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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 4, 2008
Contents
Endocrine and Antineoplastic Actions of Growth Hormone Releasing
Hormone Antagonists Pp. 314-321
Magdolna Kovács, Andrew V. Schally, József L.
Varga and Márta Zarándi
[Abstract]
Detection and Specific Targeting of Hypoxic Regions within
Solid Tumors: Current Preclinical and ClinicalStrategies
Pp. 322-238
M. Bache, M. Kappler, H. M. Said, A. Staab and D. Vordermark
[Abstract]
Human Leukemia and Lymphoma Cell Lines as Models
and Resources Pp. 339-359
Roderick A.F. MacLeod, Stefan Nagel, Michaela Scherr,
Björn Schneider, Wilhelm G. Dirks, Cord C. Uphoff, Hilmar
Quentmeier and Hans G. Drexler
[Abstract]
DNA Damage Repair and Response Proteins as Targets
for Cancer Therapy Pp. 360-367
Howard B. Lieberman
[Abstract]
Role of Sulfonamide Group in Matrix Metalloproteinase
Inhibitors Pp. 368-373
Xian-Chao Cheng, Qiang Wang, Hao Fang and Wen-Fang Xu
[Abstract]
Advances in Matrix Metalloproteinase Inhibitors Based
on Pyrrolidine Scaffold Pp. 374-385
Xian-Chao Cheng, Qiang Wang, Hao Fang and Wen-Fang Xu
[Abstract]
Post-Translational Modifications of Nuclear Co-repressor
RIP140: A Therapeutic Target for Metabolic Diseases
Pp. 386-392
M.D. Mostaqul Huq, Pawan Gupta and Li-Na Wei
[Abstract]
Synthetic Pulmonary Surfactant Preparations: NewDevelopments
and Future Trends Pp. 393-403
Ismael Mingarro, Dunja Lukovic, Marçal Vilar and
Jesús PérezGil
[Abstract]
Antioxidants and Free Radical Scavengers for th Treatment
Of Stroke, Traumatic Brain Injury and Aging Pp. 404-414
J.E. Slemmer, J.J. Shacka, M.I. Sweeney and J.T. Weber
[Abstract]
Medical Treatment of Malignancy-Associated Hypercalcemia
Pp. 415-421
F. Lumachi, A. Brunello, A. Roma and U. Basso
[Abstract]
Abstracts
[Back to top]
Endocrine and Antineoplastic Actions of Growth Hormone Releasing
Hormone Antagonists
Magdolna Kovács, Andrew V. Schally, József L.
Varga and Márta Zarándi
Potent antagonists of growth hormone-releasing hormone
(GHRH) have been developed for the treatment of disorders
caused by excessive GHRH or growth hormone (GH) production
and for therapy of cancers. GHRH antagonists suppressed the
release of GH and insulin-like growth factor (IGF)-I in transgenic
mice overexpressing human (h) GHRH gene, an animal model of
human acromegaly. It was also shown in GH3 rat pituitary tumor
cells overexpressing the human pituitary GHRH receptor (pGHRH-R)
that GHRH antagonists can inhibit c-AMP production and GH
secretion through the human receptor. These observations indicate
that GHRH antagonists could be used clinically in disorders
characterized by excessive GHRH/GH secretion. Many recent
studies demonstrate that GHRH antagonists can inhibit tumor
growth by several mechanisms. By indirect action through pGHRH-Rs
these antagonists suppress circulating GH/IGF-I level, which
results in the inhibition of cancers that depend on GH and/or
IGF-I as growth factors. However, GHRH antagonists are also
effective inhibitors of tumor IGF-II production, which is
a potent mitogen but independent of GH. GHRH antagonists can
inhibit tumor cell proliferation by direct action on tumor
cell receptors, suppressing the IGF-II and other growth factor
production of tumor cells. In addition, various human tumors
and tumor cell lines secrete GHRH peptide and respond to GHRH
with proliferation. This finding suggests that GHRH functions
as an autocrine growth factor and that GHRH antagonists can
block its effects on tumor growth. Recently, we demonstrated
the expression of hGHRH-R and its splice variants in various
human cancers. Antiproliferative action of GHRH antagonists
on these cancers indicates that the direct inhibitory effects
of GHRH antagonists are mediated by tumoral GHRH receptors.
