Current Cancer Drug Targets, Volume 2, No. 1, 2002
Prospects for Anti-Neoplastic Therapies Based
on Telomere Biology Pp.1-17
Sheila
A. Stewart and William C. Hahn
Diphtheria Fusion Protein Therapy of
Chemoresistant Malignancies
Pp.19-36
Arthur
E. Frankel, Patrick Rossi, Timothy M. Kuzel and Francine Foss
Integrins as Novel Drug Targets for
Overcoming Innate Drug Resistance Pp.37-43
Jason
S. Damiano
WT1 as a Novel Target Antigen for Cancer
Immunotherapy Pp.45-54
Y.
Oka, A. Tsuboi, O. A. Elisseeva, K. Udaka and H. Sugiyama
Sulfonamides and Sulfonylated Derivatives as
Anticancer Agents Pp. 55-75
Angela
Casini, Andrea Scozzafava, Antonio Mastrolorenzo and Claudiu T. Supuran
Receptor Selective Synthetic Retinoids as
Potential Cancer Chemotherapy Agents Pp.77-86
D. L. Crowe
[Back to top]
Prospects for Anti-Neoplastic Therapies Based
on Telomere Biology
Sheila A. Stewart and William C. Hahn
The maintenance of
specialized nucleoprotein structures at the ends of human chromosomes called
telomeres is essential for chromosome stability, and plays a fundamental role
in the regulation of cellular lifespan. Without new synthesis of telome-res,
chromosome ends shorten with progressive cell division, eventually triggering
either replicative senescence or apoptosis when telomere length becomes
critically short. The regulation of telomerase activity in human cells plays a
significant role in the development of cancer. Telomerase is tightly repressed
in the vast majority of normal human
somatic cells but becomes activated during cell immortalization and in cancers.
Recent work has demonstrated that inhibiting or targeting telomerase shows
promise as a novel anti-neoplastic
strategy; however, the biology of telomeres and telomerase predict that
such approaches will differ in important ways from traditional cytotoxic drug
therapies. Understanding telomerase biology may eventually lead to several
types of clinically effective, telomerase-based therapies for neoplastic
disease.
[Back to top]
Diphtheria Fusion Protein Therapy of
Chemoresistant Malignancies
Arthur
E. Frankel, Patrick Rossi, Timothy M. Kuzel and Francine Foss
Patients with
widespread cancer respond initially to combination chemotherapy, immunotherapy,
and/or radiotherapy, but most relapse with chemoresistant disease. Novel
methods of killing resistant neoplastic stem cells are needed. One such
approach is therapy with targeted toxins composed of tumor cell selective
ligands covalently linked to group I peptide toxins (group II and III peptide
toxins act on the cell surface). The targeted toxin is delivered to the cell by
a tumor selective ligand. Once bound, the ligandreceptor complex is
internalized. The catalytic domain escapes to the cytosol. The toxin then
enzymatically modifies a critical cell function (protein synthesis, p21 Rho
activity, protein kinase signaling, cyclic AMP signaling or others). The
irreversibly damaged cells fails to divide and, eventually, undergoes lysis or
programmed cell death. Targeted peptide toxins used to date in the treatment of
chemotherapy refractory cancers include ricin toxin, Pseudomonas exotoxin, pokeweed
antiviral protein, saporin, gelonin and diphtheria toxin. In this review, we
have focused on the applications of genetically engineered diphtheria toxin for
cancer therapy.
[Back to
top] Integrins as Novel Drug Targets for
Overcoming Innate Drug Resistance
Jason S. Damiano
Acquired drug
resistance continues to be one of the major obstacles hindering the successful
treatment of many forms of cancer. Compounds utilized as antagonists of these
cytoprotective mechanisms have, for the most part, proven to be ineffective at
overcoming clinical resistance to cytotoxic drugs. Recently, the tumor
cell microenvironment has been found to
have a significant bearing on the survival of tumor cells following exposure to
a wide variety of anti-neoplastic agents, prior to the acquisition of known
drug resistance mechanisms. Specifically, interactions between cell surface
integrins and extracellular matrix components have been shown to be responsible
for this phenomenon of innate drug resistance, which we have termed Cell
Adhesion Mediated Drug Resistance, or CAM-DR. Following its discovery using a
multiple myeloma cell line model, evidence for CAM-DR has been found in a
multitude of other human tumor cell types. In contrast to many other drug
resistance mechanisms, integrin-mediated cell signaling is capable of
protecting against death induced by an extremely wide variety of structurally
and functionally diverse agents from traditional DNA damaging agents to the
promising novel kinase inhibitor STI-571. This review examines the role of
integrins in regard to their ability to protect tumor cells from drug- and
radiation-induced apoptosis through numerous intracellular mechanisms. Current
and future antagonists of specific integrin heterodimers may have the potential
to sensitize tumor cells when used in combination with standard chemotherapy
regimens. Specific signal transduction pathways initiated by integrin ligation
will also be discussed as potential bridge points for inhibiting cell survival
during cytotoxic drug exposure.
