Current Drug Targets, Volume 5, No. 4, 2004
Contents
Cellular
Targets for Anti-Cancer Therapy
Guest
Editor: Alexander A. Shtil
Intractable Cancers: The Many Faces of
Multidrug Resistance and the Many Targets it Presents for Therapeutic Attack Pp.333-346
Stein
W.D., Bates S.E. and Fojo T.
Cellular Targets for Anticancer Strategies Pp.347-355
Caterina
A.M. La Porta
DNA-Binding Properties of Poly(ADP-Ribose)
Polymerase: A Target for Anti-Cancer Therapy Pp.357-365
V.A.
Soldatenkov and V.N. Potaman
CARD Proteins as Therapeutic Targets in
Cancer Pp.367-374
Jason
S. Damiano and John C. Reed
Sphingolipid Metabolism Enzymes as Targets
for Anti-Cancer Therapy
Pp.375-382
J.W.
Kok, and H. Sietsma
Potential for Predicting Toxicity and
Response of Fluoropyrimidines in Patients. Pp 383-388
James F. Eliason and Attila Megyeri
Molecular Targeting of Drug Delivery Systems
to Cancer . Pp 389-406
T. Minko, S.S. Dharap, R.I. Pakunlu and Y. Wang
Abstracts
[Back to top] Intractable Cancers: The Many Faces of
Multidrug Resistance and the Many Targets it Presents for Therapeutic Attack
Stein
W.D., Bates S.E. and Fojo T.
Some types of
cancer respond far less favorably to treatment than do others. A quantitative
estimate of this intuition can
be obtained from the.The SEER (Surveillance, Epidemiology and
End-Results) Cancer Statistics Review. Of particular interest, from a drug resistance contextperspective,,
are the five-year survival data for patients presenting with tumors that were
diagnosed as “distant”. A good correlation can be found between those numbers
and an estimate of treatment successes obtained from a survey of current
literature on chemotherapy applied to cancers originating from these various
tissues. These two measures, considered together, define “the axis of
intractability”, a parameter that characterizes the (possibly) inherent,
physiological basis of the tissue-by-tissue intractability of cancers.
Exploring the basis of this intractability, it appears that factors other than
the classical ABC transporter-based, multidrug resistance systems probably play
a major role. An ineffective DNA repair system, coupled to reduced apoptosis,
is the basis for the inherent tractability of testicular cancer. For other
tissues, important contributions to resistance arise from cell
adhesion-mediated drug resistance, which is overcome when cells are released
from tissues during anoikis. Making a direct comparison between gene expression
in solid tumors and their corresponding cell lines, genes controlling the
extracellular matrix and cell-cell communication appear among the genes that
are over-expressed in the solid tumors, while genes coding for the protein
biosynthesis system are over-expressed in the cell lines. The more tractable
cancers are closer to the cell lines in their expression profiles of these sets
of genes.
[Back to top] Cellular Targets for Anticancer Strategies
Caterina
A.M. La Porta
Since late 1950s the
main strategies to treat cancer, besides surgery, have been radiotherapy or
chemotherapy. These approaches work primarily by damaging proliferating cells
at the level of DNA replication or cell division, and inducing apoptotic cell
suicide as a secondary response to the damage. In recent years, efforts to
improve cancer therapy have focused on the development of more selective,
biological mechanism based approaches that can help to overcome tumor
resistance as well as minimize toxic side effects. In the present review new
strategies and new targets for biological cancer therapy will be discussed. In
particular, new angiogenic pathways discovered in melanoma will be discussed in
relationship to a more efficient anticancer strategy. In summary, this review
tries to identify the most logical targets and the most useful mechanisms of
tumor inhibition in light of new knowledge from the basic research including
human genome project.
[Back to top] DNA-Binding Properties of Poly(ADP-Ribose)
Polymerase: A Target for Anti-Cancer Therapy
V.A.
Soldatenkov and V.N. Potaman
Poly(ADP-ribose)
polymerization is a unique post-translation protein modification that utilizes
an ADP-ribose moiety from NAD+ to form long and branched polymers
attached via glutamic acid residues to nuclear acceptor proteins. The
corresponding enzyme, poly(ADP-ribose) polymerase (PARP-1), is a zinc
finger-containing protein, which allows PARP-1 binding to either double- or
single-strand DNA breaks. The catalytic activity of PARP-1 is strictly
dependent on the presence of strand breaks in DNA, and is modulated by the
level of automodification. PARP-1 is regarded as an intracellular sensor for
DNA strand breaks, and its function has been implicated in cellular processes
that require DNA cleavage and rejoining reactions, such as DNA replication,
recombination and repair. Recent studies have also implicated PARP-1 in the
regulation of gene expression through modification of transcription factors by
poly(ADP-ribosyl)ation or its direct binding to gene-regulating DNA sequences.
The latter is attributable to PARP’s ability to recognize and bind to various
structural discontinuities in the DNA duplex in the absence of DNA strand
breaks, such as three- or four-way junctions, bent DNA, and base unpaired
regions. Cumulatively, these findings indicate that PARP-1 plays a pivotal role
in the maintenance of the genome integrity during the normal functioning of
eukaryotic cells as well as in the cellular responses to DNA damage, and that
PARP-DNA interactions are indispensable for PARP function. This review
summarizes the data on DNA-binding properties of PARP-1 and relates them to the
development of strategies for sensitizing tumor cells to genotoxic treatments.
