Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer

Cancer Gene Ther. 2006 Apr;13(4):357-66. doi: 10.1038/sj.cgt.7700908.

Abstract

Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system is a well-characterized tool for cancer gene therapy; however, it does not yet exhibit sufficient efficacy to cure patients of malignancies. We have reported that adenovirally delivered monocyte chemoattractant protein (MCP)-1 augmented the antitumor effects of the HSV-tk/GCV system in an athymic nude mouse model. The current study, which uses an immunocompetent mouse model of colon cancer, was designed to evaluate the antitumor effects of MCP-1 gene delivery in conjunction with this suicide gene therapy system. Subcutaneous tumor foci were directly transduced with both recombinant adenoviruses (rAds) expressing an HSV-tk gene and either of the MCP-1, CD80 and LacZ genes, followed by GCV administration. The growth of tumors was markedly suppressed by codelivery of HSV-tk and MCP-1 genes, which was exclusively associated with the recruitment of monocytes/macrophages, T helper 1 (Th1) cytokine gene expression and cytotoxic activity of the splenocytes. Furthermore, the antitumor effects were more efficient than that obtained by the combination of HSV-tk and CD80 genes. These results suggest an immunomodulatory effect of MCP-1 in the context of suicide gene therapy of colon cancer via orchestration of innate and acquired immune responses.

Publication types

  • Comparative Study

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antiviral Agents / therapeutic use*
  • B7-1 Antigen / biosynthesis
  • B7-1 Antigen / genetics
  • B7-1 Antigen / immunology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chemokine CCL2 / biosynthesis
  • Chemokine CCL2 / genetics*
  • Chemokine CCL2 / immunology
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Ganciclovir / therapeutic use*
  • Genetic Therapy*
  • Genetic Vectors
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Animal
  • Neoplasm Transplantation
  • Simplexvirus / metabolism
  • Thymidine Kinase / biosynthesis
  • Thymidine Kinase / genetics*

Substances

  • Antiviral Agents
  • B7-1 Antigen
  • Chemokine CCL2
  • Cytokines
  • Thymidine Kinase
  • Ganciclovir