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Endocrine,
Metabolic & Immune Disorders - Drug Targets
ISSN: 1871-5303
Endocrine, Metabolic &
Immune Disorders - Drug Targets
Volume 6, Number 3, September 2006
Contents
Targeting Tumor-Related Immunosuppression for
Cancer Immunotherapy Pp. 223-237
G. Frumento, T. Piazza, E. Di Carlo and S. Ferrini
[Abstract]
Drug Therapy Aimed at Adenylyl Cyclase to Regulate
Cyclic Nucleotide Signaling Pp. 239-247
K. Iwatsubo, S. Okumura and Y. Ishikawa
[Abstract]
Vasopressin-Receptor Antagonists: A New Class
of Agents for the Treatment of Hyponatremia Pp. 249-258
B.R. Olson
[Abstract]
Type 1 11β-hydroxysteroid
Dehydrogenase as Universal Drug Target in Metabolic Diseases?
Pp. 259-269
U. Oppermann
[Abstract]
Drug Targets to Pro-Angiogenetic Factors with
Special Reference to Primary Peritoneal Mesothelioma Pp.
271-277
G. Ranieri, E. Ruggieri, G. Falco, N. Zizzo, E. Mattioli,
A.F. Zito, R. Patruno and G. Gasparini
[Abstract]
Antioxidant Effects of Glutathione and IGF in
a Hyperglycaemic Cell Culture Model of Fibroblasts: Some Actions
of Advanced Glycaemic end Products (AGE) and Nicotine Pp.
279-286
Z.A. Rahman and M. Soory
[Abstract]
Origin and Biological Significance of Shed-Membrane
Microparticles Pp. 287-294
A. Tesse, M.C. Martínez, F. Meziani, B. Hugel,
M.A. Panaro, V. Mitolo, J.-M. Freyssinet and R. Andriantsitohaina
[Abstract]
Microparticles are small vesicles released during cell activation
or apoptosis, originating from various cell types. Elevated
levels of circulating MPs, detected in cardiovascular and
immune-mediated diseases, displayed pro-inflammatory and procoagulant
properties involved in vascular dysfunction.
Anthracyclines-Contra Cruciform Extrusion in DNA
Regulating Sequences Pp. 295-302
V. Viglasky
[Abstract]
Abstracts
[Back to top]
Targeting Tumor-Related Immunosuppression for
Cancer Immunotherapy
G. Frumento, T. Piazza, E. Di Carlo and S. Ferrini
Tumors produce several factors, such as Prostaglandins (PGs),
Interleukin (IL)-10, Vascular Endothelial Growth Factor (VEGF)
and Transforming Growth Factor (TGF)-β,
which may directly or indirectly inhibit the immune response
and may hamper immunotherapy. Furthermore, cells of innate
or adaptive immunity, recruited by tumor-derived factors,
may contribute in immunosuppression. Regulatory T (Treg) cells
such as the “naturally occurring” CD4+/CD25+
Treg and the IL-10-induced Tr1 cells are major players in
this arena. Paradoxically Treg cells are stimulated by IL-2,
which is used in tumor immunotherapy. Treg cells suppress
T cell responses through soluble factors or by contact-dependent
mechanisms, such as the Cytotoxic T Lymphocyte Antigen (CTLA)-4-mediated
induction of Indoleamine 2,3-Dioxygenase (IDO) in dendritic
cells (DC). IDO inhibits T cell responses by depleting Tryptophan
and producing Kynurenine, which is toxic to lymphocytes. Macrophages,
granulocytes or myeloid suppressor cells (MSC) suppress immunity
by other enzymatic mechanisms, involving Arginase and Nitric
Oxide Synthase (NOS). Subversion of tumor immunosuppression
is required for successful immunotherapy. Attempts to block
or eliminate Treg cells have been made by the use of chemotherapy,
anti-CD25 or anti-CTLA-4 antibodies, IL-2-toxin chimeric proteins
or Glucocorticoid-induced TNF-like Receptor (GITR) and CD134/OX-40
ligands. Tumor cells genetically modified to secrete IL-21
(an immune-stimulatory “IL-2-like” cytokine, which
is not involved in immune regulation) cured experimental metastases
in combination with anti-CD25 monoclonal antibodies (mAbs).
