Angiogenesis and Cancer Research Group, University of Otago, Christchurch, New Zealand.
Molecules. 2009 Nov 10;14(11):4517-45. doi: 10.3390/molecules14114517.
Gene directed enzyme prodrug therapy (GDEPT) of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV), cytosine deaminase (CD) from bacteria or yeast with 5-fluorocytodine (5-FC), and bacterial nitroreductase (NfsB) with 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), and their respective derivatives.
基因导向酶前药疗法（GDEPT）旨在通过基因转移提高化疗的选择性，从而使靶细胞能够将无毒的前体药物转化为细胞毒性药物。由于转移有毒代谢物而导致的基因修饰细胞周围的细胞杀伤区，即旁观者效应，导致肿瘤消退。在这里，我们将讨论是通过努力增强旁观者效应来克服基因转移不良，还是通过避免旁观者效应来减少潜在的全身效应，这三种成功的 GDEPT 系统为我们提供了帮助。本综述集中讨论了这些酶前药组合的旁观者效应和药物开发，即单纯疱疹病毒胸苷激酶（HSV-TK）与更昔洛韦（GCV）、细菌或酵母中的胞嘧啶脱氨酶（CD）与 5-氟胞嘧啶（5-FC）以及细菌硝基还原酶（NfsB）与 5-（氮杂-1-基）-2,4-二硝基苯甲酰胺（CB1954）及其各自的衍生物。
