| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 19, 2006
Contents
Therapeutic Modulation of Prostanoids and Cytokines
in Chronic Diseases
Executive Editor: Anna Dongari-Bagtzoglou
Editorial Pp. 2327-2328
Therapeutic Modulation of Cytokines in Chronic Infectious
Diseases Pp. 2329-2348
C.C. Villar and A. Dongari-Bagtzoglou
[Abstract]
Cytokines as a Therapeutic Target for Allergic
Diseases: A Complex Picture Pp. 2349-2363
J.A. Woodfolk
[Abstract]
Toll-Like Receptors, Cytokines and the Immunotherapeutics
of Asthma Pp. 2365-2374
P. Camateros, J. Moisan, J. Hénault, J. De Sanctis,
E. Skamene and D. Radzioch
[Abstract]
Roles of Prostanoids in Colon Carcinogenesis and
their Potential Targeting for Cancer Chemoprevention Pp.
2375-2382
M. Mutoh, M. Takahashi and K. Wakabayashi
[Abstract]
New Frontiers in the Therapeutic Management of
Transplant Rejection Pp. 2383-2395
J. De Sanctis, J.V. Garmendia, A. Radzioch and D. Radzioch
[Abstract]
Therapeutic Modulation of Growth Factors and Cytokines
in Regenerative Medicine Pp. 2397-2408
E. Ioannidou
[Abstract]
General Articles
Slow-Onset Inhibition of 2-trans-Enoyl-ACP (CoA)
Reductase from Mycobacterium tuberculosis
by an Inorganic Complex Pp. 2409-2424
J.S. Oliveira, E.H. S. de Sousa, O.N. de Souza, Í.S.
Moreira, D.S. Santos and L.A. Basso
[Abstract]
Pharmacogenetics of Antithrombotic Drugs Pp.
2425-2435
D. Tàssies
[Abstract]
Novel Targets for Antiinflammatory and Antiarthritic
Agents Pp. 2437-2454
R.G. Kulkarni, G. Achaiah and G.N. Sastry
[Abstract]
Abstracts
[Back
to top]
Editorial
Therapeutic Modulation of Prostanoids and Cytokines in Chronic
Diseases
Prostanoids and cytokines are secreted or cell-surface associated
effector molecules, which mediate cell-to-cell communication
and regulate complex biological processes in health and disease.
Some of these molecules are synthesized by cells having highly
specialized functions (such as cells of the endocrine system),
but most are ubiquitously expressed in more than one cell
type or tissue. Originally, such regulatory molecules involved
in inflammation or immunity were termed cytokines, as opposed
to mediators of cell growth and movement, which were named
growth factors and chemokines, respectively. Today this distinction
does not exist as all these “functional” categories
essentially fall into one large family of cytokines. More
than 100 cytokines with quite divergent functions are now
characterized.
As human life expectancy has risen in the last decades, due
to advances in medicine, the prevalence of chronic, inflammatory,
debilitating diseases of infectious or autoimmune origin has
risen as well. Recently, inflammatory cytokines have been
shown to play a central regulatory role not only in infection
and immunity, but also in carcinogenesis, transplantation
and other more common chronic conditions such as cardiovascular
disease. As soon as a role for these molecules in the pathogenesis
of such common diseases was established, novel therapeutic
strategies were devised attempting to correct existing inflammatory
mediator or cytokine imbalances, by either blocking the effects
of certain cytokines or enhancing the presence of others.
The first steps toward developing cytokine therapeutics were
in the early 1980’s. Since then there has been an explosion
of interest in this area. The numerous animal and human cytokine
based studies in the treatment of such disorders within the
last twenty-five years are impossible to cover in a single
journal issue. This issue therefore focuses on recent advances
in this topic in 6 representative areas of research: chronic
infections, allergy, asthma, cancer, transplant medicine and
regenerative medicine.
In the first article [1], Villar and Dongari-Bagtzoglou present
recent information on advances in the use of cytokines as
a therapeutic strategy in chronic bacterial, parasitic, fungal
and viral infections. In all chronic infections it is generally
accepted that for immune protection to take place, generation
of a dominant Th1 or Th2 cell type cytokine response is required.
