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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 35, 2007
Contents
Angiogenesis Agents
Executive Editor: Cezary Marcinkiewicz
Editorial Pp. 3543-3544
Antiangiogenic Therapy in Malignant Glioma: Promise
and Challenge Pp. 3545-3558
S. Sathornsumetee and J.N. Rich
[Abstract]
CD36-TSP-HRGP Interactions in the Regulation of Angiogenesis
Pp. 3559-2567
R.L. Silverstein and M. Febbraio
[Abstract]
The Role of Annexin II in Angiogenesis and Tumor Progression:
A Potential Therapeutic Target Pp. 3568-3575
M.C. Sharma and M. Sharma
[Abstract]
Identification of Novel Drug Targets for Angiostatic
Cancer Therapy; It Takes Two to Tango Pp. 3576-3583
V.L.J.L. Thijssen, J.R. van Beijnum, K.H. Mayo and A.W.
Griffioen
[Abstract]
Modulation of Angiogenesis for Cancer Prevention:
Strategies Based On Antioxidants and Copper Deficiency
Pp. 3584-3590
G.N. Khan and S.D. Merajver
[Abstract]
Nitric Oxide-Dependent Neovascularization Role in
the Lower Extremity Disease Pp. 3591-3596
M.G.A. Mendoza, H.V. Robles, E. Romo, A. Rios and B. Escalante
[Abstract]
Modified Fibrin Hydrogel Matrices: Both, 3D-Scaffolds
and Local and Controlled Release Systems to Stimulate Angiogenesis
Pp. 3597-3607
H. Hall
[Abstract]
Type I Collagen and Collagen Mimetics as Angiogenesis Promoting
Superpolymers Pp. 3608-3621
T. Twardowski, A. Fertala, J.P.R.O. Orgel and J.D.S. Antonio
[Abstract]
General Articles
Emerging Indications for Statins: A Pluripotent
Family of Agents with Several Potential Applications
Pp. 3622-3636
K.I. Paraskevas, A.A. Tzovaras, D.D. Briana and D.P. Mikhailidis
[Abstract]
Weight Loss in Older Persons: New Therapeutic Approaches
Pp. 3637-3647
J.E. Morley
[Abstract]
Abstracts
[Back to top]
Editorial: Angiogenesis Agents
Angiogenesis, a process of growing new vasculature from pre-existing
vessels, is a phenomenon that is the focus of investigation
of many laboratories. The pharmacological research targeting
this process is related into two aspects, inhibition of pathological
angiogenesis such as in cancer development, and therapeutic
angiogenesis promoting a vessel growth during several cardiovascular
disorders. Highly advance studies are performed on the angiostatic
drugs, which target a variety of factors and biological molecules
involved in the progression of neovascularization. Structurally,
these pharmaceuticals are humanized monoclonal antibodies,
short synthetic or recombinant peptides or peptidomimetics
and biologically active chemical molecules. Many of these
compounds have been isolated from natural sources. The most
effective as angiostatic targets are pro-angiogenic growth
factors (e.g. VEGF, FGF), receptors present on the surface
of endothelial cells (e.g. integrins, growth factors receptors),
and intracellular signaling molecules regulating the survival/death
cell process (e.g. PKC-β,
HIF-1). This issue of journal presents review articles showing
the recent progress in development of anti-angiogenic therapy
in cancer treatment as well as perspectives in the application
of new targets for this therapy. Other papers will overview
the application of biopolymers in tissue repair and stimulation
of angiogenesis in this process.
In the first paper [1] the authors overview the current stage
of investigation of anti-angiogenic agents in therapy of malignant
glioma. This brain tumor is considered as the most vascularized
and extremely difficult to treat, because of the limited penetration
of pathological tissue by oncostatic drugs. This phenomenon
is related to the tight junction of the brain blood barrier,
which makes designing an effective pharmaceutical for this
tumor a big challenge. The promising clinical trials showed
the application of anti-angiogenic therapy in combination
with chemo- or radio-therapy. The angiostatic agents are usually
well tolerated by the patients and further development of
these drugs has good pharmaceutical perspectives.
