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Anti-Cancer
Agents in Medicinal Chemistry
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 5, Number 3, May 2005
Contents
DNA Helicases as Targets for Anti-Cancer Drugs Pp. 183-199
Sudha Sharma, Kevin M. Doherty and Robert M. Brosh Jr.
[Abstract]
Prospects for Plant-Derived Chemopreventive Agents Exhibiting
Multiple Mechanisms of Action Pp. 201-213
L.M. Howells and M.M. Manson
[Abstract]
Synthesis and Biological Activity of New Class of Dioxygenated
Anticancer Agents Pp. 215-237
Maria Dolors Pujol, Manel Romero and Isabel Sanchez
[Abstract]
Anti-Cancer Potential of Sesquiterpene Lactones: Bioactivity
and Molecular Mechanisms Pp. 239-249
Siyuan Zhang, Yen-Kim Won, Choon-Nam Ong and Han-Ming Shen
[Abstract]
Cisplatin is a DNA-Damaging Antitumour Compound Triggering
Multifactorial Biochemical Responses in Cancer Cells: Importance
of Apoptotic Pathways Pp. 251-265
Yuliya Sedletska, Marie-Josephe Giraud-Panis and Jean-Marc
Malinge
[Abstract]
Multi-Nuclear Platinum Drugs: A New Paradigm in Chemotherapy
Pp. 267-279
Nial J. Wheate, and J. Grant Collins
[Abstract]
Progress in the Development of Aminopeptidase N (APN/CD13)
Inhibitors Pp. 281-301
Yuliya Sedletska, Marie-Josephe Giraud-Panis and Jean-Marc
Malinge
[Abstract]
Lanthanide Bearing Microparticulate Systems for Multi-Modality
Imaging and Targeted Therapy of Cancer Pp. 303-313
S.W. Zielhuis, J.F.W. Nijsen, J.H. Seppenwoolde, B.A. Zonnenberg,
C.J.G. Bakker, W.E. Hennink, P.P. van Rijk and A.D. van het
Schip
[Abstract]
Abstracts
[Back to top]
DNA Helicases as Targets for Anti-Cancer Drugs
Sudha Sharma, Kevin M. Doherty and Robert M. Brosh
Jr.
DNA helicases have essential roles in nucleic acid metabolism
by facilitating cellular processes including replication,
recombination, DNA repair, and transcription. The vital roles
of helicases in these pathways are reflected by their emerging
importance in the maintenance of genomic stability. Recently,
a number of human diseases with cancer predisposition have
been shown to be genetically linked to a specific helicase
defect. This has led researchers to further investigate the
roles of helicases in cancer biology, and to study the efficacy
of targeting human DNA helicases for anti-cancer drug treatment.
Helicase-specific inhibition in malignant cells may compromise
the high proliferation rates of cancerous tissues. The role
of RecQ helicases in response to replicational stress suggests
a molecular target for selectively eliminating malignant tumor
cells by a cancer chemotherapeutic agent. Alternate DNA secondary
structures such as G-quadruplexes that may form in regulatory
regions of oncogenes or G-rich telomere sequences are potential
targets for cancer therapy since these sequence-specific structures
are proposed to affect gene expression and telomerase activation,
respectively. Small molecule inhibitors of G-quadruplex helicases
may be used to regulate cell cycle progression by modulating
promotor activation or disrupting telomere maintenance, important
processes of cellular transformation. The design of small
molecules which deter helicase function at telomeres may provide
a molecular target since telomerase activity is necessary
for the proliferation of numerous immortal cells. Although
evidence suggests that helicases are specifically inhibited
by certain DNA binding compounds, another area of promise
in anti-cancer therapy is siRNA technology. Specific knockdown
of helicase expression can be utilized as a means to sensitize
oncogenic proliferating cell lines. This review will address
these topics in detail and summarize the current avenues of
research in anti-cancer therapy targeting helicases through
small molecule inhibitors of DNA-protein complexes, DNA binding
drugs, or down-regulation of helicase gene expression.
[Back to top]
Prospects for Plant-Derived Chemopreventive Agents Exhibiting
Multiple Mechanisms of Action
L.M. Howells and M.M. Manson
There is great potential for the use of plant-derived agents
in the fight to prevent onset or delay progression of the
carcinogenic process. Epidemiological evidence for their chemopreventive
action is compelling, but even though many of these compounds
have an extensive history of use within the human populace,
it is of increasing importance to determine more precisely
the primary targets contributing to their efficacy, prior
to embarking on large-scale clinical trials.
