Current Cancer Drug Targets, Volume 2, No. 4, 2002
Contents
Natural Products and Derivatives as Leads to
Cell Cycle Pathway Targets in Cancer Chemotherapy Pp.279-308
David
J. Newman, Gordon M. Cragg, Susan Holbeck and Edward A. Sausville
Modulating Cell Cycle: Current Applications
and Prospects for Future Drug Development Pp.309-336
Hala
Gali-Muhtasib and Nadine Bakkar
Identifying Molecular Targets Mediating the
Anticancer Activity of Histone Deacetylase Inhibitors: A Work in Progress Pp.337-353
B.G.
Gabrielli, R.W. Johnstone and N.A. Saunders
The Use of Synthetic Oligonucleotides as Protein
Inhibitors and Anticode Drugs in Cancer Therapy: Accomplishments and
Limitations Pp.355-368
Marcella
Faria and Henning Ulrich
[Back to top] Natural
Products and Derivatives as Leads to Cell Cycle Pathway Targets in Cancer
Chemotherapy
David J. Newman, Gordon M. Cragg, Susan Holbeck and Edward A. Sausville
The influence of
natural products upon drug discovery in general has been quite impressive; one
only has to look at the number of clinically active drugs that are in use in
cancer therapy to see how many either are natural products or have a natural
pro-duct pharmacophore. What is now
becoming quite apparent is that materials from natural sources are excellent
probes (indicators) for cellular targets that when modulated, may well have a
deleterious effect upon the cycling of a tumor cell through the conventional
cell cycle. If the particular target is not expressed in normal cell cycling, then
a directed “perturbation” of the tumor cell’s cycle may well lead to a novel
method of treatment for specific tumor types. In this review we have not
attempted to be exhaustive but have given a current overview of how natural
products from marine, microbial and plant sources have permitted in-depth
analyses of various parts of the cell cycle under varying conditions with the
ultimate aims of attempting to “control or perturb” the cycling of tumor cells
in a fashion that permits their ultimate removal via cellular death, with a
minimum of trauma to the host.
[Back to top] Modulating Cell Cycle: Current Applications
and Prospects for Future Drug Development
Hala
Gali-Muhtasib and Nadine Bakkar
The cell cycle is
a highly conserved and ordered set of events, culminating in cell growth and
division. It is tightly controlled by many regulatory mechanisms that either
permit or restrain its progression. The main families of regulatory proteins
that play key roles in controlling cell cycle progression are the cyclins, the
cyclin dependent kinases (Cdks), their substrate proteins, the Cdk inhibitors
(CKI) and the tumor suppressor gene products, p53 and pRb. Many cell cycle
control genes, when deregulated, can cause cells that are not dividing to enter
the cell cycle and begin to proliferate leading to cancer development. They
do so by interfacing with the basic cell cycle–regulatory machinery to
activate cell cycle entry. There is at present much optimism about the
possibility of finding anticancer drug treatment strategies that modulate cell
cycle regulatory molecules. Candidate targets for such strategies include
crucial cell cycle molecules involved in G1 to S phase or G2
to M phase transition. This review will outline the basic regulatory machinery
responsible for catalyzing cell cycle entry and describe the latest advances
made in the field of cell cycle regulation. The basis of targeting the cell
cycle particularly the Cdks as an approach to developing novel, specific and perhaps
more effective anticancer treatments will be discussed. Examples of novel cell
cycle-targeting agents that are in, or are close to being in clinical trials
will be provided.
[Back to top] Identifying Molecular Targets Mediating the
Anticancer Activity of Histone Deacetylase Inhibitors: A Work in Progress
B.G. Gabrielli, R.W. Johnstone and N.A. Saunders
The anticancer
properties of histone deacetylase inhibitors have been known for some time.
However, it is only recently that the functional identities of the
intracellular targets mediating the anticancer properties have started to be
revealed. These targets appear to play significant roles in cell cycle control,
apoptosis and differentiation. Importantly, the modulation of these activities
is likely to be mediated by alterations in the acetylation status of both
histone and non-histone targets. Identification of these targets, and the
specific histone deacetylase enzymes that modulate them, is an important step
in designing rational-based therapies for the treatment of cancer. In this
review we discuss the state of progress in identifying the molecular
pathways/events mediating the anticancer activity of histone deacetylase
inhibitors.
[Back to top] The Use of Synthetic Oligonucleotides as Protein
Inhibitors and Anticode Drugs in Cancer Therapy: Accomplishments and
Limitations
Marcella Faria and
Henning Ulrich
The function of gene
products can be altered at many levels, including the mutation of gene sequence
and the change in steady state levels of mRNA and/or protein by various
mechanisms. The cumulative malfunction of specific gene products underlies many
pathological conditions such as the multi-step and multi-cause acquisition of
cancer. Here we discuss two oligonucleotide-based strategies in which these
compounds target defective gene products acting either as antiprotein or
anticode agents. The SELEX technique (systematic evolution of ligands by
exponential enrichment) is an antiprotein approach in which nuclease-resistant
DNA or RNA aptamers are selected
by their ability to bind their protein
targets with high affinity and specificity of the same range as antibodies. Such
inhibitors were previously evolved against a great variety of targets,
including receptors, growth factors and adhesion molecules implicated in the
genesis of some kinds of cancer. Moreover, some results have already been
obtained in animal models. The antigene technology interferes with earlier
steps in the information flow leading from gene to protein. In this approach
selective gene silencing is provided by the formation of stable and specific
complexes between triplex forming molecules and their DNA targets. The
feasibility of this strategy as well as a molecular mechanism for the action of
antigene oligonucleotides has been demonstrated in cellular systems and in
vivo. The use of oligonucleotide drugs (of either the antiprotein or the
anticode type) as a viable approach to cancer therapy is limited by some common
problems that will be discussed.