Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells. Academic Article uri icon

Overview

abstract

  • The hypoxic microenvironment, an important feature of human solid tumors but absent in normal tissue, may provide an opportunity for cancer-specific gene therapy. The purpose of the present study was to investigate whether hypoxia-driven triple suicide gene TK/CD/UPRT expression enhances cytotoxicity to ganciclovir (GCV) and 5-fluorocytosine (5-FC), and sensitizes human colorectal cancer to radiation in vitro and in vivo. Stable transfectant of human colorectal HCT8 cells was established which expressed hypoxia-inducible vectors (HRE-TK/eGFP and HRE-CD/UPRT/mDsRed). Hypoxia-induced expression/function of TK, CD and UPRT was verified by western blot analysis, flow cytometry, fluorescent microscopy and cytotoxicity assay of GCV and 5-FC. Significant radiosensitization effects were detected after 5-FC and GCV treatments under hypoxic conditions. In the tumor xenografts, the distribution of TK/eGFP and CD/UPRT/mDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC and GCV in mice in combination with local irradiation resulted in tumor regression, as compared with prodrug or radiation treatments alone. Our data suggest that the hypoxia-inducible TK/GCV+CDUPRT/5-FC triple suicide gene therapy may have the ability to specifically target hypoxic cancer cells and significantly improve the tumor control in combination with radiotherapy.

publication date

  • June 6, 2014

Research

keywords

  • Antineoplastic Agents
  • Colorectal Neoplasms
  • Genes, Transgenic, Suicide
  • Genetic Therapy
  • Radiation-Sensitizing Agents

Identity

PubMed Central ID

  • PMC4091884

Scopus Document Identifier

  • 84903216444

Digital Object Identifier (DOI)

  • 10.3892/or.2014.3238

PubMed ID

  • 24912473

Additional Document Info

volume

  • 32

issue

  • 2