Current Molecular Pharmacology
ISSN: 1874-4672 - Volume 1, 3 Issues 2008
Current Molecular Pharmacology
Volume 1, Number 1, January 2008
Contents
Organ- and Cell-Type Specific Delivery of Kinase Inhibitors:
A Novel Approach in the Development of Targeted Drugs
Pp. 1-12
Kai Temming, Marjan M. Fretz and Robbert J. Kok
[Abstract] [Full
Text Article]
Gene Therapy: The First Approved Gene-Based Medicines,
Molecular Mechanisms and Clinical Indications Pp.
13-23
J.K. Räty, J.T. Pikkarainen, T. Wirth and S. Ylä-Herttuala
[Abstract] [Full
Text Article]
Inhibitors of the Ubiquitin-Proteasome System and
the Cell Death Machinery: How Many Pathways are Activated?
Pp. 24-37
Claudio Brancolini
[Abstract] [Full
Text Article]
Apoptosis-Regulatory Factors as Potential Drug Targets
in the Epithelium of Normal and Inflamed Airways Pp.
38-49
P.D. Zalewski and R.E. Ruffin
[Abstract] [Full
Text Article]
Pharmacology and Therapeutic Applications of Enediyne
Antitumor Antibiotics Pp. 50-60
Rong-Guang Shao
[Abstract] [Full
Text Article]
Pharmacologic Intervention in Axonal Excitability:
In Vivo Assessment of Nodal Persistent Sodium Currents
in Human Neuropathies Pp. 61-67
Satoshi Kuwabara and Sonoko Misawa
[Abstract] [Full
Text Article]
Immunomodulatory Properties of Antibiotics
Pp. 68-79
S.C. Tauber and R. Nau
[Abstract] [Full
Text Article]
Targeting Cancer Cells by an Oxidant-Based Therapy
Pp. 80-92
J. Verrax, H. Taper and P. Buc Calderon
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Organ- and Cell-Type Specific Delivery of Kinase Inhibitors:
A Novel Approach in the Development of Targeted Drugs
Kai Temming, Marjan M. Fretz and Robbert J. Kok
[Full
Text Article]
During the past years, we have explored the cellular delivery
of kinase inhibitors. Kinase inhibitors have selectivity for
specific kinases but they lack cellular selectivity. This
is exemplified by recent reports on cardiotoxicity of kinase
inhibitors used in cancer treatment. We postulate that targeted
cellular delivery of kinase inhibitors can improve their safety/toxicity
profiles, as will be exemplified by recent published studies.
Cell specific delivery of therapeutics is a quickly growing
area of investigation. This innovative strategy employs carrier
molecules that bind to receptors exposed on the surface of
cell types involved in disease processes. Binding and receptor
mediated internalization of the carrier facilitates local
accumulation of the product in target cells. Upon systemic
administration, this may create local drug depots in specific
organs, while other tissues are avoided, thus favoring enhanced
localized drug efficacy and reduced side-effects.
Synthesis of targeted kinase inhibitor-carrier conjugates
was achieved using a new approach, in which kinase inhibitors
were bound to a platinum(II) atom, the so-called Universal
Linkage System (ULS). We review this novel linkage chemistry
and demonstrate the applicability of ULS for drug targeting
approaches aiming at angiogenic endothelial cells, hepatic
stellate cells, and kidney tubular cells. We will review important
issues like drug release mechanism, safety of the linker,
and pharmacokinetics of the products in animals. Finally,
we review the pharmacological efficacy of the cellular targeted
drug conjugates in experimental animal models, especially
in renal and liver fibrosis models.
[Back to top]
Gene Therapy: The First Approved Gene-Based Medicines,
Molecular Mechanisms and Clinical Indications
J.K. Räty, J.T. Pikkarainen, T. Wirth and S. Ylä-Herttuala
[Full Text
Article]
As gene therapy has matured from clinical trials to the first
commercial products, understanding of the mechanisms of gene
delivery has increased tremendously. This has also been reflected
in viral vector development, creating a number of new approaches
to tackle issues in transduction efficiency, biodistribution
and viral safety. This review will highlight the most important
issues and advancements in vector development, administration,
surface modification, integration to host genome and safety.
