Investigation of the potential utility of a linomide analogue for treatment of choroidal neovascularization.
The aim of this study was to test the selectivity, in-vivo effectiveness, and potential mechanism of action of a linomide analogue (N-phenyl-1,2-dihydro-4-hydroxyl-2-oxo-quinoline-3-carboxamide, Lin05) for inhibition of choroidal neovascularization. The selectivity of Lin05 was tested in cell proliferation assays with human umbilical vein endothelial cells (HUVEC) and a retinal pigmented epithelial cell line(ARPE-19). In-vivo anti-angiogenic effect of Lin05 was investigated utilizing an experimental laser-induced choroidal neovascularization (ECNV) model in adult Brown Norway rats. Western blot and/or reverse transcriptase-PCR was used to test the effect of Lin05 on potential targets. Our results indicate that Lin05 is at least an 8-fold more selective inhibitor of endothelial cell proliferation compared to RPE cells. Systemic administration of Lin05 in an ECNV model was associated with a significant decrease in both vascular leakage on fluorescein angiography and lesion size by histopathology (p = 0.02). No systemic toxicity was detected for Lin05 in major organs such as the liver, lung and kidneys. Lin05 did not inhibit VEGF-induced VEGFR2 (KDR) phosphorylation in HUVEC nor was associated with decreased VEGF gene expression. Also it did not inhibit insulin-like growth factor (IGF-1) and Epidermal Growth Factor (EGF) induced activation of p42/p44 MAPK activation. It inhibited both PDGF- and bFGF-induced p42/p44 MAPK phosphorylation. However, the effect on PDGF was variable in different HUVEC cells. In conclusion, Lin05 is a potential anti-angiogenic agent for the treatment of eye diseases associated with pathological neovascularization. The anti-angiogenic effect of Lin05 is likely through inhibition of bFGF but not through inhibition of the VEGF/KDR pathway.
Department of Ophthalmology, College of Medicine, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Mohamed.abdel-rahman@osumc.edu
M H
MH
Abdel-Rahman
Y
Y
Yang
M M
MM
Salem
S
S
Meadows
James B
JB
Massengill
P-K
PK
Li
F H
FH
Davidorf
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors; D005451:Fluorescein Angiography; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; C554562:N-phenyl-1,2-dihydro-4-hydroxyl-2-oxoquinoline-3-carboxamide; D010982:Platelet-Derived Growth Factor; D015363:Quinolones; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D040301:Vascular Endothelial Growth Factor Receptor-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3