The next review by Silverstein and Febbraio [2] is devoted
to the summary of current knowledge about the importance of
thrombospondin in angiogenesis in the context of its interaction
with e CD36, a cell membrane anchored receptor expressed on
endothelial cells. The authors discuss the mechanisms occurring
in endothelial cells following the binding of thrombospondin
to CD36, that lead to the blocking of cells proliferation.
The regulatory effect on angiogenesis in this system is complemented
by the circulating histidine-rich glycoprotein (HRGP), which
contains the CD36 homology domain. HRGP, by binding to thrombospondin,
blocks its anti-angiogenic activities and in consequence promotes
angiogenesis. This is a very interesting system for controlling
angiogenesis. Its elements may be targeted for the modulation
of pathological vascularization process or therapeutic angiogenesis.
The role of annexin II in angiogenesis is discussed in the
paper by Sharma and Sharma [3]. This is a multifunctional
molecule appearing on the endothelial cell surface and on
a variety of other cell types including cancer. It is receptors
for plasminogen and tissue and urokinase plasminogen activators,
tPA and uPA, respectively. Interestingly, annexin II also
binds angiostatin, a fragment of plasminogen, which was characterized
as a potent inhibitor of angiogenesis. Moreover, annexin II
participates in the conversion of plasminogen to plasmin.
This enzyme increases neovascularization and tumoral cells
invasion processes by the degradation of extracellular matrix.
Therefore annexin II appears to be an interesting pharmaceutical
target for the protection of tissues against pathological
angiogenesis.
The review paper presented by Thijssen and his colleagues
[4] summarizes the approaches for selective identification
of target molecules on pathological endothelial cells that
are activated during the progression of tumor or other angiogenesis-related
disorders such as certain inflammatory diseases. To achieve
this goal, the authors propose two strategies: (i) random
genetic screening to establish markers that diverse normal
and activated endothelium; (ii) screening of known inhibitors
of angiogenesis to find their molecular targets. Summary of
the work that was performed in these contexts clearly showed
that although the targeting pro-angiogenic growth factors
are effective, the direct inhibition of the vascularization
process on the level of endothelial cells may have other benefits.
This may include but is not limited to decrease toxicity and
diminish drug-induced resistance therapy.
A very interesting article is presented by Khan and Merajver
[5]. The authors discuss possible targeting angiogenesis for
cancer prevention. They focus on evaluating the role of the
anti-oxidants and copper deficiency in angiogenesis as a cancer
chemoprevention mechanism. Currently, several pre-clinical
and clinical trials are in progress for a variety of cancers
(e.g. lung, prostate, breast) to select the most effective
anti-oxidants in chemoprevention and decrease the occurrence
of cancer in high risk patients such as lung cancer in smokers.
Clinical trials with a lowered copper have been performed
using tetrathimolybdate as a copper-binding drug. These studies
showed a significant decrease of pro-angiogenic factors in
blood plasma and a stabilization of the cancer. Based on this,
the authors concluded that copper deficiency may be a good
chemoprevention for small or incipient tumors.
Therapeutic angiogenesis is described by Arellano Mendoza
et al. [6] in application of the patients with peripheral
arterial disease (PAD). The major problem of the PAD patients
is their loss of ability of revascularization. The authors
discuss the correlation of the decreasing level of NO on the
limitation of angiogenesis in the ischemic hindlimb, that
leads to development of PAD. Hindlimb revascularization was
improved following increasing the NO to the normal level.
Therefore, the authors propose a restoration of the NO in
PAD patients as a therapeutic approach. Although this concept
is very interesting, and some pre- and clinical studies were
performed, the complete development of this therapy requires
more basic science work to completely understand mechanisms
that are involved in pro-angiogenic activity of NO.
The last two papers are devoted to the promotion of angiogenesis
in the biopolymers matrices in the context of its clinical
application in regenerative medicine. Tissue engineering is
one of the fast developing branches of biomedical science.
The artificial scaffold materials are constantly improving
and are useful in several tissue recovery medical interventions,
including burning skin. The article by Hall [7] discusses
the potential application of 3D-fibrin hydrogel matrices containing
pro-angiogenic factors for reparation of ischemic tissues.
