Combination of oncolytic adenovirotherapy and Bax gene therapy in human cancer xenografted models. Potential merits and hurdles for combination therapy
Combination of oncolytic adenovirotherapy and Bax gene therapy in human cancer xenografted models. Potential merits and hurdles for combination therapy
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DOI：
10.1002/ijc.23438
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发表时间：
2008-06-01
影响因子：
6.4
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
--
作者：
Hioki, Masayoshi;Kagawa, Shunsuke;Fujiwara, Toshiyoshi
肿瘤基因治疗和溶瘤病毒治疗得到了广泛的研究。然而，它们的抗癌活性较弱，阻碍了它们的临床应用。我们之前构建了一种复制腺病毒（OBP-301，端粒酶），其中人类端粒酶逆转录酶（hTERT）启动子驱动腺病毒El基因的表达，并导致人类癌细胞的选择性裂解。我们假设含有OBP-301和表达促凋亡Bax基因的非复制腺病毒的联合腺病毒治疗可以克服每种方式的弱点并增强其抗癌效果。在体外细胞活力测定中，与单独处理相比，联合处理显著提高了Bax蛋白的表达和疗效。然而，与OBP-301单独治疗相比，联合治疗在抑制皮下和胸膜播散性肿瘤方面效果不佳。进一步的研究表明，联合治疗导致EIA蛋白表达受到抑制，这与病毒复制减少有关。我们的研究结果表明，Bax基因治疗联合溶瘤腺病毒治疗可能会增强它们的抗肿瘤活性，但为了使Bax基因表达避免干扰溶瘤病毒的产生，可能需要进一步的改进来最大化体内的组合效果。(c) 2008 Wiley-Liss, Inc。
Cancer gene therapy and oncolytic virotherapy have been studied extensively. However, their clinical application is hampered by their weak anticancer activity. We previously constructed a replicating adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of the adenoviral El genes, and causes selective lysis of human cancer cells. We hypothesized that combination adenoviral therapy containing OBP-301 and a nonreplicating adenovirus expressing the proapoptotic Bax gene could overcome the weakness and augment the anticancer efficacy of each modality. Combination treatment resulted in marked Bax protein expression and enhanced efficacy in in vitro cell viability assay, when compared with either single treatment. However, combination treatment was not as effective in suppressing both subcutaneous and pleural disseminated tumors compared with OBP-301 treatment alone. Further investigation revealed that combination treatment resulted in suppressed EIA protein expression associated with reduced viral replication. Our results suggest that Bax gene therapy in combination with oncolytic adenovirotherapy potentially augments their antitumor activity, but further improvements may be required to maximize the combinatorial effect in vivo, for the Bax gene expression to avoid interference with production of the oncolytic virus. (c) 2008 Wiley-Liss, Inc.