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Current
Pharmaceutical Biotechnology
ISSN: 1389-2010
Current Pharmaceutical Biotechnology
Volume 12, Number 4, April 2011
Contents
Hot Topic
Molecular Imaging in Current Pharmaceuticals
Guest Editor: Ramasamy Paulmurugan
Editorial:
Pp. 458
Applications of Molecular Imaging in Drug Discovery
and Development Process Pp. 459-468
B.-C. Ahn
[Abstract] [Purchase
Article]
Stem Cells Therapies in Basic Science and Translational
Medicine: Current Status and Treatment Monitoring Strategies
Pp. 469-487
C. Banerjee
[Abstract] [Purchase
Article]
Non-Invasive Imaging of Ferucarbotran Labeled INS-1E
Cells and Rodent Islets in Vitro and in Transplanted
Diabetic Rats Pp. 488-496
V.J. Auer, J. Bucher, E. Schremmer-Danninger,
R. Paulmurugan, P. Maechler, M.F. Reiser, M.J. Stangl and
F. Berger
[Abstract] [Purchase
Article]
Advances in Imaging Gene-Directed Enzyme Prodrug Therapy
Pp. 497-507
S. Bhaumik
[Abstract] [Purchase
Article]
Imaging Cellular Receptors in Breast Cancers: An Overview
Pp. 508-527
T.V. Sekar, A. Dhanabalan and R. Paulmurugan
[Abstract] [Purchase
Article]
Molecular Targeting of Breast Cancer: Molecular Imaging
and Therapy Pp. 528-538
P. Padmanabhan, J. Goggi, R. Bejot and
K.K. Bhakoo
[Abstract] [Purchase
Article]
The Pivotal Role of Multimodality Reporter Sensors
in Drug Discovery: From Cell based Assays to Real Time Molecular
Imaging Pp. 539-546
P. Ray
[Abstract] [Purchase
Article]
Dual Energy CT for Monitoring Targeted Therapies in Patients
with Advanced Gastrointestinal Stromal Tumor: Initial Results
Pp. 547-557
N. Schramm, M. Schlemmer, E. Englhart, M. Hittinger,
C. Becker, M. Reiser and F. Berger
[Abstract] [Purchase
Article]
The New Era of Bioluminescence Resonance Energy Transfer
Technology Pp. 558-568
A. De
[Abstract] [Purchase
Article]
Hot Topic
ABC Transporters in Pharmacology/Physiology and Human Diseases
Guest Editor: Zhe-Sheng (Jason) Chen
Editorial:
Pp. 569
Revisiting the ABCs of Multidrug Resistance in Cancer
Chemotherapy Pp. 570-594
A.K. Tiwari, K. Sodani, C.-L. Dai, C.R. Ashby
Jr. and Z.-S. Chen
[Abstract] [Purchase
Article]
The Challenge of Exploiting ABCG2 in the Clinic
Pp. 595-608
R.W. Robey, C. Ierano, Z. Zhan and S.E.
Bates
[Abstract] [Purchase
Article]
Discovering Natural Product Modulators to Overcome
Multidrug Resistance in Cancer Chemotherapy Pp. 609-620
C.-P. Wu, S. Ohnuma and S.V. Ambudkar
[Abstract] [Purchase
Article]
Regulation of ABC Transporter Function Via
Phosphorylation by Protein Kinases Pp. 621-635
E.I. Stolarczyk, C.J. Reiling and C.M.
