Potent anti-tumor activity of telomerase-dependent and HSV-TK armed oncolytic adenovirus for non-small cell lung cancer in vitro and in vivo

J Exp Clin Cancer Res. 2010 May 20;29(1):52. doi: 10.1186/1756-9966-29-52.

Abstract

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer related mortality, any improvements in therapeutic strategies are urgently required. In this study we generated a novel 'suicide gene' armed oncolytic adenoviral vector and investigated its antitumor effect both in vitro and in vivo.

Methods: Since the up-regulated expression of human telomerase reverse transcriptase (hTERT) is a hallmark of alltypes of NSCLC, we chose hTERT promoter to transcriptionally control E1A gene expression to obtain adenoviral replication in NSCLC. In order to further enhance anti-tumor effect of this oncolytic adenoviral vector, we inserted a 'suicide gene' i.e. Herpes Simplex Virus Thymidine Kinase (HSV-TK) into oncolytic adenoviral vector to engineer a novel armed oncolytic adenoviral vector 'Ad.hTERT-E1A-TK'.

Results: Ad.hTERT-E1A-TK efficiently killed different types of tumor cells including two types of NSCLC cells in vitro, causing no damage to normal primary fibroblasts. Furthermore, Ad.hTERT-E1A-TK infection combined with administration of prodrug gancyclovir (GCV) resulted in more potent cytotoxicity on NSCLC cells, and synergistically suppressed human NSCLC tumor growth in nude mice.

Conclusion: The results from this study showed that Ad.hTERT-E1A-TK/GCV could be a potent but safe anti-tumor strategy for NSCLC biotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae Infections / genetics
  • Adenoviridae Infections / pathology
  • Adenoviridae Infections / therapy
  • Animals
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cell Line
  • Combined Modality Therapy
  • Ganciclovir / administration & dosage
  • Genes, Transgenic, Suicide
  • Genetic Therapy
  • Humans
  • In Vitro Techniques
  • Kidney / cytology
  • Kidney / metabolism
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oncolytic Virotherapy / methods*
  • Simplexvirus / genetics*
  • Telomerase / genetics*
  • Thymidine Kinase / genetics*

Substances

  • Thymidine Kinase
  • TERT protein, human
  • Telomerase
  • Ganciclovir