Tumor-specific transcriptional targeting of suicide gene therapy

Gene Ther. 2002 Feb;9(3):168-75. doi: 10.1038/sj.gt.3301618.


Transcriptional targeting of gene expression has been plagued by the weakness of tissue-specific promoters. Thus, to increase promoter strength while maintaining tissue specificity, we constructed a recombinant adenovirus containing a binary promoter system with a tumor-specific promoter (CEA; carcinoembryonic antigen) driving a transcription transactivator, which then activates a minimal promoter to express a suicide gene (HSV-tk; herpes simplex virus thymidine kinase). This ADV/binary-tk induced equal or greater cell killing in a CEA-specific manner in vitro compared with the CEA-independent killing of a vector with a constitutive viral promoter driving HSV-tk (ADV/RSV-tk). To monitor adenovirus-mediated HSV-tk gene expression in vivo, we employed noninvasive nuclear imaging using a radioiodinated nucleoside analog ([((1)31)I]-FIAU) serving as a substrate for HSV-tk. [((1)31)I]-FIAU-derived radioactivity accumulated after intratumoral injection of ADV/binary-tk only in the area of CEA-positive tumors with significantly less spread to the adjacent liver tissue than after administration of the universally expressed ADV/RSV-tk. Both viruses exhibited similar antitumor efficacy upon injection of liver metastases. Importantly, in vivo dose escalation studies demonstrated significantly reduced toxicity after intravenous administration of ADV/binary-tk versus ADV/RSV-tk. In summary, the increased therapeutic index of this novel, amplified CEA-driven suicide gene therapy vector is a proof of principle for the powerful enhancement of a weak tissue-specific promoter for effective tumor restricted gene expression.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Breast Neoplasms / therapy*
  • Carcinoembryonic Antigen / genetics*
  • Gene Expression
  • Gene Targeting / methods*
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • HeLa Cells
  • Herpes Simplex Virus Protein Vmw65 / genetics
  • Humans
  • Injections, Intralesional
  • Liver Neoplasms / secondary
  • Liver Neoplasms / therapy
  • Mice
  • Mice, Inbred BALB C
  • Promoter Regions, Genetic
  • Retroviruses, Simian / enzymology
  • Simplexvirus / enzymology
  • Thymidine Kinase / genetics
  • Transcription, Genetic*
  • Tumor Cells, Cultured


  • Carcinoembryonic Antigen
  • Herpes Simplex Virus Protein Vmw65
  • Thymidine Kinase