Iron-Chelating Agents in Non-Iron Overload Conditions

  1. E. E. Voest;
  2. G. Vreugdenhil; and
  3. J. J. M. Marx
  1. From the University Hospital Utrecht, Utrecht, and the University Hospital Nijmegen, Nijmegen, the Netherlands. Requests for Reprints: J. J. M. Marx, MD, PhD, Department of Internal Medicine, Utrecht University Hospital, P.O. Box 85500, 3508 GA Utrecht, the Netherlands.
     
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    Abstract

    Purpose: To review the current clinical experience with iron chelators in non-iron overload conditions.

    Data Sources: The English-language literature was searched from 1983 through 1992 manually and using MEDLINE.

    Study Selection: Original articles, case reports, and abstracts addressing iron chelation.

    Data Extraction: Selected reports that described clinical applications of iron chelators in non-iron overload conditions were classified according to their stated mechanism of interference with disease activity. Articles stating the rationale for clinical use of iron chelators were also included.

    Results: Iron chelators were used in non-iron overload conditions to produce antioxidant effects, antiproliferative effects, and antiprotozoal effects and for aluminum chelation. In addition, several reports described singular observations in various diseases. Deferoxamine is the only iron chelator available for clinical studies. The treatment-related (side) effects appear to be associated with patient iron levels.

    Conclusions: Randomized clinical trials are needed to confirm the promising effects of iron chelators in non-iron overload conditions. Oral iron chelators with fewer toxic effects are especially needed.

    Iron is an essential element in cellular metabolism and growth. Many enzymes and proteins contain iron, which allows electron shuttling or oxygen binding and transport. Cellular iron deficiency may inhibit those systems. Besides its physiologic importance, iron has an important role in the generation of toxic oxygen species [1]. Catalytically active iron allows the highly reactive hydroxyl radical to form, as shown in the following equation Figure 1:

    Figure 1. No caption available.
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      Figure 1. No caption available.

      This is the iron-catalyzed Haber-Weiss reaction. Because iron can generate radicals, it can initiate or maintain inflammatory reactions and ultimately cause tissue damage [2-5]. In addition, reaction products of oxygen and iron may contribute to oxidative damage without the intermediate generation of hydroxyl radicals [6]. A well-documented form of iron poisoning is secondary hemosiderosis resulting from repeated blood transfusion. Intramuscular and subcutaneous administration of the iron-chelating agent deferoxamine prevents the deleterious effects of iron overload in thalassemia and sickle cell disease [7, 8]. Insight into the mechanisms of iron and oxygen radical poisoning extended the use of iron chelators to conditions with no iron overload [9]. Deferoxamine is the most widely used iron chelator and is considered to be relatively safe when given to patients with iron overload. In patients without iron overload, however, adverse reactions are more common [10]. Deferoxamine is inactive when taken orally, and that and the high cost of the drug prompted researchers to develop other iron chelators. Some of these are being tested in clinical trials. Besides a strong affinity for iron, most iron chelators also have a high affinity for other transition metals, such as aluminum and copper, and thus they can be used to treat aluminum or copper poisoning [11]. Table 1 lists novel applications of iron-chelating agents in non-iron overload conditions and their toxicity profiles.

      View this table:
      Table 1. Applications of Iron Chelators in Non-Iron Overload Conditions
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      Inhibition of Free Radical-Mediated Tissue Damage

      Rheumatoid Arthritis

      In synovial fluid of patients with rheumatoid arthritis, both low molecular weight iron species and ferritin-bound iron levels are increased [12, 13] because iron is retained by the mononuclear phagocyte system and microbleeding recurs [14, 15]. Several clinical observations show the proinflammatory effects of iron in rheumatoid arthritis. Many patients with rheumatoid arthritis have the anemia of chronic disease that is associated with low serum iron concentrations and usually with normal or increased iron storage [16]. Iron-deficient patients with rheumatoid arthritis have lower levels of disease activity. If anemic patients with rheumatoid arthritis are treated with iron, synovitis is exacerbated in many of them [17]. Moreover, patients with iron overload caused by hereditary hemochromatosis often have arthralgia or arthritis without evidence of rheumatoid arthritis or other inflammatory joint diseases [18].

