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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 7, 2007
Contents
The Importance of c-Kit and PDGF Receptors as Potential Targets
for Molecular Therapy in Breast Cancer Pp. 735-743
A.E. Roussidis, A.D. Theocharis, G.N. Tzanakakis and N.K.
Karamanos
[Abstract]
The Effect of Ageing on Cytochrome P450 Enzymes: Consequences
for Drug Biotransformation in the Elderly Pp. 745-757
V. Wauthier, R.K. Verbeeck and P. Buc Calderon
[Abstract]
Recent Advances in Antimalarial Compounds and their
Patents Pp. 759-773
Alka Mital
[Abstract]
The Search for a Topical Dual Action Spermicide/ Microbicide
Pp. 775-786
Louise M. Hughes, Renate Griffith and R.J. Aitken
[Abstract]
Inflammation in Chronic Obstructive Pulmonary Disease:
Implications for New Treatment Strategies Pp. 787-796
Liam Gabriel Heaney, John Thomas Lindsay and Lorcan Patrick
Augustine McGarvey
[Abstract]
Survival Factors from Activated Accessory Cells and
their Role in Triggering Autoimmune Diseases Pp.
797-809
Xiaolei Tang
[Abstract]
Some Recent Insights into the Prothrombogenic Mechanisms
of Antiphospholipid Antibodies Pp. 811-826
Maria Todorova and Marta Baleva
[Abstract]
SAR and QSAR of the Antioxidant Activity of Flavonoids
Pp. 827-845
Dragan Amic, Dušanka Davidovic-Amic, Drago Bešlo,
Vesna Rastija, Bono Lucic and Nenad Trinajstic
[Abstract]
Abstracts
[Back to top]
The Importance of c-Kit and PDGF Receptors as Potential Targets
for Molecular Therapy in Breast Cancer
A.E. Roussidis, A.D. Theocharis, G.N. Tzanakakis and N.K.
Karamanos
Molecular therapies target key functional molecules in order
to halter viable operation of cancer cells. Receptor tyrosine
kinases (RTKs) constitute attractive targets, as quite often
their abnormal signaling has been associated with tumor development
and growth. Overexpression of growth factor receptors, including
IGF, EGF, TGF-α,
SCF and PDGF receptors, has been associated with poor prognosis
in breast cancer. Therefore, a number of RTKs are already
targets for novel designed drugs, which involve tyrosine kinase
inhibitors and monoclonal antibodies. Despite the fact that
c-Kit and PDGF-R have been effective targets in a number of
cancers, the experimental results in breast have not yet clarified
their importance. The expression and function of c-Kit in
breast cancer is a quite controversial subject. Several studies
propose that the loss of c-Kit expression has been associated
with tumor progress, whereas other reports indicate not only
its expression but also the implication of c-Kit in breast
cancer. On the other hand, the expression of PDGF-R in breast
cancer is not in question. A number of inhibitors against
tyrosine kinases are currently in trials as to demonstrate
their importance in breast cancer treatment. Imatinib (STI571),
which is a selective tyrosine kinase inhibitor and particularly
of c-Kit and PDGF-R, exhibited encouraging results in respect
to its inhibitory effect in cell growth and invasion potential
in a panel of human breast cancer cell lines. In this review,
the importance of RTKs in human cancer and of c-Kit and PDGF-R
as molecular targets in breast cancer treatment, in the view
of their expression profiles and the in vitro effects
of STI571 is discussed.
[Back to top]
The Effect of Ageing on Cytochrome P450 Enzymes: Consequences
for Drug Biotransformation in the Elderly
V. Wauthier, R.K. Verbeeck and P. Buc Calderon
Ageing is an aggravating factor leading to alterations in
the biotransformation of drugs, and therefore their therapeutic
efficacy and safety. In this review we discuss the influence
of ageing on drug metabolizing enzymes in male Wistar rats.
We report that drug metabolizing enzymes can be affected by
ageing either by post-translational modifications or by transcriptional
modifications. The post-translational modifications could
be due to an increase of oxidative stress during ageing. Although
it is now well established that transcriptional modifications
are due to a change in the GH secretion profile in senescent
rats, the intracellular mechanisms underlying these modifications
are still unclear. In addition to the strong decrease in the
activity of the main CYPs of male rats, we discuss the potential
consequences on human drug metabolism in the elderly.
