Presence of iron catalytic for free radical reactions in patients undergoing chemotherapy: implications for therapeutic management

doi:10.1016/0304-3835(95)03852-N

Cancer Letters

Volume 94, Issue 2, 1 August 1995, Pages 219-226

https://doi.org/10.1016/0304-3835(95)03852-N Get rights and content

Abstract

We investigated the kinetics of generation of iron ‘catalytic’ for free radical reactions in children with diagnosed acute lymphoblastic leukaemia (ALL) who received high-dose methotrexate infusions. In 76% of the chemotherapy courses studied, ‘catalytic’ iron appeared in plasma in the concentration range from 0.1 to 3μmol/l. Positive correlations between maximum levels of ‘catalytic’ iron and plasma hepatic enzymes could be established in the majority of cases and in one subset of patients (low and medium risk ALL) mean ‘catalytic’ iron levels correlated well to clinically observable toxicities. The damaging potential of ‘catalytic’ iron was also demonstrated experimentally: oxidative damage to proteins was significantly (P < 0.05) higher in plasma samples showing the presence of ‘catalytic’ iron and in addition a strong correlation (r = 0.95, P < 0.02) was seen between plasma concentration of ‘catalytic’ iron and the ability of the plasma to stimulate lipid peroxidation. Our data show that chemotherapy releases ‘catalytic’ iron which may relate to toxic side effects. Hence binding this ‘catalytic’ iron by judicious co-administration of iron chelating agents could be beneficial in minimizing the iatrogenic adverse effects of chemotherapy of acute leukaemia.

