|
Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 8, 2008
Contents
Conventional and Gene Therapy Strategies for the Treatment
of Brain Tumors Pp. 729-742
J.A. Benítez, G. Domínguez-Monzón and
J. Segovia
[Abstract]
Entry of Oximes into the Brain: A Review
Pp. 743-753
D.E. Lorke, H. Kalasz, G.A. Petroianu and K. Tekes
[Abstract]
New Tubulin Polymerization Inhibitor Derived
from Thalidomide: Implications for Anti-Myeloma Therapy
Pp. 754-765
Masahiro Kizaki and Yuichi Hashimoto
[Abstract]
Amyloid-Related Biomarkers for Alzheimer’s
Disease Pp. 766-771
Niels Andreasen and Henrik Zetterberg
[Abstract]
The Other Side of the Opioid Story: Modulation
of Cell Growt and Survival Signaling Pp. 772-778
Yulong L. Chen, Ping Yee Law and Horace H. Loh
[Abstract]
Lessons from Viruses: Controlling the Function
of Transmembrane Proteins by Interfering Transmembrane Helices
Pp. 779-785
F. Cymer and D. Schneider
[Abstract]
Hyaluronic Acid: Targeting Immune Modulatory
Components of the Extracellular Matrix in Atherosclerosis
Pp. 786-791
Pieter T. Bot, Imo E. Hoefer, Jan J. Piek and Gerard Pasterkamp
[Abstract]
Novel Molecules Targeting Dyslipidemia and Atherosclerosis
Pp. 792-802
A. Tavridou and V.G. Manolopoulos
[Abstract]
Testing of Compounds in Models of Pulmonary Emphysema
Pp. 803-808
Concetta Gardi, Beatrice Arezzini and Piero A. Martorana
[Abstract]
Biopharmaceutics, Pharmacokinetics and Pharmacodynamics
of Antituberculosis Drugs Pp. 809-825
Nageshwar R. Budha, Richard E. Lee and Bernd Meibohm
[Abstract]
Microarray Gene Expression Profiling in Meningiomas
and Schwannomas Pp. 826-833
V. Martinez-Glez, C. Franco-Hernandez and J.A. Rey
[Abstract]
Abstracts
[Back to top]
Conventional and Gene Therapy Strategies for the Treatment
of Brain Tumors
J.A. Benítez, G. Domínguez-Monzón and
J. Segovia
There are several types of primary tumors of the central
nervous system (CNS), and almost half of them are gliomas.
In particular, glioblastoma multiforme (GBM) is very aggressive
and infiltrates into the CNS parenchyma. Despite intense clinical
efforts, the prognosis of patients with this type of tumors
remains very poor, and has not improved in decades, with a
median survival of approximately one year after diagnosis.
Current treatments include surgical resection, radiotherapy
and chemotherapy. However, our knowledge regarding the genetic
basis, as well as the molecular signaling pathways involved
in the origin and progression of the tumors has increased
significantly in the last few years, thus allowing the generation
of new chemotherapeutic agents that are used together with
sophisticated surgical and radiation techniques. Nevertheless,
new approaches are necessary to develop effective treatments
for these tumors. One of these novel strategies is gene therapy
which is particularly well suited to treat gliomas. In this
review we will discuss current therapeutic approaches, as
well as critically analyzing gene therapy methods, the use
of diverse viral and non-viral vectors, different genes and
strategies to treat gliomas, from experimental models to clinical
applications.
[Back to top]
Entry of Oximes into the Brain: A Review
D.E. Lorke, H. Kalasz, G.A. Petroianu and K. Tekes
The passage of hydrophilic drugs, such as oxime acetylcholinesterase
reactivators, into the central nervous system is restricted
by the blood-brain and the blood-cerebrospinal fluid barriers.
The present review summarizes morphological and functional
properties of the blood-brain barrier, blood-cerebrospinal
fluid barrier and cerebrospinal fluid-brain interface and
reviews the existing data on brain entry of oximes.
Due to the virtual absence of transcytosis, lack of fenestrations
and unique properties of tight junctions in brain endothelial
cells, the blood-brain barrier only allows free diffusion
of small lipophilic molecules. Various carriers transport
hydrophilic compounds and extrude potentially toxic xenobiotics.
The blood-cerebrospinal fluid barrier is formed by the choroid
plexus epithelium, whose tight junctions are more permeable
than those of brain endothelial cells. The major function
of plexus epithelium cells is active transport of ions for
the production of the cerebrospinal fluid. The cerebrospinal
fluid-brain interface is not a biological barrier and allows
free diffusion. However, in contrast to passage via
the blood-brain barrier or the blood-cerebrospinal fluid barrier,
direct penetration from the cerebrospinal fluid into the brain
is very slow, since much longer distances have to be covered.
A bulk flow of brain interstitial fluid and cerebrospinal
fluid speeds up exchange between these two fluid compartments.
Oximes, by reactivating acetylcholinesterase, are important
adjunct therapeutics in organophosphate poisoning. They are
very hydrophilic and therefore cannot diffuse freely into
the central nervous system. Changes in brain acetylcholinesterase
activity, oxime concentration and some biological effects
elicited by oxime administration in the periphery indicate,
however, that oximes can gain access to the brain to a certain
degree, probably by carrier-mediated transport, reaching in
the brain about 4-10% of their respective plasma levels. The
clinical relevance of this effect is hotly debated. Possible
strategies to improve brain penetration of oximes are discussed.
[Back to top]
New Tubulin Polymerization Inhibitor Derived from Thalidomide:
Implications for Anti-Myeloma Therapy
Masahiro Kizaki and Yuichi Hashimoto
Despite the conventional and high-dose chemotherapy with
hematopoietic stem cell transplantation, multiple myeloma
eventually relapses, resulting in an incurable hematological
malignancy. Therefore, novel therapeutic approaches in clinical
settings are desired. Recently, thalidomide was introduced
for the treatment of myeloma, and many clinical trials have
since confirmed its efficacy in patients with relapsed/refractory
or newly diagnosed multiple myeloma. Multiple mechanisms have
been proposed to explain thalidomide’s anti-myeloma
activity. However, the precise mechanism underlying this activity
remains unclear, because thalidomide rapidly undergoes spontaneous,
nonenzymatic, hydrolytic cleavage to numerous metabolites
in vivo. To elucidate the exact anti-myeloma mechanism
of thalidomide in vivo, we have performed structural
development studies of thalidomide, and obtained various analogs
with specific molecular properties. Among these derivatives,
we found that a new thalidomide analog, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione
(5HPP-33), has the most potent anti-myeloma effect with tubulin
polymerization inhibiting activity. 5HPP-33 directly inhibited
the growth and survival of various myeloma cells in a dose-dependent
manner with IC50 of 1-10
μM.
In contrast, thalidomide itself did not inhibit RPMI8226 cell
growth. A tubulin polymerization assay using microtubule protein
from porcine brain revealed that 5HPP-33 had potent tubulin
polymerization inhibiting activity with IC50
of 8.1 μM,
comparable to that of rhizoxin, a known tubulin po-lymerization
inhibitor. Moreover, its activity was more potent than that
of a known thalidomide metabolite, 5-hydroxythalidomide. Our
data suggest that 5HPP-33 is a promising candidate as a therapeutic
agent for multiple myeloma. In addition, the results suggest
that thalidomide’s tubulin polymerization inhibiting
activity might be the mechanism underlying the induction of
apoptosis in myeloma cells.
[Back to top]
Amyloid-Related Biomarkers for Alzheimer’s Disease
Niels Andreasen and Henrik Zetterberg
Alzheimer's disease (AD) is an age-related disorder that
causes brain damage resulting in progressive cognitive impairment
and death. Three decades of progress have given us a detailed
understanding of the underlying molecular mechanisms. Over
the past 10 years, this knowledge has translated into a range
of targets for therapy, the most promising of which is amyloid
β (Aβ).
An imbalance between the production and clearance of Aβ
is thought by many to represent the earliest event in the
pathogenesis of AD. Aβ
is known to be subject to oligomerisation, a process that
increases its synaptotoxicity. The oligomers may aggregate
further to proto-fibrils and fibrils, eventually forming senile
plaques, the neuropathological hallmark of AD. In this article
we review the key aspects of Aβ
as a biomarker for AD, including its pathogenicity, the diagnostic
performance of different Aβ
assays in different settings, and the potential usefulness
of Aβ
as a surrogate marker for treatment efficacy in clinical trials
of novel Aβ-targeting
drugs.
[Back to top]
The Other Side of the Opioid Story: Modulation of Cell Growth
and Survival Signaling
Yulong L. Chen, Ping Yee Law and Horace H. Loh
Opioids have been used as pain control medications for
thousands of years. Opioids are highly effective analgesics
clinically available for controlling moderate and severe pain.
Recent genetic knockout and knockin studies have definitively
demonstrated that the analgesic effect is mediated through
opioid receptors. In addition to their analgesic effect, opioids
also have the potential to develop tolerance and physical
dependence. Moreover, opioids can modulate cell proliferation
and survival. Attempts to design better opioid drugs to eliminate
or diminish these undesirable effects for clinical benefits
have achieved limited success. In recent years, investigation
of the effects of opioid-mediated cell proliferation and survival
has been very active, resulting in many publications. However,
the molecular targets of such non-analgesic effects are complex.
Several important pathways that control cell proliferation,
survival, and apoptosis have been reported to be associated
with the non-analgesic effects, which may be mediated through
both opioid receptor signaling and other non-opioid receptor
molecular entity-mediated signaling. This review tries to
bring the attention of the medicinal chemistry community to
new developments and advances in the research areas of opioid-mediated
cell proliferation and survival. Further investigation of
the molecular mechanism of these non-analgesic opioid effects
may eventually yield useful information such as new drug targets,
which may be explored to benefit for clinical treatments such
as targeted cancer therapy, cancer pain management, regeneration
of neurons, and recovery from drug addiction.
[Back to top]
Lessons from Viruses: Controlling the Function of Transmembrane
Proteins by Interfering Transmembrane Helices
F. Cymer and D. Schneider
Viral proteins sometimes interfere with human transmembrane
receptors to gain access into a cell or they use transmembrane
domains to interfere with cellular signal cascades in human
cells. Such interference can lead to a deregulation of tightly
regulated processes and eventually to different forms of cancer.
There is still little knowledge about how proteins act and
interact in biological membranes but the membrane environment
restricts the fold and composition of membrane proteins when
compared to water soluble proteins. These restrictions and
a sometimes related functional principle of different viral
transmembrane proteins for gaining access to a host cell or
to intervene with cellular processes may offer a great opportunity
to interfere with those processes in a simplified manner.
A close collaboration of various disciplines may result in
the development of drugs that specifically target membranes
and interfere with viral transmembrane domains or even regulate
the function of cellular membrane proteins. In this review
we describe the function of interactions between human and
viral membrane proteins in a cellular membrane, and perspectives
to intervene with those processes are discussed.
[Back to top]
Hyaluronic Acid: Targeting Immune Modulatory Components of
the Extracellular Matrix in Atherosclerosis
Pieter T. Bot, Imo E. Hoefer, Jan J. Piek and Gerard Pasterkamp
Purpose of review: Atherosclerosis is
a chronic inflammatory disease of the vessel wall. Although
it has become common knowledge that hyaluronic acid (HA),
an important component of the extracellular matrix, is strongly
involved in atherosclerotic disease development it has only
recently become evident that HA, instead of being a static
matrix polymer, is an active modulator of proliferation and
inflammation of the atherosclerotic plaque. This review discusses
the regulatory capacity of HA in atherosclerotic lesions and
its effects on plaque stability.
Recent Findings: The mechanisms by which
HA might alter plaque stability are diverse. It regulates
cellular migration and proliferation, lipid accumulation,
and intraplaque angiogenesis. Smooth muscle cell migration
is enhanced upon accumulation of HA, potentially stabilizing
atherosclerotic plaques. On the other hand, HA is an important
ligand for CD44, which stimulates inflammatory cell recruitment
to lesions, leukocyte migration and cell proliferation in
atherosclerotic plaques. Furthermore, HA forms complexes with
low density lipoproteins, and uptake of these complexes by
macrophages is increased compared to native LDL, indicating
a more detrimental effect on atherosclerosis. The dynamic
functional role of HA might be based on the functional difference
between short and larger size fragments of this polymer, with
either an inflammatory or an anti-inflammatory besides a pro-mitogenic
and anti-mitogenic effect. Low molecular weight HA has been
shown to be pro-angiogenic, whereas high molecular weight
HA has an anti-angiogenic effect. The cause of these differential
actions might be that HA synthesis is regulated by three different
genes: HAS1, 2 and 3 leading to different size HA products.
These genes are specifically expressed under certain conditions,
e.g. HAS1 and HAS3 are selectively induced in inflammation,
suggesting an important role of their products in this process.
Summary: Hyaluronic acid is an active regulatory
component of atherosclerotic lesions. Further studies are
warranted to gain more insight into the mechanisms which decide
on the role of HA in atherosclerosis and plaque stability.
[Back to top]
Novel Molecules Targeting Dyslipidemia and Atherosclerosis
A. Tavridou and V.G. Manolopoulos
Atherosclerotic cardiovascular disease (CVD) is the leading
cause of morbidity and mortality worldwide. Dyslipidemia is
one of the main risk factors leading to atherosclerosis. Moreover,
there is evidence for a role of oxidation in linking lipids
and inflammation to development and progression of atherosclerosis.
Current therapeutic approaches with lipid-lowering agents,
such as statins, fail to protect more than half of patients
from cardiovascular events. Therefore, there is a need for
additional and alternative treatment options. There are several
novel molecules undergoing preclinical or clinical development
for the treatment of dyslipidemia or against distinct pathways
which contribute to the development of atherosclerosis. Novel
squalene synthase inhibitors with significant cholesterol-lowering
and antiatherosclerotic properties are under development.
Targeting the production of apolipoprotein B-100 with an antisense
oligonucleotide is another interesting approach for lowering
low density lipoprotein(LDL)-cholesterol levels. Raising high
density lipoprotein(HDL)-cholesterol levels or improving its
antiatherosclerotic properties constitute additional attractive
targets for protection against CVD. Such compounds include
the cholesteryl ester transfer protein inhibitors, HDL-derived
proteins, and mimetic peptides/lipids. Direct targeting of
atherosclerosis remains a challenge. Molecules against oxidation
and/or inflammation could be beneficial in reducing atherosclerosis.
Other targets involved in distinct pathways of atherosclerosis
include the lipoprotein-associated phospholi-pase A2,
5-lipoxygenase-activating protein, acyl-CoA:cholesterol acyltransferase,
chemokine receptors, and protein kinases. In conclusion, there
are several promising novel therapeutic approaches for dyslipidemia
and atherosclerosis under development which are expected to
be of great benefit for patients at risk of CVD.
[Back to top]
Testing of Compounds in Models of Pulmonary Emphysema
Concetta Gardi, Beatrice Arezzini and Piero A. Martorana
There is a pressing need for the development of new therapies
for emphysema, particularly as no existing treatment has been
shown to reduce disease progression. Compounds with a potential
activity against the pathological mechanisms postulated to
play a role in the development and progression of emphysema
should be tested in vivo in animal models of this
disease. The choice of the model is of capital importance.
