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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 6, 2007
Contents
Microscopic Simulation in Biology and Medicine Pp.
625-637
Filippo Castiglione, Arcangelo Liso, Massimo Bernaschi
and Sauro Succi
[Abstract]
The Structure and Main Functions of Aminopeptidase
N Pp. 639-647
Yepeng Luan and Wenfang Xu
[Abstract]
The Janus Face of CD4+CD25+
Regulatory T Cells in Cancer and Autoimmunity Pp.
649-666
S. Danese and S. Rutella
[Abstract]
Perspectives in Biomolecular Therapeutic Intervention
in Cancer: From the Early to the New Strategies With Type
I Interferons Pp. 667-679
S. Vannucchi, M.V. Chiantore, G. Mangino, Z.A. Percario,
E. Affabris, G. Fiorucci and G. Romeo
[Abstract]
The Antitumoral Mode of Action of Imiquimod and Other
Imidazoquinolines Pp. 681-687
Margarete Schön and Michael P. Schön
[Abstract]
Human Multidrug Transporter ABCG2, a Target for Sensitizing
Drug Resistance in Cancer Chemotherapy Pp. 689-701
Junkang Xu, Hui Peng and Jian-Ting Zhang
[Abstract]
Insights into Oxidative Stress: The Isoprostanes
Pp. 703-717
Paolo Montuschi, Peter Barnes and L. Jackson Roberts II
[Abstract]
Current Drug Targets and Future Therapy of Pulmonary
Arterial Hypertension Pp. 719-733
Takayuki Ito, Keiya Ozawa and Kazuyuki Shimada
[Abstract]
Abstracts
[Back to top]
Microscopic Simulation in Biology and Medicine
Filippo Castiglione, Arcangelo Liso, Massimo Bernaschi
and Sauro Succi
Mathematical models are finding an increasing use in
bio-medical scientific investigations as effective means of
putting the interpretation of biological phenomena on a more
quantitative basis.
Besides the well established mathematical paradigm based on
differential equations, another approach that takes full advantage
of the steadily increasing computing power, is gaining increasing
consensus: micro-simulation. Micro-simulation is based on
the idea of mimicking the behavior of the system under investigation
through the specification of the rules of interaction among
its individual constituents.
This rule-driven (sometimes called equation-free) approach
allows a smoother upgrade of models sophistication and reduces
the gap between the abstract level of description typical
of mathematical models and the complexity of the biological
world.
In this article we aim at illustrating, through specific examples,
some of the potential advantages that micro-simulation has
to offer in order to gain a better grasp and understanding
of complex phenomena in biology and medicine.
[Back to top]
The Structure and Main Functions of Aminopeptidase
N
Yepeng Luan and Wenfang Xu
Aminopeptidase N (APN)/CD13 is a type II metalloprotease that
belongs to the M1 family of the MA clan, which consists of
967 amino acids with a short N-terminal cytoplasmic domain,
a single transmembrane part, and a large cellular ectodomain
containing the active site. APN has a molecular weight of
110,000. The APN exists in two forms namely the membrane aminopeptidase
N and the soluble aminopeptidase N. Moreover, it exhibits
the presence of various isozymes with different functions.
APN is a ubiquitous enzyme present in a wide variety of human
organs, tissues and cell types (endothelial, epithelial, fibroblast,
leukocyte). It is a multifunctional enzyme, related with tumorigenesis,
immune system, pain etc. Furthermore, it also serves as a
receptor for coronaviruses and other human viruses. Besides
the manifestation of various other functions, APN is also
involved in the trimming of antigen and the process of antigen
presentation. These functions facilitate the modulation of
bioactive peptide responses (pain management, vasopressin
release) and influence immune functions and major biological
events (cell proliferation, secretion, invasion, angiogenesis)
thereby providing treatment options for many kinds of diseases.
This review will introduce the structure and main functions
of APN briefly.
[Back to top]
The Janus Face of CD4+CD25+
Regulatory T Cells in Cancer and Autoimmunity
S. Danese and S. Rutella
Regulatory T cells (Treg) encompass a heterogeneous family
of T cells implicated in maintenance of tolerance to self
antigens. Treg cells might be qualitatively and/or quantitatively
deficient in human autoimmune diseases, including multiple
sclerosis, graft versus host disease, systemic lupus erythematosus,
type I diabetes, and rheumatoid arthritis. In animal models
of autoimmunity, infusion of ex vivo-expanded Treg
cells and/or in vivo enhancement of Treg cell suppressor
function by pharmacological agents and cytokines attenuate
disease manifestations and restore tolerance. However, Treg
cells represent a double-edged sword, as Treg cells with specificity
for tumour-associated antigens contribute to cancer pathogenesis
and progression. In vivo depletion of Treg cells
by monoclonal antibodies and/or selected drugs is an encouraging
therapeutic strategy which improves tumour eradication in
animal models of cancer. In addition, elimination and/or functional
inactivation of Treg cells might boost anti-tumour immunity
in tumour-bearing hosts receiving anti-cancer vaccination.
