Kamizono Junichi, Nagano Satoshi, Murofushi Yoshiteru, Komiya Setsuro, Fujiwara Hisayoshi, Matsuishi Toyojiro, Kosai Ken-ichiro
Division of Gene Therapy and Regenerative Medicine, Cognitive and Molecular Research Institute of Brain Diseases, Kurume University, Kurume, Japan.
Cancer Res. 2005 Jun 15;65(12):5284-91. doi: 10.1158/0008-5472.CAN-04-2657.
Although a conditionally replicating adenovirus (CRA) exhibiting cancer-selective replication and induction of cell death is an innovative potential anticancer agent, current imperfections in cancer specificity and efficient viral replication limit the usefulness of this technique. Here, we constructed survivin-responsive CRAs (Surv.CRAs), in which expression of the wild-type or mutant adenoviral early region 1A (E1A) gene is regulated by the promoter of survivin, a new member of the inhibitor of apoptosis gene family. We explored the cancer specificity and effectiveness of viral replication of Surv.CRAs, evaluating their potential as a treatment for cancer. The survivin promoter was strongly activated in all cancers examined at levels similar to or even higher than those seen for representative strong promoters; in contrast, low activity was observed in normal cells. Surv.CRAs efficiently replicated and potently induced cell death in most types of cancer. In contrast, minimal viral replication in normal cells did not induce any detectable cytotoxicity. A single injection of Surv.CRAs into a preestablished tumor expressing survivin, even at relatively low levels, induced significant tumor death and inhibition of tumor growth. Furthermore, Surv.CRAs were superior to telomerase-dependent CRAs, one of the most effective CRAs that have been examined to date, both in terms of cancer specificity and efficiency. Thus, Surv.CRAs are an attractive potential anticancer agent that could effectively and specifically treat a variety of cancers.
尽管一种表现出癌症选择性复制和诱导细胞死亡的条件性复制腺病毒（CRA）是一种具有创新潜力的抗癌药物，但目前在癌症特异性和高效病毒复制方面的缺陷限制了该技术的实用性。在此，我们构建了存活素反应性CRA（Surv.CRA），其中野生型或突变型腺病毒早期区域1A（E1A）基因的表达受凋亡抑制基因家族新成员存活素启动子的调控。我们探究了Surv.CRA的癌症特异性和病毒复制有效性，评估了它们作为癌症治疗手段的潜力。存活素启动子在所有检测的癌症中均被强烈激活，其水平与代表性强启动子相似甚至更高；相比之下，在正常细胞中观察到的活性较低。Surv.CRA在大多数癌症类型中能有效复制并有力地诱导细胞死亡。相反，在正常细胞中极少的病毒复制并未诱导任何可检测到的细胞毒性。向预先建立的表达存活素（即使表达水平相对较低）的肿瘤中单次注射Surv.CRA，可诱导显著的肿瘤死亡并抑制肿瘤生长。此外，Surv.CRA在癌症特异性和效率方面均优于端粒酶依赖性CRA，端粒酶依赖性CRA是迄今为止已检测的最有效的CRA之一。因此，Surv.CRA是一种有吸引力的潜在抗癌药物，可有效且特异性地治疗多种癌症。
