The development of hypoxia activated DNA repair inhibitors

The human body’s vast network of blood vessels provides oxygen and nutrients throughout the body, however hypoxic cells (cells with lower than normal physiological oxygen levels) are found in human tumours. Hypoxic cells are resistant to ionizing radiation and therefore are an impediment to the effectiveness of radiotherapy. Ionizing radiation kills cells by causing DNA damage; the principal lethal lesion formed is the DNA double strand break (DSB). This work concerns the development of a hypoxia activated DNA repair inhibitor prodrug. The specific target of the prodrug is a critical DSB repair enzyme of the non-homologous end joining pathway (NHEJ), called DNA dependent protein kinase (DNA-PK). This work concerns the development of pharmaceutical screening tools for agents that act as radiosensitizers of oxic and hypoxic cells. These tools were then used to demonstrate that DNA-PK deficiency can sensitize hypoxic mammalian cells to the effects of ionizing radiation, and that 2-nitroimidazole derivatives of the DNA-PK inhibitor IC86621 cellbased screening results from hypoxia activated DNA repair inhibitors that display hypoxia selective radiosensitization of CB.17 murine embryonic fibroblast and HeLa human cervical carcinoma cells.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat