Recent
Advances in the Chemistry and Biology of Folypoly-g-glutamate Synthetase
Substrates and Inhibitors Pp. 331-355
Aleem Gangjee, Nauzer P. Dubash, Yibin Zeng and John J. McGuire
[Abstract]
The
Molecular Mechanisms for the Antitumorigenic Effect of Curcumin Pp. 357-370
Tzeng-Horng
Leu and Ming-Chei Maa
[Abstract]
Perspectives
in Melanoma Treatment with Signal Transduction Pp. 371-385
Caterina
A.M. La Porta
[Abstract]
Drug
Resistance and Apoptosis in Cancer Treatment: Development of New Apoptosis-Inducing
Agents Active in Drug Resistant Malignancies Pp. 387-401
M.
Tolomeo and D. Simoni
[Abstract]
Chemokines
as Therapeutic Targets in Non-Small Cell Lung Cancer Pp. 403-417
E.S.
White, R.M. Strieter, and D.A. Arenberg
[Abstract]
Recent
Progress in the Development of Anticancer Agents Pp. 419-439
Sلndor Eckhardt
[Abstract]
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Recent
Advances in the Chemistry and Biology of Folypoly-g-glutamate Synthetase Substrates
and Inhibitors
Aleem
Gangjee, Nauzer P. Dubash, Yibin Zeng and John J. McGuire
The
importance of folylpoly-g-glutamate synthetase (FPGS) in cancer chemotherapy arises
from its function of adding g-L-glutamate moieties to classical antifolates
which contain an L-glutamate. Polyglutamylation of classical antifolates used
in cancer chemotherapy have certain advantages. The polyglutamylated
antifolates are trapped within the cell and hence are retained for a longer
duration. In addition some polyglutamylated forms of classical antifolates also
inhibit the target folate-dependent enzyme to a greater extent than those
monoglumate form. There are however certain drawbacks to this enzymatic
transformation of classical antifolates. For those analogs which need
polyglutamylation for activation either for retention within tumor cells or to
increase inhibitory activity against the target folate-dependent enzyme(s)
(both of which could contribute to the antitumor activity of the analog),
resistance to the antifolates can be manifested by reduction in the level of
FPGS activity. In addition retention of polyglutamate forms of antifolates
within normal cells may be a cause of toxicity. Thus the structural
requirements for substrate activity for FPGS are of critical importance in the
design of classical antifolates as cancer chemotherapeutic agents. In addition classical
antifolates which lack the necessity of polyglutamation could circumvent the
resistance due to a decrease in the level and activity of FPGS. FPGS activity
on natural folate is essential to cell proliferation and survival. Thus
inhibition of FPGS activity itself has been suggested as a chemotherapeutic
strategy. Structural requirement for inhibition of FPGS have also been studied
extensively. This review highlights the synthesis and the structural
requirement for substrate and inhibitory activity of classical antifolates for
FPGS and their relevance to cancer chemotherapy.
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The
Molecular Mechanisms for the Antitumorigenic Effect of Curcumin
Tzeng-Horng
Leu and Ming-Chei Maa
Curcumin, an active yellow pigment of turmeric and curry,
possesses anti-inflammatory, antioxidative and anticarcinogenic properties.
Analysis of its structure revealed the presence of b-diketone moiety and
phenolic hydroxyl groups that were believed to contribute to antioxidation.
And vanillin, ferulic acid and a dimer of curcumin were identified as the
curcumin-derived radical reaction products. In addition to antioxidation,
curcumin could also induce apoptosis by targeting mitochondria, affecting
p53-related signaling and blocking NF-kB activation. To further dissect its anticarcinogenic
mechanisms, a number of curcumin targets were identified. These included the
aryl hydrocarbon receptor, cytochrome P450, glutathione S-transferase,
serine/threonine kinases, transcription factors, cyclooxygenase, ornithine
decarboxylase, nitric oxide synthase, matrix metalloproteinases and tyrosine
kinases. This review will summarize our current knowledge on how these
important proteins are affected by curcumin, and hopefully, may provide a whole
picture illustrating how the chemopreventive and antitumorigenic effect of
curcumin is achieved.
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to top] [Purchase
Issue/Articles]
Perspectives in Melanoma Treatment with Signal Transduction
Caterina
A.M. La Porta
Data
from all parts of the world show a rising incidence of cutaneous malignant melanoma.
The latter is one of the most difficult malignancies to treat. Early stage
melanoma is curable but once metastatic it is almost uniformly fatal.
Systemic therapy for advanced melanoma includes chemotherapy,
either with dacarbazine alone or a multiagent combination chemotherapy, and
biological therapy with recombinant interferon-alpha and/or interleukine-2.
However none of these treatments options has produced long-term control of the
disease except on rare occasion.
