Current Pharmaceutical Design, Volume 10, No. 1, 2004
Contents
Angiogenesis
Agents
Executive
Editor : Cezary Marcinkiewicz
Angiogenesis Inhibitors: Current & Future
Directions Pp.1-9
Shaker
A. Mousa and Ahmed S. Mousa
Angiogenesis: A Target for Cancer Therapy Pp.11-26
Giampaolo
Tortora, Davide Melisi and Fortunato
Ciardiello
Antiangiogenic Therapy Pp.27-37
Daniel
Albo, Thomas N. Wang and George P. Tuszynski
The Urokinase Plasminogen Activator System:
Role in Malignancy Pp.39-49
Michael J. Duffy
Resistance to Anti-VEGF Agents Pp.51-64
Molecular Targeting of Lymphatics for Therapy Pp.65-74
Development and Engineering of Lymphatic
Endothelial Cells: Clinical Implications Pp.75-80
Jörg Wilting and Lothar Schweigerer
Abstracts
[Back to top] Angiogenesis Inhibitors: Current & Future
Directions
Shaker
A. Mousa and Ahmed S. Mousa
The field of angiogenesis modulation is at a major crossroad. A
tremendous advancement in basic science in this field is providing an excellent
support for the concept, which is in contrast to a lack of strong clinical
support to date. With regard to the large gap between experimental data and
clinical data, the best model of human malignancy is in human cancer patients
and the best model of human ocular angiogenesis-mediated disorders such as
diabetic retinopathy (DR) and age related macular degeneration (AMD) is in
human RD and AMD patients. Additionally, clinical outcomes should include
benefit/risk ratios, hard end points (mortality and quality of life as opposed
to increased microvascular density with pro-angiogenic agents or tumor size
reduction with anti-angiogenesis agents) as well as cost effectiveness.
Experimental models should be used to provide guidance, placebo effect,
comparative data, and mechanistic understanding as opposed to being used for
expected clinical efficacy. We also have to understand existing strategies and
how angiogenesis modulation can add further value (i.e. not to replace existing
strategy but rather improve efficacy/safety).
Recent investigation defined numerous strategies in the modulation of
angiogenesis. Those strategies are driven from haemostatic, fibrinolytic, cell
adhesion molecules, extracellular matrix, growth factors, and other endogenous
systems involved in the modulation of angiogenesis.
[Back to top] Angiogenesis: A Target for Cancer Therapy
Giampaolo
Tortora, Davide Melisi and Fortunato
Ciardiello
The induction of neoangiogenesis is a critical step already present at
the early stages of tumor development and dissemination. The progressive
identification of molecules playing a relevant role in neoangiogenesis has
fostered the development of a wide variety of new selective agents.
Antiangiogenic drugs should be integrated with conventional therapies; however,
the design of the best sequence and timing for such combined treatments are
still under investigation. In this review will be discussed the signal
transduction mechanisms of angiogenic molecules, the development of specific
inhibitors and their translation into clinical studies and, finally, the new
perspectives in antiangiogenic therapy.
[Back to top] Antiangiogenic Therapy
Daniel
Albo, Thomas N. Wang and George P.
Tuszynski
Angiogenesis, the formation of blood vessels from preexisting ones,
plays a crucial role in tumor progression. Activation of an “angiogenic switch”
allows tumor cells to invade and metastasize. The growing interest in the use
of antiangiogenic agents in the treatment and prevention of cancer lies in the
theoretical advantages of this molecularly targeted modality of chemotherapy.
Delivery of antiangiogenic agents are not complicated by having to penetrate
large bulky masses but, instead, have easy access to tumoral endothelial cells.
Antiangiogenic drugs may not cause cytopenias and thus will avoid many of the
unwarranted toxicities of standard chemotherapeutic agents. Because they act
directly on nascent endothelial cells, antiangiogenic agents may avoid tumor
resistance mechanisms. If antiangiogenic agents are successful, they might be
applicable to many tumor types and not be dependent on cell type or growth
fraction of cells within a tumor. However, several important obstacles remain
with regards to using antiangiogenic drugs in clinical trials with which we
must contend in order to determine accurately the efficacy of these agents. In
this article, we review the different classes of antiangiogenic agents
available, ongoing clinical trials, as well as potential pitfalls and future
directions in this exciting field.
