The kinase inhibitor PKC412 suppresses epiretinal membrane formation and retinal detachment in mice with proliferative retinopathies.
OBJECTIVE
Platelet-derived growth factor (PDGF) is an important stimulatory factor for proliferative retinopathies. Expression of PDGF-B in the retinas of transgenic mice (hemizygous rho/PDGF-B mice) results in rapid-onset retinal detachment caused by proliferation of glial cells, endothelial cells, and pericytes, whereas expression of PDGF-AA (homozygous rho/PDGF-A or PDGF-AA mice) causes slowly progressive retinal detachment from proliferation of glial cells. In this study, we investigated the effect in rho/PDGF-B and rho/PDGF-AA mice of several different receptor kinase inhibitors.


METHODS
Hemizygous rhoPDGF-B or homozygous rho/PDGF-A mice were treated orally with PKC412 (an inhibitor of PDGF, VEGF, and c-kit receptor kinases and several isoforms of PKC), PTK787 (an inhibitor of PDGF, VEGF, and c-kit receptor kinases), SU1498 (an inhibitor of VEGF receptor kinases), imatinib mesylate (an inhibitor of PDGF, c-kit, and v-abl receptor kinases), or vehicle, and at appropriate time points epiretinal membrane (ERM) formation and retinal detachment were quantified.


RESULTS
In either rho/PDGF-B or rho/PDGF-A mice, oral administration of PKC412 or PTK787, but not SU1498 or imatinib mesylate, significantly reduced ERM formation. PKC412 reduced the incidence of severe retinal detachments in both models and PTK787 did so in homozygous rho/PDGF-A mice.


CONCLUSIONS
These data indicate that PKC412 (and possibly PTK787) has appropriate activity and sufficient intraocular bioavailability after oral administration to prevent retinal detachment in models of proliferative retinopathy. PKC412 should be considered for treatment of vascular and nonvascular proliferative retinopathies in humans.
Saishin
Yoshitsugu
Y
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Saishin
Yumiko
Y
Takahashi
Kyoichi
K
Seo
Man-Seong
MS
Melia
Michele
M
Campochiaro
Peter A
PA
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D019773:Epiretinal Membrane / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010793:Phthalazines / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D011725:Pyridines; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012163:Retinal Detachment / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D010793:Phthalazines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011725:Pyridines; C075278:platelet-derived growth factor A; C404768:vatalanib; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin