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Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA

Cancer Gene Therapy volume 11, pages 539–546 (2004)Cite this article

Abstract

Fanconi anemia (FA) is a rare genetic disorder characterized by bone-marrow failure and cellular hypersensitivity to crosslinking agents, including cisplatin. Here, we studied the use of the FA pathway as a possible target for cancer gene therapy with the aim to sensitize tumor cells for cisplatin by interfering with the FA pathway. As proof-of-principle, FA and non-FA lymphoblast-derived tumors were grown subcutaneously in scid mice and treated with two different concentrations of cisplatin. As predicted, the antitumor response was considerably improved in FA tumors. An adenoviral vector encoding a dominant-negative form of FANCA, FANCA600DN, was generated that interfered with endogenous FANCA–FANCG interaction resulting in the disruption of the FA pathway as illustrated by disturbed FANCD2 monoubiquitination. A panel of cell lines, including non-small-cell lung cancer cells, could be sensitized approximately two- to three-fold for cisplatin after Ad.CMV.FANCA600DN infection that may increase upon enhanced infection efficiency. In conclusion, targeting the FA pathway may provide a novel strategy for the sensitization of solid tumors for cisplatin and, in addition, provides a tool for examining the role of the FA pathway in determining chemoresistance in different tumor types.

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Acknowledgements

This work was supported by The Netherlands Organization for Scientific Research (NWO), Grant VUA 9-02-21-221. We thank Hans Joenje for providing the VU and EUFA FA lymphoblast cell lines, Bonnie Molenaar for her valuable assistance in performing the in vivo animal experiments and Patrick Bier for affinity purification of the FA antibodies.

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Authors and Affiliations

  1. Department of Medical Oncology, Division of Gene Therapy, VU University Medical Center, Amsterdam, The Netherlands

    Miriam Ferrer, D C Jeroen Mastenbroek, Winald R Gerritsen, Giuseppe Giaccone & Frank AE Kruyt

  2. Department of Clinical Genetics and Human Genetics, VU University Medical Center, Amsterdam, The Netherlands

    Johan P de Winter

  3. Gene Therapy Center, University of Alabama, Birmingham, Alabama, USA

    David T Curiel

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  1. Miriam Ferrer
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  2. Johan P de Winter
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  3. D C Jeroen Mastenbroek
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  4. David T Curiel
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  5. Winald R Gerritsen
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  6. Giuseppe Giaccone
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  7. Frank AE Kruyt
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Correspondence to Frank AE Kruyt.

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Ferrer, M., de Winter, J., Jeroen Mastenbroek, D. et al. Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA. Cancer Gene Ther 11, 539–546 (2004). https://doi.org/10.1038/sj.cgt.7700734

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