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Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Current Medicinal Chemistry
- Anti-Cancer Agents
Volume 5, Number 6, November 2005
Contents
Inhibition of PI3K/Akt Signaling: An Emerging Paradigm for
Targeted Cancer Therapy Pp.575
Y.L. Chen, P.-Y. Law and H.H. Loh
[Abstract] [Purchase
Article]
Lanthanides as Anticancer Agents Pp.591
I. Kostova
[Abstract] [Purchase
Article]
Current Drug Therapy for Prostate Cancer: An Overview
Pp.603
A.B. Stewart, B.A. Lwaleed, D.A. Douglas and B.R. Birch
[Abstract] [Purchase
Article]
Sulfo-Quinovosyl-Acyl-Glycerol (SQAG), a Eukaryotic
DNA Polymerase Inhibitor and Anti-Cancer Agent Pp.613
Y. Mizushina, N. Kasai, H. Iijima, F. Sugawara, H. Yoshida
and K. Sakaguchi
[Abstract] [Purchase
Article]
Lycopene: A Review of Its Potential as an Anticancer
Agent Pp.627
V. Bhuvaneswari and S. Nagini
[Abstract] [Purchase
Article]
Selenium Derivatives as Cancer Preventive Agents Pp.637
T. Aboul-Fadl
[Abstract] [Purchase
Article]
Abstracts
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Inhibition of PI3K/Akt Signaling: An Emerging Paradigm
for Targeted Cancer Therapy
Yulong L. Chen, Ping-Y. Law and Horace H. Loh
The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase
B, PKB) signaling pathway plays a critical role in cell growth
and survival. Dysregulation of this pathway has been found
in a variety of cancer cells. Recently, constitutively active
PI3K/Akt signaling has been firmly established as a major
determinant for cell growth and survival in an array of cancers.
Blocking the constitutively active PI3K/AKT signaling pathway
provides a new strategy for targeted cancer therapy. Thus,
inhibitors of this signaling pathway would be potential anticancer
agents, particularly for cancer cells whose survival and growth
are dominated by constitutively active PI3K/Akt signaling.
This review describes the current understanding of small molecule
drugs targeting this pathway both in vitro and in
vivo. Inhibitors and functions of the upstream and downstream
molecular targets of the PI3K/Akt pathway are discussed in
the context of using the inhibitors to block this pathway
for targeted cancer therapy. Special emphasis is placed on
the following targets: receptor tyrosine kinases, PI3K, Akt,
and the mammalian target of rapamycin. While the molecular
therapeutic strategy holds great promise for the treatment
of a variety of cancers, few small molecule inhibitors with
potential high therapeutic indexes are available. Thus, new
inhibitors with high selectivity, bioavailability, and potency
are greatly needed. Novel approaches toward the development
of PI3K/Akt pathway inhibitors as anticancer therapeutics
are discussed in detail, with emphasis on chemical genetics-based
and structure-based drug design.
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Lanthanides as Anticancer Agents
Irena Kostova
The application of inorganic chemistry to medicine is a rapidly
developing field, and novel therapeutic and diagnostic metals
and metal complexes are now having an impact on medical practice.
Advances in biocoordination chemistry are crucial for improving
the design of compounds to reduce toxic side effects and understand
their mechanisms of action. A lot of metal-based drugs are
widely used in the treatment of cancer. The clinical success
of cisplatin and other platinum complexes is limited by significant
side effects acquired or intrinsic resistance. Therefore,
much attention has focused on designing new coordination compounds
with improved pharmacological properties and a broader range
of antitumor activity. Strategies for developing new anticancer
agents include the incorporation of carrier groups that can
target tumor cells with high specificity. Also of interest
is to develop complexes that bind to DNA in a fundamentally
different manner than cisplatin, in an attempt to overcome
the resistance pathways that have evolved to eliminate the
drug. This review focuses on recent advances in developing
lanthanide anticancer agents with an emphasis on lanthanide
coordination complexes. These complexes may provide a broader
spectrum of antitumor activity. They were compared with classical
platinum anticancer drugs. Lanthanides are also of interest
because of their therapeutic radioisotopes. The dominant pharmacological
applications of lanthanides are as agents in radioimmunotherapy
and photodynamic therapy.
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Current Drug Therapy for Prostate Cancer: An Overview
Alistair B. Stewart, Bashir A. Lwaleed, David A. Douglas
and Brian R. Birch
Prostate cancer is the most common cancer amongst men in
the USA and the second most common malignant cause of male
death worldwide after lung cancer. The life time risk of having
microscopic evidence of prostate cancer for a 50 year old
man is 42%. Prostate cancer is thus becoming an increasingly
significant global health problem in terms of mortality, morbidity,
as well as economically. This review, discusses current medical
therapeutic options for prostate cancer including traditional
treatments using luteinising hormone releasing analogues (LHRH),
anti-androgens and es-trogen treatments, and the use of novel
drugs directed against molecular targets considered important
in oncogenesis and metastasis. Prostate cancer chemoprevention
using 5α-reductase
inhibitors and the role of gene therapy are also considered.
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Sulfo-Quinovosyl-Acyl-Glycerol (SQAG), a Eukaryotic DNA
Polymerase Inhibitor and Anti-Cancer Agent
Yoshiyuki Mizushina, Nobuyuki Kasai, Hiroshi Iijima,
Fumio Sugawara, Hiromi Yoshida and Kengo Sakaguchi
It was found that a class of sulfolipids known as sulfo-quinovosyl-acyl-glycerols
(SQAGs) from ferns and algae are potent inhibitors of eukaryotic
DNA polymerase α
& β and effective anti-neoplastic agents. In developing
a procedure for the chemical synthesis of sulfolipids, many
derivatives and stereoisomers of SQAGs have been obtained
including sulfo-quinovosyl-monoacyl-glycerols (SQMGs) and
sulfo-quinovosyl-diacyl-glycerols (SQDGs). This review describes
studies on the structure-function relationship between synthetic
SQAGs and DNA polymerase α
& β,
and the re-lationship to cytotoxic activity. The major action
was probably dependent on the fatty acid effect, which was
reported previously, although each of the SQAGs was a much
stronger inhibitor than just the fatty acid present in the
SQAGs. The inhibitory effect could be influenced by the chain
size of fatty acids in the SQAGs. The sulfonyl group in quinovose
was also needed to inhibit the enzymes. Lineweaver-Burk plots
of SQAGs indicated that DNA polymerase a was non-competitively
inhibited, but the SQAGs were effective as antagonists of
both the template-primer DNA-binding and the nucleotide substrate-binding
of DNA polymerase β.
Based on these results, the molecular actions of SQAGs and
drug design strategies for developing new anti-neoplastic
agents were discussed.
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Lycopene: A Review of Its Potential as an Anticancer Agent
V. Bhuvaneswari and S. Nagini
Dietary chemoprevention has emerged as a cost effective approach
to control most prevalent chronic diseases including cancer.
In particular, tomato and tomato products are recognised to
confer a wide range of health benefits. Epidemiological studies
have provided evidence that high consumption of tomatoes effectively
lowers the risk of reac-tive oxygen species (ROS)-mediated
diseases such as cardiovascular disease and cancer by improving
the antioxidant capacity. Tomatoes are rich sources of lycopene,
an antioxidant carotenoid reported to be a more stable and
potent singlet oxygen quenching agent compared to other carotenoids.
In addition to its antioxidant properties, lycopene shows
an array of biological effects including cardioprotective,
anti-inflammatory, antimutagenic and anticarcinogenic activi-ties.
The anticancer activity of lycopene has been demonstrated
both in in vitro and in vivo tumour models.
The mecha-nisms underlying the inhibitory effects of lycopene
on carcinogenesis could involve ROS scavenging, upregulation
of de-toxification systems, interference with cell proliferation,
induction of gap-junctional communication, inhibition of cell
cycle progression and modulation of signal transduction pathways.
This review outlines the sources, structure, absorp-tion,
metabolism, bioavailability and pharmacological properties
of lycopene with special reference to its antioxidant and
anticarcinogenic effects.
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Selenium Derivatives as Cancer Preventive Agents
Tarek Aboul-Fadl
The role of selenium in the prevention of cancer has been
recently established by laboratory experiments, clinical trials,
and epidemiological data. Most of the effects are related
to the function of selenium in antioxidant enzyme systems.
Animal data, epidemiological data, and intervention trials
have shown a clear role for sele nium derivatives in both
prevention of specific cancers and antitumorigenic effects
in postinitiation phases of cancer. Consequently, selenium
supplementation has moved from the realm of correcting nutritional
deficiencies to one of pharmacological intervention, especially
in the clinical domain of cancer chemoprevention. Accordingly,
there has been substantial interest directed toward the synthesis
of selenium-containing derivatives in recent years that could
be used as cancer chemopreventive agents. The current review
aims to outline recent developments in the application of
selenium derivatives as cancer preventive agents.
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