In the first part of the article, the role of Th1, Th2 and
proinflammatory cytokines as regulators of phagocytic cell
function, cell-mediated immunity and humoral immunity, is
described. Subsequently, the article discusses the regulation
of host protective immunity by specific cytokines in some
of the most common chronic infections and addresses potential
therapeutic applications of such cytokines in animal models
of infection and human trials when data are available.
The paper by Woodfolk [2] addresses the role of cytokines
in the pathogenesis of allergic disorders, such as asthma.
Emerging concepts in the existing Th1/Th2 cytokine paradigm
and the identification of a relevant molecular target for
therapy are described. This article particularly highlights
the challenges of dissecting the role of each cytokine as
part of a complex network, in the development of allergic
responses to antigens and the manifestation of allergic symptoms.
The effects of existing and emerging therapies, which target
Th1, Th2 and regulatory cytokines on established allergic
responses are discussed.
Camateros and coworkers [3] expand the information provided
in this issue on allergic diseases by focusing on the role
of Toll-like receptor (TLR)-regulated cytokines in the pathogenesis
of asthma. In the introductory segment of this article TLR-mediated
signaling is linked to specific immunomodulating cytokines,
which contribute to the asthmatic phenotype. Specific therapeutic
applications of TLR agonists and antagonists in animal models
of the disease and future therapeutic prospects are extensively
covered.
In the fourth paper in this series Mutoh and coworkers [4]
address the role of cyclooxygenase-derived mediators of inflammation
(prostanoids) in the pathogenesis of cancer. Specific cellular
mechanisms of disease pathogenesis, mediated by prostaglandins
are addressed such as cell proliferation, modulation of apoptosis,
angiogenesis and immune surveillance. Evidence in colon carcinogenesis
for the contribution of cyclooxygenases in disease progression
is presented. Furthermore, potential applications of prostanoid
receptor inhibitors or agonists for cancer chemoprevention
are discussed.
In the article by De Sanctis et al. [5], cytokines
and inflammatory mediators are discussed in the context of
allotransplantation and allograft rejection. The specific
cytokine-regulated immunologic mechanisms involved in acute
and chronic graft rejection, are described. Cell signaling
cascades and molecular mechanisms of organ injury are also
defined. Finally, the state of the science in the pharmacological
modulation of cytokines and prostanoids as it applies to the
prevention of transplant rejection is presented.
The final paper in this issue by Ioannidou [6] addresses the
therapeutic applications of cytokines acting as growth factors
in regenerative medicine. The therapeutic potential of stem
cells in conjunction with growth factors in the regeneration
of vascular, hematopoietic, neural, skeletal, pancreatic and
oral tissues is discussed. Both animal and human clinical
studies are reviewed.
In conclusion this issue presents a concise and critical review
of the science in the area of cytokine therapeutics in such
diverse areas as chronic infections, allergy, asthma, cancer,
transplant medicine and regenerative medicine. The reader
will therefore have the opportunity to benefit from existing
and emerging paradigms from multiple disciplines on the same
topic.
References
[1] Villar CC, Dongari-Bagtzoglou A. Therapeutic Modulation
of Cytokines in Chronic Infectious Diseases. Curr Pharm Design
2006; 12(19): 2329-2348.
[2] Woodfolk JA. Cytokines as a Therapeutic Target for Allergic
Diseases: A Complex Picture. Curr Pharm Design 2006; 12(19):
2349-2363.
[3] Camateros P, Moisan J, Hénault J, De Sanctis J,
Skamene E, Radzioch D. Toll-Like Receptors, Cytokines and
the Immunotherapeutics of Asthma. Curr Pharm Design 2006;
12(19): 2365-2374.
[4] Mutoh M, Takahashi M, Wakabayashi K. Roles of Prostanoids
in Colon Carcinogenesis and their Potential Targeting for
Cancer Chemoprevention. Curr Pharm Design 2006; 12(19): 2375-2382.
[5] De Sanctis J, Garmendia J, Radzioch A, Radzioch D. New
Frontiers in the Therapeutic management of Transplant Rejection.
Curr Pharm Design 2006; 12(19): 2383-2395.
[6] Ioannidou E. Therapeutic Modulation of Growth factors
and Cytokines in Regenerative Medicine. Curr Pharm Design
2006; 12(19): 2397-2408.