This rapidly moving field now concentrates in particular,
on the modulating effects these agents can have on cellular
signalling pathways involved in the apoptotic, proliferative
and angiogenic processes, perturbances to which, are common
in many cancers. It is perhaps the ability of these agents
to exhibit multi-site mechanisms of action that offers their
key to success where conventional single-site agents have
disappointed in the past. As well as being promising chemopreventive
agents, there is also an exciting role for these compounds
in combinatorial therapy with more traditional chemotherapeutics,
potentially in lowering of toxicity and enhancing efficacy
for treatment of more advanced cancers.
This review will summarise known and proposed mechanisms
of action for various chemopreventive agents of interest highlighting
their potential in combination therapy, and will address benefits
and problems of using such multi-site agents in long-term
prevention/therapeutic regimes.
[Back to top]
Synthesis and Biological Activity of New Class of Dioxygenated
Anticancer Agents
Maria Dolors Pujol, Manel Romero and Isabel Sanchez
This paper describes extensive research on the activity of
more of 100 cytotoxic compounds containing an oxygenated ring
in their structure and isolated from natural plants or prepared
by semisynthesis or synthesis from available intermediates.
Anticancer drugs have been classified according to the chemical
structure of the natural products that are considered to lead
the series. The origin and mechanism of action involved in
each case have been considered.
This new family of natural, semisynthetic and synthetic
products includes compounds with interesting antitumor activity
such as podophyllotoxin derivatives, NK-611 (15), TOP-53
(16), NPF (24) and Tafluposide (28);
camptothecin analogs such as 45 with a considerable
cytotoxicity against b-cell chronic
lymphocytic leukemia (CLL), and 52 (new piperazinyl-CPT
analog). New dioxygenated ellipticine analogs showed more
activity and stability than the natural pattern when the structure
incorporated a lactone function instead of the pyridine ring.
In the acridine series the new tetracyclic derivatives 75
and 76 containing ethylenedioxy groups at the 2- and
3-positions of the acridine system exhibited the same activity
as m-AMSA in vivo against murine P-388 leukemia.
Other isolated compounds containing a dioxygenated ring in
their structure such as 100 and 101 showed antitumor
activities related to kinase inhibition, and are attractive
candidates for development of new synthetic antitumor agents.
[Back to top]
Anti-Cancer Potential of Sesquiterpene Lactones: Bioactivity
and Molecular Mechanisms
Siyuan Zhang, Yen-Kim Won, Choon-Nam Ong and Han-Ming
Shen
Sesquiterpene lactones (SLs) are the active constituents
of a variety of medicinal plants used in traditional medicine
for the treatment of inflammatory diseases. In recent years,
the anti-cancer property of various SLs has attracted a great
deal of interest and extensive research work has been carried
out to characterize the anti-cancer activity, the molecular
mechanisms, and the potential chemopreventive and chemotherapeutic
application of SLs. In this review, we attempt to summarize
the current knowledge of the anti-cancer properties of SLs
by focusing on the following important issues. First, we discuss
the structure-activity relationship of SLs. All SLs contain
a common functional structure, an a-methylene-g-lactone
group, and this important chemical characteristic means that
the thiol-reactivity of SLs is an underlying mechanism responsible
for their bioactivities. Second, we assess the experimental
evidence for the anti-cancer function of SLs obtained from
both in vitro cell culture and in vivo animal
models. Various SLs have been demonstrated to execute their
anti-cancer capability via inhibition of inflammatory responses,
prevention of metastasis and induction of apoptosis. Thirdly,
we outline the molecular mechanisms involved in the anti-cancer
activity of SLs, in particular, the SL-thiols reaction, the
effect of SLs on cell signaling pathways such as nuclear transcription
factor-kappaB (NF-kB) and mitogen-activated protein
kinases (MAPK). Finally, we recapitulate some important SLs
with regards to their anti-cancer activities and their potential
in anti-cancer drug development. Taken together, many SLs
are emerging as promising anti-cancer agents with potential
applications in both cancer chemotherapy and chemoprevention.
[Back to top]
Cisplatin Is a DNA-Damaging Antitumour Compound Triggering
Multifactorial Biochemical Responses in Cancer Cells: Importance
of Apoptotic Pathways
Yuliya Sedletska, Marie-Josephe Giraud-Panis and Jean-Marc
Malinge
cis-Diamminedichloroplatinum(II) (cisplatin) is among
the most active antitumour agent used in human chemotherapy.
The purpose of this review is to give an insight in several
molecular mechanisms that mediate the sensitivity of cancer
cells to this drug and to show how recent progress in our
knowledge on some critical molecular events should lay the
foundations of a more rational approach to anticancer drug
design. Cisplatin is primarily considered as a DNA-damaging
anticancer drug, mainly forming different types of bifunctional
adducts in its reaction with cellular DNA. We will address
the question of cellular activity disruption that cisplatin
could cause through binding to more sensitive region of the
genome such as telomeres. Cellular mechanisms of resistance
to cisplatin are multifactorial and contribute to severe limitation
in the use of this drug in clinics. They include molecular
events modulating the amount of drug-DNA interaction, such
as a reduction in cisplatin accumulation inside cancer cells
or inactivation of cisplatin by thiol-containing species.
