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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 16, 2006
Contents
Vascular Endothelial Growth Factor (VEGF) as a Target of Bevacizumab
in Cancer: From the Biology to the Clinic Pp. 1845-1857
Girolamo Ranieri, Rosa Patruno, Eustachio Ruggieri, Severino
Montemurro, Paolo Valerio and Domenico Ribatti
[Abstract]
Multidrug Resistance: Retrospect and Prospects in Anti-Cancer
Drug Treatment Pp. 1859-1876
Ricardo Pérez-Tomás
[Abstract]
Targeting the Inflammatory Response in Healing Myocardial
Infarcts Pp. 1877-1893
Nikolaos G. Frangogiannis
[Abstract]
Transglutaminase-Catalyzed Reactions Responsible for the Pathogenesis
of Celiac Disease and Neurodegenerative Diseases: From Basic
Biochemistry to Clinic Pp. 1895-1902
A. Martin, G. Romito, I. Pepe, G. De Vivo, M.R. Merola, A.
Limatola and V. Gentile
[Abstract]
Cerebral Amyloidoses: Molecular Pathways and Therapeutic
Challenges Pp. 1903-1913
Salvatore Monaco, Gianluigi Zanusso, Sara Mazzucco and Nicola
Rizzuto
[Abstract]
The Role of the MAGUK Protein CASK in Neural Development
and Synaptic Function Pp. 1915-1927
Yi-Ping Hsueh
[Abstract]
Computational Studies of Competitive Inhibitors of
Nitric Oxide Synthase (NOS)Enzymes: Towards the Development
of Powerful and Isoform-Selective Inhibitors Pp.
1929-1946
A. Tafi, L. Angeli, G. Venturini, M. Travagli, F. Corelli
and M. Botta
[Abstract]
Chemistry and Biology of Anti-Inflammatory Marine
Natural Products: Molecules Interfering with Cyclooxygenase,
NF-κ B
and Other Unidentified Targets Pp. 1947-1969
Stefania Terracciano, Manuela Rodriquez, Maurizio Aquino,
Maria Chiara Monti, Agostino Casapullo, Raffaele Riccio and
Luigi Gomez-Paloma
[Abstract]
Abstracts
[Back to top]
Vascular Endothelial Growth Factor (VEGF) as a Target
of Bevacizumab in Cancer: From the Biology to the Clinic
Girolamo Ranieri, Rosa Patruno, Eustachio Ruggieri, Severino
Montemurro, Paolo Valerio and Domenico Ribatti
Angiogenesis is important in the growth and progression
of solid tumours. The main pro-angiogenic factor, namely vascular
endothelial growth factor (VEGF), also known as vascular permeability
factor, is a potent angiogenic cytokine that induces mitosis
and also regulates the permeability of endothelial cells.
The soluble isoform of VEGF is a dimeric glycoprotein of 36-46
kDa, induced by hypoxia and oncogenic mutation and it binds
to two specific tyrosine-kinase receptors: VEGF-1 (flt-1)
and VEGF-2 (KDR/flk1). An increase in VEGF expression in tumour
tissue or some blood compartments (i.e. serum or plasma) has
been found in solid and haematological malignancies of various
origins and is associated with metastasis formation and poor
prognosis.
Bevacizumab, a recombinant humanised monoclonal antibody developed
against VEGF, binds to soluble VEGF, preventing receptor binding
and inhibiting endothelial cell proliferation and vessel formation.
Pre-clinical and clinical studies have shown that bevacizumab
alone or in combination with a cytotoxic agent decreases tumour
growth and increases median survival time and time to tumour
progression. Bevacizumab is the first anti-angiogenetic treatment
approved by the American Food and Drug Administration in the
first-line treatment of metastatic colorectal cancer. It has
shown preliminary evidence of efficacy for breast, non-small-cell
lung, pancreatic, prostate, head and neck and renal cancer
as well as haematological malignancies. Common toxicities
associated with bevacizumab include hypertension, proteinuria,
bleeding episodes and thrombotic events.
This review summarises the critical role of VEGF and discusses
the data available on bevacizumab, from the humanisation of
its parent murine monoclonal antibody (mAb) A.4.6.1 to its
use in cancer clinical trials.
