| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 9, Number 9, November 2009
Contents
Imaging Agents for Apoptosis
Guest Editor: Wenbin Zeng
Editorial Pp.
943
Apoptosis Imaging: Anti-Cancer Agents in Medicinal Chemistry
Pp. 944-951
F.G. Blankenberg
[Abstract] [Purchase
Article] [PMID:
20225999 PubMed - indexed for MEDLINE]
Apoptosis and Apoptosis-Based Therapy in Lung Cancer
Pp. 952-957
C.-X. Xu, H. Jin and M.-H. Cho
[Abstract] [Purchase
Article] [PMID:
19663788 PubMed - indexed for MEDLINE]
Translational Imaging of Apoptosis Pp. 958-967
G. Smith, Q.-D. Nguyen and E.O. Aboagye
[Abstract] [Purchase
Article] [PMID:
19663785 PubMed - indexed for MEDLINE]
Molecular Imaging of Apoptosis In Vivo with
Scintigraphic and Optical Biomarkers – A Status Report
Pp. 968-985
A. Faust, S. Hermann, S. Wagner, G. Haufe, O. Schober,
M. Schäfers and K. Kopka
[Abstract] [Purchase
Article] [PMID:
19663786 PubMed - indexed for MEDLINE]
Development of Small Molecular Probes for the Molecular
Imaging of Apoptosis Pp. 986-995
W. Zeng and W. Miao
[Abstract] [Purchase
Article] [PMID:
19663780 PubMed - indexed for MEDLINE]
Progress in Imaging Agents of Cell Apoptosis
Pp. 996-1002
R.F. Wang
[Abstract] [Purchase
Article] [PMID:
19663781 PubMed - indexed for MEDLINE]
Molecular Imaging of Apoptosis with Radio-Labeled
Annexin A5 Focused on the Evaluation of Tumor Response to
Chemotherapy Pp. 1003-1011
Y. Kuge, S. Zhao, T. Takei and N. Tamaki
[Abstract] [Purchase
Article] [PMID:
19663783 PubMed - indexed for MEDLINE]
Reduced Nicotinamide Adenine Dinucleotide (NADH) Fluorescence
for the Detection of Cell Death Pp. 1012-1017
H.-W. Wang, Y.-H. Wei and H.-W. GuoIn Vivo Apoptosis Imaging
Agents and Strategies M. Zhao
[Abstract] [Purchase
Article] [PMID:
19663784 PubMed - indexed for MEDLINE]
In Vivo Apoptosis Imaging Agents and Strategies
Pp. 1018-1023
M. Zhao
[Abstract] [Purchase
Article] [PMID:
19663782 PubMed - indexed for MEDLINE]
General Article
Regulation and Importance of the PI3K/Akt/mTOR Signaling
Pathway in Hematologic Malignancies Pp. 1024-1038
K. Kawauchi, T. Ogasawara, M. Yasuyama, K. Otsuka and
O. Yamada
[Abstract] [Purchase
Article] [PMID:
19663778 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial
A number of evidences indicate apoptosis plays an
important role in the pathogenesis, etiology, cancers and
numerous medical disorders. Molecular imaging of apoptosis
may therefore be very useful in clinical practice, assisting
in diagnosis, staging and monitoring of disease, monitoring
of the course of disease, or assessment of efficacy of the
treatment.
Several review articles, including the journal papers and
books, published within last few years provide good illustration
how broad these efforts made [1-7]. However, there are increasing
interests and demands for the development of non-invasive
imaging methodologies and strategies for the quantification
of apoptosis. To quantitatively assess apoptosis would facilitate
pre-clinical and clinical evaluation of novel diagnosis and
therapeutics. In this regards, to design, evaluate and develop
a biomarker for imaging apoptosis with corresponding molecular
imaging modality will be of great challenges. Despite both
the diagnosis and treatment of varied diseases benefiting
from imaging of apoptosis, most new drugs are thought to induce
apoptotic tumor cells or their supportive vasculatures. Therefore,
imaging agents that can noninvasively monitor apoptosis in
response to these new drugs could help streamline the drug
development process.
