Bioreductive and gene therapy approaches to hypoxic diseases

Hypoxia is a feature that exists in most, if not all, solid tumours and hypoxia has been shown to exist in a variety of other diseases. Bioreductive prodrugs have been developed to preferentially target the hypoxic cells in tumours. They are prodrugs, that are reductively activated (catalysed by reductive enzymes) to afford their active (toxic) species. More recently, bioreductive delivery agents that "release" a therapeutic entity preferentially under hypoxic conditions have also been developed to target hypoxia, not only in tumours, but also in a host of other diseases. This new technology platform is described in this review. In addition, we discuss the potential of utilising hypoxia to deliver selective gene therapy based upon the transcription factor HIF-1 and the use of unique genetic sequences termed HRE's (hypoxia responsive elements) that specifically control gene expression under hypoxic conditions. Finally, we describe how these drugs and gene-based therapeutic approaches can be combined to potentially deliver a highly selective form of therapy for cancer and other diseases where hypoxia plays a major pathophysiological role.