Miki K, Xu M, Gupta A, Ba Y, Tan Y, Al-Refaie W, Bouvet M, Makuuchi M, Moossa A R, Hoffman R M
AntiCancer Incorporated, San Diego, California 92111, USA.
Cancer Res. 2001 Sep 15;61(18):6805-10.
In this study, we report a novel approach to gene-directed enzyme prodrug therapy for cancer. This gene therapy strategy exploits the toxic pro-oxidant property of methylselenol, which is released from selenomethionine (SeMET) by cancer cells with the adenoviral-delivered methionine alpha,gamma-lyase (MET) gene cloned from Pseudomonas putida. In MET-transduced tumor cells, the cytotoxicity of SeMET is increased up to 1000-fold compared with nontransduced cells. A strong bystander effect occurred because of methylselenol release from MET gene-transduced cells and uptake by surrounding tumor cells. Methylselenol damaged the mitochondria via oxidative stress and caused cytochrome c release into the cytosol, thereby activating the caspase cascade and apoptosis. Adenoviral MET-gene/SeMET treatment also inhibited tumor growth in rodents and significantly prolonged their survival. Recombinant adenovirus-encoding MET gene-SeMET treatment thereby offers a new paradigm for cancer gene therapy.
在本研究中，我们报告了一种用于癌症的基因导向酶前药疗法的新方法。这种基因治疗策略利用了甲基硒醇的有毒促氧化剂特性，癌细胞通过从恶臭假单胞菌克隆的腺病毒传递的甲硫氨酸α,γ-裂解酶（MET）基因将其从硒代蛋氨酸（SeMET）中释放出来。在转导了MET的肿瘤细胞中，与未转导的细胞相比，SeMET的细胞毒性增加了多达1000倍。由于甲基硒醇从转导了MET基因的细胞中释放并被周围肿瘤细胞摄取，从而产生了强烈的旁观者效应。甲基硒醇通过氧化应激损伤线粒体，并导致细胞色素c释放到细胞质中，从而激活半胱天冬酶级联反应和细胞凋亡。腺病毒MET基因/SeMET治疗也抑制了啮齿动物的肿瘤生长并显著延长了它们的生存期。因此，重组腺病毒编码MET基因-SeMET治疗为癌症基因治疗提供了一种新的范例。
