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Current
Cancer Therapy Reviews
ISSN: 1573-3947
Current Cancer Therapy Reviews
Volume 4, Number 1, February 2008
Contents
Recent Advances in T Cell Adoptive Immunotherapy of Cancer
Pp. 1-13
Pouneh Dokouhaki and Li Zhang
[Abstract]
Apoptosis Signaling Pathways in Anticancer Therapy
Pp. 14-20
Simone Fulda and Klaus-Michael Debatin
[Abstract]
The Role of Nucleoside Transport in the Antineoplastic
Activity of Purine Nucleoside Chemotherapeutic Agents
Pp. 21-30
Karen M. King and Carol E. Cass
[Abstract]
Membrane Tyrosine Kinase Receptors are an Important
Target for the Therapy of Acute Myeloid Leukemia
Pp. 31-49
Ugo Testa
[Abstract]
Cancer Therapeutics: Emerging Targets and Trends
Pp. 50-56
Mohd. Fahad Ullah
[Abstract]
HER2 in the Era of Molecular Medicine: A Review
Pp. 57-65
Karen A. Callaghan, Rachel E. Ellsworth, Darrell L. Ellsworth
and Craig D. Shriver
[Abstract]
Molecular Replacement in Cancer Therapy: Reversing
Cancer Metabolic and Mitochondrial Dysfunction, Fatigue and
the Adverse Effects of Cancer Therapy Pp.
66-76
Kenneth A. Conklin and Garth L. Nicolson
[Abstract]
Abstracts
[Back to top]
Recent Advances in T Cell Adoptive Immunotherapy of
Cancer
Pouneh Dokouhaki and Li Zhang
Adoptive cell therapy using cytotoxic CD8 +
T lymphocytes (CTL) has shown promising results in recent
clinical trials for cancer patients. Although significant
advances have been achieved in this field, there are still
many issues that need to be addressed before wide application
of adoptive cellular immunotherapy as an adjuvant or mainstream
therapy for various cancers. Difficulties related to the ex
vivo generation of large number of effective antigen-specific
CTLs, their in vivo tracking and short term survival
following adoptive transfer are among the barriers decelerating
the clinical use of this approach. In this review, we focus
on recent developments in adoptive cell therapy using CD8
T cells and discuss the hurdles that need to be overcome.
In addition, current status of adoptive cell transfer using
other T cell populations for cancer immunotherapy that may
circumvent some of the problems related to current protocols
of using CTL is also discussed.
[Back to top]
Apoptosis Signaling Pathways in Anticancer Therapy
Simone Fulda and Klaus-Michael Debatin
One of the most important advances in cancer research
in recent years is the recognition that killing of tumor cells
by anticancer therapies commonly used in the treatment of
cancer, e.g. chemotherapy, γ
-irradiation, immunotherapy or suicide gene therapy, is predominantly
mediated by triggering cell death pathways including apoptosis
in cancer cells. Thus, failure to undergo apoptosis may result
in treatment resistance of cancers. Understanding the molecular
events that regulate apoptosis in response to anticancer therapy
and how cancer cells evade apoptotic cell death, provides
novel perspectives for a more rational approach to develop
molecular targeted therapies for combating cancer.
[Back to top]
The Role of Nucleoside Transport in the Antineoplastic
Activity of Purine Nucleoside Chemotherapeutic Agents
Karen M. King and Carol E. Cass
Purine nucleoside analogues are extensively used in the
treatment of malignancies and viral diseases. For example,
cladribine and fludarabine are two purine nucleoside analogues
that have activity in the treatment of chronic lymphocytic
leukemias. These chemotherapeutic agents exert their cytotoxic
actions through interactions with intracellular targets. Due
to their hydrophilic nature, many purine nucleoside analogues
do not readily diffuse across cell membranes at therapeutic
concentrations. The presence or absence of mediated transport
systems will therefore have an impact on their pharmacological
activities.
There are two families of nucleoside transporters with members
in human (h) cells and tissues: the equilibrative nucleoside
transporters (hENTs) and the concentrative nucleoside transporters
(hCNTs). These transporter proteins mediate the uptake of
both physiologic nucleosides and nucleoside analogue chemotherapeutic
agents. It has been documented that permeant specificity,
tissue distribution and cellular localization of these transporters
contribute to the antineoplastic activity of the purine nucleoside
analogues. This article will review current knowledge of the
role of nucleoside transport proteins in the cytotoxic actions
of purine nucleoside analogues.
[Back to top]
Membrane Tyrosine Kinase Receptors are an Important
Target for the Therapy of Acute Myeloid Leukemia
Ugo Testa
KIT and FLT3 are class III trans membrane tyrosine kinases
playing key roles in the control of hematopoietic stem cell
survival and proliferation. KIT is mutated in about 2.5-3%
of acute myeloid leukemia (AML) patients mainly by point mutations
occurring at the level of tyrosine kinase domains. FLT3 is
mutated in about 30% of AML patients, either by internal tandem
duplication of the juxtamembrane domain or by point mutations
occurring at the level of tyrosine kinase domains. All these
types of mutations lead to the constitutive activation of
KIT and FLT3 receptors, respectively. The occurrence of FLT3/ITD
mutation is associated with a poor prognosis.
