Patterson Adam V, Saunders Mark P, Greco Olga
Auckland Cancer Society Research Center, Private Bag 92019, University of Auckland, New Zealand.
Curr Pharm Des. 2003;9(26):2131-54. doi: 10.2174/1381612033454117.
Improvements in the radiotherapeutic management of solid tumors through the concurrent use of gene therapy is a realistic possibility. Of the broad array of candidate genes that have been evaluated, those encoding prodrug-activating enzymes are particularly appealing since they directly complement ongoing clinical chemoradiation regimes. Gene-Directed Enzyme-Prodrug Therapy (GDEPT) only requires a fraction of the target cells to be genetically modified, providing that the resultant cytotoxic prodrug metabolites redistribute efficiently (the bystander effect). This transfer of cytotoxicity to neighboring non-targeted cancer cells is central to the success of any gene therapy strategy, irrespective of the therapeutic gene employed. In the context of genetic chemoradiotherapy, efficient prodrug metabolite diffusion will be a prerequisite for efficient radiosensitization. Some, but not all GDEPT approaches have been analysed in combination with radiotherapy. Examples of prodrugs of clinically established chemotherapeutic agents currently used in conjunction with radiotherapy include: 5-fluorocytosine (5FC), cyclophosphamide (CPA), irinotecan (CPT-11), gemcitabine (dFdC), capecitabine, mitomycin C (MMC) and AQ4N. Other GDEPT paradigms, such as ganciclovir (GCV) and Herpes Simplex thymidine kinase (HSV-tk), dinitrobenzamide (DNB) mustard or aziridinyl analogs and the E. coli nitroreductase (NTR), CMDA or ZP2767P with Pseudomonas aeruginosa carboxypeptidase G2 (CPG2), and indole-3-acetic acid (IAA) activated by horseradish peroxidase (HRP) have no clinically established chemotherapeutic counterpart. Each prodrug is discussed in this review in the context of GDEPT, with a particular attention to translational research and clinical utility in combination with radiotherapy.
通过同时使用基因疗法改善实体瘤的放射治疗管理是切实可行的。在已评估的众多候选基因中，那些编码前药激活酶的基因特别有吸引力，因为它们直接补充了正在进行的临床放化疗方案。基因导向酶前药疗法（GDEPT）只需要对一小部分靶细胞进行基因改造，前提是产生的细胞毒性前药代谢物能有效重新分布（旁观者效应）。这种细胞毒性向邻近未靶向癌细胞的转移是任何基因治疗策略成功的关键，无论采用何种治疗基因。在基因放化疗的背景下，有效的前药代谢物扩散将是有效放射增敏的先决条件。一些（但不是全部）GDEPT方法已与放射疗法联合进行了分析。目前与放射疗法联合使用的临床已确立的化疗药物的前药实例包括：5-氟胞嘧啶（5FC）、环磷酰胺（CPA）、伊立替康（CPT-11）、吉西他滨（dFdC）、卡培他滨、丝裂霉素C（MMC）和AQ4N。其他GDEPT模式，如更昔洛韦（GCV）和单纯疱疹病毒胸苷激酶（HSV-tk）、二硝基苯甲酰胺（DNB）芥子气或氮丙啶类似物以及大肠杆菌硝基还原酶（NTR）、与铜绿假单胞菌羧肽酶G2（CPG2）联合的CMDA或ZP2767P，以及由辣根过氧化物酶（HRP）激活的吲哚-3-乙酸（IAA），在临床上没有已确立的化疗对应物。本综述在GDEPT的背景下讨论了每种前药，特别关注与放射疗法联合的转化研究和临床应用。
