| Current
Cancer Therapy Reviews
ISSN: 1573-3947
Current Cancer Therapy Reviews
Volume 1, Number 1, January 2005
Contents
Targeting Established Tumor Vasculature: A Novel
Approach to Cancer Treatment Pp.1-9
Lloyd R. Kelland
[Abstract] [Full
text article]
RNA Interference: A New Targeted Tumour Therapy?
Pp.11-17
Jane M.E. Withey and Mark R. Crompton
[Abstract] [Full
text article]
Therapeutic Strategies for Papillary Microcarcinoma
of the Thyroid Pp.19-25
Yasuhiro Ito and Akira Miyauchi
[Abstract] [Full
text article]
EBV-Associated Tumors: Pathogenetic Insights for
Improved Disease Monitoring and Treatment Pp.27-44
Riccardo Dolcetti, Massimo Guidoboni, Annunziata Gloghini
and Antonino Carbone
[Abstract] [Full
text article]
Src Family Kinases as Regulators of Angiogenesis:
Therapeutic Implications Pp.45-50
Donald P. Lesslie III and Gary E. Gallick
[Abstract] [Full
text article]
Membrane Receptor and Antiangiogenic Targeted
Therapies in the Treatment of Cancer Pp.51-61
Antonio Jimeno and Hernan Cortes-Funes
[Abstract] [Full
text article]
New Approaches to Postoperative Radiotherapy for
Cancer of the Head and Neck Pp.63-70
Perri Prellop and Roger Ove
[Abstract] [Full
text article]
Metastasis and Recurrence After Surgical Resection
of Hepatocellular Carcinoma: Recent Progress in Clinical and
Related Basic Aspects Pp.71-80
Lun-Xiu Qin and Zhao-You Tang
[Abstract] [Full
text article]
The Role of Chemokines and their Receptors in
Tumor Progression and Invasion: Potential New Targets of Biological
Therapy Pp.81-92
Paola Allavena, Federica Marchesi and Alberto Mantovani
[Abstract] [Full
text article]
Imatinib Mesylate: Targeted Therapy of Gastrointestinal
Stromal Tumor Pp.93-108
Jonathan C. Trent, Jheri Dupart and Wei Zhang
[Abstract] [Full
text article]
Cancer Prevention with Green Tea Polyphenols for
the General Population, and for Patients Following Cancer
Treatment Pp.109-114
Hirota Fujiki, Masami Suganuma, Satoru Matsuyama and Kohji
Miyazaki
[Abstract] [Full
text article]
Abstracts
[Back to top]
Targeting Established Tumor Vasculature: A Novel Approach
to Cancer Treatment
Lloyd R. Kelland
[Full text
article]
The selective targeting of established tumor vasculature
represents an attractive new anticancer drug strategy, distinct
from inhibiting angiogenesis. This is based on the concept
that, in contrast to targeting individual tumor cells, the
killing of relatively few vascular endothelial cells could
result in the death of a large area of tumor (from lack of
oxygen and nutrients), drug delivery to vasculature is less
challenging than to large solid tumors (which may harbor regions
of hypoxia) and, moreover, cells that comprise vasculature
(such as endothelial cells) are more genetically stable than
tumor cells and hence less likely to acquire changes causing
drug resistance. There is accumulating evidence that there
are inherent differences in the vasculature of tumors, both
morphologic and biochemical, in comparison to normal organs,
thus providing a rational basis for this approach. Vascular
disrupting agents (VDAs) are now being tested clinically;
several are also in late preclinical development. A major
class of small molecule VDA is those targeting tubulin, e.g.,
combretastatin A4 phosphate (CA4P), ZD6126 and AVE8062A. Another
distinct non-tubulin based compound, the flavonoid 5,6-dimethyl
xanthenone 4-acetic acid (DMXAA, AS1404) induces direct apoptosis
of endothelial cells and secondary induction of various vasoactive
agents (such as serotonin and tumor necrosis factor α).
