| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 11, 2010
Contents
Pyrimidine Nucleosides in Molecular PET Imaging of Tumor Proliferation
Pp. 1010-1029
M.M. Alauddin and J.G. Gelovani
[Abstract] [Purchase
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20156163 PubMed - indexed for MEDLINE]
The Emerging Role of Histology in the Choice of First-Line
Treatment of Advanced Non-Small Cell Lung Cancer: Implication
in the Clinical Decision-Making Pp. 1030-1038
A. Rossi, P. Maione, M.A. Bareschino, C. Schettino,
P.C. Sacco, M.L. Ferrara, V. Castaldo and C. Gridelli
[Abstract] [Purchase
Article] [PMID:
20156162 PubMed - indexed for MEDLINE]
Dehydroepiandrosterone (DHEA): A Steroid with Multiple Effects.
Is there Any Possible Option in the Treatment of Critical
illness? Pp. 1039-1047
R. Oberbeck and P. Kobbe
[Abstract] [Purchase
Article] [PMID:
20156161 PubMed - indexed for MEDLINE]
The Role of Oligodendrocytes in the Molecular Pathobiology
and Potential Molecular Treatment of Cervical Spondylotic
Myelopathy Pp. 1048-1058
S.K. Karadimas, Ch. Gialeli, G. Klironomos, G.N. Tzanakakis,
E. Panagiotopoulos, N.K. Karamanos and G. Gatzounis
[Abstract] [Purchase
Article] [PMID:
20156160 PubMed - indexed for MEDLINE]
The Role of Endothelin-1 in Obstructive Sleep Apnea Syndrome
and Pulmonary Arterial Hypertension: Pathogenesis and Endothelin-1
Antagonists Pp. 1059-1066
K. Karkoulias, D. Lykouras, F. Sampsonas, P. Drakatos, S.
Canova, G. Tsoukalas and K. Spiropoulos
[Abstract] [Purchase
Article] [PMID:
20156159 PubMed - indexed for MEDLINE]
Editor’s
Choice
An Overview on Different Classes of Viral Entry and
Respiratory Syncitial Virus (RSV) Fusion Inhibitors Pp.
1067-1091
G. Murineddu, C. Murruzzu and G.A.
Pinna
[Abstract] [Purchase
Article] [PMID:
20156158 PubMed - indexed for MEDLINE]
Click-Chemistry Reactions in Radiopharmaceutical Chemistry:
Fast & Easy Introduction of Radiolabels into Biomolecules
for In Vivo Imaging Pp. 1092-1166
C. Wängler, R. Schirrmacher, P. Bartenstein
and B. Wängler
[Abstract] [Purchase
Article] [PMID:
20156157 PubMed - indexed for MEDLINE]
Abstracts
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20156163 PubMed - indexed for MEDLINE]
Pyrimidine Nucleosides in Molecular PET Imaging of Tumor Proliferation
M.M. Alauddin and J.G. Gelovani
Human thymidine kinase (TK1) is a key enzyme that is up-regulated
in cancer cells and phosphorylates thymidine and some of its
analogs to their monophosphates. The monophosphates are converted
to their di- and triphosphates by the nucleoside kinases,
and some of these nucleoside triphosphates are incorporated
into DNA by DNA polymerase. The nucleoside analogs are transported
into cells by concentrative nucleoside transporter or equilibrative
nucleoside transporter. Given the unique property of TK1 and
the nucleoside transporter systems, thymidine and its analogs
have been radiolabeled for positron emission tomography (PET)
imaging of tumor proliferation and DNA synthesis. Because
thymidine is catabolized in vivo by thymidine phosphorylase,
radiolabeled thymidine has not been successful in PET imaging
of tumor proliferation. However, some of its analogs have
been radiolabeled and successfully used in PET imaging of
cell proliferation as well as DNA synthesis. Much work has
been done in synthesis, radiosynthesis, and biological evaluation
of these analogs for PET imaging of tumor proliferation. We
review the chemistry, radiochemistry, and biological studies
published to date, including structure activity relationship
and PET imaging of the radiolabeled thymidine analogs. Information
on radiolabeling and PET imaging with various nucleoside analogs
is presented.
