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immediately withdrawn and binding of 125I-TGF-b to the proteinase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