These observations have represented the basis for the development
of a relatively large number of Tyrosine Kinase Inhibitors
(TKI) with activity against KIT and FLT3. The majority of
these inhibitors are still in the preclinical phase of study,
while few of them have been tested in phase I/II clinical
studies. Although these inhibitors when used as single agents
have lead to a significant reduction of the number of leukemic
blasts, they have produced only transient and limited clinical
responses. This efficacy may be related to the occurrence
of resistance and to the complexity of the genetic abnormalities
occurring in AMLs. The efficacy of FLT3 TKIs in combination
with standard anti-leukemic chemotherapeutics has been evaluated
in preclinical models and several combination clinical trials
are ongoing and have been planned. It is expected that these
trials could determine an improvement in the negative prognosis
of AML patients with FLT3/ITD mutations. Finally, the combination
of FLT3 TKIs with other molecularly targeted agents inhibiting
other pathways activated in leukemic cells would determine
a major progress in leukemia therapy.
[Back to top]
Cancer Therapeutics: Emerging Targets and Trends
Mohd. Fahad Ullah
Several decades of investigation concerning the cause
and cure of cancer have revealed major discrepancies in the
response of different cancer types towards a particular therapy
and therefore a need for more effective approaches has been
conceived. It is known that cancer development irrespective
of its origin occurs due to the compromises that normal cells
make in critical pathways, thereby allowing to transform into
a tumor. It is thus conceivable that the most effective cancer
therapy requires multiple targeting of molecular alterations
responsible for malignant transformation. In this context,
the development of combinational therapies aimed at multi-cornered
attack on cancer cells is of particular significance. The
present article is a brief review of the novel trends emerging
in cancer therapeutics with special emphasis on epigenetic
therapy, cancer stem cell therapy, modern radiotherapy, target
based cancer therapy and polyphenol therapy.
[Back to top]
HER2 in the Era of Molecular Medicine: A Review
Karen A. Callaghan, Rachel E. Ellsworth, Darrell L. Ellsworth
and Craig D.Shriver
Human epidermal growth factor receptor 2 (HER2) is over-expressed
in 15%–30% of breast cancers. Women with HER2-positive
breast cancer tend to have more aggressive cancer, increased
risk of recurrence, and less favorable survival outcomes than
women with HER2-negative breast cancer. This review focuses
on HER2 and its role in breast cancer pathogenesis. We begin
by providing background information on the biological function
of HER2 and how this gene contributes to breast cancer development
and progression. Next, we review the ongoing debate surrounding
the accuracy of available modalities for detecting HER2, namely
fluorescence in-situ hybridization (FISH) versus
immunohistochemistry (IHC). We include current data examining
the relationship between HER2 and possible genetic modifiers,
such as topoisomerase II
α, BRCA1, and genomic instability in breast cancer
subjects, and how these relationships may influence response
to current therapies directed against HER2. We then discuss
trastuzumab, a monoclonal antibody used to treat HER2+ breast
cancers, and, after providing an overview of the molecular
processes involved in targeted therapy, we summarize the current
literature regarding outcomes, as well as the potential impact
on the overall health of patients, with special attention
to cardiac risk involved with such therapy. Finally, we touch
on future directions in this field, including newer targeted
therapies in development.
[Back to top]
Molecular Replacement in Cancer Therapy: Reversing
Cancer Metabolic and Mitochondrial Dysfunction, Fatigue and
the Adverse Effects of Cance Therapy
Kenneth A. Conklin and Garth L. Nicolson
Introduction: Cancers are associated
with excess cellular oxidative stress, and during cancer treatment
the addition of drug-induced oxidative stress can limit the
effectiveness of therapy and cause a number of side effects,
such as fatigue, nausea, vomiting and diarrhea, as well as
more serious adverse effects, including cardiomyopathy, peripheral
neuropathy, hepatotoxicity and pulmonary fibrosis.
Method: Review of the pertinent
literature on oxidative stress during cancer cytotoxic therapy
and the use of Molecular Replacement methods to reduce adverse
effects by replacement of damaged cellular molecules.
Discussion: Most of the adverse
effects of cancer therapy are due to oxidative stress-mediated
damage to normal tissues. For example, loss of efficiency
in the electron transport chain caused by membrane peroxidation
and reduction in coenzyme Q 10
can occur during cytotoxic therapy using anthracyclines, alkylating
agents, platinum coordination complexes, epipodophyllotoxins
and camptothecins. Molecular Replacement and antioxidant administration
mitigates the damage to normal tissues and reduces the adverse
effects of cancer therapy without loss of therapeutic effect.
Summary: The acute and chronic adverse
effects of cancer chemotherapy can be reduced by Molecular
Replacement. Molecular Replacement of membrane lipids and
enzymatic cofactors, such as coenzyme Q
10 by administering nutritional supplements with
antioxidants can prevent oxidative membrane damage and reductions
of cofactors in normal tissues, respectively, restoring mitochondrial
and other cellular functions and reducing chemotherapy adverse
effects, such as cardiotoxicity, without significantly affecting
therapeutic benefit. Recent clinical trials using cancer and
non-cancer patients with chronic fatigue have shown the benefit
of Molecular Replacement Therapy plus antioxidants in reducing
the damage to mitochondrial membranes, restoring mitochondrial
electron transport function, reducing fatigue and protecting
cellular structures and enzymes from oxidative damage.
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