| Current Medicinal
Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 12, Number 23, 2005
Contents
Regulatory Molecules and Chelators Used for
the Control of Essential and Toxic Metals in Health and Disease:
From Molecular Interactions to Clinical Effects and Applications
Guest Editor: George J. Kontoghiorghes
Editorial Pp.2661
Advances in Iron Overload Therapies. Prospects
for Effective Use of Deferiprone (L1), Deferoxamine, the New
Experimental Chelators ICL670, GT56-252, L1NAll and their
Combinations Pp.2663
George J. Kontoghiorghes, Eleni Eracleous, Charalambos
Economides and Annita Kolnagou
[abstract]
Structure/Function Overview of Proteins Involved
in Iron Storage and Transport Pp.2683
Peter J. Sargent, Sebastien Farnaud and Robert
W. Evans
[abstract]
Molecular Factors and Mechanisms Affecting Iron
and Other Metal Excretion or Absorption in Health and Disease.
The Role of Natural and Synthetic Chelators Pp. 2695
George J. Kontoghiorghes and Annita Kolnagou
[abstract]
Molecular Mechanisms of Iron Uptake by Cells and
the Use of Iron Chelators for the Treatment of Cancer
Pp.2711
Des R. Richardson
[abstract]
Superoxide and Nitric Oxide in Pathological Conditions
Associated with Iron Overload. The Effects of Antioxidants
and Chelators Pp.2731
I.B. Afanas’ev
[abstract]
Hemoglobin and Myoglobin Associated Oxidative
Stress: from Molecular Mechanisms to Disease States
Pp. 2741
Brandon J. Reeder and Michael T. Wilson
[abstract]
Essentiality, Toxicology and Chelation Therapy
of Zinc and Copper Pp.2753
Lu Cai, Xiao-Kun Li, Ye Song and M. George Cherian
[abstract]
Chelating Agents Used for Plutonium and Uranium
Removal in Radiation Emergency Medicine Pp.2765
Satoshi Fukuda
[abstract]
Chelators as Antidotes of Metal Toxicity: Therapeutic
and Experimental Aspects Pp.2771
Maja Blanusa, Veda M. Varnai, Martina Piasek and
Krista Kostial
[abstract]
Soluble Paramagnetic Chelates and Stabilized Colloidal
Particle Solutions of Iron Oxides as Contrast Agents for Magnetic
Resonance Imaging Pp.2795
Bernd Tombach and Peter Reimer
[abstract]
Abstracts
[Back to top]
Editorial
All organisms and cells require essential metal ions such
as Fe, Zn and Cu for their normal growth and development.
Metal ions are essential functional components of thousands
of proteins. They are also involved in biochemical reactions
and metabolic pathways, which are essential for normal metabolic
function. Specific proteins and metabolic pathways have been
evolved for controlling the homeostasis of essential metals.
However, there are many conditions of abnormal metal metabolism
leading to disease and many xenobiotic metals causing serious
toxic side effects.
Natural and synthetic metal binding molecules can affect
the transport, metabolism and toxicity of metal ions. Specific
metal chelating drugs have been designed to remove excess
toxic metals from the body. Chelators can also be used to
target metal containing proteins involved in a variety of
diseases such as cancer and inflammation. Chelators can form
complexes with metal ions such as Pt, which can be used in
the treatment of cancer or with metal ions such as Gd and
Tc, which can be used in clinical diagnosis.
The interactions of chelating molecules and metal ions can
be used to modify pharmacological, toxicological and biological
effects. Chelating drugs can be used to inhibit free radical
toxicity catalysed by Fe and Cu in tissue damage and other
conditions, whereas metal ions can affect the absorption,
metabolism and toxicity of drugs.
The special issue is dealing with the present state of knowledge
and new developments in the area of metal ions and chelators
from molecular interactions to biological pathways, toxicological
effects and clinical applications. It covers areas on the
mechanism of action and molecular structures of proteins,
metal ions, chelators and metal chelator complexes in relation
to health and disease. It gives many examples of how imbalance
in essential metal ions and introduction of xenobiotic metal
ions can cause toxicity or disease. It provides evidence that
specific chelators can be designed and used to treat metal
imbalance and toxicity conditions and also how chelators can
target and affect key metal containing enzymes involved in
many diseases.
The article by G.J. Kontoghiorghes, E. Eracleous, Ch. Economides
and A. Kolnagou reviews the mechanism involved in iron overload
in idiopathic haemochromatosis and thalassaemia and the therapeutic
use of deferiprone (L1), deferoxamine and their combination.
