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Current
Drug Therapy
ISSN: 1574-8855
Current Drug Therapy
Volume 3, Number 3, September 2008
Contents
Current Advances in the Development of Anticancer Drugs Targeting
Tyrosine Kinases of the Src Family Pp. 158-176
Silvia Schenone, Samantha Zanoli, Chiara Brullo,
Emmanuele Crespan and Giovanni Maga
[Abstract]
New Targets for Therapy in Polyglutamine (polyQ)
Expansion Diseases Pp. 177-189
Lorena Perrone and Mariarosa A.B. Melone
[Abstract]
Who’s Winning the War? Molecular Mechanisms
of Antibiotic Resistance in Helicobacter pylori
Pp. 190-203
Kathleen R. Jones, Jeong-Heon Cha and D. Scott
Merrell
[Abstract]
Therapy and Further Development of Anti-Leishmanial
Drugs Pp. 204-208
Joana A. Pinto da Costa Tavares, Ali Ouaissi
and Anabela Cordeiro da-Silva
[Abstract]
Nanogel Engineered Polymeric Micelles for Drug
Delivery Pp. 209-217
Supriya Shidhaye, Vishwanath Lotlikar, Sheetal
Malke and Vilasra Kadam
[Abstract]
Sphingomyelinase Inhibition Suggests a Possible
New Strategy for the Treatment of Inflammatory Bowel Disease
Pp. 218-225
Shinji Soeda, Akira Sakata, Takashi Ochiai,
Kazuya Yasuda, Yukako Kuramoto, Hiroshi Shimeno, Akihisa Toda,
Reiko Eyanagi, Sadao Hikishima, Tsutomu Yokomastu and
Shiroshi Shibuya
[Abstract]
Genetically Modified Hepatitis B Surface Antigen:
A Powerful Vaccine Technology for the Delivery of Disease-Associated
Foreign Antigens 226-234
Scott Thomson, Oscar Haigh, Allan Gould
and Robert Tindle
[Abstract]
Abstracts
[Back to top]
Current Advances in the Development of Anticancer Drugs Targeting
Tyrosine Kinases of the Src Family
Silvia Schenone, Samantha Zanoli, Chiara Brullo,
Emmanuele Crespan and Giovanni Maga
Protein kinases, either membrane-embedded receptorial or cytosolic
non-receptorial ones, are important transducers of cell proliferation
signals. In almost all tumor cells, the activity of some kinases
is deregulated, either because of the presence of cancer-specific
aberrant forms, or as a consequence of alterations in regulatory
pathways, at the transcriptional or post-transcriptional level,
which increase the activity of protein kinases with respect
to normal cells. The study of the non-receptor tyrosine kinase
Src plays a pivotal role in the field of the molecular genetics
of cancer. The Src family of kinases (SFKs) comprises nine
members, Src, Fyn, Yes, which are expressed in most tissues,
and Blk,Yrk, Fgr, Hck, Lck and Lyn, which are more selectively
expressed in particular tissues. To date, cellular (c-) Src
has been implicated in the development of human cancer. Like
oncogenic v-Src, activated mutants of c-Src can transform
cells in culture and induce tumours in chickens. In addition,
Src protein expression and/or activity is elevated in epithelial
cancers, or cell lines derived from these, and there is often
an association with advancement of disease or with malignancy.
During the past decade, examples of tyrosine kinases inhibitors
have been reported. Many of these compounds were highly active
in vitro, but only a few demonstrated
in vivo activity. These approaches led to the characterization
of the PP1/PP2 derivatives as very strong and selective inhibitors
of the c-Src family of kinases. Unfortunately, attempts to
improve the biological profile of the latter compounds have
so far met little success. Following these studies, some other
inhibitors, possessing different chemical structures and interesting
c-Src inhibitory activity, have been recently reported. Some
of these molecules showed potent inhibition of tumor cell
proliferation, which was due to the interference with the
signalling pathway at the level of Src tyrosine kinase, providing
proof-of-principle for the targeting of Src in anticancer
chemotherapy.