[Back to top]
Multidrug Resistance: Retrospect and Prospects in
Anti-Cancer Drug Treatment
Ricardo Pérez-Tomás
Conventional cancer chemotherapy is seriously limited
by the multidrug resistance (MDR) commonly exhibited by tumour
cells. One mechanism by which a living cell can achieve multiple
resistances is via the active efflux of a broad range
of anticancer drugs through the cellular membrane by MDR proteins.
Such drugs are exported in both ATP-dependent and -independent
manners, and can occur despite considerable concentration
gradients. To the ATP-dependent group belongs the ATP-binding
cassette (ABC) transporter family, which includes P-gp, MRP,
BCRP, etc. Another protein related to MDR, though not belonging
to the ABC transporter family, is lung resistance-related
protein (LRP). All of these proteins are involved in diverse
physiological processes, and are responsible for the uptake
and efflux of a multitude of substances from cancer cells.
Many inhibitors of MDR transporters have been identified over
the years. Firstly, MDR drugs were not specifically developed
for inhibiting MDR; in fact, they had other pharmacological
properties, as well as a relatively low affinity for MDR transporters.
They included compounds of diverse structure and function,
such as verapamil and cyclosporine, and caused side effects.
Secondly, the new drugs were more inhibitor-specific, in terms
of MDR transport, and were designed to reduce such side effects
(e.g., R-verapamil, dexniguldipine, etc.). Unfortunately,
they displayed poor response in clinical studies. Recently,
new compounds obtained from drug development programs conducted
by the pharmaceutical industry are characterized by a high
affinity to MDR transporters and are efficient at nanomolar
concentrations. Some of these compounds (e.g., MS-209) are
currently under clinical trials for specific forms of advanced
cancers.
We aim to provide an overview of the properties associated
with those mammalian MDR transporters known to mediate significant
transport of relevant drugs in cancer treatments. We also
summarize recent advances concerning resistance to cancer
drug therapies with respect to the function and overexpression
of ABC and LRP multidrug transporters.
[Back to top]
Targeting the Inflammatory Response in Healing
Myocardial Infarcts
Nikolaos G. Frangogiannis
Healing of myocardial infarcts depends on an inflammatory
cascade that ultimately results in clearance of dead cells
and matrix debris and formation of a scar. Myocardial necrosis
activates complement, Nuclear Factor (NF)-κB
and Toll-like Receptor (TLR)-dependent pathways, and generates
free radicals, triggering an inflammatory response. Chemokines
and cytokines are markedly induced in the infarct and mediate
recruitment and activation of neutrophils and mononuclear
cells. Extravasation of platelets and plasma proteins, such
as fibrinogen and fibronectin, results in formation of a clot,
consisting of platelets embedded in a mesh of crosslinked
fibrin. This provisional matrix provides a scaffold for migration
of cells into the infarct. Monocytes differentiate into macrophages
and secrete fibrogenic and angiogenic growth factors inducing
formation of granulation tissue, containing myofibroblasts
and neovessels. Repression of proinflammatory cytokine and
chemokine synthesis, mediated in part through Transforming
Growth Factor (TGF)-β
and Interleukin (IL)-10, is critical for resolution of the
inflammatory infiltrate and transition to fibrous tissue deposition.
Infarct myofibroblasts deposit extracellular matrix proteins
and a collagen-based scar is formed. As the wound matures,
fibroblasts undergo apoptosis and neovessels regress, resulting
in formation of a scar with a low cellular content containing
dense, cross-linked collagen. The pathologic and structural
changes associated with infarct healing directly influence
ventricular remodeling and affect prognosis in patients with
myocardial infarction. Understanding the mechanisms involved
in the regulation of the post-infarction inflammatory response,
and the spatial and temporal parameters of wound healing is
necessary in order to identify specific molecular targets
for therapeutic intervention.
