Inhibition of choroidal neovascularisation in mice by systemic administration of the multikinase inhibitor, sorafenib.
BACKGROUND
To investigate the effect of orally administered sorafenib, a multikinase inhibitor, in a mouse model of choroidal neovascularisation (CNV).


METHODS
Sorafenib or vehicle was administered orally to female C57BL/6 mice at the onset (day 0) of experiments. CNV was induced by laser photocoagulation the following day. After 14 days, mice were perfused with fluorescein-labelled dextran, and the area of CNV was measured on choroidal flat mounts by image analysis. In some groups of mice, treatments were started 7 days after the laser photocoagulation to determine the effect of the agent on established CNV. Expression of phosphorylated extracellular signal-regulated kinase (p-ERK) in choroidal tissues was measured by Western blot analysis to demonstrate the kinase-inhibitory effect of sorafenib in intracellular signalling pathways involved in CNV formation.


RESULTS
Sorafenib significantly reduced the extent of CNV in a dose-dependent manner. The area of CNV was reduced by 43% in the 30 mg/kg/day group and by 61% in the 60 mg/kg/day group compared with vehicle-treated controls (both p<0.0001). Oral administration of sorafenib also caused significant regression of established CNV. The area of CNV was reduced by 59% in the 30 mg/kg/day group and by 66% in the 60 mg/kg/day group compared with both baseline and control measurements (p<0.0001). The expression of p-ERK in choroidal tissues was increased within 1 day of laser photocoagulation and remained elevated for 2 weeks. The expression of p-ERK was suppressed by sorafenib.


CONCLUSIONS
Sorafenib demonstrated antiangiogenic properties in a mouse model of CNV and may be useful in the treatment of CNV.
Chung
E J
EJ
Department of Ophthalmology, National Health Insurance Corporation Ilsan Hospital, Gyounggi-do, Korea.
Yoo
S
S
Lim
H J
HJ
Byeon
S H
SH
Lee
J H
JH
Koh
H J
HJ
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001557:Benzenesulfonates / Q000008:administration & dosage*; D015153:Blotting, Western; D020256:Choroidal Neovascularization / Q000188:drug therapy*; D003911:Dextrans / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D005452:Fluoresceins / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage*; D000077157:Sorafenib
D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; D003911:Dextrans; D005452:Fluoresceins; D010671:Phenylurea Compounds; D011725:Pyridines; C052526:fluorescein-dextran; D009536:Niacinamide; D000077157:Sorafenib