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Evaluation of systemic targeting of RET oncogene-based MTC with tumor-selective peptide-tagged Ad vectors in clinical mouse models

Gene Therapy volume 18, pages 418–423 (2011)Cite this article

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Abstract

Significant advantage of targeted antitumoral treatment consists in the possibility to restrict maximum therapeutic efficacy to the malignant cell population by reducing toxicity in healthy tissues. Using different clinical models for aggressive medullary thyroid carcinoma (MTC), we have recently identified peptide ligands that bind highly selective to tumor cells. By linking the most convincing SRESPHP peptide to an adenoviral (Ad) vector expressing the MTC-related oncogene inhibitor RETΔTK, gene transfer was specifically directed to neoplastic tissue after systemic virus administration. We show that peptide-mediated delivery of RETΔTK significantly enhanced apoptosis, resulting in a strong inhibition of orthotopic and xenograft tumor growth. Conversely, tumors treated with controls expanded their initial size without notable cell death. According to the therapeutic effect, strong virus accumulation was found exclusively in thyroid carcinomas. Strikingly, application of native tropism depleted viral vector linked to tumor-selective peptide was accompanied by a substantial reduction of Ad binding to the liver. Of note, single systemic injection of a low dose (10e8 pfu/mouse) of MTC-specific Ad.RETΔTK induced regression of multiple tumors at different sites in all treated animals. In sum, our results open up the possibility for an efficient cancer cell-specific therapy of primary MTC, their migrating populations and potentially metastases.

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Acknowledgements

We thank Anja Stoll for excellent technical assistance, Kathrin Sievert-Küchenmeister for expert support in animal surgery and Thomas Brüning for immunohistochemistry. This work was supported by DFG Grants PU 188/5-1/5-2, PU 188/5-3 and the FORUN program (Grant 889017) of Rostock University Medical Faculty.

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Authors and Affiliations

  1. Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center (BMFZ), University of Rostock, Rostock, Germany

    A Schmidt, K Fürst, N Sommer & B M Pützer

  2. Institute of Experimental Surgery, University of Rostock, Rostock, Germany

    C Eipel

  3. Neurodegeneration Research Lab, Clinic of Neurology, University of Rostock, Rostock, Germany

    J Pahnke

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  1. A Schmidt
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  2. C Eipel
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  3. K Fürst
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  4. N Sommer
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  5. J Pahnke
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  6. B M Pützer
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Correspondence to B M Pützer.

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The authors declare no conflict of interest.

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Schmidt, A., Eipel, C., Fürst, K. et al. Evaluation of systemic targeting of RET oncogene-based MTC with tumor-selective peptide-tagged Ad vectors in clinical mouse models. Gene Ther 18, 418–423 (2011). https://doi.org/10.1038/gt.2010.165

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  • DOI: https://doi.org/10.1038/gt.2010.165

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