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Medicinal Chemistry Reviews - Online, Volume 2, No. 2, 2005
Contents
Studies on Target Genes of General
Anesthetics-Version 2 Pp.97-109
Sumiko
Gamo
Evolving Phage Vectors for Cell Targeted Gene
Delivery – An Update Pp.111-114
David
Larocca, Michael A. Burg and Andrew Baird
Recent Developments in the Understanding and
Treatment of Neurodegenerative Disorders Involving Protein Conformational
Misfolding and Amyloid Formation Pp.115-125
A.J.
Thompson and C.J. Barrow
In Vivo Methods to Estimate Drug Transport to
the Brain Across the Blood-Brain Barrier Pp.127-131
A.G.
de Boer and P.J. Gaillard
Scintigraphic Imaging of HSVtk Expression in
Gene Therapy Pp.133-147
Erik
F.J. de Vries, Anne Rixt Buursma and Willem Vaalburg
IL-4 and IL-13: Their Pathological Roles in
Allergic Diseases and their Potential in Developing New Therapies-Update Pp.149-152
K.
Izuhara, K. Arima, K. Masumoto, S. Kanaji and T. Kanaji
Update to: The Aryl Hydrocarbon Receptor in
Anticancer Drug Discovery: Friend or Foe? Pp.153-161
T.D.
Bradshaw, C.G. Mortimer and A.D. Westwell
Therapeutic Implications of Gene Deletion of
Ligands and Receptors of Members of TNF Superfamily Pp.163-175
Shishir
Shishodia, Yasunari Takada and Bharat B. Aggarwal
Abstracts
[Back to top] Studies on Target Genes of General
Anesthetics-Version 2
Sumiko
Gamo
Generally
speaking, we cannot fully understand the mechanisms of general anesthesia until
the molecular mechanisms of consciousness are fully elucidated. Loss of
consciousness induced by general anesthetics might involve sensation, motor
activity, behaviour, memory and consciousness. The effects of many anesthetics
are not limited to humans but also extend to animals. Similar levels of minimum
anesthetic concentrations are required to induce anesthesia in animals and
human; i.e., the minimum alveolar concentration (MAC). Such similarity probably
reflects similar anesthetic target molecules and functional conservation based
on gene conservation. Thus, to study the mechanisms of anesthetic action,
various animal models that are accessible to genetic manipulation, such as
nematodes (Caenorhabditis elegans), fruit flies (Drosophila
melanogaster) and mice can be used. Genetic techniques allow for the rapid
identification and characterisation of genes involved in the actions of general
anesthetics. In this review, I will describe the genetic mutations and putative
target genes of general anesthetics.
[Back to top] Evolving Phage Vectors for Cell Targeted Gene
Delivery – An Update
David
Larocca, Michael A. Burg and Andrew Baird
Bacteriophage
vectors are an attractive alternative to synthetic and animal viral gene delivery
vectors. We have demonstrated that ligand targeted bacteriophage particles can
be used to deliver a functional transgene to mammalian cells that bear the
appropriate receptors. Because transduction of mammalian cells by untargeted
phage is negligible, the specificity of phage-mediated gene delivery can be
determined by the choice of targeting ligand that is displayed on the phage
surface. Thus, phage display vectors can potentially be targeted genetically
for gene delivery to specific cells in the body with little or no delivery to
non-targeted cells. Moreover, since bacteriophage have not evolved to replicate
in mammalian cells they are not likely to have toxicity problems associated
with many animal viral vectors. Although the efficiency of phage-mediated gene
delivery has been low compared to animal viral vectors, studies demonstrating
increased gene transfer using agents that stimulate DNA repair indicate the
potential for improving phage-mediated gene delivery. Indeed, the same
principles of phage display that have been applied extensively to the directed
evolution of binding ligands can now be applied to the adaptation of the phage
particles, themselves for safe and effective therapeutic gene delivery.
[Back to top] Recent Developments in the Understanding and
Treatment of Neurodegenerative Disorders Involving Protein Conformational
Misfolding and Amyloid Formation
A.J.
Thompson and C.J. Barrow
Conformational
disease represents an intriguing but devastating class of neurodegenerative
disorders that includes prion disease, Alzheimer’s disease, Parkinson’s disease
and Huntington’s disease. Although symptoms, on-set times and prognosis among
the diseases can vary markedly, the deposition of neurotoxic protein aggregates
is a significant commonality, and as such is an attractive therapeutic target.
Understanding the mechanisms of protein misfolding and deposition in these
conditions is critical to developing effective diagnostic and therapeutic
agents. This review serves as an update for the sister publication “Protein
Conformational Misfolding and Amyloid Formation: Characteristics of a New Class
of Disorders that Include Alzheimer’s and Prion Diseases” in Curr. Med.
