| Pharmaceutical preparations containing mixtures of various
proteolytic and nonproteolytic enzymes have been suggested for use in
the treatment of malignant diseases. However, the mode of action of
such preparations was not clear. We have shown before that intact
bromelain, papain or amylase, which are components of a commercial
polyenzyme preparation, induce cytokine production in peripheral
blood mononuclear cells in vitro. IFN-alpha and IFN-gamma which had
no effect alone, synergistically increased TNF production when
applied together with the enzymes. Here we show that trypsin alone
had only a small inducing effect. The tryptic but not the autolytic
fragments of papain and bromelain have a higher (10- to 40-fold)
inducing capacity for TNF production than the untreated enzyme.
Additionally we demonstrate that after ingestion of milligram doses
of the polyenzyme preparation (as recommended for clinical use),
PBMNC of healthy donors acquire the ability to produce TNF-alpha, IL-
1 beta and IL-6 when incubated ex vivo with IFN-gamma. Our results
indicate that the biological effects observed after oral
administration of polyenzyme preparations are related to their
ability to induce cytokine production. This may explain the antitumor
effects of such enzymes. Our results also suggest that polyenzyme
preparations may have a stronger immunomodulary effect when used in
combination with IFN-gamma.
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