These agents have all completed Phase I clinical evaluation;
dose-limiting toxicities are generally non-overlapping with
conventional cytotoxics; there has been evidence of efficacy.
A common theme, now being pursued clinically, is that VDAs
are expected to show maximum therapeutic benefit when used,
intermittently rather than chronically and in combination
with either conventional cytotoxics (such as platins or taxanes)
or radiotherapy. Thereby, complementary kill of the central
compartment of tumors (by VDAs) and the proliferating, well
oxygenated, periphery (by cytotoxics or radiotherapy), is
predicted. Non-invasive imaging techniques such as dynamic
contrast enhanced magnetic resonance imaging (DCE-MRI) have
proven useful in the clinical monitoring of VDAs. A variety
of additional small molecule anti-tubulin agents, N-cadherin
inhibitors and antibody-based products (e.g., delivering effectors
such as tissue factor to tumor blood vessels) are in earlier
stages of development. The vascular targeting field is entering
a particularly exciting phase; the next 1-2 years will be
crucial in establishing clinical proof of principle for this
approach.
[Back to top]
RNA Interference: A New Targeted Tumour Therapy?
Jane M.E. Withey and Mark R. Crompton
[Full text
article]
RNA interference (RNAi) is a mechanism in which double-stranded
(ds) RNA acts as a guide to sequence-specifically suppress
gene expression. To achieve targeted ‘knock-downs’
of gene function in mammalian cells, in vitro synthesised
small interfering RNAs (siRNAs) can be introduced transiently
into cells or, for more stable suppression by RNAi, various
vector strategies can be employed to achieve prolonged in
vivo synthesis of targeting RNA sequences.
RNAi, beyond being a powerful experimental tool, has been
widely promoted as a future gene-targeted therapeutic strategy
of exquisite specificity. In the context of cancer, in which
mutation, over-expression and de-novo acquisition
of tumour-promoting genes are of central importance to the
pathology, multiple molecular targets have been proposed for
RNAi-based therapies. In this review, we will summarise what
is known about the biology of RNAi in mammalian cells, outline
the various expression and delivery strategies that have been
developed, and discuss the features of possible therapeutic
gene targets. We will also highlight the present technical
limitations of RNAi that will need to be addressed if it is
to be developed therapeutically, including the important issues
of effective delivery and the potential for development of
tumour resistance.
[Back to top]
Therapeutic Strategies for Papillary Microcarcinoma
of the Thyroid
Yasuhiro Ito and Akira Miyauchi
[Full text
article]
Papillary carcinoma of the thyroid is a common malignancy
originating from the endocrine organs. The recent prevalence
of ultrasonography (US) and US-guided fine needle aspiration
biopsy (FNAB) can make us easily diagnose papillary carcinoma
of 1.0 cm or less in maximal diameter, which is called papillary
microcarcinoma. How to treat papillary microcarcinoma has
been controversial. In autopsy studies, papillary carcinoma
of 3-9.9 mm is frequently found as an occult carcinoma. Furthermore,
papillary carcinoma of more than 3 mm was detected in 3.5%
of otherwise healthy women aged 30 years or older by mass
screening using US and FNAB, and 84% of them were less than
1.5 cm in diameter. These findings indicate that papillary
microcarcinoma frequently remains occult. Thus, recently,
a trial of observation without surgical treatment has been
performed, which demonstrates that most papillary microcarcinoma
do not grow or only slowly grow and observation can be a therapeutic
strategy. On the other hand, previous reports demonstrated
that papillary microcarcinoma frequently metastasizes to cervical
lymph nodes and shows multiple tumor formation in the thyroid.
Furthermore, cases with palpable nodal metastasis often show
rapid progression and dire prognosis. In this review, we discuss
the appropriate application of observation and surgical treatment
of papillary microcarcinoma.