Paumi
[Abstract] [Purchase
Article]
ABC Transporters, Bile Acids, and Inflammatory Stress
in Liver Cancer Pp. 636-646
R. Wang, J.A. Sheps and V. Ling
[Abstract] [Purchase
Article]
The Role of ABCG2 and ABCB6 in Porphyrin Metabolism
and Cell Survival Pp. 647-655
P. Krishnamurthy and J.D. Schuetz
[Abstract] [Purchase
Article]
ABC Transporters in the CNS - An Inventory
Pp. 656-673
A.M.S. Hartz and B. Bauer
[Abstract] [Purchase
Article]
ATP-Binding Cassette Efflux Transporters in Human
Placenta Pp. 674-685
Z. Ni and Q. Mao
[Abstract] [Purchase
Article]
Advances in the Molecular Detection of ABC Transporters
Involved in Multidrug Resistance in Cancer Pp. 686-692
J.-P. Gillet and M.M. Gottesman
[Abstract] [Purchase
Article]
Pharmacogenomics of Human ABC Transporters: Detection
of Clinically Important SNPs by SmartAmp2 Method
Pp. 693-704
W. Aw, I. Ota, Y. Toyoda, A. Lezhava, Y. Sakai,
T. Gomi, Y. Hayashizaki and T. Ishikawa
[Abstract] [Purchase
Article]
Abstracts
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Applications of Molecular Imaging in Drug Discovery
and Development Process
B.-C. Ahn
The process of drug discovery and development requires enormous
resources and time, with increasing cost for new drug development.
Molecular imaging techniques have tremendous potential for
improving the efficiency of drug screening, assessing the
pharmacokinetics of new drugs, and evaluating drug effects.
Appropriate application of molecular imaging to drug discovery
and development can markedly reduce costs and the time required
for new drug development. This review focuses on the contributions
of molecular imaging for drug discovery and development, particularly
drug screening, pharmacokinetic, preclinical and clinical
drug evaluation, and for personalized and lesionalized medicine.
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Stem Cells Therapies in Basic Science and Translational
Medicine: Current Status and Treatment Monitoring Strategies
C. Banerjee
Stem-cell technology is a major area within cell therapy
that promises significant therapeutic outcome. The plasticity
and self-renewal capabilities of stem cells make them valuable
tools for potential application in regenerative medicine and
tissue replacement following injury or disease. Here, we discuss
the different types of stem cells currently used in research,
preclinical and early clinical development, their potential
therapeutic and diagnostic applications, and current barriers
to translating basic research into clinical therapies. Biomedical
imaging is increasingly being used to monitor the fate of
transplanted stem cells, including their survival, proliferation,
differentiation and homing to targeted organs and tissues.
We discuss different imaging modalities currently utilized
to track stem calls, the advantages and challenges, and future
implications in clinical applications.
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Article]
Non-Invasive Imaging of Ferucarbotran Labeled INS-1E
Cells and Rodent Islets in Vitro and in Transplanted
Diabetic Rats
V.J. Auer, J. Bucher, E. Schremmer-Danninger,
R. Paulmurugan, P. Maechler, M.F. Reiser, M.J. Stangl and
F. Berger
Transplantation of pancreatic islets is a promising
strategy for restoring insulin secretion in diabetes mellitus.
To monitor transplanted islets, a method to evaluate the distribution
in a non-invasive manner in vivo is needed. INS-1E,
a stable differentiated insulin secreting cell line, and rodent
islets were used to monitor cell transplantation by MRI. For
labeling INS-1E cells in vitro, increasing concentrations
of Resovist® in culture medium were tested. For MR imaging
in a clinical 3T scanner, we placed a layer of labeled INS-1E
cells between two layers of 4% gelatin. Viability assay was
performed. Cell function was evaluated by static incubation
assay to assess insulin secretion. For in vivo imaging,
iron labeled rodent islets were transplanted into the liver
of streptozotocin induced diabetic rats and visualized by
MRI. Blood sugar values were controlled and liver tissue was
removed for histological analysis. SPIO labeled INS-1E cells
did not show altered viability or reduced glucose stimulated
insulin secretion in vitro. Double staining of labeled
and unlabeled INS-1E cells showed no difference in the staining
pattern. Labeling of rodent islets with SPIOs does not reduce
their secretory activity or alter their viability. We visualized
SPIO-labeled INS-1E cells and rat islets in vitro
using a clinical 3T scanner. Diabetic rats transplanted with
SPIO-labeled islets became normoglycemic. MR imaging successfully
verified the distribution of labeled transplanted cells
in vivo. Labeling INS-1E cells and rat islets with SPIOs
does not alter their viability, while enabling MR imaging
of labeled cells in vitro and within the living organism.