Anna Dongari-Bagtzoglou, DDS, PhD
Department of Oral Health and Diagnostic Sciences
School of Dental Medicine
University of Connecticut Health Center
USA
E-mail: adongari@uchc.edu
[Back to top]
Therapeutic Modulation of Cytokines in Chronic Infectious
Diseases
C.C. Villar and A. Dongari-Bagtzoglou
The recent increase in immunocompromised patient populations,
including HIV-infected patients, cancer patients with chemotherapy-induced
neutropenia, and transplant recipients receiving immunosuppressive
therapy, has led to an increased incidence of clinically significant
chronic opportunistic infections. Traditional treatment of
chronic persistent infections has strongly relied on the use
of antimicrobial drugs. However, unsatisfactory results with
drug monotherapy and emergence of resistant strains have prompted
the use of adjunctive cytokine therapies for the treatment
of these infections. During the past decade, a wide spectrum
of immunomodulators has been tested in human clinical trials
and animal models of chronic infections caused by a variety
of bacteria, fungi, viruses and parasites. This review compiles
recent information on advances in the use of cytokines as
a therapeutic strategy in chronic bacterial, parasitic, fungal
and viral infections.
[Back to top]
Cytokines as a Therapeutic Target for Allergic
Diseases: A Complex Picture
J.A. Woodfolk
Production of IgE antibodies promotes the development of allergic
disorders such as asthma, rhinitis and atopic eczema. Though
Th2 cytokines play a pivotal role in the allergic inflammatory
cascade, therapeutic strategies which target these factors
have not been curative in clinical trials. In humans, the
allergic phenotype encompasses a broad spectrum of diverse
clinical entities, which are dictated by genetics as well
as the nature of the allergen and the time in life at which
al-lergen is encountered. The disparate findings in animal
and human systems highlight the complexity of cytokine-mediated
events in allergic responses in man. Different allergic phenotypes
cannot be distinguished strictly on the basis of Th1 and Th2
cytokines. These observations coupled with an emerging role
for regulatory T cells in modulation of the allergic response
warrant re-examination of the cytokine network in allergic
disease. This article highlights the challenges of dissecting
the role of individual cytokines in the development of allergic
responses and manifestation of allergic symptoms. Regulatory
T cells have been implicated in modulation of the activity
of allergen-specific Th1 and Th2 effector cells and immune
outcome; however, the characteristics of these regulatory
T cells remain largely undefined. The effects of existing
and emerging therapies which target Th1, Th2 and regulatory
cytokines on established allergic responses are examined in
the context of this new paradigm. Taken together, existing
data suggest that a multi-faceted approach, which is tailored
to each patient, will be required in order to attain clinical
benefit.
[Back to top]
Toll-Like Receptors, Cytokines and the Immunotherapeutics
of Asthma
P. Camateros, J. Moisan, J. Hénault, J. De Sanctis,
E. Skamene and D. Radzioch
Asthma is a complex disease caused by a poorly characterized
set of genetic and environmental factors whose pathology is
a result of immune dysregulation. Toll-like receptors are
pathogen associated molecular pattern receptors expressed
by many airway and pulmonary tissues as well as cells of the
innate and adaptive immune system. Ligation of toll-like receptors
can lead to a change in the expression levels of multiple
inflammatory and anti-inflammatory mediators which are involved
in the pathogenesis of asthma. These ligands and their receptors
are therefore prime candidates in the search for immunotherapeutic
treatments of asthma. The use of murine models of allergic
asthma as tools for the genetic dissection of this disease
should allow the molecular mechanisms underlying asthma to
be identified and possibly used as further immunotherapeutic
targets.
[Back to top]
Roles of Prostanoids in Colon Carcinogenesis and
their Potential Targeting for Cancer Chemoprevention
M. Mutoh, M. Takahashi and K. Wakabayashi
Prostanoids are produced in response to numerous growth factors
and environmental stimuli. Their synthesis is dependent on
two cyclooxygenase (COX) enzymes, COX-1 and COX-2, which are
rate-limiting for the production of prostaglandins (PGs) and
thromboxanes from free arachidonic acid. Selective inhibitors
of both COX forms have the potential to inhibit colon tumorigenesis,
and there is abundant documented evidence of elevated expression
of COX-2 in colon tumors and a variety of other malignancies.
