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Medicinal Chemistry Reviews - Online, Volume 1, No. 3, 2004
Contents
Annexins in the Central Nervous System: Are
they Neuroprotective or Proapoptotic Agents? Pp.233-252
Chemokines as Therapeutic Targets in
Non-Small Cell Lung Cancer: Update Pp.253-256
D.A.
Arenberg
Chemotherapeutic Effects of Acridine
Derivatives Pp.257-266
William
A. Denny
Intriguing Classes of Acridine Derivatives as
DNA-binding Antitumour Agents: From Pyrimido[5,6,1-de]acridines to
Bis(acridine-4-carboxamides) Pp.267-290
Ippolito
Antonini
Effects of Specific Cyclooxygenase-2
Inhibitors on Carcinogenesis Pp.291-295
John
W. Ho, Jing Zheng Song and Qian Li
Peroxisome Proliferator-Activated Receptors
and the Control of Inflammation Update Pp.297-298
Manuel
Vazquez Carrera
Advances in Therapeutic Drug Monitoring of
Atypical Antipsychotic Drugs Pp.299-316
M.A.
Raggi, R. Mandrioli, V. Pucci and C. Sabbioni
Differential Developmental Origin of
Arteries: Impact on Angiogenesis and Arteriogenesis Pp.317-326
Jaroslav
Pelisek, Masumi Shimizu and Sigrid Nikol
Direct Selection of cDNAs from Filamentous
Phage Surface Display Libraries: An Update Pp.327-329
Claudio
Rhyner, Michael Weichel, Sabine Fluckiger and Reto Crameri
Novel Molecular Targets for Systemic Lupus
Erythematosus and Other Immune-Complex and T-Cell Mediated Autoimmune Diseases
– Update Pp.331-332
Maria
Marino and Giorgio Fassina
Mechanisms of Antihistamines and Mast Cell
Stabilizers in Ocular Allergic Inflammation Pp.333-347
E.B.
Cook, J.L. Stahl, N.P. Barney and F.M. Graziano
Quantitative Structure-Activity Relationship
Studies on Cholecystokin Antagonists† Pp.349-350
Satya
P. Gupta, and Anantha N. Nagappa
Cells of the Macrophage Lineage and their
Role in the Pathogenesis of HIV-1 Infection: An Update Pp.351-360
Katherine
Kedzierska, Clare L.V. Maslin, and Suzanne M. Crowe
Tumor Necrosis Factor-a Blockade in
Rheumatoid Arthritis: Responders Vs Non Responders Pp.361-368
Yasser
El-Miedany
Induction of Tumour Cell Senescence: A New
Strategy in Anticancer Treatment Pp.369-379
Xianghong
Wang and Yong-Chuan Wong
Abstracts
[Back to top] Annexins in the Central Nervous System: Are
they Neuroprotective or Proapoptotic Agents?
Joanna
Bandorowicz-Pikula
Chronic and age-related neurodegenerative diseases are
characterised by a selective loss of specific subsets of neurons over a period
of years. The underlying causes of these diseases are not clear, however, the
death of neurons and the loss of cell-cell contacts seem to be key features.
Understanding molecular mechanisms that control neuronal cell death and
survival and identification of factors involved in these processes is crucial
for the development of preventing strategies and further treatment of
neurodegenerative disorders. In the present review accumulated evidence is
presented that members of a ubiquitous family of annexins, homologous Ca2+-
and membrane-binding proteins expressed in the central nervous system (CNS),
are playing a role in regulation of neuron life span, as either potent
neuroprotective or proapoptotic agents. It was also found that annexins might
be related to some CNS pathologies and disorders. In addition, annexins are
important partners in many vital neuronal processes, as they exhibit
neurotransmitter precursor- and nucleotide-binding properties in vitro, interact with
nucleotide-binding proteins in brain, as well as are involved in the cellular
response to inflammation and oxidative stress. These properties suggest that
some annexins may couple calcium homeostasis and cellular metabolism in neurons
and neuroendocrine cells.
[Back to top] Chemokines as Therapeutic Targets in
Non-Small Cell Lung Cancer: Update
D.A.
Arenberg
This update focuses on recent advances in the knowledge of
roles which chemokines play in the biology of a tumor, and on ways of
exploiting this knowledge to achieve therapeutic advances in the treatment of
non-small cell lung cancer (NSCLC). Chemokines were once thought to play
important roles only in the trafficking of leukocytes in the immune response. That
this large family of proteins can play a role in homeostasis, cancer, and many
chronic diseases is now widely recognized by many investigators in these
diverse fields. In the filed of cancer in particular, recent findings indicate
that chemokines function in; 1) Directing organ-specific patterns of metastatic
disease that characterize solid tumors 2) Providing prognostic information for
patients undergoing surgery for NSCLC by means of their angiogenic properties,
and 3) Initiation and control of tumor-specific immune responses, such that
chemokines may actually be used therapeutically to augment cytotoxic T-cell
responses to tumors. Recent findings in three areas, as well as their
implications for therapeutic advances in NSCLC, will be the focal point of this
update.
