期刊
CANCER CHEMOTHERAPY AND PHARMACOLOGY
卷 47, 期 -, 页码 S4-S9出版社
SPRINGER-VERLAG
DOI: 10.1007/s002800170002
关键词
proteinase therapy; TGF-beta; alpha 2-macroglobulin; cancer; fibrosis
Purpose: To investigate the binding of transforming growth factor-beta (TGF-beta) to human alpha2-macroglobulin upon oral treatment of patients with proteases. Methods: Volunteers were given a cocktail of active proteinases (Phlogenzym) composed of trypsin, bromelain and the additive rutoside orally over a period of 7 days at low dose followed by a bolus application. Before and after medication plasma was immediately withdrawn and binding of I-125-TGF-beta to the proteinase inhibitor alpha2-macroglobulin was determined by electrophoresis and gamma -counting. Cell culture experiments were performed to study the effect of transformed alpha2-macroglobulin on TGF-beta -stimulated proliferation of skin fibroblasts. Results: Ingestion of proteinases was found to trigger the formation of intermediate forms of alpha2-macroglobulin displaying high affinity to TGF-beta. Maximum binding of TGF-beta was observed 1-2 h after bolus ingestion, and steadily levelled off with time. In vitro experiments demonstrated that complex formation of diverse proteinases (trypsin, alpha -chymotrypsin, bromelain and plasmin) with alpha2-macroglobulin conferred binding of I-125-TGF-beta. alpha2-Macroglobulin transformed by methylamine or proteinases was found to abolish the TGF-beta effect on fibroblasts in cell culture. Conclusions: Intestinal absorption of proteinases triggers the formation of TGF-beta binding species of alpha2-macroglobulin in blood. Mediated by this process high concentrations of TGF-beta might be reduced via enhanced clearance of alpha2-macroglobulin-TGF-beta complexes. Thus, proteinase therapy may have beneficial effects in treatment of fibrosis and certain cancers accompanied by excessively high TGF-beta concentrations.
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