MODELING OF MIXED LIGAND THERAPY FOR IRON OVERLOAD

King'S College London, London

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Abstract

DESCRIPTION (adapted from the application) Currently available iron chelation therapy is slow, inefficient and inconvenient. With the most widely evaluated drugs, deferoxamine and deferiprone, only 10% and 4% respectively of the drugs are excreted in the iron bound form when given to iron overloaded patients. Because of the finite available chelatable iron at any moment in time and the narrow therapeutic safety margin of both of these compounds, dose escalation results a further reduction in the chelation efficiency and an increased risk of chelator induced toxicity. In principle by combining a bidentate hydroxypyridinone with deferoxamine (DFO), increased chelation efficiency will be obtained by a process whereby low molecular weight bidentate ligands, which have rapid access to chelatable iron pools, shuttle iron onto the DFO which has slower kinetic access but greater stability of the ligand -metal complex. However, little is known about how combinations of these compounds interact with chelatable pools of iron and other metals. This is important because such mixed ligand combinations have the potential not only to enhance the efficiency, but also the toxicity of iron chelation therapy. We propose to examine how variation in the properties of bidentate hydroxypyridinone chelators affects the efficiency and toxicity of iron chelation. The models used to examine these interactions are established in the investigator's laboratories and have been previously shown to be predictive for the efficacy and toxicity of single ligand therapy. Bidentate hydroxypyridinones will be synthesised so as to examine the effects of pM, lipid solubility and molecular bulk on chelation efficiency and toxicity when combined with DFO at clinically achievable concentrations. Bidentate ligands will be screened in primate in vitro systems to exclude those inactivated by unfavorable metabolism. Iron mobilisation from hepatocytes and from rats will then be examined to test the efficiency of mixed ligand combinations. Potential toxicities will be evaluated by measuring inhibition rates of key non-heme iron containing enzymes (ribonucleotide reductase and lipoxygenase) as well as interaction with zinc containing enzymes (phospholipase C) and zinc finger containing transcription factors. Toxicity will be evaluated more directly by examining apoptotic effects on bone marrow progenitors and thymocytes and examining toxicity in target organs in repeat dose studies in mice. We aim to define the principles and potential candidates for optimal mixed ligand therapy for iron overload.