| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 7, Number 3, May 2007
Contents
Imaging and Treatment of Oncological Diseases
Guest Editor: J.F.W. Nijsen
Editorial Pp. 269
The Bright Future of Radionuclides for Cancer
Therapy Pp. 271-290
J.F.W. Nijsen, G.C. Krijger and A.D. van het Schip
[Abstract]
MRI Contrast Agents: Current Status and Future
Perspectives Pp. 291-305
G.J. Strijkers, W.J.M. Mulder, G.A.F. van Tilborg and
K. Nicolay
[Abstract]
Contrast Agents in X-Ray Computed Tomography and Its
Applications in Oncology Pp. 307-316
A. Rutten and M. Prokop
[Abstract]
Factors Affecting the Sensitivity and Detection
Limits of MRI, CT, and SPECT for Multimodal Diagnostic and
Therapeutic Agents Pp. 317-334
P.R. Seevinck, J.-H. Seppenwoolde, T.C. de Wit, J.F.W.
Nijsen, F.J. Beekman, A.D. van het Schip and C.J.G. Bakker
[Abstract]
Radionuclide Therapy of Cancer with Radiolabeled Antibodies
Pp. 335-343
O.C. Boerman, M.J. Koppe, E.J. Postema, F.H. Corstens
and W.J. Oyen
[Abstract]
Radiolabelled Regulatory Peptides for Imaging and
Therapy Pp. 345-357
W.A.P. Breeman, D.J. Kwekkeboom, E. de Blois, M. de Jong,
T.J. Visser and E.P. Krenning
[Abstract]
General Articles
Targeting the Ubiquitin-Proteasome Pathway in Cancer Therapy
Pp. 359-365
Y. Ishii, S. Waxman and D. Germain
[Abstract]
Labeling Biomolecules with Radiorhenium - A Review
of the Bifunctional Chelators Pp. 367-377
G. Liu and D.J. Hnatowich
[Abstract]
Abstracts
Editorial
The rapid development of clinical diagnostic imaging technology,
in combination with medical and pharmaceutical research, has
led to important improvements in healthcare. Imaging of biologic
processes at cellular and molecular levels termed “molecular
imaging” is one of the most innovative examples. In
contradistinction to “conventional” diagnostic
imaging, it sets forth to probe abnormalities that are the
basis of diseases, rather than imaging advanced stage disease.
This will be of great importance for the detection of early
stages of malignant tumours. The development of highly sensitive
agents will result in early tumour detection, which is expected
to cause a substantial shift in healthcare procedures. Much
more emphasis will be placed on diagnosing and treating disease
before late symptoms occur, which demands a new category of
therapy strategies. Development of innovative drugs and carrier
systems is desired. Visualization of drug targeting and efficacy
with high-resolution molecular imaging offers the opportunity
to test and improve treatment in detail. However, not all
presently used “high-end” imaging technologies
can obtain molecular information.
The different imaging modalities each have their own characteristics,
strengths and weaknesses, which makes it beneficial to combine
them. Therefore imaging techniques like single photon emission
computed tomography (SPECT), positron emission tomography
(PET), computed tomography (CT) and magnetic resonance imaging
(MRI) are combined resulting in SPECT-CT, PET-CT and PET-MRI.
This offers the opportunity to merge the image of the agent
distribution with the anatomy of the patient. Further improvements
of these combined imaging apparatus are currently under investigation.
Most interestingly, there is an increasing interest in the
development of imaging contrast agents for these new opportunities
provided by the combined imaging modalities. Drug carriers
such as liposomes, micro- and nanoparticles, peptides and
antibodies are able to modify the distribution of an associated
substance. They can therefore be used to improve the therapeutic
index of drugs increasing their efficacy and/or reducing their
toxicity. If these delivery systems are carefully designed
with respect to the target and route of administration, they
will increase the specific targeting of the tumour. In addition,
if these systems could be equipped with components that can
be visualized with dedicated imaging modalities as MRI, nuclear
imaging (SPECT and PET), CT or ultrasound or preferably a
combination of these techniques, non-invasive imaging of the
kinetic of the drug and/or image guided drug delivery is achievable.
