Systemic administration of radiation-potentiated anti-angiogenic gene therapy against primary and metastatic cancer based on transcriptionally controlled HSV-TK
| Autor: | Israel Hodish, Raphael Pfeffer, Iris Barshack, Shaly Mazaki-Tovi, Dikla Ben-Shushan, Iris Goldberg, Dror Harats, Eyal Breitbart, A. Shaish, Michael Peled, Nira Varda-Bloom, Ana Waitsman, Shoshana Greenberger, Ariela Rauchwerger, Livnat Bangio, Reshef Tal, Bela Feder |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cancer Research Angiogenesis Genetic enhancement Biology Gene delivery Antiviral Agents Thymidine Kinase Adenoviridae Cell Line Mice Cell Line Tumor medicine Animals Humans Simplexvirus Neoplasm Metastasis Protein Precursors Promoter Regions Genetic Ganciclovir Cells Cultured Pharmacology Regulation of gene expression Mice Inbred BALB C Endothelin-1 Neovascularization Pathologic Radiotherapy Lewis lung carcinoma Cancer Genetic Therapy Neoplasms Experimental medicine.disease Combined Modality Therapy Survival Analysis Tumor Burden Mice Inbred C57BL Cell killing Oncology Gene Expression Regulation Systemic administration Cancer research Molecular Medicine |
| Zdroj: | Cancer biologytherapy. 8(5) |
| ISSN: | 1555-8576 |
| Popis: | Transcription-targeted gene delivery directed against angiogenic endothelial cells is a new approach against advanced cancer. Moreover, the herpes simplex virus-thymidine kinase (HSV-TK) gene coupled with low dose radiotherapy is an efficient and externally controlled cytotoxic system. We have previously demonstrated enhanced endothelial-specific cell expression and killing using the modified murine pre-proendothelin-1 promoter (PPE1-3x) to direct adenoviral expression of a pro-apoptotic gene. The purpose of this study was to create an externally potentiated systemic antiangiogenic gene delivery system based on an adenoviral vector expressing HSV-TK under the regulation of PPE1-3X promoter combined with radiotherapy for eradicating metastatic cancer. Ad-PPE1-3x-TK induced endothelial-specific cell killing in-vitro upon introduction of the prodrug ganciclovir (GCV). BALB/c mice bearing a primary CT-26 colon carcinoma tumor showed tumor growth suppression and diminished tumor angiogenesis when the vector was administered intravenously, activated with GCV and potentiated with a single sub-therapeutic and non-toxic radiation dose. Moreover, intravenous administration of the vector, activated with GCV and potentiated with chest aimed radiation, to C57BL/6 mice bearing Lewis lung carcinoma metastases resulted in prolongation of mice survival. PPE1-3x-regulated HSV-TK expression was detected only in lung metastases in contrast to CMV-regulated expression. This novel system may benefit patients with metastatic disease. |
| Databáze: | OpenAIRE |
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