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Current Pharmacogenomics
ISSN: 1570-1603
Current Pharmacogenomics
Volume 3, Number 4, December 2005
Contents
Selection of Microbial T-Cell Epitopes for Immune-Diagnosis,Immune-Therapy
and Vaccine Design Pp.247
F. Seghrouchni, F. Berretta and M. Amicosante
[Abstract]
Pharmacological Suppression of Premature Stop Mutations
thatCause Genetic Diseases Pp.259
K.M. Keeling and D.M. Bedwell
[Abstract]
Hypertensive Pharmacogenomics in African Americans
Pp.271
A. Chapman, F. Millhouse-Jones, J. Lea, F. Rahbari and
E. Baranco-Pryor
[Abstract]
Genomics and Proteomics of Nucleoside Transporters
Pp.281
G. Reyes and I.R. Coe
[Abstract]
DNA Microarray-Based Gene Expression Profiling in
Cancer: Aiding Cancer Diagnosis, Assessing Prognosis and Predicting
Response to Therapy Pp.289
M.J. Duffy, Z.D. Kelly, A.C. Culhane, S.L. O’Brien
and W.M. Gallagher
[Abstract]
A Candidate Pathway Strategy for Integration of PharmacogenomicComponents
of Variability in Antipsychotic Treatment Outcomes:A Focus
on Aripiprazole Pp.305
C. Reist, L.J. Albers, S.R. Marder, B. Williams-Jones,
J.C. Wu, S. Mee, K. Shimoda, T. Someya and V. Ozdemir
[Abstract]
Identifying Biomarkers of Lung Cancer in the Post-Genomic
Era Pp.319
J. Xie
[Abstract]
Abstracts
[Back to top]
Selection of Microbial T-Cell Epitopes for Immune-Diagnosis,
Immune-Therapy and Vaccine Design
Fouad Seghrouchni, Floriana Berretta and Massimo Amicosante
The ability to induce and/or monitor an immune response to
a broad repertoire of epitopes universally recognized across
continents and genetic backgrounds is considered a critical
characteristic of an effective vaccine and diagnostic tool.
Opportunities for epitope identification are expanding as
the number of entirely sequenced pathogens approaches 500
and access to this data improves. The pace of vaccine design
will accelerate as bioinformatics are systematically applied
to whole genomes and used in combination with in vitro
methods for screening and confirming epitopes. Given access
to bioinformatic tools, epitope-driven diagnostic tools and
both preventive and therapeutic vaccines (for infectious diseases
of worldwide impact such as tuberculosis and HIV) are now
within our reach. This review describes the structural basis
of the bioinformatic tools for epitope prediction methods
as well as the recent use of these approaches at genomic level
in the development of diagnostic tools and vaccine design
as example of structural bioinformatic system applied to pharmacogenomics.
[Back to top]
Pharmacological Suppression of Premature Stop Mutations
that Cause Genetic Diseases
K.M. Keeling and D.M. Bedwell
Aminoglycoside antibiotics have long been used as antibacterial
agents due to their ability to inhibit bacterial translation.
However, aminoglycosides also stimulate translation errors
in mammalian cells. Aminoglycosides bind to a pocket formed
in a domain of the ribosomal RNA (rRNA) of the small ribosomal
subunit that constitutes the decoding site in both prokaryotes
and eukaryotes. Normally, accurate base pairing takes place
between each successive codon and its cognate aminoacyl-tRNA
within this region of the ribosome. When aminoglycosides bind
to the decoding site, a conformational change decreases discrimination
between cognate and near-cognate tRNAs, leading to errors
in the decoding process. The ability of aminoglycosides to
bind to the decoding site and induce translational misreading
in eukaryotic cells is less efficient than in prokaryotic
cells due to subtle differences in the sequence of the decoding
site rRNA. The observation that aminoglycosides induce low
levels of misreading in eukaryotic cells has inspired many
investigations to determine whether aminoglycosides can suppress
nonsense mutations that cause human diseases. Disease models
in which aminoglycosides have been shown to efficiently suppress
nonsense mutations include cystic fibrosis, Duchenne muscular
dystrophy, Hurler syndrome, infantile neuronal lipfuscinosis,
cystinosis, x-linked nephrogenic insipidus, spinal muscular
atrophy, and cancer. However, if aminoglycosides are to be
used clinically for suppression therapy, their efficacy must
be improved and their toxicity reduced. The co-administration
of other compounds that reduce aminoglycoside toxicity or
the development of new compounds that suppress stop mutations
may allow the realization of suppression therapy as a clinical
treatment to suppress disease-causing stop mutations.
