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Current Cancer
Therapy Reviews
ISSN: 1573-3947
Current Cancer Therapy Reviews
Volume 2, Number 2, May 2006
Contents
Human T-Cell Leukemia Virus Type 1: Transition from
Latent Infection to Pathogenic Progression and Implications
for Molecular Therapy Pp. 101-113
Yulia Tabakin-Fix, Inbal Azran-Shaish, Yana Schavinsky
Khrapunsky, Rachel Chamias, Lilach Gohari, Mahmoud Huleihel,
Min Li-Weber and Mordechai Aboud
[Abstract]
Role of NF-κB
and NF-κB-regulated
Gene Products in Chemoresistance and Radioresistance Pp.
115-125
Gautam Sethi and Bharat B. Aggarwal
[Abstract]
Epigenetic Therapies of Cancer Pp. 127-135
Yasmin Bootwala and Debdutta Bandyopadhyay
[Abstract]
Genetic Polymorphisms of Drug Metabolising Enzymes
and Drug Transporters in Relation to Cancer Risk Pp.
137-155
Tessa M. Bosch, Irma Meijerman, Jos H. Beijnen
and Jan H.M. Schellens
[Abstract]
The Insulin-Like Growth Factor (IGF) Signaling Pathway:
Strategies for Successful Therapeutic Tasks in Cancer Treatment
Pp. 157-167
Kai Breuhahn, Tanja Nussbaum, Stephan Singer and
Peter Schirmacher
[Abstract]
Treatment Strategies for Multiple Myeloma in the Age
of Novel Therapies Pp. 169-183
Laurence Catley and Kenneth C. Anderson
[Abstract]
Mechanism of Action and Therapeutic Potential of Novel
Adamantyl Retinoid-Related Molecules Pp. 185-198
F. Javier Piedrafita and Maria A. Ortiz
[Abstract]
Abstracts
[Back to top]
Human T-Cell Leukemia Virus Type 1: Transition from
Latent Infection to Pathogenic Progression and Implications
for Molecular Therapy
Yulia Tabakin-Fix, Inbal Azran-Shaish, Yana Schavinsky
Khrapunsky, Rachel Chamias, Lilach Gohari, Mahmoud Huleihel,
Min Li-Weber and Mordechai Aboud
HTLV-1 is etiologically implicated with adult T-cell leukemia
(ATL) and tropical spastic paraparesis/HTLV-1 associated myelopathy
(TSP/HAM). Neither of them is curable by presently known therapy.
Therefore, both disorders are waiting for novel therapeutic
approaches. Developing such approaches requires comprehensive
insight into the viral and cellular factors involved in the
genesis of these diseases. It is widely accepted that the
viral Tax protein plays a key role in initiating the process
leading to ATL, as well as in the pathogenesis of TSP/HAM.
Therefore, its various activities are attractive targets for
novel molecular or/and immunological therapies. This review
describes the effects of Tax that confer its oncogenic potential.
These effects require a sufficiently high level of Tax protein,
whereas shortly after human infection, the virus enters into
a latent state in which no or very low viral gene expression
and Tax protein can be detected in the infected cells of the
virus carriers. This implies that the dormant virus must be
activated in order to elevate Tax protein to its effective
level. We review here our and others’ data suggesting
that this activation can be triggered by stress-inducing environmental
agents and discuss the mechanism of this activation. In addition,
we discuss the pathogenic progression following this virus
activation and finally we present perspectives for molecular
therapeutic approach for HTLV-1 related clinical disorders.
[Back to top]
Role of NF-κB
and NF-κB-regulated
Gene Products in Chemoresistance and Radioresistance
Gautam Sethi and Bharat B. Aggarwal
Resistance of tumor cells to chemotherapeutic agents and
to radiation is one of the major obstacles in the treatment
of human cancers. The exact mechanism by which cells develop
resistance to chemotherapeutic and radiotherapeutic agents
is not well understood. Accumulating evidences over the last
decade suggests however that transcription factor nuclear
factor-kappa B (NF-κB)
may play an important role in both chemoresistance and radioresistance.
Three lines of evidence support this position. First, most
chemotherapeutic agents and gamma radiation activate NF-κB
in vitro and in vivo. Second, induction
of chemoresistance and radioresistance is mediated via
genes regulated by NF-κB.
Third, inhibition of NF-κB
and NF-κB-regulated
gene products increases sensitivity of cancer cells to apoptotic
action of chemotherapeutic agents and to radiation exposure.
This review focuses on current knowledge of the regulation
of resistance of tumors cells to chemotherapeutic agents and
gamma radiation by NF-κB
and the therapeutic potential of targeting NF-κB
in cancer treatment.
[Back to top]
Epigenetic Therapies of Cancer
Yasmin Bootwala and Debdutta Bandyopadhyay
Modification of chromatin without actually altering its nucleotide
sequence is termed epigenetic modification. These modifications
include changes in methylation, acetylation and phosphorylation
levels of histones as well as methylation of CpG islands in
DNA. Besides these covalent modifications, ATP-dependent alterations
of chromatin topology also represent another level of chromatin
remodeling. All these changes eventually affect expression
of various proteins. Condensation of chromatin structure to
a heterochromatin form leads to silencing of genes whereas
decondensation to euchromatin structures is associated with
de-repression. In general, acetylation of lysine residues
in histones leads to increased expression while methylation
of these residues results in silencing. Methylation of CpG
islands can also lead to gene silencing.
Since cancer is associated with aberrant expression of various
genes caused by epigenetic alteration that are essentially
reversible, targeting epigenetic modifications may serve as
a useful tool to design strategies for cancer therapy. In
the past few years, serious efforts were bestowed to explore
this possibility and different pathways are being tested for
their usefulness as anti-cancer targets. These targets include
the cell cycle, apoptosis and angiogenesis regulatory genes.