[Back to top]
EBV-Associated Tumors: Pathogenetic Insights for Improved
Disease Monitoring and Treatment
Riccardo Dolcetti, Massimo Guidoboni, Annunziata
Gloghini and Antonino Carbone
[Full text
article]
Epstein-Barr virus (EBV) is a ubiquitous γ-herpes
virus that is a well-established risk factor for Hodgkin’s
lymphoma, Burkitt’s lymphoma, a subset of T cell lymphomas
and various tumors of epithelial cell origin with nasopharyngeal
carcinoma as the most representative. Furthermore, EBV-associated
lymphoproliferative disorders are a well recognized major
complication of immune suppression. EBV generally establishes
a life-long asymptomatic infection in memory B lymphocytes,
by mimicking cellular signaling pathways that regulate antigen-dependent
B cell differentiation. In the long-lived memory B lymphocyte
pool, the virus is almost completely silent or expresses a
very restricted set of latent proteins, evading thus the immune
control by EBV-specific effectors. EBV-associated lymphoid
and epithelial malignancies are characterized by a peculiar
geographic distribution and distinctive epidemiologic and
histopathologic and histogenetic features. Moreover, new histogenetic
and molecular features have contributed to the recognition
and the diagnosis of specific disease categories. The ability
of the virus to establish life-long persistent infections
in humans and to contribute to cell transformation is related
to the biologic properties of a set of EBV-encoded proteins,
differently expressed in both normal and transformed cells.
In the last decade, our understanding of the latency programs
activated by EBV in cellular backgrounds and the function
of EBV-encoded proteins has considerably improved. The emerging
picture indicates that EBV proteins are able to hijack critical
cellular pathways to promote the proliferation and survival
of infected cells, while impairing anti-viral immune responses.
The recent advances in the elucidation of the mechanisms underlying
EBV-induced cell transformation and immune evasion help to
design novel treatment approaches for EBV-related malignancies.
Moreover, it has been clearly shown that the quantification
of circulating EBV DNA is a valuable tool in the diagnosis,
clinical monitoring and prognosis of some EBV-associated tumors.
[Back to top]
Src Family Kinases as Regulators of Angiogenesis: Therapeutic
Implications
Donald P. Lesslie III and Gary E. Gallick
[Full text
article]
Despite its discovery nearly a century ago, the functions
of the Src family of protein tyrosine kinases (SFKs) remain
incompletely understood. While much has been learned regarding
the functions of Src family kinases in the last few years,
new roles for Src, particularly in promoting the progression
of cancer towards the metastatic phenotype, continue to emerge.
SFKs, through their functions as kinases and adapter proteins
in signaling complexes, regulate such diverse cellular events
as proliferation, migration, cell cycle control, and apoptosis.
In tumor cells, the kinase activity of Src is frequently activated,
with greater increases during progressive stages. Likewise,
resistance to chemotherapy also corresponds with Src kinase
activity. Thus, Src activation is predictive of poor prognosis
in several tumors. Recently, selective SFK inhibitors are
showing promise in clinical trials in imatinib mesylate (Gleevec,
Novartis) resistant chronic myelogenous leukemia. However,
in vitro studies have suggested that Src inhibitors may
hold promise in the treatment of solid tumors such as colon
and pancreatic cancer in which new therapeutic inhibitors
are desperately needed. This review will summarize briefly
the structure and function of Src and the evidence for Src
in promoting tumor progression and metastasis. As recent work
in this laboratory and others has demonstrated that Src is
a regulator of expression of diverse pro-angiogenic factors
produced by tumor cells, and a regulator of the endothelial
cells that respond to these factors, this review will focus
on the role of Src in angiogenesis and potential roles of
Src inhibitors as antiangiogenic agents.