[Back to top] Chemotherapeutic Effects of Acridine
Derivatives
William
A. Denny
Acridine
derivatives show a broad range of biological activities. They have primarily
been explored as chemotherapeutic agents (anticancer, antibacterial,
antiprotozoal), because of the ability of the acridine chromophore to
intercalate DNA and inhibit topoisomerase and telomerase enzymes. Research
continues to be focussed primarily in these areas, but recent work shows they
are active also as anticholinesterase agents.
[Back to top] Intriguing Classes of Acridine Derivatives
as DNA-binding Antitumour Agents: From Pyrimido[5,6,1-de]acridines to
Bis(acridine-4-carboxamides)
Ippolito Antonini
In the field of antitomour DNA-binding agents, the class
of acridine derivatives plays an important role both in terms of number of
compounds and their anticancer activities. We have synthesised a number of
acridine derivatives as potential antitomour drugs, in which the chromophore is
fully or partially constituted either by an acridine or by a 9-acridone ring
system: pyrimido[5,6,1-de]acridines, pyrimido[4,5,6-kl]acridines, bis(amine-functionalised)
9-acridone-4-carboxamides, bis(amine-functionalised) acridine-4-carboxamides,
pyrazolo[3,4,5-kl]acridine-5-carboxamides,
pyrazolo [3,4,5-mn]pyrimido[5,6,1-de]acridines, [1,2,6]thiadiazino[3,4,5-kl]acridines and bis(acridine-4-carboxamides). In the present
review we will describe the rational design, the synthesis and the salient
biological characteristics of these classes of acridine derivatives.
[Back to top] Effects of Specific Cyclooxygenase-2
Inhibitors on Carcinogenesis
John
W. Ho, Jing Zheng Song and Qian Li
A growing body of research reveals that malignant cells
can induce cyclooxygenase-2 (COX-2) and prostaglandin expression. Induction of
COX-2 has been reported not only in isolated hepatic cells, but also in cancer
cells. Both proteins are part of complex hormonal cycles involving the
production of estrogen. Imbalance of hormone secretion can generate alteration
at the cellular level. COX-2 inhibitors have been shown to mediate signal
transduction and consequently prevent specific cancer in man. In this review,
we focus on the recent study of COX-2 inhibitors for cancer prevention. The
biologic action of COX-2 inhibitor on key pathway in signal transduction was
discussed. The signal transduction pathway culminates with the ultimate target
hepatic cells. The study provides information on the roles of COX-2 and its
inhibitors. The mode of action of COX-2 inhibitor may lead to development of
potential chemopreventive agents for cancer in humans. Information on the
expression of COX-2 may reveal modulation of cellular functions by COX-2
inhibitors.
[Back to top] Peroxisome Proliferator-Activated Receptors
and the Control of Inflammation Update
Manuel
Vazquez Carrera
Peroxisome proliferator-activated receptors (PPARs) are
ligand-activated transcription factors that regulate lipid and carbohydrate
metabolism. In addition, in the last few years it has been highlighted that
these receptors play a role in regulating inflammatory processes. Here, we
update, in a concise way, the latest advances concerning the anti-inflammatory
effects of PPARs, previously reported in Current
Drug Targets-Inflammation and Allergy, I, 243-248, 2002.
[Back to top] Advances in Therapeutic Drug Monitoring of
Atypical Antipsychotic Drugs
M.A.
Raggi, R. Mandrioli, V. Pucci and C. Sabbioni
The introduction in clinical practice of new antipsychotic drugs neurologically safer and with a broader spectrum of efficacy than "classical" neuroleptics has brought about significant improvement in the therapy of schizophrenic patients. These second-generation antipsychotics usually called "atypical" antipsychotics, have several therapeutical features in common, such as their effectiveness against the negative symptoms of schizophrenia and the advantage of not causing severe extrapyramidal symptoms and hyperprolactinemia.
The therapeutic drug monitoring of patients treated with atypical antipsychotics is however, still advisable. In many cases, it can avoid the onset of side and toxic effects due to high plasma levels of the drug caused by overdose or interactions with other drugs. Furthermore, monitoring can significantly improve the patient's compliance, thus leading to higher treatment efficacy.
The pharmacological properties of the most widely used atypical antipsychotics (clozapine, olanzapine, risperidone and quetiapine) will be treated herein with particular attention paid to metabolism, side effects and pharmacokinetics. The analytical methods suitable for the therapeutical drug monitoring of these drugs will also be discussed, in terms of sensitivity, selectivity and usefulness in clinical settings. Other recent atypical agents (ziprasidone, aripiprazole, iloperidone, sertindole and zotepine) will be described as well.