The therapeutic strategy is based on the application of 3D
scaffolds that will have endothelial cell pro-adhesive compounds,
such as ligands, for αvβ3
integrin, while releasing pro-angiogenic factors such as VEGF
and FGF that will target specific responses. Interestingly,
improvement of revascularization may be achieved by supplying
these biomaterials by coding pro-angiogenic factors plasmid
DNA that will be released during therapy and transfect surrounding
cells. These angiogenesis promoting 3D scaffolds may, have
in the nearest future, an application in the vasculature renewal
in implant or a wound site by non-invasive techniques.
Another variant of biomaterials, which will increase vascularization
of the regenerated tissue, is discussed by Twardowski and
his colleagues [8]. They propose to design an angiogenic superpolymer
based on the structure of collagen type I. The authors showed
pro-angiogenic activity of collagen in their past several
papers. The mechanism of this activity is still under investigation,
however, the first trials to obtain angiogenic superpolymer
are in progress. The major approaches are directed into biotechnological
modification of collagen to improve its biological half-life,
immunogenicity and integrin capacity, as well as to remove
unnecessary or deleterious sequences without compromising
fibril integrity. Another strategy may include the generation
of biomaterials based on the synthetic and natural collagen
mimetics. This material may be applied as an alternative biopolymer
and may improve vascularization of ischemic tissue or implants.
References
[1] Sathornsumetee S, Rich JN. Antiangiogenic Therapy in Malignant
Glioma: Promise and Challenge. Curr Pharm Des 2007; 13(35):
3545-3558.
[2] Silverstein RL, Febbraio M. CD36-TSP-HRGP Interactions
in the Regulation of Angiogenesis. Curr Pharm Des 2007; 13(35):
3559-3567.
[3] Sharma MC, Sharma M. The Role of Annexin II in Angiogenesis
and Tumor Progression: A Potential Therapeutic Target. Curr
Pharm Des 2007; 13(35): 3568-3575.
[4] Thijssen VLJL, van Beijnum JR, Mayo KH, Griffioen AW.
Identification of Novel Drug Targets for Angiostatic Cancer
Therapy; It Takes Two to Tango. Curr Pharm Des 2007; 13(35):
3576-3583.
[5] Khan GN, Merajver SD. Modulation of Angiogenesis for Cancer
Prevention: Strategies Based On Antioxidants and Copper Deficiency.
Curr Pharm Des 2007; 13(35): 3584-3590.
[6] Mendoza MGA, Robles HV, Romo E, Rios A, Escalante B. Nitric
Oxide-Dependent Neovascularization Role in the Lower Extremity
Disease. Curr Pharm Des 2007; 13(35): 3591-3596.
[7] Hall H. Modified Fibrin Hydrogel Matrices: Both, 3D-Scaffolds
and Local and Controlled Release Systems to Stimulate Angiogenesis.
Curr Pharm Des 2007; 13(35): 3597-3607.
[8] Twardowski T, Fertala A, Orgel JPRO, Antonio JDS. Type
I Collagen and Collagen Mimetics as Angiogenesis Promoting
Superpolymers. Curr Pharm Des 2007; 13(35): 3608-3621.
Cezary Marcinkiewicz Ph.D.
