用 TGF-β2 反义寡核苷酸治疗恶性神经胶质瘤。
Treatment of malignant gliomas with TGF-beta2 antisense oligonucleotides.
机构信息
Department of Neurology, University of Regensburg, Medical School, Regensburg, Germany.
出版信息
Expert Rev Anticancer Ther. 2009 Nov;9(11):1663-74. doi: 10.1586/era.09.138.
Antisense oligodeoxynucleotides (AS-ODNs) have been widely used to determine gene function, validate drug targets and as novel therapeutics for human diseases. In this review, we describe the development of AS-ODNs, including their modifications, pharmacokinetics and toxicity in animal models and humans, and their preclinical and clinical development in the therapy of human high-grade gliomas. The most advanced AS-ODN for the therapy of high-grade gliomas is a phosphorothioate-modified AS-ODN, AP 12009 (trabedersen), which targets mRNA encoding TGF-beta2. AP 12009 is administered intratumorally using convection-enhanced delivery. A series of Phase I and II clinical trials have evaluated the toxicity profile and optimal dose of the substance. A randomized, controlled international Phase III study was initiated in March 2009 and will compare trabedersen 10 microM versus conventional alkylating chemotherapy in patients with recurrent or refractory anaplastic astrocytoma after standard radio- and chemotherapy.
反义寡核苷酸（AS-ODNs）已被广泛用于确定基因功能、验证药物靶点以及作为人类疾病的新型治疗方法。在这篇综述中，我们描述了 AS-ODNs 的发展，包括它们在动物模型和人类中的修饰、药代动力学和毒性，以及它们在治疗人类高级别神经胶质瘤中的临床前和临床开发。用于治疗高级别神经胶质瘤的最先进的 AS-ODN 是一种修饰的 AS-ODN，AP 12009（trabedersen），其针对编码 TGF-β2 的 mRNA。AP 12009 通过增强的传递进行瘤内给药。一系列 I 期和 II 期临床试验已经评估了该物质的毒性特征和最佳剂量。一项随机、对照的国际 III 期研究于 2009 年 3 月启动，将比较 10 μM trabedersen 与标准放射和化学疗法后复发或难治性间变性星形细胞瘤患者的常规烷化剂化疗。
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