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Current Pharmacogenomics & Personalized
Medicine
ISSN: 1875-6913 (Online)
ISSN: 1875-6921 (Print)
Current Pharmacogenomics
& Personalized Medicine
Volume 6, Number 2, June 2008
Contents
Feature Article
Pharmacogenomics: Don’t Forget the Children
Pp. 77-84
Y. Joly, G. Sillon, T. Silverstein, M. Krajinovic
and D. Avard
[Abstract]
Expert Reviews
Therapy Related Markers and Response Prediction Towards Multimodal
Treatment of Carcinomas of the Upper Gastrointestinal Tract
Pp. 85-97
G. Keller, R. Langer and H. Höfler
[Abstract]
Pharmacogenomics and Sepsis-Induced Renal Failure:
Effects of β2-Adrenoceptor
Function on the Course of Sepsis pp. 98-107
A. Nakamura and Y. Yanagawa
[Abstract]
Personalized Medicine, Bioethics and Social Responsibilities:
Re-thinking the Pharmaceutical Industry -to Remedy Inequities
in Patient Care and International Health Pp. 108-120
C. Olivier, B. Williams-Jones, B. Godard, B.
Mikalson and V. Ozdemir
[Abstract]
Pharmacogenomics of Open-Angle Glaucoma
Pp. 121-125
S.G. Schwartz, J.A. Ayala-Haedo, K.S. Kishor
and M.E. Fini
[Abstract]
Effect of Brain-Derived Neurotrophic Factor (BDNF)
Gene Variants on the Therapeutic Response and the Risk for
Mood Disorders Pp. 126-133
S.-J. Tsai and C.-J. Hong
[Abstract]
Pharmacogenomics of Human Multidrug Resistance
Associated Proteins Pp. 134-149
S.-F. Zhou and J. Fulcher
[Abstract]
Abstracts
[Back to top]
Pharmacogenomics: Don’t Forget the Children
Y. Joly, G. Sillon, T. Silverstein, M. Krajinovic
and D. Avard
Does the inclusion of children in pharmacogenomic research
raise new ethical issues? Through an exploration of the relevant
laws, policies, guidelines and literature, we have identified
five areas of concern and assessed their potential impact.
These include (1) the difficulty of assessing risk and the
ethics of invasive sampling, (2) the consent and assent process,
(3) the circumstances under which and to whom the results
of trials should be returned, (4) the effect of pharmacogenomics
on identifying and treating orphan groups, and (5) the effect
of pharmacogenomics on the pediatric drug approval process
and patient recruitment. We conclude that while including
pharmacogenomics in research projects involving children does
indeed raise ethical concerns, none of these are insurmountable,
and in fact, pharmacogenomics provides a promising outlook
for the development of research that will benefit children.
[Back to top]
Therapy Related Markers and Response Prediction Towards Multimodal
Treatment of Carcinomas of the Upper Gastrointestinal Tract
G. Keller, R. Langer and H. Höfler
Adenocarcinomas of the upper gastrointestinal tract are
characterized by a high mortality rate. Various multimodal
therapy regimens are used to improve the patient`s prognosis,
but the majority of patients does not respond to treatment.
Thus, the identification of biomarkers that could predict
response is highly demanding. The chemotherapeutic regimens
most commonly used for the treatment of adenocarcinomas of
the upper gastrointestinal tract are mainly based on 5-fluorouracil
(5FU), cisplatin and taxan derivates. Molecular markers related
to the efficiency of these components have been analyzed in
various studies. One example is thymidylate synthase
(TS) the major target of 5FU. Expression of TS in
tumors of the upper gastrointestinal tract has been found
to correlate with the outcome of the patient in some studies,
but the results are inconsistent. Polymorphisms in the promotor
region of the gene have been reported, which influence the
expression of the protein and a correlation of the genoytpes
with patient`s survival has been demonstrated. Markers related
to the efficiency of cisplatin, encompass the DNA-repair genes.