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Article]
Advances in Imaging Gene-Directed Enzyme Prodrug Therapy
S. Bhaumik
Gene-directed enzyme prodrug therapy (GDEPT) is one of
the promising alternatives to conventional chemotherapy. Suicide
gene therapy based anticancer strategy involves selective
introduction of a foreign gene into tumor cells to produce
a foreign enzyme that can activate an inert prodrug to its
cytotoxic form and cause tumor cell death. In this review,
we present three most promising suicide gene/prodrug combinations
(1) herpes simplex virus thymidine kinase (HSV1-TK) with ganciclovir
(GCV), (2) cytosine deaminase (CD) from bacteria or yeast
with 5-fluorocytodine (5- FC) and (3) bacterial nitroreductase
(NTR) with 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954)
and discuss how molecular imaging may improve therapy strategies.
Current advances in noninvasive imaging technologies can measure
vector dose, tumor selectivity, transgene expression and biodistribution
of therapeutic gene with the aid of reporter genes and imageable
probes from live animal. In this review we will discuss various
imaging modalities - Optical, Magnetic Resonance Imaging (MRI),
Positron Emission Tomography (PET) and Single Photon Emission
Computed Tomography (SPECT), and highlight some of the approaches
that can advance prodrug cancer therapy from bench to clinic.
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Imaging Cellular Receptors in Breast Cancers: An Overview
T.V. Sekar, A. Dhanabalan and R. Paulmurugan
Breast cancer, a leading cause of cancer death in women,
is strongly correlated with the up- and downregulation of
hormone and growth factor receptors. Therefore, improving
our understanding of such receptor status in different stages
of breast cancer will help in the development of novel diagnostic
and therapeutic solutions. In particular, molecular imaging
technology in association with advanced molecular and cell
biology techniques could reveal in detail dynamic molecular
events in cells, allowing the study of crucial molecular pathological
changes occurring in cancer and other diseases. Molecular
imaging techniques such as PET, SPECT, MRI, and the combinatorial
techniques have made tremendous strides in elucidating the
role of cellular receptors, helping to monitor the course
of breast cancer development and the therapeutic efficacy
of novel drugs. Optical imaging of cellular receptors is emerging
as a powerful tool given the advancement of fluorescent and
bioluminescent proteins. Estrogen receptor, progesterone receptor,
and HER2/neu have been adopted clinically to detect different
types of breast cancer and to test novel treatment strategies;
however, other cellular receptors may also be involved in
breast cancer subtyping and could emerge as treatment prospects.
This review will focus on the recent developments of imaging
various cellular receptors pertaining to the growth and development
of breast cancer.
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Article]
Molecular Targeting of Breast Cancer: Molecular Imaging
and Therapy
P. Padmanabhan, J. Goggi, R. Bejot and
K.K. Bhakoo
Breast cancer is increasing at an alarming rate in women
around the world, where medical biology is confronted by this
disease on two crucial fronts. The first step is the early
accurate diagnosis, which is very critical and the second
step involves the appropriate clinical management. The current
trend in molecular imaging of breast cancer provides not only
an excellent tool in diagnosing the disease but also useful
in validating the potentiality of pharmaceutical interventions.
This review addresses the effectiveness of targeted imaging
technologies to resolve the molecular characterisation and
pathological evidences in breast cancer. The focus is on the
present practices in breast cancer imaging, specifically targeting
cellular machineries such as hormone receptors and angiogenic
factors.
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Article]
The Pivotal Role of Multimodality Reporter Sensors
in Drug Discovery: From Cell based Assays to Real Time Molecular
Imaging
P. Ray
Development and marketing of new drugs require stringent validation
that are expensive and time consuming. Non-invasive multimodality
molecular imaging using reporter genes holds great potential
to expedite these processes at reduced cost. New generations
of smarter molecular imaging strategies such as Split reporter,
Bioluminescence resonance energy transfer, Multimodality fusion
reporter technologies will further assist to streamline and
shorten the drug discovery and developmental process. This
review illustrates the importance and potential of molecular
imaging using multimodality reporter genes in drug development
at preclinical phases.
