Abstract
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.
Highlights
Pancreatic cancer is one of the most lethal human cancers and continues to be a major health problem
When co-culture of BxPC3 pancreatic cancer cells and F3.CE cells were exposed to 1 μM CPT-11 for 48 hr, less than 20% of BxPC3 cancer cells survived, indicating that F3.CE cells processed prodrug CPT-11 efficiently into cytotoxic SN-38 (Figure 2)
We observed that human pancreatic cancer cell line BxPC3 treated with F3.neural stem cells (NSCs) expressing rabbit carboxylesterase (F3.CE) and application of prodrug CPT-11 showed marked growth inhibition and increased apoptosis in vitro
Summary
Pancreatic cancer is one of the most lethal human cancers and continues to be a major health problem. Conventional therapeutic approaches, such as surgery, radiation, chemotherapy, or combinations of these modalities, have little impact on the course of pancreatic cancer [1]. The aggressive nature and disappointing treatment results of advanced pancreatic cancer requires novel approach. The recent discovery of the inherent tumor-tropic properties of neural stem cells (NSCs) [5] has led to the development of enzyme-prodrug gene therapy approach for malignant tumors in the brain including gliomas and medulloblastomas [6,7,8,9]. We have previously generated a clonally derived immortalized human NSC line via a retroviral vector encoded with v-myc gene, and the HB1.F3 (F3) human NSCs were utilized in stem cell-based therapy in animal models of human neurological disorders [10,11,12,13]
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