Iron-Chelating Therapy

Hershko, Chaim; Weatherall, D. J.; Finch, Clement A.

doi:10.3109/10408368809105894

Cited by 128 publications

(63 citation statements)

References 180 publications

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“…Iron-chelation therapy is mandatory for the treatment of patients with secondary iron overload (1)(2)(3)(4)(5)(6). In these patients, iron chelation prevents labile iron from engaging in radical-mediated damage of crucial organs such as the heart and liver.…”

Section: Discussionmentioning

confidence: 99%

Chelation and Mobilization of Cellular Iron by Different Classes of Chelators

et al. 1997

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SUMMARYIron chelators belonging to three distinct chemical families were assessed in terms of their physicochemical properties and the kinetics of iron chelation in solution and in two biological systems. Several hydroxypyridinones, reversed siderophores, and desferrioxamine derivatives were selected to cover agents with different iron-binding stoichiometry and geometry and a wide range of lipophilicity, as determined by the octanol-water partition coefficients. The selection also included highly lipophilic chelators with potentially cell-cleavable ester groups that can serve as precursors of hydrophilic and membrane-impermeant chelators. Iron binding was determined by the chelator capacity for restoring the fluorescence of iron-quenched calcein (CA), a dynamic fluorescent metallosensor. The iron-scavenging properties of the chelators were assessed under three different conditions: (a) in solution, by mixing iron salts with free CA; (b) in resealed red cell ghosts, by encapsulation of CA followed by loading with iron; and (c) in human erythroleukemia K562 cells, by loading with the permeant CA-acetomethoxy ester, in situ formation of free CA, and binding of cytosolic labile iron. The time-dependent recovery of fluorescence in the presence of a given chelator provided a continuous measure for the capacity of the chelator to access the iron/CA-containing compartment. The resulting rate constants of fluorescence recovery indicated that chelation in solution was comparable for the members of each family of chelators, whereas chelation in either biological system was largely dictated by the lipophilicity of the free chelator. For example, desferrioxamine was among the fastest and most efficient iron scavengers in solution but was essentially ineffective in either biological system when used at Յ200 M over a 2-hr period at 37°. On the other hand, the highly lipophilic and potentially cell-cleavable hydroxypyridinones and reversed siderophores were highly efficient in all biological systems tested. It is implied that in K562 cells, hydrolysis of these chelators is relatively slower than their ingress and binding of intracellular iron. The chelator-mediated translocation of iron from cells to medium was assessed in 55 Fe-transferrinloaded K562 cells. The speed of iron mobilization by members of the three families of chelators correlated with the lipophilicity of the free ligand or the iron-complexed chelator. The acquired information is of relevance for the design of chelators with improved biological performance.

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Section: Discussionmentioning

confidence: 99%

Chelation and Mobilization of Cellular Iron by Different Classes of Chelators

et al. 1997

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“…These issues are of physiological relevance, since it is generally assumed that LIP must be under strict homeostatic control not only for long-term metabolic purposes, but for minimizing the potentially damaging effects of LIP [9]. This assumption is based primarily on the correlation found between cellular resistance to oxidative stress and depletion of cell iron pools induced by iron chelators [4,5,9,13]. In this work we provide experimental evidence for the existence of rapidly acting homeostatic mechanisms for maintaining LIP at stable levels.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of the cytosolic chelatable iron pool of K562 cells

1996

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The labile iron pool of cells (LIP) constitutes the primary source of metabolic and catalytically reactive iron in the eytosol. We studied LIP homeostasis in K562 cells using the fluorescent metal-sensitive probe calcein. Following brief exposure to iron(ll) salts or to oxidative or reductive stress, LIP rose by up to 120% relative to the normal level of 350 nM. However, the rate of recovery to normal LIP level differed markedly with each treatment (respective tl/2s of 27, 65-88 and -<17 min). We show that the capacity of K562 cells to adjust LIP levels is highly dependent on the origin of the LIP increase and on the pre-existing cellular iron status.

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“…13 There have been already reported exhaustive audits with respect to the poisonous quality of iron. 14 Here, we will quickly consider the locales and poisonous quality of chelatable iron vital in patients with thalassemia. …”

Section: Discussionmentioning

confidence: 99%

“…14 Numerous reasonable issues are however connected with chelation treatment including exact appraisal of body iron load, important for the viability of deferoxamine, and also to that of new chelators entering clinical trials. There are sure issues, that emerge as often as possible in the administration of patients with thalassemia, for instance, identified with fitting age for the start of deferoxamine treatment, the support of harmony between its viability and poisonous quality, and the issues of consistence with deferoxamine.…”

mentioning

confidence: 99%