The resultant high level PGE2
production may play an important role in cell proliferation,
modulation of apoptosis, angiogenesis, inflammation and immune
surveillance. Prostanoids exert their biological actions through
binding to eight specific membrane receptors; the four subtypes
EP1
to EP4
for PGE2;
DP for PGD2;
FP for PGF2;
IP for PGI2;
and TP for thromboxane A2.
Recently, genetic and pharmacologic experiments have suggested
that all PGE2
receptors can contribute to colon tumorigenesis. Moreover,
it is suggested that EP1
and EP4
play roles in polyp formation independently. It is important
to determine details of the down-stream signaling pathways
of prostanoid receptors for further understanding of the mechanisms
of cancer development. Furthermore, it is anticipated that
development of specific receptor antagonists will provide
new advantageous tools for chemoprevention.
[Back to top]
New Frontiers in the Therapeutic Management of
Transplant Rejection
J. De Sanctis, J.V. Garmendia, A. Radzioch and D. Radzioch
Understanding of the mechanisms of transplant and xenotransplant
rejection represents one of the most important aspects of
both basic and clinical immunology. This review discusses
the roles of 1) immune response and 2) the influence of various
products of arachidonic acid metabolism on immune response
in graft survival. The review also includes an overview of
novel therapeutic approaches developed to prevent, or at least
delay, graft rejection. New discoveries in basic and clinical
immunology have generated new areas of research in pharmacology
that may prevent rejection more efficiently, a key issue in
modern medicine.
[Back to top]
Therapeutic Modulation of Growth Factors and Cytokines
in Regenerative Medicine
E. Ioannidou
Regeneration that takes place in the human body is limited
throughout life. Therefore, when organs are irreparably damaged,
they are usually replaced with an artificial device or donor
organ. The term “regenerative medicine” covers
the restoration or replacement of cells, tissues, and organs.
Stem cells play a major role in regenerative medicine by providing
the way to repopulate organs damaged by disease.
Stem cells have the ability to self renew and to regenerate
cells of diverse lineages within the tissue in which they
reside. Stem cells could originate from embryos or adult tissues.
Growth factors are proteins that may act locally or systemically
to affect the growth of cells in several ways. Various cell
activities, including division, are influenced by growth factors.
Cytokines are a family of low-molecular-weight proteins that
are produced by numerous cell types and are responsible for
regulating the immune response, inflammation, tissue remodeling
and cellular differentiation. Target cells of growth factors
and cytokines are mesenchymal, epithelial and endothelial
cells. These molecules frequently have overlapping activities
and can act in an autocrine or paracrine fashion. A complex
network of growth factors and cytokines guides cellular differentiation
and regeneration in all organs and tissues.
The aim of this paper is to review the role of growth factors
and cytokines in different organs or systems and explore their
therapeutic application in regenerative medicine. The role
of stem cells combined with growth factors and cytokines in
the regeneration of vascular and hematopoietic, neural, skeletal,
pancreatic, periodontal, and mucosal tissue is reviewed. There
is evidence that supports the use of growth factors and cytokines
in the treatment of neurological diseases, diabetes, cardiovascular
disease, periodontal disease, cancer and its complication,
oral mucositis. After solving the ethical issues and establishing
clear and reasonable regulations, regenerative medicine through
stem cell application combined with specific growth factors
and cytokines will have great potential in curing a variety
of human diseases.
[Back to top]
Slow-Onset Inhibition of 2-trans-Enoyl-ACP (CoA)
Reductase from Mycobacterium tuberculosis
by an Inorganic Complex
J.S. Oliveira, E.H. S. de Sousa, O.N. de Souza, Í.S.
Moreira, D.S. Santos and L.A. Basso
Tuberculosis (TB) remains the leading cause of mortality due
to a bacterial pathogen, Mycobacterium tuberculosis.
