Iron chelators: biological, pharmacological and toxicological aspects; application in iron overload and in immune-deficiency diseases.
Iron is an essential element in all living organisms. The element, however, is potentially toxic to the same cells that need iron for its many biological functions. The toxic effects of iron mainly stem from its catalytic function in generation of oxygen free radicals. The toxicity of iron is evident in diseases associated with iron overload (haemochromatosis). These conditions are associated with multiple organ damage, mainly of the liver, the heart, the joints and organs of the endocrine system. Iron overload prevails in patients with genetic haemochromatosis and secondary haemochromatosis as a result of haemolytic anaemia, especially if regular blood transfusions are needed. Iron-induced cell damage has been associated with non-transferrin bound plasma iron and an intracellular pool of the metal which is referred to as the chelatable or labile iron pool (LIP). This form has been identified as the immediate target for iron chelators, of which only desferrioxamine (DFO) has been approved for clinical use. The need for new families of iron chelators with distinct properties for cell targeting and for oral therapy of iron overloaded individuals has been underscored, as has been the need for new assays for monitoring drug performance, both in vitro and in vivo. This project aims at applying novel agents and novel methodologies which were developed in the laboratories of the four co-operating partners for assessing the efficacy of novel iron chelators (ICs) in various cell models and animal systems. Newly developed hydroxypyridinones (HPOs) will be screened by systematically assessing their capacity for scavenging iron from erythroid and rat liver cells and exerting a cyto-protective effect on hepatocellular iron-induced toxicity. Selected agents will also be assessed in terms of their capacity to induce biliary iron release from normal and iron overloaded animals. The same agents will be investigated for their effects on intracellular signalling processes and regulation of cytokine production in important target cells for iron chelators: Monocytes and monocyte-derived macrophages. Special emphasis will be given to the influence of iron chelators on, oxygen species regulated, expression of cytokines (especially interleukin-10) which play an important role in the pathogenesis of human immunodeficiency virus (HIV) disease. The general aim is to obtain essential information regarding the pharmacological profiles, and their beneficial or toxic effects on target cells, of agents with therapeutic potential as oral iron chelators, both in iron overload diseases as in oxygen radical-mediated pathology in non-iron overload conditions.
Funding SchemeCSC - Cost-sharing contracts
SW3 6LX London