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Current Pharmacogenomics & Personalized
Medicine
ISSN: 1875-6913 (Online)
ISSN: 1875-6921 (Print)
Current Pharmacogenomics
& Personalized Medicine
Volume 6, Number 1, March 2008
Contents
Personalized Medicine: Pharmacogenetics in Psychiatry
Pp. 1-11
J.W.J. Hinrichs and J.van der Weide
[Abstract]
Pharmacogenetics in Laboratory Diagnostics
Pp. 12-22
H.-G. Klein and B. Busse
[Abstract]
Novel Applications of the Paired-End diTag (PET)
Technology in Pharmacogenomics Pp. 23-32
K.P. Chiu
[Abstract]
Role of Monitoring Thiopurine Methyltransferase
(TPMT) Activity in the Individualized Therapy with Azathioprine
or 6-Mercaptopurine Pp. 33-44
J.P. Gisbert
[Abstract]
Genomics and Pharmacogenomics in the Management
of Breast Cancer Pp. 45-55
J. Pascoe, D.H. Palmer, D. Spooner, D.W. Rea and S.A.
Hussain
[Abstract]
Genetic Polymorphisms in Relation to Immunosuppressive
Drug Pharmacokinetics in Organ Transplantation: Current Knowledge
and Perspectives Pp. 56-62
M. Mourad, P. Wallemacq, J. Lerut, M. De Meyer, J. Malaise,
D. Chaib Eddour, O. Ciccarelli, D. Lison and V. Haufroid
[Abstract]
Pharmacogenomics and the Treatment of Sporadic
Alzheimer's Disease: A Decade of Progress Pp. 63-76
J. Poirier and S. Gauthier
[Abstract]
Abstracts
[Back to top]
Personalized Medicine: Pharmacogenetics in Psychiatry
J.W.J. Hinrichs and J.van der Weide
Pharmacogenetics has made its entrance in psychiatry
since the discovery of the first polymorphism directly correlated
to individual variability in Cytochrome P450 (CYP) metabolism.
Currently, most of the major drug-metabolizing CYP enzymes,
their specific CYP-drug relationships and many of their gene
variants are known. This has led to the development of elegant
models predicting individualized dose recommendations. This
has however not yet resulted in a widespread implementation
of CYP genotyping in daily practice, mainly due to
unfamiliarity and lack of prospective data. Recently it has
been shown that therapeutic drug monitoring with additional
CYP genotyping improved the treatment with antidepressants
of patients in the general practice setting. Considerable
effort has been put into developing a FDA approved DNA microarray,
identifying multiple clinical relevant CYP polymorphisms
at once. This could pave the way for a wide implementation
of pharmacogenetic testing in the clinical environment. Individual
variability in drug response is not explained by variation
of drug metabolism alone. Polymorphisms in neurotransmitter-receptor
genes are gaining more interest since they are at the end
of the line in determining psychotropic drug effects. Several
studies have already shown that the response of antipsychotic
drugs and antidepressants can be predicted by genotyping polymorphisms
in serotonin receptors and transporter genes. The increased
predictability of the different determinants in drug efficacy
brings us a step closer to personalized medicine in psychiatry.
[Back to top]
Pharmacogenetics in Laboratory Diagnostics
H.-G. Klein and B. Busse
Pharmacogenetics (PGt) is a fast evolving field in medical
science, since adverse drug reactions (ADR) and therapy failure
may be due to variations in the genes of drug metabolizing
enzymes, drug transporters and drug targets. There are many
different techniques available for the detection of mutations,
Single Nucleotide Polymorphisms (SNPs) and gene copy number
variations (CNVs) that allow the scientist to apply the best
suited method for defined diagnostic questions. This article
reviews some of the most important genes of pharmacogenetic
relevance, gives an overview of several methods frequently
used for genotyping and provides insight into routine pharmacogenetic
testing in the clinical laboratory.
[Back to top]
Novel Applications of the Paired-End diTag (PET) Technology
in Pharmacogenomics
K.P. Chiu
Genomics is becoming the integral part of Pharmacogenomics,
and the Paired-End diTag (PET) technology is creating a new
paradigm in Genomics. The PET technology directly links the
5’ terminal tags of cDNAs or genomic sequences with
their corresponding 3’ terminal tags to form PET ditags
and concatenates them for efficient sequencing. The GIS (Gene
Identification Signature)-PET analysis was developed for studying
transcriptomes and pathway aberrations. It can precisely demarcate
the alternative transcription start site (TSS) and the alternative
polyadenylation site (PAS). The paired-end nature makes the
identification of fusion genes, fusion transcripts, and pseudogenes
very straightforward. Additionally, PET-associated genes can
be correlated to pathway database to systematically reveal
global pathway aberrations. Changes in metabolic and signal
transduction pathways can be compared across different cell
types. Later, the ChIP (Chromatin immunoprecipitation)-PET
analysis was developed. This approach facilitates genome-wide
mapping of transcription factor binding sites (TFBSs), as
shown in the studies of p53, c-Myc, estrogen receptor, Oct4/Nanog/Sox2,
STAT1, NFκB.