[Back to top] The Urokinase Plasminogen Activator System:
Role in Malignancy
Michael J. Duffy
The urokinase plasminogen activator (uPA) system consists of the serine
protease uPA, its glycolipid-anchored receptor, uPAR and its 2 serpin
inhibitors, plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator
inhibitor- 2 (PAI-2). Recent findings suggest that the uPA system is causally
involved at multiple steps in cancer progression. In particular, uPA has been
implicated in remodelling of the extracellular matrix, enhancing both cell
proliferation and migration and modulating cell adhesion. Consistent with its
role in cancer progression, multiple groups have shown that high levels of uPA
in primary breast cancers are independently associated with adverse outcome. Paradoxically,
high levels of PAI-1 also correlate with poor prognosis in patients with breast
cancer. The prognostic value of uPA/PAI-1 in axillary node-negative breast
cancer patients was recently validated using both a prospective randomised
trial and a pooled analysis, i.e., in 2 different Level 1 Evidence studies.
Assay of uPA and PAI-1 may thus help identify low risk node-negative patients
for whom adjuvant chemotherapy is unnecessary. Finally, preclinical studies
show that either inhibition of uPA catalytic activity or prevention of uPA
binding to its receptor reduces tumor growth, angiogenesis and metastasis.
[Back to top] Resistance to Anti-VEGF Agents
Ton N.C. and Jayson G.C.
The number of anti-angiogenic agents developed for clinical use has
risen greatly over the past decade. Currently, more than 80 are in trials
ranging from phase I through to phase III studies and many more are in
preclinical evaluation. Much hope was envisaged for these new agents to become
the panacea of anti-tumoural treatment.Unfortunately the single agent activity
to date has proven to be disappointing although one trial has recently reported
a survival advantage when chemotherapy was administered with anti-VEGF
antibodies in the setting of advanced colorectal cancer.To an extent, this may
be due to great expectations of cytostatic compounds, but recently many factors
have been examined to explain the differences between clinical and experimental
findings. In this review, some of the factors responsible for the discrepancy
are examined, with a specific focus on inhibitors of VEGF. The key factors
responsible for the lack of activity are tumour heterogeneity and redundancy in
the VEGF signalling system. An increased understanding of these factors is
critical to the development of effective anti-angiogenic agents and need to be
taken into account as new generations of drugs emerge
[Back to top] Molecular Targeting of Lymphatics for Therapy
S.A. Stacker, R.A. Hughes
and M.G. Achen
The dysfunction or proliferation of lymphatic vessels
(lymphangiogenesis) is linked to a number of pathological conditions including
lymphedema and cancer. The recent discovery and characterisation of the
lymphangiogenic growth factors vascular endothelial growth factor-C (VEGF-C)
and VEGF-D and of their receptor on lymphatic endothelial cells, VEGFR-3, has
provided an understanding of the molecular mechanisms controlling the growth of
lymphatic vessels. In addition, other genes and protein markers have been
identified with specificity for lymphatic endothelium that have enhanced the
characterization and isolation of lymphatic endothelial cells. Our growing
understanding of the molecules that control lymphangiogenesis allows us to
design more specific drugs with which to manipulate the relevant signalling
pathways. Modulating these pathways and other molecules with specificity to the
lymphatic system could offer alternative treatments for a number of important
clinical conditions.
[Back to top] Development and Engineering of Lymphatic Endothelial Cells: Clinical
Implications
Jörg Wilting and
Lothar Schweigerer
Studies on the lymphatic endothelium have been hampered by the
difficulty to identify lymphatic endothelial cells (LECs) and to distinguish
them from blood vascular endothelial cells (BECs). The situation was greatly
improved by the identification of molecules with high specificity for LECs. A
great deal of progress in the field of lymphangiogenesis research has been due
to the detection of lymphangiogenic growth factors and their receptors, and
there is growing evidence that these molecules are also involved in
tumor-induced lymphangiogenesis and lymphatic dissemination of tumor cells.
There is a considerable spectrum of congenital and acquired
lymphedema-lymphangiodysplasia syndromes ranging from primary aplasia,
hypoplasia and hyperplasia to secondary (acquired) obstructive, obliterative
and surgical hindrance of lymph drainage. Consequently, there are a number of
clinical applications for therapeutics that either inhibit or induce
lymphangiogenesis. Although natural lymphatic regeneration is mostly very
efficient, engineering of LECs may be useful in cases of lymphatic aplasia or
hypoplasia. To achieve these goals, studies on the embryonic development and
differentiation of LECs will reveal the key regulatory factors that need to be
targeted.