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Article]
Dual Energy CT for Monitoring Targeted Therapies in
Patients with Advanced Gastrointestinal Stromal Tumor: Initial
Results
N. Schramm, M. Schlemmer, E. Englhart, M. Hittinger,
C. Becker, M. Reiser and F. Berger
Purpose: Advanced gastrointestinal stromal
tumors (GISTs) are treated with tyrosine kinase inhibitors,
which also have antiangiogenic properties. Dual-energy CT
(DECT) allows to acquire semi-quantitative iodine images which
might correlate with blood pool and tumor vascularity. In
this feasibility-study, we correlated lesional iodine uptake
estimations in correlation to tumor size changes under targeted
therapy as first step in the evaluation of dedicated DECT
based strategies for monitoring molecular therapies in GIST.
Patients and Methods: 48 tumor lesions in
18 patients with metastasized histologically proven GIST under
tyrosine kinase inhibitor (TKI) therapy were analyzed. Patients
were examined with a dual-source CT in dual-energy mode (Voltage
tube A: 80 kV, tube B: 140 kV). Using the dual-energy software
virtual unenhanced, selective iodine (overlay) and mixed CT
numbers (similar to CT numbers at 120 kV) of lesions were
calculated. The largest diameter of each lesion on cross-sectional
axial images was measured. The mean difference of overlay
CT numbers in the baseline and follow-up examinations was
calculated and this marker of lesional iodine uptake was compared
to lesional size changes under molecular therapy.
Results: Utilizing the cut-off value 15 HU
of change in overlay, DECT allowed to identify lesions with
a stable, increased or decreased lesional iodine uptake with
corresponding typical lesion size change patterns after 3
months of targeted therapy: 30 lesions had no significant
change of overlay CT numbers (OL) (mean: -2.4 HU) or lesion
size (mean: +1.5%). A strong decline of the OL (mean: - 24
HU) in 13 lesions was combined with a pronounced growth (mean:
+ 26%). 5 lesions showed a strong increase of the absolute
OL (mean: + 23 HU) associated with a moderate increase in
size (+ 8%).
Conclusion: Determination of the overlay CT
number with DECT enables to stratify metastases with stable,
increasing or decreasing iodine uptake over time with –in
our collective- typical lesion size change patterns. Investigation
of a larger patient cohort, comparison to histology, alternate
imaging biomarkers and correlatrion to long-term response
will further clarify the significance of these findings for
monitoring targeted therapies in GIST.
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The New Era of Bioluminescence Resonance Energy Transfer
Technology
A. De
Bioluminescence resonance energy transfer (BRET) assay is
a comparatively new cell-based assay technology that is assuming
more prominent roles in the field of studying protein-protein
interactions, protein dimerization and signal transduction.
In the last few years BRET related research has gained significant
momentum in terms of adding versatility in the assay format
as well as a variety of new applications where it has been
suitably used. Beyond the scope of quantitative measurement
of protein-protein interactions and protein dimerization,
molecular imaging applications based on BRET assays have broaden
its scope as a great tool for high-throughput screening (HTS)
of pharmacologically important compounds. This article will
highlight the landmarks in BRET research, with those which
have significant contributions towards making it an attractive
single format assay that shuttles between in vitro
and in vivo measurements.
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Revisiting the ABCs of Multidrug Resistance in Cancer
Chemotherapy
A.K. Tiwari, K. Sodani, C.-L. Dai, C.R. Ashby
Jr. and Z.-S. Chen
The adenosine triphosphate binding cassette (ABC) transporters
are one of the largest transmembrane gene families in humans.
The ABC transporters are present in a number of tissues, providing
protection against xenobiotics and certain endogenous molecules.
Unfortunately, their presence produces suboptimal chemotherapeutic
outcomes in cancer patient tumor cells. It is well established
that they actively efflux antineoplastic agents from cancer
cells, producing the multidrug resistance (MDR) phenotype.
The inadequate response to chemotherapy and subsequent poor
prognosis in cancer patients can be in part the result of
the overexpression of ABC transporters. In fact, one of the
targeted approaches for overcoming MDR in cancer cells is
that directed towards blocking or inhibiting ABC transporters.
