| Current
Pharmacogenomics
ISSN: 1570-1603
Current Pharmacogenomics
Volume 5, Number 3, September 2007
Contents
Using Pharmacogenomic Tumor Profiling to Identify
Biomarkers of 5-fluorouracil Response in Colorectal Cancer
Pp. 167-177
P.M. De Angelis
[Abstract]
Pharmacogenomics of Nicotine Dependence and Impact
on Smoking Cessation Pp. 178-189
E.C. Johnstone and M.F.G. Murphy
[Abstract]
Application of Pharmacogenomics to Dietary Cancer
Chemoprevention Pp. 190-200
A. Prawan, T.O. Khor, W. Li and A.-N.T. Kong
[Abstract]
Analysis of the Molecular Determinants of the Response
of Chronic Myelogenous Leukaemia to Tyrosine Kinase Inhibitors
Pp. 201-213
H. Labussière, S. Hayette and F.E. Nicolini
[Abstract]
Pharmacogenomics of Osteoporosis Pp. 214-227
J.L. Hernández and J.A. Riancho
[Abstract]
Pharmacogenomics of Non-Small Cell Lung Cancer
Pp. 228-234
J. Spicer, A. Futreal and J. De Bono
[Abstract]
Pharmacogenetics of Therapy in Inflammatory Bowel
Disease Patients Pp. 235-247
J.L. Mendoza, R. Lana, M. Díaz-Rubio, E.G. de la
Concha and E. Urcelay
[Abstract]
Abstracts
[Back to top]
Using Pharmacogenomic Tumor Profiling to Identify Biomarkers
of 5-fluorouracil Response in Colorectal Cancer
P.M. De Angelis
The chemotherapeutic agent 5-fluorouracil (5-FU) remains
the drug of choice for the treatment of metastatic colorectal
cancer, despite the fact that poor patient response to the
drug due to acquired or inherent drug resistance is a major
clinical problem. To be able to predict an individual patient’s
response to 5-FU would facilitate the design of chemotherapeutic
regimens tailored according to the individual patient and
tumor profile. Pharmacogenomic studies provide information
as to how variability on a genome-wide scale influences drug
response, and are facilitated by high throughput technologies
such as genomic and expression microarrays and single nucleotide
polymorphism (SNP) assays. Not surprisingly, such investigations
are taking the place of genetic studies that investigate associations
between drug response and genetic alterations for one individual
gene. This reflects the growing awareness that cancer drug
response is multi-faceted. The cellular mechanisms underlying
drug resistance can involve alterations at the single gene
and/or genomic level on multiple biological regulatory pathways,
e.g., cell cycle progression, apoptotic, and DNA repair pathways.
This review will provide an update on how pharmacogenomic
studies are being used to dissect the cellular mechanisms
underlying drug response and drug resistance in colorectal
cancer in order to identify novel biomarkers of 5-FU response,
and how knowledge gained from transcriptional profiling studies
of colorectal tumors is serving as a guide for optimization
of current chemotherapeutic strategies and for design of new
treatment strategies.
[Back to top]
Pharmacogenomics of Nicotine Dependence and Impact
on Smoking Cessation
E.C. Johnstone and M.F.G. Murphy
Pharmacogenomic research into smoking behaviour and smoking
cessation holds promise for understanding why people smoke
and how we can better help people to quit. As smoking prevalence
declines in the United States and Western Europe through social
and clinical action, average level of tobacco and nicotine
dependence amongst smokers may increase. The place of the
pharmacogenomic contribution to understanding residual dependence
and how to further lower smoking prevalence may increasingly
come to the fore. This review examines the influence of genetic
variation on smoking initiation, progression to dependence,
and persistent regular smoking (including amount smoked) as
well as response to smoking cessation pharmacotherapies. Although
research is still at an early stage, a future in which individualised
treatment is tailored to genotype now seems possible. However,
there are substantial practical, ethical, and social considerations
that must be addressed before such research can be translated
into clinical practice.
[Back to top]
Application of Pharmacogenomics to Dietary Cancer
Chemoprevention
A. Prawan, T.O. Khor, W. Li and A.-N.T. Kong
Many lines of evidence demonstrate that certain dietary phytochemicals
have cancer chemopreventive effects. These dietary phytochemicals
or chemo-preventive agents can suppress or block carcinogenesis
by (1) enhancing the bio-transformation enzymatic activities
for efficient elimination of carcinogens or reactive oxidative
or nitrosative species (ROS/RNS); (2) suppressing the growth/inflammatory
signaling pathways involved in cancer cell proliferation;
and (3) modulating phase II detoxifying/antioxidant enzymes,
e.g. glutathione S-transferases (GST), NAD(P)H-quinone reductase
1 (NQO1), UDP-glucuronosyltransferases (UGT), and antioxidant
enzymes such as gamma-glutamylcysteine synthetase (γ-GCS)
and heme oxygenase 1 (HO1). Comparison of gene expression
profiles among Nrf2 wild type and Nrf2 knock-out mice showed
that these genes are induced in an Nrf2-dependent manner in
response to phytochemical treatments. The potential roles
of different types of polymorphisms or pharmacogenetics in
carcinogenesis and prevention/treatment of some of these genes
will be described in this review. Finally, the potential usage
of these dietary compounds in combination with conventional
cancer chemotherapy will also be considered. The applications
of pharmacogenomics to dietary cancer chemopreventive studies
will be essential for understanding the cancer protective
mechanisms and could lead to individualized drug therapies
in the future.
