Alternative treatment paradigm for thalassemia using iron chelators
Received 27 June 2007; received in revised form 16 January 2008; accepted 23 January 2008. published online 06 May 2008.
Objective
β-thalassemia major, or Cooley's anemia, is a red blood cell disorder requiring lifelong blood transfusions for survival. Erythrocytes accumulate toxic iron at their membranes, triggering an oxidative cascade that leads to their premature destruction in high numbers. We hypothesized that removing this proximate iron compartment as a primary treatment, using standard and alternative orally active iron chelators, could prevent hastened red cell removal and, clinically, perhaps alleviate the need for transfusion.
Materials and Methods
Iron chelators of the pyridoxal isonicotinoyl hydrazone family (pyridoxal isonicotinoyl hydrazone and its analog pyridoxal ortho-chlorobenzoyl hydrazone) were evaluated in addition to the present mainstay, desferrioxamine and deferiprone, in vitro and in vivo.
Results
Treatment of human β-thalassemic erythrocytes with chelators resulted in significant depletion of membrane-associated iron and reduction of oxidative stress, as evaluated by methemoglobin levels. When administered to β-thalassemic mice, iron chelators mobilized erythrocyte membrane iron, reduced cellular oxidation, and prolonged erythrocyte half-life. The treated thalassemic mice also showed improved hematological abnormalities. Remarkably, a beneficial effect as early as the erythroid precursor stage was manifested by normalized proportions of mature vs immature reticulocytes. All four compounds were also found to mitigate iron accumulation in target organs, a critical determinant for patient survival. In this respect, pyridoxal ortho-chlorobenzoyl hydrazone displayed higher activity relative to other chelators tested, further diminishing iron in liver and spleen by up to approximately fivefold and twofold, respectively.
Conclusion
Our study demonstrates the ability of iron chelators to improve several of the fundamental pathological disturbances of thalassemia, and reveals their potential for clinical use in diminishing requirement for transfusion when administered early in disease development.
aDepartments of Physiology, Medicine, and Experimental Medicine, McGill University, Montreal, Quebec, Canada
bLady Davis Institute for Medical Research, Sir Mortimer B. Davis, Jewish General Hospital, Montreal, Quebec, Canada
cDepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
dDepartment of Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Quebec, Canada
eDepartment of Medicine, Université de Montreal, Quebec, Canada
Offprint requests to: Prem Ponka, M.D., Ph.D., Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
∗ Drs. Trudel and Ponka contributed equally to this work as co-senior authors.
ABSTRACT