In the present review, new strategies in the treatment of
malignant melanoma that are now under investigations are discussed. Such new
strategies might could be open new perspectives avoiding the toxicity of the
conventional treatments too. In particular, possible agents acting on signal
transduction pathways, such as Protein Kinase C modulators, and on the cell
cycle are reviewed.
Melanoma is the most immunogenic tumor among all tumor
neoplasia. The feature has led to test several immunological strategies for
manipulating immune responses in order to induce tumor growth control in
vivo. Thus, the most interesting and recent strategies in this
field and in particular the possibility to use specific vaccines are also
considered.
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Drug
Resistance and Apoptosis in Cancer Treatment: Development of New Apoptosis-Inducing
Agents Active in Drug Resistant Malignancies
M.
Tolomeo and D. Simoni
Modulation of multidrug resistance (MDR) has been
extensively studied in vitro and
in vivo. However, several clinical trials
have failed to show any important benefits in terms of response to chemotherapy
or the length of survival using MDR reversing agents. This may be due to the
expression or co-expression of other drug resistance mechanisms in malignant
cells. Several studies have shown that most, if not all, chemotherapeutic
agents exert their anticancer activity by inducing apoptosis; therefore,
resistance to apoptosis may be a major factor limiting the effectiveness of
anticancer therapy. In the last few years, effort has been made to understand
the biochemical alterations of apoptotic pathways in cancer. Many of these
alterations confer a multidrug resistant phenotype to malignant cells. In this
context, the new recently developed anticancer therapies based on drugs that
modulate apoptosis may have importance for the treatment of tumors that are
scarcely responsive to the conventional anticancer chemotherapy. In this review,
we discuss the current knowledge about drug resistance, apoptosis and cancer and
report the recently developed apoptosis modulating strategies that have
potential therapeutic implications for the drug resistant tumors.
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Chemokines
as Therapeutic Targets in Non-Small Cell Lung Cancer
E.S.
White, R.M. Strieter, and D.A. Arenberg
Angiogenesis,
defined as the generation of new blood vessels from pre-existing vessels, is
one of life’s essential processes. Inflammation and angiogenesis, while
distinct and separable, are closely related processes. One of the hallmarks
of chronic inflammation is granulation tissue, a prominent feature of which is
neovascularization. Whenever tissue constituents proliferate, repair, or hypertrophy,
such change must be accompanied by a proportional increase in capillary blood
supply to assure delivery of nutrients, and removal of metabolic waste. This
absolute dependence suggests two characteristics of angiogenesis. First, under
normal conditions the process must be tightly controlled. Second, in the
absence of such strict control, abnormal physiology, or disease is likely to
result.
The
role of angiogenesis in solid tumor growth has attracted a great deal of
attention as a potential therapeutic target. Lung cancer is a particularly
devastating disease in industrialized countries. The majority of patients with
lung cancer are faced with very poor therapeutic options, and gaining insight
to the mechanism of angiogenesis in this disease has obvious implications
for the design of therapeutic agents. Research in our laboratories has
demonstrated that chemokines (chemotactic cytokines) are pivotal determinants
of the angiogenic activity of non-small cell lung cancer (NSCLC). This review
will focus on the evidence supporting the central role of these molecules in
lung cancer angiogenesis, and focus on potential novel means of targeting this family
of angiogenic regulators.
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Recent
Progress in the Development of Anticancer Agents
Sلndor Eckhardt
Cancer chemotherapy started with the discovery of the
cytostatic effect of N-mustard and its derivatives more than five decades ago.
This observation opened the way for the synthesis of various alkylating agents,
antimetabolites and antimitotics expliciting antitumour activity against several
human malignancies. The considerable toxicity of these drugs however, limited
their application and only hormone-active products were relatively well
tolerated. Besides, the majority of human malignant tumours proved to be
chemoresistant. Consequently, there was still an urgent need for finding less
toxic compounds possessing broader antitumour spectrum.
Therefore, it became obvious that better understanding of
the cellular metabolism - due to revolution in molecular biology - yielded new
targets for cancer chemotherapeutic agents. Key enzymes active in signal
transduction pathways could be blocked by new substances. Cell cycle control
could be influenced by apoptosis inducers. Mitotic division could be inhibited
by antitubulin agents. Multidrug resistance (MDR) could be modified by revertants.
New concepts also emerged: a) chemoprevention, which is
based on the principle, that since carcinogenesis is a genetically determined,
progressive multistep process it can timely be reconverted into the direction
of normal cellular metabolism by redifferentiating agents; b) antimetastatic
therapy: originally performed postoperatively as an adjuvant therapy nowadays
before surgical intervention, in order to block vascular dissemination of tumor
cells (neoadjuvant therapy); c) antiangiogenic therapy: substances capable to
hinder the vessel production essential for the development of metastasis; d)
antitelomerase molecules inhibiting the immortal division capacity of DNA in malignant
cells.
All these new research approaches necessitate to review the existing drugs which are in clinical use or are investigational agents against human malignancies.