The authors also review the properties of new iron chelators,
from the molecular level to clinical use, such as ICL670,
GT56-252, L1NAll and deferoxamine polymers, all of which have
reached the stage of clinical development. P. J. Sargent,
S. Farnaud and R. W. Evans reviewed the structure and function
of the iron transport protein transferrin and of the iron
storage protein ferritin. They also reviewed the molecular
mechanisms involved in iron transport and storage and the
role of transferrin to carry many other metal ions in addition
to iron. The article by G.J. Kontoghiorghes and A. Kolnagou
refers to the general interactions of metal ions with chelators
and the basic mechanisms and factors affecting iron and other
metal metabolic imbalance. Special emphasis is given to the
role of natural and synthecic chelators such as deferiprone
(L1) and deferoxamine in iron excretion. It also examines
the general role of iron excretion in the development of iron
overload and iron deficiency. D.R. Richardson reviewed the
molecular mechanisms of iron uptake by cells and the use of
iron chelators for the treatment of cancer and other diseases.
He discussed the use of iron chelators in the inhibition of
DNA synthesis and other target molecules involved in angiogenesis
and metastasis suppression in cancer. I. B. Afanasi’ev
discussed the role of NO, superoxide and other free radicals
in thalassaemia, Fanconi’s anaemia and other diseases.
He also discussed the use of antioxidants and chelators in
preventing the toxicity of free radicals in some of these
diseases. B.J. Reeder and M.T. Wilson discussed the oxidative
stress that may be caused by haemoglobin and myoglobin under
certain conditions, which may lead to the oxidation of biomolecules,
the generation of cytotoxic products and the pathology of
a number of conditions such as rabdomyolysis and brain haemorrhage.
Lu Cai, Xiao-Kun Li, Ye Song and M. George Cherian examined
the metabolism and toxicity of Zn and Cu and the role of metallothioneins
in the homeostasis of these metals. The prospect of using
chelation therapy or other forms of therapy strategies such
as the up-regulation of metallothionein against the toxicity
of these metals is also discussed. S. Fuguda reviewed the
effects of chelators on Pu and U removal within the context
of radiation emergency medicine. He discussed the effects
of radiation toxicity and the use of DTPA or the prospect
of using other drugs such as deferiprone (L1), for the removal
of these metals from the body. M. Blanusa, V. M. Varnai, M.Piasek
and K. Kostial reviewed the clinical use of chelating drugs
as antidotes for the toxicity of Pb, Cd, Hg, Mn, Al, Fe, Cu,
Tm, As, Cr, Ni and Pt, which are involved in human poisoning.
The pharmacokinetic data and toxic side effects of the chelating
drugs are discussed. Emphasis is also given on the effect
of age in relation to the efficacy and toxicity of the chelating
drugs. B. Tombach and P. Reimer reviewed the development and
expanding use of soluble paramagnetic chelator Gd complexes
and stabilised colloidal particle solutions of iron oxides
as contrast agents for magnetic resonance imaging (MRI) in
the clinical diagnosis of many conditions.
I would like to thank all the authors and reviewers for
their hard effort to produce the timely reviews on metals
and chelators, which could be used as a reference point for
basic reading for those involved in each specialist field
and also for newcomers and others involved in related fields.
It is hoped that the special issue will stimulate further
interactive research with other specialist areas and will
increase the prospect for the development of more effective
drugs, diagnostics and therapies.
George J. Kontoghiorghes
Postgraduate Research Institute of Science,
Technology, Environment and Medicine
3, Ammochostou Street,
Limassol 3021,
Cyprus.
E-mail: pri_gjk@cylink.com.cy
[Back to top]
Advances in Iron Overload Therapies. Prospects for
Effective Use of Deferiprone (L1), Deferoxamine, the New Experimental
Chelators ICL670, GT56-252, L1NAll and their Combinations
George J. Kontoghiorghes, Eleni Eracleous, Charalambos
Economides and Annita Kolnagou
Effective new therapies and mechanisms have been developed
for the targeting and prevention of iron overload and toxicity
in thalassaemia and idiopathic haemochromatosis patients.
