Project 171879

Hypoxic cells occur in human tumours and represent a population of cells resistant to ionizing radiation. Clinical studies in several tumour sites indicate that the effectiveness of radiotherapy is inversely related to the hypoxia measured in human tumours. Hypoxic cells therefore represents a valid target and their eradication would improve the response and cure rate of radiotherapy and therefore could have huge significance for the management of cancer. The proposed research adopts a previously untried strategy whereby the repair of radiation-induced DNA damage is inhibited selectively in hypoxic cells thereby reducing their resistance to radiotherapy. This strategy will be accomplished by linking inhibitors of DNA repair with hypoxia activating moieties based on established 'trigger' chemistry. The drug will be inactive in oxygenated cells, but in hypoxic cells the drug will release an active inhibitor of DNA repair. Since only cells with DNA damage are affected only hypoxic cells within the radiation field will be sensitized. Cells in other parts of the body will be unaffected so the drug should have a favourable safety profile.