Temple University, School of Medicine
Department of Neuroscience
Center for Neurovirology
1900 N.12th Street
Philadelphia, PA 19122
USA
[Back to top]
Antiangiogenic Therapy in Malignant Glioma: Promise and Challenge
S. Sathornsumetee and J.N. Rich
Malignant glioma represents one of the most lethal and
angiogenic cancers. Angiogenesis is a fundamental process
of blood vessel growth that is a hallmark of cancer. Although
several molecular mechanisms contribute to tumor angiogenesis
in gliomas, the vascular endothelial growth factor (VEGF)
pathway appears particularly important and has been a prominent
therapeutic target in cancer treatment. Several preclinical
studies have demonstrated efficacy of antiangiogenic agents
in both subcutaneous and orthotopic malignant glioma xenograft
models. Recently, a phase II clinical trial of bevacizumab,
a neutralizing monoclonal antibody to VEGF, in combination
with irinotecan has demonstrated promising radiographic response
and survival benefit in patients with recurrent malignant
glioma. Several other antiangiogenic agents such as inhibitors
to platelet derived growth factors (PDGFs), fibroblast growth
factors (FGFs), angiopoietins/Tie-2 system, protein kinase
C and integrins are currently in preclinical and clinical
development. Despite the encouraging results of antiangiogenic
therapies in malignant glioma, there are several challenges
to be overcome to achieve optimal clinical benefit. Identification
of biomarkers to predict response or resistance and to monitor
antiangiogenic effects is important to enrich for patients
who are likely to respond to therapy and to define the optimal
biological dose. At present, antiangiogenic therapies remain
palliative suggesting that overcoming antiangiogenic resistance
may require multi-targeted agents, combination of agents targeting
different angiogenic pathways or multi-modality combination
with radiation, chemotherapy, other targeted therapeutics
or immunotherapy. In this review, we will discuss the current
development, promise and challenge of antiangiogenic therapy
in malignant glioma.
[Back to top]
CD36-TSP-HRGP Interactions in the Regulation of Angiogenesis
R.L. Silverstein and M. Febbraio
Thrombospondin (TSP)-1 and -2 are potent inhibitors of
angiogenesis in vivo and of microvascular endothelial
cell responses to angiogenic factors in vitro. The
anti-angiogenic activity of thrombospondins is contained in
a structural domain known as the TSP type I repeat or TSR.
TSR domains are present in many other proteins, several of
which have also been shown to have anti-angiogenic activity
and a peptide-mimetic drug based on the domain is in clinical
trials as an anti-angiogenic anti-cancer therapy. We have
identified CD36 as the endothelial cell receptor for TSP-1
and -2 and showed that it is necessary for their anti-angiogenic
activity. CD36-mediated anti-angiogenic activity in endothelial
cells is due to its ability to activate a specific signaling
cascade that results in diversion of a pro-angiogenic response
to an apoptotic response. Recently we identified a circulating
protein, histidine-rich glycoprotein (HRGP), that contains
a CD36 homology domain and that acts as a soluble decoy to
block the anti-angiogenic activities of TSPs, thereby promoting
angiogenesis. The tripartite interactions among CD36, TSR
domains and HRGP in tissues may play an important role in
regulating physiological and pathological angiogenesis.
[Back to top]
The Role of Annexin II in Angiogenesis and Tumor Progression:
A Potential Therapeutic Target
M.C. Sharma and M. Sharma
It is well established that human tumors overproduce
plasmin a serine protease that is known to promote angiogenesis,
tumor growth and metastasis. However, the mechanism by which
endothelial or tumor cells regulate the proteolytic activity
of plasmin is not well understood. Cell surface receptors
regulate activation of plasminogen to plasmin and its proteolytic
activity. Annexin II is one of the well studied receptors
for plasminogen and tPA, which binds to plasminogen and converts
it to plasmin. Plasmin is a highly reactive enzyme which is
physiologically involved in fibrinolysis. Since the proteolytic
activity of plasmin is very tightly regulated, uncontrolled
production of plasmin can degrade extracelluar matrix (ECM)
and basement membrane (BM) of the surrounding blood vessels.
Thus plasmin plays an important role in neoangiogenesis and
cancer invasion and metastasis. Therefore, the receptor which
regulates plasmin generation may be an attractive target for
the development of anti-cancer/anti-metastatic agents. Angiostatin
(AS), internal fragment of plasminogen, has been reported
to inhibit human tumor growth and metastasis. We have shown
that AS binds to endothelial/cancer cell surface annexin II
with high affinity and interferes with plasmin generation
suggesting that the role of plasmin/plasminogen system may
be more complex than we previously thought. In this review
we provide a comprehensive analysis of the literature in context
of the role of annexin II in angiogenesis, tumor progression
and metastasis. Compelling evidence from the literature and
our own findings suggest that annexin II may be a potential
target for the development of effective therapeutic strategies
for the treatment of cancer and its induced metastasis.
