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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 9, 2007
Contents
Inhibitory Effect on Replicative DNA Polymerases, Human Cancer
Cell Proliferation, and In Vivo Anti-Tumor Activity
by Glycolipids from Spinach Pp. 955-967
Naoki Maeda, Takahiko Hada, Hiromi Yoshida and Yoshiyuki
Mizushina
[Abstract]
Targeting Cell Cycle Kinases for Cancer Therapy Pp.
969-985
Guillermo de Cárcer, Ignacio Pérez de Castro
and Marcos Malumbres
[Abstract]
Mass Spectrometric Profiling of Low-Molecular-Weight
Volatile Compounds - Diagnostic Potential and Latest Applications
Pp. 987-995
Matthias Lechner and Josef Rieder
[Abstract]
Porphycenes: Facts and Prospects in Photodynamic Therapy
of Cancer Pp. 997-1026
J.C. Stockert, M. Cañete, A. Juarranz, A. Villanueva,
R.W. Horobin, J.I. Borrell, J. Teixidó and S. Nonell
[Abstract]
Chemical Events Behind Leukoaraiosis: Medicinal Chemistry
Offers New Insight into a Specific Microcirculation Disturbance
in the Brain (a Chemical Approach to a Frequent Cerebral Phenotype)
Pp. 1027-1036
Zoltán Szolnoki
[Abstract]
Biomarkers in COPD Pp. 1037-1048
Eleni G. Tzortzaki, Irini Lambiri, Eleni Vlachaki and
Nikolaos M. Siafakas
[Abstract]
Evaluation and Management of Severe Asthma
Pp. 1049-1059
Mina Gaga, Eleftherios Zervas, Spiros Grivas, Mario Castro
and Pascal Chanez
[Abstract]
Abstracts
[Back to top]
Inhibitory Effect on Replicative DNA Polymerases, Human Cancer
Cell Proliferation, and In Vivo Anti-Tumor Activity
by Glycolipids from Spinach
Naoki Maeda, Takahiko Hada, Hiromi Yoshida and Yoshiyuki
Mizushina
We succeeded in purifying a major glycolipids fraction (i.e.,
Fraction-II) in the class of monogalactosyl diacylglycerol
(MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl
diacylglycerol (SQDG) from spinach using hydrophobic column
chromatography. Fraction-II inhibited the activities of replicative
DNA polymerases (pols) such as α,
δ and
ε,
and mitochondrial pol γ
with IC50 values of 43 – 79 μg/ml,
but had no influence on the activity of repair-related pols
β and
λ.
MGDG, DGDG, SQDG were purified from Fraction-II of spinach
using silica gel column chromatography, and SQDG was the strongest
inhibitor of mammalian pols in the three glycolipids. Therefore,
SQDG and its related compounds were chemically synthesized,
and the sulfate group and fatty acid moiety of the compound
were suggested to be important for pol inhibition. These glycolipids
showed no effect even on the activities of plant pols, prokaryotic
pols and other DNA metabolic enzymes such as T4 polynucleotide
kinase, T7 RNA polymerase and deoxyribonuclease I. Fraction-II
also inhibited the proliferation of human cervix carcinoma
(HeLa) cells with LD50 values of 57 μg/ml,
and could halt the cell cycle at the G1-phase, and subsequently
induced severe apoptosis. In an in vivo anti-tumor
assay on nude mice bearing solid tumors of HeLa cells, Fraction-II
was shown to be a promising suppressor of solid tumors. Histopathological
examination revealed that tumor necrosis with hemorrhage was
significantly enhanced with Fraction-II in vivo.
The spinach Fraction-II containing SQDG might be a potent
anti-tumor compound, and may be a healthy food substance with
anti-tumor activity.
