title: In vivo, in vitro toxicity and in vitro angiogenic inhibition of sunitinib malate.
abstract: OBJECTIVE
  To evaluate the in vivo and in vitro toxicity of sunitinib malate, a multikinase inhibitor molecule.
  
  
  METHODS
  Experimental, Prospective, Controlled.
  
  
  METHODS
  Human retinal pigment epithelial (ARPE-19) and human umbilical vein endothelialcells (HUVECS) were used in a culture toxicity test and exposed to different concentrations of sunitinib malate for 18 hours. The HUVECs also were cultured to evaluate the angiogenesis inhibitory effect of sunitinib malate. Fundus photography and angiographic, electrophysiologic, and histopathologic evaluations with light and electron microscopy were performed in two groups of five rabbits each that received different intravitreal concentrations of the drug. Each rabbit received 0.1 ml of sunitinib malate in the right eye (one group with 12.5 mg/ml, the other group with 25 mg/ml); all animals received 0.1 ml of physiologic saline solution in the left eye. After sacrifice, the eyes were enucleated and fixed with modified Karnovsky solution.
  
  
  RESULTS
  No toxicity related to sunitinib malate was observed using an in vitro model with the 12.5 and 25 mg/ml solutions in HUVEC and ARPE cell cultures. No toxicity was observed in the in vivo model with 12.5 mg/ml, but light microscopy showed that the 25 mg/ml solution damaged the photoreceptors layer. No functional changes in the electroretinogram were observed in any group.
  
  
  CONCLUSIONS
  Sunitinib malate 12.5 mg/ml caused no toxicity in in vivo and in vitro models, but the 25 mg/ml concentration caused retinal changes suggesting toxicity in the in vivo model. Further research with the drug is needed in models of ocular neovascularization.
authors.affiliation: Ophthalmology Department, São Paulo Federal University, São Paulo, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Dib
authors.forename: Mauricio
authors.initials: M
authors.lastname: Maia
authors.forename: Acácio de Souza
authors.initials: Ade S
authors.lastname: Lima
authors.forename: Elaine
authors.initials: E
authors.lastname: de Paula Fiod Costa
authors.forename: Milton Nunes
authors.initials: MN
authors.lastname: de Moraes-Filho
authors.forename: Eduardo Büchele
authors.initials: EB
authors.lastname: Rodrigues
authors.forename: Fernando Marcondes
authors.initials: FM
authors.lastname: Penha
authors.forename: Larissa Pereira
authors.initials: LP
authors.lastname: Coppini
authors.forename: Nilana Meza Tenório
authors.initials: NM
authors.lastname: de Barros
authors.forename: Rita de Cassia Sinigaglia Galli
authors.initials: Rde C
authors.lastname: Coimbra
authors.forename: Octaviano
authors.initials: O
authors.lastname: Magalhães Júnior
authors.forename: Tarcisio
authors.initials: T
authors.lastname: Guerra
authors.forename: Bruno de Albuquerque
authors.initials: Bde A
authors.lastname: Furlani
authors.forename: Edna
authors.initials: E
authors.lastname: Freymuller
authors.forename: Michel Eid
authors.initials: ME
authors.lastname: Farah
mesh_terms: D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002452:Cell Count; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D005451:Fluorescein Angiography; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D058449:Intravitreal Injections; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000648:ultrastructure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000633:toxicity*; D011817:Rabbits; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000648:ultrastructure; D055213:Retinal Pigment Epithelium / Q000187:drug effects*; D000077210:Sunitinib; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib