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(American Journal of Pathology. 1998;153:1573-1578.)
© 1998 American Society for Investigative Pathology

Regular Articles

Thymidine Phosphorylase Activity and Prodrug Effects in a Three-Dimensional Model of Angiogenesis

Implications for the Treatment of Ovarian Cancer

Darren Paul Stevenson* , William Patrick Collins* , Farzin Farzaneh{dagger} , Kohkichi Hata{ddagger} and Kohji Miyazaki{ddagger}

From the Departments of Obstetrics and Gynaecology* and Molecular Medicine,{dagger} King's College School of Medicine and Dentistry, London, United Kingdom, and the Department of Obstetrics and Gynecology,{ddagger} Shimane Medical University, Izumo, Japan

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 µmol/L) gradually reduced the size and number of microvessels over 17 days of culture (100 µmol/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 µmol/L) or at a lower dose (100 µmol/L) in the presence of ovarian cancer cyst fluid was not reversible after culture day 11.






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Copyright © 1998 by the American Society for Investigative Pathology.