      Although iron is probably not the only factor involved in the pathogenesis of rheumatoid arthritis, the findings described above prompted some investigators to study the effects of iron chelators in rheumatoid arthritis, based on the iron-mobilizing capacity of these compounds. Blake and colleagues [19] showed that the chronic inflammatory phase in the chronic allergic monoarthritis model was reduced in male Wistar rats treated with deferoxamine. Andrews and colleagues [20] showed that deferoxamine treatment in male Wistar rats decreased soft tissue swelling and bone erosion.

      Rheumatoid arthritis activity improved dramatically and the acute-phase response decreased in seven patients with rheumatoid arthritis who were treated with subcutaneous deferoxamine [21]. Single doses of deferoxamine given to patients with rheumatoid arthritis decreased plasma ferritin levels [22], which may have been the result of an anti-inflammatory effect because it is unlikely that a single dose of deferoxamine has any noticeable influence on iron stores. In another study, Giordano and coworkers [23] treated patients with rheumatoid arthritis for 14 days with deferoxamine and noted slight decreases in rheumatoid arthritis activity. Decreases in radiolabeled iron were noted in the joints of patients with rheumatoid arthritis who were treated with deferoxamine for 14 days but with no clear effects on rheumatoid arthritis activity [24]. Polson and associates [25] showed that rheumatoid arthritis activity improved during treatment with deferoxamine in two of five patients, but no effects were seen in the other three. The number of patients was small and most were iron deficient before starting deferoxamine treatment. Magaro and coworkers [26] treated 18 patients with rheumatoid arthritis with deferoxamine for 14 days and found a significant reduction in clinical variables of rheumatoid arthritis activity, such as morning stiffness and Ritchie index, whereas grip strength increased. The hydroxypyridinones, particularly 1,2-dimethyl-3-hydroxypyridine-4-one (L1), are promising new iron chelators that are active when given orally, in contrast with deferoxamine [27]. In a preliminary study, patients with rheumatoid arthritis were treated for 3 weeks with L1. In these persons, rheumatoid arthritis activity improved clinically, but serologic variables of rheumatoid arthritis disease did not change [28].

      The pathogenesis of anemia of chronic disease, associated with active rheumatoid arthritis, has many factors [16]. One of them is iron retention by the mononuclear phagocyte system, leading to decreased erythroblast iron availability. Both deferoxamine and L1 mobilized iron in anemic patients with rheumatoid arthritis and increased hemoglobin levels [23, 28]. The mechanism remains uncertain because chelator-bound iron is thought to leave the body by urinary or biliary excretion. Possible beneficial effects include iron mobilization from macrophages, an increased transferrin receptor expression, and an increase in responsiveness to erythropoietin [29].

      Most data concerning iron chelators used in rheumatoid arthritis are based on small numbers of patients treated only for a short time. Interpretation of small clinical trials in rheumatoid arthritis is notoriously difficult because of frequent spontaneous remissions and disease exacerbation. Nevertheless, beneficial effects on rheumatoid arthritis activity and the degree of anemia were noted in studies that used iron chelators. Larger studies, however, are needed to determine the role of iron chelators in the treatment of rheumatoid arthritis, with special attention given to potential toxicity.

