Current Cancer Drug Targets, Volume 5, No. 4, 2005
Contents
Antiangiogenic Therapy in Acute Myelogenous
Leukemia: Targeting of Vascular Endothelial Growth Factor and Interleukin 8 as
Possible Antileukemic Strategies Pp.229-248
Kimberley
J. Hatfield, Astrid M. Olsnes, Bjorn Tore Gjertsen and Oystein Bruserud
The Chick Embryo Chorioallantoic Membrane as
a Model System for the Study of Tumor Angiogenesis, Invasion and Development of
Anti-Angiogenic Agents Pp.249-266
A.
Cevik Tufan and N. Lale Satiroglu-Tufan
Squalamine: A Polyvalent Drug of the Future? Pp.267-272
Jean
Michel Brunel, Chanaz Salmi, Celine Loncle, Nicolas Vidal and Yves Letourneux
The MYCN Oncogene as a Specific and Selective
Drug Target for Peripheral and Central Nervous System Tumors Pp.273-283
Andrea
Pession and Roberto Tonelli
Matrix Metalloproteinase Inhibitors as
Anticancer Therapeutics Pp.285-298
F.
Mannello, G. Tonti and S. Papa
The Anti-Tumor Effect and Mechanisms of
Action of Penta-Acetyl Geniposide Pp.299-305
C.H.
Peng, C.N. Huang and C.J. Wang
Abstracts
[Back to top] Antiangiogenic Therapy in Acute Myelogenous
Leukemia: Targeting of Vascular Endothelial Growth Factor and Interleukin 8 as
Possible Antileukemic Strategies
Kimberley J. Hatfield, Astrid M. Olsnes, Bjorn Tore Gjertsen and Oystein Bruserud
Acute myelogenous
leukemia (AML) is an aggressive disorder with an overall disease-free survival
of 40-50% even for the younger patients under 60 years of age who can receive
the most intensive treatment. The median age at the time of diagnosis is 60-65
years, and the large majority of elderly patients usually receive less
intensive chemotherapy or only supportive therapy due to the high
treatment-related mortality when using intensive therapy for elderly
individuals. Thus, there is a need for new therapeutic approaches to improve
the treatment in younger patients and to make AML-directed therapy with
acceptable toxicity possible in elderly individuals. Angiogenesis seems to be
important both for leukemogenesis and susceptibility to intensive chemotherapy,
and antiangiogenic strategies are therefore considered for the treatment of
AML. The two proangiogenic mediators vascular endothelial growth factor (VEGF)
and interleukin 8, (IL-8, also referred to as CXCL8) seem to be important in
human AML: VEGF is released at increased levels due to interactions between AML
cells and neighboring nonleukemic cells, whereas IL-8 is released at high
levels by native human AML cells. Thus, VEGF as a therapeutic target in AML is
suggested both by experimental and clinical observations, whereas IL-8 as a
target is mainly suggested by experimental evidence. In the present review we
describe and discuss (i) the angioregulatory network of soluble mediators in
AML, including both the systemic levels and local release by native human AML
cells; and (ii) various therapeutic approaches to target VEGF and IL-8.
Although single angioregulatory mediators can be targeted, it should be
emphasized that the final effect of soluble mediators on angioregulation is
determined by a complex angioregulatory network that varies between AML
patients, and the final effect of targeting single mediators may therefore
differ between patient subsets.
[Back to top] The Chick Embryo Chorioallantoic Membrane as
a Model System for the Study of Tumor Angiogenesis, Invasion and Development of
Anti-Angiogenic Agents
A.
Cevik Tufan and N. Lale Satiroglu-Tufan
Angiogenesis, the
formation of new blood vessels, is essential for tumor growth, progression and
metastasis. The development of agents that target tumor vasculature is
ultimately dependent on the availability of appropriate preclinical screening
assays. The chorioallantoic membrane (CAM) assay is well established and widely
used as a model to examine angiogenesis, and anti-angiogenesis. This review 1)
summarizes the currently used angiogenesis assays and the importance of CAM
model among them; 2) summarizes the current knowledge about the development and
structure of the CAM’s capillary bed; 3) reports findings regarding the role played
by molecular signaling pathways in angiogenesis process; 4) discusses the use,
advantages and limitations of the CAM as a model for studying tumor
angiogenesis and invasiveness, as well as development of angiogenic and/or
anti-angiogenic agents; 5) discusses the importance of standardization of the
major methodologies for all aspects of the use of the CAM in
angiogenesis-related studies; 6) and finally, summarizes major findings
regarding the agents developed by the use of CAM model in the study of tumor
angiogenesis, invasion and development of anti-angiogenic agents.
[Back to top] Squalamine: A Polyvalent Drug of the Future?
Jean
Michel Brunel, Chanaz Salmi, Celine Loncle, Nicolas Vidal and Yves Letourneux
The purpose of
this mini-review is to summarize and highlight the different advances in our
understanding of the antimicrobial and antiangiogenic activity of squalamine, a
cationic steroid isolated in 1993 from the dogfish shark Squalus Acanthias.
Indeed, squalamine has shown to be useful for the treatment of important
diseases such as cancers (lung, ovarian, brain and others), age-related macular
degeneration (AMD) and the control of body weight in man. All these results led
to a question: could we consider squalamine as a polyvalent drug of the future?
