Fu X, Tao L, Zhang X
Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Gene Ther. 2007 Aug;14(16):1218-25. doi: 10.1038/sj.gt.3302971. Epub 2007 May 31.
The N-terminus of the ICP10 gene of type 2 herpes simplex virus (HSV-2) encodes a serine/threonine protein kinase (PK) domain that facilitates HSV-2 replication by activating the Ras/MEK/MAPK mitogenic pathway and suppressing apoptosis. We recently demonstrated that deletion of this oncogenic PK domain converts it to a potent oncolytic agent. This mutant, which we have designated FusOn-H2, preferentially replicates in and thus lyses tumor cells in which the Ras signaling pathway is constitutively activated. Here we show that FusOn-H2 exerts strong ability in inducing apoptosis in different lines of human tumor cells and in esophageal tumors growing in mice. The apoptotic effect produced by FusOn-H2 was not restricted to infected cells but extended to uninfected bystander cells, thereby increasing the lethality of the virus. These results add a novel killing mechanism to those previously assigned to FusOn-H2, rendering it an attractive candidate for clinical trials.
2型单纯疱疹病毒（HSV-2）的ICP10基因的N端编码一个丝氨酸/苏氨酸蛋白激酶（PK）结构域，该结构域通过激活Ras/MEK/MAPK促有丝分裂途径和抑制细胞凋亡来促进HSV-2复制。我们最近证明，删除这个致癌的PK结构域可将其转化为一种有效的溶瘤剂。我们将这种突变体命名为FusOn-H2，它优先在Ras信号通路持续激活的肿瘤细胞中复制并裂解这些细胞。在此我们表明，FusOn-H2在诱导不同系的人肿瘤细胞以及小鼠体内生长的食管肿瘤细胞凋亡方面具有很强的能力。FusOn-H2产生的凋亡效应不仅限于感染细胞，还扩展到未感染的旁观者细胞，从而增加了病毒的致死性。这些结果为先前赋予FusOn-H2的作用机制增添了一种新的杀伤机制，使其成为一个有吸引力的临床试验候选物。
