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Cardiovascular
& Hematological Disorders - Drug Targets
ISSN: 1871-529X
Cardiovascular
& Hematological Disorders - Drug Targets
Volume 9, Number 1, March 2009
Contents
Promising Therapies in Sickle Cell Disease Pp. 1-8
R. Raghupathy and H.H. Billett
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Article] [PMID:
19275572 PubMed - indexed for MEDLINE]
Von Willebrand Factor: Drug and Drug
Target Pp. 9-20
Simon F. De Meyer, Bauke De Maeyer, Hans Deckmyn and
Karen Vanhoorelbeke
[Abstract] [Purchase
Article] [PMID:
19275573 PubMed - indexed for MEDLINE]
Resistance to Imatinib in Chronic Myeloid Leukemia and Therapeutic
Approaches to Circumvent the Problem Pp. 21-28
Massimo Breccia and Giuliana Alimena
[Abstract] [Purchase
Article] [PMID:
19275574 PubMed - indexed for MEDLINE]
Electrocardiographic Abnormalities in Thalassemia Patients
with Heart Failure Pp. 29-35
Luigi Mancuso, Andrea Mancuso, Elvira Bevacqua
and Paolo Rigano
[Abstract] [Purchase
Article] [PMID:
19275575 PubMed - indexed for MEDLINE]
Thrombotic Microangiopathies: Towards a Pathophysiology Based
Classification Pp. 36-50
Paul Coppo and Agnès Veyradier
[Abstract] [Purchase
Article] [PMID:
19275576 PubMed - indexed for MEDLINE]
Chromatin Structure and Epigenetics of Tumour Cells: A Review
Pp. 51-61
Eva Bártová, Jana Krejcí,
Roman Hájek, Andrea Harnicarová and
Stanislav Kozubek
[Abstract] [Purchase
Article] [PMID:
19275577 PubMed - indexed for MEDLINE]
Antiproliferative and Proapoptotic Effects
of Proteasome Inhibitors and their Combination with Histone
Deacetylase Inhibitors on Leukemia Cells Pp. 62-77
Ota Fuchs, Dana Provaznikova, Iuri Marinov, Katerina
Kuzelova and Ivan Spicka
[Abstract] [Purchase
Article] [PMID:
19275578 PubMed - indexed for MEDLINE]
Abstracts
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19275572 PubMed - indexed for MEDLINE]
Promising Therapies in Sickle Cell Disease
R. Raghupathy and H.H. Billett
Despite the fact that sickle cell anemia was one of the
first diseases to have a demonstrated genetic etiology, to
date there is still only one approved therapy for this disease.
Recent increases in our understanding of the pathophysiology
of the disease should translate into improved and more rapid
development of newer therapies. This review will focus on
the following current and potential therapeutic strategies
to reduce the morbidity of sickle cell anemia. 1) Therapies
such as decitabine, hydroxyurea, butyrate, lenalidomide and
pomalidomide, which decrease the polymerization rate of HbS
by increasing the concentration of Hb F; 2) Drugs that decrease
relative intracellular HbS concentration by increasing total
cell volume via inhibition of normal membrane ion
exchange channels, such as KCL Cotransporter and Gardos Channels.
These inhibitors include magnesium pidolate, imidazole antimycotics,
arginine and Senicapoc; 3) Treatment of sickle cell vasoocclusion
through inhibition of endothelial or cell surface adhesion
molecules, such ICAM 4 and
αvβ3
integrins, by drugs related to the GPIIbIIIa
inhibitors or adhesion molecule modulators, and 4) Attempts
to achieve vasodilation by nitric oxide and antioxidant therapy.
This review will discuss the status of these emerging therapies
in the treatment of sickle cell anemia.