A new era in the development of chelating drugs began with
the introduction of deferiprone or L1, which as a monotherapy
or in combination with deferoxamine can be used universally
for effective chelation treatments, rapid iron removal, maintenance
of low iron stores and prevention of heart and other organ
damage caused by iron overload. Several experimental iron
chelators such as deferasirox (4-[3,5-bis (2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic
acid) or ICL670, deferitrin (4,5-dihydro-2- (2,4-dihydroxyphenyl)-4-methylthiazole-4
(S)-carboxylic acid) or GT56-252, 1-allyl-2-methyl-3-hydroxypyrid-4-one
or L1NAll and starch deferoxamine polymers have reached different
stages of clinical development. The lipophilic ICL670, which
can only be administered once daily is generally ineffective
in causing negative iron balance but is effective in reducing
liver iron. It is suspected that it may increase iron absorption
and the redistribution of iron from the liver to the heart
and other organs. The experimental iron chelators do not appear
to have significant advantages in efficacy and toxicity by
comparison to deferiprone, deferoxamine or their combination.
However, the prospect of combination therapies using deferiprone,
deferoxamine and new chelators will provide new mechanisms
of chelator interactions, which may lead to higher efficacy
and lower toxicity by comparison to monotherapies. A major
disadvantage of the experimental chelators is that even if
they are approved for clinical use, they are unlikely to be
as inexpensive as deferiprone and become available to the
vast majority of thalassaemia patients, who live in developing
countries.
[Back to top]
Structure/Function Overview of Proteins
Involved in Iron Storage and Transport
Peter J. Sargent, Sebastien Farnaud and Robert
W. Evans
Iron, the major trace element in the body, is an essential
component of many proteins and enzymes. As low-molecular-weight
iron is potentially toxic to cells, higher organisms express
a number of proteins for the transport and storage of iron.
We review our current understanding of the intestinal absorption
of iron in the light of recently identified membrane proteins,
namely the ferrric reductase, Dcytb, the two iron(II) transport
proteins, DMT1 and ferroportin/Ireg1, and hephaestin, the
membrane-bound homologue of the ferroxidase ceruloplasmin.
Two types of mammalian transferrin receptor, TfR1 and TfR2,
are now known to exist. The structure of TfR1 and its role
in the process of receptor-mediated cellular uptake of iron
are presented together with structural information on the
iron storage protein ferritin. Mechanisms for the regulation
of levels of TfR1 and ferritin, as well as other proteins
involved in iron homeostasis, are discussed. Our current knowledge
and understanding of the structure of members of the transferrin
family of iron-binding proteins and the nature of the iron-binding
centres in transferrins is presented, together with information
on the processes of iron-uptake and iron-release by transferrin
and a summary of the elements that have been found to bind
to transferrins.
[Back to top]
Molecular Factors and Mechanisms Affecting Iron and
Other Metal Excretion or Absorption in Health and Disease.
The Role of Natural and Synthetic Chelators
George J. Kontoghiorghes and Annita Kolnagou
The maintenance of iron and other essential metal ion balance
in humans is based on the presence of homeostatic mechanisms
of regulatory absorption, storage, re-utilisation and excretion.
There are a number of factors and mechanisms that can affect
the level of iron excretion or absorption and overall body
iron stores. Net iron loss due to increased iron excretion
by comparison to dietary iron absorption is considered as
one of the causes of iron deficiency anaemia. Body iron loss
greater than normal has been shown in many other conditions.
These include the increase in urinary iron excretion observed
in iron loaded patients, the substantial reduction in serum
ferritin and liver iron of ex-thalassaemia patients several
years following bone marrow transplantation and the increase
in iron excretion in normal individuals following long term
sport activities. There are differences in the metabolism,
mode of action, interactions with the iron pools and routes
of iron excretion, of the iron chelating drugs deferiprone
(L1), deferoxamine and other experimental chelators such as
ICL670 in iron-loaded patients. Naturally occurring chelators
and some synthetic drugs are known to bind iron and affect
iron absorption and excretion. The molecular characteristics
of naturally occurring or synthetic chelators can influence
other aspects of iron metabolism in addition to iron absorption
or excretion. Similar mechanisms and factors can affect the
metabolism of other essential metals. The understanding of
the mechanisms involved in iron excretion and their overall
effects on body iron levels can facilitate the design of new
chelators and improved therapeutic protocols for the treatment
of conditions of iron and other metal metabolic imbalance
and toxicity.
[Back to top]
Molecular Mechanisms of Iron Uptake by Cells and the Use of
Iron Chelators for the Treatment of Cancer
Des R. Richardson
The field of iron (Fe) metabolism has been invigorated in
the past 10 years with the discovery of a variety of new molecules
involved in the homeostatic control of this critical nutrient.
These proteins include the transferrin receptor 2, frataxin,
hephaestin, hepcidin, hemojuvelin and others. Basic understanding
of the metabolism of Fe in cells is vital in order to develop
Fe chelators for the treatment of a variety of disease states.
