title: A self-contained enzyme activating prodrug cytotherapy for preclinical melanoma.
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.
authors.affiliation: Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, Manhattan, KS, 66506, USA.
authors.forename: Gwi-Moon
authors.initials: GM
authors.lastname: Seo
authors.forename: Raja Shekar
authors.initials: RS
authors.lastname: Rachakatla
authors.forename: Sivasai
authors.initials: S
authors.lastname: Balivada
authors.forename: Marla
authors.initials: M
authors.lastname: Pyle
authors.forename: Tej B
authors.initials: TB
authors.lastname: Shrestha
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Basel
authors.forename: Carl
authors.initials: C
authors.lastname: Myers
authors.forename: Hongwang
authors.initials: H
authors.lastname: Wang
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tamura
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Bossmann
authors.forename: Deryl L
authors.initials: DL
authors.lastname: Troyer
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism; D043182:Carboxylesterase / Q000378:metabolism; D017690:Cell Transplantation / Q000379:methods*; D017931:DNA Primers / Q000235:genetics; D004337:Drug Carriers / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D005260:Female; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008280:Magnetics; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055017:Monocyte-Macrophage Precursor Cells / Q000378:metabolism*; D053758:Nanoparticles; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D004337:Drug Carriers; D011355:Prodrugs; D000077146:Irinotecan; D043182:Carboxylesterase; D002166:Camptothecin