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Endocrine,
Metabolic & Immune Disorders - Drug Targets
ISSN: 1871-5303
Current Drug Targets - Immune,
Endocrine and Metabolic Disorders
Volume 5, Number 4, December 2005
Contents
Amino Acid Transporter ATB0,+ as a Delivery System
for Drugs and Prodrugs Pp.357
M.E. Ganapathy & V. Ganapathy
[Abstract]
Augmenting T Helper Cell Immunity in Cancer Pp.365
K.L. Knutson & M.L. Disis
[Abstract]
Management of Liver Disease in Thalassemia: Main Drug Targets
for a Correct Therapy Pp.373
G.C. Del Vecchio, A. Nigro, P. Giordano & D. De Mattia
[Abstract]
Molecular Basis of Therapeutic Strategies for Breast Cancer
Pp.379
J. Huang, X. Li, R. Hilf, R.A. Bambara & M. Muyan
[Abstract]
The New Immunosuppression: Intervention at the Dendritic
Cell-T-Cell Interface Pp.397
A.M. Paterson, S.F. Yates, K.F. Nolan & H. Waldmann
[Abstract]
Failure of Immune Homeostasis – The Consequences
of Under and Over Reactivity Pp.413
B. Crimeen-Irwin, K. Scalzo, S. Gloster, P.L. Mottram
& M. Plebanski
[Abstract]
Insulin Regulation of PEPCK Gene Expression: A Model for
Rapid and Reversible Modulation Pp.423
P.G. Quinn & D. Yeagley
[Abstract]
Hormonal Effects on Drug Metabolism Through the CYP System:
Perspectives on Their Potential Significance in the Era of
Pharmacogenomics Pp.439
N.J. Sarlis & L. Gourgiotis
[Abstract]
Signal Transducer and Activator of Transcription 5 (STAT5),
a CrucialRegulator of Immune and Cancer Cells Pp.449
I. Wittig & B. Groner
[Abstract]
Boosting Interleukin-10 Production: Therapeutic Effects
and Mechanisms Pp.465
X. Zhou, P. Schmidtke, F. Zepp & C.U. Meyer
[Abstract]
Abstracts
[Back to top]
Amino Acid Transporter ATB0,+ as a Delivery
System for Drugs and Prodrugs
M.E. Ganapathy & V. Ganapathy
ATB0,+is a unique amino acid transporter because
of its broad substrate specificity and concentrative ability.
This transporter recognizes neutral as well as cationic amino
acids. It is energized by Na+ and Cl- gradients
and membrane potential. Many of the amino acids and amino
acid derivatives that are substrates for ATB0,+ serve as therapeutic
agents (e.g., D-serine, carnitine, and nitric oxide synthase
inhibitors). Recent studies have shown that the potential
of ATB0,+ as a drug delivery system may be greater than previously
envisaged. ATB0,+ can transport antiviral drugs such as acyclovir
and ganciclovir when they are covalently coupled to the side
chain of anionic amino acids. Chemical modification of the
carboxyl groups in the side chain of aspartate and glutamate
with drugs converts these anionic amino acids into neutral
amino acid derivatives. Therefore, the modified drugs are
recognized by ATB0,+. Interestingly, even when acyclovir and
ganciclovir are coupled as esters with -carboxyl group of
neutral amino acids, the modified drugs are transported via
ATB0,+. Similarly, the hydroxyl group in the side chains of
serine and threonine can also be used to covalently couple
drugs for delivery into cells via ATB0,+. This increases
the potential for designing a wide variety of amino acid-based
prodrugs that can utilize ATB0,+ as drug delivery system.
Furthermore, the transporter is expressed in the colon, lung,
and eye, the tissues easily amenable for drug delivery. These
findings argue strongly in support of ATB0,+ as a potential
delivery system for a wide variety of drugs and prodrugs.
