Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1992-08-25
1994-02-15
Withyshyn, Michael G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530350, 530413, 530416, 530420, A61K 3700
Patent
active
052867161
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
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 vessel 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, the turnover rate of the endothelial cells in the organism is generally 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 of angiogenesis is abolished in 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. Avascular tumours remain limited to a very small size due to the limited diffusion of the supply of gases and nutrients and with the removal of waste products. This 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 caused a great interest in research into compounds which inhibit angiogenesis.
The commercial application of such inhibitors is for the inhibition of tumour growth in general, in particular for the inhibition of tumours based on endothelial cells such as Kaposi 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 use is in the treatment of wounds in which 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 Edothelial Cells, Vol. II, edited 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). For some of these inhibitors an inhibition of tumour growth or regression was observed in vivo but not with all tumours. Furthermore 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 the neovascularization in vivo. This compound is apparently a glycoprotein with a molecular weight of 140 kD. However, this inhibitor only has a low stability and in particular it is not thermally stable.
It was therefore the object of the present invention to provide a more stable angiogenesis inhibitor which can hence be more readily used therapeutically.
The object according to the present invention is achieved by a protein which acts as an inhibitor of the proliferat
REFERENCES:
patent: 4210719 (1980-07-01), Tolbert et al.
patent: 4229531 (1980-10-01), Tolbert et al.
Drexler Hannes
Risau Werner
Max Planck Gesellschaft zur Forderung der Wissenschaften e.V.
Sayala C.
Withyshyn Michael G.
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