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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 30, 2007
Contents
Targeting Tumorangiogenesis in Lung Cancer by Suppression
of VEGF and its Receptor – Results from Clinical Trials
and Novel Experimental Approaches Pp. 3157-3165
H. Kuhn, S. Hammerschmidt and H. Wirtz
[Abstract]
Adhesion Molecules and Kinases Involved in γδ
T Cells Migratory Pathways: Implications for Viral and Autoimmune
Diseases Pp. 3166-3170
Alessandro Poggi, Silvia Catellani, Daniela Fenoglio,
Giovanna Borsellino, Luca Battistini and Maria Raffaella Zocchi
[Abstract]
PDE4D Gene in the STRK1 Region on
5q12: Susceptibility Gene for Ischemic Stroke Pp.
3171-3178
Tomohiro Nakayama, Satoshi Asai, Naoyuki Sato and Masayoshi
Soma
[Abstract]
Biodistribution Processes as Underestimated Confounders
in Translational Stroke Research Pp. 3179-3184
Dirk M. Hermann
[Abstract]
The Heterogeneity of Amyotrophic Lateral Sclerosis:
Possible Explanation of Treatment Failure Pp. 3185-3200
Ettore Beghi, Tiziana Mennini, Caterina Bendotti, Paolo
Bigini,Giancarlo Logroscino,Adriano Chiò,
Orla Hardiman, Douglas Mitchell, Robert Swingler, Bryan J.
Traynor and Ammar Al-Chalabi
[Abstract]
Endomorphin Analogs Pp.
3201-3208
Anna Janecka, Renata Staniszewska and Jakub Fichna
[Abstract]
Role of Lysophosphatidylcholine (LPC) in Atherosclerosis
Pp. 3209-3220
Takayuki Matsumoto, Tsuneo Kobayashi and Katsuo Kamata
[Abstract]
Origin and Evolutionary Process of the Genetic Code
Pp. 3221-3231
Kenji Ikehara and Yuka Niihara
[Abstract]
Glycosylation of HIV-1 gp120 V3 Loop: Towards the
Rational Design of a Synthetic Carbohydrate Vaccine
Pp. 3232-3242
Suzanne Sirois, Mohamed Touaibia, Kuo-Chen Chou and René
Roy
[Abstract]
Chemical Instability Determines the Biological Action
of the Artemisinins Pp. 3243-3259
F. Herwig Jansen and Shahid A. Soomro
[Abstract]
Abstracts
[Back to top]
Targeting Tumorangiogenesis in Lung Cancer by Suppression
of VEGF and its Receptor – Results from Clinical Trials
and Novel Experimental Approaches
H. Kuhn, S. Hammerschmidt and H. Wirtz
Tumor vascularisation, the formation of blood vessels
is a central process to allow tumor growth beyond limited
sizes and to facilitate metastasis formation. Angiogenesis
is regulated by a balance of stimulatory and inhibitory factors.
Angiogenic factors have been the focus of intense research
since the prospects of new therapeutic approaches seemed enormous.
Vascular endothelial growth factor (VEGF) has emerged as the
most potent and most specific growth factor for endothelial
cells and therefore a relevant target for novel anticancer
therapy. A wide range of agents have been designed for their
ability to interfere the VEGF signalling pathway. In addition,
several drugs are currently in advanced clinical development.
This review describes the current experimental strategies
to inhibit VEGF and will also summarize and discuss the results
of recent clinical trials involving anti-VEGF compounds either
as standalone therapy or in combination with chemotherapy
in lung cancer.
