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Blood, 15 February 2001, Vol. 97, No. 4, pp. 1115-1122
RED CELLS
ICL670A: a new synthetic oral chelator: evaluation in
hypertransfused rats with selective radioiron probes of hepatocellular
and reticuloendothelial iron stores and in iron-loaded rat heart
cells in culture
Chaim Hershko,
Abraham M. Konijn,
Hans Peter Nick,
William Breuer,
Zvi Ioav Cabantchik, and
Gabriela Link
From the Department of Medicine, Shaare Zedek Medical
Center, Department of Human Nutrition and Metabolism, Hebrew University
Hadassah Medical School, Jerusalem, Israel; Novartis Pharma AG Basel,
Basel, Switzerland; and Department of Biological Chemistry, Institute
of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
ICL670A (formerly CGP 72 670) or
4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]- benzoic acid
is a tridentate iron-selective synthetic chelator of the
bis-hydroxyphenyl-triazole class of compounds. The present studies used
selective radioiron probes of hepatocellular and reticuloendothelial
(RE) iron stores in hypertransfused rats and iron-loaded heart cells to
define the source of iron chelated in vivo by ICL670A and its mode of
excretion, to examine its ability to remove iron directly from
iron-loaded myocardial cells, and to examine its ability to interact
with other chelators through a possible additive or synergistic effect. Results indicate that ICL670A given orally is 4 to 5 times more effective than parenteral deferoxamine (DFO) in promoting the excretion
of chelatable iron from hepatocellular iron stores. The pattern of iron
excretion produced by ICL670A is quite different from that of DFO and
all iron excretion is restricted to the bile regardless of whether it
is derived from RE or hepatocellular iron stores. Studies in heart cell
cultures have shown a favorable interaction between DFO and ICL670A
manifested in improved chelating efficiency of ICL670A, which is most
probably explained by an exchange of chelated iron between ICL670A and
DFO. These unique chelating properties of ICL670A may have practical
implications for current efforts to design better therapeutic
strategies for the management of transfusional iron overload.
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