Targeting the p53 pathway in retinoblastoma with subconjunctival Nutlin-3a.
Targeting the p53 pathway in retinoblastoma with subconjunctival Nutlin-3a.
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DOI：
10.1158/0008-5472.can-11-0058
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发表时间：
2011-06-15
期刊：
影响因子：
11.2
通讯作者：
Dyer MA
中科院分区：
文献类型：
--
作者：
Brennan RC;Federico S;Bradley C;Zhang J;Flores-Otero J;Wilson M;Stewart C;Zhu F;Guy K;Dyer MA
视网膜母细胞瘤是一种罕见的儿童视网膜癌症，始于子宫内，在生命的最初几年被诊断出来。视网膜母细胞瘤治疗的目标是挽救眼球，保护视力，减少短期和长期的副作用，而不会因肿瘤扩散而死亡。为了鉴定用于治疗视网膜母细胞瘤的更好的化学治疗组合，几个小组已经开发了用于临床前测试的人视网膜母细胞瘤的遗传小鼠模型和原位异种移植模型。先前的研究表明MDMX蛋白参与视网膜母细胞瘤中p53通路的抑制，并表明MDM 2/MDMX拮抗剂nutlin-3a可以有效诱导视网膜母细胞瘤细胞系中p53介导的细胞死亡。然而，nutlin-3a不能全身给药治疗视网膜母细胞瘤，因为它穿过血眼屏障的渗透性很差。因此，我们开发了nutlin-3a的眼部制剂nutlin-3aOC，并在视网膜母细胞瘤的遗传和人视网膜母细胞瘤原位异种移植模型中测试了这种新制剂的药代动力学和功效。在这里，我们表明nutlin-3aOC特异性和有效地靶向p53通路，并且nutlin-3aOC与全身性拓扑替康的组合对于视网膜母细胞瘤的治疗比目前在人类原位异种移植物中使用的化疗显著更好。我们的研究提供了一种新的标准化方法来评估和优先考虑新的药物，以纳入未来的视网膜母细胞瘤临床试验。
Retinoblastoma is a rare childhood cancer of the retina that begins in utero and is diagnosed in the first years of life. The goals of retinoblastoma treatment are ocular salvage, vision preservation, and reduction of short-and long-term side effects without risking mortality due to tumor dissemination. To identify better chemotherapeutic combinations for the treatment of retinoblastoma, several groups have developed genetic mouse models and orthotopic xenograft models of human retinoblastoma for preclinical testing. Previous studies have implicated the MDMX protein in the suppression of the p53 pathway in retinoblastoma and shown that the MDM2/MDMX antagonist, nutlin-3a, can efficiently induce p53-mediated cell death in retinoblastoma cell lines. However, nutlin-3a cannot be administered systemically to treat retinoblastoma, because it has poor penetration across the blood-ocular barrier. Therefore, we developed an ocular formulation of nutlin-3a, nutlin-3aOC, and tested the pharmacokinetics and efficacy of this new formulation in genetic and human retinoblastoma orthotopic xenograft models of retinoblastoma. Here we show that nutlin-3aOC specifically and efficiently targets the p53 pathway and that the combination of nutlin-3aOC with systemic topotecan is a significantly better treatment for retinoblastoma than currently used chemotherapy in human orthotopic xenografts. Our studies provide a new standardized approach to evaluate and prioritize novel agents for incorporation into future clinical trials for retinoblastoma.