title: The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors.
abstract: Thymidine phosphorylase (TP) is an enzyme involved in the reversible conversion of thymidine to thymine and is identical to an angiogenic factor, platelet-derived endothelial cell growth factor. TP is expressed at higher levels in a wide variety of solid tumors than in the adjacent nonneoplastic tissues. Patients with TP-positive colon and esophageal tumors have a poorer prognosis 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 cells transfected with platelet-derived endothelial cell growth factor cDNA, KB/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. Furthermore, 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 tumors was higher than that in KB/CV tumors, and TPI did not significantly change 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 increased 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 tumor growth by increasing the proportion of apoptotic cells and probably inhibiting angiogenesis.
authors.affiliation: Department of Cancer Chemotherapy, Institute for Cancer Research, Kagoshima University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Matsushita
authors.forename: T
authors.initials: T
authors.lastname: Nitanda
authors.forename: T
authors.initials: T
authors.lastname: Furukawa
authors.forename: T
authors.initials: T
authors.lastname: Sumizawa
authors.forename: A
authors.initials: A
authors.lastname: Tani
authors.forename: K
authors.initials: K
authors.lastname: Nishimoto
authors.forename: S
authors.initials: S
authors.lastname: Akiba
authors.forename: K
authors.initials: K
authors.lastname: Miyadera
authors.forename: M
authors.initials: M
authors.lastname: Fukushima
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: T
authors.initials: T
authors.lastname: Kanzaki
authors.forename: S
authors.initials: S
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D006801:Humans; D007624:KB Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C119063:5-chloro-6-(1-(2-iminopyrrolidinyl) methyl)uracil hydrochloride; D011759:Pyrrolidines; D014498:Uracil; D013939:Thymidine Phosphorylase