[Back to top] The MYCN Oncogene as a Specific and
Selective Drug Target for Peripheral and Central Nervous System Tumors
Andrea Pession and Roberto Tonelli
MYCN belongs to the MYC family of
proto-oncogenes, which encode for transcription factors of the
basic-helix-loop-helix-zipper (bHLHZ) class and is fundamental in the
development of the peripheral and central nervous systems (PNS and CNS). While
Myc is ubiquitous, MYCN has a very restricted expression pattern: it is
mainly expressed during embryonic development, but then becomes downregulated,
while in adults it is usually detected in B-cell development. Identification of
selective inhibitors of MYCN and its mRNA and protein could be important
for the development of more specific, effective and less toxic therapeutic
agents for tumors of the PNS and CNS.
In children, the
most common tumors of the PNS and CNS are neuroblastomas and medulloblastomas, respectively.
About 30% of neuroblastoma (NB) tumors present MYCN
amplification/over-expression, which is associated with rapid progression and
poor prognosis. N-Myc is essential during neurogenesis for the rapid expansion
of progenitor cells in the brain. MYCN amplification and over-expression
has been reported in medulloblastoma, and especially in the desmoplastic type.
Other tumors associated with MYCN overexpression include retinoblastoma, small cell lung
carcinoma, glioblastoma and certain embryonal tumors.
A cell-based,
N-Myc-dependent luciferase reporter gene assay to identify specific N-Myc
small-molecule inhibitors has allowed identification of five compounds showing
significant activity. Antisense oligodeoxynucleotides have been shown to
inhibit N-Myc production and anti-tumoral activity in vitro and in
vivo for NB. Peptide nucleic acids (PNA), which belong to the most recent
(third) generation of nucleic acid therapeutics, form highly stable duplexes
with DNA and RNA, and are resistant to degradation by nucleases and proteases.
Encouraging results have been reported utilizing a PNA-based antisense strategy
for inhibition of N-Myc expression in neuroblastoma.
[Back to top] Matrix Metalloproteinase Inhibitors as Anticancer
Therapeutics
F.
Mannello, G. Tonti and S. Papa
Matrix
metalloproteinases (MMPs), also designated as matrixins, play a central role in
many biological processes and are involved both in physiologic cellular
processes and in pathologic situations such as tumor growth, invasion and
metastasis. For more than 30 years MMPs have been considered as promising
targets for cancer therapy and a number of different synthetic and natural MMP
inhibitors have been identified as cytostatic and anti-angiogenic agents and
have begun clinical testing in view of their specific implication in malignant
tissues. Although preclinical studies were so compelling to encourage several
clinical trials, the past years have seen a consistent number of
disappointments and limited success. The critical examination of previous
studies shed light on new information about the cellular source, substrates and
mode of action of MMPs, focusing the attention of future research on the
identification of specific MMP targets in tumors at different stage of tumor
progression, both in order to improve efficacy and to reduce the side effect
profile. In this review we discuss the current view on the feasibility of MMPs
as target for therapeutic intervention in cancer, taking into account that the perspective
may be of great value for molecular medicine for the twenty-first century,
providing intriguing information about the MMPs as mediators in biology and
pathology, and as targets for disease therapies.
[Back to top] The Anti-Tumor Effect and Mechanisms of Action of Penta-Acetyl
Geniposide
C.H. Peng, C.N. Huang and C.J. Wang
Gardenia, the fruit of Gardenia jasminoides Ellis,
has been widely used to treat liver and gall bladder disorders in Chinese
medicine. It has been shown recently that geniposide, the main ingredient of Gardenia
Fructus, exhibits the anti-tumor effect. In this review, we discuss the
anti-tumor effect and possible mechanisms of a derivative from Gardenia
Fructus, penta-acetyl geniposide ((Ac)5GP). It has been
demonstrated that (Ac)5GP plays more potent roles than geniposide in
chemoprevention. (Ac)5GP decreased DNA damage and
hepatocarcinogenesis induced by aflatoxin B1 (AFB1) by
activating the phase II enzymes glutathione S-transferase (GST) and GSH peroxidase
(GSH-Px). It reduced the growth and development of inoculated C6 glioma cells
especially in pre-treated rats. In addition to the preventive effect, (Ac)5GP
exerts its actions on apoptosis and growth arrest. Treatment of (Ac)5GP
caused DNA fragmentation of glioma cells. (Ac)5GP induced sub- G1
peak through the activation of apoptotic cascades PKCd/ JNK/ Fas/ caspase8 and
caspase 3. Besides, p53/ Bax signaling was suggested to be involved in (Ac)5GP-induced
apoptosis, though its downstream cascades needs further clarified. (Ac)5GP
has also been shown to inhibit DNA synthesis of tumor cells. It arrested cell
cycle at G0/ G1 by inducing the expression of p21, thus
suppressing the cyclin D1/ cdk4 complex formation and the
phosphorylation of E2F. The phosphorylation status of p53 on serine
392 correlated with the process of growth arrest. Evidences from the in vivo
experiments showed that (Ac)5GP is not harmful to liver, heart and
kidney. In conclusion, (Ac)5GP is highly suggested to be an
anti-tumor agent for development in the future.