Ahn M, Lee S-J, Li X, Jiménez J A, Zhang Y-P, Bae K-H, Mohammadi Y, Kao C, Gardner T A
Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cancer Gene Ther. 2009 Jan;16(1):73-82. doi: 10.1038/cgt.2008.59. Epub 2008 Sep 5.
Enzyme pro-drug suicide gene therapy has been hindered by inefficient viral delivery and gene transduction. To further explore the potential of this approach, we have developed AdIU1, a prostate-restricted replicative adenovirus (PRRA) armed with the herpes simplex virus thymidine kinase (HSV-TK). In our previous Ad-OC-TK/ACV phase I clinical trial, we demonstrated safety and proof of principle with a tissue-specific promoter-based TK/pro-drug therapy using a replication-defective adenovirus for the treatment of prostate cancer metastases. In this study, we aimed to inhibit the growth of androgen-independent (AI), PSA/PSMA-positive prostate cancer cells by AdIU1. In vitro the viability of an AI- PSA/PSMA-expressing prostate cancer cell line, CWR22rv, was significantly inhibited by treatment with AdIU1 plus GCV (10 microg ml(-1)), compared with AdIU1 treatment alone and also cytotoxicity was observed following treatment with AdIU1 plus GCV only in PSA/PSMA-positive CWR22rv and C4-2 cells, but not in the PSA/PSMA-negative cell line, DU-145. In vivo assessment of AdIU1 plus GCV treatment revealed a stronger therapeutic effect against CWR22rv tumors in nude mice than treatment with AdIU1 alone, AdE4PSESE1a alone or in combination with GCV. Our results demonstrate the therapeutic potential of specific-oncolysis and suicide gene therapy for AI-PSA/PSMA-positive prostate cancer gene therapy.
酶前药自杀基因疗法因病毒递送效率低下和基因转导而受到阻碍。为了进一步探索这种方法的潜力，我们开发了AdIU1，一种携带单纯疱疹病毒胸苷激酶（HSV-TK）的前列腺限制性复制腺病毒（PRRA）。在我们之前的Ad-OC-TK/ACV I期临床试验中，我们使用基于组织特异性启动子的TK/前药疗法，采用复制缺陷型腺病毒治疗前列腺癌转移，证明了其安全性和原理验证。在本研究中，我们旨在通过AdIU1抑制雄激素非依赖性（AI）、PSA/PSMA阳性前列腺癌细胞的生长。在体外，与单独使用AdIU1相比，用AdIU1加GCV（10μg ml(-1)）处理可显著抑制表达AI-PSA/PSMA的前列腺癌细胞系CWR22rv的活力，并且仅在用AdIU1加GCV处理后，在PSA/PSMA阳性的CWR22rv和C4-2细胞中观察到细胞毒性，而在PSA/PSMA阴性细胞系DU-145中未观察到。对AdIU1加GCV治疗的体内评估显示，与单独使用AdIU1、单独使用AdE4PSESE1a或与GCV联合使用相比，对裸鼠CWR22rv肿瘤的治疗效果更强。我们的结果证明了特异性溶瘤和自杀基因疗法对AI-PSA/PSMA阳性前列腺癌基因治疗的治疗潜力。
