| Autor: |
Margarita Gutova, Leanne Goldstein, Marianne Metz, Anahit Hovsepyan, Lyudmila G. Tsurkan, Revathiswari Tirughana, Lusine Tsaturyan, Alexander J. Annala, Timothy W. Synold, Zesheng Wan, Robert Seeger, Clarke Anderson, Rex A. Moats, Philip M. Potter, Karen S. Aboody |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Oncolytics, Vol 4, Iss C, Pp 67-76 (2017) |
| Druh dokumentu: |
article |
| ISSN: |
2372-7705 |
| DOI: |
10.1016/j.omto.2016.11.004 |
| Popis: |
Despite improved survival for children with newly diagnosed neuroblastoma (NB), recurrent disease is a significant problem, with treatment options limited by anti-tumor efficacy, patient drug tolerance, and cumulative toxicity. We previously demonstrated that neural stem cells (NSCs) expressing a modified rabbit carboxylesterase (rCE) can distribute to metastatic NB tumor foci in multiple organs in mice and convert the prodrug irinotecan (CPT-11) to the 1,000-fold more toxic topoisomerase-1 inhibitor SN-38, resulting in significant therapeutic efficacy. We sought to extend these studies by using a clinically relevant NSC line expressing a modified human CE (hCE1m6-NSCs) to establish proof of concept and identify an intravenous dose and treatment schedule that gave maximal efficacy. Human-derived NB cell lines were significantly more sensitive to treatment with hCE1m6-NSCs and irinotecan as compared with drug alone. This was supported by pharmacokinetic studies in subcutaneous NB mouse models demonstrating tumor-specific conversion of irinotecan to SN-38. Furthermore, NB-bearing mice that received repeat treatment with intravenous hCE1m6-NSCs and irinotecan showed significantly lower tumor burden (1.4-fold, p = 0.0093) and increased long-term survival compared with mice treated with drug alone. These studies support the continued development of NSC-mediated gene therapy for improved clinical outcome in NB patients. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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