[Back to top]
Hypertensive Pharmacogenomics in African Americans
Arlene Chapman, Frieda Millhouse-Jones, Janice Lea, Frederic
Rahbari and Evelyn Baranco-Pryor
Hypertension affects 60 million Americans and is the most
common disorder for which medications are prescribed in the
USA. Hypertension associates with serious complications including
stroke, heart failure, ischemic heart disease, and renal failure.
Racial background associates with the prevalence and complications
of hypertension with African Americans more frequently and
severely affected. Hypertensive African Americans demonstrate
different responses to antihypertensive medications compared
to other ethnic groups and specific candidate gene polymorphisms
associate with the responses found.
Differences between African Americans and other racial groups
are present with regard to endothelial dysfunction and activation
of the renin-angiotensin-aldosterone system. In addition the
frequency of polymorphisms of genes involved in the regulation
of endothelial function and the renin-angiotensin-aldosterone
system differ between African Americans and other ethnic groups.
This review highlights the current information available with
regard to the genetics of hypertension in African Americans
with particular attention to pharmocogenomic studies of antihypertensive
therapy.
[Back to top]
Genomics and Proteomics of Nucleoside Transporters
German Reyes and Imogen R. Coe
Nucleoside transporters are a group of poorly understood
membrane proteins involved in the movement of nucleoside and
many nucleoside analogs across cell membranes. Nucleoside
analog drugs are used routinely in various types of chemotherapy.
These drugs have been widely used for many years with good
results. However, variability in patient response and both
de novo and acquired resistance continue to be major obstacles
in effective chemotherapy. In combination with the development
of new nucleoside analog drugs, a concerted effort is underway
to improve our understanding of the genomics and proteomics
of nucleoside transporters in order to identify the factors
that influence individual patient responses. Here, we describe
recent important contributions to our understanding of the
genomics and proteomics of this group of proteins with reference
to drug bioavailability. In addition, we discuss future approaches,
which will provide further insights into nucleoside transporters
structure and function.
[Back to top]
DNA Microarray-Based Gene Expression Profiling in
Cancer: Aiding Cancer Diagnosis, Assessing Prognosis and Predicting
Response to Therapy
Michael J. Duffya,b, Zoë D. Kellyc, Aedín
C. Culhaned, Sallyann L. O’Briena and William M. Gallagherc
A DNA microarray is a solid support such as a glass slide,
silicon chip or nylon membrane on which DNA molecules are
attached at precise locations. Using DNA microarrays, the
expression of tens of thousands of genes in a biological sample
can be detected in one experiment. Emerging data suggests
that the use of DNA microarrays can aid the differentiation
of tumors with similar morphological appearance, predict patient
outcome independently of conventional prognostic factors and
select for response or resistance to specific anti-cancer
therapies. DNA microarray technology thus has the potential
to supplement standard diagnostic procedures in oncology and
permit a more individualized approach to patient management.
Prior to clinical application, however, this methodology must
be simplified, standardized, evaluated in external quality
assessment schemes and made available at relatively low costs.
Most importantly, the preliminary, but promising, early findings
must be validated by high-level evidence studies, such as
large prospective randomized trials or meta-analyses.
