Generation of an adenovirus-parvovirus chimera with enhanced oncolytic potential |
| |
Authors: | Nazim El-Andaloussi Serena Bonifati Johanna K Kaufmann Laurent Mailly Laurent Daeffler François Deryckère Dirk M Nettelbeck Jean Rommelaere Antonio Marchini |
| |
Institution: | Tumour Virology Division F010, German Cancer Research Center (DKFZ), Heidelberg, Germany. |
| |
Abstract: | In this study, our goal was to generate a chimeric adenovirus-parvovirus (Ad-PV) vector that combines the high-titer and efficient gene transfer of adenovirus with the anticancer potential of rodent parvovirus. To this end, the entire oncolytic PV genome was inserted into a replication-defective E1- and E3-deleted Ad5 vector genome. As we found that parvoviral NS expression inhibited Ad-PV chimera production, we engineered the parvoviral P4 early promoter, which governs NS expression, by inserting into its sequence tetracycline operator elements. As a result of these modifications, P4-driven expression was blocked in the packaging T-REx-293 cells, which constitutively express the tetracycline repressor, allowing high-yield chimera production. The chimera effectively delivered the PV genome into cancer cells, from which fully infectious replication-competent parvovirus particles were generated. Remarkably, the Ad-PV chimera exerted stronger cytotoxic activities against various cancer cell lines, compared with the PV and Ad parental viruses, while being still innocuous to a panel of tested healthy primary human cells. This Ad-PV chimera represents a novel versatile anticancer agent which can be subjected to further genetic manipulations in order to reinforce its enhanced oncolytic capacity through arming with transgenes or retargeting into tumor cells. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|