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Anti-cancer effect of neural stem cells transfected with carboxylesterase and sTRAIL genes in animal model of metastatic brain tumor from lung cancer : 폐암 뇌전이 동물모델에서 카르복실에스터라제/sTRAIL 유전자재조합 신경줄기세포의 항암효과

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의과대학 의학과
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서울대학교 대학원
metastatic brain tumorcell therapyneural stem cellcarboxylesteraseCPT-11 (irinotecan)tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2014. 8. 왕규창.
Introduction: Metastatic brain tumor is the most common type of malignancy in the central nervous system, which is one of the leading causes of death in patients with lung cancer. The purpose of this study is to evaluate the efficacy of the novel treatment using neural stem cells (NSCs) encoding genes for rabbit carboxylesterase (rCE) and secretable form of tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) as a vector to deliver therapeutic materials into the brain in animal model of metastatic brain tumor with lung cancer and whether it augment the efficacy of the chemotherapeutic agent.
Methods: The therapeutic cells were immortalized human fetal NSCs (HB1.F3s) transduced with rCE and/or sTRAIL genes to express rCE (F3.CE), sTRAIL (F3.sTRAIL), or both (F3.CE.sTRAIL). The cytotoxic effects of the therapeutic cells on A549 and H460 human lung cancer cells were evaluated in vitro with a co-culture assay in the presence of CPT-11. The expression levels of DR4 and DR5,cell surface receptors for sTRAIL, and DcR1 and DcR2, decoy receptors for sTRAIL, were measured by ELISA in A549 and H460 cells after CPT-11 treatment in vitro. Immune-deficient mice were inoculated with lung cancer cells, intracardially injected with therapeutic cells, and then treated with CPT-11. Histology and survival were analyzed to determine the anti-cancer efficacy of each therapeutic cell type by measuring tumor volumes in brain sections.
Results: . Human NSCs encoding rCE (F3.CE and F3.CE.sTRAIL) significantly inhibited the growth of A549 and H460 cells in the presence of CPT-11 in vitro. F3.sTRAIL cells also showed a mild cytotoxic effect on lung cancer cells that was enhanced by CPT-11 treatment. All therapeutic cells exerted cytotoxic effects on tumor cells in the co-culture assay, with more apoptosis induced as the proportion of therapeutic cells to tumor cells increased. In the resting state, over 70% of H460 cells expressed DR4, but A549 and NSCs showed low (<30%) rates of DR4 expression. For DcR2 expression, however, less than 5% of H460 cells expressed surface DcR2, whereas 40% and 71% of A549 and NSCs expressed DcR2. After CPT-11 addition, DR4 expression in A549 cells and DcR1 in NSCs increased up to 70% and 90%, respectively. Tumor volume in immune-deficient mice was significantly smaller when the mice were transplanted with F3.CE.sTRAIL cells and subsequently treated with CPT-11. Mice treated with F3.CE plus CPT-11 and with F3.sTRAIL alone showed a smaller tumor size than control mice or mice treated with F3.CE or CPT-11 alone. Survival was also significantly prolonged following treatment with F3.sTRAIL, F3.CE plus CPT-11, and F3.CE.sTRAIL plus CPT-11.
Conclusions: NSCs transduced with rCE and sTRAIL genes showed significant anti-cancer effects on brain metastatic lung cancer in vivo (in the brain) and in vitro and the effect may be synergistic when rCE/CPT-11 and sTRAIL are combined. This stem cell-based study using two therapeutic genes with different biological effects could be translatable to clinical application.
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