| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 12, 2008
Contents
Aminobisphosphonates as New Weapons for γδ
T Cell-Based Immunotherapy of Cancer Pp. 1147-1153
Nadia Caccamo, Serena Meraviglia, Giuseppe Cicero, Gaspare
Gulotta, Francesco Moschella, Adriana Cordova, Eliana Gulotta,
Alfredo Salerno and Francesco Dieli
[Abstract]
Src Family Kinases as Potential Therapeutic Targets
for Malignancies and Immunological Disorders Pp.
1154-1165
Daniela Benati and Cosima T. Baldari
[Abstract]
Targeted Therapies in the Treatment of Renal Cell
Carcinoma Pp. 1166-1174
Carmel Pezaro and Ian D. Davis
[Abstract]
Targeting Protein Kinase C (PKC) in Physiology
and Cancer of the Gastric Cell System Pp. 1175-1191
Michael Fährmann
[Abstract]
The mTOR Signaling Network: Insights from Its
Role During Embryonic Development Pp. 1192-1208
M. Hwang, C.A. Perez, L. Moretti and B. Lu
[Abstract]
Natural Products and their Derivatives as Cholinesterase
Inhibitors in the Treatment of Neurodegenerative Disorders:
An Update Pp. 1209-1228
Monica Rosa Loizzo, Rosa Tundis, Federica Menichini and
Francesco Menichini
[Abstract]
Gadolinium-Enhanced Magnetic Resonance Imaging,
Renal Failure and Nephrogenic Systemic Fibrosis /Nephrogenic
Fibrosing Dermopathy Pp. 1229-1235
Piero Stratta, Caterina Canavese and Silvo Aime
[Abstract]
Dietary Antioxidants as Potential Pharmacological
Agents for Ischemic Stroke Pp. 1236-1248
A. Cherubini, C. Ruggiero, C. Morand, F. Lattanzio,
G. Dell’Aquila, G. Zuliani, A. Di Iorio and
C. Andres-Lacueva
[Abstract]
Abstracts
[Back to top]
Aminobisphosphonates as New Weapons for γδ
T Cell-Based Immunotherapy of Cancer
Nadia Caccamo, Serena Meraviglia, Giuseppe Cicero, Gaspare
Gulotta, Francesco Moschella, Adriana Cordova, Eliana Gulotta,
Alfredo Salerno and Francesco Dieli
Several observations in mice and in humans have collectively
laid the foundation for examining the potential of γδ
T cells to exert tumor immunotherapy. Human γδ
T cells can be activated in a non-MHC dependent fashion either
by low molecular mass phosphoantigens, or by agents that provoke
the accumulation of endogenous pyrophosphates such as isopentenylpyrophosphate.
Among the latter, aminobisphosphonates are well-established
in the clinic, and extensive data are available on the compounds’
antiangiogenic, antiosteolytic and pro-apoptotic properties.
In this review we discuss on the possibility that the intentional
activation of γδ
T cells in vivo by aminobisphosphonates may represent
a promising target for the design of novel and highly innovative
immunotherapy in patients with different types of cancer.
[Back to top]
Src Family Kinases as Potential Therapeutic Targets
for Malignancies and Immunological Disorders
Daniela Benati and Cosima T. Baldari
The Src family consists of eight non-receptor protein
tyrosine kinases characterised by a common structure. Based
on their amino acid sequence, Src family kinases are grouped
into two subfamilies, which are also characterised by different
tissue specificity. Src kinases are involved in signal transduction
pathways triggered by a wide variety of surface receptors,
including receptor tyrosine kinases, integrins, G-protein-coupled
receptors and antigen receptors. Several pieces of evidence
implicate Src family kinases in cancer development, as a consequence
of changes in protein expression and/or kinase activity, and
have prompted the design of potent specific inhibitors, the
most common of which are adenine mimetics, as tools of relevant
clinical interest for the treatment of both solid tumours
and leukaemias. In addition, the finding that some Src kinases
expressed in haematopoietic cells play pivotal roles in lymphocyte
maturation and activation has fostered the development of
safe and effective inhibitors selective for specific Src family
members, which are currently being tested in clinical trials
as immunosuppressants for the treatment of immunological disorders.
