| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 16, 2010
Contents
Editor’s Choice
Recent Advances in the Research and Development of B-Raf Inhibitors
Pp. 1618-1634
Hui-Fang Li, Yadong Chen, Sha-Sha Rao, Xiu-Mei
Chen, Hai-Chun Liu, Ji-Hong Qin, Wei-Fang Tang, Yue-Wang,
Xiang Zhou and Tao Lu
[Abstract] [Purchase
Article] [PMID: 20345352 PubMed - indexed for MEDLINE]
Herbal Interactions with Anticancer Drugs:
Mechanistic and Clinical Considerations Pp. 1635-1678
An-Kui Yang, Shu-Ming He, Liang Liu, Jun-Ping Liu, Ming
Qian Wei and Shu-Feng Zhou
[Abstract] [Purchase
Article] [PMID: 20345351 PubMed - indexed for MEDLINE]
Enzyme Replacement Therapy in Fabry Disease: Influence on
Cardiac Manifestations Pp. 1679-1689
L. Caballero, V. Climent, D. Hernández-Romero, M.A.
Quintanilla, G. de la Morena and F. Marín
[Abstract] [Purchase
Article] [PMID: 20345350 PubMed - indexed for MEDLINE]
Inflammatory Biomarkers Predicting Events in Atherosclerosis
Pp. 1690-1707
E. Stefanadi, D. Tousoulis, N. Papageorgiou, A. Briasoulis
and C. Stefanadis
[Abstract] [Purchase
Article] [PMID: 20345349 PubMed - indexed for MEDLINE]
Interaction of Nerve Agent Antidotes with Cholinergic Systems
Pp. 1708-1718
O. Soukup, G. Tobin, U.K. Kumar, J. Binder, J. Proska,
D. Jun, J. Fusek and K. Kuca
[Abstract] [Purchase
Article] [PMID: 20345348 PubMed - indexed for MEDLINE]
Potential of a Cytomics Top-Down Strategy for Drug
Discovery Pp. 1719-1729
A. Tárnok, A. Pierzchalski and G. Valet
[Abstract]
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Article] [PMID: 20345347 PubMed - indexed for MEDLINE]
Abstracts
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Recent Advances in the Research and Development of
B-Raf Inhibitors
Hui-Fang Li, Yadong Chen, Sha-Sha Rao, Xiu-Mei Chen,
Hai-Chun Liu, Ji-Hong Qin, Wei-Fang Tang, Yue-Wang, Xiang
Zhou and Tao Lu
Oncogenic B-Raf has been identified in a variety of cancers
with high incidence, especially in malignant melanoma and
thyroid cancer. Most B-Raf mutations elicit elevated kinase
activity and the constitutive activation of Ras/Raf/MEK/ERK
pathway, which induces proliferation and promotes malignant
transformation. Therefore, B-Raf inhibitors, targeting B-Raf
or mutated B-Raf, have received increasing momentum in oncology
drug discovery arena. This review focuses on the diverse small-molecule
inhibitors of B-Raf kinase recently reported in the literature,
including those currently in clinical and preclinical phase.
They are described as two categories, type I or type II kinase
inhibitors, based on their different mechanism of action with
active or inactive conformations of the B-Raf kinase derived
from the available crystal structures or molecular docking
analysis. A particular emphasis is placed on their binding
modes and the structure-activity relationship (SAR) of each
chemical structure class.
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Herbal Interactions with Anticancer Drugs: Mechanistic and
Clinical Considerations
An-Kui Yang, Shu-Ming He, Liang Liu, Jun-Ping Liu, Ming
Qian Wei and Shu-Feng Zhou
A large number of herbal remedies (e.g. garlic, mistletoe,
Essiac, Lingzhi, and astragalus) are used by cancer patients
for treating the cancer and/or reducing the toxicities of
chemotherapeutic drugs. Some herbal medicines have shown potentially
beneficial effects on cancer progression and may ameliorate
chemotherapy-induced toxicities. However, there is no or weak
scientific basis for the clinical use of these herbal medicines
in cancer management and almost none of these plant medicines
have been tested in rigorous clinical trials. There are increased
reports on the interaction of herbal medicines and anticancer
drugs that is becoming a safety concern. For example, a clinical
study in cancer patients reported that treatment of St John’s
wort at 900 mg/day orally for 18 days decreased the plasma
levels of the active metabolite of irinotecan, SN-38, by 42%.
In healthy subjects, 2 weeks of treatment with St John's wort
at 900 mg/day significantly decreased the systemic exposure
of imatinib by 32%. In women with advanced breast cancer,
coadministration of garlic sup-plement reduced the clearance
of docetaxol by 23.1-35.1%, although the difference did not
achieve statistical significance. Most anticancer drugs undergo
Phase I and/or II metabolism and are substrates of P-glycoprotein,
breast cancer resistance protein, multidrug resistance associated
proteins, and/or other transporters. Induction and inhibition
of these enzymes and transporters are considered as important
mechanisms for herb-anticancer drug interactions. Further
studies are warranted to investigate potentially harmful herbal
interactions with anticancer drugs in patients.
