Hypoxia-activated anticancer drugs

Whilst hypoxia is increasingly recognised as a limiting factor in the successful treatment of solid tumours by conventional radiotherapy and chemotherapy, its unique occurrence in such tumours is also viewed as offering the possibility of selective chemotherapy. Prodrugs designed to be selectively activated in hypoxic tissue by oxygen-sensitive reductases have been a common design motif for some time, and include such chemical classes as quinones, nitro-aromatics, aliphatic and heteroaromatic N-oxides, and transition metal complexes. This review discusses the mechanistic aspects of the activation of such prodrugs and the key overall properties needed. Prominent among the latter properties are efficient extravascular diffusion of the prodrug to the tumour, and back-diffusion of the activated drug (effector) in the tumour. The appropriate design of clinical trials for these prodrugs is also important. Exciting new mechanisms for prodrug research include activation by therapeutic radiation and the use of hypoxia-selective gene therapy vectors, such as Clostridia.