The occurrence of hypoxic cells in solid
tumors, and their resistance to
radiotherapy and many chemotherapeutic drugs, has engendered an interest in non-toxic
prodrugs that can be activated selectively under hypoxic conditions. Despite this, no such compounds are yet registered for clinical use, due to the difficulty of their design and of measuring the extent of
hypoxia clinically, and the failure of early examples. A new appreciation of the critical importance of the extravascular diffusion of the parent
prodrug from the blood vessels to the remote hypoxic cells, and the back-diffusion of the activated
cytotoxin from the hypoxic cells to surrounding
tumor cells, is now guiding drug design in this area. New principles for the selective activation of
prodrugs have also been reported, including using the reducing species generated in cells by
radiotherapy itself, and using non-pathogenic anaerobic bacteria as a
hypoxia-dependent vector for the delivery of
prodrug-activating
enzymes in a suicide gene therapy context.