[Back to top]
Transglutaminase-Catalyzed Reactions Responsible for
the Pathogenesis of Celiac Disease and Neurodegenerative Diseases:
From Basic Biochemistry to Clinic
A. Martin, G. Romito, I. Pepe, G. De Vivo, M.R. Merola, A.
Limatola and V. Gentile
Transglutaminases (TGases) are enzymes which catalyze the
cross linking of a glutaminyl residue of a protein/peptide
substrate to a lysyl residue of a protein/peptide co-substrate
with the formation of an N-gamma-(epsilon-L-glutamyl)-L-lysine
[GGEL] cross link (isopeptidic bond) and the concomitant release
of ammonia. Such cross-linked proteins are often highly insoluble.
The TGases are closely related enzymes and can also catalyze
other important reactions for cell life. Recently, several
findings concerning the relationships between the biochemical
activities of the TGases and the basic molecular mechanisms
responsible for some human diseases, have been reported. For
example, some neurodegenerative diseases, such as Alzheimer’s
disease (AD), Huntington’s disease (HD), Parkinson’s
disease (PD), supranuclear palsy, etc., are characterized
in part by aberrant cerebral TGase activity and by increased
cross-linked proteins in affected brains. Our article describes
the biochemistry and the physio-pathological roles of the
TGase enzymes, with particular reference to human pathologies
in which the molecular mechanism of disease can be due to
biochemical activities of the tissue TGase enzyme (tTGase,
type 2), such as in a very common human disease, Celiac Disease
(CD), and also in certain neuropsychiatric disorders.
[Back to top]
Cerebral Amyloidoses: Molecular Pathways and Therapeutic
Challenges
Salvatore Monaco, Gianluigi Zanusso, Sara Mazzucco and Nicola
Rizzuto
Alzheimer disease (AD) and Creutzfeldt-Jakob disease
(CJD) are sporadic and genetic neurodegenerative conditions
characterized by brain accumulation and deposition of protein
aggregates. In AD, the key pathogenic event is linked to the
formation of a 4-kDa amyloid β
(Aβ)
peptide, generated by sequential cleavages of the amyloid
precursor protein (APP). In CJD and other prion diseases,
the process is initiated by conformational changes of the
cellular prion protein, or PrPC,
into a β-sheet
rich isoform, named PrPSc,
which acquires protease-resistance and detergent insolubility.
Once generated, Aβ
and PrPSc are highly prone
to misassembly under thermodynamically favourable oligomeric
forms and protofibril/fibril structures. The variety of physicochemical
states exhibited by Aβ
and PrPSc is accounted for
by distinct molecular forms with different amino and/or carboxyl
termini and alternative conformations. Unlike Aβ,
PrPSc is also infectious,
and this feature poses public health concerns, as in the case
of iatrogenic and variant CJD (vCJD).
Several lines of evidence suggest that Aβ
and PrPSc are the main factors
responsible for death of selected neuronal populations in
brains of AD and prion disease’s victims. Therefore,
in addition to symptomatic treatment of dementia, therapeutic
efforts are currently aimed at testing the efficacy of disease-modifying,
anti-amyloid therapies. Experimental and clinical therapeutic
interventions include passive and active immunization against
amyloidogenic peptides, non immunological strategies, as well
as drugs enhancing the nonamyloidogenic protein processing.
In this review, we focus on molecular mechanisms of AD and
prion diseases, and on novel treatment approaches.
[Back to top]
The Role of the MAGUK Protein CASK in Neural Development
and Synaptic Function
Yi-Ping Hsueh
CASK, which belongs to the family of membrane-associated guanylate
kinase (MAGUK) proteins, is recognized as a multidomain scaffolding
protein highly expressed in the mammalian nervous system.
MAGUK proteins generally target to neuronal synapses and regulate
trafficking, targeting, and signaling of ion channels. However,
CASK is a unique MAGUK protein in several respects. It not
only plays a role in synaptic protein targeting but also contributes
to neural development and regulation of gene expression. Several
CASK-interacting proteins have been identified from yeast
two-hybrid screening and biochemical isolation. These proteins,
whose interactions with CASK are reviewed here, include the
Parkinson’s disease molecule parkin, the adhesion molecule
neurexin, syndecans, calcium channel proteins, the cytoplasmic
adaptor protein Mint1, Veli/mLIN-7/MALS, SAP97, caskin and
CIP98, transcription factor Tbr-1, and nucleosome assembly
protein CINAP. More important, CASK may form different complexes
with different binding partners and perform different functions.