One example is the nucleotide excisison repair gene ERCC1,
for which gene expression in upper gastrointestinal tumors
as well as polymorphisms in the gene have been analyzed in
relation to the patient`s outcome. Genome wide screening methods,
as cDNA-microarrays or differential qualitative and quantitative
protein expression analysis recently have been reported to
give promising results for the pretherapeutic discrimination
of therapy responders and nonresponders. In this review we
will summarize the current state on genetic alterations in
upper gastrointestinal malignancies and on the role of polymorphisms
and their implications for response prediction, with a focus
on parameters in therapy related genes in the group of patients
treated in the neoadjuvant setting.
[Back to top]
Pharmacogenomics and Sepsis-Induced Renal Failure:
Effects of β2-Adrenoceptor
Function on the Course of Sepsis
A. Nakamura and Y. Yanagawa
Endotoxemia caused by Gram-negative bacteria can result
in sepsis and organ dysfunction, which includes kidney damage
and renal failure. Genetic polymorphisms in cytokine-encoding
genes contribute to individual variance in inflammatory responses
and have been postulated as being associated with an increased
risk for cytokine-mediated disorders, such as sepsis-induced
acute renal failure. There is a growing body of evidence that
the β2-adrenoceptor
(β2-AR)
system has an anti-inflammatory influence on the cytokine
network during the course of immunological responses. Indeed,
activation of β2-ARs
can modulate the production of pro- and anti-inflammatory
cytokines, such as TNF-α
and interleukin(IL)-1, -6, -10, -12, in some tissues and organs.
An altered expression or function of β2-ARs
has been considered to be a pathogenetic factor in some inflammatory
states; for example, allergy, heart failure and renal failure.
Previously, we demonstrated that the application of adenoviral
mediated β2-AR
gene delivery to enhance renal β2-AR
activity afforded the kidney protection against endotoxin-induced
acute renal failure. These observations would suggest the
possibility that the level of
β2-AR activity
might be associated with β2-AR
polymorphisms which may pre-determine the increased risk of
organ dysfunction following severe sepsis. At present it seems
that β2-AR
polymorphisms do not play a role as sepsiscausing genes; however,
they might be risk factors, might modify sepsis, and/or might
influence the progression of sepsis. Thus, genomic information
on β2-AR
polymorphisms has a potential use to identify groups of patients
with a raised risk of developing severe sepsis and multiple
organ dysfunctions.
[Back to top]
Personalized Medicine, Bioethics and Social Responsibilities:
Re-thinking the Pharmaceutical Industry to Remedy Inequities
in Patient Care and International Health
C. Olivier, B. Williams-Jones, B. Godard, B.
Mikalson and V. Ozdemir
US Senator Barack Obama recently proposed the Genomics
and Personalized Medicine Act of 2006, which should it
be enacted, would establish a Genomics and Personalized Medicine
Interagency Working Group to coordinate personalized medicine
efforts, fund genomics research to improve drug safety and
establish a US Biobanking Research Initiative similar to efforts
deployed in other countries. But what impact could personalized
medicine have on the drug development process, the pharmaceutical
industry and international health, including that in developing
countries? Can personalized medicines support innovation,
sustainability and growth in the pharmaceutical industry and
also respond to changing world realities, emerging public
demands for safer and more efficacious medicines and equitable
access to pharmaceuticals? The present paper examines these
socio-ethical and science policy questions by first elucidating
their intrinsic and often complex interactions with other
economic and policy issues (and the often divergent interests
of stakeholders). We then present some examples from other
industries (e.g., the case of hybrid cars and attendant growth
of consumer interest and confidence in high quality sustainable
products), with a view to identifying the factors that might
contribute to a successful integration of pharmacogenomics
and related biomarker technologies in patient care, international
health and public policy. In particular, we propose ways to
integrate the concept of sustainability into corporate and
investor models of pharmaceutical industry development. While
the power of pharmacogenomics to serve as a driver for the
pharmaceutical industry remains to be evaluated, we submit
that biomedical innovation and economic prosperity can co-exist
with ethical drug development and the sustainable commercialization
of customized drug therapies.