Chem. 2002, 9, 1751-62, and focuses primarily on recent developments in
understanding prion disease and Alzheimer’s disease in context with other
conformational disease. New research in amyloid-related therapeutic strategies
is also discussed.
[Back to top] In Vivo Methods to Estimate Drug
Transport to the Brain Across the Blood-Brain Barrier
A.G. de Boer and P.J. Gaillard
In this paper, we
review the in vivo methods to estimate drug transport to the brain. These vary
from invasive ones like the brain uptake index (BUI), multiple pass techniques,
brain efflux index (BEI), in situ brain perfusion, CSF (cerebrospinal fluid)
sampling (unit impulse response), quantitative autoradiography (QAR), and
intracerebral microdialysis to non invasive ones like positron emission
tomography (PET), and magnetic resonance techniques (imaging (MRI),
spectroscopy (MRS)). The latter two methods can be applied in human also. In
addition, in this review an overview is given for which purposes these methods
can be applied.
[Back to top] Scintigraphic Imaging of HSVtk Expression in
Gene Therapy
Erik
F.J. de Vries, Anne Rixt Buursma and Willem Vaalburg
Suicide gene
therapy is under investigation as a treatment for cancer. In this therapy, a
suicide gene is introduced into tumor cells, enabling the conversion of a
prodrug into a toxic metabolite that selectively kills the transfected tumor
cells. In the most investigated strategy, the herpes simplex virus thymidine
kinase (HSVtk) suicide gene is used in combination with the prodrug
ganciclovir. To assess the efficiency and safety of gene therapy protocols, a
noninvasive method to assay the magnitude, kinetics and spatial distribution of
transgene expression is essential. Imaging methods for repetitive monitoring of
HSVtk transgene expression in living animals and humans, using single photon
emission computed tomography (SPECT) or positron emission tomography (PET),
have been developed. For many therapeutic genes, however, no imaging method is
available. In these cases, reporter genes can be applied. Expression of the
therapeutic gene can be determined indirectly by imaging a reporter gene, like
HSVtk, that is linked to the therapeutic gene. Reporter genes can also be
applied to monitor the expression of endogenous genes and to track the fate of
transplanted cells. This paper presents an updated review on the progress in
the field of non-invasive nuclear imaging of HSVtk transgene expression in gene
therapy.
[Back to top] IL-4 and IL-13: Their Pathological Roles in
Allergic Diseases and their Potential in Developing New Therapies-Update
K.
Izuhara, K. Arima, K. Masumoto, S. Kanaji and T. Kanaji
Bronchial asthma
is a complex disease in which a lot of cells and mediators are involved.
However, a substantial body of evidence has accumulated pointing to the pivotal
role of Th2-cytokines, interleukin (IL)-4, and IL-13, based on expression of
these cytokines in the bronchial lesions, genetic association of the signaling
molecules of these cytokines, and analyses of mouse models. We previously
reviewed the signal transduction of these cytokines, the correlation of these
cytokines with the pathogenesis of allergic diseases, and trials to develop
reagents targeting these cytokines. Since we published that article, several
progresses have been made in this field, so in this article, we summarize the
recent topics as for the issues that we picked up before.
[Back to top] Update to: The Aryl Hydrocarbon Receptor in Anticancer
Drug Discovery: Friend or Foe?
T.D.
Bradshaw, C.G. Mortimer and A.D. Westwell
Major advances in
our understanding of the mechanistic features and regulation of Aryl
hydrocarbon Receptor (AhR) mediated signal transduction have been made in recent
years. This review updates our previously published article “The Aryl
Hydrocarbon Receptor in Anticancer Drug Discovery: Friend or Foe” (Current
Pharmaceutical Design, 2002, 8, 2475-2490), focussing on the most recent
developments in the field. Discussion of receptor regulation and crosstalk,
structural studies on the ligand binding domain, the search for endogenous
ligands, and therapeutic possibilities in the cancer field associated with AhR
ligands, feature prominently here.
[Back to top] Therapeutic Implications of Gene Deletion of
Ligands and Receptors of Members of TNF Superfamily
Shishir
Shishodia, Yasunari Takada and Bharat B. Aggarwal
TNF superfamily
consists of 19 ligands and 29 different receptors. TNF, the first member of the
family was discovered about two decades ago as a protein involved in
suppression of tumor cell proliferation. Most of them have been found to
mediate a wide variety of diseases including cancer, arthritis, bone
resorption, allergy, diabetes, atherosclerosis, myocardial infarction, graft
versus host disease and AIDS. The signaling mechanism induced by members of
this family is becoming increasingly more apparent and serve as a potential
target for the development of therapeutics. All the members of the TNF
superfamily are known to activate NF-kB,
JNK and mediate apoptosis or cell proliferation. The current review focuses on
the effects of deletion of genes that mediate the signaling pathways induced by
members of TNF superfamily.