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The role of iron in promoting atherosclerosis, and hence the cardiovascular, neurodegenerative and other diseases that result from atherosclerosis, has been fiercely controversial. Many studies have been carried out on various rodent models of atherosclerosis, especially on apoE-knockout (apoE^−/−) mice, which develop atherosclerosis more readily than normal mice. These apoE^−/− mouse studies generally support a role for iron in atherosclerosis development, although there are conflicting results. The purpose of the current article is to describe studies on another animal model that is not genetically manipulated; New Zealand White (NZW) rabbits fed a high-cholesterol diet. This may be a better model than the apoE^−/− mice for human atherosclerosis, although it has been given much less attention. Studies on NZW rabbits support the view that iron promotes atherosclerosis, although some uncertainties remain, which need to be resolved by further experimentation.
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In this mini-reflection, I explain how during my doctoral work in a Botany Department I first became interested in H₂O₂ and later in my career in other reactive oxygen species, especially the role of “catalytic” iron and haem compounds (including leghaemoglobin) in promoting oxidative damage. The important roles that H₂O₂, other ROS and dietary plants play in respect to humans are discussed.
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Mini-Review: Oxidative stress, redox stress or redox success?
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Citation Excerpt :
The iron has been shown to be associated with ligands such as citrate [1,41], and to be a virulence factor for the growth of certain organisms [1,35]. It is also pro-oxidant, catalysing oxidative damage, demonstrated in haemochromatosis [42,43], thalassaemia [44] and in patients with iron overload due to chemotherapy [45], among other conditions. The importance of “catalytic” iron has recently been re-illustrated by the growing literature about “ferroptosis”, a form of programmed cell death driven by catalytic iron [46].
The first life forms evolved in a highly reducing environment. This reduced state is still carried by cells today, which makes the concept of “reductive stress” somewhat redundant. When oxygen became abundant on the Earth, due to the evolution of photosynthesis, life forms had to adapt or become extinct. Living organisms did adapt, proliferated and an explosion of new life forms resulted, using reactive oxygen species (ROS) to drive their evolution. Adaptation to oxygen and its reduction intermediates necessitated the simultaneous evolution of select antioxidant defences, carefully regulated to allow ROS to perform their major roles. Clearly this “oxidative stress” did not cause a major problem to the evolution of complex life forms. Why not? Iron and oxygen share a close relationship in aerobic evolution. Iron is used in proteins to transport oxygen, promote electron transfers, and catalyse chemical reactions. In all of these functions, iron is carefully sequestered within proteins and restricted from reacting with ROS, this sequestration being one of our major antioxidant defences. Iron was abundant to life forms before the appearance of oxygen. However, oxygen caused its oxidative precipitation from solution and thereby decreased its bioavailability and thus the risk of iron-dependent oxidative damage. Micro-organisms had to adapt and develop strategies involving siderophores to acquire iron from the environment and eventually their host. This battle for iron between bacteria and animal hosts continues today, and is a much greater daily threat to our survival than “oxidative stress” and “redox stress”.
Therapeutic use of transferrin to modulate anemia and conditions of iron toxicity
2017, Blood Reviews
Citation Excerpt :
Patients who receive high-dose chemotherapy in preparation of a stem cell transplantation often have a decrease in Tf levels and an increased total serum iron content with a pronounced rise in NTBI [35–37]. NTBI is cytotoxic and is anticipated to play a role in the pathophysiology of organ injury caused by chemotherapy [36]. NTBI is cleared from the circulation by hepatocytes where it generates ROS and causes oxidative damage to proteins [36,38].
As the main iron transporter, transferrin delivers iron to target tissues like the bone marrow for erythropoiesis. Also, by binding free iron, transferrin prevents formation of reactive oxygen species. Transferrin deficiency due to congenital hypotransferrinemia is characterized by anemia as well as oxidative stress related to toxic free iron. Transferrin supplementation may be beneficial in two ways. First, transferrin can correct anemia by modulating the amount of iron that is available for erythropoiesis. This is obvious for patients that suffer from hypotransferrinemia, but may also have beneficial effects for β-thalassemia patients. Second, under conditions of iron overload, transferrin reduces oxidative stress by binding free iron in the circulation and in tissues. Hereby, transferrin protects the host against the reactive oxygen species that can be formed as a consequence of free iron. This beneficial effect is shown in hematological patients undergoing chemotherapy and stem cell transplantation. Transferrin may also be beneficial in lung injury, ischemia-reperfusion injury and hypomyelination.
This review summarizes the preclinical and clinical data on the efficacy of exogenous transferrin administration to modulate certain forms of anemia and to prevent the toxic effects of free iron. Thereby, we show that transferrin has promising therapeutic potential in a wide variety of conditions.
Toxicity of iron overload and iron overload reduction in the setting of hematopoietic stem cell transplantation for hematologic malignancies
2017, Critical Reviews in Oncology/Hematology
Iron is an essential element for key cellular metabolic processes. However, transfusional iron overload (IOL) may result in significant cellular toxicity. IOL occurs in transfusion dependent hematologic malignancies (HM), may lead to pathological clinical outcomes, and IOL reduction may improve outcomes. In hematopoietic stem cell transplantation (SCT) for HM, IOL may have clinical importance; endpoints examined regarding an impact of IOL and IOL reduction include transplant-related mortality, organ function, infection, relapse risk, and survival. Here we review the clinical consequences of IOL and effects of IOL reduction before, during and following SCT for HM. IOL pathophysiology is discussed as well as available tests for IOL quantification including transfusion history, serum ferritin level, transferrin saturation, hepcidin, labile plasma iron and other parameters of iron-catalyzed oxygen free radicals, and organ IOL by imaging. Data-based recommendations for IOL measurement, monitoring and reduction before, during and following SCT for HM are made.
The Prognostic Significance of Elevated Serum Ferritin Levels Prior to Transplantation in Patients With Lymphoma Who Underwent Autologous Hematopoietic Stem Cell Transplantation (autoHSCT): Role of Iron Overload
2016, Clinical Lymphoma, Myeloma and Leukemia
Hematopoietic stem cell transplantation is a common and preferred treatment of lymphomas in many centers. Our goal was to determine the association between pretransplant iron overload and survival in patients who underwent autologous hematopoietic stem cell transplantation (autoHSCT).
A total of 165 patients with lymphoma, who underwent autoHSCT between the years of 2007 and 2014, were included in this study. Ferritin levels were used to determine iron status; the cut-off value was 500 ng/mL. The relationship between iron overload and survival was assessed by statistical analysis.
The median ferritin level in the normal ferritin (ferritin < 500) group was 118 ng/mL (range, 9-494 ng/mL) and in the high-ferritin group (ferritin ≥ 500), it was 908 ng/mL (range, 503-4549 ng/mL). A total of 64 (38.8%) patients died during follow-up. Of these patients that died, 52 (81.25%) were in the high-ferritin group, and 12 (18.75%) were in the normal ferritin group (P ≤ .001). Twelve (14.1%) of 85 patients died in the normal ferritin group, and 52 (65.0%) of 80 patients died in the high-ferritin group. The overall mortality was significantly higher in the high-ferritin group (P < .001). The median overall survival was 42 months (range, 25-56 months) in the normal-ferritin group and20 months (range, 5-46) in the high-ferritin group. The difference between the groups was statistically significant (P < .001). The median disease-free survival was 39 months (range, 16-56) in the normal ferritin group and 10 months (range, 3-29) in the high-ferritin group. The difference between the groups was statistically significant (P < .001).
Elevated serum ferritin levels might predict poorer survival in autoHSCT recipients.

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Presence of iron catalytic for free radical reactions in patients undergoing chemotherapy: implications for therapeutic management

Abstract

Entry of iron into cells: a new role for the transferrin receptor in modulating iron release from transferrin

Ann. Neurol.

Association of iron with respiratory tract neoplasia

J. Trace Elem. Exp. Med.

Superoxide-dependent formation of hydroxyl radicals in the presence of iron salts — detection of ‘free’ iron in biological systems by using bleomycin-dependent degradation of DNA

Biochem. J.

Role of free radicals and catalytic metal ions in human disease: an overview

Methods Enzymol.

Iron overload disorders: natural history, pathogenesis, diagnosis, and therapy

Crit. Rev. Clin. Lab. Sci.

Low-molecular-weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis

Clin. Sci.

Non transferrin bound iron in plasma from hemochromatosis patients: effect of phlebotomy therapy

Blood

A direct method for quantification of non-transferrin-bound iron

Anal. Biochem.

Bleomycin-detectable iron in serum from leukemic patients before and after chemotherapy

FEBS Lett.

Bleomycin-reactive iron in patients with acute non-lymphocytic leukemia

FEBS. Lett

Metabolism and reactions of quinoid anti-cancer agents

Pharmacol. Ther.