The gene therapy products currently available or near market
approval, based on p53 expression (Gendicine™ and Advexin™),
conditionally replicative adenoviruses (Oncorine™) and
thymidine kinase + ganciclovir therapy (Cerepro®), are
introduced with emphasis on the molecular mechanisms of action.
[Back to top]
Inhibitors of the Ubiquitin-Proteasome System and
the Cell Death Machinery: How Many Pathways are Activated?
Claudio Brancolini
[Full
Text Article]
Over the past decade, the promising results of UPSIs (UPS
inhibitors) in eliciting apoptosis in various cancer cells,
and the approval of the first UPSI (Bortezomib/Velcade/PS-341)
for the treatment of multiple myeloma have raised interest
in assessing the death program activated upon proteasomal
blockage.
Several reports indicate that UPSIs stimulate apoptosis in
malignant cells by operating at multiple levels, possibly
by inducing different types of cellular stress. Normally cellular
stress signals converge on the core elements of the apoptotic
machinery to trigger the cellular demise. In addition to eliciting
multiple stresses, UPSIs can directly operate on the core
elements of the apoptotic machinery to control their abundance.
Alterations in the relative levels of anti and pro-apoptotic
factors can render cancer cells more prone to die in response
to other anti-cancer treatments. Aim of the present review
is to discuss those core elements of the apoptotic machinery
that are under the control of the UPS.
[Back to top]
Apoptosis-Regulatory Factors as Potential Drug Targets
in the Epithelium of Normal and Inflamed Airways
P.D. Zalewski and R.E. Ruffin
[Full Text
Article]
Airway epithelium (AE) lines the conducting airways of the
respiratory system and functions to maintain airway integrity
by providing both a physical barrier to inhaled noxious agents
and a mechanism for their clearance via the mucociliary
escalator. Normal AE cells are relatively refractory to a
number of apoptotic stimuli and survival mechanisms are in
place to maintain the integrity of the epithelial barrier
that is exposed to agents such as reactive oxygen species
(ROS) and death receptor ligands secreted by immune cells
during inflammation. When damage to AE does occur, there is
increased AE apoptosis, such as in the airway damage that
occurs in the chronically inflamed airways in diseases like
asthma where rates of AE apoptosis can be increased many-fold.
The usual treatment for persistent asthma in humans involves
a combination of bronchodilator and inhaled corticosteroid;
there is however a need to develop strategies to better control
other aspects of the disease, including minimizing the ongoing
damage to AE and consequent airway remodeling. Targeting of
the major apoptosis-regulatory factors in AE may be one such
strategy. Here we review what is known about apoptosis and
its regulatory factors in normal AE and abnormalities in these
factors in the inflamed airways of mice and humans.
[Back to top]
Pharmacology and Therapeutic Applications of Enediyne
Antitumor Antibiotics
Rong-Guang Shao
[Full
Text Article]
The natural compounds that interfere with cellular DNA such
as enediyne antitumor antibiotics might be important chemotherapeutic
agents for the treatment of cancer. In this article, the pharmacology
and anticancer activity of the enediyne antitumor agents that
are approved for clinical use and undergoing pre-clinical
or clinical evaluation are reviewed. Most enediyne compounds
have shown potent activity against the proliferation of various
cancer cells, including cells that display resistance to other
chemotherapeutic drugs. Enediyne derivatives, such as an immunoconjugate
com-posed of an enediyne compound and monoclonal antibody,
reveal stronger activity and selectivity for human cancer
cells. The mechanism underlying the anticancer activity of
these enediyne antitumor agents may mainly lie in their generation
of DNA double-strand breaks. Increasing evidence shows that
the enediyne-induced DNA double-strand breaks can engage the
activation of DNA damage response proteins, arresting cell
cycle progression and eventually leading to apoptotic cell
death. Continued investigation of the mechanisms of action
and development of new enediyne derivatives and conjugates
may provide more effective therapeutics for cancer treatments.