[Back to top]
Membrane Receptor and Antiangiogenic Targeted Therapies in
the Treatment of Cancer
Antonio Jimeno and Hernan Cortes-Funes
[Full text
article]
The rapidly expanding knowledge of the pathogenesis of a
variety of forms of cancer at the molecular level is now providing
new targets for drug discovery and development. This has enabled
us to successfully develop rationally designed therapies for
cancer patients, and the results of their clinical evaluation
are now becoming available. The optimal clinical development
of target-based anticancer drugs will require fundamental
changes to the way trials are designed, outcome is evaluated,
and patients are selected to receive therapy. A thorough knowledge
of what is accomplished so far is the cornerstone to optimally
develop and implement these new strategies.
[Back to top]
New Approaches to Postoperative Radiotherapy for Cancer
of the Head and Neck
Perri Prellop and Roger Ove
[Full text
article]
Historically, patients with resectable stage III and IV tumors
were treated with combined surgery and radiation. Early attempts
at improving results by incorporating chemotherapy in the
postoperative setting have been largely unsuccessful or inconsistent.
However, longer follow-up of recent landmark trials exploring
concurrent chemotherapy and radiotherapy have clarified the
issue, supporting concurrent cisplatin based chemotherapy
for high risk patients. The survival benefit seen in the concurrent
chemoradiotherapy trials appears to stem from improved locoregional
control, as no reduction in systemic failure has been observed.
Another evolving approach to post-operative head and neck
radiotherapy is the use of altered fractionation schedules.
There are several recent studies exploring either hyperfractionated
or accelerated radiotherapy, as a response to the issue of
accelerated tumor repopulation, providing evidence that such
treatment is beneficial in selected patients. There are several
questions worthy of further clinical research, and these will
likely continue to follow the lead of nonsurgically managed
head and neck cancer. Preliminary data suggests that IMRT
can be tailored to postoperative patients, and target volumes
defined such that morbidity can be minimized without jeopardizing
tumor control. Biological modifiers of radiotherapy may allow
selective radiosensitization without the morbidity of concurrent
chemotherapy.
[Back to top]
Metastasis and Recurrence After Surgical Resection
of Hepatocellular Carcinoma: Recent Progress in Clinical and
Related Basic Aspects
Lun-Xiu Qin and Zhao-You Tang
[Full text
article]
Metastasis and recurrence, which is caused either by intrahepatic
metastasis (IM) or by metachronously multicentric carcinogenesis,
has become one major obstacle for further improving the survival
and prognosis of HCC patients. Many factors, such as the patient’s
general conditions (age, sex, co-existing hepatitis, liver
function, AFP level), macroscopic tumor morphology (tumor
size, number, capsule status, intraor extra-hepatic spreading,
vessel invasion), and tumor pathohistological features, as
well as treatment-related factors (surgical techniques, blood
transfusion), have been determined as risk factors, and proven
of predicting significance for HCC recurrence. In recent years,
with the understanding of tumor biology and the development
of molecular biology techniques, many molecular factors (biomarkers)
have been developed. Various neoadjuvant or adjuvant therapeutic
approaches including pre-operative transcatheter arterial
chemoembolization (TACE), post-operative TACE, systemic or
locoregional chemotherapy, immunotherapy, interferon, and
acyclic retinoic acid have been hoped to decrease or eliminate
recurrence of HCC. However, there is no evidence demonstrate
benefit from the various neoadjuvant and adjuvant therapies
investigated. Most of them deserve further evaluation by randomized
control trial (RCT), and among them, biotherapy could be an
ideal strategy. Many kinds of treatment strategies, including
surgical treatment (repeat resection and salvage transplantation),
TACE, regional cancer therapies such as radiofrequency ablation
(RFA), chemotherapy have been tried and proven to be potentially
helpful for the control of HCC recurrence and metastasis.
However, there are few RCT to evaluate the effect of these
modalities on the recurrence and metastasis of HCC.
