Ahmed A, Jevremovic D, Suzuki K, Kottke T, Thompson J, Emery S, Harrington K, Bateman A, Vile R
Molecular Medicine Program, Mayo Clinic, Rochester, MN 55902, USA.
Gene Ther. 2003 Sep;10(19):1663-71. doi: 10.1038/sj.gt.3302064.
We describe here a novel strategy to enhance the in vivo efficacy of replicating adenovirus therapy, using coinjection of plasmid DNA encoding a fusogenic viral glycoprotein. The combination of fusogenic membrane glycoprotein (FMG)-induced tumor cell fusion and infection with replicating adenovirus effectively treats even large established tumors at doses of plasmid DNA and virus that alone are ineffective. Adenoviral infection appears to increase the transduction of the tumor cells to a modest degree thereby boosting the FMG-mediated component of the therapy. Simultaneously, syncytial formation enhances the therapeutic effects of viral infection by increasing spread of adenoviral particles through the tumor cell population and by increasing titer of virus released from the tumor cells. This effect is due probably to release of intracellular viral particles upon tumor cell death and also to increased levels of E1A protein within syncytia, whose increased metabolic rate is associated with enhanced levels of protein expression. Cotransduction of tumor cells with replicating adenovirus and FMG-expressing vectors could either be combined within single replicating vectors or could be used in strategies using separate administration of two components, both at lower doses than required for either therapy alone.
我们在此描述一种新策略，即通过共注射编码融合性病毒糖蛋白的质粒DNA来增强复制型腺病毒疗法的体内疗效。融合性膜糖蛋白（FMG）诱导的肿瘤细胞融合与复制型腺病毒感染相结合，即使在单独使用无效的质粒DNA和病毒剂量下，也能有效治疗甚至大型的已形成肿瘤。腺病毒感染似乎在一定程度上增加了肿瘤细胞的转导，从而增强了该疗法中FMG介导的部分。同时，多核体形成通过增加腺病毒颗粒在肿瘤细胞群体中的传播以及增加从肿瘤细胞释放的病毒滴度，增强了病毒感染的治疗效果。这种效应可能是由于肿瘤细胞死亡时细胞内病毒颗粒的释放，也可能是由于多核体内E1A蛋白水平的增加，其代谢率的提高与蛋白质表达水平的增强相关。用复制型腺病毒和表达FMG的载体对肿瘤细胞进行共转导，可以在单个复制载体中进行组合，也可以用于分别给予两种成分的策略中，两种成分的剂量均低于单独使用任何一种疗法所需的剂量。