[Back to top]
Pharmacologic Intervention in Axonal Excitability:
In Vivo Assessment of Nodal Persistent Sodium Currents
in Human Neuropathies
Satoshi Kuwabara and Sonoko Misawa
[Full
Text Article]
Axonal excitability testing can provide new insights into
the ionic mechanisms underlying the pathophysiology of hyperexcitability
of motor and sensory axons in human neuropathies. Threshold
tracking was developed in the 1990's to non-invasively measure
a number of axonal excitability indices that depend on sodium
and potassium channel function, and this makes it possible
to monitor the effects of pharmacologic intervention with
ion channel modulators. This paper reviews recent advances
in ionic-pathophysiological studies in humans. (1) Neuropathic
pain or muscle cramp/fasciculation is partly caused by hyperexcitability
of the injured axons. The enhanced excitability can result
from altered ion channel function; such as an increase in
persistent sodium currents. Persistent sodium currents can
be reliably estimated using threshold tracking. In peripheral
neuropathy, persistent sodium currents usually increase possibly
due to over-expression of sodium channels associated with
axonal regeneration, and could be responsible for ectopic
firings. Administration of sodium channel blockers such as
mexiletine, results in marked alleviation of muscle cramping
in parallel with a decrease in nodal persistent sodium currents.
(2) In diabetic neuropathy, the activation of the polyol pathway
mediated by an enzyme, aldose reductase, leads to reduced
Na+/K+
pump activity, and intra-axonal sodium accumulation; sodium
currents are reduced presumably due to decreased trans-axonal
sodium gradient. Aldose reductase inhibitiors improve nodal
sodium currents, as well as nerve conduction, and this can
be objectively assessed by threshold tracking. Studies of
ion-channel pathophysiology in human subjects have recently
begun. Investigating ionic mechanisms by monitoring the corresponding
ionic currents. is of clinical relevance, because once a specific
ionic conductance is identified, pharmacologic blocking or
modulation could provide a new therapeutic option.
[Back to top]
Immunomodulatory Properties of Antibiotics
S.C. Tauber and R. Nau
[Full Text Article]
There is growing evidence that certain antibiotics exert their
beneficial effects not only by killing or inhibiting the growth
of bacterial pathogens but also indirectly by immunomodulation.
This review aims at giving an overview of the immunomodulatory
properties of antibiotics in different diseases: The antiinflammatory
properties of macrolides in chronic inflammatory pulmonary
disorders were recognized more than 15 years ago and have
been well documented in the last decade. Recent data suggest
that several antibiotics such as tetracyclines and cephalosporins
may have a beneficial immunomodulatory or neuroprotective
effect on neuroimmunological and neurodegenerative diseases
including multiple sclerosis and amyotrophic lateral sclerosis.
Moreover, the non-bacteriolytic but bactericidal antibiotics
rifampicin, clindamycin and aminoglycosides kill bacteria
without releasing high quantities of proinflammtory cell wall
components. The use of bactericidal, non-bacteriolytic protein
synthesis inhibitors reduces mortality and long-term sequelae
in experimental bacterial sepsis, plague and meningitis. Clinically,
macrolides have been well established as an adjunctive treatment
to β-lactam
antibiotics in pulmonary diseases. For other indications,
appropriate clinical trials are necessary before using the
immunomodulatory properties of antibiotics in clinical practice.
[Back to top]
Targeting Cancer Cells by an Oxidant-Based Therapy
J. Verrax, H. Taper and P. Buc Calderon
[Full
Text Article]
Despite the progress achieved in chemo- and radiotherapy,
cancer is still a leading life-threatening pathology. In that
sense, there is a need for novel therapeutic strategies based
on our current knowledge of cancer biology. Among the phenotypical
features of cancer cells, two of them are of particular interest:
their nearly universal glycolytic phenotype and their sensitivity
towards an oxidative stress, both resulting from the combination
of high anabolic needs and hypoxic growth conditions. By using
menadione (vitamin K3) and ascorbate (vitamin C), we took
advantage of these features to develop an original approach
that consists in the exposure of cancer cells to an oxidant
insult. When used in combination, these compounds exhibit
a synergistic action and are devoid of major toxicity in
vivo. Thus, this review is dedicated to the analysis
of the molecular pathways by which this promising combination
exerts its antitumoural effect.
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