      Anthracycline Cardiac Poisoning

      Anthracyclines are very effective anticancer compounds. Irreversible cardiac damage, resulting in cardiomyopathy, limits the use of more high-dose anthracycline-containing regimens [30]. Generation of oxygen free radicals by anthracycline-iron complexes is the mechanism of cardiac poisoning accepted by most researchers [31]. Anthracyclines can form strong complexes with Fe3+. In the presence of a reducing system (for example, nicotinamide adenine dinucleotide phosphate-reductase or thiols), bound Fe3+ is reduced to Fe2+. Oxygen or hydrogen peroxide rapidly oxidizes Fe2+ to Fe3+. In this reaction, an electron is transferred to oxygen and superoxide or the hydroxyl radical is formed [for a review, see reference 32]. Because of the central role of iron in the redox cycling of anthracycline-iron complexes, iron chelators have been studied for possible protection against cardiac injury. The mechanism of protection is based on three assumptions: 1) prevention of the formation of iron-anthracycline complexes; 2) removal of iron from the anthracycline-iron complex; and 3) direct scavenging of oxygen free radicals. Animal studies have shown a protective effect of the following iron-chelating agents: deferoxamine, hydroxypyridinones (CP51 and CP93), flavonoids, and the bisdioxopiperazine ICRF-187 [33-36]. Deferoxamine and ICRF-187 remove iron from the anthracycline-iron complex, preventing the generation of oxygen radicals [37]. In a randomized trial in 92 women with advanced breast cancer, the cardiac poisoning induced by fluorouracil, doxorubicin, and cyclophosphamide with or without ICRF-187 (1000 mg/m2) was compared. Treatment with ICRF-187 offered significant protection against cardiac poisoning caused by doxorubicin without disturbing the antitumor effect [38]. Clinical studies are under way to confirm the results of this study. If iron chelators are valuable in the prevention of anthracycline-induced cardiac poisoning, they may have important consequences for patients who respond to doxorubicin or who might benefit from it, because they may then safely receive higher cumulative doses of this potent cytostatic drug.

      Reperfusion Injury

      Cardiopulmonary bypass surgery, coronary angioplastic procedures, and other thrombolytic procedures are often associated with transient ischemia. After a short period of coronary artery occlusion, reperfusion is associated with arrhythmias and injury to a population of myocytes that are viable at the time of reflow [39, 40]. Furthermore, pressure sores, a complication of severe illness, may result from reperfusion damage [41]. The precise mechanism of reperfusion injury is controversial, but evidence exists that iron and oxygen free radical formation is involved [42]. A prospective, epidemiologic study in which the iron storage protein ferritin was associated with an increased risk for coronary heart disease corroborates this empirically [43]. In vitro studies have shown improvement of myocardial recovery and prevention of arrhythmias after treatment with deferoxamine, hydroxyethyl starch-conjugated deferoxamine, and neocuproine [44-47]. Based on these observations, deferoxamine (30 mg/kg body weight for 4 hours) was given during operation to 10 patients having bypass surgery [48]. The susceptibility of circulating low-density lipoproteins to lipid peroxidation, which was used as a measure of toxic oxygen species generation, was significantly decreased in the patients having surgery compared with 10 control patients. These findings indicate that iron chelators may be clinically useful for limiting reperfusion injury. However, the free radical hypothesis is being reviewed [49] and a recent in vitro study showed that deferoxamine failed to protect against myocardial ischemia-reperfusion injury [50].

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      Antiproliferative Effects

      Iron is an essential element for the proliferation of cells. Rapidly dividing cells need more iron, as shown by a high transferrin receptor expression on the cell membrane and increased cellular iron uptake [51]. Many studies have reported a correlation between transferrin receptor expression and response to treatment in various malignant conditions [52-54]. Several approaches to modify cellular iron metabolism in the treatment of cancer are being studied: 1) antitransferrin receptor antibodies to prevent transferrin receptor-mediated iron uptake; 2) antitransferrin receptor used as a vehicle for cytotoxic drugs; 3) gallium nitrate, which interferes with the release of iron from the endocytotic vesicles; and 4) intracellular iron-chelating agents.

      In vitro studies using deferoxamine as an anticancer agent were done in cell lines derived from solid tumors and in leukemic cell lines [55-57].

