Generation of an adenovirus-parvovirus chimera with enhanced oncolytic potential

• Verfasst von: El-Andaloussi, Nazim [VerfasserIn]
• Verfasst von: Bonifati, Serena [VerfasserIn]
• Verfasst von: Kaufmann, Johanna K. [VerfasserIn]
• Verfasst von: Nettelbeck, Dirk M. [VerfasserIn]
• Verfasst von: Marchini, Antonio [VerfasserIn]
• Titel: Generation of an adenovirus-parvovirus chimera with enhanced oncolytic potential
• Verf.angabe: Nazim El-Andaloussi, Serena Bonifati, Johanna K. Kaufmann, Laurent Mailly, Laurent Daeffler, François Deryckère, Dirk M. Nettelbeck, Jean Rommelaere, and Antonio Marchini
• E-Jahr: 2012
• Jahr: 11 July 2012
• Umfang: 14 S.
• Teil: volume:86
• Teil: year:2012
• Teil: number:19
• Teil: pages:10418-10431
• Teil: extent:14
• Fussnoten: Published ahead of print 11 July 2012 ; Gesehen am 27.06.2019
• Titel Quelle: Enthalten in: Journal of virology
• Ort Quelle: Baltimore, Md. : Soc., 1967
• Jahr Quelle: 2012
• Band/Heft Quelle: 86(2012), 19, Seite 10418-10431
• ISSN Quelle: 1098-5514
• DOI: doi:10.1128/JVI.00848-12
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 166806345X

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.