Here we shall review the recent literature on the involvement
of Src family kinases in human neoplasias and immunological
disorders and the goals reached in the search for selective
pharmacological inhibitors.
[Back to top]
Targeted Therapies in the Treatment of Renal Cell
Carcinoma
Carmel Pezaro and Ian D. Davis
The management of renal cell carcinoma (RCC) has undergone
rapid and radical evolution over the last few years. An improved
understanding of the underlying biology of RCC has led to
the approval of several new therapies directed against specific
and relevant biological targets, so-called “targeted
therapies.” These highly effective treatments are now
entering routine use, however many questions still remain
as to how best to use these agents and integrate them into
the broader therapeutic armamentarium. This review summarizes
the major published clinical trials of the new agents, discusses
the controversies and research questions that have arisen
as a result, and considers some of the issues that remain.
[Back to top]
Targeting Protein Kinase C (PKC) in Physiology
and Cancer of the Gastric Cell System
Michael Fährmann
Protein kinase C (PKC) family members are multifunctional
kinases that have been implicated in many cell biological
and physiological tasks including acid, pepsinogen, and mucous
production. Through the use of small-molecule PKC modulators,
PKC has been found to be involved in gene expression, the
control of cytoskeleton, membrane and secretagogue-dependent
signal transduction for secretion of acid. Gastric carcinoma
and adenocarcinoma cells often show dysregulated PKC-dependent
cell signal transduction compared to normal gastric cells.
Moreover, PKC was the first known target of tumor promoting
phorbol esters. These findings support PKC as a potential
chemotherapy target in gastric cancer. Various approaches
have been launched in directly targeting PKC for chemotherapy
of gastric cancer. The macrocyclic lactone bryostatin-1 is
a promising agent that acts as a modulator of PKC activity,
and enhances the effect of chemotherapeutic agents such as
paclitaxel. This article provides an overview of the findings
to date regarding the physiological role of PKC in the gastric
cell system by various pharmacological approaches and examines
PKC as a target in gastric (adeno-)carcinoma chemotherapy.
[Back to top]
The mTOR Signaling Network: Insights from Its
Role During Embryonic Development
M. Hwang, C.A. Perez, L. Moretti and B. Lu
Target of Rapamycin (TOR) signaling, originally discovered
as the pathway affected by an antifungal macrolide, exemplifies
the potential of medicinal chemistry as a discovery tool.
Three decades from its identification, signaling involving
the TOR kinase has evolved into a complex network with a crucial
role in vertebrate growth control. Specifically, it integrates
signals to coordinate cell growth (i.e., enhanced mass and
size) and cell cycle progression with sufficiency of nutrients,
energy, and growth factors. In this review, we discuss multiple
aspects of TOR signaling, including cellular regulators and
mediators, human diseases related to TOR dysregulation such
as cancer, and signaling nodes in the pathway amenable to
targeted drug inhibition. The functions and mechanisms of
TOR during embryonic development highlight the dynamic role
of TOR signaling and reveal additional functions beyond cell
growth control. Embryonic TOR signaling has differential tissue-specific
and temporal effects, and is involved in organogenesis, sexual
differentiation, and epithelial-to-mesenchymal transition
signaling. Molecular mechanisms that may contribute to embryonic-specific
TOR functions are also examined here. Finally, this review
discusses the complex signaling of mTOR in cancer and the
development of mTOR inhibitors for cancer therapy.