[Back to top]
Pharmacogenomics of Open-Angle Glaucoma
S.G. Schwartz, J.A. Ayala-Haedo, K.S. Kishor
and M.E. Fini
Pharmacogenomics is an evolving research discipline within
ophthalmology. An early application appears to involve open-angle
glaucoma, a common cause of worldwide preventable blindness.
Primary open-angle glaucoma is primarily treated with medications,
and the two most common classes of drugs are β-adrenergic
receptor antagonists and prostaglandin analogs. One small
clinical trial has documented a pharmacogenomic relationship
between polymorphisms in the β1-adrenergic
receptor with the selective β1-antagonist
betaxolol. A second small clinical trial has documented a
pharmacogenomic relationship between polymorphisms in the
prostaglandin F2α
receptor and the prostaglandin analog latanoprost. A small
pilot study has not found any significant pharmacogenomic
relationship between polymorphisms in the glucocorticoid receptor
and intraocular pressure elevation following treatment with
intravitreal triamcinolone acetonide. Pharmacogenomics may
explain some of the well-documented variability in response
to common glaucoma medications.
[Back to top]
Effect of Brain-Derived Neurotrophic Factor (BDNF)
Gene Variants on the Therapeutic Response and the Risk for
Mood Disorders
S.-J. Tsai and C.-J. Hong
Mood disorders, such as major depressive disorder and
bipolar disorder, are common, severe and chronic psychiatric
diseases. There is an increasing recognition that the pathophysiology
of mood disorders could be the result of dysregulation of
synaptic plasticity with alterations in the levels of neurotrophins.
Brain-derived neurotrophic factor (BDNF), the most abundant
neurotrophin in the brain, has been investigated extensively
in mood disorder. BDNF is important for neuronal growth, development,
differentiation and survival. In addition, BDNF can modulate
synaptic plasticity and its molecular mediators across multiple
neurotransmitter systems, as well as the intracellular signal-transduction
pathway. From findings in animal as well as clinical studies,
the BDNF gene is considered an attractive candidate for predicting
mood disorders or antidepressant/mood stabilizer therapeutic
response. In this review, we summarize the findings of recent
investigations of the effects of the BDNF gene on therapeutic
response and the risk for mood disorders. Although the general
conclusion to be drawn from the findings of these genetic
studies, is that BDNF genetic variants have implications for
the pathogenesis and treatment of mood disorders, the findings
of these studies are sometimes inconsistent. Several recommendations
are proposed for future genetic studies of BDNF signaling
pathways in mood disorders.
[Back to top]
Pharmacogenomics of Human Multidrug Resistance Associated
Proteins
S.-F. Zhou and J. Fulcher
Inter-individual variations in response to pharmacotherapy
such as adverse effects, treatment resistance and toxicities
affect all patient populations. Multidrug resistance associated
proteins (MRPs) work as efflux pumps for many xenobiotics
and endogenous substances and hence, can affect the drug concentration
at the target site which governs therapeutic response. Genetic
polymorphisms of the MRPs can lead to an over- or under-expression
of these transporter proteins. These polymorphisms can therefore
play an integral role in drug disposition and therapeutic
outcomes via pharmacokinetic and pharmacodynamic
changes. These changes may cause drug-drug interactions, treatment
resistance and/or toxicity. Overexpression of certain MRPs
is thought to correlate with multidrug resistance in pharmacotherapy,
especially with anticancer drugs. It is also evident that
some genetic variants linked with MRP genes can lead
to disease states such as pseudoxanthoma elasticum. With further
research, more definitive functional characterization of MRPs
and the understanding of this relationship with genetic polymorphisms
can be achieved. This article highlights the genetic polymorphisms
of MRPs and their clinical implications with an emphasis on
MRP1-4. It also provides an insight into the role that these
proteins can play in disease states and toxicities as well
as the implications for future research and patient management.
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