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Combination of a MDR1-targeted replicative adenovirus and chemotherapy for the therapy of pretreated ovarian cancer

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Abstract

Purpose

Targeted oncolytic adenoviruses capable of replication selectively in cancer cells are an appealing approach for the treatment of various cancer types refractory to conventional therapies. The aim of this study was to evaluate the effect of Ad5/3MDR1E1, a multidrug resistance gene 1 (MDR1)-targeted fiber-modified replication-competent adenovirus for the therapy of platinum-pretreated ovarian cancer in combination with cytostatic agents.

Methods

MDR1-specific tumor cell killing of Ad5/3MDR1E1 was systematically evaluated in chemotherapy naïve and pretreated ovarian cancer cells in vitro. Combinations of Ad5/3MDR1E1 and cytostatic agents were studied in vivo and in vitro. An in vivo hepatotoxicity model was used to evaluate liver toxicity.

Results

We demonstrate efficient oncolysis of Ad5/3MDR1E1 in chemotherapy-resistant ovarian cancer cells as well as therapeutic efficacy in an orthotopic mouse model. Further, combining Ad5/3MDR1E1 with paclitaxel resulted in greater therapeutic benefit than either agent alone.

Conclusion

These preclinical data suggest that a fiber-modified adenovirus vector under the control of the MDR1 promoter represents a promising treatment strategy for platinum-pretreated ovarian cancer as a single agent or in combination with conventional anticancer drugs.

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Conflict of interest

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Düsseldorf Medical Center, Moorenstrasse 5, 40225, Düsseldorf, Germany

    Daniel T. Rein, Anne Volkmer, Gerd Bauerschmitz, Ines M. Beyer, Wolfgang Janni, Markus C. Fleisch & Anne Kathrin Welter

  2. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA

    Ines M. Beyer

  3. Department of Obstetrics and Gynecology, Rhine-Westphalian Technical University, Aachen, Germany

    Dirk Bauerschlag & Martina Breidenbach

  4. Institute for Clinical Research and Development, Mainz, Germany

    Thomas Schöndorf

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  1. Daniel T. Rein
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  2. Anne Volkmer
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  3. Gerd Bauerschmitz
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  4. Ines M. Beyer
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  5. Wolfgang Janni
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Correspondence to Daniel T. Rein.

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Rein, D.T., Volkmer, A., Bauerschmitz, G. et al. Combination of a MDR1-targeted replicative adenovirus and chemotherapy for the therapy of pretreated ovarian cancer. J Cancer Res Clin Oncol 138, 603–610 (2012). https://doi.org/10.1007/s00432-011-1135-5

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  • DOI: https://doi.org/10.1007/s00432-011-1135-5

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