Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, UK.
Cancer Gene Ther. 2010 Jun;17(6):420-8. doi: 10.1038/cgt.2009.86. Epub 2010 Jan 15.
Gene-directed enzyme prodrug therapy is a form of targeted cancer therapy, in which an enzyme is used to convert a non-toxic prodrug to a cytotoxin within the tumor. Horseradish peroxidase (HRP) is able to convert the indole prodrugs indole-3-acetic acid (IAA) and the halogenated derivative 5-bromo-IAA (5Br-IAA) to toxic agents able to induce cell kill in vitro. This study characterized HRP-directed gene therapy in vivo. Human nasopharyngeal squamous cell carcinoma cells, FaDu, stably expressing HRP were grown as xenografts in SCID mice. Pharmacokinetic analysis of IAA and 5Br-IAA showed satisfactory drug profiles, and millimolar concentrations could be achieved in tumor tissue at non-toxic doses. HRP-expressing tumors showed a modest growth delay when treated with IAA compared with drug-vehicle controls. Treatment response could not be improved using different drug scheduling or drug vehicle, nor by combining HRP-directed gene therapy with fractionated radiotherapy.
基因导向酶前药疗法是一种靶向癌症疗法，其中酶用于将非毒性前药转化为肿瘤内的细胞毒素。辣根过氧化物酶（HRP）能够将吲哚前体药物吲哚-3-乙酸（IAA）和卤代衍生物 5-溴-IAA（5Br-IAA）转化为能够诱导体外细胞杀伤的有毒物质。本研究对 HRP 定向基因治疗进行了体内特征描述。稳定表达 HRP 的人鼻咽鳞状细胞癌细胞 FaDu 作为异种移植物在 SCID 小鼠中生长。IAA 和 5Br-IAA 的药代动力学分析显示出令人满意的药物特征，在非毒性剂量下，肿瘤组织中可以达到毫摩尔浓度。与药物载体对照相比，用 IAA 治疗表达 HRP 的肿瘤时，肿瘤生长略有延迟。使用不同的药物方案或药物载体，或结合 HRP 定向基因治疗与分割放射治疗，均不能改善治疗反应。