      Solid Tumors

      Neuroblastoma is a solid tumor that occurs predominantly in childhood and often has a poor prognosis. Plasma of patients with neuroblastoma frequently contains high concentrations of the iron storage protein ferritin, which correlates with poor outcome in advanced stages of the disease [58]. Plasma ferritin in these patients was at least partially tumor derived [59]. Iron may be essential for growth of neuroblastoma cells. Although deferoxamine cannot remove iron from ferritin and hemosiderin at physiologic pH levels and at in vivo concentrations [60], it may compete for iron entering the plasma. Incubation of neuroblastoma cells with 60 µmol/L deferoxamine caused severe cytotoxicity after prolonged exposure (> 72 hours) [57]; L1 and the iron chelator omadine were even more cytotoxic [61]. In vitro studies with neuroblastoma cells showed that the combination of deferoxamine and the widely used cytotoxic agent doxorubicin had a cumulative effect [62]. Based on these experiments, we conclude that iron is required for growth of neuroblastoma and probably other solid tumors, and iron chelators may have antitumor activity. Based on the in vitro results, a phase II trial was begun to evaluate the activity of a single course of deferoxamine in patients with neuroblastoma [63]. Nine patients were given deferoxamine as an 8-hour intravenous infusion for 5 days at 150 mg/kg per day. This treatment schedule was based on the experience of the investigators with deferoxamine in patients with thalassemia and iron overload. The response variables were bone marrow infiltration, plasma ferritin, urinary vanillylmandelic acid, and tumor volume. Although a reduction in tumor volume was observed in only one of six patients with measurable disease, marrow infiltration was decreased by more than 50% in seven of nine patients. Absolute serum ferritin levels did not correlate with response to treatment in this study. However, if the results from in vitro experiments are extrapolated to an in vivo treatment schedule, a prolonged (> 72 hours) and continuous infusion may improve response to treatment. Encouraged by these findings, deferoxamine was included in a novel chemotherapy program consisting of cyclophosphamide, etoposide, carboplatin, and thiotepa to treat 25 patients with advanced neuroblastoma and primitive neuroectodermal tumors [64]. Myelosuppression was the major adverse effect. Although this feasibility study was presented as “a breakthrough for patients with neuroblastoma,” a randomized clinical trial must establish the additive value of deferoxamine to this regimen. Experience with deferoxamine in tumors other than neuroblastoma is limited and no clinical trials have been conducted. However, in vitro studies showed that deferoxamine was cytotoxic to breast cancer (MCF-7), hepatoma (HepG2), and hepatocellular carcinoma [65, 66]. The in vitro antitumor activity of deferoxamine against hepatocellular carcinoma was confirmed in an animal model and may have clinical potential [67].

      Hematologic Malignancies

      In vitro studies with cell lines derived from human leukemias showed a cytotoxic effect at concentrations of deferoxamine that can be achieved in humans [55, 65]. This corroborates observations reported with solid tumors. The combination of iron chelators with other antineoplastic drugs was effective in L1210 leukemia cells and dependent on the time frame in which the combination was presented to the cells [68]. The combination of iron chelators with compounds inhibiting cellular iron incorporation (gallium nitrate) and blocking iron uptake (anti-transferrin receptor antibodies), and inhibitors of ribonucleotide reductase (fludarabine) was effective in vitro [69, 70]. Information from in vivo studies, however, was obtained only from case reports. In two of four patients with refractory leukemia treated with deferoxamine (10 mg/kg per hour) combined with the conventional cytostatic drug arabinosyl cytosine [71-73], an objective response was observed [71, 72]. In a phase I clinical trial, nine patients with malignant refractory tumors were treated with the combination of deferoxamine (50 mg/kg per 24 hours for 72 hours), iron sorbitol citrate, and a regimen of doxorubicin alone or in combination with cyclophosphamide, vincristine, and prednisone [74]. The authors of this study postulated that pretreatment of tumors with deferoxamine has a direct antitumor effect and increases the iron uptake of tumor cells. When iron is subsequently presented to these cells with the iron-dependent anticancer drug doxorubicin, the oxidative damage-mediated antitumor activity of doxorubicin is enhanced. Four of the nine patients in the study had heavily pretreated non-Hodgkin lymphoma, and two of them achieved partial remissions despite previous resistance to cyclophosphamide, doxorubicin, vincristine, and prednisone. This is very encouraging and warrants further study. Nevertheless, these studies were based on a limited number of patients and no definite conclusions can be drawn. Initiation of phase II trials may provide further data on toxicity and efficacy to determine the role of deferoxamine in the treatment of hematologic cancers.

