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SJ Ford P Obeidy DB Lovejoy M Bedford L Nichols C Chadwick O Tucker GYL Lui DS Kalinowski PJ Jansson TH Iqbal D Alderson DR Richardson C Tselepis 《British journal of pharmacology》2013,168(6):1316-1328
Background and Purpose
Growing evidence implicates iron in the aetiology of gastrointestinal cancer. Furthermore, studies demonstrate that iron chelators possess potent anti-tumour activity, although whether iron chelators show activity against oesophageal cancer is not known.Experimental Approach
The effect of the iron chelators, deferoxamine (DFO) and deferasirox, on cellular iron metabolism, viability and proliferation was assessed in two oesophageal adenocarcinoma cell lines, OE33 and OE19, and the squamous oesophageal cell line, OE21. A murine xenograft model was employed to assess the effect of deferasirox on oesophageal tumour burden. The ability of chelators to overcome chemoresistance and to enhance the efficacy of standard chemotherapeutic agents (cisplatin, fluorouracil and epirubicin) was also assessed.Key Results
Deferasirox and DFO effectively inhibited cellular iron acquisition and promoted intracellular iron mobilization. The resulting reduction in cellular iron levels was reflected by increased transferrin receptor 1 expression and reduced cellular viability and proliferation. Treating oesophageal tumour cell lines with an iron chelator in addition to a standard chemotherapeutic agent resulted in a reduction in cellular viability and proliferation compared with the chemotherapeutic agent alone. Both DFO and deferasirox were able to overcome cisplatin resistance. Furthermore, in human xenograft models, deferasirox was able to significantly suppress tumour growth, which was associated with decreased tumour iron levels.Conclusions and Implications
The clinically established iron chelators, DFO and deferasirox, effectively deplete iron from oesophageal tumour cells, resulting in growth suppression. These data provide a platform for assessing the utility of these chelators in the treatment of oesophageal cancer patients.Linked Article
This article is commented on by Keeler and Brookes, pp. 1313–1315 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12093 相似文献63.
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Chang HH Lu MY Liao YM Lin PC Yang YL Lin DT Chiou SS Jou ST Lin KH Chang TT 《Pediatric blood & cancer》2011,56(3):420-424
Background
Deferasirox is an oral iron‐chelating agent taken once‐daily by patients with transfusion‐dependent iron overload. However, some patients are unresponsive or unable to tolerate once‐daily deferasirox. The current study evaluated whether twice‐daily deferasirox treatment showed increased efficacy or tolerability in unresponsive or intolerant patients.Procedure
Patients from two Taiwanese hospitals with transfusion‐dependent β‐thalassemia, including those who showed increasing serum ferritin levels for six consecutive months, with at least one level >2,500 ng/dl, while treated with >30 mg/kg/day of once‐daily deferasirox (unresponsive) or developed deferasirox‐related adverse events (AEs) at the dosage required to maintain the iron burden balance (intolerant) and were treated twice‐daily with the same total daily dose of deferasirox since 2008, were enrolled in the study and evaluated retrospectively by medical record review.Results
Eighteen patients were included for analysis. A statistically significant median decrease in serum ferritin levels was detected in the 11 unresponsive patients after 6 months of continuous twice‐daily deferasirox treatment. Five out of the seven intolerant patients experienced either no deferasirox‐related AEs or less severe AEs. The 12 patients from both groups (11 unresponsive, 1 intolerant) who received continuous twice‐daily deferasirox for 6 months showed a mild but significant median increase in serum creatinine levels.Conclusions
Twice‐daily deferasirox dosing is effective in iron chelation and improves tolerability in transfusion‐dependent β‐thalassemia patients who are unresponsive to or intolerant of once‐daily deferasirox. Future studies with greater patient numbers will be required to confirm the results reported herein. Pediatr Blood Cancer 2011;56:420–424. © 2010 Wiley‐Liss, Inc. 相似文献65.
