Enzymes to die for: exploiting nucleotide metabolizing enzymes for cancer gene therapy.
Enzymes to die for: exploiting nucleotide metabolizing enzymes for cancer gene therapy.
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DOI：
10.2174/156652312800099571
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发表时间：
2012-04-01
影响因子：
3.6
通讯作者：
Black ME
中科院分区：
文献类型：
--
作者：
Ardiani A;Johnson AJ;Ruan H;Sanchez-Bonilla M;Serve K;Black ME
自杀基因治疗是一种有吸引力的策略，可以选择性地破坏癌细胞，同时最大限度地减少对正常细胞的不必要毒性。自从二十多年前首次引入这一想法以来，已经进行了许多研究，并取得了重大进展，以进一步将其应用于主流癌症治疗。自杀基因治疗策略的主要局限性阻碍了其临床应用，包括低效的癌细胞定向递送和自杀酶的前药活化能力差。这篇评论的重点是努力，已经和目前正在追求提高个别自杀酶对各自的前药的活性，特别注意核苷酸代谢酶在自杀癌基因治疗中的应用。已经采用了许多蛋白质工程策略，我们在这里的讨论将集中在使用诱变方法来创建和评估具有增强的前药活化能力和增加的热稳定性的核苷酸代谢酶。这些研究中的一些已经产生了与癌症基因治疗应用相关的临床上重要的酶变体，因为它们的利用可以用于最大化癌细胞杀伤，同时最小化前药剂量，从而限制不期望的副作用。
Suicide gene therapy is an attractive strategy to selectively destroy cancer cells while minimizing unnecessary toxicity to normal cells. Since this idea was first introduced more than two decades ago, numerous studies have been conducted and significant developments have been made to further its application for mainstream cancer therapy. Major limitations of the suicide gene therapy strategy that have hindered its clinical application include inefficient directed delivery to cancer cells and the poor prodrug activation capacity of suicide enzymes. This review is focused on efforts that have been and are currently being pursued to improve the activity of individual suicide enzymes towards their respective prodrugs with particular attention to the application of nucleotide metabolizing enzymes in suicide cancer gene therapy. A number of protein engineering strategies have been employed and our discussion here will center on the use of mutagenesis approaches to create and evaluate nucleotide metabolizing enzymes with enhanced prodrug activation capacity and increased thermostability. Several of these studies have yielded clinically important enzyme variants that are relevant for cancer gene therapy applications because their utilization can serve to maximize cancer cell killing while minimizing the prodrug dose, thereby limiting undesirable side effects.