Machitani Mitsuhiro, Sakurai Fuminori, Wakabayashi Keisaku, Nakatani Kosuke, Tachibana Masashi, Kato Nobuyuki, Fujiwara Toshiyoshi, Mizuguchi Hiroyuki
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Mol Ther Oncolytics. 2017 Oct 26;7:76-85. doi: 10.1016/j.omto.2017.10.003. eCollection 2017 Dec 15.
Telomerase-specific replication-competent adenoviruses (Ads), i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver). We reported that inhibition of nuclear factor-κB (NF-κB) leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα) expression cassette (TRAD-DNIκBα). Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.
端粒酶特异性具有复制能力的腺病毒（Ads），即TRADs，其拥有由人端粒酶逆转录酶启动子驱动的E1基因表达盒，是很有前景的癌症治疗药物。然而，尽管包括TRAD在内的溶瘤腺病毒是瘤内给药，但它们会从肿瘤扩散到体循环，引发对溶瘤腺病毒介导的肝毒性的担忧（主要是由于腺病毒基因在肝脏中的渗漏表达）。我们报道过抑制核因子κB（NF-κB）可通过减少腺病毒基因在肝脏中的渗漏表达来抑制无复制能力的腺病毒载体介导的肝毒性。在此，为了开发一种安全性更高的TRAD，我们设计了一种携带肝脏特异性启动子驱动的显性负性IκBα（DNIκBα）表达盒的TRAD（TRAD-DNIκBα）。与传统TRAD相比，TRAD-DNIκBα对NF-κB信号传导表现出肝细胞特异性抑制，并显著降低了正常人肝细胞系中腺病毒基因的表达和复制。静脉注射TRAD-DNIκBα后，小鼠体内TRAD诱导的肝毒性在很大程度上受到抑制。然而，TRAD-DNIκBα在人非肝肿瘤细胞中的复制情况和溶瘤活性与传统TRAD相当。这些结果表明，含有肝脏特异性DNIκBα表达盒的溶瘤腺病毒在不抑制溶瘤活性的情况下具有更高的安全性。