[Back to top]
Adhesion Molecules and Kinases Involved in γδ
T Cells Migratory Pathways: Implications for Viral and Autoimmune
Diseases
Alessandro Poggi, Silvia Catellani, Daniela Fenoglio,
Giovanna Borsellino, Luca Battistini and Maria Raffaella Zocchi
γδ
T lymphocytes are involved in the defence from viral and mycobacterial
infections; however they are also responsible for autoimmune
reactions. Herein, we discuss the characteristics of these
cells, focusing on the mechanism(s) underlying extravasation
and tissue localization. We show that Vδ1
and Vδ2
γδT
cells display differential expression of adhesion molecules
and chemokine receptors, the former being preferentially PECAM-1+CXCR4+,
the latter expressing NKRP1A and CXCR3. The two cell populations
transmigrate across endothelial cells by activation of distinct
kinase pathways and in response to interferon-γ-inducing
protein-10 (IP-10/CXCL10) or stromal-derived factor-1 (SDF-1/CXCL12)
according to the expression of the specific receptors CXCR3
and CXCR4. IP-10/CXCL10 and SDF-1/CXCL12-induced transmigration
are phosphoinositide-3 kinase (PI-3K) and Akt/PKB-dependent.
In addition, occupancy of CXCR3, but not of CXCR4, leads to
CAMKII activation; blocking of CAMKII decreases IP-10/CXCL10
and 6Ckine/SLC/CCL21-driven transmigration.
We report that HIV-1-infected patients have an increased number
of circulating Vδ1
T cells possibly due to the interference of Tat protein on
the function of chemokine receptors. In turn, patients with
relapsing-remitting multiple sclerosis (MS), display an increase
in peripheral Vδ2
γδ
T cells and this is related to interleukin-12-mediated upregulation
of NKRP1A. Finally, the possible role of γδ
T lymphocytes in post-transplantation immune reconstitution
is discussed.
[Back to top]
PDE4D Gene in the STRK1 Region on
5q12: Susceptibility Gene for Ischemic Stroke
Tomohiro Nakayama, Satoshi Asai, Naoyuki Sato and Masayoshi
Soma
Stroke is thought to be a multifactorial disease that is affected
by several environmental factors and genetic variants. In
2002, a candidate locus for stroke (STRK1) was identified
with a significant logarithm of odds (LOD) score at 5q12 in
Caucasians, and in 2003, the PDE4D gene was subsequently
identified as a susceptibility gene at this locus. Some investigators
have recently examined whether polymorphisms in the PDE4D
gene are associated with stroke in population studies. Some
of these studies have reported the polymorphisms to be associated
with a risk of stroke, while others have reported the exact
opposite. These discrepancies have been attributed to racial
differences or differences in methodologies and analyses.
In 2006, a powerful method for isolating the susceptibility
region at 5q12 was reported in a haplotype-based case-control
study. In the present paper, we review both current issues
and progress in the isolation of susceptibility genes for
ischemic stroke, with particular emphasis on the PDE4D
gene in the STRK1 region of 5q12.
[Back to top]
Biodistribution Processes as Underestimated Confounders
in Translational Stroke Research
Dirk M. Hermann
Pharmacological therapies in ischemic stroke have made
limited progress in recent years. After many negative neuroprotection
trials in humans, considerable concerns have been raised about
future research strategies. This led to expert rounds, the
so-called STAIR conferences, which critically reviewed previous
studies and provided research recommendations. Hopes were
raised that STAIR might lead to breakthroughs in neuroprotection
strategies in the near future. Whether this will indeed become
true, remains to be awaited. An important aspect in the context
of brain pharmacotherapies is the blood-brain barrier, which
prevents drugs from brain entrance. The blood-brain barrier
not only acts as passive diffusion barrier, it expresses active
transporters that eliminate drugs from the brain and thereby
profoundly influence drug tissue levels. These transporters
exhibit strong variabilities between animals and humans, which
make it hardly possible to predict brain concentrations of
drugs over species barriers. As such, drug biodistribution
turns out to be a major confounder in pharmacological therapies.
This paper claims that more precise brain accumulation studies
are needed in preparation for clinical trials both in animals
and in humans. This might lead to better dose selections and
higher success rates of future pharmacological trials.
[Back to top]
The Heterogeneity of Amyotrophic Lateral Sclerosis:
Possible Explanation of Treatment Failure
Ettore Beghi, Tiziana Mennini, Caterina Bendotti, Paolo
Bigini,Giancarlo Logroscino,Adriano Chiò,
Orla Hardiman, Douglas Mitchell, Robert Swingler, Bryan J.
