Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn 'On' Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model
| Autor: | Daniel Zamler, Maria G. Castro, Pedro R. Lowenstein, Philip Ng, Nicholas Raja, Henry D. Appelman, Elizabeth Yi, Marta Dzaman, Donna Palmer, Nathan VanderVeen |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Ganciclovir Male Transgene Genetic Vectors Gene Expression Pharmacology Biology medicine.disease_cause Applied Microbiology and Biotechnology Thymidine Kinase Biomarkers Pharmacological Adenoviridae 03 medical and health sciences Glioma Cell Line Tumor Genetics medicine Animals Humans Genetics (clinical) Research Articles Doxycycline Kinase Membrane Proteins Genetic Therapy Prodrug medicine.disease Rats 030104 developmental biology Thymidine kinase Molecular Medicine Glioblastoma medicine.drug |
| Zdroj: | Human gene therapy methods. 27(3) |
| ISSN: | 1946-6544 |
| Popis: | Glioblastoma multiforme (GBM) is the most commonly occurring primary brain cancer in adults, in whom its highly infiltrative cells prevent total surgical resection, often leading to tumor recurrence and patient death. Our group has discovered a gene therapy approach for GBM that utilizes high-capacity “gutless” adenoviral vectors encoding regulatable therapeutic transgenes. The herpes simplex type 1-thymidine kinase (TK) actively kills dividing tumor cells in the brain when in the presence of the prodrug, ganciclovir (GCV), whereas the FMS-like tyrosine kinase 3 ligand (Flt3L) is an immune-stimulatory molecule under tight regulation by a tetracycline-inducible “Tet-On” activation system that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we evaluated the safety and efficacy of Food and Drug Administration (FDA)–approved doses of the tetracycline doxycycline (DOX) allometrically scaled for rats. DOX initiates the expression of Flt3L, which has been shown to recruit dendritic cells to the brain tumor microenvironment—an integral first step in the development of antitumor immunity. The data revealed a highly safe profile surrounding these human-equivalent doses of DOX under an identical therapeutic window as proposed in the clinical trial. This was confirmed through a neuropathological analysis, liver and kidney histopathology, detection of neutralizing antibodies, and systemic toxicities in the blood. Interestingly, we observed a significant survival advantage in rats with GBM receiving the 300 mg/day equivalent dosage of DOX versus the 200 mg/day equivalent. Additionally, rats rejected “recurrent” brain tumor threats implanted 90 days after their primary brain tumors. We also show that DOX detection within the plasma can be an indicator of optimal dosing of DOX to attain therapeutic levels. This work has significant clinical relevance for an ongoing phase I clinical trial in humans with primary GBM and for other therapeutic approaches using Tet-On transactivation system in humans. |
| Databáze: | OpenAIRE |
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