Molecular Biology Reports

, Volume 39, Issue 1, pp 157–165

A self-contained enzyme activating prodrug cytotherapy for preclinical melanoma

Authors

  • Gwi-Moon Seo
    • Department of Anatomy and Physiology, College of Veterinary MedicineKansas State University
  • Raja Shekar Rachakatla
    • Department of Anatomy and Physiology, College of Veterinary MedicineKansas State University
  • Sivasai Balivada
    • Department of Anatomy and Physiology, College of Veterinary MedicineKansas State University
  • Marla Pyle
    • Department of Anatomy and Physiology, College of Veterinary MedicineKansas State University
  • Tej B. Shrestha
    • Department of Anatomy and Physiology, College of Veterinary MedicineKansas State University
  • Matthew T. Basel
    • Department of Anatomy and Physiology, College of Veterinary MedicineKansas State University
  • Carl Myers
    • Department of Diagnostic Medicine/Pathobiology, College of Veterinary MedicineKansas State University
  • Hongwang Wang
    • Department of ChemistryKansas State University
  • Masaaki Tamura
    • Department of Anatomy and Physiology, College of Veterinary MedicineKansas State University
  • Stefan H. Bossmann
    • Department of ChemistryKansas State University
    • Department of Anatomy and Physiology, College of Veterinary MedicineKansas State University
Article

DOI: 10.1007/s11033-011-0720-7

Cite this article as:
Seo, G., Rachakatla, R.S., Balivada, S. et al. Mol Biol Rep (2012) 39: 157. doi:10.1007/s11033-011-0720-7

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.

Keywords

B16-F10Mouse lung melanomaMouse monocytesTargeted cell deliverySuicide therapy

Supplementary material

11033_2011_720_MOESM1_ESM.pptx (3.2 mb)
Supplementary material 1 (PPTX 3302 kb)

Copyright information

© Springer Science+Business Media B.V. 2011