title: [Multikinase inhibitors as a new approach in neovascular age-related macular degeneration (AMD) treatment: in vitro safety evaluations of axitinib, pazopanib and sorafenib for intraocular use].
abstract: BACKGROUND
  Multikinase inhibitors (MKI) interfere effectively at different levels of the neovascularisation cascade. Early clinical and experimental data suggest that MKIs represent a promising novel approach for the treatment of neovascular age-related macular degeneration (AMD). However, so far little is known about the biocompatibility of MKIs regarding human ocular cells. This in vitro study investigates and compares the biocompatibility of three MKIs, axitinib, pazopanib, and sorafenib regarding ocular cells of the anterior and posterior segments, as well as organ-cultured donor corneas.
  
  
  METHODS
  Primary human optic nerve head astrocytes (ONHA), trabecular meshwork cells (TMC), and retinal pigment epithelium (RPE), human corneal endothelial and lens epithelial cells (CEC and LEC) were treated with different concentrations of axitinib, pazopanib, or sorafenib (0.1 to 100 µg/mL). To simulate oxidative stress, the cells were additionally co-incubated with 400 µM hydrogen peroxide. Induction of cell death and cellular viability were examined by live-dead assay and tetrazolium dye reduction assay (MTT). In addition, the influence of the three substances on human corneal endothelium was evaluated in seropositive donor corneas in organ culture by phase contrast microscopy.
  
  
  RESULTS
  Up to a concentration of 7.5 mg/mL of the substances tested in any cell type examined, no toxic effects were found. Even after 10 days of incubation of organ-cultured donor corneas with 7.5 µg/mL, axitinib, pazopanib, or sorafenib, no evidence for endothelial toxicity was found.
  
  
  CONCLUSIONS
  All three MKIs tested, axitinib, pazopanib, and sorafenib showed a good biocompatibility on the investigated ocular cells. Even under conditions of oxidative stress, there were no toxic effects up to a concentration of 7.5 µg/mL. Only at higher concentrations, there was a dose-dependent decrease in cellular viability and pronounced induction of cell death. These effects on cellular viability and induction of cell death appeared to be stronger with pazopanib, followed by sorafenib, than with axitinib.
authors.affiliation: Augenklinik, Ludwig-Maximilians-Universität München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Thiele
authors.forename: R G
authors.initials: RG
authors.lastname: Liegl
authors.forename: S
authors.initials: S
authors.lastname: König
authors.forename: J
authors.initials: J
authors.lastname: Siedlecki
authors.forename: J
authors.initials: J
authors.lastname: Langer
authors.forename: K
authors.initials: K
authors.lastname: Eibl
authors.forename: C
authors.initials: C
authors.lastname: Haritoglou
authors.forename: A
authors.initials: A
authors.lastname: Kampik
authors.forename: M
authors.initials: M
authors.lastname: Kernt
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D000077784:Axitinib; D002470:Cell Survival / Q000187:drug effects*; D003315:Cornea / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004728:Endothelium, Corneal / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology*; D007191:Indazoles / Q000009:adverse effects / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000187:drug effects / Q000473:pathology; D008858:Microscopy, Phase-Contrast; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D009898:Optic Disk / Q000187:drug effects / Q000473:pathology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000473:pathology; D000077157:Sorafenib; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology*; D014129:Trabecular Meshwork / Q000187:drug effects / Q000473:pathology; D057135:Wet Macular Degeneration / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D009536:Niacinamide; C516667:pazopanib; D000077157:Sorafenib; D000077784:Axitinib