[Back to top]
Augmenting T Helper Cell Immunity in Cancer
K.L. Knutson & M.L. Disis
Cancer specific immunity elicited with vaccines has traditionally
focused on the activation of the CD8 cytolytic T lymphocyte
(CTL) often involving direct stimulation of immunity using
HLA-class I binding peptide epitopes. Recently it has become
clear that activation of the CTL immune effector arm alone
is insufficient to mediate an anticancer response. A major
problem is that CD8 T cells alone can not be sustained without
the concomitant activation of CD4 T helper (Th) cells. In
fact, it is now widely recognized that the Th cell regulates
nearly all aspects of the adaptive immune response. In addition,
Th cells can recruit the innate immune system during immune
augmentation. Therefore, the focus of the immune response
in cancer has shifted away from activating CTL immunity alone
to activating Th cell immunity alone or concurrently with
CTL. Evidence suggests that activating the Th cell is sufficient
to get a complete adaptive immune response because, once activated,
the Th cell will elicit endogenous CD8 T cell and humoral
immunity. In this review, we discuss the role of the Th cell
in the adaptive immune response to cancer, how peptides that
are capable of activation of Th cells are identified, and
the clinical translation of newly identified candidate Th
cell peptide epitopes to human cancer specific vaccine. Over
the next decade, studies should begin to further define how
we can manipulate the Th immune effector arm to achieve effective
antitumor immunity.
[Back to top]
Management of Liver Disease in Thalassemia: Main Drug Targets
for a Correct Therapy
G.C. Del Vecchio, A. Nigro, P. Giordano & D. De Mattia
Liver disease is the second cause of mortality in thalassemia
major. We present a review on the hepatic damage in thalassemic
patients aimed at a knowledge of current preventive, diagnostic
and therapeutic approaches, useful to guide in clinical judgment
and treatment decisions. Transfusion related iron overload
and hepatitis are the causes of liver damage in thalassemic
patients. We examined means of primary prevention, anti-hepatitis
vaccinations, blood donors screening; diagnostic tests for
secondary prevention (computed tomography, magnetic resonance
imaging, super conducting quantum interference device and
biopsy) were also discussed about. A survey of treatment methods
and strategies ( chelation therapy, antiviral treatments and
liver and bone marrow transplantation) follows.
[Back to top]
Molecular Basis of Therapeutic Strategies for Breast Cancer
J. Huang, X. Li, R. Hilf, R.A. Bambara & M. Muyan
The development of breast cancer is the consequence of uncontrolled
growth and division of breast-ductal epithelial cells. While
many factors contribute to its etiology, estrogen hormones
within the context of many interrelated growth signaling pathways
play critical roles for the initiation and development of
breast cancer. The effects of estrogens are primarily mediated
by the estrogen receptors (ERs) and . ER mediates a complex
array of genomic and nongenomic events that orchestrate cellular
metabolism, mitogenesis, morphogenesis, motogenesis, and apoptosis.
The current modalities for the treatment of breast cancer
have centered on the development of agents with diverse pharmacology
to reduce/ablate the circulating estrogens or to alter/prevent
ER function. Approaches to perturb the estrogen environment
are successful usually in the remission of established tumors.
However, many breast tumors are not responsive or eventually
develop resistance to endocrine therapies. Despite considerable
effort, the mechanism for the non-responsiveness and acquisition
of resistance remains unclear. The establishment of hormone
responsiveness is one of the current approaches for the development
of an effective therapeutic modality for de novo
resistant breast tumors. Reestablishment of loss of ER synthesis/function,
on the other hand, constitutes a primary therapeutic goal
for acquired resistance neoplasms. We have recently engineered
transregulatory proteins that specifically targeted and robustly
regulated estrogen responsive genes independent of ligand,
ER-subtype and cell-context. The targeted regulation of estrogen
responsive gene networks by these designer transregulators
could provide a basis for the development of novel approaches
for experimental biology and medicine.
[Back to top]
The New Immunosuppression: Intervention at the Dendritic
Cell-T-Cell Interface
A.M. Paterson, S.F. Yates, K.F. Nolan & H. Waldmann
Dendritic cells (DCs) play an important role in initiating
and directing T-cells towards immunity or tolerance. An important
aim of emerging immunosuppressive strategies is to ensure
that antigen is perceived in a ‘tolerogenic context’.
This would have obvious benefit in minimising the need for
long-term drug maintenance in organ transplantation, hypersensitivity
and autoimmune diseases. Here we review the biology of the
interplay between the DC and T-cell, with a specific focus
on therapeutic drugs targeting molecules that effect their
interaction and function.