In addition, examination of the role of Fe in the regulation
of cell cycle progression and angiogenesis has led to investigations
of the use of novel Fe chelators as anti-proliferative agents.
These studies have resulted in the identification of new ligands
that show selective and potent anti-tumor activity in
vitro and in vivo. Moreover, the ability of
these chelators to inhibit growth is not only limited to the
inhibition of DNA synthesis. In fact, there is a range of
targets that are affected by Fe-depletion, such as molecules
involved in cell cycle control, angiogenesis and metastasis
suppression. These include hypoxia-inducible factor-1α
(HIF-1α),
vascular endothelial growth factor-1 (VEGF1), p21CIP1/WAF1,
cyclin D1 and the protein product of the N-myc downstream
regulated gene-1 (Ndrg1). As such, Fe chelators can now
be designed to target molecules to induce specific effects,
for instance, angiogenesis or metastasis suppression.
[Back to top]
Superoxide and Nitric Oxide in Pathological Conditions Associated
with Iron Overload. The Effects of Antioxidants and Chelators
I.B. Afanas’ev
Free radicals are a one of damaging factors in diseases associated
with iron overload. This review considers two principal questions:
the mechanisms of free radical-mediated damage in cells and
tissue and findings concerning the discovery of iron-stimulated
free radical cascades in thalassemia and Fanconi anemia. There
are two major precursors of all reactive oxygen and nitrogen
species formed in living organism – superoxide (O2.-)
and nitric oxide (NO). However, it has been shown that in
addition to well-known mechanisms of the formation of reactive
hydroxyl radicals and peroxynitrite from superoxide and NO,
there are signal pathways by which these “physiological”
radicals directly induce apoptosis, proton leak in mitochondria
and an increase in oxygen consumption leading to cell death.
In present review the mechanisms of free radical damage are
considered with the particular emphasis of iron-induced free
radical formation in thalassemia and Fanconi anemia. Furthermore
free radical reactions leading to lipid peroxidation, LDL
oxidation, the stimulation of apoptosis and other damaging
processes are discussed. An importance of the chelating and
antioxidant treatments of thalassemic and Fanconi anemia patients
is also considered within the context of free radical damage
and its prevention.
[Back to top]
Hemoglobin and Myoglobin Associated Oxidative Stress: from
Molecular Mechanisms to Disease States
Brandon J. Reeder and Michael T. Wilson
The heme based respiratory proteins myoglobin and hemoglobin
can, under certain conditions, exhibit a peroxidase-like enzymic
activity, in which a catalytic cycle, driven by peroxides,
leads to oxidation of bio molecules. These heme proteins are
implicated in what is termed “oxidative stress”
as this catalytic cycle, when it occurs in vivo,
generates cytotoxic product that are implicated in the pathology
of a number of disease states. Here we review the evidence
that such reactions occur in vivo, in particular
in animal models and human patients and examine the underlying
chemical mechanism. This mechanism involves the production
of ferryl heme (FeIV=O2-) and it is this and associated radicals
that initiate processes such as lipid peroxidation and the
generation of bioactive molecules such as isoprostanes. The
reactivity of the high oxidation state of the heme also allows
us to identify unambiguous biomarkers for its presence in
vivo in such conditions as rhabdomyolysis and brain hemorrhage.
Ways to inhibit the peroxidatic cycle are discussed and the
role of iron chelators such as desferrioxamine is discussed
in terms of their often neglected properties as reducing agents.
Suppression of the peroxidatic activity of hemoglobin is discussed
in the context of the development of blood substitutes.
[Back to top]
Essentiality, Toxicology and Chelation Therapy of Zinc and
Copper
Lu Cai, Xiao-Kun Li, Ye Song and M. George Cherian
Both zinc and copper are essential minerals that are required
for various cellular functions. Although these metals are
essential, they can be toxic at excess amounts, especially
in certain genetic disorders. Zinc and copper homeostasis
results from a coordinated regulation by different proteins
involved in uptake, excretion and intracellular storage/trafficking
of these metals. Apart from zinc transporters (ZnT) families
and Cu-ATPase, metallothionein is an important storage protein
for zinc and copper. Metallothioneins are intracellular polypeptides
with a remarkable ability to bind metallic ions. These proteins
bind both essential metals indispensable for the organism
and also toxic metals (e.g. cadmium or lead). Metallothioneins
play a critical role to maintain zinc and copper homeostasis.