Indeed, for almost three decades, research has been conducted
to overcome MDR through pharmacological inhibition of ABC
transporters with limited clinical success. Therefore, contemporary
strategies to identify or to synthesize selective "resensitizers"
of ABC transporters with limited nonspecific toxicity have
been undertaken. Innovative approaches en route to
understanding specific biochemical roles of ABC transporters
in MDR and tumorigenesis will prove essential to direct our
knowledge towards more effective targeted therapies. This
review briefly discusses the current knowledge regarding the
clinical involvement of ABC transporters in MDR to antineoplastic
drugs and highlights approaches undertaken so far to overcome
ABC transporter-mediated MDR in cancer.
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The Challenge of Exploiting ABCG2 in the Clinic
R.W. Robey, C. Ierano, Z. Zhan and S.E.
Bates
ABCG2, or breast cancer resistance protein (BCRP), is
an ATP-binding cassette half-transporter that has been shown
to transport a wide range of substrates including chemotherapeutics,
antivirals, antibiotics and flavonoids. Given its wide range
of substrates, much work has been dedicated to developing
ABCG2 as a clinical target. But where can we intervene clinically
and how can we avoid the mistakes made in past clinical trials
targeting P-glycoprotein? This review will summarize the normal
tissue distribution, cancer tissue expression, substrates
and inhibitors of ABCG2, and highlight the challenges presented
in exploiting ABCG2 in the clinic. We discuss the possibility
of inhibiting ABCG2, so as to increase oral bioavailability
or increase drug penetration into sanctuary sites, especially
the central nervous system; and at the other end of the spectrum,
the possibility of improving ABCG2 function, in the case of
gout caused by a single nucleotide polymphism. Together, these
aspects of ABCG2/BCRP make the protein a target of continuing
interest for oncologists, biologists, and pharmacologists.
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Discovering Natural Product Modulators to Overcome
Multidrug Resistance in Cancer Chemotherapy
C.-P. Wu, S. Ohnuma and S.V. Ambudkar
Multidrug resistance caused by the overexpression of ABC drug
transporters is a major obstacle in clinical cancer chemotherapy.
For several years, it appeared that direct inhibition of ABC
transporters would be the cheapest and most efficient way
to combat this problem. Unfortunately, progress in finding
a potent, selective inhibitor to modulate ABC transporters
and restore drug sensitivity in multidrug-resistant cancer
cells has been slow and challenging. Candidate drugs should
ideally be selective, potent and relatively non-toxic. Many
researchers in recent years have turned their attention to
utilizing natural products as the building blocks for the
development of the next generation of inhibitors, especially
after the disappointing results obtained from inhibitors of
the first three generations at the clinical trial stage. The
first step is to discover natural substances (distinct from
the first three generation inhibitors) that are potent, selective
and relatively non-toxic in order to be used clinically. Here,
we present a brief overview of the prospect of using natural
products to modulate the function of ABC drug transporters
clinically and their impact on human physiology and pharmacology.
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Regulation of ABC Transporter Function Via
Phosphorylation by Protein Kinases
E.I. Stolarczyk, C.J. Reiling and C.M.
Paumi
ATP-binding cassette (ABC) transporters are multispanning
membrane proteins that utilize ATP to move a broad range of
substrates across cellular membranes. ABC transporters are
involved in a number of human disorders and diseases [1].
Overexpression of a subset of the transporters has been closely
linked to multidrug resistance in both bacteria and viruses
and in cancer. A poorly understood and important aspect of
ABC transporter biology is the role of phosphorylation as
a mechanism to regulate transporter function. In this review,
we summarize the current literature addressing the role of
phosphorylation in regulating ABC transporter function. A
comprehensive list of all the phosphorylation sites that have
been identified for the human ABC transporters is presented,
and we discuss the role of individual kinases in regulating
transporter function. We address the potential pitfalls and
difficulties associated with identifying phosphorylation sites
and the corresponding kinase(s), and we discuss novel techniques
that may circumvent these problems. We conclude by providing
a brief perspective on studying ABC transporter phosphorylation.
