Can gene therapy overcome the problem of hypoxia in radiotherapy?

Studies have shown that reduced oxygen tension (hypoxia) in solid tumours a dversely affects the outcome of radiotherapy. Despite being an independent prognostic marker of poor treatment outcome, hypoxia represents a physiolog ical difference that can be utilised for selective cancer treatment. Since severe hypoxia (pO(2)<0.3%; 2.5 mmHg) does not occur in normal tissue, it m ay be exploited for therapeutic gain. Accurate targeting of oxygen-deprived cells within a tumour mass may be achieved using hypoxia-targeted gene the rapy. For gene therapy three separate issues need to be considered: 1) deli very of a gene to the tumour, 2) regulation of gene expression and 3) thera peutic efficacy. Each of these aspects is outlined here, with a view to gen e therapy of the hypoxic tumour environment. It is proposed that by combini ng hypoxia-selective gene delivery with hypoxia-specific gene expression an d oxygen-sensitive prodrug activation, radioresistant hypoxic tumour tissue s may be effectively targeted.