[Back to top]
Identification of Novel Drug Targets for Angiostatic Cancer
Therapy; It Takes Two to Tango
V.L.J.L. Thijssen, J.R. van Beijnum, K.H. Mayo and A.W.
Griffioen
The development of novel treatment strategies for therapy
of angiogenesis-dependent diseases requires identification
of specific tumor endothelial cell markers to which therapeutic
agents can be targeted. This can be achieved by random or
targeted approaches. Random approaches are based on genomic
screening to identify differences between normal and activated
endothelium. Targeted approaches utilize known angiogenesis
inhibitors to find their molecular targets. Both approaches
may lead to the development of angiostatic therapies that
are directly targeted towards activated endothelial cells.
This review summarizes the recent developments in both approaches.
[Back to top]
Modulation of Angiogenesis for Cancer Prevention: Strategies
Based On Antioxidants and Copper Deficiency
G.N. Khan and S.D. Merajver
Although anti- angiogenesis strategies have generated
much enthusiasm for therapeutic applications, it is still
unknown wheth-er they would be feasible for prevention. The
possibility of interfering very early in tumor progression
by modulating the cancer angiogenic switch is appealing. In
this chapter, we review progress with in vitro and
in vivo models that show that anti-angiogenic interventions
may be amenable to long- term chemopreventive measures. In
particular, some approaches that are nearly ready for major
applications are anti-oxidant nutraceuticals and copper deficiency.
We use these strategies as paradigms of how to make progress
in this difficult but important area of translational research.
[Back to top]
Nitric Oxide-Dependent Neovascularization Role in the Lower
Extremity Disease
M.G.A. Mendoza, H.V. Robles, E. Romo, A. Rios and B. Escalante
Peripheral arterial occlusive disease (PAD) describes
vascular disorders associated with ischemia and PAD affects
about 8 million people in the United States. Moreover, PAD’s
prevalence can increase dramatically if cardiovascular disease
is present. In healthy individuals reducing blood flow through
the lower extremity is followed by a physiological process
to limit ischemia in the distal tissue. This process is called
revascularization and impairing revascularization results
in PAD. Studies suggest nitric oxide (NO) maybe involved in
the ischemia-dependent hindlimb revascularization process.
NO is increased in the ischemic hindlimb and eliminating NO
impairs the revascularization process. Moreover, restoring
NO improves hindlimb revascularization. NO may be acting through
its effects on vascular tone, cell migration, or extracellular
matrix degradation. The present review illustrates nitric
oxide’s critical role in the ischemia-induced hindlimb
revascularization. Thus, restoring normal NO levels in diseased
arteries may represent a viable therapeutic avenue by supplementing
exogenous NO or employing therapeutic strategies to either
increase NO synthesis and its messengers or decrease NO catabolism.
[Back to top]
Modified Fibrin Hydrogel Matrices: Both, 3D-Scaffolds and
Local and Controlled Release Systems to Stimulate Angiogenesis
H. Hall
Sufficient blood perfusion is essential for all tissues
to guarantee nutrient- and gas exchange. As many diseases
are induced by the reduction of blood perfusion such that
these tissues gradually loose their ability to function properly,
therapeutic angiogenesis aims to increase blood flow in ischemic
tissues by stimulating the patient’s endogenous capacity
to develop new blood vessels. These studies include application
of angiogenesis stimulating (growth) factors and adhesion
sequences as well as local gene therapy.
One approach is to rationally design 3D-fibrin hydrogel matrices
that provide specific adhesion sequences such as a receptor
for αvβ3-integrin
expressed on angiogenic endothelial cells and that, in addition,
are able to store and release angiogenic growth factors such
as VEGF-A165 and bFGF that
target cell type-specific responses. Moreover, these matrices
can be modified to release complexed plasmid DNA that transfect
surrounding cells and improve angiogenesis. During wound healing,
cells infiltrate into the scaffold and degrade it, thereby
releasing entrapped growth factors or complexed plasmid DNA,
and with the speed of tissue regeneration the scaffold is
completely removed when tissue healing is achieved.
The long-term aim is to develop biomimetic 3D-matrices for
applications in a biomaterials context that can be applied
directly at the site of injury by minimal invasive surgery.