In this special issue the current developments in “imaging
and treatment of oncological diseases” are described.
In particular novel and future imaging agents for nuclear,
MR and CT imaging will be explicated. The recent awareness
of the advantages in combining imaging modalities linked to
the development of new probes, which can be visualized by
more than one imaging modality, is discussed in this issue.
Furthermore, promising carriers like liposomes, antibodies
and peptides to which imaging agents and therapeutic compounds
as well can be attached are reviewed in this issue. Also dedicated
therapeutic agents and devices that have proven their value
in the treatment of specific oncological diseases like bone
metastases, thyroid and liver cancer, are discussed in depth.
Visualization of these treatment agents is an essential aspect
in adequately treating these patients.
In addition this theme issue offers insight into the advantages
and disadvantages of the above mentioned imaging modalities
among which the differences in detection limits and resolution,
and will support the concerns that have to be considered by
emerging new imaging agents.
I would like to thank all authors for their contribution to
this special issue. In my opinion this theme issue will give
an excellent overview of the “ins and outs” of
imaging agents and their explicit position in the battle to
conquer cancer.
Dr. Frank (Johannes Franciscus Wilhelmus) Nijsen,
Ph.D.
Guest Editor
Anti-Cancer Agents in Medicinal Chemistry
Department of Nuclear Medicine
Division of Radiology, Radiotherapy and Nuclear Medicine
University Medical Centre Utrecht
Heidelberglaan 100
3584 CX Utrecht
The Netherlands
E-mail: F.Nijsen@umcutrecht.nl
[Back to top]
The Bright Future of Radionuclides for Cancer
Therapy
J.F.W. Nijsen, G.C. Krijger and A.D. van het Schip
Originally, nuclear medicine focused on radiopharmaceuticals
trapped in organ structures, based on their function, and
the presence of disease was seen by the absence of radioactivity.
More recently, target-specific radiopharmaceuticals have been
developed to visualize and/or treat oncological diseases.
Since radiopharmaceuticals have historically a leading position
in the search for “molecular imaging”, it would
be a waste not to learn from the pitfalls and opportunities
that have been and are found during the development of radiopharmaceuticals.
This knowledge can be used in the improvement of contrast
agents for other imaging modalities like MRI and CT. In this
article the aspects that are needed for the use of current
and future therapeutic and diagnostic radiopharmaceuticals
are described. Especially the production and development of
therapeutic and imageable radiopharmaceuticals are demonstrated.
MRI or CT can sometimes also image stable isotopes of elements
that contain useful radionuclides. This can result in real
multimodality imaging. Combining imaging modalities and imaging
agents will result in better patient care and can only be
advantageous if all departments and institutes will collaborate
on their research work. The combination of approaches together
with the fast progress in developments in the medical imaging
world will result in a bright future for imaging driven therapy
of cancer.
[Back to top]
MRI Contrast Agents: Current Status and Future
Perspectives
G.J. Strijkers, W.J.M. Mulder, G.A.F. van Tilborg and
K. Nicolay
Magnetic Resonance Imaging (MRI) is increasingly used in clinical
diagnostics, for a rapidly growing number of indications.
The MRI technique is non-invasive and can provide information
on the anatomy, function and metabolism of tissues in
vivo. MRI scans of tissue anatomy and function make use
of the two hydrogen atoms in water to generate the image.
Apart from differences in the local water content, the basic
contrast in the MR image mainly results from regional differences
in the intrinsic relaxation times T1 and
T2, each of which can be independently
chosen to dominate image contrast. However, the intrinsic
contrast provided by the water T1 and
T2 and changes in their values brought
about by tissue pathology are often too limited to enable
a sensitive and specific diagnosis. For that reason increasing
use is made of MRI contrast agents that alter the image contrast
following intravenous injection. The degree and location of
the contrast changes provide substantial diagnostic information.
Certain contrast agents are predominantly used to shorten
the T1 relaxation time and these are mainly
based on low-molecular weight chelates of the gadolinium ion
(Gd3+). The most widely used
T2 short-ening agents are based on iron
oxide (FeO) particles. Depending on their chemical composition,
molecular structure and overall size, the in vivo
distribution volume and pharmacokinetic properties vary widely
between different contrast agents and these largely determine
their use in specific diagnostic tests.
