title: The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells.
abstract: Thymidine phosphorylase (TP) is an enzyme involved in reversible conversion of thymidine to thymine. TP is identical to an angiogenic factor, pletelet-derived endothelial cell growth factor (PD-ECGF) and the expression levels of TP in a variety of malignant tumors were higher than the adjacent non-neoplastic tissues. To investigate the molecular basis for the effect of TP on the metabolic process and the anticancer effect of 5-fluorouracil (5-FU), human gastric carcinoma AZ521 cells and epidermoid carcinoma KB cells were transfected with TP cDNA, and AZ521/TP and KB/TP were cloned. AZ521/TP and KB/TP cells overexpressed TP and were more sensitive to 5-FU than the counterpart parental cells. TPI, a newly synthesized inhibitor for TP (Ki=2.36 x 10(-9) M), decreased the sensitivity to 5-FU of the TP expressing cells but not of the parental cells. 5-Formyl-tetrahydrofolate (leucovorin; LV) stabilized the complex of thymidylate synthase (TS) and 5-fluoro-deoxyuridine-monophosphate (FdUMP), increased the sensitivity to 5-FU of TP expressing AZ521 cells, but not of the parental cells. The levels of FdUMP in TP expressing cells were significantly higher than in parental cells and TPI considerably decreased FdUMP to the level comparable to that in the parental cells. 5-FU increased the expression of early growth response protein-1 (Egr-1) and an angiogenesis inhibitor, thrombospondin-1 (TSP-1), in KB/TP cells but only slightly in KB/CV cells, if any. TPI attenuated the induction of Egr-1 and TSP-1 mRNA by 5-FU, while LV increased the expression of Egr-1 and TSP-1 mRNA in KB/TP cells. These findings demonstrate that the TP has a principal role in the production of FdUMP and the enhanced responses to 5-FU by leucovorin in TP-overexpressing KB and AZ521 cells, and FdUMP but not FUTP is implicated in the induction of Egr-1 and TSP-1 in KB cells.
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Matsushita
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Nishizawa
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Che
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Miyadera
authors.forename: Sho
authors.initials: S
authors.lastname: Tabata
authors.forename: Mina
authors.initials: M
authors.lastname: Ushiyama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tajitsu
authors.forename: Masatatsu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeda
authors.forename: Kentaro
authors.initials: K
authors.lastname: Minami
authors.forename: Hironori
authors.initials: H
authors.lastname: Mataki
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Kanzaki
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamada
authors.forename: Takuro
authors.initials: T
authors.lastname: Kanekura
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Akiyama
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D054306:Dideoxynucleotides / Q000494:pharmacology; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis*; D005468:Fluorodeoxyuridylate / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019700:Thrombospondin 1 / Q000096:biosynthesis*; D013939:Thymidine Phosphorylase / Q000378:metabolism*; D014542:Uridine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; D054306:Dideoxynucleotides; D051766:Early Growth Response Protein 1; D019700:Thrombospondin 1; C083401:2',3'-dideoxyuridine 5'-monophosphate; D005468:Fluorodeoxyuridylate; D014542:Uridine Monophosphate; D013939:Thymidine Phosphorylase; D005472:Fluorouracil