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Antithrombin III therapy of angiogenesis-dependent diseases

13.12.2006
During growth, tumours secrete enzymes, which proteolytically cleave known proteins, such as collagen XVIII and antithrombin III (AT III), or alter their conformation (e.g. to latent AT III). The fragments formed in this way (cleavage products) show in vitro and in vivo antiangiogenic properties and function as negative regulators of an-giogenesis.

One approach is to manufacture these negative regulators, for example the antiangiogenic functioning cleavage products, in order to use these therapeutically with patients in the form of a pharmaceutical. This has already been realised in the case of endostatin, however with the disadvantage that the genetically modified proteins, depending on the expression system used, show no exact consensus and 100% effectiveness in comparison to naturally occurring cleavage products. The invention shows that antiangiogenic antithrombin III is also a cleavage product or protein with modified conformity derived from native antithrombin III. Since the tumour cells are capable of decomposing antithrombin or changing its conformation, the application of native antithrombin III in vivo leads to a reduction or a stoppage of growth through inhibition of the vascular growth. This means that native antithrombin III can also be directly applied in therapy. An expensive, complex and time-consuming separate approval as a medicinal product is not necessary, since native antithrombin III is a medicine that can already be found on the market for the treatment of inflammation reactions. Experiments show that antithrombin III leads to a reduction in the growth of the blood vessels and thereby a reduction of the tumour. It is very suitable for application in tumour angiogenesis. In vivo experiments with mice confirm this; a therapy with 50 mg/kg/day antithrombin III leads to a clear inhibition of angiogenesis through reduced microvessel density and finally causes a complete obstruction of the growth of the tumour.

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Dr. Peter Stumpf

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