Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice

Gene Ther. 2003 Jan;10(1):51-8. doi: 10.1038/sj.gt.3301837.

Abstract

The application of adeno-associated virus (AAV) vectors to cancers is limited by their low transduction efficiency. Previously, we reported that gamma-ray enhanced the second-strand synthesis, leading to the improvement of the transgene expression, and cytocidal effect of the herpes simplex virus type-1 thymidine kinase (HSVtk) and ganciclovir (GCV) system. In this study, we extended this in vitro findings to in vivo. First, the laryngeal cancer cell line (HEp-2) and HeLa were treated with AAVtk/GCV, the number of surviving cells was reduced as the concentration of GCV increased. Furthermore, the 4 Gy irradiation enhanced the killing effects of AAVtk/GCV by four-fold on HeLa cells and 15-fold on HEp-2 cells. Following the in vitro experiments, we evaluated the transgene expression and the antitumor activity of the AAV vectors in combination with gamma-ray in nude mice inoculated with HEp-2 subcutaneously. The LacZ expression was observed in the xenografted tumors and significantly increased by gamma-ray. The AAVtk/GCV system suppressed the tumors growth, and gamma-ray augmented the antitumor activity by five-fold. These findings suggest that the combination of AAVtk/GCV system with radiotherapy is significantly effective in the treatment of cancers and may lead to reduction of the potential toxicity of both AAVtk/GCV and gamma-ray.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / therapeutic use
  • Combined Modality Therapy
  • Dependovirus / genetics
  • Dose-Response Relationship, Drug
  • Ganciclovir / administration & dosage*
  • Ganciclovir / therapeutic use
  • Gene Expression / radiation effects
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage*
  • Genetic Vectors / genetics
  • HeLa Cells
  • Head and Neck Neoplasms / radiotherapy*
  • Head and Neck Neoplasms / therapy*
  • Humans
  • Mice
  • Mice, Nude
  • Radiotherapy Dosage
  • Simplexvirus / enzymology
  • Thymidine Kinase / genetics
  • Transduction, Genetic / methods*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • beta-Galactosidase / genetics

Substances

  • Antiviral Agents
  • Thymidine Kinase
  • beta-Galactosidase
  • Ganciclovir