|
Current
Pharmacogenomics
ISSN: 1570-1603
Current Pharmacogenomics
Volume 5, Number 4, December 2007
Contents
Renin--Angiotensin System Gene Polymorphism and
Regression of Left Ventricular Hypertrophy in Hypertension
Pp. 248-254
E.V. Shlyakhto and A.O. Conrady
[Abstract]
Prognostic and Predictive Markers in
Colorectal Cancer The Role of New Genomic Technologies
Pp. 255-261
V.M. Coyle, W.L. Allen, D.B. Longley and P.G. Johnston
[Abstract]
Genetic Polymorphisms of Human Sulfate Transporters
Pp. 262-274
P.A. Dawson and D. Markovich
[Abstract]
Tumour Necrosis Factor α
Gene Promoter and its Role in Rheumatoid Arthritis
Outcome and Pharmacogenetics Pp. 275-279
J.E. Fonseca, J. Teles and M.V. Queiroz
[Abstract]
Should the Status of the Pathway Mediated by BRCA1
and BRCA2 be Evaluated Before Selecting Cancer Chemotherapy
Drugs? Pp. 280-291
B. Friedenson
[Abstract]
The Flavin-Containing Monoooxygenases (FMOs): Genetic
Variation and its Consequences for the Metabolism of Therapeutic
Drugs Pp. 292-313
I.R. Phillips, A.A. Francois and E.A. Shephard
[Abstract]
Connexin Genes as Promising Therapeutic Targets
in Cancers Pp. 314-318
T. Yano, H. Sato, H. Hagiwara and N. Virgona
[Abstract]
Abstracts
[Back to top]
Renin--Angiotensin System Gene Polymorphism and Regression
of Left Ventricular Hypertrophy in Hypertension
E.V. Shlyakhto and A.O. Conrady
Evidence is beginning to accumulate that not only development
and progression of left ventricular hypertrophy (LVH) in hypertension
is genetically predisposed, but its regression during therapy
has several genetic determinants. Renin-angiotensin system
(RAS) is generally considered to be the major contributor
to LVH development. I/D polymorphism of angiotensin-converting
enzyme (ACE) gene was shown to determine plasma ACE concentrations
and LVH severity in hypertension. Several studies have also
documented association of angiotensin II type I receptor gene
(AT1R) polymorphism (A1166C) with LVH. Impact of angiotensinogen
(ATG) genetic polymorphisms (-6G/A or M235T) in LVH is not
so well established. Gene-gene interactions between these
genes are also described.
Since pharmacogenetic approach has been introduced to testing
of antihypertensive drug efficacy, the influence of RAS genetic
polymorphisms on LVH regression during treatment was also
analyzed in several studies. The data obtained no-wadays are
rather controversial. Large proportion of studies documented
lower LVH regression in patients carrying D allele (or DD
genotype) of ACE gene. C allele of AT1R gene is also shown
to influence LVH reversal during treatment. However, major
clinical studies concerning effects of different drugs on
hypertensive LVH did not include genetic investigations; the
existing data are obtained on rather small patient samples,
do not take into account gene-environmental interactions,
and need to be tested in larger trials.
[Back to top]
Prognostic and Predictive Markers in Colorectal Cancer –
The Role of New Genomic Technologies
V.M. Coyle, W.L. Allen, D.B. Longley and P.G. Johnston
Colorectal cancer (CRC) is one of the most frequently
occurring malignancies worldwide, and the second leading cause
of cancer related death in the Western World. Although early
stage disease is curable by surgical resection alone, one
half of patients with CRC will present with metastatic disease
at some stage in the course of their disease. The most active
drug in the treatment of CRC is 5-fluorouracil (5-FU) which
is used in both the adjuvant and advanced settings. The use
of adjuvant therapy is of proven benefit in Stage III CRC,
however, its role in Stage II disease is less clear. There
is therefore a need to identify those patients with early
stage disease who will develop recurrent disease, and who
would therefore benefit most from adjuvant treatment. In the
advanced setting, the use of irinotecan and oxaliplatin in
combination with 5-FU has proven beneficial, with yet further
improvements in survival reported with the addition of new
targeted agents such as bevacizumab. Despite this, a significant
number of patients with advanced disease do not derive any
benefit from the chemotherapy they receive, highlighting a
need for the development of molecular or genomic markers predictive
of response to these chemotherapeutic agents. This review
will evaluate the recent advances in pharmacogenomics in CRC,
in particular the development of predictive markers of response
to chemotherapy. The successful identification of these markers
of response will herald an era of personalised treatment,
reducing treatment-related toxicity and improving outcome
of patients with CRC.
