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Differential toxicity of α‐keto hydroxypyridine iron chelators and desferrioxamine to human haemopoietic precursors in vitro
Author(s) -
Cunningham J. M.,
AlRefaie F. N.,
Hunter A. E.,
Sheppard L. N.,
Hoffbrand A.V.
Publication year - 1994
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.1994.tb01310.x
Subject(s) - toxicity , bone marrow , in vitro , medicine , myeloid , myelodysplastic syndromes , pharmacology , chelation , chelation therapy , gastroenterology , chemistry , immunology , biochemistry , thalassemia , organic chemistry
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 (L 1 ) in both preclinical and clinical trials. Five patients have developed reversible agranulocytosis during treatment with this agent. We have now studied the effects of L 1 , other α‐ketohydroxypyridines and DF on bone marrow myeloid progenitors using the CFU‐GM system. The results show that L 1 is less toxic than DF to normal bone marrow myeloid progenitors (ID 50 :130 μmol/l versus 7.9 μmol/l). The L 1 ID 50 is within the previously reported range of peak plasma values (80–450 μmol/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. L 1 ID 50 , 567 μmol/l; DF ID 50 , > 1000 μmol/l. The toxicity of L 1 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 L 1 ‐induced agranulocytosis.