[Back to top] Differential Developmental Origin of
Arteries: Impact on Angiogenesis and Arteriogenesis
Jaroslav
Pelisek, Masumi Shimizu and Sigrid Nikol
The growth and maintenance of tissue is impossible without
the formation, growth and remodeling of functional vascular networks. The
understanding of mechanisms of vessel development becomes increasingly
important in the successful treatment of many vascular diseases. Angiogenesis
and arteriogenesis play an important role in these processes. Whether
angiogenesis or arteriogenesis predominate may depend on several factors: the
pre-existing collateral vessel network, the type and location of occlusion and
the different developmental origin of arteries. Further investigation of
signaling pathways within vascular cells may lead to better understanding of
the role of angiogenic factors in angiogenesis and/or arteriogenesis. This may
allow for better control of each of these processes for the development of
efficient therapy. Often, the treatment of vascular disorders using the
administration of single angiogenic factor does not achieve the desired
therapeutic effect. Therefore, new therapeutic strategies need to be developed,
which may include the use of combined gene therapy, including site-specific
angiogenic factors optimized not only for various vascular diseases but also
for different blood vessels regarding the developmental origin of vascular
tree.
[Back to top] Direct Selection of cDNAs from Filamentous
Phage Surface Display Libraries: An Update
Claudio
Rhyner, Michael Weichel, Sabine Fluckiger and Reto Crameri
Since the
first description of phage surface display in 1985, more than 2500 publications
report the use of this technology in different fields of life science. Phage
display is based on presenting recombinant proteins or peptides fused to a
phage coat protein by using appropriately designed phage surface-display
vectors in combination with in vitro
selection procedures. These technologies have now revolutionized the way in
which we can generate and manipulate ligands. The ability to create and survey
large molecular libraries for the presence of specific clones using the
discriminative power of affinity selection has strongly contributed to a rapid
progress in life science. However, the potential of phage display applications
to directly select genes from phage surface-displayed cDNA libraries has lagged
behind the impressive progress of phage display technology achieved during the
last years. Here we present an update of our earlier review (1) devoted to this promising field of
research.
[Back to top] Novel Molecular Targets for Systemic Lupus
Erythematosus and Other Immune-Complex and T-Cell Mediated Autoimmune Diseases
– Update
Maria
Marino and Giorgio Fassina
Receptors
for the constant fragment (Fc) of IgGs (FcgRs) are largely involved in the
pathogenesis of haematological and rheumatic autoimmune disorders, triggering a
wide variety of effector functions including phagocytosis, antibody-dependent
cellular cytotoxicity, and release of inflammatory mediators, as well as immune
complex clearance and regulation of antibody production.
The
availability of single and multiple Fc-receptor-deficient mice has allowed to
get considerable progresses on the in vivo regulation of these
responses, through the appreciation of the importance of balancing activation
responses with inhibitory signalling. These new insights have a profound impact
on our understanding of inflammation in autoimmune diseases, and might lead to
new therapeutic approaches for human disorders including Systemic Lupus
Erythematosus (SLE) and rheumatoid arthritis.
[Back to top] Mechanisms of Antihistamines and Mast Cell
Stabilizers in Ocular Allergic Inflammation
E.B.
Cook, J.L. Stahl, N.P. Barney and F.M. Graziano
Mast cells play a central role in allergic reactions and
inflammation. Successful anti-allergic therapies have typically targeted mast
cell mediators, particularly histamine. Antihistaminic compounds interact with
the various histamine receptors found on many cells, whereas other compounds
are referred to as mast cell stabilizers, as they inhibit degranulation. Some
of the most successful compounds developed recently are dual-action, in that
they have both anti-histaminic and mast cell stabilizing activities. Recent trends
in pharmaceutical intervention, however, have been focused on the secondary
effects of mast cell mediators on epithelial cell adhesion molecule expression
and mediator release in the process of allergic inflammation. Since, the ocular
mucosa is highly exposed to environmental allergens it is commonly involved in
allergic reactions and, as such, has been a useful and accessible model in
which to test new therapies in vivo.
These ocular allergen provocation studies permit analysis of ocular surface
cells and evaluation of tear film mediators. Furthermore, techniques to purify
conjunctival mast cells have facilitated the study of the effects of mast cell
stabilizing compounds on other mast cell mediators, such as cytokines, and the
direct effects of mast cell mediators on epithelial cells in vitro. This review discusses current understanding of how
anti-histamines and mast cell stabilizers work, particularly in the context of
molecular mechanisms of ocular allergic inflammation.