[Back to top]
Genetic Polymorphisms of Human Sulfate Transporters
P.A. Dawson and D. Markovich
Sulfate (SO42-)
is an abundant nutrient in the blood and is essential for
normal growth and development. (SO42-
is conjugated (sulfonated) to many compounds in the body,
including glycosaminoglycans, steroid hormones and bile acids.
Sulfonation also plays an important role in the metabolism
of xenobiotics and certain drugs, such as acetaminophen. (SO42-
enters and exits cells via plasma membrane (SO42-
transporters. To date, ten human (SO42-
transporters belonging to the Solute Linked Carrier 13 (SLC13)
or 26 (SLC26) gene families have been identified. Clinical
interest has focused on two SLC26 (SO42-
transporters which are associated with recessive human disorders:
SLC26A2 is defective in four different chondrodysplasias (MED,
DTD, AO2 and ACG1B) and SLC26A3 is associated with congenital
chloride diarrhea (CLD). Ongoing studies are focused on the
physiological significance of the other eight (SO42-
transporters (SLC13A1, A4, and SLC26A1, A6, A7, A8, A9, A11),
yet to be characterized in human diseases. Our Slc13a1
null (Nas1-/-) mouse studies, have revealed
several pathophysiological features associated with this transporter:
hyposulfatemia, hypersulfaturia, reduced growth, seizures,
behavioural abnormalities, hypercholesterolemia, fatty liver,
reduced fertility and enhanced acetaminophen-induced hepatotoxicity.
These findings can be relevant to single nucleotide polymorphisms
(SNPs) in human SLC13A1, which lead to changes in
(SO42-
transport function. This paper summarises non-synonymous SNPs
(nsSNPs) found in the sulfate transporters SLC13A1, A4, and
SLC26A1, A6, A7, A8, A9, A11, with a special focus on SLC13A1,
which we have identified to be responsible for maintaining
blood (SO42-
concentrations.
[Back to top]
Tumour Necrosis Factor α
Gene Promoter and its Role in Rheumatoid Arthritis
Outcome and Pharmacogenetics
J.E. Fonseca, J. Teles and M.V. Queiroz
Rheumatoid arthritis (RA) is a chronic inflammatory disease
which affects approximately 1% of the world population. A
considerable effort has been put into understanding the genetic
factors associated with this complex disease. Sequencing of
the human genome has opened new prospects for the detection
of genetic variants associated with increased susceptibility,
poor prognosis and inadequate response to therapy. One of
the most promising candidate genes is TNFα,
not only due to its pivotal role in the inflammatory process,
but also because anti-TNFα
drugs have become the golden standard in RA therapy. Of particular
interest are the highly abundant single nucleotide polymorphisms
(SNPs), particularly when they occur in regulatory regions,
such as the promoter of the gene, upregulating or downregulating
the production of TNFα
by changing the affinity of transcription factors to their
binding sites. In this review, we address the influence exerted
by TNFα
gene promoter SNPs in RA, focusing particularly on their effect
on TNFα
production. Subsequently, we review the results of association
studies addressing the influence of these polymorphisms on
RA susceptibility, prognosis and response to therapy, with
special concern on specific anti-TNFα
drugs.
[Back to top]
Should the Status of the Pathway Mediated by BRCA1 and BRCA2
be Evaluated Before Selecting Cancer Chemotherapy Drugs?
B. Friedenson
This review brings together evidence to show that chemotherapy
agents that cause DNA double strand breaks have increased
success in treating model cancers with deficits in the pathway
containing BRCA1/2 proteins. In people who do not have BRCA1
or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian
cancer. However BRCA1 and BRCA2 proteins have multiple functions
including participating in a pathway that mediates error-free
repair of DNA double strand breaks. Inactivation of BRCA1,
BRCA2 or any other critical protein within this “BRCA
pathway” due to a gene mutation should inactivate this
error-free repair process. DNA fragments produced by double
strand breaks are then left to non-specific processes that
rejoin them without regard for preserving normal gene regulation
or function, so rearrangements and deletions of DNA segments
are more likely. This mechanism contributes to the gross chromosomal
rearrangements found in a large majority of human cancers.
