Differential toxicity of alpha-keto hydroxypyridine iron chelators and desferrioxamine to human haemopoietic precursors in vitro.

Compliance with iron chelation therapy improves life expectancy in transfusion-dependent haematological disorders. However, failure of compliance with parenteral desferrioxamine (DF) therapy and the expense incurred makes this drug unavailable for most patients in the developing world. We have been evaluating the orally active iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in both preclinical and clinical trials. Five patients have developed reversible agranulocytosis during treatment with this agent. We have now studied the effects of L1, other alpha-ketohydroxypyridines and DF on bone marrow myeloid progenitors using the CFU-GM system. The results show that L1 is less toxic than DF to normal bone marrow myeloid progenitors (ID50:130 mumol/l versus 7.9 mumol/l). The L1 ID50 is within the previously reported range of peak plasma values (80-450 mumol/l). When saturating concentrations of iron were added to the cultures, the mean toxicity of all the chelators was significantly decreased over the range of doses tested, e.g. L1 ID50, 567 mumol/l; DF ID50, > 1000 mumol/l. The toxicity of L1 in vitro was similar for marrows from 3 normal donors and for the recovery marrow from a patient with thalassaemia major who had experienced agranulocytosis. Further studies are required to elucidate the mechanisms of L1-induced agranulocytosis.