Abstract
Abstract: :
Purpose:It has previously been demonstrated that VEGF receptor (VEGFR) kinase inhibitors suppress choroidal neovascularization (CNV). In this study, we tested 3 novel VEGFR kinase inhibitors, AL–37440, AL–38950, and AL–39324, with different structures but similar receptor inhibition profiles, for their ability to suppress CNV and cause regression of established CNV. Methods: Mice with laser–induced rupture of Bruch’s membrane were treated with systemic administration (AL–37440 ip QD or AL–38950 po BID) or intravitreal (ivt) injection (AL–38950 or AL–39324) of a VEGFRi or vehicle starting immediately after laser (prevention protocol) or at 7 days after laser when CNV was already established (regression protocol). In both paradigms, mice were euthanized 14 days post–laser and perfused with fluorescein–labeled dextran. CNV area was measured on choroidal flat mounts by image analysis. Results: Compared to vehicle injections, once daily intraperitoneal (ip) injections of 5, 15, or 30 mg/kg of AL–37440 between days 0 and 14 resulted in significant reductions in CNV area (36, 32, and 64%, respectively). When the same treatments were given between days 7 and 14, the 30 mg/kg QD dose caused a significant 40% regression of CNV area. AL–38950 (50 mg/kg twice a day) given by oral gavage between days 0 and 14 caused a significant, but very modest suppression of CNV. However, local delivery of either AL–38950 or –39324 via ivt injection provided dose–dependent suppression and regression of CNV. Notably, i.v.t. injections of 1–3% AL–38950 or –39324 on days 0 and 7 resulted in >50% suppression of CNV, and injections on days 7 and 10 resulted in significant regression (between 30–50%) of CNV. Periocular injection of AL–37440 was not effective. Conclusions: Like other VEGFR kinase inhibitors, AL–37440, AL–38950, and AL–39324 cause significant suppression of CNV when treatment is begun at the time of rupture of Bruch’s membrane; however, they also cause regression of established CNV, something that has not been previously documented with VEGF signaling antagonists. Additional work is needed to elucidate the mechanism by which regression is achieved by these agents.
Keywords: retinal neovascularization • choroid: neovascularization