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Von Willebrand Factor: Drug and Drug Target
Simon F. De Meyer, Bauke De Maeyer, Hans Deckmyn and Karen Vanhoorelbeke
One of the key players in many thrombotic complications
is von Willebrand factor (VWF), a large, multimeric glycoprotein
that is present in plasma where it fulfils a crucial role
in haemostasis. First, VWF recruits platelets to vascular
lesions by acting as a linker molecule between the exposed
collagen and free-flowing platelets in the circulation. Second,
by serving as a carrier protein for the coagulation factor
VIII, VWF protects this anti-haemophilic factor from rapid
degradation. Quantitative or qualitative defects in VWF result
in the most common bleeding disorder in man, known as von
Willebrand disease, illustrating the central role of VWF in
haemostasis. On the other hand, a thrombotic risk emerges
when over-reactive VWF molecules can bind spontaneously to
platelets. It is clear that because of its pivotal role in
maintaining the fine balance between bleeding and thrombosis,
VWF is an attractive but delicate drug target. This review
focuses on the role of VWF in both haemostasis and thrombosis
with special attention to the molecule as drug and drug target
respectively.
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Resistance to Imatinib in Chronic Myeloid Leukemia and Therapeutic
Approaches to Circumvent the Problem
Massimo Breccia and Giuliana Alimena
The majority of patients with chronic phase chronic myeloid
leukaemia (CP-CML) treated with imatinib achieves cytogenetic
disease remission. Molecular monitoring for residual disease
has prognostic significance: rising BCR-ABL levels may provide
earliest indication that a patient has become resistant to
treatment. The emergence of resistance to imatinib has dampened
the enthusiasm for this drug. The most common cause of resistance
is the selection of leukemic clones mutated in ABL kinase
domain due to amino acid substitutions with prevention of
appropriate binding of the drug. Amplification and over-expression
of BCR-ABL, acquired cytogenetic aberrations and modulation
of drug efflux or influx transporters have been reported.
These observations have established the rationale for the
creation of new compounds that have been explored in clinical
trials. This review will discuss the underlying mechanisms
of imatinib-resistance and new strategies to avoid and overcome
this phenomenon.
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Electrocardiographic Abnormalities in Thalassemia Patients
with Heart Failure
Luigi Mancuso, Andrea Mancuso, Elvira Bevacqua
and Paolo Rigano
Data concerning electrocardiographic (ECG) abnormalities
in thalassemic cardiomyopathy are scanty. Current techniques
to detect early findings of myocardial involvement in thalassemia
(Magnetic Resonance, Stress Echo, Tissue Doppler Imaging)
are not widely available. We sought to determine whether new
ECG abnormalities emerge in thalassemia patients when heart
failure due to cardiomyopathy occurs. ECG and Echo Doppler
examinations of 28 consecutive adult thalassemia patients
with heart failure observed at our hospital were compared
with ECG and Echo Doppler examinations performed before the
onset of heart dysfunction and with those of 60 age and sex-matched
patients with thalassemia without evidence of cardiac involvement.
All the patients with heart failure had new ECG abnormalities.
New onset supraventricular arrhythmias, T wave inversion,
low voltages, right QRS axis deviation and S1Q3 pattern developed
respectively in 46%, 79%, 43%, 18% and 15% of thalassemic
patients with heart failure. None of the patients without
heart failure showed any ECG abnormality (P<0.001).
In conclusion this study suggests that new onset ECG abnormalities
are always evident in patients with and always absent in patients
without heart failure due to thalassemic cardiomyopathy.
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Thrombotic Microangiopathies: Towards a Pathophysiology Based
Classification
Paul Coppo and Agnès Veyradier
Thrombotic microangiopathies (TMA) encompass various
diseases characterized by a microangiopathic hemolytic anemia,
platelet clumping, and organ failure of variable severity.
Thrombotic thrombocytopenic purpura (TTP) is a particularly
severe form of TMA characterized by systemic organ failure
which results from a severe defect in ADAMTS13, a plasma enzyme
specifically involved in the cleavage of highly hemostatic
unusually large (UL) von Willebrand factor (VWF) multimers
into smaller and less adhesive VWF forms. Failure to degrade
these UL-VWF multimers leads to excessive platelet aggregates
and capillary occlusion. ADAMTS13 deficiency results from
bi-allelic mutations in hereditary TTP, whereas in acquired
forms it results from autoantibodies that alter the protein
function. Patients with acquired idiopathic TTP have a trend
to develop autoimmunity, since a clinical context of autoimmunity
may be found in 30 p. cent of cases. Moreover, the remarkable
efficiency of monoclonal antibodies directed against CD20
antigen of B lymphocytes in refractory or chronic relapsing
forms provides an additional indirect argument to consider
acquired TTP as an autoimmune disease.