[Back to top]
Detection and Specific Targeting of Hypoxic Regions
within Solid Tumors: Current Preclinical and Clinical Strategies
M. Bache, M. Kappler, H. M. Said, A. Staab and D. Vordermark
Poor oxygenation of solid tumors is a major indicator
of adverse prognosis after standard treatment, e. g. radiotherapy.
This observation founded on intratumoral pO2
electrode measurements has been supported more recently by
studies of injected hypoxia markers (pimonidazole, EF5) or
hypoxia-related proteins (hypoxia-inducible factor-1α,
carbonic anhydrase IX) detected immunohistochemically. Alternative
approaches include imaging of tumor hypoxia by nuclear medicine
studies and the measurement of hypoxia-related proteins (osteopontin)
in patient plasma.
Low oxygen levels as found in tumors are rarely observed in
normal tissues. The presence of hypoxic tumor cells is therefore
regarded not only as an adverse prognostic factor but as an
opportunity for tumor-specific treatment. Classic approaches
to normalize tumor oxygenation involve the breathing of modified
gas mixtures and pharmacologic modification of blood flow
as in the “accelerated radiotherapy, carbogen, nicotinamide”
(ARCON) scheme. Specific killing of hypoxic tumor cells can
potentially be achieved by hypoxia-selective cytotoxins (model
substance tirapazamine), which has shown promise in head and
neck cancer. Direct targeting of hypoxia-related molecules
such as hypoxia-inducible factor-1α,
the central regulator of the hypoxic response in tumor cells,
is an attractive approach currently tested in preclinical
models.
For clinical applications, the appropriate combination of
hypoxia detection for patient selection with a hypoxia-specific
treatment is essential. A therapeutic benefit has been suggested
for the selection of patients by plasma osteopontin level
and treatment with the hypoxic radiosensitizer nimorazole
in addition to radiotherapy, for selection by F-misonidazole
positron-emmission tomography (PET) and treatment with tirapazamine
in addition to chemoradiation and for selection by pimonidazole
immunohistochemistry and ARCON treatment, all in head and
neck cancer.
[Back to top]
Human Leukemia and Lymphoma Cell Lines as Models an
Resources
Roderick A.F. MacLeod, Stefan Nagel, Michaela Scherr,
Björn Schneider, Wilhelm G. Dirks, Cord C. Uphoff, Hilmar
Quentmeier and Hans G. Drexler
Tumor cell lines are widely used as oncologic models
and resources, forming, along with primary patient material
and animal models, one of three major subjects for cancer
investigation. With the advent of the Human Genome Project
(HGP) and the ensuing provision of sequencing data and mapped
clones, human cancer cell lines, notably those derived from
leukemia-lymphoma (LL) have become increasingly productive
tools for cancer gene ascertainment and characterization.
Hence, the roles of putative novel cancer genes may be investigated
using diverse panels of LL cell lines, both individually by
PCR-based methods, and globally by transcriptional chip-profiling.
Similar studies have also enabled the faithfulness with which
cancer cell lines model their supposed in vivo counterparts
to be quantified at last. Several recent transcriptional profiling
studies indicate that of all tumor types well characterized
human LL cell lines most accurately model the gene expression
patterns of their corresponding primary tumors. Analysis using
genomic arrays tells a similar story for the stability of
chromosome rearrangements in LL cell lines. Well characterized
LL cell lines also provide ideal tools for investigating the
druggability of individual gene products, e.g. by measuring
their transcript levels using q(uantitative)-PCR methods in
cells subjected to treatments with small interfering (si)-RNAs.
We provide a list of authentic, well characterized examples
for prospective in-vestigators, since many circulating cell
lines have been cross-contaminated and describe DNA profiling
methods which, together with classic and molecular cytogenetic
analyses, inform authentication. We also review the problem
of mycoplasma contamination and means for its eradication.
[Back to top]
DNA Damage Repair and Response Proteins as Targets
for Cancer Therapy
Howard B. Lieberman
The cellular response to DNA damage is critical for determining
whether carcinogenesis, cell death or other deleterious biological
effects will ensue. Numerous cellular enzymatic mechanisms
can directly repair damaged DNA, or allow tolerance of DNA
lesions, and thus reduce potential harmful effects. These
processes include base excision repair, nucleotide excision
repair, nonhomologous end joining, homologous recombinational
repair and mismatch repair, as well as translesion synthesis.
