Current Medicinal Chemistry - Anti-Cancer Agents, Vol. 3, No. 2, 2003
Contents
Resveratrol and
Cancer: Chemoprevention, Apoptosis, and Chemoimmunosensitizing Activities
Pp. 77-93
Cal, C., Garban, H., Jazirehi, A., Yeh, C., Mizutani, Y., and Bonavida, B.
[Abstract]
Vascular Endothelial
Cell Growth Factor (VEGF), An Emerging Target for Cancer Chemotherapy Pp.
95-117
S. Shinkaruk, M.
Bayle, G. Laïn and G. Déléris
[Abstract]
New Approach to Cancer
Therapy: The Application of Signal Transduction to Anti-Cancer Drug Pp.
119-131
Shinji Osada and
Shigetoyo Saji
[Abstract]
Second Generation
Taxanes: from the Natural Framework to the Challenge of Drug Resistance Pp.
133-138
Cristiano Ferlini,
Iwao Ojima, Mariagrazia Distefano, Daniela Gallo, Antonella Riva, Paolo
Morazzoni, Ezio Bombardelli, Salvatore Mancuso, and Giovanni Scambia
[Abstract]
Glucuronides in
Anti-Cancer Therapy Pp. 139-150
Xi Chen, Bingyuan Wu,
and Peng George Wang
[Abstract]
Cardiac Toxicity of
Antineoplastic Anthracyclines Pp. 151-171
Riccardo Zucchi, and
Romano Danesi
[Abstract]
Abstracts
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Resveratrol and Cancer:
Chemoprevention, Apoptosis, and Chemoimmunosensitizing Activities
Cal, C., Garban, H.,
Jazirehi, A., Yeh, C., Mizutani, Y., and Bonavida, B.
The
polyphenolic compound Resveratrol is a naturally occurring phytochemical and
can be found in many plant species, including grapes, peanuts and various
herbs. Several studies have established that Resveratrol can exert antioxidant
and anti-inflammatory activities. It also has activity in the regulation of
multiple cellular events associated with carcinogenesis. This review describes
the general properties of Resveratrol including its relationship to estrogen,
its effect on lipid metabolism, its cardiovascular effects, and its role on
gene expression. Resveratrol has also been examined in several model systems
for its potential effect against cancer. Its anti-cancer effects include its
role as a chemopreventive agent, its ability to inhibit cell proliferation, its
direct effect in cytotoxicity by induction of apoptosis and on its potential therapeutic
effect in pre-clinical studies. In addition, Resveratrol has been shown to
exert sensitization effects on cancer cells that will result in a synergistic
cytotoxic activity when Resveratrol is used in combination with cytotoxic drugs
in drug-resistant tumor cells. Clearly, the studies with Resveratrol provide
support for the use of Resveratrol in human cancer chemoprevention and
combination with chemotherapeutic drugs or cytotoxic factors in the treatment
of drug refractory tumor cells.
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Vascular Endothelial
Cell Growth Factor (VEGF), An Emerging Target for Cancer Chemotherapy
S. Shinkaruk, M.
Bayle, G. Laïn and G. Déléris
Angiogenesis is a process of development and of growth of new capillary blood vessels from pre-existing vessels. When pathological, it contributes to the development of numerous types of tumors, and the formation of metastases. In order to grow, carcinoma need new blood vessels to form so that they can feed themselves. Therefore, nowadays the concept according to which the development of cancer is angiogenesis dependant is generally recognized. This concept makes the control of tumoral angiogenesis one of the promising therapeutic ways in cancerology.
The transition from the latent phase to the invasive and metastatic phase of a cancer is linked to what is called the angiogenic switch. It implies complex cellular and molecular interactions between cancerous cells, endothelial cells and the components of the extra-cellular matrix and namely the existence of specific proteins secreted by the tumoral cells able to stimulate the proliferation of capillary endothelial cells. Among them, VEGF, Vascular Endothelial Growth Factor
was found in several types of tumors. It has shown a tumoral angiogenic activity in vitro and in vivo, and thus is a privileged target for the control of angiogenesis in an anti-tumoral goal.
The role of VEGF in tumoral angiogenesis has been extensively studied. It has been proved to undergo as well autocrine as paracrine stimulation of tumoral angiogenesis.
During the last few years, several members of the VEGF family have been described namely the VEGF-A, B, C, D, E and placenta growth factor (PlGF) among which VEGF-A (121 aminoacids) plays a role of prime importance in angiogenesis. VEGF is a 45 kDA glycoprotein, homodimeric, basic, and able to bind heparin. The three-dimensional structure of VEGF has been recently determined, by X-rays diffraction, and NMR spectroscopy.
The different forms of the VEGF bind to receptors that exhibit a tyrosine-kinase activity (RTK). The specific action of the VEGF on the endothelial cells is mainly regulated by two types of RTK of the VEGF family, VEGFR1, or Flt-1, and VEGFR2, or KDR/Flk-1. Mutagenesis studies have shown that only a small number of VEGF residues are important and essential for the binding with RTK. Data described to date from the studies of VEGF/RTK interactios agree to the hypothesis that KDR receptor is the main human receptor responsible for the VEGF activity in both physiological and pathological vascular development, and VEGF-KDR signalling pathway has been validated as a priority target for the development of anti- and pro- angiogenic agents.
Therefore angiogenesis mediated by VEGF constitutes a new target for anti-cancer therapy which has explored through different ways of intervention aiming at the blocking of the tumoral angiogenesis. The main ones are:
-Struggle against the stroma degradation and invasion by the neo-vessels
-Inhibition of activated endothelial cells.
-Inhibition of angiogenic factors production and of their receptors.
-Inhibition of the VEGF signal pathway,
by peptides blocking the bond between VEGF and its receptors
through the inhibition of intracellular transduction of VEGF signal.