Hemolytic uremic syndrome (HUS) is characterized prominently
by a renal failure. In most cases, HUS is caused by entero-hemorrhagic
Escherichia coli (diarrhea-positive HUS). Diarrhea-negative
HUS, termed atypical HUS, was associated with a dysfunction
in complement pathway involving mutations in factor H, factor
I, CD46/MCP, factor B and C3 components.
The major improvement in our understanding of TMA pathophysiology
allows now a more accurate molecular classification of TMA
syndromes, which opens fascinating perspectives of targeted
therapies in the forthcoming years.
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Chromatin Structure and Epigenetics of Tumour Cells: A Review
Eva Bártová, Jana Krejcí,
Roman Hájek, Andrea Harnicarová and Stanislav
Kozubek
Tumour cells are characterized by karyotype instability,
which is accompanied by specific events in the chromatin structure
and epigenetic patterns. Epigenetics involves heritable changes
in the physical and biochemical state of chromatin, which
have no effect on DNA sequences; therefore, changes in the
nuclear radial arrangement of chromosomes can also be considered
epigenetic events. Nuclear radial distributions of select
genomic regions have been studied in many tumour cells and
are not influenced by aberrations in chromosome number. On
the other hand, genes involved in translocations take up new
positions midway between the original coding sequences. The
differentiation of leukaemia cells with clinically used agents
is often accompanied by nuclear repositioning of tumour-related
genes. However, the nuclear rearrangement is cell-type specific
and not always associated with changes in the transcriptional
activity. Similarly, cell type-specific chromatin structure
is observed in tumour cells treated with select cytostatics
and inhibitors of epigenetic processes, which have significant
influences on the histone code. Chromatin structure and histone
modifications were also affected by gamma radiation in leukaemia,
multiple myeloma, and solid tumour cells. Interestingly, gamma
radiation induced loci proximity, which has been suggested
to increase the probability of exchange aberrations typically
associated with tumour progression.
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[Purchase
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19275578 PubMed - indexed for MEDLINE]
Antiproliferative and Proapoptotic Effects of Proteasome Inhibitors
and their Combination with Histone Deacetylase Inhibitors
on Leukemia Cells
Ota Fuchs, Dana Provaznikova, Iuri Marinov, Katerina
Kuzelova and Ivan Spicka
New chemotherapeutic agents are still required to further
optimise treatment of leukemia patients. Proteasome inhibition
by bortezomib, PR-171 (carfilzomib) and NPI-0052 (salinosporamide
A) has been successfully used for the treatment of multiple
myeloma and mantle cell lymphoma and is considered also as
novel treatment strategy in leukemia. Combination of proteasome
inhibitors bortezomib and NPI-0052 induces synergistic anti-multiple
myeloma activity both in vitro using multiple myeloma
cells and in vivo in a human plasmacytoma xenograft
mouse model. Cell death resulting from proteasome inhibition
requires caspase activation and increased levels of reactive
oxygen species. While bortezomib induces several caspases,
NPI-0052 activates predominantly caspase-8-dependent pathway.
We studied the effect of borte-zomib (10 nM) on DNA synthesis
and apoptosis in human acute myeloid cell lines KASUMI-1,
ML-1, ML-2 and CTV-1 cells. Bortezomib was potent inhibitor
of DNA synthesis in all four types of leukemia cells and induced
apoptosis in KA-SUMI-1, ML-2 and CTV-1 cells but not in ML-1
cells. Other research groups showed that histone deacetylase
inhibitors (valproic acid or benzamide derivative MS-275)
in combination with NPI-0052 or PR-171 induced greater levels
of acute leukemia cell death than in combination with bortezomib.
Proteasome inhibition as monotherapy and its combination with
many conventional therapies as novel treatment strategies
in leukemia are promising. Malignant cells are more sensitive
to this treatment than normal hematopoietic cells.
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