The iron chelator deferasirox affects redox signalling in haematopoietic stem/progenitor cells 下载免费PDF全文
Tiziana Tataranni Francesca Agriesti Carmela Mazzoccoli Vitalba Ruggieri Rosella Scrima Ilaria Laurenzana Fiorella D'Auria Franca Falzetti Mauro Di Ianni Pellegrino Musto Nazzareno Capitanio Claudia Piccoli 《British journal of haematology》2015,170(2):236-246
The iron chelator deferasirox (DFX) prevents complications related to transfusional iron overload in several haematological disorders characterized by marrow failure. It is also able to induce haematological responses in a percentage of treated patients, particularly in those affected by myelodysplastic syndromes. The underlying mechanisms responsible for this feature, however, are still poorly understood. In this study, we investigated the effect of DFX‐treatment in human haematopoietic/progenitor stem cells, focussing on its impact on the redox balance, which proved to control the interplay between stemness maintenance, self‐renewal and differentiation priming. Here we show, for the first time, that DFX treatment induces a significant diphenyleneiodonium‐sensitive reactive oxygen species (ROS) production that leads to the activation of POU5F1 (OCT4), SOX2 and SOX17 gene expression, relevant in reprogramming processes, and the reduction of the haematopoietic regulatory proteins CTNNB1 (β‐Catenin) and BMI1. These DFX‐mediated events were accompanied by decreased CD34 expression, increased mitochondrial mass and up‐regulation of the erythropoietic marker CD71 (TFRC) and were compound‐specific, dissimilar to deferoxamine. Our findings would suggest a novel mechanism by which DFX, probably independently on its iron‐chelating property but through ROS signalling activation, may influence key factors involved in self‐renewal/differentiation of haematopoietic stem cells. 相似文献
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Porter J Galanello R Saglio G Neufeld EJ Vichinsky E Cappellini MD Olivieri N Piga A Cunningham MJ Soulières D Gattermann N Tchernia G Maertens J Giardina P Kwiatkowski J Quarta G Jeng M Forni GL Stadler M Cario H Debusscher L Della Porta M Cazzola M Greenberg P Alimena G Rabault B Gathmann I Ford JM Alberti D Rose C 《European journal of haematology》2008,80(2):168-176
Objectives/methods: This 1-yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3–81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond–Blackfan anaemia (DBA; n = 30), other rare anaemias ( n = 22) or β-thalassaemia ( n = 85). Dosage was determined by baseline liver iron concentration (LIC).
Results: In patients with baseline LIC ≥7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC ( P < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 ± 0.14 mg/kg/d; greatest in DBA: 0.4 ± 0.11 mg/kg/d). Overall, LIC changes were dependent on dose ( P < 0.001) and transfusional iron intake ( P < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group ( r = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases.
Conclusions: Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups. 相似文献
Results: In patients with baseline LIC ≥7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC ( P < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 ± 0.14 mg/kg/d; greatest in DBA: 0.4 ± 0.11 mg/kg/d). Overall, LIC changes were dependent on dose ( P < 0.001) and transfusional iron intake ( P < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group ( r = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases.