[Back to top]
Natural Products and their Derivatives as Cholinesterase
Inhibitors in the Treatment of Neurodegenerative Disorders:
An Update
Monica Rosa Loizzo, Rosa Tundis, Federica Menichini and
Francesco Menichini
Alzheimer’s disease (AD) is the most common form
of neurodegenerative disorders. If more effective therapies
than the ones currently available are not developed that either
prevent AD or other neurodegenerative or block progression
of the diseases in its very early stages, the economic and
societal cost of caring for AD patients will be devastating.
Besides the neuropathologic hallmarks of the diseases, namely
neurofibrillary tangles and AD neuritic plaques, the disease
is characterized neurochemically by a consistent deficit in
cholinergic neurotransmission, particularly affecting cholinergic
neurons in basal forebrain. AD and other forms of dementia
could be treated by the use of agents which restore the level
of acetylcholine through inhibition of both two major forms
of cholinesterase: acetylcholinesterase (AChE) and butyrylcholinesterase
(BChE). Moreover, the inhibition of AChE holds a key role
not only to enhance cholinergic transmission in the brain
but also to reduce the aggregation of β-amyloid
and the formation of the neurotoxic fibrils in AD. Following
this view, in recent years, an increased interest has emerged
directed to finding drugs able to inhibit both of these events.
This review summarizes and highlights recent advances in current
knowdlege on natural products as cholinesterase inhibitors
and how these compounds have also served as the starting points
for semi-synthetic analogs with improved properties.
[Back to top]
Gadolinium-Enhanced Magnetic Resonance Imaging,
Renal Failure and Nephrogenic Systemic Fibrosis /Nephrogenic
Fibrosing Dermopathy
Piero Stratta, Caterina Canavese and Silvo Aime
First described in 2000, nephrogenic systemic fibrosis
(NSF)/nephrogenic fibrosing dermopathy (NFD) is a recently
defined and sometimes fatal condition that, so far, has occurred
only in people with some degree of renal failure, either during
the conservative phase of chronic renal disease, the dialysis
phase, or the kidney transplantation phase.
The association between NSF/NFD and gadolinium-based magnetic
resonance (MR) examination is so strong that public health
agencies have sent out warnings concerning the use of gadolinium-enhanced
MR in patients with renal failure. The prolonged residence
of some gadolinium-chelates in the uremic milieu may allow
free toxic gadolinium released from its chelate to extravasate
into the extravascular space where it may accelerate fibrillogenesis.
The medical community must be apprised of the concern surrounding
the use of gadolinium contrast agent in patients with even
moderate renal failure, considering that the number of at
risk persons is 20 times greater than that of patients needing
dialysis/transplantation, remember that the risk is particularly
high in patients with liver transplantation in the presence
of functional renal impairment, and not to forget that MR
examination remains one of the three pillars of molecular
medicine.
[Back to top]
Dietary Antioxidants as Potential Pharmacological
Agents for Ischemic Stroke
A. Cherubini, C. Ruggiero, C. Morand, F. Lattanzio,
G. Dell’Aquila, G. Zuliani, A. Di Iorio and
C. Andres-Lacueva
Acute ischemic stroke is a leading cause of death and
severe disability in industrialised countries and also in
many developing countries. An excessive amount of free radicals
is generated during cerebral ischemia, which significantly
contributes to brain damage. Therefore, an increasing interest
has been devoted to the potential benefits of antioxidant
compounds in ischemic stroke patients. In this review, we
examined the most relevant observational studies concerning
the relationship between dietary antioxidants and ischemic
stroke as well as clinical trials investigating the effects
of single or multiple antioxidant supplementation in the prevention
or treatment of acute ischemic stroke. Furthermore, we reviewed
the most promising antioxidant compounds, i.e. dehydroascorbic
acid, α-tocotrienol,
γ-tocopherol,
flavonoids, resveratrol and gingko biloba, tested in animal
models of acute ischemic stroke. Finally, we carefully evaluated
the reasons for the discrepancy between experimental and clinical
studies, and provided recommendations to improve the translation
of the results obtained in animal models to patients with
acute ischemic stroke.
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