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A self-contained enzyme activating prodrug cytotherapy for preclinical melanoma

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Abstract

Gene-directed enzyme prodrug therapy (GDEPT) has been investigated as a means of cancer treatment without affecting normal tissues. This system is based on the delivery of a suicide gene, a gene encoding an enzyme which is able to convert its substrate from non-toxic prodrug to cytotoxin. In this experiment, we have developed a targeted suicide gene therapeutic system that is completely contained within tumor-tropic cells and have tested this system for melanoma therapy in a preclinical model. First, we established double stable RAW264.7 monocyte/macrophage-like cells (Mo/Ma) containing a Tet-On® Advanced system for intracellular carboxylesterase (InCE) expression. Second, we loaded a prodrug into the delivery cells, double stable Mo/Ma. Third, we activated the enzyme system to convert the prodrug, irinotecan, to the cytotoxin, SN-38. Our double stable Mo/Ma homed to the lung melanomas after 1 day and successfully delivered the prodrug-activating enzyme/prodrug package to the tumors. We observed that our system significantly reduced tumor weights and numbers as targeted tumor therapy after activation of the InCE. Therefore, we propose that this system may be a useful targeted melanoma therapy system for pulmonary metastatic tumors with minimal side effects, particularly if it is combined with other treatments.

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Acknowledgements

This work was supported by NIH 1R21CA135599, the Terry C. Johnson Center for Basic Cancer Research at Kansas State University, Kansas State University Targeted Excellence, Kansas State Legislative Appropriation, and the Kansas Agricultural Experiment Station.

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Authors and Affiliations

  1. Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, Manhattan, KS, 66506, USA

    Gwi-Moon Seo, Raja Shekar Rachakatla, Sivasai Balivada, Marla Pyle, Tej B. Shrestha, Matthew T. Basel, Masaaki Tamura & Deryl L. Troyer

  2. Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, 66506, USA

    Carl Myers

  3. Department of Chemistry, Kansas State University, Manhattan, KS, 66506, USA

    Hongwang Wang & Stefan H. Bossmann

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  1. Gwi-Moon Seo
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Correspondence to Deryl L. Troyer.

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Seo, GM., Rachakatla, R.S., Balivada, S. et al. A self-contained enzyme activating prodrug cytotherapy for preclinical melanoma. Mol Biol Rep 39, 157–165 (2012). https://doi.org/10.1007/s11033-011-0720-7

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