PD0325901, a Mitogen-Activated Protein Kinase Kinase Inhibitor, Produces Ocular Toxicity in a Rabbit Animal Model of Retinal Vein Occlusion

J Ocul Pharmacol Ther. 2009 Dec;25(6):519-30. doi: 10.1089/jop.2009.0060.

Abstract

Objective: PD0325901, a selective inhibitor of mitogen-activated protein kinase kinase (MEK), was associated with the occurrence of ocular retinal vein occlusion (RVO) during clinical trials in patients with solid tumors. As previous animal safety studies in rats and dogs did not identify the eye as a target organ of toxicity, this work was conducted to develop a rabbit model of ocular toxicity with PD0325901.

Methods: Dutch-Belted rabbits were administered a single intravitreal injection of PD0325901 (0.5 or 1 mg/eye) or saline control, and ophthalmic examinations and retinal angiography were conducted over a 2-week period post-dose. In addition, mechanism of ocular toxicity was further explored in rat with microarray analysis.

Results: PD0325901 treatment produced RVO with retinal vasculature leakage and hemorrhage within 48-h postinjection in Dutch-Belted rabbits. Subsequent retinal detachment and degeneration were also detected on day 8 postinjection. To evaluate the potential mechanism(s) of PD0325901-mediated RVO, male Brown Norway rats were orally administered PD0325901 (45 mg/kg/day) up to 5 days and retinal tissue was collected for gene array analysis. Although PD0325901 did not produce clinical evidence of RVO in rats, retinal gene expression suggested an increased oxidative stress and inflammatory response, endothelium and blood-retinal barrier damage, and prothrombotic effects. Moreover, soluble endothelial protein C receptor (sEPCR), a biomarker for RVO, was elevated in human umbilical vascular endothelial cells (HUVECs) cultured with PD0325901.

Conclusions: This work has developed a rabbit model of PD0325901-induced RVO that may be used to characterize the cellular and molecular mechanisms of this effect in humans.

MeSH terms

  • Administration, Oral
  • Animals
  • Antigens, CD / drug effects
  • Antigens, CD / metabolism
  • Benzamides / administration & dosage
  • Benzamides / toxicity*
  • Cells, Cultured
  • Diphenylamine / administration & dosage
  • Diphenylamine / analogs & derivatives*
  • Diphenylamine / toxicity
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Endothelial Protein C Receptor
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Female
  • Fluorescein Angiography / methods
  • Gene Expression Regulation / drug effects
  • Humans
  • Male
  • Microarray Analysis
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Oxidative Stress / drug effects
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / toxicity*
  • Rabbits
  • Rats
  • Rats, Inbred BN
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / metabolism
  • Retinal Vein Occlusion / chemically induced*
  • Species Specificity
  • Umbilical Veins / cytology
  • Umbilical Veins / drug effects

Substances

  • Antigens, CD
  • Benzamides
  • Endothelial Protein C Receptor
  • PD 0325901
  • PROCR protein, human
  • Protein Kinase Inhibitors
  • Receptors, Cell Surface
  • Diphenylamine
  • Mitogen-Activated Protein Kinase Kinases