Systemic administration of radiation-potentiated anti-angiogenic gene therapy against primary and metastatic cancer based on transcriptionally controlled HSV-TK

Cancer Biol Ther. 2009 Mar;8(5):424-32. doi: 10.4161/cbt.8.5.7589. Epub 2009 Mar 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antiviral Agents / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Combined Modality Therapy
  • Endothelin-1 / genetics
  • Ganciclovir / pharmacology*
  • Gene Expression Regulation
  • Genetic Therapy / methods*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neoplasms, Experimental / blood supply
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / therapy
  • Promoter Regions, Genetic / genetics
  • Protein Precursors / genetics
  • Radiotherapy
  • Simplexvirus / enzymology
  • Survival Analysis
  • Thymidine Kinase / genetics
  • Thymidine Kinase / metabolism*
  • Tumor Burden / drug effects
  • Tumor Burden / radiation effects


  • Antiviral Agents
  • Endothelin-1
  • Protein Precursors
  • proendothelin 1
  • Thymidine Kinase
  • Ganciclovir