The thymidine phosphorylase inhibitor 5'-O-tritylinosine (KIN59) is an antiangiogenic multitarget fibroblast growth factor-2 antagonist.
5'-O-Tritylinosine (KIN59) is an allosteric inhibitor of the angiogenic enzyme thymidine phosphorylase. Previous observations showed the capacity of KIN59 to abrogate thymidine phosphorylase-induced as well as developmental angiogenesis in the chicken chorioallantoic membrane (CAM) assay. Here, we show that KIN59 also inhibits the angiogenic response triggered by fibroblast growth factor-2 (FGF2) but not by VEGF in the CAM assay. Immunohistochemical and reverse transcriptase PCR analyses revealed that the expression of laminin, the major proteoglycan of the basement membrane of blood vessels, is downregulated by KIN59 administration in control as well as in thymidine phosphorylase- or FGF2-treated CAMs, but not in CAMs treated with VEGF. Also, KIN59 abrogated FGF2-induced endothelial cell proliferation, FGF receptor activation, and Akt signaling in vitro with no effect on VEGF-stimulated biologic responses. Accordingly, KIN59 inhibited the binding of FGF2 to FGF receptor-1 (FGFR1), thus preventing the formation of productive heparan sulphate proteoglycan/FGF2/FGFR1 ternary complexes, without affecting heparin interaction. In keeping with these observations, systemic administration of KIN59 inhibited the growth and neovascularization of subcutaneous tumors induced by FGF2-transformed endothelial cells injected in immunodeficient nude mice. Taken together, the data indicate that the thymidine phosphorylase inhibitor KIN59 is endowed with a significant FGF2 antagonist activity, thus representing a promising lead compound for the design of multitargeted antiangiogenic cancer drugs.
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium. sandra.liekens@rega.kuleuven.be
Sandra
S
Liekens
Annelies
A
Bronckaers
Mirella
M
Belleri
Antonella
A
Bugatti
Rebecca
R
Sienaert
Domenico
D
Ribatti
Beatrice
B
Nico
Alba
A
Gigante
Elena
E
Casanova
Ghislain
G
Opdenakker
María-Jesús
MJ
Pérez-Pérez
Jan
J
Balzarini
Marco
M
Presta
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007288:Inosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection; D014320:Triphenylmethyl Compounds / Q000494:pharmacology*
C514067:5'-O-tritylinosine; D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D014320:Triphenylmethyl Compounds; D016222:Fibroblast Growth Factor 2; D007288:Inosine; D013939:Thymidine Phosphorylase