Conclusions: Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups. 相似文献
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The hypothesis that two known chelators deferiprone (L1) and deferasirox (DFS) might be more efficient as combined treatment than monotherapies in the mobilization of copper was tested in copper-exposed rats. Male Wistar rats were exposed to 70?mg/kg body weight copper (II) chloride in drinking water for 42 d, followed by treatment with DFS (60?mg/kg body weight, oral, once daily), L1 (60?mg/kg body weight, oral, once daily) either alone or in combination DFS?+?L1 (30?mg/kg body weight, oral, once daily), for 10 consecutive days. After chelation therapy, these rats were anesthetized by ether vapor and immobilized by cervical dislocation. Then their heart, kidneys, liver and intestine were sampled for determination of copper, iron and zinc concentration with an atomic absorption spectrophotometer. The treatment with DFS and L1 appreciably decreased the depletion of endogenous copper, but the combined treatments were more efficient than the individuals in restoring the tissue copper levels. Furthermore, iron and zinc concentration after chelation therapy significantly decreased, thus consumption of iron and zinc tablet is recommended to return iron and zinc level to its normal state. Our results support the usefulness of this animal model for preliminary in vivo testing of copper chelators. The result of combined chelators treatment should be confirmed in a different experimental model before extrapolation to other systems. 相似文献
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Shahina Daar Anil Pathare Hanspeter Nick Ulrike Kriemler-Krahn Abdel Hmissi Dany Habr Ali Taher 《European journal of haematology》2009,82(6):454-457
This subgroup analysis evaluated the effect of once-daily oral deferasirox on labile plasma iron (LPI) levels in patients from the prospective, 1-yr, multicentre ESCALATOR study. Mean baseline liver iron concentration and median serum ferritin levels were 28.6 ± 10.3 mg Fe/g dry weight and 6334 ng/mL respectively, indicating high iron burden despite prior chelation therapy. Baseline LPI levels (0.98 ± 0.82 μmol/L) decreased significantly to 0.12 ± 0.16 μmol/L, 2 h after first deferasirox dose (P = 0.0006). Reductions from pre- to post-deferasirox administration were also observed at all other time points. Compared to baseline, there was a significant reduction in preadministration LPI that reached the normal range at week 4 and throughout the remainder of the study (P ≤ 0.02). Pharmacokinetic analysis demonstrated an inverse relationship between preadministration LPI levels and trough deferasirox plasma concentrations. Once-daily dosing with deferasirox ≥20 mg/kg/d provided sustained reduction in LPI levels in these heavily iron-overloaded patients, suggesting 24-h protection from LPI. Deferasirox may therefore reduce unregulated tissue iron loading and prevent further end-organ damage. 相似文献
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Ali Taher Amal El-Beshlawy Mohsen S. Elalfy Kusai Al Zir Shahina Daar Dany Habr Ulrike Kriemler-Krahn Abdel Hmissi Abdullah Al Jefri 《European journal of haematology》2009,82(6):458-465
Objective: Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20–30 mg/kg/d reduces iron burden, depending on transfusional iron intake. Methods: The prospective, open-label, 1-yr ESCALATOR study in the Middle East was designed to evaluate once-daily deferasirox in patients ≥2 yr with β-thalassaemia major and iron overload who were previously chelated with deferoxamine and/or deferiprone. Most patients began treatment with deferasirox 20 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as a reduction in liver iron concentration (LIC) of ≥3 mg Fe/g dry weight (dw) if baseline LIC was ≥10 mg Fe/g dw, or final LIC of 1–7 mg Fe/g dw for patients with baseline LIC of 2 to <10 mg Fe/g dw. Results: Overall, 233/237 enrolled patients completed 1 yr’s treatment. Mean baseline LIC was 18.0 ± 9.1 mg Fe/g dw, while median serum ferritin was 3356 ng/mL. After 1 yr’s deferasirox treatment, the intent-to-treat population experienced a significant treatment success rate of 57.0% (P = 0.016) and a mean reduction in LIC of 3.4 mg Fe/g dw. Changes in serum ferritin appeared to parallel dose increases at around 24 wk. Most patients (78.1%) underwent dose increases above 20 mg/kg/d, primarily to 30 mg/kg/d. Drug-related adverse events were mostly mild to moderate and resolved without discontinuing treatment. Conclusions: The results of the ESCALATOR study in primarily heavily iron-overloaded patients confirm previous observations in patients with β-thalassaemia, highlighting the importance of timely deferasirox dose adjustments based on serum ferritin levels and transfusional iron intake to ensure patients achieve their therapeutic goal of maintenance or reduction in iron burden. 相似文献