ECGF/TP or ovarian cancer cyst fluids (from day 1 or day 11 of culture) enhanced the vasoclastic activity of the drug. The effect of Furtulon at the highest dose (1000 micromol/L) or at a lower dose (100 micromol/L) in the presence of ovarian cancer cyst fluid was not reversible after culture day 11.
Stevenson
D P
DP
Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry, London, United Kingdom.
Collins
W P
WP
Farzaneh
F
F
Hata
K
K
Miyazaki
K
K
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005260:Female; D005467:Floxuridine / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D008833:Microcirculation / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011355:Prodrugs; D011994:Recombinant Proteins; D005467:Floxuridine; D013939:Thymidine Phosphorylase; C025034:doxifluridine