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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-08-2382.
Submitted August 7, 2002
Accepted December 29, 2002
Effects of combined chelation treatment with pyridoxal isonicotinoyl hydrazone (PIH) analogs and deferoxamine in hypertransfused rats and in iron-loaded rat heart cells
Gabriela Link, Prem Ponka, Abraham M Konijn, William Breuer, Z I Cabantchik, and Chaim Hershko*
Department of Human Nutrition and Metabolism, Hebrew U Hadassah Medical Faculty, Jerusalem, Israel
Department of Biological Chemistry, Hebrew U of Jerusalem Institute of Life Sciences, Jerusalem, Israel
Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel
Department of Physiology, Lady Davis Institute for Medical Research, Montreal, PQ, Canada
* Corresponding author; email: hershko{at}szmc.org.il.
Although iron chelation therapy with deferoxamine (DFO) results in improved life expectancy of thalassemic patients, compliance with parenteral DFO treatment is unsatisfactory, underlining the need for alternative drugs and innovative ways of drug administration. We examined the chelating potential of pyridoxal isonicotinoyl hydrazone (PIH) analogs alone, or in combination with DFO, employing hypertansfused rats with labeled hepatocellular iron stores and cultured iron-loaded rat heart cells. Our in vivo studies employing two representative PIH analogs 108-o and 109-o, have shown that the PIH analogs given orally are 2.6 to 2.8 times more effective in mobilizing hepatocellular iron in rats, on a weight-per-weight basis, than parenteral DFO administered by i.p. injection. The combined effect of DFO and 108-o on hepatocellular iron excretion was additive and response at a dose range of 25 to 200 mg/kg was linear. In vitro studies in heart cells showed that DFO was more effective in heart cell iron mobilization than all PIH analogs studied. Response to joint chelation with DFO and PIH analogs was similar to an increase in the equivalent molar dose of DFO alone, rather than the sum of the separate effects of PIH analog and DFO. This finding is most likely the result of iron transfer from PIH analogs to DFO, a conclusion supported directly by iron-shuttle experiments employing fluorescent DFO. These findings provide a rationale for the combined, simultaneous use of iron chelating drugs, and may have useful practical implications for designing novel strategies of iron chelation therapy.
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