[Back to top]
Failure of Immune Homeostasis – The Consequences
of Under and Over Reactivity
B. Crimeen-Irwin, K. Scalzo, S. Gloster, P.L. Mottram
& M. Plebanski
The immune system is a tightly regulated network that is
able to maintain a balance of immune homeostasis under normal
physiological conditions. Normally, when challenged with foreign
antigen, specific appropriate responses are initiated that
are aimed at restoring homeostasis. However under particular
circumstances, this balance is not maintained and immune responses
either under or over react. Cancer is an example of a situation
where the immune response can be inefficient or unresponsive,
resulting in uncontrolled growth of the cancer cells. Conversely,
when the immune response over-reacts, this can result in conditions
such as autoimmunity or pathology following infection. Many
drug therapies have been developed that aim to alleviate or
prevent such immune disorders and restore immune homeostasis.
This review highlights recent advances in immunotherapies,
with an emphasis on specific examples in the treatment of
cancer, autoimmune disease (multiple sclerosis) and viral
infection (respiratory syncytial virus).
[Back to top]
Insulin Regulation of PEPCK Gene Expression: A Model for
Rapid and Reversible Modulation
P.G. Quinn & D. Yeagley
Insulin and glucagon regulate the expression and/or activity
of a variety of proteins to maintain blood glucose within
normal limits. A key target is the gene encoding phosphoenolpyruvate
carboxykinase (PEPCK), which catalyzes the first committed
step in hepatic gluconeogenesis. Acute regulation of PEPCK
is achieved by modulating transcription of the gene, which
is tightly regulated by cAMP (the mediator of glucagon and
catecholamines), glucocorticoids and insulin. Normally, PEPCK
expression is induced by glucagon, catecholamines and glucocorticoids
during periods of fasting and in response to stress, but is
dominantly inhibited by glucose-induced increases in insulin
secretion upon feeding. The incomplete effectiveness of insulin
action, whether due to intermittent insulin injection in type
I diabetics or insulin resistance in type II diabetics, contributes
to hyperglycemia and complications, resulting in damage to
the eyes, nerves, kidneys and other organs over time. Thus,
defining a molecular mechanism for insulin inhibition of PEPCK
gene transcription has been a major goal of research in several
labs, because it would allow the development of drugs to prevent
episodic increases in circulating glucose in diabetics. Here,
we review the main lines of investigation into this complex
problem and the likely properties of an inhibitor. Any mechanism
must account for the rapidity, specificity and dominance with
which insulin is known to act in regulating PEPCK transcription.
To date Foxo1 (FKHR) is the only transcription factor for
which a complete path from the insulin receptor to gene regulation
has been described. While this explains the regulation of
some genes, such as IGFBP-1, Foxo1 appears not to play a requisite
role in regulating PEPCK transcription. Investigation of cis-acting
elements in the PEPCK promoter has shed considerable light
on the mechanisms of activation by cAMP and glucocorticoids
but has failed to identify a regulatory element that mediates
insulin inhibition of transcription. This, together with evidence
from analysis of the inducing mechanisms, has prompted us,
and others, to investigate the possibility that insulin disrupts
activation rather than independently promoting repression.
Thus, we hypothesize that insulin-induced modification of
a key transcription regulatory protein prevents an essential
factor from participating in the induction process, leading
to rapid but reversible inhibition, as is seen in animals.
The ability to alter the sensitivity of a key transcription
factor to improve insulin-regulated control of blood glucose
would be a major improvement in the treatment of diabetes,
a growing problem in the industrialized world.
[Back to top]
Hormonal Effects on Drug Metabolism Through the CYP
System: Perspectives on Their Potential Significance in the
Era of Pharmacogenomics
N.J. Sarlis & L. Gourgiotis
Cytochrome P450 (CYP) is a group of enzymes that metabolize
drugs to a more water-soluble form, rendering them available
for renal excretion. The major site of CYP expression is the
liver. Nearly 50% of all medications currently on the market
are metabolized by the enzyme CYP3A4, while metabolism of
another 35-40% occurs through enzymes CYP1A2, CYP2C19, CYP2D6,
CYP3A5 CYP3A6, and CYP3A7. Here, we summarize the current
knowledge of the effects of hormones on the CYP family. The
term “hormone” is used in its broad sense and
includes products of the major endocrine glands (i.e., thyroid,
adrenals, gonads, pancreas) and compounds that are not classically
considered hormones, such as neurogenic amines, cytokines,
interleukins, and eicosanoids. In addition, we comment on
the effects on CYP expression of states associated with profound
hormonal changes, such as pregnancy, malnutrition, obesity,
diabetes mellitus, systemic inflammation, and conditions of
altered extracellular fluid volume or osmolality. Available
data are limited and are derived primarily from in vitro
and animal studies. Moreover, the picture is obscured by conflicting
results among studies and the complexity of the regulation
of the expression and activity of elements of the CYP system.