Also strategies aimed at blocking enzyme-based immune-suppressive
mechanisms are suitable, as suggested by experimental evidences
in mouse tumor models.
[Back to top]
Drug Therapy Aimed at Adenylyl Cyclase to Regulate
Cyclic Nucleotide Signaling
K. Iwatsubo, S. Okumura and Y. Ishikawa
Conventional drug screening has been targeted, in many cases,
on cell surface receptors, e.g., G-Protein coupled receptors,
to regulate cellular signaling and thus function. There is
emerging evidence, however, that such targets can be expanded
to effector enzymes of receptors because effector enzymes
have multiple subtypes that differ in tissue distribution,
and thus targeting such molecules may lead to organ-specific
pharmacological regulation. An example is phosphodiesterase,
which degrades cyclic nucleotides. Subtype-specific phosphodiesterase
inhibitors, such as sildenafil citrate, a type 5 phosphodiesterase
inhibitor, and milrinone, a type 3 phosphodiesterase inhibitor,
are now widely used in the treatment of erectile dysfunction
and heart failure, respectively. Adenylyl cyclase, which synthesizes
cyclic AMP, has at least 9 isoforms that differ in tissue
distribution. Transgenic mouse studies utilizing such isoforms
have identified the roles of each isoform. Forskolin, a natural
plant extract, was first identified as a general stimulator
of adenylyl cyclase more than 20 years ago. Recently, 6-[3-(dimethylamino)propionyl]forskolin,
a water-soluble forskolin derivative with high selectivity
for type 5 (cardiac) adenylyl cyclase was developed and has
been widely used in the treatment of acute heart failure.
Adenine analogs or P-site inhibitors, which are classic, but
not isoform-specific adenylyl cyclase inhibitors, are now
utilized to develop isoform-specific inhibitors as well. Putting
together, targeting adenylyl cyclase isoforms, either of isoform-specific
stimulation or inhibition, may be a novel strategy to develop
new drugs in the next decade.
[Back to top]
Vasopressin-Receptor Antagonists: A New Class
of Agents for the Treatment of Hyponatremia
B.R. Olson
Hyponatremia is a very common electrolyte disorder often caused
by the dysregulation of arginine vasopressin (AVP) secretion
and the effects of the hormone at its receptors and is associated
with significant morbidity and mortality. Recent developments
in the understanding of water homeostasis and AVP actions
at the kidney, both in normal circumstances and in pathologic
conditions, has created the possibility of new therapies that
directly target the inappropriate excess of AVP stimulation
of vasopressin V2 receptors (V2Rs) in the kidney. Preclinical
and clinical trial results indicate that AVP V2R antagonism
is a highly promising and rational approach for the treatment
of dilutional hyponatremia caused by excessive retention of
water. This review of hyponatremia and its therapy is intended
to educate clinicians who manage patients who have hyponatremia
and its complications. Background information on hyponatremia
is presented and the pertinent published literature with regard
to the diagnosis and therapy of this disorder is summarized
with a specific focus on AVP-receptor antagonists. Agents
that antagonize AVP V2Rs and promote aquaresis, the electrolyte-sparing
excretion of free water, are likely to be effective and well
tolerated therapies for the treatment of dilutional hyponatremia.
[Back to top]
Type 1 11β-hydroxysteroid
Dehydrogenase as Universal Drug Target in Metabolic Diseases?
U. Oppermann
Glucocorticoid hormones play essential roles in adaptation
to stress, regulation of metabolism and inflammatory responses.
