Current Pharmaceutical Design, Volume 8, No.19, 2002
Gene Therapy Approaches for the Selective
Killing of Cancer Cells
Pp.1683-1694
Eva
Maria Westphal and Harald von Melchner
Chemotherapeutic Potential of Curcumin for
Colorectal Cancer
Pp.1695-1706
D.P.
Chauhan
Epothilones: A Novel Class of Non-taxane
Microtubule-stabilizing Agents
Pp.1707-1712
Ramin
Altaha, Tito Fojo, Eddie Reed and Jame Abraham
Structure Based Design of Benzophenone-Based
Non-Thiol Farnesyltransferase Inhibitors Pp.1713-1722
Martin
Schlitzer
Anti-Cancer Drugs of Today and Tomorrow: Are
we Close to Making the Turn from Treating to Curing Cancer? Pp.1723-1734
Shazib
Pervaiz
Influence of Genomics on Cancer Vaccine
Development – from Guess to Prediction Pp.1735-1748
Joachim
L. Schultze and Heribert Bohlen
Monoclonal
Antibody-Based Therapy Strategies: Providing Options for the Cancer Patient Pp.1749-1764
Diane
E. Milenic
Immune Modulation
by Ionizing Radiation and its Implications for Cancer Immunotherapy Pp.1765-1780
Eric
J. Friedman
[Back to top] Gene Therapy Approaches for the Selective
Killing of Cancer Cells
Eva
Maria Westphal and Harald von Melchner
This review describes gene therapy strategies that take advantage of
defective signal transduction pathways to selectively kill cancer cells without
adversely affecting normal cells. The distinctive features of cancer cells
currently exploited by gene therapy include mitosis, cell permissiveness to
infection, specific protease activity, and the activity of the p53, Rb/E2F and
wnt/catenin signal transduction pathways. In most cases, proof of concept has
been obtained in vitro and in vivo, but only a few approaches made it to the
clinic. Overall, the clinical success rate has been disappointing and it is
concluded that the gene therapy of cancer requires more innovation and hard
work before its potential can be fully realized.
[Back to top] Chemotherapeutic Potential of Curcumin for
Colorectal Cancer
D.P.
Chauhan
Colorectal cancer is one of the leading causes of cancer deaths in the
Western world. More than 56,000 newly diagnosed colorectal cancer patients die
each year in the United States. Available therapies are either not effective or
have unwanted side effects. Epidemiological data suggest that dietary
manipulations play an important role in the prevention of many human cancers.
Curcumin the yellow pigment in turmeric has been widely used for centuries in
the Asian countries without any toxic effects. Epidemiological data also
suggest that curcumin may be responsible for the lower rate of colorectal
cancer in these countries. Curcumin is a naturally occurring powerful
anti-inflammatory medicine. The anticancer properties of curcumin have been
shown in cultured cells and animal studies. Curcumin inhibits lipooxygenase
activity and is a specific inhibitor of cyclooxygenase-2 expression. Curcumin
inhibits the initiation of carcinogenesis by inhibiting the cytochrome P-450
enzyme activity and increasing the levels of glutathione-S-transferase.
Curcumin inhibits the promotion/progression stages of carcinogenesis. The
anti-tumor effect of curcumin has been attributed in part to the arrest of cancer
cells in S, G2/M cell cycle phase and induction of apoptosis. Curcumin inhibits
the growth of DNA mismatch repair defective colon cancer cells. Therefore,
curcumin may have value as a safe chemotherapeutic agent for the treatment of
tumors exhibiting DNA mismatch repair deficient and microsatellite instable
phenotype. Curcumin should be considered as a safe, non-toxic and easy to use
chemotherapeutic agent for colorectal cancers arise in the setting of
chromosomal instability as well as microsatellite instability.
[Back to top] Epothilones: A Novel Class of Non-taxane
Microtubule-stabilizing Agents
Ramin
Altaha, Tito Fojo, Eddie Reed and Jame Abraham
The epothilones are a novel class of non-taxane microtubule-stabilizing
agents obtained from the fermentation of the cellulose degrading myxobacteria,
Sorangium cellulosum. Preclinical studies have shown that the epothilones are
more potent than the taxanes and active in some taxane-resistant models.
Similar to paclitaxel and other taxanes, the epothilones block cells in
mitosis, resulting in cell death. The chief components of the fermentation
process are epothilones A and B, with epothilones C and D found in smaller
amounts. Trace amounts of other epothilones have also been detected.
Pre-clinical studies have shown that epothilone B is the most active form,
exhibiting significantly higher antitumor activity than paclitaxel and
docetaxel. Several phase I and phase II clinical trials are ongoing with
epothilone B and BMS 247550, an epothilone B analog. Preliminary reports
indicate these agents are active against human cancers in heavily pretreated
patients. The epothilones appear to be well tolerated, with a side effect
profile that is similar to that reported with the taxanes. This article will
review some basic aspects of epothilone chemistry and biology, and pre-clinical
and preliminary clinical experience with epothilone B and its analog, BMS
247550.
[Back to top] Structure Based Design of Benzophenone-Based
Non-Thiol Farnesyltransferase Inhibitors
Martin
Schlitzer
Farnesyltransferase catalyzes the transfer of a farnesyl residue from
farnesylpyrophosphate to the thiol of a cysteine side chain of proteins which
carry at the C-terminus the so called CAAX-sequence. Although the exact
cellular events affected by farnesyltransferase inhibiton remain to be
determined, farnesyltransferase has become a major target in the development of
potential anti-cancer drugs. Numerous farnesyltransferase inhibitors have been
described from which the majority are CAAX-peptidomimetics possessing a free
thiol group which coordinates the enzyme-bound zinc ion. The development of
farnesyltransferase inhibitors is clearly directed towards the so-called
non-thiol farnesyltransferase inhibitors because of adverse drug effects
connected to free thiols. This review mainly deals with the efforts of the
authers group towards the design of non-thiol-farnesyltransferase inhibitors.
