Subconjunctival doxifluridine administration suppresses rat choroidal neovascularization through activated thymidine phosphorylase.
OBJECTIVE
Doxifluridine (5'-deoxy 5-fluorouridine) is an oral anticancer drug with antiangiogenic effects, with vasoclastic action that is enhanced by a major member of the pyrimidine phosphorylases, thymidine phosphorylase (TP). Previous studies have demonstrated that TP is upregulated in the lesions where pathologic angiogenesis occurs and TP itself promotes angiogenesis. To investigate the possible role of TP and doxifluridine in choroidal neovascularization (CNV), the expression level of TP was measured and the effect of doxifluridine was investigated in rat eyes with experimental CNV.


METHODS
CNV was induced in rat eyes by diode laser photocoagulation. The expression level of TP in the laser-treated and control eyes was examined with high-performance liquid chromatography (HPLC). For the evaluation of CNV activity, the intensity of fluorescein leakage from the photocoagulated lesions was scored, and the areas of CNV lesions were measured histologically in the control eyes and eyes treated with a subconjunctival injection of doxifluridine 14 days after photocoagulation.


RESULTS
The expression level of TP was higher in the laser-treated eyes than in the control eyes. Fluorescein leakage from the CNV lesions significantly decreased in the eyes given a subconjunctival injection of doxifluridine compared with the control. Histologic analysis demonstrated that both the areas of CNV lesions and the degree of vascular formation in the subretinal membrane were reduced in the doxifluridine-treated eyes compared with the control eyes.


CONCLUSIONS
TP may be involved in the formation of CNV. Subconjunctival injection of doxifluridine significantly reduced experimental CNV activity without apparent adverse effects. These results suggest the possibility that doxifluridine can be beneficial in treating CNV.
Yanagi
Yasuo
Y
Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan. yanagi-tky@umin.ac.jp
Tamaki
Yasuhiro
Y
Inoue
Yuji
Y
Obata
Ryo
R
Muranaka
Kimimasa
K
Homma
Noriko
N
D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D020256:Choroidal Neovascularization / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002851:Chromatography, High Pressure Liquid; D003228:Conjunctiva; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D005467:Floxuridine / Q000494:pharmacology*; D005451:Fluorescein Angiography; D007267:Injections; D051381:Rats; D011914:Rats, Inbred BN; D013939:Thymidine Phosphorylase / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D013939:Thymidine Phosphorylase; C025034:doxifluridine