| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 17, 2008
Contents
Combination of Photodynamic Therapy with Anti-Cancer
Agents Pp. 1655-1673
M.-F. Zuluaga and N. Lange
[Abstract]
Current Adjuvant and Targeted Therapies for Pancreatic
Adenocarcinoma Pp. 1674-1683
Sabrina E. Sanchez and Jose G.
Trevino
[Abstract]
Storage, Expression and Function of Fas Ligand, The
Key Death Factor of Immune Cells Pp. 1684-1696
Marcus Lettau, Maren Paulsen, Dieter Kabelitz
and Ottmar Janssen
[Abstract]
Human Endotoxemia as a Model of Systemic Inflammation
Pp. 1697-1705
A.S. Andreasen, K.S. Krabbe, R. Krogh-Madsen, S. Taudorf,
B.K. Pedersen and K. Møller
[Abstract]
Advances in Parallel Screening of Drug Candidates
Pp. 1706-1719
Paolo Bergese, Marina Cretich, Claudio Oldani,
Giulio Oliviero, Gabriele Di Carlo, Laura E. Depero and
Marcella Chiari
[Abstract]
Small Molecule Inhibitors of the p53-MDM2 Pp.
1720-1730
Chun-Qi Hu and Yong-Zhou Hu
[Abstract]
Regulation of Cardiac Nerves: A New Paradigm in
The Management of Sudden Cardiac Death? Pp. 1731-1736
Masaki Ieda, Kensuke Kimura, Hideaki Kanazawa
and Keiichi Fukuda
[Abstract]
Recent Developments in the Design of Anti-Depressive
Therapies: Targeting the Serotonin Transporter Pp.
1737-1761
S.G. Butler and M.J. Meegan
[Abstract]
Abstracts
[Back to top]
Combination of Photodynamic Therapy with
Anti-Cancer Agents
M.-F. Zuluaga and N. Lange
Degenerative diseases such as cancer usually involve
more than one pathological process. Therefore, attempts to
combat such diseases with monotherapeutic approaches may not
always do so efficiently. For this reason, the use of combination
therapy with modalities that target different disease pathways
represents an alternative strategy. Photodynamic therapy (PDT)
has already been established as an alternative therapy for
the treatment of various types of malignant disorders, including
oesophageal, lung and bladder cancer as well as other degenerative
diseases. This technique involves the administration of a
tumor localizing photosensitizer followed by its activation
with light of a specific wavelength. In the presence of tissue
oxygen, the photoactive sensitizer triggers a series of photochemical
and photobiological processes that may lead to direct cancer
cell damage, tumor microvascular occlusion and host immune
response. Due to these multiple actions, PDT has increasingly
gained recognition as a potential adjuvant for conventional
cancer treatments. Several pre-clinical studies and some clinical
trials suggest that the use of PDT in combination with established
treatments or with newly-developed modalities may be of benefit
as compared to the individual modalities. In this review,
we briefly introduce the reader to the main photo-biological
aspects of PDT, and then discuss the use of PDT in combination
with other pharmacological approaches for the treatment of
cancer.
[Back to top]
Current Adjuvant and Targeted Therapies for Pancreatic
Adenocarcinoma
Sabrina E. Sanchez and Jose G.
Trevino
Pancreatic cancer is one of the deadliest malignancies,
costing the lives of more than 30,000 patients every year.
It often presents in advanced stages not amenable to surgery.
Gemcitabine is currently considered to be the standard of
care for the treatment of advanced pancreatic cancer. Combination
of gemcitabine with certain other cytotoxic drugs, including
cisplatin, oxaliplatin, capecitabine, and 5-fluorouracil have
been undertaken, but all have failed to provide substantial
increases in survival benefit. However, neoadjuvant algorithms
and targeted therapies, including combinations of gemcitabine
with erlotinib suggest more promising results. New targeted
therapies in combination with gemcitabine are currently in
Phase II and III trials, possibly implicating a primary position
for them in future treatment. In this paper we present an
overview of the current treatment options for the different
presenting stages of pancreatic cancer, including adjuvant,
neoadjuvant, and targeted therapies, and attempt to provide
a comprehensive analysis of the disparate research indicated
on this front.
