Modulation of growth factor binding properties of a2-macroglobulin by enzyme therapy
Lauer D., Müller R., Cott C., Otto A., Naumann M., Birkenmeier
Institute of Biochemistry, University of Leipzig, Leipzig,
Cancer Chemother Pharmacol (2001) 47: 4 - 9.
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Before and after medication plasma was immediately withdrawn and binding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