Stein C A, Benimetskaya Luba, Mani S
Department of Oncology, Albert Einstein-Montefiore Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
Semin Oncol. 2005 Dec;32(6):563-72. doi: 10.1053/j.seminoncol.2005.09.003.
Antisense oligonucleotides have been evaluated as antineoplastic agents in a series of clinical trials, with mixed results. However, phase III trials incorporating G3139, a phosphorothioate oligomer targeted to the initiation codon region of the bcl-2 mRNA, have recently been completed in advanced melanoma, myeloma, and chronic lymphocytic leukemia (CLL). This article discusses the mechanism of the antisense effect and its dependence on the cellular internalization of oligonucleotides and the activity of RNase H. It also describes the properties, specific and nonspecific, of phosphorothioate oligonucleotides, the predominant species in current clinical trials, and discusses pharmacokinetic data obtained from earlier phase I and II trials employing these molecules. While the application of antisense technology to the treatment of human cancer is conceptually straightforward, in practice there are many complicated, mechanistically based questions that must be considered.
在一系列临床试验中，反义寡核苷酸已作为抗肿瘤药物进行了评估，结果喜忧参半。然而，针对晚期黑色素瘤、骨髓瘤和慢性淋巴细胞白血病（CLL）的III期试验最近已经完成，该试验纳入了G3139，一种靶向bcl-2 mRNA起始密码子区域的硫代磷酸酯寡聚物。本文讨论了反义效应的机制及其对寡核苷酸细胞内化和核糖核酸酶H活性的依赖性。它还描述了硫代磷酸酯寡核苷酸（当前临床试验中的主要类型）的特性，包括特异性和非特异性，并讨论了从使用这些分子的早期I期和II期试验中获得的药代动力学数据。虽然将反义技术应用于人类癌症治疗在概念上很简单，但在实践中存在许多复杂的、基于机制的问题需要考虑。