This review describes the current status, as well as recent
and future developments of MRI contrast agents with focus
on applications in oncology. First the basis of MR image contrast
and how it is altered by contrast agents will be discussed.
After some considerations on bioavailability and pharmacokinetics,
specific applications of contrast agents will be presented
according to their specific purposes, starting with non-specific
contrast agents used in classical contrast enhanced magnetic
resonance angiography (MRA) and dynamic contrast enhanced
MRI. Next targeted contrast agents, which are actively directed
towards a specific molecular target using an appropriate ligand,
functional contrast agents, mainly used for functional brain
and heart imaging, smart contrast agents, which generate contrast
as a response to a change in their physical environment as
a consequence of some biological process, and finally cell
labeling agents will be presented. To conclude some future
perspectives are discussed.
[Back to top]
Contrast Agents in X-Ray Computed Tomography and Its
Applications in Oncology
A. Rutten and M. Prokop
Intravascular iodinated contrast agents are required
for a large proportion of computed tomography (CT) studies.
Contrast media are indispensable to more clearly differentiate
anatomic structures and to detect and characterize abnormalities.
Depending on the indication up to 200 ml of these agents are
injected during CT. Despite these large amounts adverse effects
are rare and have further decreased with the introduction
of non-ionic substances. However, it took 10 to 20 years until
these non-ionic agents replaced the older ionic agents in
clinical practice. In recent years no new substance has been
brought to the market. The introduction of rapid scanning
using multislice CT technology, however, has led to the development
of more sophisticated contrast injection techniques. Current
research focuses on optimizing contrast application techniques
and on further evaluating the safety profiles of the various
substances. The amount of contrast enhancement obtained in
individual patients for instance depends on the contrast agent
characteristics, such as iodine concentration, and the parameters
of the contrast injection protocol, such as iodine flux and
iodine dose. Meanwhile, contrast agent characteristics such
as osmolality and viscosity play a role in the safety profile
of an agent. This paper provides a current overview of CT
contrast media, CT contrast dynamics, and CT contrast applications
with a special focus on oncological imaging.
[Back to top]
Factors Affecting the Sensitivity and Detection
Limits of MRI, CT, and SPECT for Multimodal Diagnostic and
Therapeutic Agents
P.R. Seevinck, J.-H. Seppenwoolde, T.C. de Wit, J.F.W.
Nijsen, F.J. Beekman, A.D. van het Schip and C.J.G. Bakker
Noninvasive imaging techniques like magnetic resonance imaging
(MRI), computed tomography (CT) and single photon emission
computed tomography (SPECT) play an increasingly important
role in the diagnostic workup and treatment of cancerous disease.
In this context, a distinct trend can be observed towards
the development of contrast agents and radiopharmaceuticals
that open up perspectives on a multimodality imaging
approach, involving all three aforementioned techniques. To
promote insight into the potentialities of such an approach,
we prepared an overview of the strengths and limitations of
the various imaging techniques, in particular with regard
to their capability to quantify the spatial distribution of
a multimodal diagnostic agent. To accomplish this task, we
used a two-step approach.
In the first step, we examined the situation for a particular
therapeutic anti-cancer agent with multimodal imaging opportunities,
viz. holmium-loaded microspheres (HoMS). Physical phantom
experiments were performed to enable a comparative evaluation
of the three modalities assuming the use of standard equipment,
standard clinical scan protocols, and signal-known-exactly
conditions. These phantom data were then analyzed so as to
obtain first order estimates of the sensitivity and detection
limits of MRI, CT and SPECT for HoMS.
In the second step, the results for HoMS were taken as a starting
point for a discussion of the factors affecting the sensitivity
and detection limits of MRI, CT and SPECT for multimodal agents
in general. In this, emphasis was put on the factors that
must be taken into account when extrapolating the findings
for HoMS to other diagnostic tasks, other contrast agents,
other experimental conditions, and other scan protocols.
