Results of Long Term Iron Chelation Treatment with Deferoxamine

Davis, Bernard A.; Porter, John B.

doi:10.1007/978-1-4615-0593-8_6

Cited by 33 publications

(24 citation statements)

References 155 publications

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“…To further prove that the growth was due to the heme iron in hemoglobin and not due to free inorganic iron, we repeated the experiment using deferoxamine (DFO). DFO is a strong chelator which can extract iron from proteins such as Tf but cannot extract iron from heme (10). Addition of DFO to TT18 further suppressed growth of H. pylori.…”

Section: Resultsmentioning

confidence: 99%

Unique Host Iron Utilization Mechanisms of Helicobacter pylori Revealed with Iron-Deficient Chemically Defined Media

et al. 2010

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Helicobacter pylori chronically infects the gastric mucosa, where it can be found free in mucus, attached to cells, and intracellularly. H. pylori requires iron for growth, but the sources of iron used in vivo are unclear. In previous studies, the inability to culture H. pylori without serum made it difficult to determine which host iron sources might be used by H. pylori. Using iron-deficient, chemically defined medium, we determined that H. pylori can bind and extract iron from hemoglobin, transferrin, and lactoferrin. H. pylori can use both bovine and human versions of both lactoferrin and transferrin, contrary to previous reports. Unlike other pathogens, H. pylori preferentially binds the iron-free forms of transferrin and lactoferrin, which limits its ability to extract iron from normal serum, which is not iron saturated. This novel strategy may have evolved to permit limited growth in host tissue during persistent colonization while excessive injury or iron depletion is prevented.

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Section: Resultsmentioning

confidence: 99%

Unique Host Iron Utilization Mechanisms of Helicobacter pylori Revealed with Iron-Deficient Chemically Defined Media

et al. 2010

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“…Siderotic cardiac disease is the complication responsible for 71% of the mortality in thalassemia, [1][2][3][4][5][6][7] largely preventable by intensive chelation, [8][9][10] like continuous infusion with deferrioxamine (DFO). 9 This and the reversal of cardiac arrhythmia achieved following DFO treatment led to the concept of depletion of toxic labile plasma iron (LPI) as the primary chelation target.…”

Section: Introductionmentioning

confidence: 99%

Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences

Glickstein

Link

et al. 2006

Blood

174

169

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Labile iron in hemosiderotic plasma and tissue are sources of iron toxicity. We compared the iron chelators deferoxamine, deferiprone, and deferasirox as scavengers of labile iron in plasma and cardiomyocytes at therapeutic concentrations. This comprised chelation of labile plasma iron (LPI) in samples from thalassemia patients; extraction of total cellular iron; accessing labile iron accumulated in organelles and preventing formation of reactive-oxidant species; and restoring impaired cardiac contractility. Neonatal rat cardiomyocytes were used for monitoring chelator extraction of LCI (labile cell iron) as 59 Fe; assessing in situ cell iron chelation by epifluorescence microscope imaging using novel fluorescent sensors for iron and reactive oxygen species (ROS) selectively targeted to organelles, and monitoring contractility by timelapse microscopy. At plasma concentrations attained therapeutically, all 3 chelators eliminated LPI but the orally active chelators rapidly gained access to the LCI pools of cardiomyocytes, bound labile iron, attenuated ROS formation, extracted accumulated iron, and restored contractility impaired by iron overload. The effect of deferoxamine at therapeutically relevant concentrations was primarily by elimination of LPI. The rapid accessibility of the oral chelators deferasirox and deferiprone to intracellular labile iron compartments renders them potentially efficacious for protection from and possibly reversal of cardiac damage induced by iron overload. (Blood. 2006;108: 3195-3203)

