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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 20, 2007
Contents
Killer Beacons for Combined Cancer Imaging and Therapy
Pp. 2110-2125
Klara Stefflova, Juan Chen and Gang Zheng
[Abstract]
Zoledronic Acid –a Multiplicity of Anti-Cancer
Action Pp. 2126-2135
Takeshi Yuasa, Shinya Kimura, Eishi Ashihara, Tomonori
Habuchi and Taira Maekawa
[Abstract]
DNA Minor Groove Binders: an Overview on Molecular
Modeling and QSAR Approaches Pp. 2136-2160
Antonino Lauria, Alessandra Montalbano, Paola Barraja,
Gaetano Dattolo and Anna Maria Almerico
[Abstract]
Prostacyclin, Atherothrombosis, and Cardiovascular
Disease Pp. 2161-2169
E. Arehart, S. Gleim, Z. Kasza, K.M. Fetalvero, K.A. Martin
and J. Hwa
[Abstract]
Contribution of Platelet-Derived CD40 Ligand to Inflammation,
Thrombosis and Neoangiogenesis Pp. 2170-2180
P. Ferroni, F. Santilli, F. Guadagni, S. Basili and G.
Davì
[Abstract]
The Role of PDE5-Inhibitors in Cardiopulmonary Disorders:
From Basic Evidence to Clinical Development Pp. 2181-2192
Marco Guazzi and Michele Samaja
[Abstract]
Diabetic Cardiomyopathy and its Prevention by Metallothionein:
Experimental Evidence, Possible Mechanisms and Clinical Implications
Pp. 2193-2203
Lu Cai
[Abstract]
Mouse Models of Asthma: Can They Give Us Mechanistic
Insights into the Role of Nitric Oxide? Pp. 2204-2213
V.C. Mathrani, N.J. Kenyon, A. Zeki and J.A. Last
[Abstract]
Abstracts
[Back to top]
Killer Beacons for Combined Cancer Imaging
and Therapy
Klara Stefflova, Juan Chen and Gang Zheng
Precisely localizing therapeutic agents in neoplastic areas
would greatly improve their efficacy for killing tumor cells
and reduce their toxicity to normal cells. Photodynamic therapy
(PDT) is a promising cancer treatment modality, and near-infrared
fluorescence imaging (NIRF-I) is a sensitive and noninvasive
approach for in vivo cancer detection. This review
focuses on the current efforts to engineer single molecule
constructs that allow these two modalities to be combined
to achieve a high level of selectivity for cancer treatment.
The primary component of these so called killer beacons is
a fluorescent photosensitizer responsible for both imaging
and therapy. By attaching other components, e.g. various DNA-
or peptide-based linkers, quenchers or cancer cell-specific
delivery vehicles, their primary diagnostic and therapeutic
functions as well as their target specificity and pharmacological
properties can be modulated. This modular design makes these
agents customizable, offering the ability to assemble a few
simple and often interchangeable functional modules into beacons
with totally different functions. This review will summarize
following three types of killer beacons: photodynamic molecular
beacons, traceable beacons and beacons with built-in apoptosis
sensor. Despite the rapid progress in killer beacon development,
numerous challenges remain before these beacons can be translated
into clinics, such as photobleaching, delivery efficiency
and cancer-specificity. In this review we outline the basic
principles of killer beacons, the current achievements and
future directions, including possible cancer targets and different
therapeutic applications.
[Back to top]
Zoledronic Acid –a Multiplicity of Anti-Cancer
Action
Takeshi Yuasa, Shinya Kimura, Eishi Ashihara, Tomonori
Habuchi and Taira Maekawa
Bisphosphonates (BPs) are inhibitors of bone-resorption and
have become the current standard of care for preventing skeletal
complications associated with bone metastases. Among BPs,
zoledronic acid (ZOL) has the strongest activity of anti-bone
resorption and shows diverse direct anti-cancer effects in
vitro. Some chemical and biological characteristics of
ZOL indicate the potential for in vivo growth inhibition
and the mechanisms responsible for the observed anti-cancer
effects are beginning to be elucidated. ZOL inhibits farnesyl
pyrophosphate synthase, a key enzyme in the mevalonate pathway.
Consequently, it inhibits the prenylation of small G-proteins
such as Ras, Rap1, Rho and Rab, reduces the signals they mediate,
and thereby prevents the growth, adhesion/spreading, and invasion
of cancer cells. ZOL, which has a high affinity for mineralized
bone, rapidly localizes to bone, resulting in therapeutically
effective local concentrations for the cancer cells in bone.
ZOL also blocks osteolysis and osteoclastgenesis, thus preventing
the release of various growth factors which are abundantly
stored in bone. Moreover, ZOL stimulates γδ
T cells, which play important roles in innate immunity against
cancer. In addition, ZOL is also a potent inhibitor of angiogenesis,
probably due to the modification of various angiogenic properties
of endothelial cells. Furthermore, ZOL synergizes with a variety
of anticancer agents including chemotherapeutic drugs, molecular
targeted agents, and other biological agents. Based on these
potential anti-cancer properties, several clinical trials
have been initiated to test the combination of ZOL and other
agents. The accumulated encouraging evidence to date indicate
that ZOL is an attractive anti-cancer agent which promises
to be the next exciting therapy for patients with various
cancers.
