Radiation-activated prodrugs as hypoxia-selective cytotoxins: model studies with nitroarylmethyl quaternary salts

Bioreductive drugs are designed to be activated by enzymatic reduction in h ypoxic regions of tumours, but activation of these drugs is not always full y suppressed by oxygen in normal tissues. A further limitation is that bior eductive drug activation depends on suitable reductases being expressed in the hypoxic zone. This essay proposes an alternative approach in which prod rugs are reduced, and thereby activated, in hypoxic regions by ionizing rad iation rather than by enzymes. This strategy is theoretically attractive, b ut design requirements for such radiation-activated cytotoxins are challeng ing. In particular the reducing capacity of radiation at clinically relevan t doses is small, which necessitates the development of prodrugs capable of releasing very potent cytotoxins efficiently in hypoxic tissue. It is show n that nitroarylmethyl quaternary (NMQ) salts possess many of the features required of a radiation-activated prodrug. In some heterocyclic NMQ compoun ds the cytotoxicity of the latent cytotoxic amine effector is suppressed by >100-fold in the prodrug form, and the effector is released rapidly by fra gmentation following reduction by a single electron. Appreciable cytotoxic activation of NMQ prodrugs can be achieved by irradiation at clinically rel evant doses in anoxic plasma. Some of the further drug design challenges re quired to develop a clinical agent based on this approach are outlined.