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ABC Transporters, Bile Acids, and Inflammatory Stress
in Liver Cancer
R. Wang, J.A. Sheps and V. Ling
The biliary secretion of bile acids is critical for
multiple liver functions including digesting fatty nutrients
and driving bile flow. When this process is impaired, accumulating
bile acids cause inflammatory liver injury. Multiple ABC transporters
in the liver are key players to safeguard the hepatocyte and
avoid toxicity due to bile acid over-accumulation. BSEP provides
for efficient secretion of bile acids across the canalicular
membrane against a steep concentration gradient. MDR3/Mdr2
and ABCG5/G8 secrete phosphatidylcholine and cholesterol,
respectively, in coordination with BSEPmediated bile acid
secretion to mask the detergent/toxic effects of bile acids
in the bile ductular space. Several lines of evidence indicate
that when these critical steps are compromised, bile acid
toxicity in vivo leads to inflammatory liver injury
and liver cancer. In bsep-/- mice, liver
cancer is rare. These mice display greatly increased expression
of alternative bile acid transporters, such as Mdr1a/1b, Mrp3
and Mrp4. We believe these alternative transport systems provide
an additional safeguard to avoid bile acid overload in liver.
Such backup systems appear to be under-utilized in humans,
as defects in BSEP and MDR3 lead to severe, often fatal childhood
diseases. It is possible, therefore, that targeting ABC transporters
and modulating the toxicity of the bile acid pool could be
vital interventions to alleviate chronic inflammation and
reduce the incidence of liver cancer in high-risk populations.
The combination of an alternative ABC transporter with a novel
substrate may prove an effective chemo-preventive or therapeutic
strategy.
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The Role of ABCG2 and ABCB6 in Porphyrin Metabolism
and Cell Survival
P. Krishnamurthy and J.D. Schuetz
The porphyrins (such as heme) are essential molecules
within cells and have multiple roles in essential cellular
processes such as: the mitochondrial electron transport chain,
free-radical detoxification, and metabolism. The porphyrins
need energy to traverse biological membranes. Our understanding
of ABC transporters role in regulating intracellular porphyrin
homeostasis is only now beginning to be understood. Two important
contributors are members of the ABC transporter gene family:
ABCB6 and ABCG2. ABCB6 is the first ABC transporter located
in the outer mitochondrial membrane and oriented to facilitate
porphyrin import. Consequently, ABCB6 can regulate and appropriately
orchestrate porphyrin synthesis. This leads to an ability
to regulate the amount of heme associated with heme requiring
proteins. This ability can facilitate a cells protective response
to an array of toxic insults. ABCG2 also binds and transports
porphyrins, however its location at the plasma membrane provides
a mechanism to remove excess porphyrins. Because ABCG2 is
upregulated by hypoxia this provides a mechanism to export
porphyrins, rebalance porphyrins and protect cells from porphyrin
overaccumulation. Such a mechanism would be important to hypoxic
cells which exhibit an increase in porphyrin synthesis under
hypoxic conditions. Finally, we propose that these two transporters
(ABCB6 and ABCG2) are coordinately regulated to modulate porphyrin
concentrations under normal physiological and pathological
conditions.
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ABC Transporters in the CNS - An Inventory
A.M.S. Hartz and B. Bauer
In the present review we provide a summary of ATP-binding
cassette (ABC) transporters in the central nervous system
(CNS). Our review is focused on transporters of the ABC A,
B, C, D, and G families that have been detected in the cells
of the neurovascular unit/blood-brain barrier including brain
capillary endothelial cells, pericytes, astrocytes, and neurons,
as well as in other brain cells, such as microglia, oligodendrocytes,
and choroid plexus epithelial cells. In this review, we provide
an overview, organized by ABC family, of transporter expression,
localization, and function. We summarize recent findings on
ABC transporter regulation in the CNS and address the role
of ABC transporters in CNS diseases including brain cancer,
seizures/epilepsy, and Alzheimer’s disease. Finally, we discuss
new therapeutic strategies focused on ABC transporters in
CNS disease.