[Back to top] CARD Proteins as Therapeutic Targets in
Cancer
Jason
S. Damiano and John C. Reed
Proteins containing a caspase-associated recruitment domain (CARD) have been established as key regulators of cell death and, more recently, cytokine production. During the last several years, the number of proteins identified within this family has grown immensely and many aspects of their function point to their potential utility as novel drug targets in the treatment of cancer. Several CARD family proteins are critical components of the conserved cell death machinery which, when dysregulated, promotes oncogenesis and contributes prominently to tumor resistance to chemotherapy. The pro-apoptotic protein Apaf1, which is inactivated in some cancers, is a CARD protein that is indispensable for mitochondria-induced apoptosis. Other anti-apoptotic CARD proteins, such as TUCAN/CARDINAL/ CARD8, have been shown to protect tumors from cell death stimuli and to be over-expressed in certain forms of cancer. Therapeutics that activate or inhibit CARD proteins may therefore be potentially utilized as novel chemo-sensitizing agents when used in conjunction with conventional chemotherapy. Other CARD proteins influence cellular processes through the regulation of NF-kB or caspase-1, which governs the levels of interleukin-1b (IL-1b). In addition to its pro-inflammatory properties, this cytokine also contributes to neoplastic progression by promoting angiogenesis, proliferation, and the metastasis of many tumors. Many of the IL-1b-regulating CARD proteins also contain a nucleotide binding/oligomerization domain known as a NACHT and may therefore be amenable to targeting by small molecule compounds. This review examines the role of CARD proteins in cytoprotection and cytokine processing in the context of neoplasia and presents strategies for using this information in devising potential novel anticancer agents.
[Back to top] Sphingolipid Metabolism Enzymes as Targets for Anti-Cancer Therapy
J.W.
Kok, and H. Sietsma
Treatment with
anti-cancer agents in most cases ultimately results in apoptotic cell death of
the target tumor cells. Unfortunately, tumor cells can develop multidrug resistance,
e.g., by a reduced propensity to engage in apoptosis by which they become
insensitive to multiple chemotherapeutics. Ceramide, the central molecule in
cellular sphingolipid metabolism, has been recognized as an important mediator
of apoptosis. Moreover, an increased cellular capacity for ceramide
glycosylation has been identified as a novel multidrug resistance mechanism.
Indeed, virtually all multidrug resistant cell types exhibit a deviating
sphingolipid composition, most typically an increased level of
glucosylceramide. Thus, the enzyme glucosylceramide synthase, which converts
ceramide into glucosylceramide, has emerged as a potential target to increase
apoptosis and decrease drug resistance of tumor cells. In addition, several
other steps in the pathways of sphingolipid metabolism are altered in multidrug
resistant cells, opening a perspective on additional sphingolipid metabolism
enzymes as targets for anti-cancer therapy. In this article, we present an
overview of the current understanding concerning drug resistance-related
changes in sphingolipid metabolism and how interference with this metabolism
can be exploited to over come multidrug resistance.
[Back to top] Potential for Predicting Toxicity and Response of Fluoropyrimidines in
Patients
James
F. Eliason and Attila Megyeri
The efficacy of
cancer therapy is compromised by the fact that there are currently no good ways
to predict which patients will benefit from treatment. This long standing goal
is closer to becoming a reality as more is learned about the molecules that
affect the activities of various therapeutic agents. The fluoropyrimidine
antimetabolites drugs have been in clinical use for over 4 decades and the
cellular proteins important for their activities have been studied in detail.
The most important are the major target enzyme, thymidylate synthase (TS) and
the rate limiting enzyme in the degradation pathway, dihydropyrimidine
dehydrogenase (DPD), equally important for the analogue capecitabine is
thymidine phosphorylase (TP), which is rate limiting for activation of this
prodrug. A number of assays are available for these enzymes, including enzyme
activity measurements, quantitative PCR for RNA expression and immunological
methods for protein expression. With each of these methods, more clinical
studies are required to validate their clinical usefulness.
[Back to top] Molecular Targeting of Drug Delivery Systems to Cancer
T.
Minko, S.S. Dharap, R.I. Pakunlu and Y. Wang
This review
presents molecular targeting approaches in anticancer drug delivery systems
(DDS) and identifies new developments in these systems. Targeting approaches
include passive targeting (enhanced permeability and retention effect),
targeting specific tumor conditions, topical delivery and active targeting,
namely, targeting organs, cells, intracellular organelles and molecules,
sandwich targeting, promoter targeting, indirect targeting and targeting by
external stimuli. A novel advanced proapoptotic anticancer DDS that utilizes
several molecular targets will be considered. Experimental data suggest that
this DDS can simultaneously: (1) induce cell death; (2) prevent adverse effects
on healthy tissues; (3) suppress and prevent multidrug resistance; and (4)
inhibit cellular antiapoptotic defense.