Current Pharmaceutical Design, Volume 9, No. 19, 2003
Contents
The
Urokinase - Type Plasminogen Activator System in Cancer
Executive
Editor:
Inhibitors of the Proteolytic Activity of
Urokinase Type Plasminogen Activator Pp.1483-1498
Todd
W. Rockway and Vincent L. Giranda
Structure-Function Relationships in the
Interaction Between the Urokinase- Type Plasminogen Activator and Its Receptor Pp.1499-1528
Michael
Ploug
Urokinase-type Plasminogen Activator (uPA)
and its Receptor (uPAR): Development of Antagonists of uPA/uPAR Interaction and
their Effects In Vitro and In Vivo Pp.1529-1543
Ute
Reuning , Stefan Sperl , Charlotte Kopitz , Horst Kessler , Achim Krüger ,
Manfred Schmitt , and Viktor Magdolen
Plasminogen Activator Inhibitor-1 in Tumor
Growth, Angiogenesis and Vascular Remodeling Pp.1545-1564
Steingrimur Stefansson , Grainne A. McMahon , Eric Petitclerc and Daniel A. Lawrence
Urokinase Receptor and Integrin Interactions Pp.1565-1574
Matthias C. Kugler, Ying Wei, and Harold A. Chapman
Abstracts
[Back to top] Inhibitors of the Proteolytic Activity of
Urokinase Type Plasminogen Activator
Todd
W. Rockway and Vincent L. Giranda
Urokinase type plasminogen activator (uPA) activates plasminogen to
plasmin and is often associated with diseases where tissue remodeling is
essential (e.g. cancer, macular degeneration, atherosclerosis). We discuss some
of the mechanisms of uPA action in diseases, and evidence that some of the
early uPA inhibitors can modulate the progression of these diseases. Recently,
a number of research groups have discovered, with the aid of structure-based
design, a new generation of uPA inhibitors. These inhibitors are much more
potent and selective than their predecessors. We will review this progress
here, and give particular attention to the structural rationale associated with
these observed increases in potency and selectivity.
[Back to top] Structure-Function Relationships in the
Interaction Between the Urokinase- Type Plasminogen Activator and Its Receptor
Michael
Ploug
Degradation of the extracellular matrix plays an important role in a
number of normal and pathological conditions involving active tissue remodeling
such as postlactational mammary gland involution, wound healing and tumor
invasion and metastasis. The expression of a high-affinity, glycolipid-anchored
receptor for the urokinase-type plasminogen activator (uPAR) is often up-regulated
during such tissue remodeling events. UPAR may, therefore, in cooperation with
various matrix metalloproteases, serve to facilitate the proteolytic breakdown
of the extracellular matrix via uPA catalyzed plasminogen activation at the
foci where cellular invasion occurs. Consistent with such a role for uPAR in
pericellular proteolysis is the observation that the membrane assembly of both
plasminogen, via its lysine binding-sites, and of pro-uPA, via its tight
binding to uPAR, is required to favor and confine plasminogen activation
potential in proximity of the cell surface.
This review will focus on molecular properties of uPAR including its
membrane attachment by glycosylphosphatidylinositol, its multidomain structure
and its relationship to the Ly-6/uPAR/a-neurotoxin
protein domain family. Furthermore a mapping of the functional epitopes for uPA
binding as well as a competitive peptide antagonist of the uPA-uPAR interaction
will be discussed.
[Back to top] Urokinase-type Plasminogen Activator (uPA)
and its Receptor (uPAR): Development of Antagonists of uPA/uPAR Interaction and
their Effects In Vitro and In Vivo
Ute
Reuning , Stefan Sperl , Charlotte Kopitz , Horst Kessler , Achim Krüger ,
Manfred Schmitt , and Viktor Magdolen
In cancer, increased levels of the tumor-associated serine protease uPA
(urokinase-type plasminogen activator) and its receptor uPAR (CD87) are linked
to tumor progression, metastasis, and shortened survival in patients afflicted
with this disease. Strong clinical and experimental evidence has accumulated
that the cell surface interaction of uPA with uPAR facilitates extravasation
and intravasation of cancer cells by regulating local proteolysis and
attachment of the cells to components of the extracellular matrix. Moreover,
the uPA/uPAR system is also implicated in proliferation of some tumor cells and
migration of tumor and endothelial cells. Thus, metastasis formation is
facilitated via tumor cell spread through the blood circulation system and
neovascularization at the metastatic site. This multifunctional potential has
rendered the uPA/uPAR system an attractive novel target for anti-metastatic
therapy. Consequently, inhibitors of the uPA/uPAR interaction have been and are
currently developed for suppression of tumor growth and angiogenesis. In
addition to antibodies and recombinant uPA- or uPAR-derived proteins, various
linear and cyclic peptides as well as small molecules have been designed and
synthesized which potently interfere with the uPA/uPAR interaction, leading to
reduced tumor progression in experimental animals. Such compounds affecting the
uPA/uPAR system represent novel tumor biology-based therapeutic agents, thereby
opening new ways for patient optimized and individualized cancer therapy.
[Back to top] Plasminogen Activator Inhibitor-1 in Tumor
Growth, Angiogenesis and Vascular Remodeling
Steingrimur Stefansson , Grainne A. McMahon , Eric
Petitclerc and Daniel A. Lawrence
Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of
urokinase type plasminogen activator (uPA) and tissue-type plasminogen
activator (tPA), and as such is thought to play an important role in the
regulation of extracellular matrix remodeling. In blood, PAI-1 is bound to the
adhesion protein vitronectin and is associated with vitronectin in fibrin clots
and the provisional matrix. Elevated levels of PAI-1 are associated with
atherosclerosis and an increased thrombotic tendency, while PAI-1 deficiency
leads to increased fibrinolysis and bleeding. PAI-1 is also elevated in many
solid tumors and is associated with a poor prognosis in cancer. PAI-1 has been
shown to be a potent regulator of both vascular cell migration in vitro and of
angiogenesis and tumor growth in vivo. PAI-1 can both promote and inhibit tumor
growth and angiogenesis. Low concentrations of PAI-1 can stimulate tumor
angiogenesis while treatment of animals with high doses of PAI-1 inhibits
angiogenesis and tumor growth. Hence, PAI-1 appears to have a multifunctional
role in regulating the migratory and fibrinolytic activity of vascular cells,
and this, in turn, may help to explain the many varied actions of PAI-1.
[Back to top] Urokinase Receptor and Integrin Interactions
Matthias C. Kugler, Ying Wei, and Harold A. Chapman
Urokinase receptors (uPAR) were initially thought to function simply as
a mechanism to concentrate the urokinase/plasmin system toward the cell
surface. However, extensive evidence has accumulated that this
glycolipidanchored receptor also functions in both the adhesive and signaling
pathways of many migratory cells. Mechanisms by which uPAR exercises these
functions involve complexing with other membrane proteins for signal
transduction. One set of functional partners for uPAR on the cell surface are
integrins. Recent studies point to important structural features of
uPAR:integrin interactions, indicating uPAR to be a cis-acting integrin ligand.
In vivo data reveal altered integrin function and cell migration when
uPAR:integrin interactions are impaired. Together these observations support
the idea that uPAR:integrin interactions may be a focal point of intervention
in pathobiology where integrin function is crucial, such as tumor metastasis.