[Back to top]
DNA Minor Groove Binders: an Overview on Molecular
Modeling and QSAR Approaches
Antonino Lauria, Alessandra Montalbano, Paola Barraja,
Gaetano Dattolo and Anna Maria Almerico
Molecular recognition of DNA by small molecules and proteins
is a fundamental problem in structural biology and drug design.
Understanding of recognition in both sequence-selective and
sequence neutral ways at the level of successful prediction
of binding modes and site selectivity will be instrumental
for improvements in the design and synthesis of new molecules
as potent and selective gene-regulatory drugs.
Minor groove is the target of a large number of non-covalent
binding agents. DNA binding with specific sequences, mostly
AT, takes place by means of a combination of directed hydrogen
bonding to base pair edges, van der Waals interactions with
the minor groove walls and generalized electrostatic interactions.
These factors are also responsible for protein-DNA recognition,
and a number of unifying rules governing the interactions
have been elucidated although it has been realized that the
earlier goal of a simple recognition code between amino acids
and bases is not attainable.
At present relatively little is understood about the mode
of action at the molecular level of the majority of minor
groove-interacting drugs, although there is increasing evidence
that they may act by directly blocking or inhibiting protein–DNA
recognition.
The present review has the aim to focus on interactions between
minor groove binders and DNA through a variety of techniques
that are commonly used to analyze the DNA binding properties
of small molecules.
In fact in the last years several articles dealing with in
silico techniques on DNA minor groove binders (molecular
modeling, molecular dynamics, QSAR) have been published. All
these studies can be considered a support in defining valid
predictive models. For this reason a compendium of all matter
could be an useful support for future developments.
[Back to top]
Prostacyclin, Atherothrombosis, and Cardiovascular
Disease
E. Arehart, S. Gleim, Z. Kasza, K.M. Fetalvero, K.A. Martin
and J. Hwa
Prostacyclin (PGI2) is a
major product of COX-2 catalyzed metabolism of arachidonic
acid in the endothelium. Recent studies have demonstrated
that PGI2 protects against
atherothrombosis. The prostacyclin receptor knockout mice
exhibit increased atherosclerosis, enhanced thrombosis, and
enhanced proliferative response to carotid vascular injury
with increased intima to media ratios [1-3]. Moreover, the
recent withdrawal of rofecoxib (Vioxx™)
due to increased cardiovascular events further supports the
critical role of prostacyclin in inhibiting atherothrombosis
in humans. Such studies have paralleled intense chemical biology
studies to develop more stable prostacyclin analogues. Indeed
a number of these analogues are currently being successfully
used for the treatment of pulmonary hypertension. In this
review we will summarize the current literature on some principles
of prostacyclin analogue development, our current understanding
of the receptor, and recent developments which implicate prostacyclin
in atherothrombotic protection. More than 68 million Americans
suffer from cardiovascular disease, which causes more deaths,
disability and economic loss than any other group of diseases.
Further clinical investigations of orally stable prostacyclin
analogues for treatment of cardiovascular diseases other than
pulmonary hypertension may now be warranted.
[Back to top]
Contribution of Platelet-Derived CD40 Ligand to Inflammation,
Thrombosis and Neoangiogenesis
P. Ferroni, F. Santilli, F. Guadagni, S. Basili and G.
Davì
CD40-CD40L interactions have been involved in inflammation
and thrombosis. Several diseases are characterized by inflammation,
hypercoagulability and increased prevalence of thromboembolic
events. In the past decade, a series of preclinical and clinical
studies has provided more insight into the pathogenetic mechanisms
linking inflammatory mediators to the activation and regulation
of the haemostatic system. In particular, the study of CD40-CD40L
interactions has greatly contributed to understanding the
role of platelets in a variety of pathophysiological conditions,
including atherothrombosis, immuno-inflammatory diseases and,
possibly, cancer. A wide variety of preclinical and clinical
studies have generated clinical interest in the use of CD40L
as a prognostic marker of thrombotic risk. However, the use
of sCD40L in clinical studies requires reliable methods. For
the correct interpretation of results, clinical and research
laboratories and physicians must be aware of the limitations
of immunoassays for this cytokine, which underlines the need
for standardization of preanalytic conditions. This review
will focus on biochemical evidence of CD40L involvement in
platelet activation, contribution of platelet-derived CD40L
to inflammation, thrombosis and neoangiogenesis, and possible
methodological pitfalls regarding the appropriate specimen
and preparation for laboratory evaluation of blood soluble
CD40L as a biomarker in various human diseases characterized
by underlying inflammation, such as atherothrombosis, cancer
and immuno-inflammatory diseases.