The opening paper of this issue by Dr. Blankenberg discusses
about the existing imaging agents and modalities that are
currently undergoing clinical testing and those that could
be rapidly translated into humans. Dr. Cho and coauthors describe
the apoptosis mechanisms and altered apoptosis regulators
expression and gene mutation in lung cancer. Next three papers
discuss the key aspects on the development of probes for molecular
imaging of apoptosis. Dr. Aboagye and coauthors summarize
the development of new apoptosis detecting probes that have
the potential for bridging different stages of the evaluation
process. Dr. Faust and coauthors describe recent progresses
in tracer development for the molecular imaging techniques
PET, SPECT and optical imaging and highlight the discussion
of breakthroughs, drawbacks and methodological issues of apoptosis
imaging. Dr. Zeng and coauthor concentrate the recent advance
of small molecular based probes for detecting apoptosis. Followed
by two papers are dealing with imaging apoptosis with Annexin
V and its application in preclinical and clinical research.
Dr. Wang RF provides the progresses on the studies with Annexin
V on preclinical and clinical application in nuclear medicine.
Dr. Yuji and coauthors are considering the apoptosis imaging
with annexin A5 radio-probes, focusing on its application
to the evaluation of the tumor response to chemotherapy. Dr.
Wang HW and coauthors provide the updated information in cell
death detection using the NADH/FAD fluorescence spectroscopy
and imaging based on measurement of the intensity or lifetime
of NADH or FAD fluorescence. The last paper of this issue
by Dr. Zhao brings tremendous progress which has been made
in applying the concept of apoptosis imaging toward diagnostic
needs.
I believe that this issue will successfully introduce the
readers to exciting and challenging area of apoptosis imaging.
REFERENCES
[1] Blankenberg, F.G.; Katsikis, P.D.; Tait, J.F.; Davis,
R.E.; Naumovski, L.; Ohtsuki, K.; Kopiwoda, S.; Abrams, M.J.;
Strauss, H.W. Imaging of apoptosis (programmed cell death)
with 99mTc annexin V. J. Nucl. Med., 1999,
40, 184-194.
[2] Blankenberg, F.G. In vivo detection of apoptosis.
J. Nucl. Med., 2008, 49,
81S-95S.
[3] Hakumaeki, J. M.; Liimatainen, T. Molecular imaging of
apoptosis in cancer. Eur. J. Radiol., 2005,
56, 143-153.
[4] Bauer, C.; Bauder-Wuest, U.; Mier, W.; Haberkorn, U.;
Eisenhut, M. 131I-Labeled peptides as caspase substrates for
apoptosis imaging. J. Nucl. Med., 2005,
46, 1066-1074.
[5] Tait, J. F. Imaging of apoptosis. J. Nucl. Med.,
2008, 49, 1573-1576.
[6] Lahorte, C.M.M.; Vandertheyden, J.L.; Steinmetz, N.; van
de Wiele, C.; Dierckx, R. A.; Slegers, G. Apoptosis-detecting
radioligands: current state of the art and future perspectives.
Eur. J. Nucl. Med. Mol. Imaging, 2004,
31, 887-919.
[7] Boersma, H.H.; Kietselaer, B.L.; Stolk, L.M.; Bennaghmouch,
A.; Hofstra, L.; Narula, J.; Heidendal, G. A.; Reutelingsperger,
C. P. Past, present, and future of annexin A5: from protein
discovery to clinical applications. J. Nucl. Med.,
2005, 46, 2035-2050.