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      Antiprotozoal Activity

      Malaria is a widespread, tropical parasitic disease caused by Plasmodium species. Increased drug resistance of the malaria parasites can cause a worldwide health problem, prompting the search for new treatments. Clinical observations suggest that iron deficiency benefits the course and outcome of malaria and may even prevent infection [75]. In a study of Gambian children, researchers found that children with iron deficiency who were treated with iron were more likely to develop fever associated with malarial parasitemia during the height of the malaria season [76]. These patients, who have a high rate of iron deficiency anemia, should not be given iron supplementation before treatment of malaria has been completed [77]. The awareness that many microbial pathogens depend on host-derived iron for their virulence prompted studies of the effects of iron chelators on the growth of malaria species. Deferoxamine was shown to be both cyto cidal and cytostatic for P. falciparum in vitro [78]. Plasmodium berghei growth was also inhibited by deferoxamine [79, 80]. Other experimental iron chelators induced similar effects on Plasmodium growth [79-82]. Underlying mechanisms of Plasmodium species growth retardation include inhibition of the iron-dependent enzyme ribonucleotide reductase, which is essential for DNA replication or generation of intracellular free radicals with subsequent cellular and tissue damage. The antimalarial action of deferoxamine in laboratory animals is independent of host iron status [83]. To determine whether iron chelation therapy with deferoxamine is active against human infection with P. falciparum, the drug (100 mg/kg body weight per day for 72 hours) was infused subcutaneously in 28 volunteers with asymptomatic parasitemia [84]. Compared with placebo, deferoxamine was associated with an almost 10-fold increase in parasite clearance. In a randomized trial in patients with cerebral malaria, deferoxamine (100 mg/kg intravenously per day for 72 hours) or placebo was given in addition to a standard regimen of quinine and sulfadoxine-pyrimethamine. The placebo and deferoxamine groups were similar with respect to relevant clinical variables. Deferoxamine shortened coma in 42 children with severe, therapy-refractory cerebral malaria, compared with 41 children who were given placebo [85]. Furthermore, the rate of parasite clearance was two times higher in deferoxamine-treated patients than in patients given placebo. Although these results are encouraging, deferoxamine must be administered parenterally and is a relatively expensive drug, which limits its use in malaria-endemic areas. In addition, deferoxamine poorly penetrates erythrocytes that have been invaded by parasites [86]. It is hoped that orally effective iron chelators will soon become available, which will facilitate the use of iron chelators in the treatment of malaria.

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      Aluminum Chelation

      Deferoxamine has a high affinity for iron and aluminum [11], and thus it has been used in disorders involving increased aluminum concentrations.

      Renal Failure

      In renal insufficiency, increased serum aluminum levels are common [87]. Aluminum-containing compounds are given to reduce phosphate absorption and to decrease high aluminum levels in dialysate. Increased aluminum levels cause erythropoiesis suppression and reduce the responsiveness to recombinant human erythropoietin in patients with anemia associated with renal failure [88, 89]. Patients whose renal failure is treated with deferoxamine have increased iron and aluminum excretion [90]. Deferoxamine given to these patients may improve anemia [91-93], and it may act synergistically with recombinant human erythropoietin [91, 94]. Because these effects also occur in patients with no aluminum poisoning, other mechanisms are probably involved. Aluminum accumulates in erythrocytes in patients with anemia associated with chronic renal failure, independent of plasma levels, and these concentrations do not change after deferoxamine treatment, whereas anemia improves [95]. Iron availability is impaired in anemia associated with chronic renal failure, which may limit the effects of recombinant human erythropoietin treatment on anemia to some extent [96]. Iron chelators mobilize iron from iron reserves, and the removed iron may be redistributed and more easily donated to erythroblasts, thus increasing hemoglobin synthesis and erythropoiesis [97]. The mechanism by which iron is removed from deferoxamine must be determined. In patients with rheumatoid arthritis and anemia associated with chronic disease, hemoglobin and plasma erythropoietin levels increased after treatment with the oral iron chelator L1 [98]. Iron mobilization might restore erythropoietin responsiveness in anemia associated with chronic disease, although this is less likely to occur in anemia caused by chronic renal failure. In addition, iron chelators may enhance transferrin receptor expression and thereby facilitate iron transport through the erythroblast membrane [99]. They may be valuable in treating patients with renal insufficiency and aluminum poisoning. The mainstay of treatment of anemia associated with chronic renal failure is elimination of the underlying disorder causing renal failure, renal transplant, or recombinant human erythropoietin. The role of iron chelators in this type of anemia is not yet established, and its use may be limited to diagnosis [100] and experimental models of iron and aluminum metabolism.

