Tracing transgene expression in cancer gene therapy: a requirement for rational progress in the field

This review summarizes the status of gene therapy in medicine and the role of molecular imaging in its development. In gene therapy, genetic material is introduced into cells in order to generate a specific biological effect. Natural (viruses) or artificial molecular constructs, named gene therapy vectors, are used to achieve efficient cell transduction. This new form of therapy can be used for treating a broad variety of conditions including hereditary diseases, infections, degenerative disorders and cancer. Monitoring transgene expression using noninvasive imaging techniques is a necessary complement for the development of clinical gene therapy. Recent developments in magnetic resonance imaging afford the possibility of detecting gene transfer in vivo, but the most promising results have been obtained with positron emission tomography (PET). PET allows imaging gene therapy products by administration of a labeled substrate when the transgene codes for an enzyme or by administration of a labeled ligand when the transgene codes for a receptor. In the latter strategy, a membrane molecule (somatostatin or dopamine receptors) is used to detect the selective trapping of its radiolabeled ligand in the transduced cells. One of the approaches for the genetic treatment of cancer consists in transferring the "suicide genes" into tumor cells, the most common being the thymidine kinase (tk) of herpes viruses. Different nucleoside analogs can be labeled for its use as PET reporter probes in order to visualize tk expression. The results of pre-clinical studies are extremely encouraging. Reliable methods for the in vivo tracing of transgene expression in humans have to be developed in order for the field of gene therapy to mature. PET has emerged as a powerful tool to assist in achieving this goal.