While the clinical significance of hormonal effects on the
CYP system remains to be determined, we anticipate that such
effects will be most pertinent to drugs with a narrow therapeutic
range. Further research is needed to determine the scope and
significance of these effects in view of rapid advances in
the field of pharmacogenomics and the ever-increasing number
of drugs available for therapeutic use.
[Back to top]
Signal Transducer and Activator of Transcription 5 (STAT5),
a CrucialRegulator of Immune and Cancer Cells
I. Wittig & B. Groner
STAT5 belongs to a small family of transcription factors
with dual functions. The seven signal transducers and activators
of transcription (STAT) act as signaling components between
the plasma membrane and the nucleus, and as transcription
factors with specific DNA binding ability in the nucleus.
STAT5 regulates the expression of genes, which determine important
cellular phenotypes. It can promote proliferation and inhibit
apoptosis, but is also involved in the regulation of differentiation
between specific gene expression. STAT5 can also contribute
to the transformed phenotype. In many leukemias and some solid
tumors, STAT5 is constitutively activated through receptors
or receptor associated tyrosine kinases and contributes to
the survival and the proliferation of malignant cells. STAT5
activity appears to be limiting for these phenotypes. Inhibition
of STAT5 in these tumor cells results in growth arrest and
apoptosis. Targeting of STATs and other downstream mediators
of oncogenic tyrosine kinases provides a promising strategy
for tumor therapy, which might be refractory to resistance
mechanisms incapacitating tyrosine kinase inhibitors. The
well-studied steps in the activation of STAT5 and its roles
in different subcellular compartments suggest original interference
strategies, which could be used to inhibit its function. The
challenge for drug developers will be the exploitation of
defined protein-protein or protein-DNA interactions as targets
of inhibition.
[Back to top]
Boosting Interleukin-10 Production: Therapeutic Effects
and Mechanisms
X. Zhou, P. Schmidtke, F. Zepp & C.U. Meyer
More than forty cytokines have been extensively researched
on the molecular structure, cell signaling and transduction
pathway. With respect to cytokine-regulating therapy in immunological
imbalance however, the reported results are conflicting because
of the pleiotropic functions and the intricate interactions
of the cytokine network. In this review, we outline the observations
on interleukin-10 (IL-10) upregulatory therapy. Despite varying
opinions on its therapeutic effects for different disorders,
IL-10 has been considered a potential anti-inflammatory cytokine.
Numerous studies support the view that IL-10 shows a strong
suppressive effect on Th1 lymphocytes, antigen presenting
cells and the production of inflammatory mediators. It is
also noticeable that recent research has revealed the relationship
between IL-10 induced antigen specific regulatory CD4+ T cells
and antigen specific immune tolerance. This specific regulation
was mediated in part through IL-10 secretion, because anti-IL-10
receptor antibody treatment reverted the inhibitory effect
of regulatory T cell clones. In different models, these cells
were shown to inhibit both Th1 and Th2-type inflammatory responses
through the secretion of IL-10. With the presence of IL- 10,
regulatory T cells may induce peripheral immune tolerance.
Exogenous administration, transgenic expression and endogenous
stimulative agents of IL-10 have been used for a variety of
inflammatory diseases, autoimmune diseases and allograft rejection
in patients and experimental models. A therapeutic intervention
with drug inducing endogenous IL-10 may be more practical
than an exogenous administration of IL-10 with transient effect.
Although further investigation on gene regulation of IL-10
is necessary, increasing studies have been reported concerning
the attempt to develop the agents, which could promote endogenous
IL-10 production for the treatment of immunological disorders
and inflammatory diseases. With some unclear mechanisms, these
agents have strongly upregulated IL-10 production in vitro
or in vivo. Reported IL-10 upregulatory agents have
shown promising prospects for remission of autoimmune diseases
and inflammatory diseases and have even induced antigen specific
immune tolerance. It is interesting that the IL-10 upregulatory
effect of several traditional immunosuppressive drugs hasbeen
detected, e.g. glucocorticoid, which is considered “not
more as an imunosuppressive drug but an immune modulating
agent”. Approximately twenty IL-10 upregulatory agents
as instances are described in the present review. In addition,
their therapeutic effects in various diseases are discussed.
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