In addition, study of trimethylations of lysine4 and lysine27
in H3 histone protein demonstrated the capability of ChIP-PET
for genome-wide mapping of epigenetic modifications. Integration
of all these PET data would produce a comprehensive picture
of genetic and epigenetic cis-acting elements, gene expression
and regulation, and pathway activities; and data can be analyzed
and compared at molecular, gene, and pathway levels. This
article reviews the advancement of the PET technology and
discusses its potential applications in Pharmacogenomics.
[Back to top]
Role of Monitoring Thiopurine Methyltransferase (TPMT) Activity
in the Individualized Therapy with Azathioprine or 6-Mercaptopurine
J.P. Gisbert
Thiopurine drugs azathioprine and 6-mercaptopurine are
inactive compounds that must be metabolized to 6-thioguanine
nucleotides to exert their immunosuppressive properties. Hypoxanthine-guanine
phosphoribosyltransferase anabolizes 6-mercaptopurine into
the 6-thioguanine nucleotides responsible for the therapeutic
activity and drug-related leucopenia. On the other hand, thiopurine
methyltransferase (TPMT) metabolizes 6-mercaptopurine into
inactive methylmercaptopurine. Therefore, reduction in TPMT
activity predisposes to bone marrow suppression because of
preferential metabolism of 6-mercaptopurine to 6-thioguanine
nucleotides.
The choice of the dose of azathioprine/6-mercaptopurine is
generally based on the patient’s weight. However, several
strategies have been suggested in choosing, in a more individualized
and safer way, the thiopurine dose, with the intention, on
one hand, to identify patients at risk of myelotoxicity and,
on the other hand, to detect patients with inadequate immunosuppressant.
In this respect, quantification of TPMT activity has been
considered a promising area, as it may identify unique metabolic
profiles in patients at high risk for adverse reaction prior
to drug exposure.
The aim of the present manuscript is to review the following
aspects related with TPMT determination: 1) TPMT activity
distribution in general population. 2) Advantages and disadvantages
of TPMT genotype and phenotype determination. 3) Relationship
between TPMT activity and azathioprine induced myelotoxicity.
4) TPMT activity and immunosuppressive efficacy of azathioprine.
5) How can azathioprine dose be adjusted based on TPMT activity?
6) Is TPMT activity monitoring indicated in all patients who
are going to receive azathioprine? 7) Can systematic blood
controls be avoided in patients treated with azathioprine
if TPMT is determined?
[Back to top]
Genomics and Pharmacogenomics in the Management of Breast
Cancer
J. Pascoe, D.H. Palmer, D. Spooner, D.W. Rea and S.A.
Hussain
There are a number of effective treatments for breast
cancer in the neo-adjuvant, adjuvant and metastatic setting.
These comprise combinations of radiotherapy, chemotherapy,
hormonal treatments and targeted molecular therapies. However
the benefit that individual patients derive from these treatments
and the toxicity that they experience varies considerably.
Differences in cancer patient’s responses to therapy
can be associated with factors such as disease burden, drug
interactions, age, gender and nutritional status amongst others.
It is now also known that genetic variations in drug target
genes, disease pathway genes and drug metabolizing enzymes
can have important role and influence on the efficacy and
toxicity of a particular therapy. These genetic variations
may be due to variations in individual’s germ line DNA
or to somatic changes in the malignant cells. Understanding
the genetic profile of the patient and the tumour will help
to further refine therapies.
Pharmacogenomics can be used to predict response to treatments
that are known to have activity against breast cancer including
anthracyclines, cyclophosphamide, methotrexate, fluorouracil,
taxanes, tamoxifen, aromatase inhibitors and her-ceptin. The
reliability and reproducibility of techniques needs to be
validated in large randomized studies before they can be incorporated
into routine clinical practice. Thus pharmacogenomics will
help develop a profile to tailor therapies with minimal toxicity
and maximum efficacy based on molecular signatures. This review
discusses clinically relevant germ line mutations that can
be used to predict response and toxicity to the above treatments
as well as microarray based expression profile studies that
may yield important information about prognosis, indication
for treatment and response to treatment.