Wenbin Zeng
Guest Editor
Anti-Cancer Agents in Medicinal Chemistry
School of Pharmaceutical Sciences
Central South University
Changsha, Hunan 410013
China
[Back to top]
[Purchase
Article] [PMID:
20225999 PubMed - indexed for MEDLINE]
Apoptosis Imaging: Anti-Cancer Agents in Medicinal Chemistry
F.G. Blankenberg
There is a rapid expansion in the number of new anti-cancer
drugs with remarkably different mechanisms of action that
can augment traditional chemotherapy. As these agents are
often used in combination with traditional chemotherapy testing
the effects of these novel agents has proven difficult requiring
large sample sizes to detect relatively small differences
in patient survival. Despite the wide variety of mechanisms,
most new drugs are thought to ultimately induce apoptosis
of tumor cells or their supportive vasculature. Imaging agents
that can non-invasively monitor apoptosis in response to these
new drugs could therefore help streamline the drug development
process. They may also help guide oncologists to identify
those patients that could best benefit from a given therapeutic
regimen, dose, or duration of drug. In this article we will
outline the existing imaging agents and modalities that are
currently undergoing clinical testing and those that could
be rapidly translated into humans.
[Back to top] [Purchase
Article] [PMID:
19663788 PubMed - indexed for MEDLINE]
Apoptosis and Apoptosis-Based Therapy in Lung Cancer
C.-X. Xu, H. Jin and M.-H. Cho
Apoptosis is natural process in the development and maintenance
of multicellular organisms. However, tumor cells often have
faulty apoptotic pathways. The defects of apoptosis are partially
caused by mutation and aberrant expression of apoptotic proteins.
The apoptosis inactivation is implicated with both tumorigenesis
and drug resistance. In addition, as compared to small-cell
lung cancers, non-small cell lung cancers are less sensitive
to radiation treatment or chemotherapy. Therefore, understanding
the mechanisms of apoptosis induction in lung cancer cells
is very important for anti-lung cancer drug development and
lung cancer therapy. In this review, we discussed about the
apoptosis mechanisms and altered apoptosis regulators expression
and gene mutation in lung cancer.
[Back to top] [Purchase
Article] [PMID:
19663785 PubMed - indexed for MEDLINE]
Translational Imaging of Apoptosis
G. Smith, Q.-D. Nguyen and E.O. Aboagye
Deregulated apoptosis is involved in several diseases including
myocardial infarction, ischemia and neurodegenerative disorders,
which are characterized by excessive apoptosis. In contrast,
resistance to apoptosis is defined as one of the hallmarks
of cancer. It therefore follows that strategies that enable
the quantitative detection of apoptosis modulation in
vivo would be of enormous benefit in the clinic for diagnosis
and patient management (evaluation of response to treatment).
In addition, such strategies could be used to evaluate the
efficacy of novel therapeutics along their development process.
During the development of novel therapeutics it would be necessary
to evaluate drug efficacy in vitro and then in experimental
animal models and, ultimately, in clinical trials. Currently
there is no one single probe that is suitable for imaging
apoptosis at every stage of evaluation, necessitating a switch
between probe types during the development process. This has
key implications for the quality and reproducibility of the
data obtained. The present review summarizes the development
of new apoptosis detecting probes that have the potential
for bridging different stages of the evaluation process such
that accurate, translational apoptosis imaging data are obtained.
[Back to top] [Purchase
Article]
[PMID:
19663786 PubMed - indexed for MEDLINE]
Molecular Imaging of Apoptosis In Vivo with
Scintigraphic and Optical Biomarkers – A Status Report
A. Faust, S. Hermann, S. Wagner, G. Haufe, O. Schober,
M. Schäfers and K. Kopka
The balance between proliferation and programmed cell death
– apoptosis – is essential for multicellular organisms
which use apoptosis to regulate and maintain the number and
type of their cells during embryogenesis, growth and homeostasis.
Increased cell proliferation or enhanced cell loss can be
caused by dysregulated apoptosis and are observed in various
diseases: in clinical scenarios such as neurodegenerative
disorders, myocardial infarction and stroke the rate of apoptosis
is upregulated compared to the physiological situation, while
in clinical scenarios such as cancer or autoimmune diseases
which are connected with pathological proliferation, apoptosis
is often downregulated. Therefore, non-invasive imaging of
apoptosis is of great clinical interest as patients would
clearly benefit from the diagnosis of cell loss post infarction
or from monitoring apoptosis triggered by chemotherapy or
radiation therapy of tumours. Several biochemical transformations
occur in apoptotic cells offering different biological targets
for the development of specific molecular biomarkers of apoptosis.
