Progress and problems with the use of suicide genes for targeted cancer therapy.
Progress and problems with the use of suicide genes for targeted cancer therapy.
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DOI：
10.1016/j.addr.2015.05.009
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发表时间：
2016-04-01
影响因子：
16.1
通讯作者：
Hatefi A
中科院分区：
文献类型：
--
作者：
Karjoo Z;Chen X;Hatefi A
在癌症的多种基因治疗方法中，自杀基因治疗因其可以在癌细胞内选择性地将无毒化合物转化为细胞毒性药物而受到特别关注。因此，通过在肿瘤环境中引入高浓度的细胞毒分子，可以显著提高治疗指数，同时将对正常组织的影响降至最低。尽管在临床前水平上取得了显著的成功，但目前还没有癌症自杀基因治疗方案提供了理想的临床意义。这篇综述对用于癌症自杀基因治疗的六种主要酶/前药系统进行了批判性的研究，并使读者熟悉该领域的最新研究和实践。对每一种酶/前药系统的作用机理、提高酶稳定性/亲和力的蛋白质工程策略以及提高前药动力学和效力的化学修饰技术进行了讨论。在每一类中，讨论了过去十年用每种酶/前药系统进行的主要临床试验，以突出迄今的进展。最后，强调了不足之处，并勾勒出需要改进的领域，以产生临床意义。
Among various gene therapy methods for cancer, suicide gene therapy attracts a special attention because it allows selective conversion of non-toxic compounds into cytotoxic drugs inside cancer cells. As a result, therapeutic index can be increased significantly by introducing high concentrations of cytotoxic molecules to the tumor environment while minimizing impact on normal tissues. Despite significant success at the preclinical level, no cancer suicide gene therapy protocol has delivered the desirable clinical significance yet. This review gives a critical look at the six main enzyme/prodrug systems that are used in suicide gene therapy of cancer and familiarizes readers with the state-of-the-art research and practices in this field. For each enzyme/prodrug system, the mechanisms of action, protein engineering strategies to enhance enzyme stability/affinity and chemical modification techniques to increase prodrug kinetics and potency are discussed. In each category, major clinical trials that have been performed in the past decade with each enzyme/prodrug system are discussed to highlight the progress to date. Finally, shortcomings are underlined and areas that need improvement in order to produce clinical significance are delineated.