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NFP37
SOMATIC GENE THERAPY
Texts for Laypersons
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Prof. Roman Klemenz;
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Universitätsspital Zürich; Pathologie;
Schmelzbergstrasse 12; 8091 Zürich; CH;
Tel 01 255 39 31; Fax 01 255 45 08;
e-mail:
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Title:
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Destruction of tumor-infiltrating blood vessels.
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Co-applicants:
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PD DR. R Schwendener (Zürich); Dr. D. Moritz
(Zürich)
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Collaborators:
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ABSTRACT | PUBLICATION |
DIVULGATIONTEXT |
BACK TO OUTLINE
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ABSTRACT FOR LAYPERSONS 1997:
The development of a life threatening tumor
is a multistep process. It is usually initiated by mutations within a
single cell which allows it to divide without a stimulus from the
outside. The resulting tumor remains small (a so-called carcinoma in
situ) and is characterized by a high proliferation rate at the
periferie which is balanced by extensive cell death in the central
regions of the tumor. There, the supply of oxygen and nutrients is
insufficient due to the lack of blood vessels within these tumors.
With time additional genetic alterations occur within single cells of
such a tumor which render them angiogenic. These altered cells
secrete factors which diffuse across the tumor and reach neighboring
blood vessels. These angiogenic factors stimultate the sprouting of
new capillaries out of mature vessels. These vessel sprouts grow
along a gradient of angiogenic factors into the tumor mass. This
vascularization provides the tumor with sufficient nutrients and
allows the removal of west products. Consequently, an extensive
enlargement of the tumor mass ensues. In most organs the endothelial
cells which line the vessel walls form a very tight barrier between
the blood and the adjacent tissues. However, tumor penetrating
vessels are very leaky and allow tumor cells to penetrate into the
blood vessel. There these metastatic cells are carried by the blood
stream to distant organs where a minority of them can extravasate and
establish metastases.
In animal models it could be shown that the
prevention of the process of new blood vessel generation
(angiogenesis) results in tumor regression. Two strategies to
interfere with angiogenesis are imaginable. The process of
angiogenesis can be prevented by the continuous application of
angiogenesis inhibitors. A long list of such inhibitors is known and
at least nine of them are currently in clinical trials. The
disadvantage of this strategy is the requirement for continuous
treatment.
Alternatively, the blood vessels in tumors
can be actively destroyed. The prerequisite for such an approach is
the identification of molecules which are exclusively expressed on
the surface of tumor penetrating blood vessels. Animal models with
experimental tumors which trigger the expression of unique molecules
on the tumor vessel wall have validated this strategy. What is badly
needed is the identification of naturally occuring tumor vessel
markers. A few molecules have been described as being overexpressed
by the endothelial cells in tumors. These molecules include endoglin,
the integrin avp3, a fibronectin isoform and the receptors Flk-1 and
Tek. We have found that endoglin is indeed overexpressed in tumor
vessels but that it is also expressed in substantial amounts in liver
and the skin and can therefore not be used as a targeting molecule.
An antibody directed against the fibronectin isoform is being linked
to liposomes. Such liposomes are expected to accumulate in tumors and
should be useable to selectively deposit drugs in tumors. We have
genetically manipulated cytotoxic T-lymphocytes such that they should
recognize the Flk-1 receptor, which is overexpressed on tumor
endothelial cells. This recognition should activate the T-lymphocyte
and lead to cytotoxicity. Unfortunately, the genetic manipulation
that we have performed did not trigger the expected response. Our
main effort is now directed towards the identification and isolation
of novel molecules which are selectively expressed on the surface of
endothelial cells lining tumor penetrating blood vessels.
ABSTRACT FOR LAYPERSONS
1998:
The development of a life threatening tumor
is a multistep process. It is usually initiated by mutations within a
single cell which allows it to divide without a stimulus from the
outside. The resulting tumor remains small and is characterized by a
high proliferation rate at the periphery which is balanced by
extensive cell death in the central region of the tumor. There, the
supply of oxygen and nutrients is insufficient due to the lack of
blood vessels within these tumors. With time additional genetic
alterations occur within single cells of such a tumor which render
them angiogenic. These altered cells secrete factors which diffuse
across the tumor and reach neighboring blood vessels. These
angiogenic factors stimulate the sprouting of new capillaries out of
mature vessels. These vessel sprouts grow along a gradient of
angiogenic factors into the tumor mass. This vascularization provides
the tumor with sufficient nutrients and allows the removal of waste
products. Consequently, an extensive enlargement of the tumor mass
ensues. In most organs the endothelial cells which line the vessel
walls form a very tight barrier between the blood stream and the
adjacent tissues. However, tumor penetrating vessels are very leaky
and allow tumor cells to penetrate into the blood vessel. There,
these metastatic cells are carried by the blood stream to distant
organs where a minority of them can extravasate and establish
metastases.In animal models it could be shown that the prevention of
the process of new blood vessel generation (angiogenesis) results in
tumor regression. Two strategies to interfere with angiogenesis are
imaginable. The process of angiogenesis can be prevented by the
continuous application of angiogenesis inhibitors. A long list of
such inhibitors is known and at least nine of them are currently in
clinical trials. The disadvantage of this strategy is the requirement
for continuous treatment. Alternatively, the blood vessels in tumors
can be actively destroyed. The prerequisite for such an approach is
the identification of molecules which are exclusively expressed on
the surface of tumor penetrating blood vessels. Animal models with
experimental tumors which trigger the expression of unique molecules
on the tumor vessel wall have validated this strategy. What is badly
needed is the identification of naturally occurring tumor vessel
markers. We have isolated endothelial cells which line the walls of
vessels in either tumors or normal organs. RNA was obtained from
these cells and used to isolate cDNA clones which encode membrane
anchored proteins. Since our endothelial cell preparations are not
very pure we have to test whether these molecules are indeed
overexpressed in endothelial cells. Once proteins are available which
are only present on vessel walls in tumors but not normal organs we
will isolate ligands which specifically bind to these molecules. Such
ligands will be coupled to toxic substances and injected into tumor
bearing animals. These targeted toxins should selectively destroy the
endothelial lining in tumor vessels and lead to tumor regression.We
have also isolated antibodies which recognize a growth factor (VEGF)
which is secreted by tumor cells and is needed for the sprouting of
new blood vessels. These antibodies are genetically engineered
artificial entities which consist only of a single protein chain
unlike natural antibodies which are heterotetramers. The anti VEGF
antibodies prevented the formation of blood vessels on chicken
chorioallantoic membranes and reduced tumor growth in mice. We are
about to improve the quality of these antibodies and will generate
cell lines which synthesize and secret these antibodies. Such cells
will be grown in semipermeable capsules and implanted into tumor
carrying mice. We expect that the constant release of this antibody
will prevent the neovascularization and consequently the growth of
tumors.
ABSTRACT FOR LAYPERSONS
1999:
text (font Courier, corps 3)
ABSTRACT FOR LAYPERSONS
2000:
text (font Courier, corps 3)
ABSTRACT FOR LAYPERSONS
2001:
text (font Courier, corps 3)
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