[Back to top]
A Candidate Pathway Strategy for Integration of Pharmacogenomic
Components of Variability in Antipsychotic Treatment Outcomes:
A Focus on Aripiprazole
Christopher Reist, Lawrence J. Albers, Stephen R. Marder,
Bryn Williams-Jones, Joseph C. Wu, Steven Mee, Kazutaka Shimoda,
Toshiyuki Someya and Vural Ozdemir
Aripiprazole is the first atypical antipsychotic introduced
to medical practice with partial dopamine-serotonin agonist
properties. Other new molecular entities such as bifeprunox,
a partial agonist at the dopamine D2 and serotonin 5-HT1A
receptors, are currently being evaluated in early stage drug
development as potential antipsychotic agents. As a partial
agonist, whether aripiprazole displays an agonist effect or
attenuates dopaminergic neurotransmission may depend on regional
variations in endogenous dopamine tone. Hence, aripiprazole
offers a therapeutic advantage to differentially modulate
dopaminergic activity in brain regions in a graded fashion.
This mechanism of action is intriguing when considered in
the context of the dopamine hypothesis of schizophrenia whereby
positive symptoms (e.g. hallucinations and delusions) are
associated with increased mesolimbic dopaminergic activity
while reduced activity in mesocortical dopaminergic pathways
underlies negative symptoms (e.g. avolition and anhedonia)
and cognitive deficits. Despite its therapeutic promise, antipsychotic
response to aripiprazole is highly variable, and some patients
do not respond at all to drug therapy. Treatment-emergent
adverse events associated with aripiprazole include insomnia,
anxiety, akathisia or worsening of psychosis in some patients.
These observations suggest that the underlying mechanism of
action of aripiprazole in psychotic disorders is more complex
than what would be anticipated solely by simple partial agonist
effects at the dopamine D2 receptor. For example, while aripiprazole
attenuates dopaminergic hyperactivity it does not increase
locomotor activity in reserpinized (hypodopaminergic) rats,
which is not fully consistent with a partial agonist mode
of action.
Aripiprazole can induce a diverse range of effects at dopamine
D2 receptors (agonism, antagonism, partial agonism) depending
on the cellular milieu defined by promiscuous interactions
with a host of signaling partners and variability in local
G protein complement and concentration. This diversity provides
an opportunity to illustrate the importance of integrating
data on genetic variation in pharmacokinetic pathways and
molecular targets for antipsychotics including biogenic amine
receptors and their downstream signaling partners. Theragnostics,
a new subspecialty of molecular medicine formed by combination
of therapeutics with diagnostics, offers the potential to
synthesize different types of biomarkers (DNA and protein-based)
in the context of antipsychotic treatment outcomes. Because
the dopamine receptor genetic variation is extensively reviewed
elsewhere, we discuss the pharmacogenomic significance of
variability in genes encoding for the 5-HT1A (HTR1A)
and 5-HT2A (HTR2A) receptors
and CYP2D6- and CYP3A4-mediated aripiprazole metabolism. As
the field moves toward predictive genetic testing for newer
antipsychotics, we emphasize the need for collaboration among
pharmacogeneticists, bioethicists and specialists in science
and technology studies.
[Back to top]
Identifying Biomarkers of Lung Cancer in the Post-Genomic
Era
Jingwu Xie
In the last two decades, we have witnessed an exponential
growth of our knowledge on cell growth and neoplastic transformation
at the molecular level. There is high expectation that these
advances will be translated into further improvement in the
care of cancer patients, especially in the areas of diagnosis,
prognosis and treatment. With the completion of the human
genome project and numerous studies on gene expression analyses
in lung cancer, our challenge is to understand the tumor morphological
changes at the molecular level, which will ultimately lead
to novel approaches for patient care. This review will summarize
methods for identifying biomarkers of lung cancer and molecular/genetic
changes that have been investigated as candidate diagnostic,
prognostic and predictive markers for lung cancer. A more
concerted and global approach to study the clinical relevance
of molecular changes in lung cancers is required in the future.
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