Preclinical safety and efficacy of in situ REIC/Dkk-3 gene therapy for prostate cancer.
Preclinical safety and efficacy of in situ REIC/Dkk-3 gene therapy for prostate cancer.
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DOI：
10.18926/amo/48076
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发表时间：
2012-03
影响因子：
0.5
通讯作者：
Keiichiro Kawauchi;Masami Watanabe;H. Kaku;Peng Huang;Kasumi Sasaki;M. Sakaguchi;K. Ochiai;N. Huh;Y. Nasu;H. Kumon
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文献类型：
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作者：
Keiichiro Kawauchi;Masami Watanabe;H. Kaku;Peng Huang;Kasumi Sasaki;M. Sakaguchi;K. Ochiai;N. Huh;Y. Nasu;H. Kumon
研究了表达REIC/Dkk-3肿瘤抑制基因的腺病毒载体（Ad-REIC）用于前列腺癌基因治疗的临床前安全性和治疗效果。Ad-人（h）和小鼠（m）REIC先前被证明在体外和体内诱导强烈的抗癌作用，并且我们在此报告了两项体内研究的结果。首先，使用PC3前列腺癌细胞系在皮下肿瘤模型中检查肿瘤内Ad-hREIC施用的毒性和治疗效果。其次，在正常小鼠中测试前列腺内Ad-mREIC施用的毒性。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价。两个实验均表明，Ad-REIC治疗组和对照组（PBS或Ad-LacZ治疗组）之间的检查参数无显著差异。在使用PC 3细胞的体外分析中，在Ad-hREIC处理后观察到显著的凋亡效应。证实了这一观察结果，在体内皮下前列腺癌模型中证明了Ad-hREIC的稳健抗肿瘤功效。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原位基因治疗前列腺癌是安全和有用的临床治疗。
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.