[Back to top]
Recent Advances in Antimalarial Compounds and their
Patents
Alka Mital
Malaria is one of the most severe tropical parasitic disease
causing 1-3 million deaths annually. In the last 25 years
very few new antimalarial molecules have been developed and
only a limited number of them are currently in various stages
of clinical development. The presently available antimalarial
drugs include artemisinin analogs, quinoline derivatives and
antifolates. This review summarizes recent advances in antimalarial
drug development and world patents published between 2000-2006
claiming new synthetic antimalarial compounds and their activities.
The most over-represented classes of compounds in malaria
patent literature in order of frequency are artemisinin analogs,
quinoline derivatives, DOXP reductoisomerase inhibitors, antifolates
and febrifugine analogues. Many of these patents describe
the novelty and potential of these synthetic derivatives with
an attempt to identify the next generation antimalarials that
may have potential commercial advantages.
[Back to top]
The Search for a Topical Dual Action Spermicide/ Microbicide
Louise M. Hughes, Renate Griffith and R.J. Aitken
There is an urgent clinical need to research novel methods
of fertility control that are also protective against sexually
transmitted diseases (STDs) such as the human immunodeficiency
virus (HIV) or Chlamydia. The most obvious way to
generate such a dual-purpose contraceptive method would be
to develop safe, effective spermicides that were also active
against a wide range of pathogenic organisms. The currently
available formulations such as nonoxynol-9, gramicidin and
benzalkonium chloride are effective spermicides but are toxic
to the vaginal epithelium and do not provide protection against
STDs. Over 60 agents are in clinical trials as potentially
safer topical spermicides and/or microbicides. Compounds that
have reached this stage of development include acid buffers,
detergents, dendrimers, non-nucleoside reverse transcriptase
inhibitors and anionic polymers. In addition, a number of
potential spermicides/microbicides are the subject of preclinical
investigation, including β-cyclodextrin,
cyanovirin, porphyrins, cyclotriazadisulfonamides, dermaseptins,
short-interfering RNA (siRNA) and HIV antibodies. The chemical
principles underlying these disparate approaches and potential
avenues for future investigation are discussed.
[Back to top]
Inflammation in Chronic Obstructive Pulmonary Disease:
Implications for New Treatment Strategies
Liam Gabriel Heaney, John Thomas Lindsay and Lorcan Patrick
Augustine McGarvey
Chronic obstructive pulmonary disease (COPD) is a treatable
and preventable disease but current predictions are that it
will continue to rise as an important cause of mortality and
morbidity worldwide. COPD is a complex inflammatory disease
with both airway and parenchymal lung injury. Currently there
is growing recognition that the inflammatory response extends
beyond the lung, with evidence of systemic inflammation, which
may account for the multi-organ effects associated with COPD.
Early diagnosis and timely therapeutic intervention are likely
to make a significant contribution to tackling this disease.
Smoking cessation remains the single most effective means
of preventing lung function decline and reducing mortality.
At present, no currently available drugs have been shown to
slow the progression of the disease. Pharmacological treatment
has focused largely on symptomatic relief and short-acting
bronchodilators have been the mainstay therapy. Long-acting
beta-2 agonists and anti-cholinergics have provided additional
benefit and anti-inflammatory agents such as inhaled corticosteroids
and theophylline seem to offer benefit in selected patients.
Combinations of the different classes of treatment, particularly
in the same inhaler device, seem to confer particular advantage
with improvements in symptoms, exercise capacity, health status
and reductions in exacerbations.
More research is needed to unravel the important cellular
and molecular processes involved in the pathophysiology of
COPD and ultimately to develop new and more effective forms
of therapy.