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“…1,[4][5][6] Outstanding results have been achieved with deferoxamine (DFO), which is administered via parenteral routes. [5][6][7][8][9][10] However, despite intensive chelation treatment, siderotic cardiac disease has been the complication responsible for 71% of thalassemic mortality, while infection accounts for only 12% (hepatic [6%], endocrine [3%], or malignancies [3%]). [7][8][9][10][11][12] A serious factor in treatment outcome has been compliance with the rigorous requirements of daily subcutaneous DFO infusions; therefore, patients who are noncompliant with continuous DFO treatment might die prematurely of cardiac complications.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7][8][9][10] However, despite intensive chelation treatment, siderotic cardiac disease has been the complication responsible for 71% of thalassemic mortality, while infection accounts for only 12% (hepatic [6%], endocrine [3%], or malignancies [3%]). [7][8][9][10][11][12] A serious factor in treatment outcome has been compliance with the rigorous requirements of daily subcutaneous DFO infusions; therefore, patients who are noncompliant with continuous DFO treatment might die prematurely of cardiac complications. The issue of noncompliance has stimulated the design of alternative, orally effective chelators that would be more convenient for use and thus improve compliance as well as protect hepatic and extrahepatic organs from the deleterious effects of iron overload.…”

mentioning

confidence: 99%

Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells

Glickstein

Shvartsman

et al. 2005

Blood

225

203

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The primary targets of iron chelators used for treating transfusional iron overload are prevention of iron ingress into tissues and its intracellular scavenging. The present study was aimed at elucidating the capacity of clinically important iron chelators such as deferiprone (DFP) , IntroductionCell damage associated with iron overload has been attributed to the emergence of levels of cell labile iron pools (LIPs) that promote production of reactive oxygen species (ROSs) exceeding cellular defense capacities. 1,2 In thalassemia major, there is an outpouring of catabolic iron that overwhelms the iron-carrying capacity of plasma transferrin and generates redox-active forms 1 that may potentially cause tissue iron overload, damaging vital organs such as heart, liver, and endocrine glands. 3,4 The major objective of iron chelation therapy in transfusional hemosiderosis is the reduction of body iron burden by safe removal of toxic iron from organs and extracellular fluids. 1,3,4 The main chelation target has been iron in the liver, the major organ of pathologic iron accumulation. 1,[4][5][6] Outstanding results have been achieved with deferoxamine (DFO), which is administered via parenteral routes. [5][6][7][8][9][10] However, despite intensive chelation treatment, siderotic cardiac disease has been the complication responsible for 71% of thalassemic mortality, while infection accounts for only 12% (hepatic [6%], endocrine [3%], or malignancies [3%]). [7][8][9][10][11][12] A serious factor in treatment outcome has been compliance with the rigorous requirements of daily subcutaneous DFO infusions; therefore, patients who are noncompliant with continuous DFO treatment might die prematurely of cardiac complications. The issue of noncompliance has stimulated the design of alternative, orally effective chelators that would be more convenient for use and thus improve compliance as well as protect hepatic and extrahepatic organs from the deleterious effects of iron overload. 1,5,13,14 This has led to the use of hydroxypyrydin-on deferiprone (DFP or L1) and bishydroxyphenyl thiazole (ICL670 or ICL) as alternatives to DFO. 5,[11][12][13] Hitherto, few studies have dealt with the routes of chelator entry into cells of relevance to iron toxicity and their respective subcellular chelation targets, particularly in iron overload. 15,16 The present work examines the modes by which the 3 clinically important chelators, DFO, ICL, and DFP, gain access to critical sites of iron accumulation in different cells and how those modes contribute to their chelation capacity. The model cell lines used are rat cardiomyocytes (H9C2), mouse macrophages (J774), and human hepatocytes (HEPG2). The analytical objects used to monitor chelator action are the LIPs, [17][18][19] which represent the redox active and chelatable forms of iron that are present in the cell cytosol [20][21][22] and in organelles such as endosome-lysosomes and mitochondria. 16,23 In previous studies, these LIPs were visualized by fluorescent metallosensors targeted principally...

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Results of Long Term Iron Chelation Treatment with Deferoxamine

Cited by 33 publications

References 155 publications

Unique Host Iron Utilization Mechanisms of Helicobacter pylori Revealed with Iron-Deficient Chemically Defined Media

Unique Host Iron Utilization Mechanisms of Helicobacter pylori Revealed with Iron-Deficient Chemically Defined Media

Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences

Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells

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