      Alzheimer Disease

      Use of deferoxamine in Alzheimer disease is based on epidemiologic studies reporting an association between the concentration of aluminum in drinking water and the occurrence of the disease [101]. Increased concentrations of aluminum were found in several brain regions of patients with Alzheimer disease [102]. In one study, 48 patients with Alzheimer disease were randomly assigned to receive intramuscular injections of deferoxamine (125 mg twice daily, 5 days per week for 24 months) or no treatment. In this single-blind study, the two groups were not substantially different with respect to mental variables. Deferoxamine treatment substantially reduced the rate of decline of daily living skills and thus might inhibit the clinical progression of dementia associated with Alzheimer disease [103]. Although the outcome of the study is encouraging, especially given the fact that no effective treatment can prevent or inhibit the disease, the treatment regimen of two injections per day is strenuous and its influence on changes in quality of life was not assessed.

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      Miscellaneous Applications

      Iron chelators can be used in several diseases. The mechanism of action is often unclear, and all clinical experience is based only on small studies or case reports. Nevertheless, these findings are interesting as clues to future indications.

      Myelofibrosis and Myelodysplastic Syndrome

      Myelofibrosis is a myeloproliferative syndrome characterized by the abnormal deposition of collagen in bone marrow that interferes with normal hematopoiesis. Deferoxamine has been reported to restore hematopoiesis in myelofibrosis [104]. The mechanism of this deferoxamine-mediated improvement in anemia may include a decrease in iron poisoning at the mitochondrial level, an increase in iron flux toward erythroblasts, an increase in transferrin receptor expression on erythroblasts, and enhanced responsiveness to erythropoietin [105]. Nevertheless, spontaneous restoration of hematopoiesis after primary and secondary myelofibrosis following polycythemia vera has been reported [106]. The myelodysplastic syndrome is a preleukemic disease often associated with transfusion-dependent anemia. Treatment with an intensive deferoxamine regimen for hemosiderosis reduces the blood transfusion requirement for patients with the myelodysplastic syndrome. This suggests that deferoxamine-mediated improvement of erythropoiesis may be possible for patients with the myelodysplastic syndrome [107].

      Multiple Sclerosis

      Deferoxamine improved the deleterious effects of experimental allergic encephalomyelitis in rats [108]. This model was used to study multiple sclerosis. Consequently, a clinical trial investigating the effects of deferoxamine in multiple sclerosis was begun [109]. Favorable therapeutic responses were observed, but long-term follow-up is needed to determine the role of iron-chelating agents in the treatment of multiple sclerosis.

      Drug-induced Lung Injury

      Paraquat, a contact herbicide, is used in the agricultural industry and has caused many deaths through accidental and intentional ingestion. The primary damage occurs in the lungs and is associated with the metabolism of paraquat to a free radical. Deferoxamine protects alveolar type II cells against paraquat [110]. Furthermore, continuous intravenous infusion of deferoxamine greatly decreased the number of deaths caused by paraquat poisoning in vitamin E-deficient rats [111].

