The evolution of molecular biology has enabled the exploration of novel sophisticated gene-directed treating modalities for cancer. Suicide gene therapy - i.e. transfection of a so-called suicide gene that sensitizes target cells towards a prodrug - may offer an attractive approach to treat malignant tumors. For the development of effective clinical suicide gene therapy protocols, a non-invasive method to assay the extent, the kinetics and the spatial distribution of transgene expression is essential. This would allow investigators and physicians to assess the efficiency of experimental and therapeutic gene transfection protocols and would enable early prognosis of therapy outcome. Radionuclide imaging techniques like single photon emission computed tomography (SPECT) and positron emission tomography (PET), which can non-invasively visualize and quantify metabolic processes in vivo, are being evaluated for repetitive monitoring of transgene expression in living animals and humans. Transgene expression can be monitored directly by imaging the expression of the therapeutic gene itself, or indirectly using a reporter gene that is coupled to the therapeutic gene. Various radiopharmaceuticals have been developed and are now being evaluated for imaging of transgene expression. This review surveys the progress that has been made in the field of non-invasive nuclear imaging of transgene expression and focuses on the herpes simplex virus type 1 thymidine kinase (HSVtk) gene therapy approaches.

Suicide gene therapy is under investigation as a treatment for cancer. In this therapy, a suicide gene is introduced into tumor cells, enabling the conversion of a prodrug into a toxic metabolite that selectively kills the transfected tumor cells. In the most investigated strategy, the herpes simplex virus thymidine kinase (HSVtk) suicide gene is used in combination with the prodrug ganciclovir. To assess the efficiency and safety of gene therapy protocols, a noninvasive method to assay the magnitude, kinetics and spatial distribution of transgene expression is essential. Imaging methods for repetitive monitoring of HSVtk transgene expression in living animals and humans, using single photon emission computed tomography (SPECT) or positron emission tomography (PET), have been developed. For many therapeutic genes, however, no imaging method is available. In these cases, reporter genes can be applied. Expression of the therapeutic gene can be determined indirectly by imaging a reporter gene, like HSVtk, that is linked to the therapeutic gene. Reporter genes can also be applied to monitor the expression of endogenous genes and to track the fate of transplanted cells. This paper presents an updated review on the progress in the field of non-invasive nuclear imaging of HSVtk transgene expression in gene therapy.