In
conclusion, this bibliographic study allows to situate works of medicinal
chemistry in the context of present knowledge concerning the vascular
endothelial growth factor (VEGF) and its role in angiogenesis.
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New Approach to Cancer
Therapy: The Application of Signal Transduction to Anti-Cancer Drug
Shinji Osada and
Shigetoyo Saji
Although
it has been widely known that extracellular signal-regulated kinase (ERK)
pathway stimulates cell growth and have a protective effect from cell death,
recent findings propose pro-apoptotic action of ERK phosphorylation. Since it
was found that Vitamin K3 (VK3) or its analog was a potent growth inhibitor and
inducer for ERK phosphorylation through specific pathway in cancer cell line,
the critical role of ERK phosphorylation in growth inhibitory actions can be
discussed. VK3 induced receptor tyrosine phosphorylation and occurred at growth
inhibitory concentrations. The phosphorylation of growth factor receptor by VK3
was indicated to be functional, since these were connected with growth factor
receptor-bound protein 2 (Grb2) and SOS1. The growth factor stimulated to
induce cyclin D1 protein and increase DNA contents. In addition, ERK inhibitor
antagonized increase of cyclin D1, suggesting that ERK phosphorylation by
growth factor might play an essential role for cell growth. By contrast, ERK
phosphorylation by VK3 was more prolonged and intense than the signal induced
by growth factors and the antagonize ERK phosphorylation protected from growth
inhibition by VK3. The additional and extra ERK spot by VK3, compared with those
obtained from growth factor, was detected on two dimensional gels, and this was
completely and selectively antagonized by ERK inhibitor. Therefore, the
overexpressed ERK phosphorylation was suggested to originate from the
additional spot, which played a critical role in growth inhibitory action,
despite ERK phosphorylation by growth factor had an essential association with
cell growth. The new approach to consider the signal transduction can be one of
the most favorite strategies for cancer therapy in the future.
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Second Generation Taxanes:
from the Natural Framework to the Challenge of Drug Resistance
Cristiano Ferlini,
Iwao Ojima, Mariagrazia Distefano, Daniela Gallo, Antonella Riva, Paolo
Morazzoni, Ezio Bombardelli, Salvatore
Mancuso, and Giovanni Scambia
Taxanes
represent the most important class of antitumor agents introduced in cancer
therapy in the last decade. The first member of the family was paclitaxel,
firstly isolated from Taxus Brevifolia and found active as antitumor agent at
the end of 60's. In the mid of 90's, a semi-synthetic taxane derived from
10-deacetylbaccatin III was introduced and thereafter named as docetaxel.
Taxanes act by inhibiting microtubule dynamics, thereby inducing the arrest in
M phase and the consequent activation of the apoptotic program. Since target of
taxanes is not directly the genome, they are effective alone or in combination
with DNA-damaging drugs in tumors not responding to conventional
chemotherapeutics, such as advanced breast and non small cell lung cancer. In
this review we will cover the aspects of clinical applications of the currently
used taxanes as well as the clinical problems related to their use. Taking into
consideration such problems, new taxanes have been developed in order to extend
the spectrum of taxane-sensitive tumors and several of them are currently
undergoing clinical trials. Among these agents, a newly developed taxane (BAY
59- 8862) appears particularly interesting for the fact that it shows excellent
oral bioavailability and activity in tumors with inherent resistance to paclitaxel.
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Glucuronides in Anti-Cancer
Therapy
Xi Chen, Bingyuan Wu,
and Peng George Wang
Glucuronide
prodrugs have shown promising efficacy in anti-cancer therapy due to their
increased specificity and reduced systemic toxicity. The prodrugs can be used
in prodrug monotherapy (PMT), which is based on elevated tumor b-glucuronidase activity. b-Glucuronidase activates the low-toxic
prodrugs into highly cytotoxic agents specifically in the tumor site. The
specificity of the prodrugs can be further improved by combined use with
monoclonal antibodies against tumor-specific antigens, namely antibody-directed
enzyme prodrug therapy (ADEPT); and the potency of the prodrugs can be greatly
enhanced with the incorporation of an appropriate radionuclide in the combined
chemo- and radio-therapy of cancer (CCRTC) strategy. The prodrugs can also be
utilized to modify liposomes for efficient delivery of anti-cancer drugs.
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Cardiac Toxicity of
Antineoplastic Anthracyclines
Riccardo
Zucchi, and Romano Danesi
Anthracyclines
play a major role in the treatment of solid malignancies, but their clinical
use is limited by acute or chronic cardiac toxicity. This is not due to the
same molecular action involved in the antineoplastic effect, i.e. topoisomerase
II inhibition, but can be attributed to different mechanisms: free radical
generation, stimulation of sarcoplasmic reticulum calcium release, binding to
anionic phospholipids, alteration of sphingolipid metabolism, modulation of
gene expression. Anthracycline metabolites, particularly 13-hydroxy
derivatives, might contribute to impair iron and calcium homeostasis.
Unresolved issues are the relative importance of such injurious mechanisms and
the relationship between acute and chronic toxicity. Attempts to reduce
anthracycline toxicity have been focused on the development of new derivatives,
on the adoption of peculiar delivery systems, and on the association with
substances able to interfere with the mechanism responsible for cardiotoxicity.
Many anthracyclines have been synthesized and screened, but no major
improvement in therapeutic index has been obtained. A possible exception might
be represented by the new disaccharidic derivatives, which have provided
promising results in preclinical studies. Liposome encapsulation and
association with the iron chelator dexrazoxane have also proved to be useful.
Novel approaches are targeted at the effects of anthracyclines on nitric
monoxide metabolism and on sphingolipid metabolism.