      Bleomycin, a drug used in cancer chemotherapy, has well-documented pulmonary toxic effects. Some researchers postulate that an oxygen free radical-generating iron-bleomycin complex induces pulmonary alveolitis and fibrosis. Intramuscular deferoxamine substantially reduced the severity of bleomycin-induced pulmonary fibrosis in one study [112]. Others, however, could not confirm these findings [113, 114].

      Acute lung injury in Long Evans rats as a result of systemic complement activation by cobra venom factor was prevented in a dose-dependent manner by intravenous deferoxamine (4 to 20 mg/kg body weight) [115].

      Immunomodulatory Properties and Transplant Rejection

      Several in vitro studies reported immunomodulatory effects of deferoxamine. Deferoxamine inhibited the proliferative response of lymphocytes induced by concanavalin A and pokeweed mitogen [116, 117]. Similar effects on mononuclear cells were seen after incubation with L1 (CP20), CP51, and CP94 [118]. Two inhibitory mechanisms of action are postulated: 1) an effect mediated by iron chelation and 2) direct inhibition of interleukin-2 receptors on lymphocytes, which is not related to iron [119, 120].

      Deferoxamine inhibited chronic pancreatic islet allograft damage in CBA/J recipient mice [121]. Under these in vivo conditions, no effect on the activation of a specific cytotoxic T-lymphocyte response and effector functions of activated T lymphocytes was observed, which suggests that chronic islet allograft damage resulted primarily from hydroxyl radical production mediated by inflammatory cells.

      A beneficial effect of deferoxamine (50 mg/kg per day for two 5-day courses) was reported in two children with graft-versus-host disease after bone marrow transplantation [122]. Although deferoxamine has immunomodulatory properties in vitro, it is unclear whether these effects occur in patients in vivo.

      Preservation of Organs for Transplant

      The small size of the organ donor pool and limited storage time has significant implications for transplant procedures. Storage damage and reperfusion injury are well-recognized phenomena in organs preserved for transplantation. Tissue damage is thought to be mediated by the formation of toxic oxygen species. Deferoxamine was used successfully in experimental models to prevent the deleterious effects of cold ischemia and reperfusion on kidney and lung preservation [123, 124]

      Glomerulonephritis

      In a rabbit model of antiglomerular basement membrane, antibody-induced glomerulonephritis, the acute phase of glomerular injury, was shown to be neutrophil dependent [125]. Deferoxamine prevented the oxygen free radical-mediated development of proteinuria in this model. In a rat model of membranous nephropathy, deferoxamine-mediated chelation of tubule fluid iron retarded both tubulointerstitial injury and superimposed glomerulosclerosis [126].

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      Toxic Effects

      Most clinical experience with deferoxamine is limited to patients with iron overload disease, and a relation between the patients' iron status and toxicity has been suggested [10]. Studies evaluating the use of iron-chelating agents in non-iron overload conditions therefore should always include an extensive analysis of toxic effects.

      Ocular Poisoning

      Several forms of deferoxamine-induced poisoning occur in the eye, but no clear dose-dependent relation between deferoxamine and ocular poisoning is known. Toxic effects to the retina include night blindness, disturbed color vision, retinal pigmentary degeneration, optic neuropathy, and visual field defects [127-129]. Pretreatment with the cytostatic drug cisplatin may enhance deferoxamine-induced retinal poisoning [74]. Fundoscopic examination reveals abnormalities of the retinal pigment epithelium in the macular region. Although most abnormalities are reversible after discontinuation of the drug, irreversible changes have been reported [130]. Because macular edema distorts vision of straight lines, the Amsler grid provides an easy method to detect retinal damage [74]. Rarely, lens opacities and cataracts have been described but whether these findings are attributable to deferoxamine use is not known [131].

      Ototoxic Effects

      High-frequency hearing loss and acute deafness have been reported with deferoxamine [127, 129, 132, 133]. The dose of deferoxamine given and the degree of iron overload, as determined by serum ferritin levels [134], determine ototoxic effects. Furthermore, younger patients were more affected than were older patients. Audiometric follow-up is necessary to detect early changes in high-frequency perception.