Other important mechanisms acting downstream to the initial
reaction of cisplatin with DNA, include an increase in adducts
repair and a decrease in induction of apoptosis. Recently
accumulating evidence suggest a role of the long patch DNA
mismatch repair system in sensing cisplatin-damaged DNA and
in triggering cell death through a c-Abl- and p73-dependent
cascade; two other important pathways have been unravelled
that are the mitogen-activated protein kinase cascade and
the tumor suppressor p53. Several of these mechanisms underlying
cisplatin resistance have been exploited to design new platinum
derivatives. This issue will be covered in the present review.
[Back to top]
Multi-Nuclear Platinum Drugs: A New Paradigm in Chemotherapy
Nial J. Wheate, and J. Grant Collins
The initial report of the therapeutic anticancer properties
of a di-nuclear platinum complex in 1988 started a new paradigm
in platinum based chemotherapy. Several multi-nuclear platinum
complexes have entered clinical trials in recent years, with
varying results. This group of charged complexes, consisting
of di- and tri-nuclear compounds linked by aliphatic ligands,
many with hydrogen bonding functionality, are able to overcome
cisplatin and carboplatin resistance in many important human
cancer cell lines. The adducts they form with DNA - which
are, to some extent, affected by their pre-covalent association
- are the reason for their increased cytotoxicity, and are
distinctly different from those formed by cisplatin. Multi-nuclear
platinum DNA adducts are broadly defined as flexible, non-directional
and mainly interstrand cross-links. These complexes are also
able to induce conformational changes in DNA, particularly
the conversion from B-type to Z- and A-type. While these complexes
are much more cytotoxic than cisplatin, they are also highly
toxic. The maximum tolerated doses range from 0.006 to 1.1
mg/m2 which is 10 to 100 fold lower than cisplatin. BBR3464
has shown in vivo activity at its MTD in several pre-clinical
and clinical trials; however, recent phase II trials have
shown that BBR3464, and other multi-nuclear platinum drugs,
did not yield results substantially different from cisplatin,
possibly due to their binding and degradation by human plasma
proteins. This review will look at the success, and limitations,
of multi-nuclear platinum drugs, and discuss their future
potential as anti-cancer agents.
[Back to top]
Progress in the Development of Aminopeptidase N (APN/CD13)
Inhibitors
Wenfang Xu and Qianbin Li
Aminopeptidase N (APN; CD13) is a member of zinc-containing
ectoenzymes family involved in the degradation of neutral
or basic amino acids (Ala>Phe>Leu>Gly) from N-terminal
of bioactive peptides and amide or arylamide derivatives of
amino acids. The expression of APN being up regulated has
been implicated in the pathogenesis of a variety of diseases
such as cancer, leukemia, diabetic nephropathy, and rheumatoid
arthritis. Thus, APN inhibitors (APNIs) are expected to be
useful for the treatment of these disorders. This article
reviews briefly the structure characteristic and possible
function of APN. The proposed biomolecular structures and
mechanism of action used in the design of APNIs are thoroughly
covered. Major emphasis is on recently published potent, small
molecular weight APNIs and their essential structure activity
relationship (SAR). Finally, available clinical results of
compounds in development are summarized in this review.
[Back to top]
Lanthanide Bearing Microparticulate Systems for Multi-Modality
Imaging and Targeted Therapy of Cancer
S.W. Zielhuis, J.F.W. Nijsen, J.H. Seppenwoolde, B.A.
Zonnenberg, C.J.G. Bakker, W.E. Hennink, P.P. van Rijk and
A.D. van het Schip
The rapid developments of high-resolution imaging techniques
are offering unique possibilities for the guidance and follow
up of recently developed sophisticated anticancer therapies.
Advanced biodegradable drug delivery systems, e.g. based on
liposomes and polymeric nanoparticles or microparticles, are
very effective tools to carry these anticancer agents to their
site of action. Elements from the group of lanthanides have
very interesting physical characteristics for imaging applications
and are the ideal candidates to be co-loaded either in their
non-radioactive or radioactive form into these advanced drug
delivery systems because of the following reasons:
Firstly, they can be used both as magnetic resonance imaging
(MRI) and computed tomography (CT) contrast agents and for
single photon emission computed tomography (SPECT).
Secondly, they can be used for radionuclide therapies which,
importantly, can be monitored with SPECT, CT, and MRI.
Thirdly, they have a relatively low toxicity, especially
when they are complexed to ligands.
This review gives a survey of the currently developed lanthanide-loaded
microparticulate systems that are under investigation for
cancer imaging and/or cancer therapy. |