[Back to top]
Radionuclide Therapy of Cancer with Radiolabeled Antibodies
O.C. Boerman, M.J. Koppe, E.J. Postema, F.H. Corstens
and W.J. Oyen
Radioimmunotherapy (RIT) using radiolabeled monoclonal antibodies
(MAbs) directed against tumor-associated antigens has evolved
from an appealing concept to one of the standard treatment
options for patients with non-Hodgkin’s lymphoma (NHL).
Inefficient localization of radiolabeled MAbs to nonhematological
cancers due to various tumor-related factors, however, limits
the therapeutic efficacy of RIT in solid tumors. Still, small
volume or minimal residual disease has been recognized as
a potentially suitable target for radiolabeled antibodies.
Several strategies are being explored aimed at improving the
targeting of radiolabeled MAbs to solid tumors thus improving
their therapeutic efficacy. In this review, various aspects
of the application of radiolabeled MAbs as anti-cancer agents
are discussed, and the clinical results of RIT in patients
with hematological and various solid cancers (colorectal,
ovarian, breast and renal carcinomas) are reviewed.
[Back to top]
Radiolabelled Regulatory Peptides for Imaging and
Therapy
W.A.P. Breeman, D.J. Kwekkeboom, E. de Blois, M. de Jong,
T.J. Visser and E.P. Krenning
Radiolabelled peptides have shown to be an important class
of radiopharmaceuticals for imaging and therapy of malignancies
expressing receptors of regulatory peptides. These peptides
have high affinity and specificity for their receptors. The
majority of these receptors are present at different levels
in different tissues and tumours. This review focuses on the
application of regulatory peptides radiolabelled with 67/68Ga
, 90Y, 111In
or 177Lu. Due attention is
given to the current status of research, limitations and future
perspectives of the application of these radiolabelled peptides
for imaging and radiotherapy. It also covers elements of the
basic science and preclinical and clinical aspects in general,
however, mostly based on somatostatin receptor-mediated imaging
and therapy. New analogues, chelators, radionuclides and combinations
thereof are discussed.
[Back to top]
Targeting the Ubiquitin-Proteasome Pathway in Cancer Therapy
Y. Ishii, S. Waxman and D. Germain
The ubiquitin-proteasome pathway plays a central role in the
degradation of proteins involved in several pathways including
the cell cycle, cellular proliferation and apoptosis. Bortezomib
is the first proteasome inhibitor to enter clinical use, and
received approval by the Food and Drug Administration (FDA)
for the treatment of patients with multiple myeloma, therefore
validating inhibition of the proteasome as an anticancer target.
The approval of Bortezomib was based on a large, international,
multicenter phase III trial showing its efficacy and safety
compared with conventional therapy. Preclinical data also
demonstrates the synergistic effect of bortezomib with other
chemotherapeutic agents and its ability to overcome drug resistance.
Since then several other proteasome inhibitors have been developed.
The anti-tumor activities of bortezomib have been attributed
to its effect on pro-apoptotic pathways including the inhibition
of NF-κB
and induction of endoplasmic reticulum stress. However, the
molecular mechanisms are not fully understood. In this review,
we will summarize the molecular mechanism of apoptosis by
bortezomib.
[Back to top]
Labeling Biomolecules with Radiorhenium - A Review
of the Bifunctional Chelators
G. Liu and D.J. Hnatowich
For radiotherapy, biomolecules such as intact antibodies,
antibody fragments, peptides, DNAs and other oligomers have
all been labeled with radiorhenium (186Re
and 188Re). Three different
approaches have been employed that may be referred to as direct,
indirect and integral labeling. Direct labeling applies to
proteins and involves the initial reduction of endogenous
disulfide bridges to provide chelation sites. Indirect labeling
can apply to most biomolecules and involves the initial attachment
of an exogenous chelator. Finally, integral labeling is a
special case applying only to small molecules in which the
metallic radionuclide serves to link two parts of a biomolecule
together in forming the labeled complex. While the number
of varieties for the direct and integral radiolabeling approaches
is rather limited, a fairly large and diverse number of chelators
have been reported in the case of indirect labeling. Our objective
herein is to provide an overview of the various chelators
that have been used in the indirect labeling of biomolecules
with radiorhenium, including details on the labeling procedures,
the stability of the radiolabel and, where possible, the influence
of the label on biological properties.
|