Traynor and Ammar Al-Chalabi
Amyotrophic lateral sclerosis (ALS) is a severe clinical
condition characterized by upper and lower motor neuron degeneration
for which there is no truly effective treatment. The absence
of an effective treatment can be explained in part by the
complex and heterogeneous genetic, biochemical, and clinical
features of ALS. While ALS accounts for the majority of the
motor neuron diseases, the recognition of disease variants
and mimic syndromes may lead to further insights into possible
causes for the generality of ALS.
From a biochemical perspective, the process of motor neuron
degeneration is complex and the multifactorial influences
and potential biomarkers of ALS have never been assessed in
the light of the clinical heterogeneity of ALS. Several genes
and environmental influences have been suggested as possible
risk factors of ALS. A better understanding of interactions
between these risk factors, potential biomarkers and heterogeneous
clinical features may lead to more clearly defined pathological
profiles among individuals or groups of ALS patients and in
turn lead to more focused therapeutic trials.
[Back to top]
Endomorphin Analogs
Anna Janecka, Renata Staniszewska and Jakub Fichna
Opiate alkaloids, such as morphine, are powerful analgesic
agents that are the drugs of choice for the treatment of severe
pain. The pharmacological effects of opiates are mediated
through the binding and activation of membrane-bound opioid
receptors that are found in the central and peripheral nervous
systems.
Opioid receptors have been classified into three different
types, μ,
δ and
κ,
and are activated by the specific ligands. It has been demonstrated
that the most potent antinociceptive effects are mediated
by the μ-receptor.
However, until 1997 no endogenous ligand for this receptor
was known. The identification of endomorphins opened a new
era in the research of the μ-opioid
system. They are the first reported brain peptides that label
μ-receptor
with high affinity and selectivity and therefore are proposed
as the endogenous μ-opioid
receptor ligands. Morphine and endomorphins act as agonists
at the same µ-opioid receptor, but the latter are thought
to inhibit pain without some of the undesired side-effects
of plant opiates. This observation encouraged extensive studies
on the possible use of endomorphin analogs as analgesics instead
of morphine.
This review summarizes a decade of research on structure-activity
relationship studies of endomorphin analogs, aimed at obtaining
compounds with increased bioavailability, in particular with
better barrier penetration and resistance against enzymatic
degradation. Chemical modifications that led to obtaining
potent and selective agonists and antagonists based on the
structure of endomorphins are discussed.
[Back to top]
Role of Lysophosphatidylcholine (LPC) in Atherosclerosis
Takayuki Matsumoto, Tsuneo Kobayashi and Katsuo Kamata
Lysophosphatidylcholine (LPC) is a bioactive proinflammatory
lipid generated by pathological activities. LPC is also a
major phospholipid component of oxidized low-density lipoprotein
(Ox-LDL) and is implicated as a critical factor in the atherogenic
activity of Ox-LDL. LPC is believed to play an important role
in atherosclerosis and inflammatory diseases by altering various
functions in a number of cell-types, including endothelial
cells, smooth muscle cells, monocytes, macrophages, and T-cells.
LPC activates several second messengers -- including protein
kinase C, extracellular-signal-regulated kinases, protein
tyrosine kinases, and Ca2+
-- implicating the engagement of transduction mechanisms in
its observed actions. Moreover, recent evidence suggests that
in several cell-types, cloned orphan G-protein-coupled receptors
may serve as the specific receptors via which LPC
modulates second messenger pathways (although LPC may not
be a direct ligand of such receptors). In addition, current
evidence suggests that LPC impairs the endothelium-dependent
relaxations mediated by endothelium-derived relaxing factors
and directly modulates contractile responses in vascular smooth
muscle. However, despite all this, and although elevated levels
of LPC have been linked to the cardiovascular complications
associated with atherosclerosis, ischemia, and diabetes, the
precise pathophysiological roles played by LPC in several
states remain to be established. In this review, we focus
in some detail on the entirety of the signal-transduction
system for LPC, its pathophysiological implications, and the
vascular abnormalities associated with it.
[Back to top]
Origin and Evolutionary Process of the Genetic Code
Kenji Ikehara and Yuka Niihara
The genetic code plots the relationship between a triplet
base sequence on RNA and an amino acid that corresponds to
a pro-tein associated with a required function in organisms.