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Enzyme Replacement Therapy in Fabry Disease: Influence on
Cardiac Manifestations
L. Caballero, V. Climent, D. Hernández-Romero, M.A.
Quintanilla, G. de la Morena and F. Marín
Fabry disease (FD) is an X-linked glycosphingolipid storage
disorder caused by deficient activity of the lysosomal enzyme
α –galactosidase
A. This leads to a progressive accumulation of globotriaosylceramide
(Gb3) in the lysosomes of different cells and tissues, causing
principally ventricular hypertrophy, renal failure and cerebrovascular
accidents, reducing lifespan both in hemizygous males and
heterozygous females. Residual enzyme activity might lead
to slow progression of the disease and result in the so-called
cardiac or renal variants with delayed presentation.
Two different forms of α-galactosidase
A enzyme replacement therapies (ERT) are available for the
treatment of FD, one genetically engineered in human cell
line (agalsidase alfa, Replagal®, Shire) and
the other produced in a Chinese hamster ovary cell line (agalsidase
beta, Fabrazyme®, Genzyme). Although both proteins
are structurally and functionally very similar, with the same
amino acid sequence as the native human enzyme, they differ
in the pattern of glycosilation of the protein depending on
the originating cell line. Studies with both preparations
have described a reduction in plasma, urinary sediment and
tissue levels of Gb3, a decrease in the frequency of pain
crisis and a reduction in left ventricular mass and improvement
or stabilization of renal function. Studies have generally
shown the greatest benefit when treatment is started at an
early stage of the disease before extensive fibrosis or other
irreversible tissue damage takes place. However, more data
are needed to document long-term treatment outcomes. The aim
of the present review is to provide an updated overview of
the two different forms of ERT for FD, their clinical effects
in cardiac manifestations and their possible differences in
terms of efficacy, side effects and safety profiles.
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Inflammatory Biomarkers Predicting Events in Atherosclerosis
E. Stefanadi, D. Tousoulis, N. Papageorgiou, A. Briasoulis
and C. Stefanadis
Recent evidence suggests that vascular inflammation plays
important role in the pathogenesis and the clinical evolution
of atherosclerosis. Several circulating inflammatory biomarkers
such as acute phase proteins, adhesion molecules and pro-inflammatory
cytokines along with biomarkers, proposed the last few years,
have clarified the role of inflammation in atherosclerosis.
In particular a number of studies have focused on the positive
predictive role of C-reactive protein in populations without
prior cardiovascular disease. As regards to fibrinogen studies
have shown a positive role in predicting cardiovascular events.
However, the potential prognostic role of adhesion molecules
and cytokines for cardiovascular events is unclear. Thus,
further studies are required to evaluate the predictive role
of such molecules, as well as others under investigation in
states of atherosclerosis.
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Interaction of Nerve Agent Antidotes with Cholinergic Systems
O. Soukup, G. Tobin, U.K. Kumar, J. Binder, J. Proska,
D. Jun, J. Fusek and K. Kuca
The poisoning with organophosphorus compounds represents a
life threatening danger especially in the time of terroristic
menace. No universal antidote has been developed yet and other
therapeutic approaches not related to reactivation of acetylcholinesterase
are being investigated. This review describes the main features
of the cholinergic system, cholinergic receptors, cholinesterases
and their inhibitors. It also focuses on the organophosphorus
nerve agents, their properties, effects and a large part describes
various possibilities in treatments, mainly traditional oxime
therapies based on reactivation of AChE. Furthermore, non-cholinesterase
coupled antidotal effects of the oximes are thoroughly discussed.
These antidotal effects principally include oxime interactions
with muscarinic and nicotinic receptors.
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Potential of a Cytomics Top-Down Strategy for Drug
Discovery
A. Tárnok, A. Pierzchalski and G. Valet
It takes about 10 to 15 years and roughly 800 mln
$ to bring a new drug to the market. Only 10% of drug molecules
entering clinical trials succeed and only 3 out of 10 drugs
generate enough profit to pay back for the investment.
Drug targets may be searched by hypothesis driven modeling
of molecular networks within and between cells by systems
biology. However, there is the potential to simplify the search
for new drugs and drug targets by an initial top-down cytomics
phase. The cytomics approach i) requires no detailed a-priori
knowledge on mechanisms of drug activity or complex diseases,
ii) is hypothesis driven for the investigated parameters (genome,
transcriptome, proteome, metabolome a.o.) and iii) is hypothesis-free
for data analysis. Moreover it iv) carries the potential to
uncover unknown molecular interrela-tions as a prerequisite
for later new hypothesis driven modeling and research strategies.
A set of discriminatory parameter patterns (molecular hotspots)
describing the cellular model (mechanism of drug action) can
be identified by differential molecular cell phenotyping.
Hereby, the immediate modeling of existing complexities by
bottom-up oriented systems biology is avoided.
The review focuses on the fast technological developments
of molecular single cell analysis in recent years. They comprise
a multitude of sensitive new molecular markers as well as
various new image and flow cytometric high-content screening
methods as facilitators of the cytomics concept. New bioinformatic
tools enable the extraction of relevant molecular hotspots
in description of cellular models, being required for the
subsequent molecular reverse engineering phase by systems
biology.
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