Furthermore, DNA damage-inducible cell cycle checkpoint systems
transiently delay cell cycle progression. Presumably, this
allows extra time for repair before entry of cells into critical
phases of the cell cycle, an event that could be lethal if
pursued with damaged DNA. When damage is excessive apoptotic
cellular suicide mechanisms can be induced. Many of the survival-promoting
pathways maintain genomic integrity even in the absence of
exogenous agents, thus likely processing spontaneous damage
caused by the byproducts of normal cellular metabolism. DNA
damage can initiate cancer, and radiological as well as chemical
agents used to treat cancer patients often cause DNA damage.
Many genes are involved in each of the DNA damage processing
mechanisms, and the encoded proteins could ultimately serve
as targets for therapy, with the goal of neutralizing their
ability to repair damage in cancer cells. Therefore, modulation
of DNA damage responses coupled with more conventional radiotherapy
and chemotherapy approaches could sensitize cancer cells to
treatment. Alteration of DNA damage response genes and proteins
should thus be considered an important though as of yet not
fully exploited avenue to enhance cancer therapy.
[Back to top]
Role of Sulfonamide Group in Matrix Metalloproteinase
Inhibitors
Xian-Chao Cheng, Qiang Wang, Hao Fang and Wen-Fang Xu
Sulfonamide hydroxamates were designed and synthesized
as efficient matrix metalloproteinase (MMP) inhibitors since
the discovery of CGS 27023A in 1994. The sulfonamide group
was incorporated in the inhibitor to improve the enzyme-inhibitor
binding, not only by forming hydrogen bonds to the enzyme
but also by properly directing the hydrophobic substituent
to the S1' pocket and enabling it to plunge in deeply. Some
researchers even presumed that the sulfonamide group, together
with the zinc binding group (ZBG), coordinated the zinc ion
within the MMP active site. This review will illustrate the
role of the sulfonamide group in MMP inhibitors.
[Back to top]
Advances in Matrix Metalloproteinase Inhibitors Based
on Pyrrolidine Scaffold
Xian-Chao Cheng, Qiang Wang, Hao Fang and Wen-Fang X
Matrix metalloproteinases (MMPs) play an important role
in many physiological and pathological processes. MMP inhibitors
have been considered as potential therapeutics for neoplasitc,
rheumatic and cardiovascular diseases. Our group and others
have been developing pyrrolidine scaffold-based MMP inhibitors
for a number of years, and numerous compounds have been reported
in the literature. These compounds can be classified as sulfonamide
pyrrolidine derivatives, proline-containing peptidomimetics
and acyl pyrrolidine derivatives. These synthetic MMP inhibitors
show low nanomolar activity for some MMP subclasses, thus
confirming pyrrolidine ring an excellent scaffold from which
to design MMP inhibitors. This review will focus primarily
on the structure, activity and selectivity profiles of pyrrolidine
scaffold-based MMP inhibitors.
[Back to top]
Post-Translational Modifications of Nuclear Co-repressor
RIP140: A Therapeutic Target for Metabolic Diseases
M.D. Mostaqul Huq, Pawan Gupta and Li-Na Wei
Most proteins undergo post-translational modification
(PTM), which is known to play roles in normal physiological
processes and the progression of many diseases. In this review,
we summarized and discussed the mass spectrometry (MS)-based
studies of various PTMs of nuclear co-repressor, receptor
interacting protein 140 (RIP140), as well as the significance
of these PTMs in modulating the biological activities of RIP140,
specifically in adipocytes. Comprehensive analyses of RIP140
by MS identified specific sites of PTMs on RIP140, including
that of phosphorylation, acetylation, pyridoxylation, and
protein arginine methylation. Studies of these PTMs revealed
their combinatorial effects on the activities of RIP140 with
respect to the regulation of hormone target genes and fat
accumulation in adipocytes. These proteomic studies have presented
evidence for the biological significance of specific PTMs
of RIP140, and uncovered nutritional and physiological factors
that trigger these PTMs in adipocytes.. This could provide
insights into potential, new therapeutic targets for diseases
concerning adipocytes such as metabolic disorders.