In many cancers, gene rearrangements and deletions are believed
to be critical events so a compromised BRCA pathway increases
cancer risk in general. Mutation specifically of the BRCA1
or the BRCA2 gene increases risk as much as about 8 times
for subsets of numerous cancers including stomach, pancreas,
prostate, colon, etc. as reported in epidemiologic studies.
Moreover, inactivating virtually any gene within a model for
the BRCA pathway increases risk up to nearly 2000 fold for
a subset of leukemias and lymphomas that frequently contain
gene rearrangements.
In tumor cells, the status of the BRCA pathway may be important
during chemotherapy. Some chemotherapy agents cause chromosome
breaks as they destroy tumor cells but other types of chemotherapy
depend on different mechanisms. A damaged BRCA pathway may
make subgroups of tumors unable to correctly repair broken
chromosomes. Because normal error-free repairs are no longer
assured, sensitivity to chemotherapy drugs that cause DNA
double strand breaks should especially increase.
The end result specifying tumor resistance vs. tumor sensitivity
to chemotherapy is complicated and may be modified by additional
mechanisms. Nevertheless this review of the literature shows
that the status of the BRCA pathway is a broadly useful criterion
in selecting chemotherapy agents for model tumors derived
from a variety of different organs. These preclinical models
show real gains depending on the chemotherapy regimen selected.
If the models are appropriate predictors in cancer patients,
then identifying patients more likely to respond to a given
chemotherapy agent should minimize serious adverse effects
and prolong survival times.
[Back to top]
The Flavin-Containing Monoooxygenases (FMOs): Genetic Variation
and its Consequences for the Metabolism of Therapeutic Drugs
I.R. Phillips, A.A. Francois and E.A. Shephard
Flavin-containing monoooxygenases (FMOs) are a family
of enzymes involved in the metabolism of foreign chemicals,
including many therapeutic drugs. In this review we focus
on the functional FMOs of humans (FMOs 1, 2, 3, 4 and 5).
For each FMO we describe its gene organization, developmental-
and tissue-specific pattern of expression, substrate specificity
and the identity, frequency and functional effect of polymorphic
variants. We also review the consequences of genetic variation
in the FMOs for the metabolism of therapeutic drugs and the
implications of this for drug efficacy and response. Some
key points are: the majority of humans are homozygous for
an allele (FMO2*2) that encodes a truncated, non-functional
polypeptide, but a substantial proportion of individuals of
African descent possess a copy of the functional ancestral
(FMO2*1) allele and thus are predicted to respond differently
to drugs and other foreign chemicals that are substrates for
FMO2; FMO3 polymorphisms that decrease catalytic
activity have been linked to increased drug efficacy; rare
mutations in FMO3 are causative of the disorder trimethylaminuria;
and the role of FMO1 and FMO3 in the oxidation of the antiestrogen
tamoxifen and the antitubercular drug thiacetazone are discussed.
[Back to top]
Connexin Genes as Promising Therapeutic Targets in Cancers
T. Yano, H. Sato, H. Hagiwara and N. Virgona
Cellular homeostasis in many organs is maintained via
gap junctions composed of connexin (Cx), a large protein family
with a number of subtypes. In fact, gap junctional intercellular
communication (GJIC) is actively involved in all aspects of
the cellular life cycle, ranging from cell growth to cell
death. It has been well known that Cx genes act as tumor suppressor
genes in GJIC-dependent and GJIC-independent manners. Actually,
cancers have two different phenotypes on Cx expression and
localization in cells; one shows complete silencing of Cx
gene, other shows normal expression of Cx gene but disruption
of localization of Cx protein. The former has the down-regulation
of Cx functions as GJIC-dependent transformation, and the
latter has disruption of Cx localization as GJIC-independent
transformation. Thus, in order to restore Cx-dependent functions
in cancers and establish the new cancer therapy based on tumor-suppressive
effects of Cx gene, we should develop different procedures
on each cancer which has the two different phenotypes. In
this mini-review, we summarize the tumor-suppressive effects
of Cx genes and refer to a possibility of development of a
new cancer therapy based on the restoration of the tumor-suppressive
effects.
|