Among these interactions, CASK, Tbr-1, and CINAP can form
a transcriptional complex regulating gene expression. Reelin
and NMDAR subunit 2b (NR2b) genes have been identified as
Tbr-1 target genes. Reelin is critical for neural development.
NR2b is an important subunit of NMDAR, which plays important
roles in neural function and neurological diseases. Regulation
of reelin and NR2b expression suggests the potential roles
of the Tbr-1-CASK-CINAP complex in neural activity, development,
and disease. The functions of these CASK protein complexes
are also discussed in detail in this review.
[Back to top]
Computational Studies of Competitive Inhibitors of
Nitric Oxide Synthase (NOS)Enzymes: Towards the Development
of Powerful and Isoform-Selective Inhibitors
A. Tafi, L. Angeli, G. Venturini, M. Travagli, F. Corelli
and M. Botta
Crystallographic structures of wild-type and mutant NOS isoforms
complexed with substrate, intermediate, inhibitor, cofactor,
and cofactor analogs are currently available. However, because
of the high level of amino-acid conservation and the consequent
similarity in dimeric quaternary structure as well as in the
active site of NOS isoforms, structure-based isoform-selective
inhibitor design is still a very challenging task. Nevertheless,
the comprehension of the structural determinants for selectivity
among the isoforms is fundamental for the design of further
potent and more selective inhibitors.
Computational techniques, based on the knowledge of the tridimensional
structure of the isozymes, have been already applied to understand
the significant isoform selectivity shown by some compounds.
Collectively these structure-based approaches, in combination
with SAR studies, have been able to explain the structural
reasons of this selectivity.
[Back to top]
Chemistry and Biology of Anti-Inflammatory Marine
Natural Products: Molecules Interfering with Cyclooxygenase,
NF-κ B
and Other Unidentified Targets
Stefania Terracciano, Manuela Rodriquez, Maurizio Aquino,
Maria Chiara Monti, Agostino Casapullo, Raffaele Riccio and
Luigi Gomez-Paloma
The majority of the anti-inflammatory drugs routinely used
nowadays are COX (cyclo-oxygenase) inhibitors. The important
role of this enzyme, once known as prostanglandin synthase,
in inflammation came a consequence of the discovery by the
Nobel prize winner John Vane with his path-breaking discovery
that aspirin and similar drugs exert their action by blocking
the biosynthesis of the prostaglandin group of lipid mediators.
(John R. Vane, Nobel Lecture, December 8, 1982 and references
cited therein) In the last five years it has become clear
that there are two such enzymes involved. One of the "cyclo-oxygenases",
called COX1 is responsible for making prostaglandins, which
among other things, protect the stomach and kidney from damage.
It is now clear that inhibition of COX1 accounts for the unwanted
side effects of aspirin-like drugs such as gastric irritation
and renal damage. The other enzyme, COX2, is induced by inflammatory
stimuli and it is prostaglandins made by this enzyme that
contribute to the inflammation in diseases such as rheumatoid
arthritis.
However, concerning inflammation-related targets, one should
not limit the interest to COX and PLA2
enzymes. In recent years, it has steadily become more clear,
that modulation in the expression of genes underlies most
cellular responses, and inflammation is certainly not an exception
in this sense. It does not come as surprise that molecules
showing ability to interfere with factors involved in the
modulation of genes expression, such as NF-kB, have also to
be considered potential anti-inflammatory agents.
Also in this respect, marine natural products (MNP) have brought
a collection of novel molecular entities displaying ability
to target COX1/COX2, NF-κB
or acting through molecular mechanisms yet-to-be-discovered.
Following, the marine natural products accounted for within
this review will be grouped on the basis of their bio-molecular
targets. Chemical synthesis of particular relevant molecules
will be also discussed, especially in those cases where the
natural products can be considered as lead compounds for the
development of simplified derivatives or analogues of potential
pharmaceutical interest.
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