Key steps that occur during apoptosis have already been evaluated;
among these are the externalisation of phospholipid phosphatidylserine
to the outer leaflet of the cell membrane, which can be visualized
by labeled annexin A5 and the activation of caspases, especially
effector caspase-3, which can be addressed by labeled enzyme
substrates or synthetic caspase inhibitors. Here, recent advances
in tracer development for the molecular imaging techniques
PET, SPECT and optical imaging are presented, the discussion
of breakthroughs is involved, drawbacks and methodological
issues of apoptosis imaging are highlighted.
[Back to top] [Purchase
Article] [PMID:
19663780 PubMed - indexed for MEDLINE]
Development of Small Molecular Probes for the Molecular
Imaging of Apoptosis
W. Zeng and W. Miao
Apoptosis, or programmed cell death, is an important physiologic
process multicellular organisms use to maintain homeostasis
by providing a means for elimination of redundant cells during
development. Furthermore, cells that have become damaged or
are defective undergo apoptosis to prevent disease. It is
an important process involved in the etiology, pathogenesis,
and response to therapy of a variety of diseases. Specific
biochemical changes occur in cell or tissue undergoing apoptosis
that offer potential targets for imaging tracers. There are
a number of tracers that can be used to identify apoptotic
cells, including morphological changes, caspase activation,
and DNA fragmentation. In this article, the recent progresses
of small molecular based probes for detecting apoptotic cells
are reviewed. In addition, the traditional and modern imaging
technologies which use to visualize these probes is also discussed.
[Back to top] [Purchase
Article] [PMID:
19663781 PubMed - indexed for MEDLINE]
Progress in Imaging Agents of Cell Apoptosis
R.F. Wang
The methods of imaging in vivo can depict biological
processes at the molecular level. Cell apoptotic imaging belongs
to be one of these novel imaging methods. The detection and
quantification of apoptosis in vivo are of significant
clinical value for diagnosis and assessment of therapeutic
efficacy. Here, we focus on discussing the development of
apoptosis imaging agents and in vivo studies that
have emerged so far, along with their possible applications
in nuclear medicine.
[Back to top] [Purchase
Article]
[PMID:
19663783 PubMed - indexed for MEDLINE]
Molecular Imaging of Apoptosis with Radio-Labeled
Annexin A5 Focused on the Evaluation of Tumor Response to
Chemotherapy
Y. Kuge, S. Zhao, T. Takei and N. Tamaki
Apoptosis, or programmed cell death, is activated in the course
of successful anti-neoplastic therapy. Determining baseline
levels of apoptosis and the increment of apoptosis induced
by therapy can serve as useful prognostic markers. Thus, non-invasive
assessment of apoptosis would be desirable to provide clinicians
with information on therapeutic efficacy as well as for the
development and testing of new anticancer drugs. In these
regards, apoptosis detecting radio-probes (radiopharmaceuticals)
have been extensively studied. Annexin A5 (annexin V) is an
endogenous protein that binds with high affinity and specificity
to phosphatidylserine, which is presented on the cell surface
in an early process of apoptosis. Accordingly, apoptotic cells
can be detected in vivo using annexin A5 labeled
with radionuclides, such as 99mTc
and 18F. To date, several
annexin A5 radio-probes have been developed. Among these,
99mTc-HYNIC-annexin A5 is
the best candidate for apoptosis imaging. The apoptosis imaging
using radio-labeled annexin A5 has been applied for detecting
apoptosis in vivo in the experimental and clinical
evaluation of the tumor response to chemotherapy or radiotherapy.
The present review describes apoptosis imaging with annexin
A5 radio-probes, focusing on its application to the evaluation
of the tumor response to chemotherapy. First, principles of
apoptosis imaging with annexin A5 radio-probes are described.
