Radiogenetic Therapy Using Radiation-Responsive Gene Promoters

The aim of cancer gene therapy is to selectively kill malignant cells at the tumour site, by exploiting traits specific to cancer cells and/or solid tumours. Strategies that take advantage of biological features common to different tumour types are particularly promising, since they have wide clinical applicability. Much attention has focused on genetic methods that complement radiotherapy, the principal treatment modality, or that exploit hypoxia the most ubiquitous characteristic of most solid cancers. The goal of this review is to highlight two promising gene therapy methods developed specifically to target the tumour volume that can be readily used in combination with radiotherapy. The first approach uses radiation-responsive gene promoters to control the selective expression of a suicide gene to irradiated tissue only, leading to targeted cell killing in the presence of a prodrug. The second method utilizes oxygen-dependent promoters to produce selective therapeutic gene expression and prodrug activation in hypoxic cells, which are refractive to conventional radiotherapy. Further refining of tumour targeting can be achieved by combining radiation and hypoxia responsive elements in chimeric promoters activated by either and dual stimuli. The in vitro and in vivo studies described in this review suggest that the combination of gene therapy and radiotherapy protocols has potential for use in cancer care, particularly in cases currently refractory to treatment as a result of inherent or hypoxia-mediated radioresistance.

Keywords: Radiation, gene therapy, hypoxia, CArG elements, HRE, GDEPT