Combinatory use of replication-competent adenoviruses and chemotherapeutic agents produces anti-tumor effects on human esophageal carcinoma cells

我们研究了一种新的治疗策略，对难治性癌症，特别是食管癌。我们将腺病毒（Ad）中E1区编码基因的转录调控区替换为在人类肿瘤中高度表达但在正常组织中不表达的基因（如中期因子、生存素和环氧合酶-2）的5'区。我们还用35型衍生的纤维区改变了传统5型Ad的纤维区，该纤维区在感染靶细胞中起关键作用。该修饰增加了病毒感染性，因为CAR分子的表达水平（其是5型Ad的细胞受体）通常在人肿瘤中下调。相反，作为35型Ad的主要受体的CD 46分子的表达在人类肿瘤中相当上调。纤维替代大大增强了CAR-低肿瘤中的Ad感染性，随后增强了Ad介导的细胞毒性，并与抗癌剂产生了组合效应。

We examined a novel therapeutic strategy for intractable cancer in particular esophageal carcinoma. We replaced a transcriptional regulatory region of the E1 region-encoded genes in adenoviruses (Ad) with a 5' region of a gene that was highly expressed in human tumors but not in normal tissues such as midkine, survivin and cyclooxygenase-2. We also changed the fiber region of conventional type 5 Ad, which played a key role in infecting target cells, with a type 35-derived fiber region. The modification increased the viral infectivity since an expression level of the CAR molecules, which were a cellular receptor of type 5 Ad, were often down-regulated in human tumors. In contract, the expression of CD46 molecules, which are the major receptor of type 35 Ad, is rather up-regulated in human tumors. The fiber replacement greatly enhanced Ad infectivity in CAR-low tumors and subsequently enhanced the Ad-mediated cytotoxicity, and produced combinatory effects with anti-cancer agents.