Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1999-12-10
2003-07-15
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S002600, C514S008100, C514S012200
Reexamination Certificate
active
06592862
ABSTRACT:
The present invention relates generally to the modulation of the growth of collateral arteries or other arteries from preexisting arteriolar connections. In particular, the present invention provides a method for enhancing the growth of collateral arteries and/or other arteries from preexisting arteriolar connections comprising contacting tissue or cells with a monocyte chemotactic protein (MCP) or a nucleic acid molecule encoding said MCP. The present invention also relates to the use of an MCP or a nucleic acid molecule encoding said MCP for the preparation of pharmaceutical compositions for enhancing collateral growth of collateral arteries and/or other arteries from preexisting arteriolar connections. Furthermore, the present invention relates to a method for the treatment of tumors comprising contacting tissue or cells with an agent which suppresses the growth of collateral arteries and/or other arteries from preexisting arteriolar connections through the attraction of monocytes. The present invention further involves the use of an agent which suppresses the growth of collateral arteries and/or other arteries from preexisting arteriolar connections through the attraction of monocytes for the preparation of pharmaceutical compositions for the treatment of tumors.
In the treatment of subjects with arterial occlusive diseases most of the current treatment strategies aim at ameliorating their effects. The only curative approaches involve angioplasty (balloon dilatation) or bypassing surgery. The former carries a high risk of restenosis and can only be performed in certain arterial occlusive diseases, like ischemic heart disease. The latter is invasive and also restricted to certain kinds of arterial occlusive diseases. There is no established treatment for the enhancement of collateral growth.
Vascular growth in adult organisms proceeds via two distinct mechanisms, sprouting of capillaries (angiogenesis) and in situ enlargement of preexisting arteriolar connections into true collateral arteries
1
. Recent studies have disclosed mechanisms leading to angiogenesis with vascular endothelial growth factor (VEGF) as a major component
2-6
. This specific endothelial mitogen is upregulated by hypoxia and is able to promote vessel growth when infused into rabbit hindlimbs after femoral artery excision
7,8
. These studies however did not distinguish between capillary sprouting, a mechanism called angiogenesis, and true collateral artery growth. Whereas VEGF is only mitogenic for endothelial cells, collateral artery growth requires the proliferation of endothelial and smooth muscle cells and pronounced remodeling processes occur
1,9-12
. Furthermore mainly capillary sprouting is observed in ischemic territories for example in the pig heart or in rapidly growing tumors
1,3,13,14
. True collateral artery growth, however, is temporally and spacially dissociated from ischemia in most models studied
1,15
. Other or additional mechanisms as those described for angiogenesis in ischemic territories are therefore needed to explain collateral artery growth. From previous studies it is known that these collateral arteries grow from preexisting arteriolar connections
1
.
However, while agents such as VEGF and other growth factors are presently being employed to stimulate the development of angiogenesis after arterial occlusion, such agents are not envisaged as being capable of modulating the growth of preexisting arteriolar connections into true collateral arteries.
Thus, the technical problem of the present invention is to provide pharmaceutical compositions and methods for the modulation of the growth of collateral arteries and/or other arteries from preexisting arteriolar connections.
The solution to this technical problem is achieved by providing the embodiments characterized in the claims.
Accordingly, the invention relates to a method for enhancing the growth of collateral arteries and/or other arteries from preexisting arteriolar connections comprising contacting tissue or cells with a monocyte chemotactic protein (MCP) or a nucleic acid molecule encoding said MCP.
For the purpose of the present invention the growth of arteries from preexisting arteriolar connections is also called “arteriogenesis”. In particular, “arteriogenesis” is the in situ growth of arteries by proliferation of endothelial and smooth muscle cells from preexisting arteriolar connections supplying blood to ischemic tissue, tumor or sites of inflammation. These vessels largely grow outside the affected tissue but are much more important for the delivery of nutrients to the ischemic territory, the tumor or the site of inflammation than capillaries sprouting in the diseased tissue by angiogenic processes.
In the context of the present invention the term “monocyte chemotactic protein” or “MCP” refers to proteins and peptides which can act on monocytes and lead to augmentation of monocyte activation accumulation and migration
35
. Thus, according to the present invention, any MCP or other substances which are functionally equivalent to an MCP, namely which are capable of activating and attracting monocytes can be used for the purpose of the present invention. The action of the MCPs employed in the present invention may not be limited to the above-described specificity but they may also act on, for example eosinophils, lymphocyte subpopulations and/or stem cells.
In accordance with the present invention, it has been found that through the attraction of monocytes by monocyte chemotactic protein-1 (MCP-1) the growth of collateral arteries and arteriogenesis could be significantly enhanced in animals after femoral artery occlusion. Experiments performed within the scope of the present invention demonstrate that local infusion of MCP-1 increases both collateral- and peripheral conductance after femoral artery occlusion due to enhanced vessel growth by augmentation of monocyte accumulation concomitant with proliferative effects on endothelial and/or smooth muscle cells. Thus, MCPs or nucleic acid molecules encoding MCPs can be used to attract monocytes to a certain tissue or cell which in turn leads to growth of collateral arteries as well as to growth of arteries from preexisting arteriolar connections, which is needed for the cure of several occlusive diseases.
MCP-1 is a 14-kDa glycoprotein secreted by many cells, including vascular smooth muscle- and endothelial cells
29-32
and induces monocyte chemotaxis at subnanomolar concentrations
33
. MCP-1 is a potent agonist for the &bgr; chemokine receptors CCR 2 and CCR 4 which are both mainly expressed by monocytes but also have been found to be present on basophils, T- and B-lymphocytes
34
. These G-protein coupled seven-transmembrane-domain receptors lead to the activation of monocytes and increased adhesiveness of integrins, a process which finally leads to monocyte arrest on endothelial cells
35
. The MCP-1 gene shows large interspecies homologies
30
and can be induced by various cytokines (e.g. Tumor necrosis factor &agr;) and immunoglobulin G
36
. Recently it has been shown in vitro that gene expression and protein secretion of MCP-1 are also upregulated by shear stress and cyclic strain
16-18
. These mechanical forces have recently been shown to increase monocyte chemotactic protein-1 (MCP-1) secretion in cultured human endothelial cells leading to increased monocyte adhesion
16-18
. These findings complement the observation that monocytes adhere and migrate into the vessel wall of collateral arteries after induction of coronary artery stenosis in the dog heart at a time when the proliferation index is maximally increased
19
. Furthermore, monocyte accumulation is also observed in the pig microembolization model of angiogenesis
20
. Moreover increased levels of MCP-1 mRNA were found in ischemic tissue of microembolized porcine myocardium
21
as well as in reperfused ischemic myocardium
37
. However, although there are several reports published that indicate that monocytes are involved in angiogenesis
22-24
monocytes were not believed to play a role in the development of c
Ito Wulf D.
Schaper Wolfgang
Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.
Mertz Prema
Sterne Kessler Goldstein & Fox P.L.L.C.
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