[Back to top]
Survival Factors from Activated Accessory Cells and
their Role in Triggering Autoimmune Diseases
Xiaolei Tang
To maintain immune homeostasis, the immune system has evolved
two “opposite” mechanisms to regulate the activation
or expansion of effectors including potential auto-reactive
lymphocytes following an immune response. One is to support
the survival of activated effectors and thereby benefit the
generation of memory response. However, an inappropriate survival
of auto-reactive lymphocytes may lead to autoimmune diseases,
e.g. multiple sclerosis (MS) and rheumatoid arthritis (RA).
The other is to induce apoptosis of most activated effectors,
thereby bringing the immune system to a baseline level after
an immune response. It is known that autoimmune diseases are
due to uncontrolled growth of auto-reactive lymphocytes, eventually
leading to damage of self-tissues or organs. Control of auto-reactive
T lymphocytes therefore constitutes an attractive therapeutic
strategy.
Many studies on accessory cells and their secreted factors
have focused on their role in the effector phase of a specific
autoimmune disease. Recent data, however, support their causative
role in triggering autoimmune diseases. In the past several
years, several cytokines from activated accessory cells were
demonstrated to promote the survival of pathogenic auto-reactive
lymphocytes in animal models of MS, RA, and other autoimmune
diseases. This review therefore focuses on the current knowledge
regarding the role of those soluble survival factors in the
initiation of different autoimmune diseases.
[Back to top]
Some Recent Insights into the Prothrombogenic Mechanisms
of Antiphospholipid Antibodies
Maria Todorova and Marta Baleva
Antiphospholipid antibodies (aPL) are a heterogeneous group
of autoantibodies, detected in the sera of patients with both
autoimmune and various non-autoimmune diseases. They are also
detected in subjects with no overt underlying disease –
the primary antiphosphilipid syndrome (PAPS). High titers
of APL are associated with arterial and venous thrombosis,
recurrent fetal loss and thrombocytopenia. There have been
many suggestions explaining the potential mechanisms of the
procoagulant effect of aPL. These include endothelial cell
(EC) activation; increased adhesion molecule expression; inhibition
of EC prostacyclin release, increased leucocyte adhesion to
EC, downregulation of thrombomodulin expression. APL induce
the procoagulant activity of monocytes via increased tissue
factor expression and directly stimulate platelet hyperactivity
with resultant production of enhanced amounts of the proaggregatory
molecule of TXA2. In vitro studies show
that prepro-endothelin-1 mRNA is induced by human monoclonal
anticardiolipin antibodies and this might contribute to vasospasm,
and, ultimately, to arterial occlusion. The hypercoagulable
state in APS patients is associated with alterations in the
protein C/S pathway. It is suggested that aPL may impair the
protein C anticoagulant system. Acquired protein C and protein
S deficiency is described in patients with APS. Beta2- glycoprotein
I, (Beta2-GPI) a natural anticoagulant, is involved in the
regulation of protein S anticoagulant activity by preventing
the binding of protein S to C4b-binding protein. APL were
shown to inhibit this effect of Beta2- GP I. As the group
of aPL is very heterogeneous, it is unlikely that a single
mechanism is responsible for the thrombogenic activity of
all aPLs associated with thrombosis.
[Back to top]
SAR and QSAR of the Antioxidant Activity of Flavonoids
Dragan Amic, Dušanka Davidovic-Amic, Drago Bešlo,
Vesna Rastija, Bono Lucic and Nenad Trinajstic
Flavonoids are a group of naturally occurring phytochemicals
abundantly present in fruits, vegetables, and beverages such
as wine and tea. In the past two decades, flavonoids have
gained enormous interest because of their beneficial health
effects such as anti-inflammatory, cardio-protective and anticancer
activities. These findings have contributed to the dramatic
increase in the consumption and use of dietary supplements
containing high concentrations of plant flavonoids. The pharmacological
effect of flavonoids is mainly due to their antioxidant activity
and their inhibition of certain enzymes. In spite of abundant
data, structural requirements and mechanisms underlying these
effects have not been fully understood. This review presents
the current knowledge about structure-activity relationships
(SARs) and quantitative structure-activity relationships (QSARs)
of the antioxidant activity of flavonoids. SAR and QSAR can
provide useful tools for revealing the nature of flavonoid
antioxidant action. They may also help in the design of new
and efficient flavonoids, which could be used as potential
therapeutic agents.
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