Mehrfach modifizierte, onkolytische Adenoviren in der präklinischen Testung an Ovarialkarzinomzellen

Abstract

Cancer gene therapy is a promising novel approach to treat cancers resistant to currently available modalities. Such treatment approaches are based on making use of the molecular differences between normal and tumor cells. Conditional replicating adenoviruses (CRAds) have proved particularly effective in initial preclinical and clinical studies. Requirements for construction of an effective CRAd are sufficient target cell specificity combined with efficient viral infection and replication. For this reason, we cloned triple-targeted oncolytic viruses with the following modifications: transcriptional targeting is under the control of the tumor-specific promoter cyclooxygenase-2 (cox2). Additional tumor-specific targeting is achieved by E1A transcomplementation, whereby specific deletions within the adenoviral E1A region restrict replication to tumor cells. In addition, the viruses are serotype chimeras. In this study, several viruses with different modifications were evaluated for their specificity and oncolytic potency for ovarian cancer cells. Our results suggest increased specificity and oncolytic efficacy for multiple-modified viruses compared to unmodified ones. Viruses under the control of the longer promoter cox2L were more specific than those under the control of the shorter fragment cox2M. Furthermore, triple-modified adenoviruses were significantly more oncolytic than single- or double-modified viruses. In vitro examinations in ovarian cancer cells and hepatocytes showed that triple-modified adenoviruses increased the therapeutic window by 10 000 - 100 000-fold compared to wildtype. Thus, triple-modified adenoviruses appear to be suitable for further clinical studies.