While models of elastase-induced emphysema are relatively
easy to execute, require low personnel capacity and provide
fast results, they also have a limited clinical relevance.
On the other hand, models of chronic smoke exposure are time-consuming,
expensive and require high personnel capacity but have a high
clinical relevance.
Presently, mainly two pharmacological approaches are being
considered and investigated in experimental studies. The first
approach consists of pharmacological interventions designed
to slow down the rate at which alveolar wall is lost in emphysema.
In this approach we find anti-inflammatory agents, protease
inhibitors and antioxidants. The attempt to reduce lung inflammatory
cell infiltration is most appealing since such an effect would
also reduce the lung burden of both proteases and oxidants.
The second approach is an attempt to reverse the process of
alveolar loss by inducing alveolar growth. To our knowledge
here only the effects of retinoids and/or retinoid receptor
agonists have been investigated.
This report presents a selected review of the literature of
animal studies using these pharmacological approaches.
[Back to top]
Biopharmaceutics, Pharmacokinetics and Pharmacodynamics of
Antituberculosis Drugs
Nageshwar R. Budha, Richard E. Lee and Bernd Meibohm
Tuberculosis (TB) is the leading cause of mortality due
to a single infectious agent. The currently used combination
drug regi-mens produce cure rates that exceed 95%, given good
patient adherence during the multiple months treatment period.
However the recent surge in HIV infections and the synergy
between HIV and TB as well as the emergence of resistance
resulted in an unforeseen increase in the number of TB cases,
including multi-drug resistant (MDR) and extensively-drug
resistant (XDR) forms of TB. Consequently, there is an urgent
need to develop novel, fast acting antituberculosis drugs
with high potency that can provide treatment options for all
forms of TB. It is well known that the current TB drugs exhibit
differences in their in vivo activity profile and
these differences are largely determined by their pharmacodynamics
(PD), i.e. intrinsic antibacterial activity, biopharmaceutical
properties such as solubility and permeability, and pharmacokinetic
(PK) properties such as drug exposure, tissue distribution,
and protein binding. An understanding of the relationships
among these properties is considered key for a rational use
of antituberculosis therapeutics. The current review provides
a comprehensive summary of physicochemical/biopharmaceutical,
PK, and PD properties of currently used antituberculosis drugs
and novel agents under development. Also, a brief review of
PK/PD parameters of current TB drugs is given and properties
of a desirable TB drug target and drug molecule are outlined.
The information provided herewith may be useful in the optimization
of biopharmaceutical and PK/PD characteristics in the development
of novel TB therapeutics and in the design of optimal treatment
regimens.
[Back to top]
Microarray Gene Expression Profiling in Meningiomas and Schwannomas
V. Martinez-Glez, C. Franco-Hernandez and J.A. Rey
Microarray gene expression profiling is a high throughput
system recently used in basic and applied research. It provides
a large amount of data —at molecular level— that
once acquired, must be functionally integrated in order to
find common patterns within a defined group of biological
samples. In addition to identification of differentially expressed
genes and the establishment of gene regulation patterns, microarrays
may also allow us to discover new tumor markers that could
have a great impact on the improvement of clinical practice
and therapeutics for cancer.
The classification method used for cancer is currently based
on the morphological characteristics of the biological samples.
The information obtained with this method is limited, omitting
many important tumor characteristics like the proliferation
rate, the capacity of invasion and metastases, as well as
the possible development of mechanisms of cellular resistance
to treatment. Microarrays can be used in combination with
conventional diagnostics as a helpful complement.
In this review we focus on how this technology has contributed
to our knowledge of the molecular pathogenesis of meningiomas
and schwannomas, its potential role as a useful tool for tumor
classification and its application in clinical practice.
|
