文章：

癌症的反义疗法

Antisense therapy for cancer

原文发布日期：2005-05-20

DOI: 10.1038/nrc1631

类型: Review Article

开放获取: 否

要点：

1. Antisense oligonucleotides (ASOs) offer one approach to target genes involved in cancer progression, particularly those that are not amenable to small-molecule or antibody inhibition.
2. ASOs inhibit translation through a mechanism that involves the formation of an mRNA–ASO duplex, leading to RNase-H-mediated cleavage of the target mRNA.
3. Several useful modifications of ASO backbones have yielded compounds that show good tissue distribution and increased resistance to nuclease digestion.
4. ASO drugs are evolving through improved chemical modifications to prolong in vivo half-life, increase potency and reduce toxicity.
5. The most promising targets for antisense therapy are those that become upregulated during tumorigenesis and several of these, including BCL2, protein kinase Cα, clusterin, X-linked inhibitors of apoptosis and survivin, are currently in or have finished early-phase clinical trials.
6. A disappointing lack of clinical efficacy for some ASOs indicates that challenges remain. However, the advanced chemistry incorporated into the second-generation ASOs has significant promise for the future.
7. A recently completed prostate cancer pre-surgery trial provides proof of concept that the second-generation 2'-MOE OGX-011 can potently suppress the target protein clusterin in humans.

要点翻译：

1. 反义寡核苷酸（ASO）为靶向癌症进展相关基因提供了一种途径，尤其适用于那些不适合小分子或抗体抑制的基因。
2. ASO通过形成mRNA-ASO双链体抑制翻译，该机制可导致RNase H介导的靶向mRNA切割。
3. 通过对ASO骨架进行若干有效修饰，已开发出具有良好组织分布和增强核酸酶抗性的化合物。
4. ASO药物正通过改进化学修饰不断发展，以延长体内半衰期、增强效力并降低毒性。
5. 反义疗法最具前景的靶点是在肿瘤发生过程中上调的基因，包括BCL2、蛋白激酶Cα、簇连蛋白、X连锁凋亡抑制蛋白和生存蛋白在内的多个靶点目前已进入或已完成早期临床试验。
6. 部分ASO令人失望的临床疗效缺失表明挑战依然存在。但第二代ASO采用的先进化学修饰为未来带来了重要希望。
7. 近期完成的前列腺癌术前试验证实，第二代2'-MOE修饰的OGX-011能够有效抑制人体内靶蛋白簇连蛋白的表达，这为该技术提供了概念验证。

英文摘要：

Improved understanding of the molecular mechanisms that mediate cancer progression and therapeutic resistance has identified many therapeutic gene targets that regulate apoptosis, proliferation and cell signalling. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those that are not amenable to small-molecule or antibody inhibition. Better chemical modifications of antisense oligonucleotides increase resistance to nuclease digestion, prolong tissue half-lives and improve scheduling. Indeed, recent clinical trials confirm the ability of this class of drugs to significantly suppress target-gene expression. The current status and future directions of several antisense drugs that have potential clinical use in cancer are reviewed.

摘要翻译： 

对介导癌症进展和治疗抵抗的分子机制的深入理解，已发现许多调控凋亡、增殖和细胞信号传导的治疗性基因靶点。反义寡核苷酸为靶向参与癌症进展的基因提供了一种途径，尤其是那些不适合小分子或抗体抑制的基因。更好的化学修饰可提高反义寡核苷酸对核酸酶消化的抵抗力、延长组织半衰期并优化给药方案。最近的临床试验已证实，这类药物能够显著抑制靶基因表达。本文综述了几种具有潜在临床应用前景的反义药物的研究现状及未来发展方向。

原文链接：

Antisense therapy for cancer