[Back to top]
Targeting Cell Cycle Kinases for Cancer Therapy
Guillermo de Cárcer, Ignacio Pérez de Castro
and Marcos Malumbres
Many tumor-associated mutations result in the abnormal regulation
of protein kinases involved in the progression throughout
the cell division cycle. The cyclin-dependent kinase (CDK)
family has received special attention due to their function
as sensors of the mitogenic signals and their central role
in cell proliferation. These kinases are frequently upregulated
in human cancer most frequently due to overexpression of their
cyclin partners or inactivation of the CDK inhibitors. A plethora
of small-molecule CDK inhibitors have been characterized in
the last years and some of them are currently under clinical
development. Other serine-threonine protein kinases such as
the Aurora proteins (mostly Aurora A and B) or Polo-like kinases
(PLK1) are receiving increased attention as putative cancer
targets. Other less studied mitotic kinases such TTK (MPS1),
BUB and NEK proteins might also be relevant candidates as
new targets of interest in cancer therapy since they play
relevant roles on mitotic progression and the spindle checkpoint.
Although targeting cell cycle kinases is an efficient procedure
to arrest cell proliferation, the best strategy to potently
and specifically inhibit tumor cell proliferation is not obvious
yet. Thus, some cell cycle kinases may be of interest as targets
to abrogate checkpoints and favor apoptotic cell death in
tumor cells. New biochemical and genetic studies are required
to clarify the use of these kinases as targets in new opportunities
to improve cancer therapy.
[Back to top]
Mass Spectrometric Profiling of Low-Molecular-Weight
Volatile Compounds - Diagnostic Potential and Latest Applications
Matthias Lechner and Josef Rieder
The theoretical use of mass spectrometric profiling of low-molecular-weight
volatile compounds, as one possible method to non-invasively
and rapidly diagnose a variety of diseases, such as cancer,
infection, and metabolic disorders has greatly raised the
profile of this technique over the last ten years.
Despite a number of promising results, this technique has
not been introduced into common clinical practice yet. The
use of mass spectrometric profiling of exhaled air is particularly
hampered by various technical problems and basic methodological
issues which have only been partially overcome. However, breath
analysis aside, recently published studies reveal completely
new ideas and concepts on how to establish fast and reliable
diagnosis by using this valuable tool. These studies focussed
on the headspace screening of various bodily fluids and sample
fluids obtained during diagnostic procedures, as well as microbial
cell cultures and demonstrated the vast diagnostic potential
of this technique in a wide variety of settings, predominantly
in vitro.
It is the aim of the present review to discuss the most commonly
detected low-molecular-weight volatile compounds and to summarize
the current potential applications, latest developments and
future perspectives of this promising diagnostic approach.
[Back to top]
Porphycenes: Facts and Prospects in Photodynamic Therapy
of Cancer
J.C. Stockert, M. Cañete, A. Juarranz, A. Villanueva,
R.W. Horobin, J.I. Borrell, J. Teixidó and S. Nonell
The photodynamic process induces cell damage and death by
the combined effect of a photosensitizer (PS), visible light,
and molecular oxygen, which generate singlet oxygen (1O2)
and other reactive oxygen species that are responsible for
cytotoxicity. The most important application of this process
with increasing biomedical interest is the photodynamic therapy
(PDT) of cancer. In addition to hematoporphyrin-based drugs,
2nd generation PSs with better photochemical properties
are now studied using cell cultures, experimental tumors and
clinical trials. Porphycene is a structural isomer of porphyrin
and constitutes an interesting new class of PS. Porphycene
derivatives show higher absorption than porphyrins in the
red spectral region (λ>
600 nm, ε>
50000 M-1•cm-1) owing to the lower
molecular symmetry. Photophysical and photobiological properties
of porphycenes make them excellent candidates as PSs, showing
fast uptake and diverse subcellular localizations (mainly
membranous organelles). Several tetraalkylporphycenes and
the tetraphenyl derivative (TPPo) induce photodamage and cell
death in vitro. Photodynamic treatments of cultured
tumor cells with TPPo and its palladium(II) complex induce
cytoskeletal changes, mitotic blockage, and dose-dependent
apoptotic or necrotic cell death. Some pharmacokinetic and
phototherapeutic studies on experimental tumors after intravenous
or topical application of lipophilic alkyl-substituted porphycene
derivatives are known. Taking into account all these features,
porphycene PSs should be very useful for PDT of cancer and
other biomedical applications.
