| 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 4, July 2007
Contents
Imaging and Treatment of Oncological Diseases
Guest Editor: J.F.W. Nijsen
Editorial Pp. 379
Bone Seeking Radiopharmaceuticals for Palliation
of Pain in Cancer Patients with Osseous Metastases
Pp. 381-397
M.G.E.H. Lam, J.M.H. de Klerk, P.P. van Rijk and B.A.
Zonnenberg
[Abstract]
Use of Radiopharmaceuticals for Diagnosis, Treatment,
and Follow-Up of Differentiated Thyroid Carcinoma
Pp. 399-409
F.A. Verburg, B. de Keizer and J.W. van Isselt
[Abstract]
Brachytherapy: State of the Art and Possible Improvements
Pp. 411-424
S. Buono, N. Burgio, M. Hamoudeh, H. Fessi, E. Hiltbrand,
L. Maciocco and S. Mehier-Humbert
[Abstract]
Targeted Multifunctional Lipid-Based Nanocarriers
for Image Guided Drug Delivery Pp. 425-440
G.A. Koning and G.C. Krijger
[Abstract]
Radionuclide Liver Cancer Therapies: From Concept
to Current Clinical Status Pp. 441-459
M.A.D. Vente, M.G.G. Hobbelink, A.D. van het Schip, B.A.
Zonnenberg and J.F.W. Nijsen
[Abstract]
General Articles
Nicotine, Lung and Cancer Pp. 461-466
A. Grozio, A. Catassi, Z. Cavalieri, L. Paleari, A. Cesario
and P. Russo
[Abstract]
Smac/DIABLO and Colon Cancer Pp. 467-473
Y.M. Anguiano-Hernandez, A. Chartier and S. Huerta
[Abstract]
Harnessing Telomerase in Cancer Therapeutics Pp.
475-483
J. Fakhoury, G.A.M. Nimmo and C. Autexier
[Abstract]
Abstracts
Editorial
In this second part of the theme issue “Imaging
and Treatment of Oncological Diseases” several image
guided radionuclide based treatment approaches are discussed
in depth: the renowned iodine-131 therapy for thyroid cancer
is reviewed and also two novel treatment options for liver
cancer patients. Furthermore, a review on bone seeking radiopharmaceuticals
and one on liposomes for multimodal imaging are included.
In these articles a clear strong point of nuclear medicine
is demonstrated: radiopharmaceuticals can often be used to
image and to treat disease. The article on liposomes is devoted
to both nuclear imaging and magnetic resonance imaging (MRI).
Currently, a very popular issue in medical imaging is the
development of MR imaging agents in the frame work of “molecular
imaging”. However, the number of non-radioactive imaging
agents available is still very low compared to the radioactive
imaging agents that are on the market. One part of the explanation
is the one century of radioisotope research. The rest of the
explanation is that research in MRI and CT has been mostly
aimed on the apparatus itself while research in the field
of nuclear medicine is aimed on the development of radiopharmaceuticals.
The gamma camera is just used as a tool to visualize the distribution
of the radioactive compounds.
Recently, some progression has been made in the development
of agents for MR imaging; nowadays a few new imaging agents
have been clinically introduced. The most widely used are
the iron oxide compounds. Other examples are liposomes and
micelles labeled with iron, gadolinium, dysprosium or holmium.
Most of these imaging agents are lanthanides which have useful
properties for MR and can be easily incorporated in or attached
to all kinds of carriers. Some of the new lanthanide systems
are described in the article on nanocarriers by Koning and
Krijger and in the article on radioembolization treatment
of liver cancer by Vente et al. Imaging of drugs could be
applied to personalize medicine. This would entail that each
patient receives an individually designed therapy regarding
dose, timing, and treatment response assessment.
The amount of imaging compounds needed for a detectable signal
or signal change in MRI is enormous compared to the quantities
used in nuclear medicine. In the article of Seevinck et al.,
in part I of this theme issue, the factors affecting the sensitivity
and detection limits of MRI and CT were compared to nuclear
imaging. While nuclear imaging will certainly remain superior
in detecting minute tracer amounts of imaging agents, it is
expected that especially MRI will further increase the ability
to depict low amounts in the patient.
Ultimately, combining imaging modalities and the emerging
development of multimodal imaging agents will overcome the
shortcomings of each individual imaging technique and will
radically advance the time of diagnosis and improve the treatment
success in oncological patients.
I would like to thank all authors for their contribution to
this special issue and especially all expert referees that
have reviewed the articles of this theme issue.
