Rohmer Stanimira, Quirin Christina, Hesse Andrea, Sandmann Stefanie, Bayer Wibke, Herold-Mende Christel, Haviv Yosef S, Wildner Oliver, Enk Alexander H, Nettelbeck Dirk M
Helmholtz-University Group Oncolytic Adenoviruses, German Cancer Research Center and Heidelberg University Hospital, Department of Dermatology, Heidelberg, Germany.
Virology. 2009 Dec 20;395(2):243-54. doi: 10.1016/j.virol.2009.09.030. Epub 2009 Oct 25.
Major strategies to increase oncolytic adenovirus efficacy, as required for clinical applications, are enhancing oncolysis by acceleration of virus release/spread and "arming" by insertion of therapeutic genes. We investigated whether these strategies can be effectively combined as it has been speculated that the arming approach rather benefits from delayed cell lysis and extended time for protein synthesis. We report that deleting adenoviral E1B19K results in an apoptosis-dependent early viral release and thus enhanced oncolysis in several tumor cells, but inhibits virus replication in others. In the former case, apoptosis induction and early cell lysis did not interfere with late transgene expression. Thus, transgene expression was dramatically increased over time due to better virus spread. In A549 cells, transgene expression by the E1B19K(-) virus at 5 days post-infection was higher than for the E1B19K(+) virus at 10 days. These properties may be of critical importance in patients, where time for virus spread is limited.
为满足临床应用需求，提高溶瘤腺病毒疗效的主要策略包括通过加速病毒释放/扩散来增强溶瘤作用，以及通过插入治疗性基因进行“武装”。我们研究了这些策略是否可以有效结合，因为有人推测，“武装”方法更受益于延迟细胞裂解和延长蛋白质合成时间。我们报告称，删除腺病毒E1B19K会导致依赖凋亡的早期病毒释放，从而增强在几种肿瘤细胞中的溶瘤作用，但会抑制其他细胞中的病毒复制。在前一种情况下，凋亡诱导和早期细胞裂解并不干扰晚期转基因表达。因此，由于病毒传播更好，随着时间的推移转基因表达显著增加。在A549细胞中，感染后5天E1B19K（-）病毒的转基因表达高于E1B19K（+）病毒在10天时的表达。这些特性在病毒传播时间有限的患者中可能至关重要。
