Modulation of growth factor binding properties of a2-macroglobulin by enzyme therapy
Lauer D., Müller R., Cott C., Otto A., Naumann M., Birkenmeier G.
Modulation of growth factor binding properties of a2-macroglobulin
by enzyme therapy. Cancer Chemother Pharmacol 2001, Vol. 47., Suppl.
July 2001, S 4 – 9. 519 KA (2-13-2)-(20-00-2).
Institute of Biochemistry, University of Leipzig, Leipzig, Germany
Purpose: To investigate the binding of transforming growth factor-beta (TGF-b) to human a2-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 Before and after medication plasma was immediately withdrawn and binding of 125I-TGF-b to the proteinase inhibitor a2-macroglobulin was determined by electrophoresis and g-counting.
Cell culture experiments were performed to study the effect of transformed a2-macroglobulin on TGF-b-stimulated proliferation of skin fibroblasts.
Results: Ingestion of proteinases was found to trigger the formation of intermediate forms of a2-macroglobulin displaying high affinity to TGF-b.
Maximum binding of TGF-b 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, a-chymotrypsin, bromelain and plasmin) with a2-macroglobulin conferred binding of 125I-TGF-b. a2-Macroglobulin transformed by methyl-amine or proteinases was found to abolish the TGF-b effect on fibroblasts in cell culture.
Conclusions: Intestinal absorption of proteinases triggers the formation of TGF-b binding species of a2-macroglobulin in blood. Mediated by this process high concentrations of TGF-b might be reduced via enhanced clearance of a2-macroglobulin-TGF-b complexes. Thus, proteinase therapy may have beneficial effects in treatment of fibrosis and certain cancers accompanied by excessively high TGF-b concentrations.
Key words: Proteinase therapy • TGF-b • a2-macroglobulin • Cancer • Fibrosis