[Back to top] Quantitative Structure-Activity Relationship Studies on Cholecystokin
Antagonists†
Satya
P. Gupta, and Anantha N. Nagappa
The following ‘updates’ re-stresses upon the importance of
the hydrophobic and steric properties of the molecules in their CCK antagonist
action. In the case of benzodiazepines, some importance of electronic
properties is also indicated, which however needs further verification.
[Back to top] Cells of the Macrophage Lineage and their Role in the Pathogenesis of
HIV-1 Infection: An Update
Katherine
Kedzierska, Clare L.V. Maslin, and Suzanne M. Crowe
Cells of macrophage lineage contribute to the pathogenesis
of HIV-1 infection throughout the course of disease. Blood monocytes and tissue
macrophages can be infected with HIV-1 in
vivo and in vitro. In contrast to
tissue macrophages, which are highly susceptible to HIV-1 infection, blood
monocytes are relatively resistant to HIV-1,
with the possible exception of their CD14lo/CD16hi
subset. Cells of macrophage lineage can be infected mainly with macrophage
(M)-tropic strains, although infection with some T cell line (T)-tropic strains
or dual-tropic isolates of HIV-1 also occurs. Following HIV-1 infection,
monocyte/macrophages are resistant to cytopathic effects of the virus. The
assembly of HIV-1 in macrophage subcellular vesicles rather than budding from
the plasma membrane may help to preserve long-term cell viability. Macrophages
can therefore persist throughout the course of infection as long-term stable
reservoirs for HIV-1 capable of disseminating the virus to tissues. These cells contribute to the
development of HIV-induced dementia via production of proinflammatory cytokines
and neurotoxins. Following HIV-1 infection, monocyte/macrophages also display
impaired effector functions such as phagocytosis, intracellular killing and
cytokine production, contributing to the development of opportunistic
infections. This review provides insights into the most recent studies on the
role of monocyte/macrophages in the pathogenesis of HIV-1 infection by serving
as viral targets and reservoirs, contributing to neuropathogenesis and
opportunistic infections.
[Back to top] Tumor Necrosis Factor-a Blockade in Rheumatoid Arthritis: Responders Vs
Non Responders
Yasser
El-Miedany
Tumour necrosis factor has been found to play a central
role in the pathogenesis of rheumatoid arthritis, leading to development of
novel drug therapies that neutralise the deleterious effects of this cytokine.
This new concept of immunological treatment of rheumatoid arthritis has yielded
successful results. Several studies have shown that the 3 available TNF-a
blockers: infliximab, etanercept and adalimumab, though differ in structure and
mechanism of action, have provided similar positive benefits both in clinical
improvement and in slowing down the progression of radiographic damage.
However, despite these successes, a significant proportion of patients with RA
as well as other inflammatory conditions do not show definite improvement with
this therapy. Therefore, the next major advance might be the identification of
predictors of treatment response, such as genetic polymorphism that may enhance
the efficiency by which these expensive therapies are used in clinical
practice. This article discusses the positive response of TNF-a
therapy as evidenced from the several clinical trials published, the
differences between the different TNF-a blocking agents, the
parameters useful in the identification of non-responders and the way to manage
such patients.
[Back to top] Induction of Tumour Cell Senescence: A New Strategy in Anticancer
Treatment
Xianghong
Wang and Yong-Chuan Wong
Replicative senescence is a programmed cellular response in normal cells, the induction of which depends on the accumulated number of cell divisions. Recently, senescent-like growth arrest has been observed in many types of human tumour cell lines after exposure to a number of chemotherapeutic drugs. These senescent-like cancer cells show similar morphology, growth arrest and b-gal expression to normal cells undergoing replicative senescence. However, unlike replicative senescence during the aging process, the chemodrug-induced senescent-like growth arrest is not entirely dependent of cell cycle distribution, telomere length or cell cycle inhibitors. These observations suggest that induction of senescent-like response may provide a novel strategy leading to permanent growth arrest in cancer cells. So far cell lines derived from more than 20 types of cancers have shown senescent-like growth arrest by either introduction of tumour suppressor genes or treatment with chemotherapeutic drugs, and increased b-gal expression has been correlated with cancer cells undergoing terminal senescent-like growth arrest. In addition, the recent demonstration that cancer cell senescence was observed in both animal models and human frozen specimens after exposure to anticancer drugs, which was also associated with b-gal expression and treatment outcome, indicates that tumour senescence may not only provide an alternative target for the treatment of human cancer but also a prognostic indicator. This review will describe the evidence on senescent-like growth arrest in human cancer cells and the molecular changes that differ between chemodrug-induced senescent-like growth arrest and apoptosis. In addition, the possible factors and mechanisms involved in this process are also discussed. Finally, the implications on how senescent-like growth arrest might be exploited as a possible new target for the development of new anti-cancer drugs are addressed.