The present review discusses Treg cell manipulation as a novel
therapeutic strategy in cancer and autoimmunity, conditions
characterised by a common regulatory basis.
[Back to top]
Perspectives in Biomolecular Therapeutic Intervention
in Cancer: From the Early to the New Strategies With Type
I Interferons
S. Vannucchi, M.V. Chiantore, G. Mangino, Z.A. Percario,
E. Affabris, G. Fiorucci and G. Romeo
Interferon (IFN) was the first cytokine produced by recombinant
DNA technology used in wide-spread clinical treatment of infectious
diseases as well as malignancies. The IFN clinical potential
was clearly realized from the outset. However, IFN represents
one of the most controversial drugs of our time, as remarkable
cycles of promise and disappointment have affected its development
and use.
Considerable evidence regarding anti-tumor activities of IFNs
has been reported. In this paper we focus on molecular bases
of the IFN system that may relate to its antitumor activities.
Many of the numerous genes transcriptionally activated by
IFNs have been shown to encode proteins that activate immune
recognition of tumor cells, directly or indirectly exert tumor
suppressor activity and/or control tumor cell cycle and programmed
cell death. In addition, a physiological relevant function
for endogenous type I IFN in cancer immunoediting process
and a new way to IFN clinical use based on gene therapy or
vaccine-like approaches have recently been suggested.
The identification of selected tissue-specific and/or tumor-specific
target pathways as well as of different type I IFN tumor escape
and resistance mechanisms may provide novel approaches in
the search for new IFN-based therapeutic strategies to circumvent
cancer disease or improve clinical outcome. Promising IFN
treatment has been recently defined by using novel pharmaceutical
preparations with a more favourable pharmacokinetic response,
also in combination with other bio-reagents or other modalities
of therapy. Translational research, linking both basic and
clinical research, will lead to a new rationale for the use
of IFN in cancer therapy.
[Back to top]
The Antitumoral Mode of Action of Imiquimod and Other
Imidazoquinolines
Margarete Schön and Michael P. Schön
Imiquimod, the lead compound of the imidazoquinoline family
of nucleoside analogues, has shown good efficacy against a
variety of tumors of different origin. The mode of action
of imiquimod and related compounds, which we have begun to
understand in some detail in recent years, is complex and
interesting inasmuch as it appears to comprise several presumably
mutually enhancing components.
Predominant amongst its actions is the induction of pro-inflammatory
cytokines through agonistic activity towards Toll-like receptor
(TLR)-7 and TLR-8, and consecutively, activation of the central
transcription factor NF-κB.
This activity stimulates the production of pro-inflammatory
cytokines, chemokines and other mediators resulting in activation
of anti-gen-presenting cells and the mounting of a profound
Th1-weighted antitumoral cellular immune response. In addition,
there are a number of secondary effects on the molecular and
cellular level that can be explained through the activation
of NF-κB.
The pro-inflammatory activity of imiquimod appears to be augmented
by suppression of a negative regulatory feedback mechanism
which normally limits inflammatory responses. This is achieved
independent of TLR-7 and TLR-8 through interference with adenosine
receptor signaling pathways, particularly the A2A subtype,
and receptor-independent reduction of adenylyl cyclase activity.
Finally, at higher, albeit therapeutically relevant concentrations,
imiquimod exerts a pro-apoptotic activitiy against tumor cells.
Induction of apoptosis by imiquimod appears to be dependent
on Bcl-2 proteins and involves caspase activation.
The combination of multiple, presumably synergistic anti-tumoral
functions by a single compound represents an interesting principle
of pathogenesis-oriented, anti-neoplastic therapy.