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]
Bone Seeking Radiopharmaceuticals for Palliation
of Pain in Cancer Patients with Osseous Metastases
M.G.E.H. Lam, J.M.H. de Klerk, P.P. van Rijk and B.A.
Zonnenberg
Many patients with cancer develop symptomatic skeletal metastases
at an advanced stage of their disease. Skeletal metastases
are often complicated by pain. They cause considerable morbidity
and mortality. Besides analgesics, treatment options include
external beam radiotherapy, bisphosphonates, chemotherapy,
surgery and bone seeking radiopharmaceuticals. Pain palliation
with bone seeking radiopharmaceuticals has proved to be an
effective treatment modality in patients with metastatic bone
pain. Radiopharmaceuticals bind to the bone matrix in areas
of increased bone turnover, due to a metastatic response.
Beta rays from the specific radionuclide, bound to its carrier
ligand, result in the therapeutic effect. Various radiopharmaceuticals
have been developed for this purpose. All have their own characteristics.
The radiopharmaceuticals Samarium-153-ethylenediaminetetramethylenephosphonic
acid (153Sm-EDTMP) and Stron-tium-89-Chloride,
which are approved in the USA and Europe, as well as the not
universally approved Rhenium-186-hydroxy-ethylidenediphosphonic
acid (186Re-HEDP), will be
discussed in greater detail. Depending on the half-life and
radiation energy of the specific radionuclide, they exert
a different effect and toxicity profile. In most cases, bone
marrow toxicity is limited and reversible, which makes repetitive
treatment relatively safe. Several studies have shown encouraging
clinical results of palliative therapy using bone seeking
radiopharmaceuticals, with an overall reported pain response
rate in the order of ± 70-80% of patients. This systemic
form of radionuclide therapy is simple to administer and complements
other treatment options. It has been associated with marked
pain reduction, improved mobility in many patients, reduced
dependence on analgesics, and improved performance status
and quality of life. Additionally, new therapeutic strategies
hold the promise of enhancement of the palliative and anticancer
effects of this form of therapy.
[Back to top]
Use of Radiopharmaceuticals for Diagnosis, Treatment,
and Follow-Up of Differentiated Thyroid Carcinoma
F.A. Verburg, B. de Keizer and J.W. van Isselt
In 1942, Dr. Seidlin of the Memorial Hospital in New York
was faced with a 51-year- old patient who had undergone a
thyroidectomy in 1923 [1]. At the time, the histologic diagnosis
was a ‘malignant adenoma’ of the thyroid. In 1938
the patient returned with overt signs of thyroid hyperfunction
(hyperthyroidism) and lower back pain. A metastasis was found
in the lower spine, and surgically removed. Over the next
years the patient remained hyperthyroid and developed more
bone metastases. At the time of presentation to Dr. Seidlin,
the patient was in an extremely poor condition: he was in
severe pain, severely hyperthyroid, and severely underweight.
At this time radioiodine therapy had just reached the clinical
arena. In 1937 Hertz, Roberts and Evans investigated the rabbit’s
thyroid function using I-128 [2]. Later they pursued therapeutic
goals for e.g. Graves’ disease using I-130. They used
dosages that we now know would have been merely diagnostic
if it were not for a probable 10% I-131 contaminant [3]. Livingood
and Seaborg identified I-131 as a separate isotope. In 1942
two groups independently reported on the successful treatment
of hyperthyroidism with I-131 sodium iodide [4,5]. Radioiodine
was so rare that it was recovered from the urine, purified
and re-administered to the patient.
The patient responded favourably to the radioiodine treatment,
and he received several more courses of I-131. Geiger-counter
examination of the patient revealed two previously unknown
metastases, thereby indicating the diagnostic capabilities
of radioiodine. The patient did very well on these courses:
the hyperthyroidism subsided, the body-weight kg increased
from 38 to 53 kilograms, and the pains diminished.
This report of a potential cure for terminally ill patients
fuelled the public imagination to a degree that it hit the
political agenda. Effective on August 1, 1946, the Atomic
Energy Act (AEA) made radioisotopes available for medical
use in the USA. This date marks the beginning of ‘atomic
medicine’, later named nuclear medicine.
[Back to top]
Brachytherapy: State of the Art and Possible Improvements
S. Buono, N. Burgio, M. Hamoudeh, H. Fessi, E. Hiltbrand,
L. Maciocco and S. Mehier-Humbert
Cancer often remains an incurable disease, despite significant
progresses in diagnosis and treatment that have been made.
