Iron availability and complex stability of iron hydroxyethyl starch and iron dextran a comparative in vitro study with liver cells and macrophages

Ternes, Nina; Scheiber-Mojdehkar, Barbara; Landgraf, Grit; Goldenberg, Hans; Sturm, Brigitte

doi:10.1093/ndt/gfm315

Cited by 21 publications

(9 citation statements)

References 21 publications

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“…Intracellular fluorescence intensity of calcein (l ex ¼ 485 and l em ¼ 520), a measure of the amount of labile iron (24), was determined as a function of time 1 minute before and 10 minutes after compound addition at 37 C using FLUOstar OPTIMA (BMG Labtech) microplate reader.…”

Section: Measurement Of Intracellular Calcein-chelatable Ironmentioning

confidence: 99%

Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers

et al. 2011

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Excessive signaling from the Wnt pathway is associated with numerous human cancers. Using a high throughput screen designed to detect inhibitors of Wnt/b-catenin signaling, we identified a series of acyl hydrazones that act downstream of the b-catenin destruction complex to inhibit both Wnt-induced and cancerassociated constitutive Wnt signaling via destabilization of b-catenin. We found that these acyl hydrazones bind iron in vitro and in intact cells and that chelating activity is required to abrogate Wnt signaling and block the growth of colorectal cancer cell lines with constitutive Wnt signaling. In addition, we found that multiple iron chelators, desferrioxamine, deferasirox, and ciclopirox olamine similarly blocked Wnt signaling and cell growth. Moreover, in patients with AML administered ciclopirox olamine, we observed decreased expression of the Wnt target gene AXIN2 in leukemic cells. The novel class of acyl hydrazones would thus be prime candidates for further development as chemotherapeutic agents. Taken together, our results reveal a critical requirement for iron in Wnt signaling and they show that iron chelation serves as an effective mechanism to inhibit Wnt signaling in humans. Cancer Res; 71(24); 7628-39. Ó2011 AACR.

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Section: Measurement Of Intracellular Calcein-chelatable Ironmentioning

confidence: 99%

Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers

et al. 2011

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“…Short-term studies indicate all available formulations are capable of generating free unbound iron which is released directly into the circulation from the iron-carbohydrate complex. However, there is a clear relationship between stability of the complex and appearance of free iron, with the likely rank order based on evaluable data being sodium ferric gluconate > iron sucrose > low molecular weight iron dextran > ferumoxytol = ferric carboxymaltose = iron maltoside 1000 21,23,43–45. Production of oxygen-based free radicals from iron-induced redox reactions can damage any tissue, protein, lipid, or RNA/DNA in close proximity of the free radical.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Ferumoxytol: a silver lining in the treatment of anemia of chronic kidney disease or another dark cloud?

Pai¹,

Garba²

2012

JBM

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Intravenous iron therapy is pivotal in the treatment of anemia of chronic kidney disease to optimize the response of hemoglobin to erythropoiesis-stimulating agents. Intravenous iron use in patients with chronic kidney disease is on the rise. Recent clinical trial data prompting safety concerns regarding the use of erythropoiesis-stimulating agents has stimulated new US Food and Drug Administration label changes and restrictions for these agents, and has encouraged more aggressive use of intravenous iron. The currently available intravenous iron products differ with regard to the stability of the iron-carbohydrate complex and potential to induce hypersensitivity reactions. Ferumoxytol is a newer large molecular weight intravenous iron formulation that is a colloidal iron oxide nanoparticle suspension coated with polyglucose sorbitol carboxymethyl ether. Ferumoxytol has robust iron-carbohydrate complex stability with minimal dissociation or appearance of free iron in the serum, allowing the drug to be given in relatively large doses with a rapid rate of administration. Clinical trials have demonstrated the superior efficacy of ferumoxytol versus oral iron with minimal adverse effects. However, recent postmarketing data have demonstrated a risk of hypersensitivity that has prompted new changes to the product information mandated by the Food and Drug Administration. Additionally, the long-term safety of this agent has not been evaluated, and its place in the treatment of anemia of chronic kidney disease has not been fully elucidated.

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“…iron dextran, in particular high-molecular weight iron dextran, this form of iron therapy is not generally recommended [15-17]. Moreover, the more labile, low molecular weight compounds, such as ferric gluconate, release larger amounts of iron into the circulation saturating transferrin and generating non-transferrin bound iron (NTBI) [14, 18]. NTBI is taken up unspecifically by the liver, endocrine tissue and heart where it may catalyze a number of reactions that lead to oxidative stress and tissue damage [19, 20].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Oxidative Stress and Inflammation Induced by Different Intravenous Iron Sucrose Similar Preparations in a Rat Model

Toblli

Cao²,

Oliveri³

et al. 2012

IADT

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Iron sucrose originator (ISORIG) has been used to treat iron deficiency and iron deficiency anemia for decades. Iron sucrose similars (ISSs) have recently entered the market. In this non-clinical study of non-anemic rats, five doses (40 mg iron/kg body weight) of six ISSs marketed in Asian countries, ISORIG or saline solution (control) were administered intravenously over four weeks to compare their toxicologic effects. Vasodilatory effects, impaired renal function and hepatic damage were only observed in the ISS groups. Significantly elevated serum iron and transferrin saturation levels were observed in the ISS groups suggesting a higher release of iron resulting in higher amounts of non-transferrin bound (free) iron compared to ISORIG. This might explain the elevated oxidative stress and increased levels of inflammatory markers and antioxidant enzymes in the liver, heart and kidneys of ISS-treated animals. Physico-chemical analyses showed that the molecular structure of most of the ISSs differed greatly from that of the ISORIG. These differences may be responsible for the organ damage and oxidative stress observed in the ISS groups. Significant differences were also found between different lots of a single ISS product. In contrast, polarographic analyses of three different ISORIG lots were identical, indicating that the molecular structure and thus the manufacturing process for ISORIG is highly consistent. Data from this study suggest that ISSs and ISORIG differ significantly. Therefore, before widespread use of these products it would be prudent to evaluate additional non-clinical and/or clinical data proving the safety, therapeutic equivalence and interchangeability of ISSs with ISORIG.

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Iron availability and complex stability of iron hydroxyethyl starch and iron dextran a comparative in vitro study with liver cells and macrophages

Abstract: Our results indicate that these new iron formulations have a good stability and availability in vitro and are comparable with the well-known iron dextran complexes.

Cited by 21 publications

References 21 publications

Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers

Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers

Ferumoxytol: a silver lining in the treatment of anemia of chronic kidney disease or another dark cloud?

Comparison of Oxidative Stress and Inflammation Induced by Different Intravenous Iron Sucrose Similar Preparations in a Rat Model

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