FEB 22, 2013
Cediranib has therapeutic potential to suppress choroidal neovascularization (CNV) in patients with wet AMD, according to the conclusions of this study conducted in mice. The researchers found that the drug, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, inhibited laser-induced CNV in the animals. They say that cediranib may serve as an adjuvant therapy with other VEGF-targeting agents, such as ranibizumab and bevacizumab.
They induced CNV in C57BL/6 mice by rupturing Bruch's membrane using laser photocoagulation. The mice were then administered vehicle or 1 mg/kg or 5 mg/kg of cediranib daily by oral gavage for two weeks. Two weeks after laser injury, the area of CNV lesions was measured by choroidal flat mounts using fluorescein-labeled dextran. Immunofluorescence staining with isolectin IB4 was also used to quantify the CNV.
Choroidal flat mount analysis revealed that cediranib reduced the extent of CNV. The groups treated with 1 and 5 mg/kg/day of cediranib showed 57.2 and 66 percent reduction of CNV lesions, respectively, compared with the vehicle-treated group (P = 0.012). The size of the fluorescently labeled CNV complex in cediranib-treated groups was much smaller than that in the vehicle-treated group (P = 0.035).
Cediranib also induced a significant decrease in the extent of isolectin IB4-labelled endothelial cells within the CNV. Western blot analyses from the retinal pigment epithelium/choroid layer revealed that the expression level of phosphorylated Erk 1/2 decreased with cediranib treatment, indicating that downstream signal transduction for angiogenesis was suppressed.
The authors note that although the laser-induced CNV mouse model is not exactly like CNV secondary to AMD, it mimics important aspects of wet AMD, suggesting that cediranib could be a potential treatment for naturally occurring CNV secondary to AMD.
They conclude that adding cediranib to standard ranibizumab treatment should be considered for refractory or recurrent wet AMD. Theoretically, combined therapy using an oral tyrosine kinase inhibitor and intravitreal anti-VEGF monoclonal antibody could suppress CNV formation more efficiently as a result of their combined mechanisms of action against pathological angiogenesis.