The completion of the human genome project and advances in
high through-put DNA sequencing and proteomic technology means
that there is a real opportunity for pharmacogenomic assessment
to become a clinically important part of the decision making
process in determining the optimum adjuvant treatment regimen
for patients with early stage breast cancer and aiding the
management of advanced breast cancer, allowing clinicians
to create an individual management plan for each breast cancer
patient based on pharmacogenomic data.
[Back to top]
Genetic Polymorphisms in Relation to Immunosuppressive Drug
Pharmacokinetics in Organ Transplantation: Current Knowledge
and Perspectives
M. Mourad, P. Wallemacq, J. Lerut, M. De Meyer, J. Malaise,
D. Chaib Eddour, O. Ciccarelli, D. Lison and V. Haufroid
The primary goal of immunosuppressive treatment after
organ transplantation is to optimize its benefit/risk ratio
in order to have the best combination of efficacy and tolerability.
Tacrolimus (Tc), Sir (SRL), cyclosporine (CsA) and mycophenolic
acid based drugs are characterized by a narrow therapeutic
index and broad interindividual variability in their pharmacokinetic
parameters. Their bioavailability is affected by a range of
factors including absorption, distribution, biotransformation
and elimination, resulting in considerable disparity in drug
safety and efficacy profiles. Therapeutic monitoring is becoming
a crucial component of routine practice to maintain time?dependent
target concentrations. Recently, special interest in polymorphisms
in genes encoding biotransformation enzymes and drug transporters
has opened promising new perspectives for the selection of
individual dosages. Several single nucleotide polymorphisms
(SNP) have been identified in both CYP3A4 and CYP3A5
as well as in UGT genes encoding metabolizing enzymes,
and in ABCB1 and ABCC2 genes encoding membranous
transporters. A particular SNP within intron 3 of the CYP3A5
gene has been shown to generate production of a truncated
protein associated with the CYP3A5*3
allele and expression of the active CYP3A5 enzyme
with its CYP3A5*1
allele. The functional significance of this SNP has been confirmed
with respect to Tc in the stable phase after kidney, liver,
heart and lung transplantation. The same effect is also seen
in the early phase after kidney transplantation, even following
initial administrations of the drug. The influence of the
CYP3A5 SNP in intron 3 is less marked in
case of CsA administration, and however, was recently demonstrated
for SRL disposition in some circumstances. Findings on the
contribution of ABCB1 SNPs to interindividual variability
in blood levels of immunosuppressive drugs remain contradictory.
Prospective studies are still needed to prove that a genetic
approach, in association with therapeutic drug monitoring,
may enhance efficacy and safety, both in the short and long
term after transplantation.
[Back to top]
Pharmacogenomics and the Treatment of Sporadic Alzheimer's
Disease: A Decade of Progress
J. Poirier and S. Gauthier
Several lines of evidence indicate that apolipoprotein
E (apoE) plays a central role in the brain’s response
to injury and neurodegeneration in the adult. The coordinated
expression of apoE and several of its accessory proteins appears
to regulate the transport and internalization of cholesterol
and phospholipids during development and normal brain reinnervation
in the adult. The discovery, a few years ago, that a genetic
variant in the apoE gene called apoE4 strongly links to both
sporadic and familial late onset Alzheimer's disease (AD)
has raised the possibility that a dysfunction of the lipid
transport system in the brain could be central to AD pathophysiology.
Pathophysiological evidence obtained in autopsy-confirmed
sporadic AD cases clearly indicate that the presence of apoE4
allele in humans directly compromises cholinergic function
in the adult brain and indirectly modulate the efficacy of
medications designed to enhance the cholinergic activity in
diseased brain. The apoE4 allele was found to significantly
increase the risk of progression to dementia for persons exhibiting
amnestic mild cognitive impairment (aMCI), a transitional
state between the cognitive changes associated with normal
aging and early AD. Furthermore, two accessory enzymes involved
in cholinergic neurotransmission called butyrylcholinesterase
and paraoxonase-1 were shown i) to display polymorphic variants
that increase the risk of developing AD and ii) to modulate
drug responsiveness in AD subjects exposed to cholinomimetic
agents. This article reviews the most critical findings in
this field and reassess the potent clinical value of pharmacogenomics
of neurodegenerative diseases and dementia.
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