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Inhibition of the Multidrug-Resistant Phenotype by Targeting YB-1 with a Conditionally Oncolytic Adenovirus: Implications for Combinatorial Treatment Regimen with Chemotherapeutic Agents

¹ Institute of Experimental Oncology and ² Department of Urology, Technical University of Munich, Klinikum rechts der Isar; ³ Xvir Therapeutics GmbH, Munich, Germany and ⁴ Charité Campus Mitte, Institute of Pathology, Berlin, Germany

Requests for reprints: Klaus Mantwill, Institute of Experimental Oncology, Technical University of Munich, Klinikum rechts der Isar, Ismaninger Str. 22, 81675 Munich, Germany. Phone: 49-89-4140-4463; Fax: 49-89-4140-4476; E-mail: klaus.mantwill{at}web.de.

Bearing in mind the limited success of available treatment modalities for the therapy of multidrug-resistant tumor cells, alternative and complementary strategies need to be developed. It is known that the transcriptional activation of genes, such as MDR1 and MRP1, which play a major role in the development of a multidrug-resistant phenotype in tumor cells, involves the Y-box protein YB-1. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In addition, it has been reported previously that YB-1 is an important factor in adenoviral replication because it activates transcription from the adenoviral E2-late promoter. Here, we report that an oncolytic adenovirus, named Xvir03, expressing the viral proteins E1B55k and E4orf6, leads to nuclear translocation of YB-1 and in consequence to viral replication and cell lysis in vitro and in vivo. Moreover, we show that Xvir03 down-regulates the expression of MDR1 and MRP1, indicating that recruiting YB-1 to the adenoviral E2-late promoter for viral replication is responsible for this effect. Thus, nuclear translocation of YB-1 by Xvir03 leads to resensitization of tumor cells to cytotoxic drugs. These data reveal a link between chemotherapy and virotherapy based on the cellular transcription factor YB-1 and provide the basis for formulating a model for a novel combined therapy regimen named Mutually Synergistic Therapy. (Cancer Res 2006; 66(14): 7195-202)

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