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20156162 PubMed - indexed for MEDLINE]
The Emerging Role of Histology in the Choice of First-Line
Treatment of Advanced Non-Small Cell Lung Cancer: Implication
in the Clinical Decision-Making
A. Rossi, P. Maione, M.A. Bareschino, C. Schettino,
P.C. Sacco, M.L. Ferrara, V. Castaldo and C. Gridelli
Lung cancer is the leading cause of cancer mortality
worldwide. Non-small cell lung cancer (NSCLC), accounting
for about 85% of all lung cancers, includes squamous carcinoma,
adenocarcinoma and undifferentiated large cell carcinoma.
The majority of patients have advanced disease at diagnosis,
and medical treatment is the cornerstone of management. Several
randomized trials comparing third-generation platinum-based
doublets concluded that all such combinations are comparable
in their clinical efficacy, failing to document a difference
based on histology. However, recent evidences, arising from
the availability of pemetrexed, have shown that histology
represents an important variable in the decision making. The
major progresses in the understanding cancer biology and mechanism
of oncogenesis have allowed the development of several potential
molecular targets for cancer treatment such as vascular growth
factor and its receptors and epidermal growth factor receptor.
Targeted drugs seem to be safer or more effective in a specific
histology subtype. All of these data have led to choose the
optimal first-line treatment of advanced NSCLC based on histologic
diagnosis. However, this scenario raises a diagnostic issue:
a specific diagnosis of NSCLC histologic subtype is mandatory.
This review will discuss these new evidences in the first-line
treatment of advanced NSCLC and their implication in the current
clinical decision-making.
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20156161 PubMed - indexed for MEDLINE]
Dehydroepiandrosterone (DHEA): A Steroid with Multiple Effects.
Is there Any Possible Option in the Treatment of Critical
illness?
R. Oberbeck and P. Kobbe
DHEA is the major circulating steroid in human blood
and it is a central intermediate in the metabolic pathway
of sex steroid hormone formation. Although the specific effect
of DHEA is still unclear it was demonstrated that DHEA modulates
several physiologic processes including metabolism and cardiovascular
function. Furthermore, a profound im-munomodulatory effect
of DHEA was reported.
Several data demonstrate the beneficial effect of DHEA in
situations of critical illness including trauma hemorrhage
and sepsis. Accordingly DHEA improved the survival rate and
physiological situation in several animal models of trauma
hemorrhage and systemic inflammation. This effect was paralleled
by profound changes of immunologic parameters, organ function,
and heat shock protein production. Therefore, it was claimed
that DHEA may be a new alternative/additive in the treatment
of trauma and sepsis.
In line, DHEA is a frequently used drug in the field of anti-aging
medicine, it is an over-the-counter drug in several countries,
and it was reported that DHEA medication is free of major
side effects. Therefore, DHEA could easily be used in a clinical
trial investigating its effects in critical ill patients.
This article reviews the reported effects of DHEA on the base
of the literature with the specific focus on trauma and sepsis/critical
illness including its clinical perspectives.
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[Purchase
Article]
[PMID:
20156160 PubMed - indexed for MEDLINE]
The Role of Oligodendrocytes in the Molecular Pathobiology
and Potential Molecular Treatment of Cervical Spondylotic
Myelopathy
S.K. Karadimas, Ch. Gialeli, G. Klironomos, G.N. Tzanakakis,
E. Panagiotopoulos, N.K. Karamanos and G. Gatzounis
Cervical spondylotic myelopathy (CSM) is a very common
and debilitating disease; however, its underlying pathocellular
process remains uncertain. Attempts have been made to reproduce
CSM in experimental animal models in order to deepen the knowledge
on the molecular pathobiology of this disease. The up-to-date
observations have established the apoptosis of oligodendrocytes
(OLGs) as the principal pathocellular process of CSM. Since
favorable neurological recovery cannot be obtained in afflicted
patients, even after the decompression surgery, elucidation
of the apoptotic cascade in OLGs may unveil possible molecular
treatments which could inhibit demyelination and ameliorate
the neurological deficits. Moreover, additional therapeutic
benefits may include improvement of myelin self-repair capability
by stimulating OLG progenitor cells to become mature and finally,
myelinating OLGs. This review focuses on the factors and mechanisms
of crucial importance for developing antiapoptotic treatments.
Critical evaluations of the role of OLGs in molecular pathobiology
of CSM as well as strategies for potential remyelination of
CSM are also provided. The analyses and evaluations of the
experimental findings can possibly lead to treatment of CSM
as well as to development of novel bio-pharmacenticals.
