HYPOXIA-ACTIVATED PRODRUGS AS ANTITUMOR AGENTS - STRATEGIES FOR MAXIMIZING TUMOR-CELL KILLING

1. Hypoxia arises in solid tumour because of inefficient blood supply, While hypoxic cells are resistant to radiotherapy and probably to man y chemotherapeutic drugs they can, in principle, be turned to advantag e through the development of hypoxia-activated cytotoxic drugs (biored uctive drugs). 2. Three general approaches to exploiting tumour hypoxi a are discussed. The first relies on fluctuating blood now in tumours and the consequent cycling of cells through the hypoxic compartment. T he second incorporates a prodrug approach in which drug activation giv es rise to cytotoxic metabolites which diffuse out of hypoxic zones, T he third utilizes selective inhibitors of tumour blood now to induce a dditional hypoxia and thus enhance bioreductive drug activation. 3. Th e latter two approaches are illustrated by recent studies with the din itrobenzamide nitrogen mustard class of bioreductive drugs and their c ombination with the tumour blood flow inhibitor 5,6-dimethylxanthenone -4-acetic acid.