Kawauchi Keiichiro, Watanabe Masami, Kaku Haruki, Huang Peng, Sasaki Kasumi, Sakaguchi Masakiyo, Ochiai Kazuhiko, Huh Nam-Ho, Nasu Yasutomo, Kumon Hiromi
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.
Acta Med Okayama. 2012;66(1):7-16. doi: 10.18926/AMO/48076.
The preclinical safety and therapeutic efficacy of adenoviral vectors that express the REIC/Dkk-3 tumor suppressor gene (Ad-REIC) was examined for use in prostate cancer gene therapy. The Ad-human (h) and mouse (m) REIC were previously demonstrated to induce strong anti-cancer effects in vitro and in vivo, and we herein report the results of two in vivo studies. First, intra-tumor Ad-hREIC administration was examined for toxicity and therapeutic effects in a subcutaneous tumor model using the PC3 prostate cancer cell line. Second, intra-prostatic Ad-mREIC administration was tested for toxicity in normal mice. The whole-body and spleen weights, hematological and serum chemistry parameters, and histological evaluation of tissues from throughout the body were analyzed. Both experiments indicated that there was no significant difference in the examined parameters between the Ad-REIC-treated group and the control (PBS- or Ad-LacZ-treated) group. In the in vitro analysis using PC3 cells, a significant apoptotic effect was observed after Ad-hREIC treatment. Confirming this observation, the robust anti-tumor efficacy of Ad-hREIC was demonstrated in the in vivo subcutaneous prostate cancer model. Based on the results of these preclinical experiments, we consider the adenovirus-mediated REIC/Dkk-3 in situ gene therapy to be safe and useful for the clinical treatment of prostate cancer.
研究了表达REIC/Dkk-3肿瘤抑制基因的腺病毒载体（Ad-REIC）在前列腺癌基因治疗中的临床前安全性和治疗效果。此前已证明Ad-人（h）和小鼠（m）REIC在体外和体内均能诱导强烈的抗癌作用，我们在此报告两项体内研究的结果。首先，在使用PC3前列腺癌细胞系的皮下肿瘤模型中，研究了瘤内注射Ad-hREIC的毒性和治疗效果。其次，检测了在正常小鼠前列腺内注射Ad-mREIC的毒性。分析了全身和脾脏重量、血液学和血清化学参数以及全身组织的组织学评估。两项实验均表明，Ad-REIC治疗组与对照组（PBS或Ad-LacZ治疗组）之间的检测参数无显著差异。在使用PC3细胞的体外分析中，Ad-hREIC处理后观察到显著的凋亡效应。在体内皮下前列腺癌模型中证实了这一观察结果，证明了Ad-hREIC具有强大的抗肿瘤功效。基于这些临床前实验的结果，我们认为腺病毒介导的REIC/Dkk-3原位基因治疗对前列腺癌的临床治疗是安全且有用的。
