Effects of platelet-derived endothelial cell growth factor/thymidine phosphorylase, substrate, and products in a three-dimensional model of angiogenesis.
Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is associated with angiogenesis and the progression of human breast and ovarian cancers. The aim of this study was to obtain information about the possible mechanisms of PD-ECGF/TP activity in an established three-dimensional model of angiogenesis. The plan was to study the effects of the enzyme, substrate, products, and further metabolites on the formation and rate of microvessel growth from cultured segments of rat aorta in serum-free media. The end-points were the number and length of microvessels compared with controls after 4, 7, 11, and 14 days in culture. Thymidine (10 to 1000 mumol/L), thymidine-5'-monophosphate (1000 mumol/L), and 2'-deoxy-D-ribose-1-phosphate (1000 mumol/L) inhibited the number of microvessels produced. Conversely PD-ECGF/TP (50 to 100 ng/ml) and beta-amino-iso-butyric acid (1000 mumol/L--a metabolite of thymine) had a significant stimulatory effect (P < 0.05, P < 0.01, P < 0.001 respectively on culture day 11). PD-ECGF (10 ng/ml), beta-amino-iso-butyric acid (1000 mumol/L), and 2-deoxy-D-ribose (100 to 1000 mumol/L) significantly (P < 0.001, P < 0.01, P < 0.01, respectively) stimulated microvessel elongation by day 11. We conclude that PD-ECGF/TP may affect angiogenesis by changing the relative concentrations of pyrimidine-based compounds and their metabolites in interstitial fluid surrounding endothelial cells. Drugs that inhibit PD-ECGF/TP activity may therefore delay abnormal angiogenesis and the progression of various cancers.
Stevenson
D P
DP
Diagnostics Research Unit, Department of Obstetrics and Gynecology, King's College School of Medicine and Dentistry, London, United Kingdom.
Milligan
S R
SR
Collins
W P
WP
D000621:Aminoisobutyric Acids / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D008833:Microcirculation / Q000033:anatomy & histology / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012266:Ribose / Q000494:pharmacology; D013936:Thymidine / Q000494:pharmacology; D013938:Thymidine Monophosphate / Q000494:pharmacology; D013939:Thymidine Phosphorylase / Q000494:pharmacology* / Q000502:physiology*; D013941:Thymine / Q000031:analogs & derivatives / Q000494:pharmacology
D000621:Aminoisobutyric Acids; D013938:Thymidine Monophosphate; D012266:Ribose; D013939:Thymidine Phosphorylase; D013941:Thymine; C033435:3-aminoisobutyric acid; D013936:Thymidine