Axitinib inhibits retinal and choroidal neovascularization in in vitro and in vivo models

Giddabasappa, Anand; Lalwani, Kush; Norberg, Rand; Gukasyan, Hovhannes J.; Paterson, David A.; Schachar, Ronald A.; Rittenhouse, Kay D.; Klamerus, Karen J.; Mosyak, Lydia; Eswaraka, Jeetendra

doi:10.1016/j.exer.2016.02.010

Cited by 37 publications

(28 citation statements)

References 34 publications

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“…Research efforts have been directed toward animal models and more recently toward in vitro cellular models for studying the pathomechanisms of AMD . The major drawback in the use of animal models is that the pathogenesis can differ significantly from those in the human eye.…”

Section: Introductionmentioning

confidence: 99%

A Novel 3D Cultured Model for Studying Early Changes in Age‐Related Macular Degeneration

Shokoohmand

Jeon

Theodoropoulos

et al. 2017

Macromolecular Bioscience

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Various in vitro culture systems have been used to investigate the pathogenesis of age-related macular degeneration (AMD). However, many still rely on oversimplified monolayer culture models. AMD is a complex disease, associated with the pathological changes to multiple structural components such as the Bruch's membrane, retinal pigment epithelium (RPE), and choroidal endothelial cells. This study aims to construct a novel 3D coculture model using the polycaprolactone (PCL)-gelatin electrospun scaffold, with human RPE cells (hRPE) and primate choroidal cells (RF-6A). Results from this study show that PCL-gelatin scaffolds have a highly porous ultrastructure that supports the attachment, proliferation, differentiation, and migration of the hRPEs and choroidal endothelial cells. It is also demonstrated that the PCL-gelatin 3D coculture model may be useful in exploring the molecular interplay between the hPRE and the choroidal endothelial cells, and their effects on growth factor modulation, which may be important in the pathogenesis of AMD.

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Section: Introductionmentioning

confidence: 99%

A Novel 3D Cultured Model for Studying Early Changes in Age‐Related Macular Degeneration

Shokoohmand

Jeon

Theodoropoulos

et al. 2017

Macromolecular Bioscience

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“…Therefore, a similar effect can be assumed for neutralizing the ligand and for inhibiting the receptor tyrosine kinase further downstream. This is supported by anecdotal clinical evidence which also supports the potential efficacy of small-molecule oral multireceptor tyrosine kinase inhibitors in nAMD [26,29]. One additional difference between ligand-and receptor targeting may be the tissue compartment that needs to be reached.…”

Section: Discussionmentioning

confidence: 83%

The Developing Regorafenib Eye drops for neovascular Age‐related Macular degeneration (DREAM) study: an open‐label phase II trial

Joussen

Wolf

Kaiser

et al. 2018

Brit J Clinical Pharma

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Aims This programme investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age‐related macular degeneration (nAMD). Methods Topical regorafenib was investigated in an open‐label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 μl, 30 mg ml–1) three times a day for 12 weeks. The primary endpoint of the phase II/a/b study was mean change in best‐corrected visual acuity (BCVA) from baseline to weeks 4 and 12. Results In nAMD patients (N = 51), mean changes in BCVA were +1.2 [90% confidence interval (CI) –0.61, 2.97] and −2.4 (90% CI −4.18, −0.54) letters at weeks 4 and 12, respectively. Ocular treatment‐emergent adverse events (TEAEs) (study eye) were reported in 21 patients by week 12. There was one serious ocular TEAE (visual acuity reduced) that was not drug related. Twenty patients required rescue (intravitreal ranibizumab). Conclusions The programme was terminated after phase IIa ended because efficacy was lower than with current nAMD treatments. According to elaborate post hoc analyses, the most likely reason was insufficient exposure in the target compartment (back of the eye).