The reemergence of tuberculosis as a potential public health
threat, the high susceptibility of human immunodeficiency
virus-infected persons to the disease, and the proliferation
of multi-drug-resistant strains have created a need for the
development of new antimycobacterial agents. Mycolic acids,
the hallmark of mycobacteria, are high-molecular-weight α
-alkyl, β-hydroxy
fatty acids, which appear mostly as bound esters in the mycobacterial
cell wall. The product of the M. tuberculosis inhA
structural gene (InhA) has been shown to be the primary target
for isoniazid (INH), the most prescribed drug for active TB
and prophylaxis. InhA was identified as an NADH-dependent
enoyl-ACP reductase specific for long-chain enoyl thioesters.
InhA is a member of the mycobacterial Type II fatty acid biosynthesis
system, which elongates acyl fatty acid precursors of mycolic
acids. Although the history of chemotherapeutic agent development
demonstrates the remarkably successful tinkering of a few
structural scaffolds, it also emphasizes the ongoing, cyclical
need for innovation. The main focus of our contribution is
on new data describing the rationale for the design of a penta-cyano(isoniazid)ferrateII
compound that requires no KatG-activation, its chemical characterization,
in vitro activity studies against WT and INH-resistant
I21V M. tuberculosis enoyl reductases, the slow-onset
inhibition mechanism of WT InhA by the inorganic complex,
and molecular modeling of its interaction with WT InhA. This
inorganic complex represents a new class of lead compounds
to the development of anti-tubercular agents aiming at inhibition
of a validated target.
[Back to top]
Pharmacogenetics of Antithrombotic Drugs
D. Tàssies
Antithrombotic therapy has improved the prognosis of
patients with venous or arterial thrombosis. However, there
is substantial interindividual variability in the response
to antithrombotic drugs. This variability is due, in part,
to genetics, which may affect the efficacy and safety of drugs
used in the treatment and prevention of thrombosis. Pharmacogenetics
studies the genetic factors related to interindividual variability
in the response to drugs. Various polymorphisms in genes of
the hemostatic system that have been reported to be markers
of susceptibility to thromboembolic disease also seem to be
implicated in the response to antithrombotic therapy. These
include polymorphisms in platelet receptors (platelet glycoproteins)
and coagulation factors (factors II, V, XII, XIII). There
is also growing evidence on genetic polymorphisms affecting
the metabolism (cytochrome P450),
disposition, transporter proteins or cellular receptors of
antithrombotic drugs.
This review summarizes current knowledge on the pharmacogenetics
of antithrombotic therapy, paying special attention to four
therapeutic groups: antiplatelet agents, anticoagulants (vitamin
K antagonists and heparin), fibrinolytics and other drugs
used for the prevention of cardiovascular risk, such as statins
and hormone replacement therapy in the menopause. The potential
relevance of pharmacogenetics in the future of antithrombotic
therapy and the design of clinical trials is also explored.
[Back to top]
Novel Targets for Antiinflammatory and Antiarthritic
Agents
R.G. Kulkarni, G. Achaiah and G.N. Sastry
Inflammation is a complex pathological condition associated
with exaggerated human immune system involving various activated
immune cells and bio-molecules. Treatment of inflammatory
diseases perticularly chronic inflammatory diseases such as
rheumatoid arthritis, inflammatory bowel disease etc. has
been a big challenge for scientists as there are no safe drugs
available for cure. Current therapeutic approaches to the
treatment of inflammatory diseases are centered on cycloxygenase
(both COX-1 and 2) proinflammatory enzymes but present available
drugs of this category are associated with undesirable gastrointestinal
and cardiovascular side effects. Recent scientific advents
draw out the secrets of inflammation cache and understanding
the involvement of several factors acting as stimulators or
inhibitors thus opening new avenues for drug discoveries.
Several bio-molecules such as proinflammatory cytokines, components
of signal trasduction and matrix degrading enzymes resolve
inflammatory responses, might be new targets for treatment
of chronic inflammatory diseases. This review gathers recent
advances in drug research focusing interleukin-1, TNF-α,
p38 kinase, c-Jun N-terminal kinase MAP kinase, NFκB,
and matrix metalloproteinases. The biological roles of these
inflammatory mediators are clearly understood thus offering
new targets for design of novel inhibitors for incurable inflammatory
diseases. This also provides an overview of the current nonsteroidal
antiinflammatory agents.
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