[Back to top]
Synthetic Pulmonary Surfactant Preparations: New Developments
and Future Trends
Ismael Mingarro, Dunja Lukovic, Marçal Vilar and
Jesús Pére Gil
Pulmonary surfactant is a lipid-protein complex that
coats the interior of the alveoli and enables the lungs to
function properly. Upon its synthesis, lung surfactant adsorbs
at the interface between the air and the hypophase, a capillary
aqueous layer covering the alveoli. By lowering and modulating
surface tension during breathing, lung surfactant reduces
respiratory work of expansion, and stabilises alveoli against
collapse during expiration.
Pulmonary surfactant deficiency, or dysfunction, contributes
to several respiratory pathologies, such as infant respiratory
distress syndrome (IRDS) in premature neonates, and acute
respiratory distress syndrome (ARDS) in children and adults.
The main clinical exogenous surfactants currently in use to
treat some of these pathologies are essentially organic extracts
obtained from animal lungs. Although very efficient, natural
surfactants bear serious defects: i) they could vary in composition
from batch to batch; ii) their production involves relatively
high costs, and sources are limited; and iii) they carry a
potential risk of transmission of animal infectious agents
and the possibility of immunological reaction. All these caveats
justify the necessity for a highly controlled synthetic material.
In the present review the efforts aimed at new surfactant
development, including the modification of existing exogenous
surfactants by adding molecules that can enhance their activity,
and the progress achieved in the production of completely
new preparations, are discussed.
[Back to top]
Antioxidants and Free Radical Scavengers for the Treatment
Of Stroke, Traumatic Brain Injury and Aging
J.E. Slemmer, J.J. Shacka, M.I. Sweeney and J.T. Weber
The overproduction of reactive oxygen species (ROS) and
reactive nitrogen species (RNS) is a common underlying mechan-ism
of many neuropathologies, as they have been shown to damage
various cellular components, including proteins, lipids and
DNA. Free radicals, especially superoxide (O2•-),
and non-radicals, such as hydrogen peroxide (H2O2),
can be generated in quantities large enough to overwhelm endogenous
protective enzyme systems, such as superoxide dismutase (SOD)
and reduced glutathione (GSH). Here we review the mechanisms
of ROS and RNS production, and their roles in ischemia, traumatic
brain injury and aging. In particular, we discuss several
acute and chronic pharmacological therapies that have been
extensively studied in order to reduce ROS/RNS loads in cells
and the subsequent oxidative stress, so-called “free-radical
scavengers.” Although the overall aim has been to counteract
the detrimental effects of ROS/RNS in these pathologies, success
has been limited, especially in human clinical studies. This
review highlights some of the recent successes and failures
in animal and human studies by attempting to link a compound’s
chemical structure with its efficacy as a free radical scavenger.
In particular, we demonstrate how antioxidants derived from
natural products, as well as long-term dietary alterations,
may prove to be effective scavengers of ROS and RNS.
[Back to top]
Medical Treatment of Malignancy-Associat Hypercalcemia
F. Lumachi, A. Brunello, A. Roma and U. Basso
Malignancy-associated hypercalcemia (MAH) is the commonest
cause of hypercalcemia in hospitalized patients. Its incidence
is 15 cases per 100,000 person-year. Such complication develops
in almost 10% of patients with advanced cancer representing,
ultimately, the most frequent cause of death in several patients
with cancer. Parathyroid hormone related protein (PTHrP),
which has strong homology to parathyroid hormone, is the commonest
hormonal mediator of MAH. Overall, about 80% of patients with
MAH have increased PTHrP serum levels. Bisphosphonates are
synthetic analogues of pyrophosphate, and represent the principal
support of treatment. Several bisphosphonates have shown to
decrease serum calcium levels by inhibiting PTH-dependent
osteoclast activation. They are potent and effective inhibitors
of osteoclast-mediated bone resorption, and have shown antiangiogenic
properties in some experimental models. At present, pamidronate,
zoledronate and ibandronate should be considered the drugs
of choice in the treatment of MAH. Old agents such as mithramycin,
calcitonine, and gallium nitrate have practically been abandoned
due to their limited activity and huge side effects, especially
for the kidney. A new experimental approach to MAH involves
the blockade of receptor activator of nuclear factor-kappa
B ligand, usually abbreviated as RANKL. RANKL is a key element
in the differentiation, function, and survival of osteoclasts,
which plays an essential role in removing Ca ++
from the bone in response to PTH stimulation. This review
provides information about the actual medical treatment of
MAH.
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