Can Gene Therapy Overcome the Problem of Hypoxia in Radiotherapy?

Radioresistance/Gene delivery/HRE/GDEPT/Bioreductive drugs Studies have shown that reduced oxygen tension (hypoxia) in solid tumours adversely affects the outcome of radiotherapy. Despite being an independent prognostic marker of poor treatment outcome, hypoxia represents a physiological difference that can be utilised for selective cancer treatment. Since severe hypoxia (pO2< 0.3%; 2.5 mmHg) does not occur in normal tissue, it may be exploited for thera-peutic gain. Accurate targeting of oxygen-deprived cells within a tumour mass may be achieved using hypoxia-targeted gene therapy. For gene therapy three separate issues need to be considered: 1) delivery of a gene to the tumour, 2) regulation of gene expression and 3) therapeutic efficacy. Each of these aspects is outlined here, with a view to gene therapy of the hypoxic tumour environment. It is proposed that by combining hypoxia-selective gene delivery with hypoxia-specific gene expression and oxygen-sensitive prodrug activation, radioresistant hypoxic tumour tissues may be effectively targeted. HYPOXIA IN SOLID TUMOURS Multiple factors contribute to the resistance of solid malignancies to radiotherapy, includ-ing intrinsic genetic and extrinsic physiological determinants. Properties such as blood flow, tissue oxygenation, nutrient supply, pH distribution and bioenergetic status can markedly