Greco O, Rossiter S, Kanthou C, Folkes L K, Wardman P, Tozer G M, Dachs G U
Gray Cancer Institute, P. O. Box 100, Northwood, Middlesex HA6 2JR, United Kingdom.
Mol Cancer Ther. 2001 Dec;1(2):151-60.
We have previously proposed the plant enzyme horseradish peroxidase (HRP) and the plant hormone indole-3-acetic acid (IAA) as an enzyme/prodrug combination for cancer gene therapy. In the current study, we evaluated the potential of HRP/IAA for gene-directed enzyme/prodrug therapy in three human tumor cell lines (T24 bladder carcinoma, MCF-7 breast adenocarcinoma, and FaDu nasopharyngeal squamous carcinoma) and one endothelial cell line (HMEC-1). The action of 10 IAA analogues in combination with HRP was studied in vitro in normoxic conditions as well as in the extreme tumor conditions of anoxia. Compounds characterized by prompt normoxic or anoxic cytotoxic activation and high HRP transfectant killing or selectivity were identified. Some variations were observed in the response of cells of different origin, with IAA, 1-Me-IAA, and 5-Br-IAA representing the most promising candidates for HRP gene therapy. In particular, 5-Br-IAA showed a very prompt and selective activation in anoxia. A strong bystander effect was produced by activated IAA and analogues because 70-90% cell kill was obtained when only 5% of the cells expressed the HRP enzyme. These results indicate that HRP/IAA represents an effective system for enzyme/prodrug-based anticancer approaches, and further improvements could be achieved by the use of novel IAA derivatives.
我们之前曾提出将植物酶辣根过氧化物酶（HRP）和植物激素吲哚-3-乙酸（IAA）作为一种用于癌症基因治疗的酶/前药组合。在当前研究中，我们评估了HRP/IAA在三种人类肿瘤细胞系（T24膀胱癌细胞、MCF-7乳腺腺癌细胞和FaDu鼻咽鳞状癌细胞）和一种内皮细胞系（HMEC-1）中进行基因导向酶/前药治疗的潜力。在常氧条件下以及缺氧这种极端肿瘤条件下，体外研究了10种IAA类似物与HRP联合使用的作用。鉴定出了具有快速常氧或缺氧细胞毒性激活以及高HRP转染细胞杀伤或选择性特征的化合物。不同来源的细胞反应存在一些差异，IAA、1-甲基-IAA和5-溴-IAA是HRP基因治疗最有前景的候选物。特别是，5-溴-IAA在缺氧时表现出非常快速且选择性的激活。活化的IAA及其类似物产生了强烈的旁观者效应，因为当仅5%的细胞表达HRP酶时就能实现70 - 90%的细胞杀伤。这些结果表明，HRP/IAA代表了一种基于酶/前药的抗癌方法的有效体系，并且通过使用新型IAA衍生物可实现进一步改进。