3D-fibrin matrices constitute a scaffold and release system
for single or combined therapeutic biomolecules and may therefore
be able to contribute to the patients’ endogenous healing
response resulting in the functional recovery of a diseased
tissue or organ.
[Back to top]
Type I Collagen and Collagen Mimetics as Angiogenesis Promoting
Superpolymers
T. Twardowski, A. Fertala, J.P.R.O. Orgel and J.D.S. Antonio
Angiogenesis, the development of blood vessels from the pre-existing
vasculature, is a key component of embryogenesis and tissue
regeneration. Angiogenesis also drives pathologies such as
tumor growth and metastasis, and hemangioma development in
newborns. On the other hand, promotion of angiogenesis is
needed in tissues with vascular insufficiencies, and in bioengineering,
to endow tissue substitutes with appropriate microvasculatures.
Therefore, much research has focused on defining mechanisms
of angiogenesis, and identifying pro- and anti-angiogenic
molecules. Type I collagen, the most abundant protein in humans,
potently stimulates angiogenesis in vitro and
in vivo. Crucial to its angiogenic activity appears to
be ligation and possibly clustering of endothelial cell (EC)
surface α1β1/α2β1
integrin receptors by the GFPGER502-507
sequence of the collagen fibril. However, additional aspects
of collagen structure and function that may modulate its angiogenic
properties are discussed. Moreover, type I collagen and fibrin,
another angiogenic polymer, share several structural features.
These observations suggest strategies for creating “angiogenic
superpolymers”, including: modifying type I collagen
to influence its biological half-life, immunogenicity, and
integrin binding capacity; genetically engineering fibrillar
collagens to include additional integrin binding sites or
angiogenic determinants, and remove unnecessary or deleterious
sequences without compromising fibril integrity; and exploring
the suitability of poly(ortho ester), PEG-lysine copolymer,
tubulin, and cholesteric cuticle as collagen mimetics, and
suggesting means of modifying them to display ideal angiogenic
properties. The collagenous and collagen mimetic angiogenic
superpolymers described here may someday prove useful for
many applications in tissue engineering and human medicine.
[Back to top]
Emerging Indications for Statins: A Pluripotent Family of
Agents with Several Potential Applications
K.I. Paraskevas, A.A. Tzovaras, D.D. Briana and D.P. Mikhailidis
Statins are pluripotent agents exhibiting multiple non-lipid-lowering
actions. Besides their established role in the management
of hypercholesterolemia, statins may also have beneficial
actions in other pathological conditions, namely: a) osteoporosis
and osteoporosis-related bone fractures, b) cancer, c) solid
organ transplantation, d) cerebrovascular events (transient
ischemic attack and stroke episodes), e) various neurological
disorders, such as Alzheimer’s disease, Parkinson’s
disease and multiple sclerosis, f) cardiac arrhythmias and
heart failure, g) renal diseases, h) rheumatoid arthritis,
i) autoimmune diseases, j) sepsis, and k) allergic asthma.
We reviewed the literature searching for studies that support
or oppose the use of statins in each proposed indication.
In some of these emerging indications, a role for statin treatment
is more firmly set; for others, current evidence is more controversial.
Future trials may reveal more convincing evidence that will
make statin use necessary in the therapeutic management of
several diseases.
[Back to top]
Weight Loss in Older Persons: New Therapeutic Approaches
J.E. Morley
There is now a large body of evidence that weight loss
in older persons not only increases mortality, but also increases
the incidence of hip fracture, functional deterioration and
institutionalization. Weight loss is a central component of
frailty. There is evidence that it is not only muscle, but
also fat loss that leads to these deleterious effects. The
reasons why fat loss can be harmful in older persons are reviewed.
There are four major causes of weight loss in older persons
viz. anorexia, sarcopenia, cachexia and dehydration. This
review concentrates on the major causes of anorexia and sarcopenia.
In particular, the emergence of new medications such as selective
androgen receptor molecules, antimyostatin analogues, megestrol
acetate (nanocrystal formulation), and ghrelin agonists are
reviewed. The potential role of anabolic steroids is also
discussed.
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