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“…0,04% Axitinib treatment was observed to be more beneficial. Giddabasappa et al also mentioned that lower dose of axitinib significantly inhibited laser-induced retinal and choroidal neovascularization both in in vitro and in vivo models 48 . Biocompatibility of axitinib, pazopanib, and sorafenib were investigated in ocular cells of the anterior and posterior segments, besides organ-cultured donor corneas.…”

Section: Discussionmentioning

confidence: 99%

Effect of axitinib on inflammation in experimental corneal neovascularization model in rats

Canacankatan¹,

Dinç²,

Kibar³

et al. 2018

Cukurova Medical Journal

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Öz Purpose:This study investigated the antiinflammatory efficacy of topical application of a selective tyrosine kinase receptor inhibitor (TKI), Axitinib in experimental corneal neovascularization (CNV) model in rats. Vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2 and VEGFR3 were evaluated as angiogenic markers, nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNFα) and cyclooxygenase-2 (COX2) were determined as inflammatory markers and also histopathological evaluations were carried out. Materials and Methods: Experimental CNV model was established by silver nitrate cauterization in right eye. 6 groups were included as Control; CNV; CNV+DMSO; CNV+0.04% Axitinib; CNV+0.08% Axitinib and CNV+0.24% Axitinib. The corneas were collected and VEGFR1, VEGFR2, VEGFR3, NF-κB, TNFα and COX2 were measured by ELISA. Results: Axitinib, significantly reduced corneal VEGFR1 and VEGFR2 compared to CNV. The most efficiency of Axitinib treatment was confirmed on VEGFR2 and especially with 0.04% dose. Increased NF-κB and TNFα level were reduced by 0.04% Axitinib treatment compared to CNV and CNV+DMSO. Conclusion: Axitinib may be suggested as a promising anti-inflammatory agent in CNV by suppressing corneal VEGFR1, VEGFR2, NF-κB and TNFα, beside improving the histological pattern.Amaç: Bu çalışmada sıçanlarda deneysel kornea neovaskülarizasyonu (CNV) modelinde bir selektif tirosin kinaz reseptör inhibitörü (TKI), Axitinib' in topikal uygulamasının anti-inflamatuar etkinliği araştırıldı. Vasküler endotelyal büyüme faktörü reseptörü 1 (VEGFR1), VEGFR2 ve VEGFR3 anjiyojenik belirteçler olarak değerlendirildi, nükleer faktör kappa B (NF-κB), tümör nekroz faktörü (TNFα) ve siklooksijenaz-2 (COX2) ise inflamatuar belirteçler olarak belirlendi ve ayrıca histopatolojik değerlendirmeler yapıldı. Gereç ve Yöntem: Sıçanların sağ gözlerinde, gümüş nitrat katerizasyonu ile deneysel CNV modeli oluşturuldu. Kontrol; CNV; CNV+DMSO; CNV+% 0.04 Axitinib; CNV+% 0.08 Axitinib ve CNV+% 0.24 Axitinib olmak üzere çalışmaya 6 grup dahil edildi. Kornealar diseke edildi ve VEGFR1, VEGFR2, VEGFR3, NF-κB, TNFα ve COX2 ELISA yöntemi ile ölçüldü. Bulgular: Axitinib, CNV ile karşılaştırıldığında korneal VEGFR1 ve VEGFR2'i anlamlı olarak azaldı. Axitinib tedavisinin en etkin sonuçları VEGFR2 üzerine ve özellikle % 0,04 dozunda saptandı. Artmış NF-κB ve TNFα seviyesi % 0.04 Axitinib tedavisi ile CNV ve CNV+DMSO'ya göre azaldığı saptandı. Sonuç: Axitinib, VEGFR1, VEGFR2, NF-κB ve TNFα'yı baskılayarak ve ayrıca histolojik paterni iyileştirerek kornea CNV de ümit verici bir anti-inflamatuar ajan olarak önerilebilir.

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Axitinib inhibits retinal and choroidal neovascularization in in vitro and in vivo models

Cited by 37 publications

References 34 publications

A Novel 3D Cultured Model for Studying Early Changes in Age‐Related Macular Degeneration

A Novel 3D Cultured Model for Studying Early Changes in Age‐Related Macular Degeneration

The Developing Regorafenib Eye drops for neovascular Age‐related Macular degeneration (DREAM) study: an open‐label phase II trial

Effect of axitinib on inflammation in experimental corneal neovascularization model in rats

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