Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Nervous system
Patent
1993-11-10
1996-06-25
Wityshyn, Michael G.
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Nervous system
424520, 424582, 514 2, 514 21, A61K 3530
Patent
active
055297927
DESCRIPTION:
BRIEF SUMMARY
The formation of new capillary vessels (angiogenesis) proceeds in an ordered series of steps: at a point at which a new vascular bud begins to grow out (usually in the region of post-capillary venules) the endothelial cells locally degrade the basal membrane, migrate towards the source of the factor stimulating angiogenesis, grow and divide, form a vascular lumen and land on other vascular buds or existing capillaries so that a new capillary section forms which finally surrounds itself with a newly formed basal membrane.
The angiogenic activity is usually almost completely inhibited in adult individuals. More intense angiogenic processes only occur in wound healing and in females in connection with the ovarian cycle. However, in general the turnover rate of endothelial cells in the organism is low. The complete renewal of an existing endothelial cell population takes years, there are however substantial organ and tissue-specific differences (Folkman, Medicine 29 (1985), 10-36).
The usual strict control under which angiogenesis normally stands is abolished during the growth of solid tumours. A strong angiogenesis is absolutely necessary for the growth of tumours with a diameter of over 1 to 2 mm. Thus avascular tumours remain limited to a very small size due to the limited diffusion in the supply of gases and nutrients and in removing waste products. The deficiency in the capability of solid tumours to grow to a clinically significant size or to form metastases in the absence of a successful induction of angiogenesis has created great interest in research into compounds which inhibit angiogenesis.
The commercial application of such inhibitors is in the inhibition of tumour growth in general, in particular in the inhibition of tumours based on endothelial cells such as Kaposi's sarcoma and haemangiomas. In addition a therapeutic use for other diseases is also possible which are due to excessive capillary growth. Particular examples of this are diabetic retinopathy and retrolental fibroplasia, both of which are eye diseases. A further possible application is the treatment of wounds whereby an inhibitor of angiogenesis can be used to regulate wound healing i.e. in delaying the regeneration of blood vessels. In addition an angiogenesis inhibitor can also be used for the treatment of rheumatoid arthritis. In this disease a vascularization of cartilage is observed (as generally seen in every inflammation in this region) which can be suppressed by an angiogenesis inhibitor.
A series of extracts which inhibit angiogenesis have been prepared from avascular tissues (see D'Amore and Braunhut, in Endothelial Cells, Vol. II, published by U.S. Ryan, CRC Press, Boca Raton, Fla., 13-37). Anti-inflammatory agents also suppress angiogenesis (Robin et al., Arch. Ophthamol. 103 (1985), 284-287; Polverini and Novak, Biochem. Biophys. Res. Comm. 140 (1986), 901-907), such as e.g. protamine (Taylor and Folkman, Nature 297 (1982), 307-312), angiostatic steroids (Crum et al., Science 230 (1985), 1375-1378), a placental RNAse inhibitor (Shapiro and Vallee, Proc. Natl. Acad. Sci. USA 84 (1987), 2238-2241) and a series of compounds which influence matrix synthesis and stability (see e.g. Ingber and Folkman, Lab. Invest. 59 (1988), 44-51). An inhibition of tumour growth or regression was found in vivo for some of these inhibitors but not in all tumours. Moreover the toxicity of these angiogenesis inhibitors also remains a problem.
An angiogenesis inhibitor was found by Rastinejad et al. (Cell 56 (1989), 345-355) in a medium with hamster cells and hamster-human hybrid cells which suppresses neovascularization in vivo. This compound is apparently a glycoprotein with a molecular weight of 140 kDa. However, this inhibitor has only a low stability and in particular it is not thermally stable.
DE 40 06 609 discloses a protein which acts as an inhibitor of the proliferation of endothelial cells obtainable from baby hamster kidney cells which has a molecular weight of ca. 60 to 100 kDa in gel filtration under native conditions and has a higher
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Drexler Hannes
Risau Werner
Max-Planck-Gesellschaft zur Forderung der Wissenschaften e.v.
Wityshyn Michael G.
Witz Jean C.
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