Our first step on the way to non-thiol farnesyltransferase inhibitors was the
development of an CAAX-peptidomimetic based on a pharmacophore model. On the
basis of this benzophenone core, bisubstrate analogues were developed as one
class of non-thiol farnesyltransferase inhibitors. In most non-thiol farnesyltransferase
inhibitors known in literature nitrogene containing heterocycles are used as
cysteine replacements supposedly coordinating the enzyme bound zinc. However,
we and others have shown that nitrogen heterocycles can be replaced by aryl
residues lacking the ability to coordinate metal atoms, an observation which
let to the postulation of two hitherto unknown aryl binding sites. Using
flexible docking of model compounds and GRID analysis we were able to locate
these postulated aryl binding sites. Subsequently, we used one of this aryl
binding sites for the structure based design of highly active non-thiol
farnesyltransferase inhibitors.
[Back to top] Anti-Cancer Drugs of Today and Tomorrow: Are
we Close to Making the Turn from Treating to Curing Cancer?
Shazib
Pervaiz
Therapeutic management of cancer has undergone tremendous conceptual
advance over the last couple of decades. Not only are we better acquainted with
the intricate mechanisms leading to oncogenic transformation, but also the
strategies to intercept and disturb these command and control pathways are
becoming more specific and target-selective. One critical change is the
realization that despite the existence of diverse mechanisms for the
development of different sub-sets of cancers, there may indeed be central
regulatory networks that serve as a common denominator in all forms of
neoplasia. These critical events could endow cells with the potential for
unabated proliferation, insensitivity to death inducing signals, and enhanced
metastatic potential. Thus, developing strategies to target these critical
events or pathways should significantly improve the outcome of cancer
chemotherapy. The purpose of this review is to briefly discuss the complexities
of the disease, highlight the current therapeutic strategies, and more
importantly provide a mechanistic approach for future drug design aimed at
targeting the traits of the disease and for favorably tailoring the response of
cancer cells to drug therapy.
[Back to top] Influence of Genomics on Cancer Vaccine Development – from Guess to
Prediction
Joachim
L. Schultze and Heribert Bohlen
After more than 100 years since the first adjuvant for a cancer vaccine
was described and more than a decade since the first tumor antigen has been
molecularly cloned, it seems possible that cancer vaccines might be integrated
into the standard care of cancer patients. Exciting new technologies concerning
tumor antigen discovery, vaccine delivery and formulation define the basis for
enormous efforts in academia as well as in the pharmaceutical and biotech
industry. With the unveiling of the human genome additional targets will emerge
that could further enhance vaccine efficacy, specificity and clinical
applicability. Most likely therefore, tumor antigen targets which are widely
expressed in cancer will be of advantage over patient-oriented approaches due
to their favorable cost-to-benefit ratio. Some widely expressed candidate tumor
antigens and methods to discover additional widely expressed tumor antigens are
discussed here. While the armamentarium of potential tools to cancer vaccine
development seems to be endless, only those that are scientifically sound yet
economically reasonable will – in the end – have a chance to become clinically
useful cancer vaccines.
[Back to top] Monoclonal Antibody-Based Therapy Strategies:
Providing Options for the Cancer Patient
Diane
E. Milenic
Treatment of patients with unconjugated MAb such as rituximab (Rituxan)
the anti-CD20 MAb or trastuzumab (Herceptin) the anti-Her2 MAb, have shown
efficacy in clinical trials and have gained approval from the Food and Drug
Administration (FDA) has a result. Likewise, an anti-CD33 MAb conjugated with
the antibiotic calicheamicin (Mylotarg) has proven efficacious in the treatment
of patients with acute myeloid leukemia and has also been approved by the FDA.
This overview presents some of the monoclonal antibody (MAb)-guided strategies
with a focus on some of the experiences reported for MAb evaluated in clinical
trials.
[Back to top] Immune Modulation by Ionizing Radiation and
its Implications for Cancer Immunotherapy
Eric
J. Friedman
Ionizing radiation exhibits immunomodulatory properties, which could
portend a future collaboration of cancer immunotherapy with radiation therapy.
The “danger” model of immunity describes antigen-specific cellular immunity
engendered by an inflammatory milieu. Dendritic cells (DCs) are attracted to
this microenvironment, undergoing maturation after internalizing apoptotic and
necrotic cellular debris.Mature DCs mediate antigen-specific cellular immunity
via presentation of processed antigen to T cells.Administration of radiation
has been utilized in vitro and in vivo to create an inflammatory setting, via
induction of apoptosis, necrosis, cell surface molecules, and secretory
molecules. Caspase-mediated cellular apoptosis is induced by radiation thro ugh
multiple signaling pathways. Radiation upregulates expression of
immunomodulatory surface molecules (MHC, costimulatory molecules, adhesion
molecules, death receptors, heat shock proteins) and secretory molecules
(cytokines, inflammatory mediators) in tumor, stromal, and vascular endothelial
cells. Results of animal studies indicate possible radiation-mediated
modulation of tumor antigen-specific immunity. Experimental data could indicate
that the radiation-induced “danger” microenvironment engenders a DC-mediated
antigen-specific immune response. Further enhancement of radiation-mediated
inflammation and cell death can be achieved via administration of
radiosensitizing pharmaceuticals. Radiation-mediated immune modulation
currently remains unquantified and poorly understood. A major research effort
will be required to elucidate mechanisms of action. With a thorough
understanding of this phenomenon, we believe that ionizing radiation could be
optimized for use with cancer vaccines and generate tumor antigen-specific
cellular immunity.