Their effects primarily depend on their binding to intracellular
receptors leading to altered target gene transcription as
well as on cell-type specific biotransformation between 11β-hydroxy
glucocorticoids and their 11-oxo metabolites. The latter effect
is accomplished by two different 11β-hydroxysteroid
dehydrogenase isozymes, constituting a shuttle system between
the receptor ligand cortisol and its non-binding precursor
cortisone. Whereas the type 1 enzyme (11β-HSD1)
is in vitro a NADP(H)- dependent bidirectional enzyme,
it reduces in most instances in vivo cortisone to
active cortisol. The type 2 enzyme is an exclusive NAD+ dependent
dehydrogenase of glucocorticoids, thus “protecting”
the mineralocorticoid receptor against illicit occupation
by cortisol.
Inhibition of tissue-specific glucocorticoid activation by
11β-HSD1
constitutes a promising target in the treatment of metabolic
and cardiovascular diseases. Pharmacological inhibition leads
in animal models to lowered hepatic glucose production and
increased insulin sensitivity, the primary goals in therapy
of diabetes mellitus. Importantly, 11β-HSD1
activity appears to be intrinsically linked to all features
of the metabolic syndrome, which could at least in animal
experiments be modulated by use of synthetic selective inhibitors.
Importantly, these features include not only insulin resistance
but also dyslipidemia, obesity and arterial hypertension.
Animal studies and pharmacological experiments suggest further
unrelated target areas, for example improvement of cognitive
function and treatment of glaucoma, due to the role of glucocorticoids
and cellular activation by 11β-HSD1
in these pathologies.
The recent development of specific 11β-HSD1
inhibitors coupled with advances on structural knowledge and
regulation of the 11β-HSD1
target has undoubtedly promoted the understanding of glucocorticoid
control of metabolic regulation. Taken together, it appears
that inhibitors against 11β-HSD1
constitute a promising avenue for novel treatment strategies
against the underlying causes of cardiovascular and other
metabolic diseases.
[Back to top]
Drug Targets to Pro-Angiogenetic Factors with
Special Reference to Primary Peritoneal Mesothelioma
G. Ranieri, E. Ruggieri, G. Falco, N. Zizzo, E. Mattioli,
A.F. Zito, R. Patruno and G. Gasparini
Angiogenesis is necessary for growth and the spread of human
tumors. Animal studies also suggest that angiogenesis is an
important interspecies biological mechanism of tumor development.
Angiogenesis is a complex multistep cascade modulated by both
positive soluble factors, such as vascular endothelial growth
factor, thymidine phosphorylase, basic-fibroblast growth factor
and negative soluble factors such as angiostatin and endostatin.
From the imbalance of the above angiogenesis regulators, tumor
endothelial cells may divide up to 50 times more frequently
than endothelial cells of normal tissue. Published studies
have suggested that the assessment of microvessel density
(MVD) or endothelial area (EA) can be considered as surrogate
markers of angiogenesis with biological and prognostic relevance.
Literature data on angiogenesis of mesothelioma are inconclusive,
with only a few studies performed in primary peritoneal mesothelioma
(PPM) due to the rarity of the disease. We assessed immunohistochemically
MVD and EA and their biological and clinical significance
in a consecutive series of 23 PPM cases. MVD and EA were detected
in “hot spots” by a computerized image analyzer.
The mean value of MVD and EA was 27 ±
14 and 26.04 ±
8.35 x10-2 µ2 per field (400x),
respectively. Patients with a high MVD or EA tumors showed
a more clinical aggressiveness due to the presence of ascites
and a shorter overall survival.
Our results suggest that PPM is an angiogenesis-dependent
neoplasia. Therefore, antiangiogenic compounds should be tested
particularly in those patients with highly vascularized PPM.
[Back to top]
Antioxidant Effects of Glutathione and IGF in
a Hyperglycaemic Cell Culture Model of Fibroblasts: Some Actions
of Advanced Glycaemic end Products (AGE) and Nicotine
Z.A. Rahman and M. Soory
The aim of this investigation was to establish potential oxidative
effects of glucose, advanced glycation end products (AGE)
and nicotine (N) in a fibroblast cell culture model using
the anti-oxidants glutathione (G) and insulin like growth
factor (IGF). Assays of androgen metabolites were used as
biomarkers of healing in this context.