[Back to top] WT1 as a Novel Target Antigen for Cancer
Immunotherapy
Y. Oka, A. Tsuboi, O. A. Elisseeva, K. Udaka and H.
Sugiyama
Wild-type Wilms’
tumor gene WT1 is expressed at high levels not only in most of acute
myelocytic, acute lymphocytic, and chronic myelocytic leukemia, but also in
various types of solid tumors including lung cancer. We tested the ability of
the gene product (WT1) to serve as a target antigen for tumor –specific
immunotherapy both in human in vitro system and mouse in vivo system. In the
latter, we can evaluate the efficacy and the side effects of WT1 vaccination in
vivo. In the human in vitro system, two WT1 peptides that contain HLA-A2.1
binding anchor motifs were determined to bind to HLA-A2.1 molecules. Peripheral
blood mononuclear cells (PBMC) from an HLA-A2.1-psitive donor were repeatedly
stimulated in vitro with TAP-deficient T2 cells pulsed with each of these two
peptides, and CD8-positive cytotoxic T lymphocytes (CTLs) that specifically
lyse WT1-expressing, HLA-A2.1-positive tumor cells were induced. Other groups
also have succeeded in generating CTLs which specifically lyse WT1-expressing
leukemia cells, and which do not inhibit colony-formation of normal
hematopoietic cells that express WT1 at physiological levels. In the mouse in
vivo system, immunization of C57BL/6 mice with one WT1 peptide with relatively
high binding affinity for H-2Db molecules, which contain H-2Db
binding anchor motifs, induced CTLs, which specifically lysed WT1-expressing
tumor cells in an H-2Db –restricted manner. Furthermore, mice
immunized with the WT1 peptide (peptide vaccination) or WT1 cDNA (DNA
vaccination) rejected challenges by WT1-expressing tumor cells and survived
with no signs of auto-aggression to WT1-expressing normal organs by the induced
CTLs. The WT1 protein has been identified as a novel tumor antigen and recent
investigations provide a rationale for developing WT1-based adoptive T cell
therapy and vaccination against various kinds of malignant neoplasms.
[Back to
top] Sulfonamides and Sulfonylated Derivatives as
Anticancer Agents
Angela Casini, Andrea Scozzafava, Antonio Mastrolorenzo
and Claudiu T. Supuran
The sulfonamides
constitute an important class of drugs, with several types of pharmacological agents
possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycemic and
antithyroid activity among others. A host of structurally novel sulfonamide
derivatives have recently been reported to show substantial antitumor activity in
vitro and/or in vivo. Although they have a common chemical motif of aromatic/heterocyclic
sulfonamide, there are a variety of mechanisms of their antitumor action, such
as carbonic anhydrase inhibition, cell cycle arrest in the G1 phase, disruption
of microtubule assembly, functional suppression of the transcriptional
activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition
among others. Some of these compounds selected via elaborate preclinical
screenings or obtained based on computer-aided drug design, are currently being
evaluated in clinical trials. This review summarizes recent classes of
sulfonamides and related sulfonyl derivatives disclosed ultimately as effective
tumor cell growth inhibitors, or for the treatment of different types of
cancer.
[Back to
top] Receptor Selective Synthetic Retinoids as
Potential Cancer Chemotherapy Agents
D. L. Crowe
For many years,
the vitamin A metabolite retinoic acid (RA) has been known to have profound
effects on development, cellular proliferation and differentiation, and tumor
growth and invasion. The wide-ranging effects of RA on cellular proliferation
and migration have made it a useful chemotherapeutic agent in the treatment of
many types of cancer. In the last fifteen years, with the discovery of nuclear
receptors for RA, the molecular basis for the effects of this molecule has
become apparent. Retinoic acid receptors (RAR) are members of a superfamily of
ligand dependent transcription factors that interact with an increasingly large
array of coactivators and repressors to regulate target gene expression through
binding to cognate recognition sequences in the promoters of these genes.
Alterations in RAR expression and function have been demonstrated in many types
of cancer. The translocation of RARa with PML
or PLZF genes in acute promyelocytic leukemia is a paradigm of the role of RARs
in cancer biology. In addition, the development of receptor selective synthetic
retinoids has greatly expanded our knowledge of RAR function in tumor cells and
provided additional treatment options for cancer patients. This review will
examine the development of receptor selective retinoids, their uses to date,
and future potential.