Accurate knowledge about the genetic code, including its origin
and evolutionary process, would be helpful for determining
the causes of genetic disorders and discovering new medical
treatments, as well as for understanding the origin of life.
This review begins with discussion of several well-known theories
on the origin of the genetic code. Then, a GNC-SNS primitive
genetic code hypothesis, which we originally proposed, is
explained in relation to the weak points of other theories.
S and N denote G or C and any of the four bases, respectively.
We also introduce our hypothesis of the GADV-protein world
hypothesis on the origin of life, where GADV stands for the
four amino acids, Gly[G], Ala[A], Asp[D] and Val[V]. Next,
we discuss the reason why genetic disorders, which should
be triggered by base replacements, are repressed at a low
level under the universal genetic code. Finally, we explain
the current difficulties we faced in treating genetic disorders,
suggesting a prospect for a new type of treatments of these
disorders.
[Back to top]
Glycosylation of HIV-1 gp120 V3 Loop: Towards the
Rational Design of a Synthetic Carbohydrate Vaccine
Suzanne Sirois, Mohamed Touaibia, Kuo-Chen Chou and René
Roy
A wide variety of proteins can bind high-mannose oligosaccharides
and are broadly neutralizing against HIV-1. However, suc-cess
in eliciting broadly neutralizing antibodies against HIV-1
has been limited to date. The rational design of an HIV-1
vaccine is based on the information gained through the structural
analysis of antibodies complexed with their epitopes. Of particular
interest to this review are the binding of mannosides to human
monoclonal antibody 2G12 recognizing Man9GlcNAc2
from HIV-1 gp120. It is widely recognized that T-cell-independent
antigens carbohydrates are poorly immunogenic, and fail to
induce memory. To increase the immunogenicity, carbohydrate
antigens have to be coupled to a highly immunogenic carrier.
The design of peptide carbohydrate mimotopes (mimetics of
carbohydrate antigens) is one approach that is currently explored
to elicit neutralizing antibodies. This work is concerned
with existing structural data on Man9GlcNAc2
as the most promising epitope (or glycotope). Structural analysis
of various torsion angles of Man9GlcNAc2
is explored. The focus is made primarily on the third variable
region (V3 loop) of gp120 due to its crucial relevance for
coreceptor usage, as a principal neutralizing determinant
(PND), and for its conserved glycosylation sites N295, N302
and N332. Valuable structural information from glycosylation
effects is taken into account for the development of a V3
loop rational structure-based vaccine strategy using N295
and N302 as potential conformational epitope.
[Back to top]
Chemical Instability Determines the Biological Action
of the Artemisinins
F. Herwig Jansen and Shahid A. Soomro
Artemisinin is a sesquiterpene compound of plant origin.
It has a low molecular weight, and it contains five oxygen
atoms, two in a lactone function, one is part of a seven membered
ring system and two forms a peroxide function bridging over
the seven-membered ring. It is a highly energetic molecule
prone to lose its activity if circumstances permit. Reduction
of its lactone function into dihydroartemisinin makes derivatization
easy. Esterification and ether formation contribute to stability.
Dihydroartemisinin exists preferably in a beta epimeric format
but flip-flops with the alpha epimer. Solvation effects play
a role. In doing so, open forms are created and they contribute
to the instability, both of the peroxide and of the seven-membered
ring. Artemisinins constitute a remarkable class of compounds
which display instability both biologically and chemically
due to the presence of various functional groups. Activity
ranges from a wonderful action against a series of parasites,
in particular malaria and schistosomiasis, to bacteria, fungi
and selected viruses. The latest developments indicate a potential
use in adjuvant cancer chemotherapy. The built-in chemical
instability, necessary for biological action, causes serious
pharmaceutical problems and only a restricted number of derivatives
are useful. Problems are accelerated under tropical conditions
and the basic active drug dihydroartemisinin cannot be used
as such since it is prone to accelerated breakdown into a
series of inactive products. The pitfalls of chemical instability
and pharmaceutical stability are discussed in relation to
the current uses of the drugs.
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