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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-08-2382.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 4172-4179
RED CELLS
Effects of combined chelation treatment with pyridoxal
isonicotinoyl hydrazone analogs and deferoxamine in hypertransfused
rats and in iron-loaded rat heart cells
Gabriela Link,
Prem Ponka,
Abraham M. Konijn,
William Breuer,
Z. Ioav Cabantchik, and
Chaim Hershko
From the Department of Human Nutrition and Metabolism,
Hebrew University Hadassah Medical School, Jerusalem; Department of
Biological Chemistry, Institute of Life Sciences, Jerusalem; Department
of Medicine, Shaare Zedek Medical Center, Hebrew University of
Jerusalem, Israel; and Lady Davis Institute for Medical
Research, Montreal, Quebec, Canada.
Although iron chelation therapy with deferoxamine (DFO) results in
improved life expectancy of patients with thalassemia, 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, using hypertansfused
rats with labeled hepatocellular iron stores and cultured iron-loaded
rat heart cells. Our in vivo studies using 2 representative PIH
analogs, 108-o and 109-o, have shown that 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
intraperitoneally. 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 the PIH analog
and DFO. This finding was most likely the result of iron transfer from
PIH analogs to DFO, a conclusion supported directly by iron-shuttle
experiments using 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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