[Back to top]
Chemical Events Behind Leukoaraiosis: Medicinal Chemistry
Offers New Insight into a Specific Microcirculation Disturbance
in the Brain (a Chemical Approach to a Frequent Cerebral Phenotype)
Zoltán Szolnoki
Leukoaraiosis (LA), one of the most frequent causes of cognitive
disturbances, is presumed to involve vascular demyelinization
and cerebral small-vessel diseases. Although it has been suggested
that the development of LA is associated with cerebral circulatory
disturbances, the pathomechanism of this circulatory problem
is not completely understood. Extensive debate is continuing
as regards the detailed features of the circulatory disturbances
in LA. An endothelial dysfunction may lead to breakdown of
the blood-brain barrier, thereby resulting in chronic toxic
edema in the perivascular areas. This can then cause the slow
development of LA. Endothelial dysfunctions may also give
rise to molecular events involving a shift in the O2
and CO2
trafficking system in the red blood cells, which will result
in special complex microcirculation disturbances in the white
matter of the brain; these molecular phenomena may therefore
account for chronic slight hypoxia leading to the development
of LA. This article discusses these hypothetical alternative
molecular events behind LA. The review also illustrates how
medicinal chemistry can offer new insight into a common, but
still mysterious cerebral phenotype.
[Back to top]
Biomarkers in COPD
Eleni G. Tzortzaki, Irini Lambiri, Eleni Vlachaki and
Nikolaos M. Siafakas
Chronic Obstructive Pulmonary Disease is characterized by
an abnormal inflammatory response of the lungs to noxious
particles and gases, caused primarily by cigarette smoking.
Although COPD affects the lung, it also produces significant
systemic consequences. Inflammation, proteases-antiproteases
imbalance, oxidative stress, tissue damage and tissue repair,
apoptosis and several genes seem to be involved in the pathogenesis
of the disease.
The cellular and molecular events underlying COPD pathogenesis
are driven by multifunctional molecules including enzymes,
cytokines, chemokines, growth factors, lipid mediators and
their respective receptors.
A large number of biomarkers evaluated in COPD, showed a high
degree of redundancy. Nevertheless, current understanding
of the pathobiology of COPD suggests a number of biomarkers
as potential candidates. The development of relevant markers
of lung damage, pulmonary inflammation, and systemic disease
will be essential to our further understanding of the natural
history of COPD and the discovery of new, effective treatments
for its progression.
This review summarizes recent findings, on potential pulmonary
biomarkers in the induced sputum, the exhaled air condensate,
the peripheral blood, the urine, the bronchoalveolar lavage
fluid, and in selective cases, in bronchial biopsies.
[Back to top]
Evaluation and Management of Severe Asthma
Mina Gaga, Eleftherios Zervas, Spiros Grivas, Mario Castro
and Pascal Chanez
Severe and difficult-to-treat asthma patients have
impaired health status and account for over half of the cost
of the disease and probably all of its mortality. Guideline-based
treatment for these refractory asthma patients includes high
doses of inhaled steroids and long acting beta2-agonists (LABA)
as well as additional medication such as theophylline, oral
steroids and leukotriene-antagonists. However, management
regimens are rarely successful in these patients, the treating
physicians are often at a loss and there are still many areas
of uncertainty regarding steroid-responsiveness, safety issues
and maximal dosing of inhaled corticosteroids (ICS) and bronchodilators
and possible differences between ICS preparations. Furthermore,
there are many other classes of medication that have been
or are currently tested in severe asthma: Anti - Immunoglobulin
E (IgE) seems to have a good clinical effect while results
on anti - Interleukin 5 (IL-5) are less promising and anti
- tumor necrosis factor alpha (TNFα)
treatment is currently being tested in controlled studies.
Other steroid sparing drugs (cyclosporine, tacrolimus, methotrexate,
gold) have been used but results are unsatisfactory and side-effects
are notable so steroids remain the cornerstone of severe asthma
treatment. The addition of macrolides is beneficial in many
cases and this is in step with the evidence of chronic chlamydia
infection in severe asthma. Although there are case reports
supporting the use of Immunoglobulin G (IgG), there are no
controlled studies supporting this type of treatment. In this
report, the authors review the various issues of guideline
based therapy but also new approaches that include anti-IgE
antibodies, anti-cytokines (anti-IL-5, anti-IL9, anti-TNF).
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