PD0325901, a Mitogen-Activated Protein Kinase Kinase Inhibitor, Produces Ocular Toxicity in a Rabbit Animal Model of Retinal Vein Occlusion
PD0325901, a Mitogen-Activated Protein Kinase Kinase Inhibitor, Produces Ocular Toxicity in a Rabbit Animal Model of Retinal Vein Occlusion
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DOI：
10.1089/jop.2009.0060
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发表时间：
2009-12-01
影响因子：
2.3
通讯作者：
Younis, Husam S.
中科院分区：
文献类型：
--
作者：
Huang, Wenhu;Yang, Amy H.;Younis, Husam S.
目的：PD 0325901是一种丝裂原活化蛋白激酶激酶（MEK）的选择性抑制剂，在实体瘤患者的临床试验期间与眼视网膜静脉阻塞（RVO）的发生相关。由于先前在大鼠和犬中进行的动物安全性研究未将眼睛确定为毒性靶器官，因此进行本工作以开发PD 0325901的兔眼毒性模型。方法：对荷兰带兔进行单次玻璃体内注射PD 0325901（0.5或1 mg/眼）或盐水对照，并在给药后2周内进行眼科检查和视网膜血管造影。结果：PD 0325901可引起兔RVO，并在48 h内出现视网膜血管渗漏和出血。在注射后第8天也检测到随后的视网膜脱离和变性。为了评价PD 0325901介导的RVO的潜在机制，雄性Brown Norway大鼠经口施用PD 0325901（45 mg/kg/天）长达5天，并收集视网膜组织用于基因阵列分析。尽管PD 0325901在大鼠中没有产生RVO的临床证据，但视网膜基因表达表明氧化应激和炎症反应增加，内皮和血视网膜屏障损伤以及促血栓形成作用。此外，PD 0325901诱导的人脐静脉内皮细胞（HUVECs）可溶性内皮蛋白C受体（sEPCR）表达增加。结论：建立了PD 0325901诱导的兔RVO模型，为进一步研究PD 0325901诱导人RVO的细胞和分子机制奠定了基础。
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.