Tumor-specific gene therapy for pancreatic cancer using human neural stem cells encoding carboxylesterase
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Sung S. Choi1,*, Kichul Yoon 1,2,3,*, Seon-A Choi4, Seung-Bin Yoon4, Seung U. Kim5, Hong J. Lee1
1Biomedical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea
2Seoul Adventist Hospital, Seoul, Korea
3Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
4Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
5Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, BC, Canada
*These authors have contributed equally to this work
Seung U. Kim, email: [email protected]
Hong J. Lee, email: [email protected]
Keywords: CPT-11, carboxyl esterase (CE), gene therapy, human neural stem cell, pancreatic cancer
Received: April 08, 2016 Accepted: September 13, 2016 Published: September 21, 2016
Advanced pancreatic cancer is one of the most lethal malignant human diseases lacking effective treatment. Its extremely low survival rate necessitates development of novel therapeutic approach. Human neural stem cells (NSCs) are known to have tumor-tropic effect. We genetically engineered them to express rabbit carboxyl esterase (F3.CE), which activates prodrug CPT-11(irinotecan) into potent metabolite SN-38. We found significant inhibition of the growth of BxPC3 human pancreatic cancer cell line in vitro by F3.CE in presence of CPT-11. Apoptosis was also markedly increased in BxPC3 cells treated with F3.CE and CPT-11. The ligand VEGF and receptor VEGF-1(Flt1) were identified to be the relevant tumor-tropic chemoattractant. We confirmed in vivo that in mice injected with BxPC3 on their skin, there was significant reduction of tumor size in those treated with both F3.CE and BxPC3 adjacent to the cancer mass. Administration of F3.CE in conjunction with CPT-11 could be a new possibility as an effective treatment regimen for patients suffering from advanced pancreatic cancer.
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