Specifically, the use of nuclear medicine in oncology is greatly
contributing to both imaging and therapy aspects. Targeted
therapies are a major field of interest since it increases
efficiency and reduces side effects. Brachytherapy is among
the most valuable of recent developments for treating localized
tumours resulting in improvements in improved quality of life.
This is primarily because it irradiates cancerous cells most
exclusively while barely effecting healthy tissue.
The use of radiochemicals implies specific management for
production, transport and handling that have limited the development
of this technique. This review article describes brachytherapy
and their latest developments. Furthermore, alternative activation
methods for the production of radioisotopes and a novel delivery
system for targeted multi-therapy by using PLA-ferrite nanospheres
are described.
[Back to top]
Targeted Multifunctional Lipid-Based Nanocarriers
for Image Guided Drug Delivery
G.A. Koning and G.C. Krijger
Lipid-based nanocarriers have proven successful in the delivery
of mainly chemotherapeutic agents, and currently they are
being applied clinically in the treatment of various types
of cancer. These drug delivery systems achieve increased therapeutic
efficacy by altering the pharmacokinetics and biodistribution
of encapsulated drugs, resulting in decreased drug toxicity
and enhanced accumulation in tumor tissue. This increased
accumulation is due to the relatively leaky immature vasculature
of a tumor. After the clinical relevance of such drug delivery
systems was demonstrated, research in this area focused on
optimization, both by cell specific targeting and including
controlled and triggered release concepts within the carrier.
These more advanced targeted nanocarriers in general have
clearly shown their potential in various animal tumor models
and await clinical application.
The development of targeted nanocarriers in which therapeutic
and imaging agents are merged into a single carrier will certainly
be of importance in the near future. Indeed, scientists active
in the field of imaging (e.g. nuclear and magnetic resonance
imaging) have already started to exploit nanocarriers for
molecular imaging. Image-guided drug delivery using these
multifunctional nanocarriers, containing therapeutic and imaging
agents, will ultimately allow for online monitoring of tumor
location, tumor targeting levels, intratumoral localization
and drug release kinetics prior and during radio- and/or chemotherapeutic
treatment. This review describes the current status and challenges
in the field of nanocarrier-aided drug delivery and drug targeting
and discusses the opportunities of combining imaging probes
with these drug carriers and the potential of these multifunctional
lipid-based nanocarriers within image-guided drug delivery.
[Back to top]
Radionuclide Liver Cancer Therapies: From Concept
to Current Clinical Status
M.A.D. Vente, M.G.G. Hobbelink, A.D. van het Schip, B.A.
Zonnenberg and J.F.W. Nijsen
Primary and secondary liver cancer have longtime
been characterized by an overall poor prognosis since the
majority of patients are not candidates for surgical resection
with curative intent, systemic chemotherapy alone has rarely
resulted in long-term survival, and the role of conventional
external beam radiation therapy has traditionally been limited
due to the relative sensitivity of the liver parenchyma to
radiation. Therefore, a host of new treatment options have
been developed and clinically introduced, including radioembolization
techniques, which are the main topic of this paper. In these
locoregional treatments liver malignancies are passively targeted
because, unlike the normal liver, the blood supply of intrahepatic
tumors is almost uniquely derived from the hepatic artery.
These internal radiation techniques consist of injecting either
yttrium-90 (90Y) microspheres,
or iodine-131 (131I) or rhenium-188
(188Re) labeled lipiodol
into the hepatic artery. Radioactive lipiodol is used exclusively
for treatment of primary liver cancer, whereas 90Y
microsphere therapy is applied for treatment of both primary
and metastatic liver cancers. Favorable clinical results have
been achieved, particularly when 90Y
microspheres were used in conjunction with systemic chemotherapy.
The main advantages of radiolabeled lipiodol treatment are
that it is relatively inexpensive (especially 188Re-HDD-lipiodol)
and that the administration procedure is somewhat less complex
than that of the microspheres. Holmium-166 (166Ho)
loaded poly(L-lactic acid) microspheres have also been developed
and are about to be clinically introduced. Since 166Ho
is a combined beta-gamma emitter and highly paramagnetic as
well, it allows for both (quantitative) scintigraphic and
magnetic resonance imaging.
[Back to top]
Nicotine, Lung and Cancer
A. Grozio, A. Catassi, Z. Cavalieri, L. Paleari, A. Cesario
and P. Russo
The respiratory epithelium expresses the cholinergic system
including nicotinic receptors (nAChRs). It was reported that
normal human bronchial epithelial cells (BEC), which are the
precursor for squamous cell carcinomas, and small airway epithelial
cells (SAEC), which are the precursor for adenocarcinomas,
have slightly different repertoires of nAChRs. Studies shown
that nAChRs expressed on lung carcinoma or mesothelioma form
a part of an autocrine-proliferative network facilitating
the growth of neoplastic cells; others demonstrated that nicotine
can promote the growth of colon, gastric, and lung cancers.