Next, experimental results with radio-labeled annexin A5 in
the evaluation of therapeutic efficacy are discussed. Finally,
clinical application of apoptosis imaging with radio-labeled
annexin A5 is addressed.
[Back to top] [Purchase
Article] [PMID:
19663784 PubMed - indexed for MEDLINE]
Reduced Nicotinamide Adenine Dinucleotide (NADH) Fluorescence
for the Detection of Cell Death
H.-W. Wang, Y.-H. Wei and H.-W. GuoIn Vivo Apoptosis Imaging
Agents and Strategies M. Zhao
NADH/FAD fluorescence spectroscopy/imaging is an extremely
useful tool to probe cellular metabolism and has been applied
in the clinic such as early cancer detection. Recently, the
potential of using NADH/FAD fluorescence as a biomarker to
detect cell death has been investigated for development of
cancer treatments with higher efficacy. This review aims to
provide the updated information in cell death detection using
the NADH/FAD fluorescence spectroscopy and imaging based on
measurement of the intensity or lifetime of NADH or FAD fluorescence.
The response of NADH fluorescence lifetime to metabolic perturbation,
hypoxic environment, and anaerobic glycolysis (e.g., in precancerous
tissues and stem cells) is also reviewed to discuss the nature
and implications of the lifetime change of NADH fluorescence.
Further studies are required to understand the actual site
and mechanism of NADH binding of a specific death pathway
for future successful in vivo detection of cell death
using the NADH fluorescence lifetime.
[Back to top]
[Purchase
Article] [PMID:
19663782 PubMed - indexed for MEDLINE]
In Vivo Apoptosis Imaging Agents and Strategies
M. Zhao
The noninvasive detection of apoptosis, or programmed cell
death, is an important biomarker for the severity/progression
of diseases and the efficacy of anticancer therapies. In the
past decade a rapid expansion in the number of apoptosis imaging
agents and techniques offers an increasingly wide selection
of approaches for the assessment of apoptosis in vivo.
The goal of this review is to provide a general account of
existing and emerging apoptosis imaging techniques based on
their modes of actions; and to critically discuss the major
advantages and obstacles facing the field of apoptosis imaging.
In conclusion, tremendous progress has been made in applying
the concept of apoptosis imaging toward diagnostic needs.
However, for imaging strategies involving exogenous agents,
we must recognize the intrinsic distinction between probe
density and target density, and appreciate the complexity
of apoptosis imaging within the context of probe behaviors
in the target tissue. For non-pharmaceutical imaging strategies,
there is a continued drive to improve the specificity and
applicability of these endogenous markers. Overall, what remains
to be addressed, and is critical to clinical translation,
is the non-invasive quantification, in addition to detection,
of apoptosis in vivo.
[Back to top]
[Purchase
Article] [PMID:
19663778 PubMed - indexed for MEDLINE]
Regulation and Importance of the PI3K/Akt/mTOR Signaling
Pathway in Hematologic Malignancies
K. Kawauchi, T. Ogasawara, M. Yasuyama, K. Otsuka and
O. Yamada
Phosphatidylinositol 3-kinase (PI3K), a heterodimeric
lipid kinase, is a key enzyme in signal transduction from
various stimuli to downstream pathways that elicit diverse
responses involving growth, proliferation, survival, differentiation,
and metabolism in many cellular systems. Activated PI3K generates
phosphatidylinositol-3,4,5-triphosphate, which recruits phosphatidylinositol-dependent
kinase 1 (PDK1) and Akt serine/threonine kinase at the plasma
membrane, resulting in activation of Akt. In turn, Akt activates
multiple down-stream targets, most notably the mTOR pathway.
There is abundant evidence implicating the PI3K/Akt/mTOR pathway
in the development and progression of a variety of tumors
including hematologic neoplasms. Therefore, this pathway is
considered a critical target for cancer therapy. We review
the regulatory mechanisms of the PI3K/Akt/mTOR signaling pathway
and the role of this pathway in oncogenesis of hematological
malignancies.
|