[Back to top]
Storage, Expression and Function of Fas Ligand, The
Key Death Factor of Immune Cells
Marcus Lettau, Maren Paulsen, Dieter Kabelitz
and Ottmar Janssen
The TNF family member Fas ligand (FasL) induces apoptosis
in Fas-expressing cells and serves as a key death factor in
the immune system. It is involved in the termination of immune
responses by activation-induced cell death, the selection
of thymocytes and T and NK cell-mediated cytotoxicity. FasL
also participates in the establishment of immune privilege
and contributes to tumor cell survival. Besides its death-inducing
capacity, FasL has been implicated in retrograde signal transduction
into FasL expressing cells by so-called “reverse signalling”.
In this context, FasL may also act as an accessory/costimulatory
molecule. Dysregulation within the Fas/FasL-system manifests
in a severe impairment of the functional integrity and maintenance
of immune homeostasis. As its receptor Fas is abundantly expressed
in several tissues, the expression of FasL has to be tightly
regulated to prevent unwanted damage. At the post-transcriptional
level, this is achieved by several independent mechanisms,
for example the safe intracellular storage, an activation-dependent
mobilization, the association with lipid rafts and the shedding
by metalloproteases. Of interest, the intracellular portion
of FasL contains a unique proline-rich domain, which plays
a major role in the control of FasL transport and expression
due to interactions with proteins containing SH3 or WW interaction
domains. The detailed analysis of FasL-interacting proteins
and their functional characterization provided novel insights
into the complex processes regulating FasL expression and
signal transduction. This knowledge should allow to improve
Fas/FasL-based therapeutical approaches that are currently
under development.
[Back to top]
Human Endotoxemia as a Model of Systemic Inflammation
A.S. Andreasen, K.S. Krabbe, R. Krogh-Madsen, S. Taudorf,
B.K. Pedersen and K. Møller
Systemic inflammation is a pathogenetic component in
a vast number of acute and chronic diseases such as sepsis,
trauma, type 2 diabetes, atherosclerosis, and Alzheimer’s
disease, all of which are associated with a substantial morbidity
and mortality. However, the molecular mechanisms and physiological
significance of the systemic inflammatory response are still
not fully understood. The human endotoxin model, an in
vivo model of systemic inflammation in which lipopolysaccharide
is injected or infused intravenously in healthy volunteers,
may be helpful in unravelling these issues. The present review
addresses the basic changes that occur in this model. The
activation of inflammatory cascades as well as organ-specific
haemodynamic and functional changes after lipopolysaccharide
are described, and the limitations of human-experimental models
for the study of clinical disease are discussed. Finally,
we outline the ethical considerations that apply to the use
of human endotoxin model.
[Back to top]
Advances in Parallel Screening of Drug Candidates
Paolo Bergese, Marina Cretich, Claudio Oldani,
Giulio Oliviero, Gabriele Di Carlo, Laura E. Depero and
Marcella Chiari
In the hit to lead process, a drug
candidate is selected from a set of potential leads by screening
its binding with potential targets. This review focuses
on the lead identification assays that employ a bio-chemical
or bio-physical test to detect molecular recognition events
between proteins and small molecules in a parallel format.These
tests require either the lead or the target immobilization
followed by incubation with the set of potential interaction
partners and detection of a signal related to the target-ligand
binding. In the first part of the review the different detection
strategies amenable for drug screening are discussed. In the
second part, a review of immobilization approaches for leads
or targets, allowing the parallel screening of arrays of molecules,
is presented.