[Back to top]
New Targets for Therapy in Polyglutamine (polyQ) Expansion
Diseases
Lorena Perrone and Mariarosa A.B. Melone
The polyglutamine (polyQ) repeat disorders are a family
of inherited disorders characterized by progressive neurodegeneration,
as well as the formation of intracellular protein aggregates.
Huntington's disease (HD) is the most prevalent disorder in
the family of polyQ diseases. This family includes nine other
neurodegenerative disorders: Dentato-rubral-pallidoluysian
atrophy (DRPLA), Bulbo-Spinal Muscular Atrophy (BSMA) and
Spinocerebellar ataxia (SCA) types 1-3, 6, 7, 12 and 17. Each
disease is caused by the expansion of a tract of repeated
CAG triplet in a distinct gene, causing transcription of proteins
with lengthened polyQ repeats. Although mutations occur frequently
in a ubiquitously expressed gene, neurodegeneration occurs
in a specific cell type. The mutant proteins involved in polyQ
disease are unrelated and they share only the glutamine extension.
As for the pathogenic mechanism by wich the repeat expansion
leads to the disease, major models include a loss of function
of the gene and a gain of function by the mutant RNA transcript
or protein product. Indeed, altered function in the ubiquitin-proteasome
system (UPS), endoplasmic reticulum (ER) and mitochondria
function, as well as a primary failure in autophagy has been
demonstrated. However, the pathogenic mechanism varies from
one disease to another, depending on the motif, length, and
intragenic location of the repeat. Understanding the molecular
mechanisms of repeat instability and pathogenic process is
not only of scientific interest but also essential for the
development of rational treatment of these diseases.
[Back to top]
Who’s Winning the War? Molecular Mechanisms
of Antibiotic Resistance in Helicobacter pylori
Kathleen R. Jones, Jeong-Heon Cha and D. Scott
Merrell
The ability of clinicians to wage an effective war against
many bacterial infections is increasingly being hampered by
skyrocketing rates of antibiotic resistance. Indeed, antibiotic
resistance is a significant problem for treatment of diseases
caused by virtually all known infectious bacteria. The gastric
pathogen Helicobacter pylori is no exception to this
rule. With more than 50% of the world’s population infected,
H. pylori exacts a tremendous medical burden and
represents an interesting paradigm for cancer development;
it is the only bacterium that is currently recognized as a
carcinogen. It is now firmly established that H. pylori
infection is associated with diseases such as gastritis, peptic
and duodenal ulceration and two forms of gastric cancer, gastric
adenocarcinoma and mucosa-associated lymphoid tissue (MALT)
lymphoma. With such a large percentage of the population infected,
increasing rates of antibiotic resistance are particularly
vexing for a treatment regime that is already fairly complicated;
treatment consists of two antibiotics and a proton pump inhibitor.
To date, resistance has been found to all primary and secondary
lines of antibiotic treatment as well as to drugs used for
rescue therapy.
[Back to top]
Therapy and Further Development of Anti-Leishmanial
Drugs
Joana A. Pinto da Costa Tavares, Ali Ouaissi
and Anabela Cordeiro da-Silva
Leishmaniasis is a parasitic infection that affects millions
of people worldwide, especially in tropical and subtropical
areas, and is responsible for high mortality and morbidity.
The therapies available up to the present are far from satisfactory
and, since leishmaniasis affects poor people in poor regions,
the development of new drugs has been neglected due to the
lack of commercial motivation. Safe and orally available drugs,
especially against the visceral form of the disease, are needed.
An overview of the main strategies for antileishmanial drug
development, mainly focused on the target-based drug development
approach, is given.