[Back to top] [Purchase
Article] [PMID:
20156159 PubMed - indexed for MEDLINE]
The Role of Endothelin-1 in Obstructive Sleep Apnea Syndrome
and Pulmonary Arterial Hypertension: Pathogenesis and Endothelin-1
Antagonists
K. Karkoulias, D. Lykouras, F. Sampsonas, P. Drakatos, S.
Canova, G. Tsoukalas and K. Spiropoulos
Obstructive Sleep Apnea Syndrome (OSAS) is a recognized
risk factor for cardiovascular disorders and in some cases
is complicated with Pulmonary Arterial Hypertension (PAH),
as the endothelium is affected.
Recent studies provide strong evidence for endothelial dysfunction
in obstructive sleep apnea. The resultant vasoconstriction,
abnormal cell proliferation and hyper-coagulability may lead
to the initiation or progression of atherosclerotic cardiovascular
and cerebrovascular disorders, which are frequently encountered
in OSA patients.
While the currently available therapies for OSAS, such as
Continuous Positive Airway Pressure therapy (CPAP therapy),
improve endothelial dysfunction, they are not well-tolerated
by patients. CPAP therapy can reduce nocturnal hypoxemias
and decrease noradrenaline circulating levels, but does not
affect ET-1 plasma levels.
Potent and selective Endothelin-1 receptor antagonists have
been developed and have shown promising results in the treatment
of cardiovascular diseases such as pulmonary arterial hypertension,
acute and chronic heart failure, hypertension, renal failure,
and atherosclerosis. However, results are often contrasting
and complicated because of the tissue-specific vasoconstrictor
actions of Endothelin-B receptors and the fact that endothelin
is an autocrine and paracrine factor whose activity is difficult
to measure in vivo.
[Back to top]
[Purchase
Article]
[PMID:
20156158 PubMed - indexed for MEDLINE]
An Overview on Different Classes of Viral Entry and
Respiratory Syncitial Virus (RSV) Fusion Inhibitors
G. Murineddu, C. Murruzzu and G.A.
Pinna
The therapeutic approach to AIDS is based on the combination
of different drugs in the highly active antiretroviral therapy
(HAART) regimen. These drugs have a wide variety of side effects,
and some strains of HIV can develop resistance: for these
reasons new anti-HIV drugs are needed.
In the wide field of anti-HIV medicine this review covers
different classes of drugs which inhibit viral entry: in particular
the classification of main categories, their mode of action
and some new candidates for AIDS therapy are contemplated.
Also covered in this review are respiratory syncytial virus
(RSV) fusion inhibitors.
[Back to top]
[Purchase
Article] [PMID:
20156157 PubMed - indexed for MEDLINE]
Click-Chemistry Reactions in Radiopharmaceutical Chemistry:
Fast & Easy Introduction of Radiolabels into Biomolecules
for In Vivo Imaging
C. Wängler, R. Schirrmacher, P. Bartenstein
and B. Wängler
Today the term “click chemistry” is often
used equivalent with the copper-catalyzed 1,3-dipolar Huisgen
cycloaddition. Originally, the concept was introduced in 2001
to describe reactions fulfilling a set of criteria that are
most useful for chemical syntheses in drug research. In radiopharmaceutical
chemistry where short lived radioisotopes are introduced into
various different substance classes for in vivo imaging
of biochemical processes, the expanding field of radioactive
bioconjugation has become predominant. Labeled biomolecules
such as peptides, proteins and oligonucleotides generated
via bioconjugation of chelators for radiometal introduction
as well as novel valuable secondary precursors for 18F
labeling have enriched the growing field of molecular imaging
substantially. When introducing radioactive nuclides with
a very short half-life into biomolecules, some of the typical
criteria defined by click-chemistry are more crucial than
others. Time is always the most important issue, whereas avoiding
the formation of by-products that have to be removed without
chromatography is of minor importance. The short-lived radionuclide
11C for example has a physical
half-life of only 20 min so that the labeling procedure cannot
exceed 40-60 minutes (2-3 half-lifes). In this contribution,
we outline reactions and molecules which meet the requirements
of click chemistry reactions and are suitable for radiosyntheses
of short lived SPECT (99mTc:
t1/2 = 6 h, 111In:
t1/2 = 2.81 d) and PET (11C:
t1/2 = 20.3 min to 64Cu:
t1/2 = 12.7 h) radiotracers
for in vivo imaging of biological processes and review the
contributions in the field of radiochemical "click-reactions"
- 1,3-dipolar Huisgen cycloadditions and beyond.
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