[Back to top]
Analysis of the Molecular Determinants of the Response
of Chronic Myelogenous Leukaemia to Tyrosine Kinase Inhibitors
H. Labussière, S. Hayette and F.E. Nicolini
The treatment of Chronic Myelogenous Leukaemia (CML) has been
revolutionized by the introduction of Tyrosine Kinase Inhibitors
(TKIs) and represents a new paradigm for the treatment of
cancer. Imatinib Mesylate (IM) specifically targets limited
numbers of tyrosine kinases (BCR-ABL, PDGFRα,
PDGFRβ,
C-ABL, c-fms and c-Kit), which explains its specific anti-tumoural
efficacy and limited toxicity. In CML, the pivotal phase III
trial has demonstrated the high superiority of IM for progression-free
survival among interferon-α
+ cytarabine. Despite this remarkable success, >90% of
the patients show long-term persistence of limited numbers
of malignant cells in their body raising the intriguing question
of the persistence of BCR-ABL+
leukaemic stem cells serving as a reservoir for the disease.
In addition, and maybe as a consequence, growing numbers of
patients escape from IM-disease control and progressively
or brutally relapse. Considerable progress has been made in
understanding the mechanisms responsible for CML resistance
to IM, and the onset of BCR-ABL oncogene point mutations
remains the most frequent and investigated event in this setting.
More than 50 mutations have been described in patients’
samples to date, which have a major impact on disease behavior
and on the management of disease control. Interestingly, the
prognosis seems quite different according to the type of mutations
identified, and moreover particular mutations are more frequent
in advanced phases of CML where their identification represents
a marker of progression. Second generation TKIs have reached
the level of clinical trials, and it is likely that they would
overcome the majority of BCR-ABL mutation-induced resistances.
However, some patients harbouring BCR-ABL mutations do not
respond to these new compounds either, suggesting the onset
of other molecular mechanisms involved in the resistance of
the disease to TKIs. The aim of this review is to summarize
the knowledge accumulated recently on the impact of BCR-ABL
mutations in the sensitivity/resistance of CML to TKIs.
[Back to top]
Pharmacogenomics of Osteoporosis
J.L. Hernández and J.A. Riancho
Osteoporosis is a prevalent disease, particularly among postmenopausal
women, characterized by low bone mass and increased skeletal
fragility. It is a complex disease resulting from the interaction
of hereditary and environmental factors. Many investigators
have studied the genetic influence on bone mass. Although
the results have been controversial and not reproduced consistently,
some genes appear to be likely candidates, including those
related to estrogen metabolism and activity. According to
their effects on bone remodeling, anti-osteoporotic drugs
can be classified as anticatabolic (estrogens, selective estrogen
receptor modulators, bisphosphonates, calcitonin, vitamin
D, calcium) or anabolic (parathyroid hormone and derivatives).
These drugs increase bone mineral density and may reduce fracture
rate. There are few data about the influence of the individual
genetic characteristics on the response to anti-osteoporotic
drug therapy. Nevertheless, a number of studies suggest that
some polymorphisms of estrogen and vitamin D receptors may
be associated with differences in the changes of bone mineral
density induced by anticatabolic agents. However, there is
a clear need of further investigations before genetic data
can be used in clinical practice to individualize drug use
in the prevention and treatment of osteoporosis.
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Pharmacogenomics of Non-Small Cell Lung Cancer
J. Spicer, A. Futreal and J. De Bono
Despite the availabilty of active chemotherapy combinations
and novel targeted agents, the prognosis in advanced non-small
cell cancer (NSCLC) remains poor. Similarly, although the
efficacy of adjuvant chemotherpy has recently been established,
the risk of disease recurrence after surgery for early stage
disease remains high. Some patients enjoy sustained benefit
from currently available drugs, but overall results in unselected
patient groups are modest. This marked inter-patient variation
reflects the molecular heterogeneity of NSCLC, a heterogeneity
which is increasingly understood to arise at the level of
the cancer genome. The wide range of somatic genetic and epigenetic
events that drive the lung cancer phenotype is now beginning
to inform the selection of patients for treatment with both
cytotoxic and targeted therapies. Furthermore, it is becoming
apparent that germline genomic variability may also need to
be taken into account in making treatment decisions for NSCLC
patients.
[Back to top]
Pharmacogenetics of Therapy in Inflammatory Bowel
Disease Patients
J.L. Mendoza, R. Lana, M. Díaz-Rubio, E.G. de la
Concha and E. Urcelay
Recent expansion of pharmacotherapy of inflammatory bowel
diseases (IBD) reflects an increasing understanding of the
mechanisms involved in its pathogenesis. Individual variation
in response to drugs is a major problem in clinical practice
and is associated with various host factors, including sex,
age, diet, alcohol consumption, smoking habits and genetic
background. The study of the genetic determinants influencing
interindividual differences in drug responses is known as
pharmacogenetics. A common disease as IBD may be caused by
different groups of genes in different people, showing smaller
genetic variation than IBD patients globally considered. The
classification of individuals based on sets of susceptibility
alleles will make treatment more predictable and effective.
Pharmacogenetics in IBD is developing in two main directions.
One involves the identification and design of novel drug targets
by exploiting current knowledge of the structure and function
of IBD susceptibility genes. Another thrust of IBD pharmacogenetic
research is directed at understanding how genetic variation
determines the response to and the side effects of existing
therapeutic agents. Pharmacogenetics holds the promise that
drugs might one day be adapted to each person’s own
genetic background and therefore be more efficacious and safe.
Therapies of future should put emphasis on the epidemiological,
molecular and genetic basis of disease with the application
to clinical practice, underscoring the final goal of personalized
medicine.
In this review, we focused on the basis of pharmacogenetics,
on the recent advances of the field in the main therapies
involved in IBD (Azathioprine / 6-Mercaptopurine, 5-Aminosalicylates,
Glucocorticoids, Methotrexate, Infliximab) and speculate on
the future of pharmacogenetics.
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