IRES连接双基因在溶瘤腺病毒中的抗肝癌作用

Antitumor Activity of IRES-Mediated Bicistronic Adenovirus in HCC

单基因治疗癌症可能杀伤力还嫌不够,故使用两个基因在癌症治疗中具有重要价值。利用IRES将双基因连接起来在溶瘤腺病毒中表达,构成ZD55-IL-24-IRES-TRAIL。研究发现,该病毒在多种肝癌细胞中能有效地介导外源双基因表达,并在很大程度上杀死肿瘤细胞,而对正常细胞WI38无明显杀伤力。并且,该病毒可以有效地抑制体内肿瘤生长,有的肿瘤甚至完全消失。

Efficient and regulated co-expression of multiple genes is an important consideration in the design of gene therapy vectors. Among the several different strategies to co-express multiple genes, the incorporation of IRES into gene therapy vector represents one of the more promising strategies. In this article, two popular therapeutic genes, Mda-7/IL-24 and TRAIL, were linked via ECMV IRES to construct a bicistron. Oncolytic adenovirus ZD55 was used as a vector to carry the bicistron for the gene therapy of HCC. Western Blotting was performed to detect the translation products, and the imbalance of these translation products was remarkable. Our data on the virus progeny suggested that the long bicistron did not attenuate the replication ability of ZD55. The anitumor efficacy of the replicative adenovirus was further investigated in experimental HCC. Treatment with ZD55-IL-24-2A-TRAIL could induce significant cytotoxicity in cancer cells in vitro. And it had potent antitumor activity in vivo, leading to significant repression of HCC xenograft tumors in all treated mice.