[Back to top]
The Role of PDE5-Inhibitors in Cardiopulmonary Disorders:
From Basic Evidence to Clinical Development
Marco Guazzi and Michele Samaja
Phosphodiesterases (PDE) are a class of proteins whose most
relevant biological activity concerns the modulation of intracellular
levels of cyclic nucleotides, e.g., cGMP and cAMP. PDE isoenzyme
5 (PDE5) is specifically involved in cGMP inactivation in
the smooth muscle cell. Chemical inhibition of PDE5 by sildenafil,
tadalafil or vardenafil recently became a valid therapeutic
option aimed at overexpressing the molecular pathway originated
from nitric oxide and expressed via increased cell
cGMP availability. Based on the optimal tolerability and proven
efficacy in various human disorders, EMEA and FDA have approved
PDE5 inhibition as an efficient therapy in some cardiovascular,
pulmonary and vascular diseases. More specifically, PDE5 inhibition
appears successful for the treatment of idiopathic arterial
pulmonary hypertension. Furthermore, PDE5 inhibition resulted
in important protective effects in the myocardium, i.e., antyhypertrophic
and antiapoptic, as well as vascular functions, i.e., increased
tolerance to ischemia/reperfusion injury and improved endothelial
function, thereby implying a potential usefulness in the treatment
of patients with heart failure and coronary artery disease.
Evidence currently available for considering PDE5-inhibition
an additional opportunity in the treatment of common cardiopulmonary
disorders is here provided.
[Back to top]
Diabetic Cardiomyopathy and its Prevention by Metallothionein:
Experimental Evidence, Possible Mechanisms and Clinical Implications
Lu Cai
Cardiac failure is a leading cause for the mortality of diabetic
patients, in part due to a specific cardiomyopathy, referred
to as diabetic cardiomyopathy, which occurs with or without
co-existence of vascular diseases. Although several mechanisms
responsible for diabetic cardiomyopathy have been proposed,
oxidative stress is widely considered as one of the major
causes for the pathogenesis of the disease. Thus, a few laboratories
are trying to develop antioxidants used to prevent diabetic
cardiomyopathy. Metallothioneins (MTs) are cysteine-rich metal-binding
proteins with several biological roles including antioxidant
property. We and others have indicated the significant cardiac
protection of MT against diabetes using cardiac-specific MT-overexpressing
transgenic mice and OVE26MT mice (cross-bred of cardiac MT
transgenic mice with genetically engineered diabetic OVE26
mice). Several possible mechanisms responsible for MT’s
cardiac protection from diabetes were revealed. These include
MT’s important roles in calcium regulation, zinc homeostasis,
insulin sensitization, and antioxidant action. Since MT is
ubiquitously expressed in mammalian tissues and is highly
inducible by a variety of reagents such as zinc, the clinical
potential for inducing cardiac MT as an antioxidant by zinc
supplementation to prevent various diabetic complications,
including cardiomyopathy, has been explored in diabetic animal
models and patients. Since zinc has been therapeutically used
for several other non-diabetic diseases in clinics, it provides
further potential use of zinc for diabetic patients. Therefore,
this review will briefly introduce the biochemical features
of MT along with its critical roles in redox homeostasis and
antioxidant function in the heart, and then discuss the current
research on the prevention of diabetic cardiomyopathy by MT
with an emphasis on experimental evidence, possible mechanisms,
and clinical implications.
[Back to top]
Mouse Models of Asthma: Can They Give Us Mechanistic
Insights into the Role of Nitric Oxide?
V.C. Mathrani, N.J. Kenyon, A. Zeki and J.A. Last
New clinical practice guidelines for patients with asthma
include the recommendation to monitor exhaled breath nitric
oxide (NO) levels. NO concentrations in exhaled breath are
increased in asthmatics and increased NO levels correlate
with worsening airway inflammation and asthma symptoms. The
multiple roles of NO in the lung have not been delineated
clearly. Clinical trials are being performed presently that
test the apparently conflicting hypotheses that either donors
or inhibitors of NO in the lung are effective strategies for
treating asthma. These strategies evolved, in part, from results
of pre-clinical studies performed in mice and other animal
models.
This review evaluates the existing literature with regard
to mouse models of asthma and explores the often conflicting
data on the role of NO, the nitric oxide synthase (NOS) enzymes,
and the arginase enzymes in allergic airway inflammation.
While we will emphasize the ovalbumin exposure mouse model,
we will also examine other models. Where inconsistencies are
identified among the studies, we attempt to determine whether
such inconsistencies arise from methodological differences
or alternative mechanisms. Ultimately, we address whether
the allergen-exposed mouse is a suitable model for identifying
promising new drugs for the treatment of human asthma. While
a consensus is building that NO is beneficial or protective
in subsets of asthmatics, results from studies using mouse
models to investigate the individual roles of NO and the NOS
enzymes in airway inflammation are often contradictory. Further
research efforts with this model will allow us to distinguish
which asthma patients may benefit best from NO donors and
which may benefit from NO inhibitors.
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