[Back to top]
Human Multidrug Transporter ABCG2, a Target for Sensitizing
Drug Resistance in Cancer Chemotherapy
Junkang Xu, Hui Peng and Jian-Ting Zhang
Human ABCG2, a member of the ATP-binding cassette transporter
superfamily which transports a wide variety of substrates,
is highly expressed in placental syncytiotrophoblasts, in
the canalicular membranes of liver, in the apical membrane
of the small intestine epithelium, and at the luminal surface
of the endothelial cells of human brain micro vessels. This
strategic tissue localization indicates that ABCG2 plays an
important role in absorption, distribution, and elimination
of xenobiotics and drugs. High ABCG2 expression has also been
detected in many hematological malignancies and solid tumors,
indicating that ABCG2 is likely responsible also for the multidrug
resistance in cancer chemotherapy. Indeed, ABCG2 can actively
transport structurally diverse conjugated- or unconjugated-organic
molecules and various anti-cancer drugs. Many chemo-sensitizing
agents have been discovered, which can be developed for increasing
drug adsorption and reversing drug resistance in cancer chemotherapy
by inhibiting ABCG2 function or expression. This review summarizes
current knowledge on ABCG2, its relevance to multidrug resistance
and drug disposition, and its ever-growing numbers of substrates
and inhibitors.
[Back to top]
Insights into Oxidative Stress: The Isoprostanes
Paolo Montuschi, Peter Barnes and L. Jackson Roberts II
Oxidative stress, characterized by an imbalance between increased
exposure to free radicals and antioxidant defenses, is a prominent
feature of many acute and chronic diseases and even the normal
aging process. However, definitive evidence for this association
has often been lacking due to recognized shortcomings with
methods previously available to assess oxidant stress status
in vivo in humans. Several in vitro markers
of oxidative stress are available, but most are of limited
value in vivo because thay lack sensitivity and/or
specificity or require invasive methods. Isoprostanes (IsoPs)
are prostaglandin (PG)-like compounds that are produced in
vivo independently of cyclooxygenase enzymes, primarily
by free radical-induced peroxidation of arachidonic acid.
F2-IsoPs
are a group of 64 compounds isomeric in structure to cyclooxygenase-derived
PGF2α.
Other products of the IsoP pathway are also formed in
vivo by rearrangement of labile PGH2-like
IsoP intermediates including E2- and D2-IsoPs,
cyclopentenone-A2- and J2-IsoPs, and
highly reactive acyclic-ketoaldehydes (isoketals).
Oxidation of docosahexaenoic acid, an abundant unsaturated
fatty acid in the central nervous system, results in the formation
of IsoP-like compounds, termed neuroprostanes.
Measurement of F2-IsoPs is the most reliable approach
to assess oxidative stress status in vivo, providing
an important tool to explore the role of oxidative stress
in the pathogenesis of human disease. Moreover, F2-IsoPs
and other products of the IsoP pathway exert potent biological
actions both via receptor-dependent and independent
mechanisms and therefore may be pathophysiological mediators
of disease. Measurement of F2-IsoPs may provide
a uniquely valuable approach to understanding of the clinical
pharmacology of antioxidants.
[Back to top]
Current Drug Targets and Future Therapy of Pulmonary
Arterial Hypertension
Takayuki Ito, Keiya Ozawa and Kazuyuki Shimada
During the last few decades, we have witnessed major
improvements in the therapy of pulmonary arterial hypertension
(PAH). PAH is characterized by abnormal remodeling of the
pulmonary artery (PA) and increased PA pressures, resulting
in a high premature mortality. Intravenous epoprostenol was
the first effective approach toward improving the symptoms
and survival of PAH patients. New prostanoids have also exhibited
substantial clinical benefits; however, their long-term effects
are under investigation. Endothelin-receptor antagonists and
sildenafil have increased the lineup of therapeutic options
against PAH. Combination therapy using these drugs is promising
and is currently undergoing scrutiny in large clinical trials.
An extensive analysis of the molecular mechanisms of PAH will
produce novel targeted therapies. Most of the promising molecules
target the inflammatory and proliferative processes underlying
pathological PA remodeling. Interestingly, drugs used for
other diseases, such as statins, Rho-kinase inhibitors, imatinib
mesylate, may control the pathological vascular remodeling
of PAH. Gene and cell therapy using vectors expressing prostacyclin
synthase, endothelial nitric oxide synthase, or vascular endothelial
growth factor are also promising strategies. However, the
efficacy and safety of these approaches should be further
tested in clinical trials. Genetic studies revealed some crucial
genetic dispositions of familial PAH, although their pathobiological
roles have not yet been fully clarified. Collaboration for
integrated research will address these issues and generate
greater clinical benefits for PAH patients.
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