Nicotine and structurally related carcinogens like NNK [4-(methylnitrosoamino)-
1-(3-pyridyl)-1-butanone] and NNN (N’-nitrosonornicotine)
could induce the proliferation of a variety of small cell
lung carcinoma cell lines and endothelial cells and nicotine
in non-neuronal tissues -including lung- induces the secretion
of growth factors (bFGF, TGF-a, VEGF and PDGF), up regulation
of the calpain family proteins, COX-2 and VEGFR-2, causing
the eventual activation of Raf/MAPK kinase/ERK (Raf/MEK/ERK)
pathway contributing to the growth and progression of tumors
exposed to nicotine through tobacco smoke or cigarette substitutes.
It has been demonstrated that nicotine promotes the growth
of solid tumors in vivo, suggesting that might induce
the progression of tumors already initiated. While tobacco
carcinogens can initiate and promote tumorigenesis, the exposure
to nicotine could confer a proliferative advantage to early
tumors but there is no evidence that nicotine itself provokes
cancer. This is supported by the findings that nicotine can
prevent apoptosis induced by various agents - such as chemotherapeutic
in NSCLC, conferring a survival advantage as well.
[Back to top]
Smac/DIABLO and Colon Cancer
Y.M. Anguiano-Hernandez, A. Chartier and S. Huerta
Apoptosis is a genetically programmed process of controlled
and orderly cell suicide, which is critical for multicellular
organisms during development and tissue homeostasis. In cancer,
the ratio of apoptosis to cell division is altered, resulting
in a net gain of malignant tissue. Tumor cells may acquire
resistance to apoptosis by the expression of anti-apoptotic
proteins, or by the down-regulation or mutation of pro-apoptotic
mediators. In the classic pathway of apoptosis, this process
is primarily coordinated by activation of caspases. Decreased
expression of caspases inversely correlates with the aggressiveness
of cancer. Increased activity of caspases renders cancer cells
susceptible to chemoradiotherapeutic modalities. Thus, caspase
activity is pivotal in carcinogenesis. The functions of activated
caspases are inhibited by the binding of inhibitors of apoptosis
(IAPs). The function of IAPs is regulated by pro-apoptotic
protein Second Mitochondria-Derived Activator of Caspases
(Smac) or Direct IAP Binding Protein with low isoelectric
point, pI (DIABLO). Induction of apoptosis leads to increased
mitochondrial permeability to Smac/DIABLO, which adheres to
IAPs inhibiting their caspase-binding activity. The role of
Smac/DIABLO, therefore, may have significant diagnostic and
therapeutic features in carcinogenesis. The role of Smac/DIABLO
in colorectal carcinogenesis is ill defined. Data continues
to accumulate to suggest that decreased levels of Smac/DIABLO
may be important in chemoradiation-resistance to apoptosis
in advanced colon cancer. The aim of this review is to provide
the available evidence of the role of Smac/DIABLO in colon
carcinogenesis.
[Back to top]
Harnessing Telomerase in Cancer Therapeutics
J. Fakhoury, G.A.M. Nimmo and C. Autexier
Telomerase is an attractive target for anti-cancer therapeutics
due to its requirement for cellular immortalization and expression
in greater than 85% of human neoplasms. Though initially promising,
strategies that inhibit telomerase with either small molecules
or antisense oligonucleotides have a major limitation, namely
the lag time required for telomere shortening before cellular
effects are attained. As alternative approaches, immunotherapy
and gene therapy have been tailored to exploit, rather than
antagonize telomerase expression and/or activity. Immunotherapy
requires the presence of the catalytic subunit of telomerase,
hTERT, to elicit an immune response directed towards hTERT
peptide-presenting cells. hTERT promoter-driven gene therapy
and mutant telomerase RNA (hTR) gene therapy depend on the
innate telomerase activity of cancer cells to drive the expression
of pro-apoptotic genes and to synthesize mutated DNA sequences
onto telomeres, respectively. In addition, we will discuss
telomestatin, a G-quadruplex binding ligand that may exert
anti-proliferative effects independently of telomere shortening.
In this review, the progress, advantages, and limitations
of these strategies in the ongoing effort to develop clinically
relevant telomerase-based cancer therapeutics will be examined.
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