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ATP-Binding Cassette Efflux Transporters in Human
Placenta
Z. Ni and Q. Mao
Pregnant women are often complicated with diseases including
viral or bacterial infections, epilepsy, hypertension, or
pregnancy-induced conditions such as depression and gestational
diabetes that require treatment with medication. In addition,
substance abuse during pregnancy remains a major public health
problem. Many drugs used by pregnant women are off label without
the necessary dose, efficacy, and safety data required for
rational dosing regimens of these drugs. Thus, a major concern
arising from the widespread use of drugs by pregnant women
is the transfer of drugs across the placental barrier, leading
to potential toxicity to the developing fetus. Knowledge regarding
the ATP-binding cassette (ABC) efflux transporters, which
play an important role in drug transfer across the placental
barrier, is absolutely critical for optimizing the therapeutic
strategy to treat the mother while protecting the fetus during
pregnancy. Such transporters include P-glycoprotein (P-gp,
gene symbol ABCB1), the breast cancer resistance
protein (BCRP, gene symbol ABCG2), and the multidrug
resistance proteins (MRPs, gene symbol ABCCs). In
this review, we summarize the current knowledge with respect
to developmental expression and regulation, membrane localization,
functional significance, and genetic polymorphisms of these
ABC transporters in the placenta and their relevance to fetal
drug exposure and toxicity.
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Advances in the Molecular Detection of ABC Transporters
Involved in Multidrug Resistance in Cancer
J.-P. Gillet and M.M. Gottesman
ATP-Binding Cassette (ABC) transporters are important mediators
of multidrug resistance (MDR) in patients with cancer. Although
their role in MDR has been extensively studied in vitro,
their value in predicting response to chemotherapy has yet
to be fully determined. Establishing a molecular diagnostic
assay dedicated to the quantitation of ABC transporter genes
is therefore critical to investigate their involvement in
clinical MDR. In this article, we provide an overview of the
methodologies that have been applied to analyze the mRNA expression
levels of ABC transporters, by describing the technology,
its pros and cons, and the experimental protocols that have
been followed. We also discuss recent studies performed in
our laboratory that assess the ability of the currently available
high-throughput gene expression profiling platforms to discriminate
between highly homologous genes. This work led to the conclusion
that high-throughput TaqMan-based qRT-PCR platforms provide
standardized clinical assays for the molecular detection of
ABC transporters and other families of highly homologous MDR-linked
genes encoding, for example, the uptake transporters (solute
carriers- SLCs) and the phase I and II metabolism enzymes.
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Pharmacogenomics of Human ABC Transporters: Detection
of Clinically Important SNPs by SmartAmp2 Method
W. Aw, I. Ota, Y. Toyoda, A. Lezhava, Y. Sakai,
T. Gomi, Y. Hayashizaki and T. Ishikawa
Genetic polymorphisms and mutations in drug metabolizing enzymes,
transporters, receptors, and other drug targets (e.g., toxicity
targets) are linked to inter-individual differences in the
efficacy and toxicity of many medications as well as risk
of genetic diseases. Validation of clinically important genetic
polymorphisms and the development of new technologies to rapidly
detect clinically important variants are critical issues for
advancing personalized medicine. A key requirement for the
advancing personalized medicine resides in the ability of
rapidly and conveniently testing patients’ genetic polymorphisms
and/or mutations. We have recently developed a rapid and cost-effective
method, named Smart Amplification Process 2 (SmartAmp2), which
enables us to detect genetic polymorphisms or mutations in
target genes within 30 to 45 min under isothermal conditions
without DNA isolation and PCR amplification. Detection of
mutations or single nucleotide polymorphisms (SNPs) in human
ABC transporter genes is becoming more important, since their
functional impairments are reportedly associated with inherited
diseases. Thus, certain genetic polymorphisms of ABC transporters
are considered important biomarkers for diagnosis of inherited
diseases and/or risk of drug-induced adverse reactions. In
this review article, we will present the new technology of
the SmartAmp2 method and its clinical applications for detection
of SNPs in human ABC transporter genes, i.e., ABCC4
and ABCC11.
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