Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer
Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer
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DOI：
10.1158/1535-7163.mct-10-0205
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发表时间：
2010-06-01
影响因子：
5.7
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
--
作者：
Sakai, Ryo;Kagawa, Shunsuke;Fujiwara, Toshiyoshi
联合不同功能药物的多模式方法是治疗人类癌症最流行的方案。了解药物组合的协同、增效和拮抗作用的分子机制有助于发现新的有效组合。我们以前表明，端粒酶特异性复制能力的腺病毒（端粒酶，OBP-301），其中人端粒酶逆转录酶启动子控制腺病毒E1基因的表达，诱导在人类癌细胞中的选择性抗肿瘤作用。在这里，使用E1缺失的复制缺陷型腺病毒表达的p53肿瘤抑制基因（Advexin，Ad-p53）和OBP-301，我们研究如何这些腺病毒杀死肿瘤细胞与不同的机制可以在人类癌症的组合工作。我们发现，E1缺陷型Ad-p53在OBP-301存在下比单独Ad-p53或单独OBP-301更有效地杀死癌细胞，因为Ad-p53可以通过从共感染的OBP-301反式提供腺病毒E1而具有复制能力。Ad-p53和OBP-301诱导高水平的p53蛋白表达而没有p21诱导，导致凋亡性细胞死亡，这通过细胞计数珠阵列的活性半胱天冬酶-3表达和细胞周期的亚二倍体凋亡分数增加来证明。对于体内评估，异种移植有人肺肿瘤的裸鼠接受OBP-301和/或Ad-p53的瘤内注射。对植入肿瘤生长的分析表明，联合治疗的抗肿瘤作用增强。我们的数据显示，Ad-p53与OBP-301组合不仅诱导溶瘤性癌细胞死亡，而且诱导凋亡性癌细胞死亡，并增强体外和体内的抗肿瘤活性，作为人类癌症的多模式治疗提供了潜在的优点。Mol Cancer Ther; 9（6）; 1884-93.（C）2010年AACR。
Multimodal approaches combining drugs that differentially function is the most popular regimen for treating human cancer. Understanding the molecular mechanisms underlying the synergistic, potentiative, and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations. We previously showed that telomerase-specific replication-competent adenovirus (Telomelysin, OBP-301), in which the human telomerase reverse transcriptase promoter controls the adenoviral E1 gene expression, induces a selective antitumor effect in human cancer cells. Here, using E1-deleted replication-deficient adenovirus expressing the p53 tumor suppressor gene (Advexin, Ad-p53) and OBP-301, we investigate how these adenoviruses that kill tumor cells with different mechanisms could work in combination on human cancer. We found that E1-deficient Ad-p53 could kill cancer cells more efficiently in the presence of OBP-301 than Ad-p53 alone or OBP-301 alone, because Ad-p53 could become replication-competent by being supplied adenoviral E1 from coinfected OBP-301 in trans. Ad-p53 plus OBP-301 induced high levels of p53 protein expression without p21 induction, resulting in apoptotic cell death documented by active caspase-3 expression with a cytometric bead array and an increased subdiploid apoptotic fraction of the cell cycle. For in vivo evaluation, nude mice xenografted with human lung tumors received intratumoral injection of OBP-301 and/or Ad-p53. Analysis of the growth of implanted tumors showed an enhanced antitumor effect in combination therapy. Our data show that Ad-p53 in combination with OBP-301 induces not only oncolytic but also apoptotic cancer cell death and enhances antitumor activity in vitro and in vivo, providing potential merits as a multimodal treatment for human cancer. Mol Cancer Ther; 9(6); 1884-93. (C)2010 AACR.