In this review, we summarize the toxicity of zinc and copper
and the potential treatment for zinc or copper toxicity by
zinc- or copper-specific chelators as well as strategy to
up-regulate metallothionein.
[Back to top]
Chelating Agents Used for Plutonium and Uranium Removal in
Radiation Emergency Medicine
Satoshi Fukuda
The prospects of using chelating agents for increasing the
excretion of actinides are reviewed. The removal of plutonium
by chelating agents is of great importance because plutonium
is extremely dangerous and induces cancer due to radiation
toxicity. Similarly, uranium is a radionuclide, which causes
severe renal dysfunction within a short time period due to
chemical toxicity. It may also induce cancers such as leukemia
and osteosarcoma in cases of long-term internal radiation
exposure. Investigations on chelating agents for the removal
of plutonium were initiated in the 1960’s and 1970’s.
Diethylenetriaminepentaacetic acid (DTPA) is recognized as
a chelating agent that accelerates the excretion of plutonium
in early treatment after an accident. Thereafter, there has
long been an interest in finding new chelating agents with
radionuclide removal properties for use in therapy, and many
chelating agents such as 3,4,3-LIHOPO and CBMIDA have been
studied for their ability to remove plutonium and uranium.
Recently, the focus has turned to drugs that have been used
successfully in the treatment of a variety of other diseases,
for example the iron chelating drug deferiprone or 1,2-dimethyl-3-hydroxypyrid-4-one
(L1), which is used in thalassaemia and ethane-1-hydroxy-1,1-bisphosphonate
(EHBP), which is used in osteoporosis. Within this context,
it is important to examine the clinical use of these two drugs
as well as the properties of the experimental chelators 3,4,3-LIHOPO
and CBMIDA in order to identify possible uses in the treatment
of radiation workers contaminated with plutonium and uranium.
[Back to top]
Chelators as Antidotes of Metal Toxicity: Therapeutic and
Experimental Aspects
Maja Blanusa, Veda M. Varnai, Martina Piasek and
Krista Kostial
The effects of chelating drugs used clinically as antidotes
to metal toxicity are reviewed. Human exposure to a number
of metals such as lead, cadmium, mercury, manganese, aluminum,
iron, copper, thallium, arsenic, chromium, nickel and platinum
may lead to toxic effects, which are different for each metal.
Similarly the pharmacokinetic data, clinical use and adverse
effects of most of the chelating drugs used in human metal
poisoning are also different for each chelating drug. The
chelating drugs with worldwide application are dimercaprol
(BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine
(DPA), N-acetyl-D-penicillamine (NAPA), calcium disodium
ethylenediaminetetraacetate (CaNa2EDTA), calcium
trisodium or zinc trisodium diethylenetriaminepentaacetate
(CaNa3DTPA, ZnNa3DTPA), deferoxamine
(DFO), deferiprone (L1), triethylenetetraamine (trientine),
N-acetylcysteine (NAC), and Prussian blue (PB). Several
new synthetic homologues and experimental chelating agents
have been designed and tested in vivo for their metal binding
effects. These include three groups of synthetic chelators,
namely the polyaminopolycarboxylic acids (EDTA and DTPA),
the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters
of DMSA) and the carbodithioates. Many factors have been shown
to affect the efficacy of the chelation treatment in metal
poisoning. Within this context it has been shown in experiments
using young and adult animals that metal toxicity and chelation
effects could be influenced by age. These findings may have
a bearing in the design of new therapeutic chelation protocols
for metal toxicity.
[Back to top]
Soluble Paramagnetic Chelates and Stabilized Colloidal Particle
Solutions of Iron Oxides as Contrast Agents for Magnetic Resonance
Imaging
Bernd Tombach and Peter Reimer
The development of contrast agents shortening the relaxation
times of protons began more than 20 years ago in order to
improve the capability of diagnosing disease by means of magnetic
resonance imaging (MRI). A variety of extracellular and tissue
specific contrast agents were developed based on two types
of molecules. One type was related to soluble paramagnetic
chelates and the other type to stabilized colloidal particle
solutions of iron oxides. The chelate or metal complex of
gadopentetate dimeglumine was the pioneering magnetic resonance
(MR) contrast agent used in 1988. Chemical modifications of
this chelate and the design of new chelates led to tissue
or blood pool specificity in MRI. Similarly, modifications
in coating materials and variations in size of iron oxide
particles allowed for tissue specificity or blood pool properties
in MRI. Both types of contrast agents offer excellent perspectives
for clinical MRI and for molecular imaging.
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