      Central Nervous System

      The combination of prochlorperazine and deferoxamine caused two patients with rheumatoid arthritis and normal iron stores to lose consciousness [22]. Deferoxamine should be administered with caution in patients taking medication for central nervous system disorders.

      Bones and Joints

      Joint symptoms associated with deferoxamine are seldom reported. DeVirgiliis and colleagues [135] described delayed linear growth in thalassemic children younger than 3 years who were treated with deferoxamine, sometimes accompanied by skeleton abnormalities such as short trunk, sternal protrusion, and genu valgum. Transient musculoskeletal pains were reported in patients with thalassemia major who were treated with L1 [136-138]. The joint symptoms are difficult to distinguish from those seen in patients with hemochromatosis. Articular complications caused by iron chelators, especially L1, should be studied in greater depth. Careful monitoring is thus required, and in some instances these complications may require discontinuation of the drug.

      Autoimmune Manifestations

      A patient with drug-induced, fatal systemic lupus erythematosus, associated with L1, has been described [139]. Although a causal relation has not been proved, lupus should be considered in patients treated with L1.

      Hematologic Poisoning

      Agranulocytosis occurred in at least three patients treated with L1 [137, 140, 141]. Thrombocytopenia also developed in one patient with Blackfan-Diamond anemia. Her bone marrow was hypoplastic [140], but she recovered completely. Another patient with a myelodysplastic syndrome also had a transient agranulocytosis episode, but it did not recur after rechallenge with a lower L1 dose [141]. The third patient with agranulocytosis associated with L1 had thalassemia major [137]. The exact mechanism causing agranulocytosis is uncertain; thus far, no factors predisposing patients to agranulocytosis have been identified. Therefore, careful hematologic monitoring is necessary during L1 treatment. Anecdotal reports have described thrombocytopenia in patients receiving renal dialysis who were treated with deferoxamine [142].

      Pulmonary Poisoning

      A pulmonary syndrome has been related to the administration of deferoxamine [143-145]. Abnormalities include diffuse interstitial infiltrates without positive cultures for microorganisms. Hypersensitivity might be the mechanism of action. Furthermore, prolonged (> 24 hours) treatment with deferoxamine may increase the risk for pulmonary complications.

      Microbiological Poisoning

      Yersinia enterocolitica or mucormycosis infections may be exacerbated after deferoxamine infusion [145, 146]. Growth of Staphylococcus aureus was enhanced by deferoxamine [147], and one report suggested an association between Pneumocystis carinii infection and deferoxamine therapy [148].

      Although the toxicity profile of deferoxamine is well documented in patients with iron overload, novel applications and use of experimental iron-chelating agents (L1, ICRF-187) should be accompanied by careful monitoring for organ poisoning. Modulation of deferoxamine poisoning and clearance by covalent attachment to biocompatible polymers may diminish toxic effects [149].

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      Conclusion

      The expanding knowledge of free radical chemistry, its role in causing various diseases, and the catalytic effects of iron in this process have generated much interest in the possible benefits of iron chelators in preventing oxidative tissue damage. Animal experiments have provided a rationale to evaluate the clinical merit of iron chelation in many diseases. Some encouraging results are emerging from these patient studies. However, iron-mediated oxidative damage occurs with non-iron overload conditions as a consequence of an underlying disease, and iron chelation only affects the pathologic sequelae of that disease. Deferoxamine is the only iron chelator available for clinical use. Because it is orally inactive, which implies parenteral use, and relatively expensive, an effective oral iron chelator is needed. Clinical experience with iron chelation is also associated with some side effects rarely encountered when iron chelators are administered in iron overload conditions. Randomized, prospective trials are needed to evaluate the use of iron chelators in oxidative damage-mediated diseases.

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      1. Ann Intern Med March 15, 1994 vol. 120 no. 6 490-499
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