[Back to top]
Nanogel Engineered Polymeric Micelles for Drug Delivery
Supriya Shidhaye, Vishwanath Lotlikar, Sheetal
Malke and Vilasra Kadam
In the past few decades nanotechnology for drug delivery
has attracted a great deal of attention. Nanogels under this
category are sub-micron sized water swellable crosslinked
structures of biocompatible hydrophillic polymers which have
wide array of applications in drug delivery, biotechnology
and biomedical field due to their nanosized structure with
characteristics of nanoparticles and hydrogels. Nanogels are
synthesized by emulsion polymerization, photo-polymerization,
pulse radiolysis, photo-Fenton reaction and physical self-assembly
techniques. Nanogels are characterized by various microscopic
techniques like scanning electron microscopy, atomic force
microscopy and analytical techniques such as dynamic light
scattering, zeta potential, fluorescence, nuclear magnetic
resonance, size exclusion chromatography. Nanogels can trap
novel nanobiomaterials and find application in delivery of
proteins, peptides, gene delivery, insulin delivery, and as
toxic scavengers. Thus nanogels can act as a carrier as well
as sustained release can be achieved by designing responsive
nanogels such as pH, thermo, photo or magneto-responsive nanogels.
Thus the article focuses on the synthesis, characterization
and applications of nanogels.
[Back to top]
Sphingomyelinase Inhibition Suggests a Possible New
Strategy for the Treatment of Inflammatory Bowel Disease
Shinji Soeda, Akira Sakata, Takashi Ochiai,
Kazuya Yasuda, Yukako Kuramoto, Hiroshi Shimeno, Akihisa Toda,
Reiko Eyanagi, Sadao Hikishima, Tsutomu Yokomastu and
Shiroshi Shibuya
Multiple lines of evidence suggest that macrophages have a
critical role in the disease pathology of inflammatory bowel
disease (IBD) by secreting inflammatory cytokines, such as
tumor necrosis factor (TNF)-α,
interleukin (IL)-1β,
IL-6 and IL-8. Therapies for IBD target one or more of these
inflammatory mediators. Recent advances in drug development
for IBD have involved the use of monoclonal antibodies to
inhibit specific inflammatory cytokines. In particular, the
anti-TNF-α
antibodies, CDP571 and Infliximab have been used clinically
to treat Crohn’s disease with some success. The inflammatory
cytokines and lipopolysaccharide (LPS) cause activation of
sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin
(SM), to generate a lipid messenger ceramide. The design of
SMase inhibitors may offer new therapies for the treatment
of LPS- and cytokine-related IBD. We synthesized a series
of difluoromethylene analogues of SM (SMAs). This review discusses
recent data from our laboratories on the effects of the most
potent SMase inhibitor, SMA-7, on the LPS-mediated releases
of the cytokines from macrophages and intestinal epithelial
cells and the pathology of dextran sulphate sodium (DSS)-induced
colitis in mice. Our findings suggest a central role of SMase/ceramide
signaling in the pathology of DSS-induced colitis in mice,
indicating a possible preventive or therapeutic role for SMase
inhibitor in IBD.
[Back to top]
Genetically Modified Hepatitis B Surface Antigen:
A Powerful Vaccine Technology for the Delivery of Disease-Associated
Foreign Antigens
Scott Thomson, Oscar Haigh, Allan Gould
and Robert Tindle
The surface antigen of hepatitis B virus (HBsAg) spontaneously
aggregates into ‘empty’ virus-like particles (VLPs)
in the absence of other viral components. The powerful immunogenicity
of HBsAg when administered either as VLPs or as naked DNA
invites it’s exploitation as a vector for the delivery
of antigenic determinants from other organisms. Here we discuss
ways in which HBsAg may be modified to derive vaccines against
disease-related pathogens. We review studies demonstrating
the induction of disease-protective antibody and T-cell responses
induced by immunization with recombinant HBsAg vaccines, and
consider how these vaccines might best be delivered. Unmodified
HBsAg VLPs are licensed for use in humans as the pan-global
vaccine to prevent hepatitis B virus infection, suggesting
that route-to-market for recombinant HBsAg vaccines might
be simplified.
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