[Back to top]
Small Molecule Inhibitors of the p53-MDM2
Chun-Qi Hu and Yong-Zhou Hu
Recent researches have discovered that MDM2 (murine double
minute 2, or HDM2 for the human congener) protein is the main
negative regulator of p53, which is an attractive therapeutic
target in oncology because its tumor-suppressor activity which
can be stimulated to eradicate tumor cells. Inhibiting the
p53–MDM2 interaction is a promising approach for activating
p53, because this association is well characterized at the
structural and biological levels. A number of drug screening
approaches and technologies have been used to identity novel
inhibitors of the p53-MDM2 interaction. This review will detail
the development history of MDM2 protein and the p53-MDM2 interaction,
the major classes of novel small-molecular p53-MDM2 binding
inhibitors, key medicinal action with the protein-protein
interaction and in vitro or in vivo biological
activtiies.
[Back to top]
Regulation of Cardiac Nerves: A New Paradigm in
The Management of Sudden Cardiac Death?
Masaki Ieda, Kensuke Kimura, Hideaki Kanazawa
and Keiichi Fukuda
The heart is extensively innervated, and its performance
is tightly regulated by the autonomic nervous system. To maintain
cardiac function, innervation density is stringently controlled,
being high in the subepicardium and the central conduction
system. In diseased hearts, cardiac innervation density varies,
which in turn leads to sudden cardiac death. After myocardial
infarction, sympathetic denervation is followed by reinnervation
within the heart, leading to unbalanced neural activation
and lethal arrhythmia. Diabetic sensory neuropathy causes
silent myocardial ischemia, characterized by loss of pain
perception during myocardial ischemia, which is a major cause
of sudden cardiac death in diabetes mellitus (DM). Despite
its clinical importance, the molecular mechanism underlying
innervation density remains poorly understood.
We found that cardiac sympathetic innervation is determined
by the balance between neural chemoattraction and chemorepulsion,
both of which occur in the heart. Nerve growth factor (NGF),
which is a potent chemoattractant, is synthesized abundantly
by cardiomyocytes and is induced by endothelin-1 upregulation
in the heart. In contrast, Sema3a, which is a neural chemorepellent,
is expressed strongly in the trabecular layer in early stage
embryos and at a lower level after birth, leading to epicardial-to-endocardial
transmural sympathetic innervation patterning. We also found
that cardiac NGF downregulation is a cause of diabetic neuropathy,
and that NGF supplementation rescues silent myocardial ischemia
in DM. Both Sema3a-deficient and Sema3a-overexpressing mice
showed sudden death or lethal arrhythmias due to disruption
of innervation patterning. The present review focuses on the
regulatory mechanisms involved in neural development in the
heart and their critical roles in cardiac performance.
[Back to top]
Recent Developments in the Design of Anti-Depressive
Therapies: Targeting the Serotonin Transporter
S.G. Butler and M.J. Meegan
The serotonin transporter protein (SERT) has been the
target for the development of several modern antidepressants
with an objective of achieving selectivity over other monoamine
transporters, thereby minimising side effects observed in
the older generation of tricyclic antidepressants. The clinical
selective serotonin reuptake inhibitors (SSRIs) have been
shown to be among the most effective therapies in the treatment
of depression. However they have clinical disadvantages over
other classes of antidepressant drugs such as slow onset of
action nausea and sleep disruption.
The negative feedback loop attributed to the presynaptic 5-HT1A
receptors has been implicated in the “time lag”
observed in many patients between the administration of the
SSRI and its observed therapeutic action. In recent years
the focus has been on developing compounds with dual affinity
for serotonergic auto-receptors along with an inhibitory activity
at SERT. These structurally diverse products promise to be
the next generation of anti-depressant medicines.
This review presents an analysis of the recently reported
structural classes with SSRI activity and rationalises the
unique relationship between their molecular properties and
biological activities. Specific emphasis is placed on the
development of molecular structures with dual serotonergic
activity. Recent advances in the design and synthesis of single
molecular entities possessing 5-HT reuptake inhibition together
with 5-HT1A,
5-HT1B, 5-HT1D,
5-HT2A, DAT, NET, α2-adrenoceptor
and acetylcholinesterase antagonism are reviewed. The structural
studies to identify proposed SERT binding sites together with
the role of structure and ligand based design in the development
of more effective SSRIs are summarised.
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