[Back to top]
The Role of Chemokines and their Receptors in Tumor Progression
and Invasion: Potential New Targets of Biological Therapy
Paola Allavena, Federica Marchesi and Alberto
Mantovani
[Full text
article]
Chemotactic cytokines (chemokines) are a family of small
proteins inducing directed cell migration (chemotaxis), via
specific G-protein coupled receptors. Initially described
as molecules regulating leukocyte recruitment at sites of
inflammation, in the last decade, it has become increasingly
clear that chemokines mediate several other functions and
therefore are more than simple traffick controllers. Chemokines
are produced by many different cell types, including tumor
cells. Indeed, tumors are major producer of chemokines and
have represented an invaluable source for their identification
and characterization. In the tumor microenvironment chemokines
are crucial regulators of the levels of tumorinfiltrating
leukocytes. In addition, these mediators control a variety
of biological activities, such as production and deposition
of collagen, activation of matrix-digesting enzymes, stimulation
of cell growth, inhibition of apoptosis and promotion of neo-angiogenesis.
The expression of chemokines, therefore, is of potential advantage
for tumor cells and may endow them with enhanced ability to
proliferate and disseminate. The complex network of chemokines
and their receptors in the tumor microenvironment is currently
the object of an intense investigation aimed at targeting
these molecules for therapeutic interventions.
[Back to top]
Imatinib Mesylate: Targeted Therapy of Gastrointestinal Stromal
Tumor
Jonathan C. Trent, Jheri Dupart and Wei Zhang
[Full text
article]
The clinical application of tyrosine kinase inhibitors for
cancer treatment represents a therapeutic breakthrough. The
rationale for development of these compounds rests on the
observation that tyrosine kinases are central components of
the cellular signaling apparatus and are deregulated in many
human malignancies. Successful tyrosine kinase inhibitors
target aberrant pathways that are critical for tumor cell
viability. Herein, we will review the current state-of-the-art
using imatinib mesylate (GleevecTM, Glivec®,
CGP57148, formerly STI571; Novartis Pharmaceuticals) as it
is used in the treatment of gastrointestinal stromal tumors
(GISTs).
GISTs, the most common mesenchymal tumors of the gastrointestinal
tract, originate from the neoplastic transformation of the
intestinal pacemaker cell, the interstitial cell of Cajal.
GISTs commonly have mutations in the kit gene, resulting
in a gain-of-function mutation and ligand-independent constitutive
activation of the Kit receptor tyrosine kinase. The use of
imatinib has greatly increased the therapeutic efficacy for
this otherwise chemotherapy-resistant tumor. Resistance to
the drug is the major cause of treatment failure, emphasizing
the need for researchers to understand Kit signaling pathways
so as to identify new therapeutic targets. This article will
review the development, pharmacology, and clinical trials
of imatinib in the setting of GIST. The potential role of
imatinib in the postoperative and preoperative setting will
be discussed.
[Back to top]
Cancer Prevention with Green Tea Polyphenols for the General
Population, and for Patients Following Cancer Treatment
Hirota Fujiki, Masami Suganuma, Satoru Matsuyama
and Kohji Miyazaki
[Full text
article]
Green tea is now known to be the most effective beverage
for cancer prevention, and evidence of this was recently extended
to clinical applications. This paper briefly reviews several
topics with regard to the development of our study on cancer
prevention with green tea, and proposes a strategy for two-stages
of cancer prevention with green tea. The topics are : 1) introduction
of our initial work on (-)-epigallocatechin gallate (EGCG),
the main constituent of Japanese green tea; 2) cancer preventive
effects of EGCG and green tea extract, the lyophilized form
of green tea infusion; 3) bioavailability of
3H-EGCG in mice; 4) delay of cancer onset
by drinking 10 Japanese-size cups of green tea per day; 5)
a prototype study for developing green tea beverage supplemented
with green tea tablets by 102 healthy volunteers; 6) cancer
prevention before cancer onset for the general population
and high risk groups; 7) cancer prevention for patients following
cancer treatment; 8) an example of a clinical trial looking
toward prevention of cancer recurrence in the liver; and 9)
possible prevention of human lung cancer. Considering all
the above, green tea is a multi-, non-toxic cancer preventive
for humans: It is nature’s remedy.
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