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

Israel Hodish, Reshef Tal, Aviv Shaish, Nira Varda-Bloom, Shoshana Greenberger, Ariela Rauchwerger, Eyal Breitbart, Livnat Bangio, Dikla Ben-Shushan, Raphael Pfeffer, Bela Feder, Ana Waitsman, Iris Barshack, Iris Goldberg, Shaly Mazaki-Tovi, Michael Peled, Dror Harats

Research output: Contribution to journalArticlepeer-review

Abstract

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 anti-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.

Original languageEnglish
Pages (from-to)435-443
Number of pages9
JournalCancer Biology and Therapy
Volume8
Issue number5
DOIs
StatePublished - 1 Mar 2009

Keywords

  • Adenovirus
  • Angiogenesis
  • Endothelium
  • Gene therapy
  • Promoter
  • Radiotherapy
  • Thymidine kinase

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