The design of drugs that target tumour hypoxia

The occurrence of hypoxia in solid tumours is increasingly recognized as a limiting factor in the success of both radiotherapy and chemotherapy treatment, but at the same time offers a tumour-specific phenomenon for the activation of prodrugs. However, the design of clinically useful prodrugs that can be selectively activated in hypoxic cells has proved elusive. Specific reasons (activation by oxygen-insensitive two-electron reductases) have been proposed for the failure of quinone-based prodrugs, but a more general contributing factor may be inappropriate clinical trial design, and the failure to understand the critical importance of drug properties, such as efficient extravascular diffusion of the prodrug and back-diffusion of the activated drug in the tumour. Activation of prodrugs by therapeutic radiation and the use of hypoxia-selective gene therapy vectors, such as Clostridia, are exciting new mechanisms for prodrug research to explore, but are in much earlier stages of evaluation.