Radiotherapy (RT) is a well established modality for treating many forms of cancer. However, despite many improvements in treatment planning and delivery, the total radiation dose is often too low for tumor cure, because of the risk of normal tissue damage. Gene therapy provides a new adjunctive strategy to enhance the effectiveness of RT, offering the potential for preferential killing of cancer cells and sparing of normal tissues. This specificity can be achieved at several levels including restricted vector delivery, transcriptional targeting and specificity of the transgene product. This review will focus on those gene therapy strategies that are currently being evaluated in combination with RT, including the use of radiation sensitive promoters to control the timing and location of gene expression specifically within tumors. Therapeutic transgenes chosen for their radiosensitizing properties will also be reviewed, these include:

• gene correction therapy, in which normal copies of genes responsible for radiation-induced apoptosis are transfected to compensate for the deletions or mutated variants in tumor cells (p53 is the most widely studied example).
• enzymes that synergize the radiation effect, by generation of a toxic species from endogenous precursors (e.g., inducible nitric oxide synthase) or by activation of non toxic prodrugs to toxic species (e.g., herpes simplex virus thymidine kinase/ganciclovir) within the target tissue.
• conditionally replicating oncolytic adenoviruses that synergize the radiation effect.
• membrane transport proteins (e.g., sodium iodide symporter) to facilitate uptake of cytotoxic radionuclides.

The evidence indicates that many of these approaches are successful for augmenting radiation induced tumor cell killing with clinical trials currently underway.

Keywords: Gene therapy; Radiotherapy; Cancer; GDEPT; and Transcriptional targeting.