Another interesting epigenetic approach under investigation
is to induce senescence in tumor cells. This is based on the
theory that senescence is a potential tumor suppressor mechanism.
In this review we summarize recent findings aimed towards
exploiting epigenetic modification as potent cancer therapeutic
strategies with special emphasis on cell cycle, senescence,
apoptosis and angiogenesis related genes.
[Back to top]
Genetic Polymorphisms of Drug Metabolising Enzymes
and Drug Transporters in Relation to Cancer Risk
Tessa M. Bosch, Irma Meijerman, Jos H. Beijnen
and Jan H.M. Schellens
There is a wide variation in cancer incidence in humans,
which, in part, has been attributed to metabolic factors of
carcinogens and genetic polymorphisms in drug metabolising
enzymes and drug transporters. Drug metabolising enzymes are
responsible for the initial activation of many (pro)carcinogens,
such as polycyclic aromatic hydrocarbons (PAH), to biologically
reactive metabolites. Besides, detoxifying enzymes are responsible
for the inactivation of these active carcinogens and deficiency
of these enzymes may result in an increase of cancer risk
in exposed individuals. Another factor influencing interindividual
variability in cancer incidence is the transporters, which
are responsible for the excretion of carcinogens. A high number
of polymorphisms have been described in drug metabolising
enzymes and drug transporter genes. These polymorphisms might
influence the activity of metabolising enzymes and drug transporters
and thereby affect cancer risk. This review will focus on
the role of genetic polymorphisms of selected drug metabolising
enzymes (CYP1A1, 2C9, 2C19, 3A4, 3A5, UGT1A1, GSTM1, GSTP1,
GSTT1, SULT1A1, NAT1 and NAT2) and ABC-transporters (P-gp
and BRCP) in relation to cancer risk.
[Back to top]
The Insulin-Like Growth Factor (IGF) Signaling Pathway:
Strategies for Successful Therapeutic Tasks in Cancer Treatment
Kai Breuhahn, Tanja Nussbaum, Stephan Singer and
Peter Schirmacher
The insulin-like growth factor (IGF) system involves a complex
network of ligands (IGF-I and IGF-II), receptors (IGF-1R and
IGF-2R), IGF-binding proteins (IGFBP-1 to IGFBP-6), and downstream
intracellular signaling elements. The IGF-axis modulates proliferation
and (anti-)apoptosis in mammals, and it is therefore not surprising
that dysregulation of different pathway components is involved
in the development and progression of several tumor entities
such as breast, prostate, lung, and liver cancer. Because
IGFs, IGF-receptors, and IGFBPs play a critical role in the
emergence of human neoplasias, these molecules have become
the center of special interest as prime targets for potential
anti-cancer therapies. In the last decade, various substances
and experimental strategies, which affect the IGF-induced
signal transduction, have successfully been used in treatment
of neoplasias in vitro and in vivo. These
approaches contain neutralizing antibodies, antagonistic peptides,
selective receptor kinase inhibitors, and (antisense-)oligonucleotides.
[Back to top]
Treatment Strategies for Multiple Myeloma in the Age
of Novel Therapies
Laurence Catley and Kenneth C. Anderson
Melphalan in combination with glucocorticoid steroids has
been an important first-line treatment option for multiple
myeloma (MM) for over 40 years, but response rates have been
only 50-60%, with less than 5% complete remissions (CRs).
More intensive combinations of chemotherapy such as vincristine,
Adriamycin and Dexamethasone (Dex) (VAD) improved objective
response rates to 40%-70%, with 10-17% complete responses,
but overall survival (OS) was not significantly improved.
High-dose therapy with autologous hematopoietic stem cell
transplantation (AHCT) has improved OS by approximately 12
months in three prospective randomized trials, but is not
available to many patients. More recently, novel therapies
thalidomide, the immunomodulatory thalidomide analogue Revlimid,
and the proteasome inhibitor bortezomib have demonstrated
significant activity to overcome drug resistance in patients
with relapsed and refractory MM. Early results indicate that
these novel therapeutics have even more impressive activity
in combination with conventional therapies prior to AHCT,
as well as following AHCT. Furthermore, these novel therapies
should be more widely available to most patients with MM.
[Back to top]
Mechanism of Action and Therapeutic Potential of Novel
Adamantyl Retinoid-Related Molecules
F. Javier Piedrafita and Maria A. Ortiz
Cancer costs the life of over 6 M human beings from around
the world every year. More than 1.3 million new cases are
predicted to be diagnosed only in the USA during 2005 with
over 570,000 deaths estimated. A better understanding of the
molecular basis of carcinogenesis has facilitated progress
towards improving early detection and prevention as well as
the development of more efficient and specific treatments
against certain types of cancer. However, very few successful
anticancer agents exist today and aggressive tumors are still
incurable. Retinoids are natural and synthetic derivatives
of vitamin A, which have shown promise for the prevention
and treatment of cancer because of their cell growth inhibition
and differentiation activities. Unfortunately, their clinical
use has been stalled by significant toxicity caused by the
broad biological responses mediated by the nuclear retinoid
receptors. Synthetic retinoid-related molecules containing
an adamantyl group have been shown to induce apoptosis and
show promising anticancer activity in animal models, therefore
representing optimal leads for the development of novel retinoid-like
anticancer drugs. These compounds induce apoptosis via
the mithochondrial pathway and seem to function independently
of nuclear retinoid receptor activity. In contrast, they have
an effect on various cytosolic signaling pathways, including
activation of stress kinases (cJun N-terminal kinase and p38
kinase) and inhibition of survival kinases (IκB
kinase).
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