The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors

Thymidine phosphorylase (TP) is an enzyme involved in the reversible conver sion of thymidine to thymine and is identical to an angiogenic factor, plat elet-derived endothelial cell growth factor. TP is expressed at higher leve ls in a wide variety of solid tumors than in the adjacent nonneoplastic tis sues. Patients with TP-positive colon and esophageal tumors have a poorer p rognosis than those with TP-negative tumors. We have recently synthesized a new TP inhibitor (TPI), 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride. We investigated the effect of TPI on angiogenesis in KB cel ls transfected with platelet-derived endothelial cell growth factor cDNA, K B/TP, and a mock transfectant, KB/CV, using the mouse dorsal air sac assay model. We found that KB/TP cells had a higher angiogenic ability than KB/CV cells and that TPI completely suppressed angiogenesis by KB/TP, Furthermor e, at a dose of 50 mg/kg/day, TPI considerably decreased the growth rate of KB/TP cells xenografted into nude mice. Microvessel density in KB/TP tumor s was higher than that in KB/CV tumors, and TPI did not significantly chang e the density in either of the tumors. The apoptotic index in KB/TP tumors was significantly lower than that in KB/CV tumors, and TPI significantly in creased the apoptotic index in KB/TP tumors but not in KB/CV tumors. These findings, taken together with previous reports, suggest that the expression of TP plays an important role in tumor growth and that TPI suppresses tumo r growth by increasing the proportion of apoptotic cells and probably inhib iting angiogenesis.