Confluent monolayer cultures of human gingival fibroblasts
were established in 24 well multiwell plates and incubated
in Eagle`s MEM for 24h using two radiolabelled androgen substrates
14C-testosterone/14C-4-androstenedione. The established effective
concentrations of G1000, glutathione and AGE were used alone
and in combination with nicotine and insulin-like growth factor.
The medium was then solvent extracted for steroid metabolites,
evaporated to dryness and subjected to thin layer chromatography
in a benzene acetone solvent system 4:1 v/v for separation
of formed metabolites. The metabolites were quantified, using
a radioisotope scanner.
Significant reduction in the yields of DHT in response to
G1000, AGE and nicotine (n=6; p<0.003) were overcome by
glutathione (n=6; p<0.002). The stimulatory effect of IGF
when combined with AGE was further enhanced by the antioxidant
effect of glutathione (n=6; p<0.003).
Glucose, AGE and nicotine had a significant inhibitory effect
on the yields of the androgen biomarker DHT, overcome by the
antioxidant glutathione and IGF, suggestive of an oxidant
role for the former agents and an anti-oxidant one for the
latter. These agents affected yields of androgen metabolites,
biomarkers of oxidative stress and repair, with potential
implications on healing in uncontrolled diabetic smokers.
[Back to top]
Origin and Biological Significance of Shed-Membrane
Microparticles
A. Tesse, M.C. Martínez, F. Meziani, B. Hugel,
M.A. Panaro, V. Mitolo, J.-M. Freyssinet and R. Andriantsitohaina
Microparticles (MPs) are small vesicles released from
the membrane surface during eukaryotic cell activation or
apoptosis. They originate from various cell types, displaying
the typical surface cell proteins and cytoplasmic components
of their cell origin. Their procoagulant properties are linked
to phosphatidylserine exposed at their surface. Numerous reports
have shown that MPs are able to mediate long-range signaling,
acting on different targets from those of their own cellular
origin. MPs-mediated binding to other cells occurs by integration
into the membrane, by adhesion to the cell surface or by ligand-receptor
interaction. Elevated levels of circulating MPs have been
detected in cardiovascular and immune-mediated diseases. Despite
extensive studies of the procoagulant and pro-inflammatory
properties of MPs, little is known about their effect on vascular
function. MPs accumulate in atherosclerotic plaques and injured
vascular wall. Circulating MPs from patients with myocardial
infarction induce endothelial dysfunction by impairing the
endothelial nitric oxide (NO) pathway, without causing changes
in endothelial NO-synthase (eNOS) expression. However, MPs
from T-cells may induce endothelial dysfunction, altering
gene expression of eNOS and caveolin-1. Moreover, MPs may
promote the expression of pro-inflammatory proteins implicated
in vascular contractility alterations. This review describes
the origin of MPs and their biological role in physiological
conditions and in various pathological states, with special
reference to the possible linkage between their pro-inflammatory
and procoagulant properties and vascular dysfunction.
[Back to top]
Anthracyclines-Contra Cruciform Extrusion in DNA
Regulating Sequences
V. Viglasky
Despite the existence of a wealth of structural and theoretical
data relating to palindromic sequences in the genome, the
mechanism of cruciform formation in the presence of anthracyclines
in miscellaneous biological processes is still poorly understood.
Generally, DNA intercalators influence the DNA superhelicity,
which plays a key role in the cruciform formation in DNA molecules.
The potential of DNA intercalating ligands on the stabilization/destabilization
of cruciform in DNA is discussed. Here, the indirect impact
of anthracyclines to cell developing and surviving is analyzed
for the first time. Primarily, the anthracycline modifies
the helical properties of DNA and the overall DNA structure,
and secondarily alters any cruciform-dependent processes,
mainly DNA replication and transcription.
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