Cytotoxic Mechanisms of Iron Chelators with Therapeutic Potential: Identification of cytotoxic mechanisms of iron chelators with potential for the treatment of cancer and iron overload

For many years iron chelators have been used for the treatment of iron overload disease and cancer. Nonetheless, the development of novel synthetic chelators with improved bioavaliability and reduced cytotoxicity remains an area of much interest. This thesis is an examination of some mechanisms through which iron binding agents cause toxicity. Two novel classes of iron chelator were compared to clinically relevant chelators with a range of cytotoxic profiles. A variety of assays were employed to categorise these agents in terms of their capacity to withdraw iron from cells, to generate oxygen radicals and to damage to DNA. In correlating these properties with in vitro effects on proliferation it emerges that toxicity of iron chelators arises from cellular iron deprivation, the induction of oxidative stress and biomolecular localisation of oxygen radicals. In identifying functional structural elements and iron binding motifs this work indicates biological consequences to be considered in the design of iron binding chemotherapeutic agents.