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Gene-directed enzyme prodrug therapy for localized chemotherapeutics in allograft and xenograft tumor models

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Abstract

Most chemotherapy regimens rely on systemic administration of drugs leading to a wide array of toxicities. Using viral-vector-mediated gene modification of muscle tissues, we have developed a method for gene-directed enzyme prodrug therapy that allows for localized drug administration. An inactive prodrug of geldanamycin was activated locally for inhibition of tumor growth without systemic toxicities. A recombinant adeno-associated virus (rAAV) was used to deliver β-galactosidase (LacZ) to the treatment group and green fluorescent protein to the control group. After 1 week, both groups received adenocarcinoma cells in the same location as the previous rAAV injection. The geldanamycin prodrug was administered 1 h later via intraperitoneal injection. Tumor growth was significantly suppressed in animals whose muscles were gene modified to express β-galactosidase compared with the control. Serum assay to access hepatotoxicity resulted in no significant differences between the animals treated with the inactive or activated form of geldanamycin, indicating minimal damage to non-target organs. Using gene-directed enzyme prodrug therapy, in combination with novel recombinant AAV vectors, we have developed a method for localized activation of chemotherapeutic agents that limits the toxicities seen with traditional systemic administration of these potent drugs.

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Acknowledgements

We would like to acknowledge Peng George Wang, PhD, of the Ohio State University Department of Chemistry, for his efforts constructing the geldanamycin prodrug (Compound 25). The project described was supported by Pilot Project No. 11876 Grant UL1TR001070 from the National Center For Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Advancing Translational Sciences or the National Institutes of Health. This project was supported by the National Center for Research Resources, the National Center for Advancing Translational Sciences and the Office of the Director, National Institutes of Health, through UCSF-CTSI Grant Number KL2 (K12) RR024130. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. This study supported through the Institutional Research Grant Number IRG-67-003-47 from the American Cancer Society, administered through the Comprehensive Cancer Center at The Ohio State University.

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Authors and Affiliations

  1. The University of Toledo College of Medicine, Toledo, OH, USA

    K H Carruthers

  2. The Ohio State University Department of Plastic Surgery, Columbus, OH, USA

    G Metzger & E Kocak

  3. The Ohio State University Department of Molecular Virology, Immunology and Medical Genetics, Columbus, OH, USA

    M J During & C Wang

  4. The University of Auckland Department of Molecular Medicine and Pathology, Auckland, New Zealand

    A Muravlev

  5. Midwest Breast and Aesthetic Surgery, Dublin, OH, USA

    E Kocak

Authors
  1. K H Carruthers
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  2. G Metzger
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  3. M J During
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  4. A Muravlev
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  5. C Wang
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  6. E Kocak
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Correspondence to E Kocak.

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Competing interests

The authors KHC, GM, MJD, AM, CW and EK have no commercial associations or financial disclosures that might pose or create a conflict of interest with information presented in the attached manuscript.

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Carruthers, K., Metzger, G., During, M. et al. Gene-directed enzyme prodrug therapy for localized chemotherapeutics in allograft and xenograft tumor models. Cancer Gene Ther 21, 434–440 (2014). https://doi.org/10.1038/cgt.2014.47

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  • DOI: https://doi.org/10.1038/cgt.2014.47

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