Proenzyme Therapy of Cancer
Proteases and their inhibitors have long been investigated in numerous tumor systems, and at the tumor growing front, their balance has been universally found to be shifted towards higher proteolytic activities. However, out of many promising serine and metalloproteinase inhibitors, none are include...
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| Published in: | Anticancer research Vol. 25; no. 2A; pp. 1157 - 1177 |
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| Main Authors: | , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Attiki
International Institute of Anticancer Research
01-03-2005
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Proteases and their inhibitors have long been investigated in numerous tumor systems, and at the tumor growing front, their
balance has been universally found to be shifted towards higher proteolytic activities. However, out of many promising serine
and metalloproteinase inhibitors, none are included in cancer treatment regimens at present. The current search for active
antiproteolytic compounds is in contrast to the classical approach developed by John Beard, who suggested treating advanced
cancer by fresh pancreatic extracts whose antitumor activity was based on their proteolytic potential. We followed John Beard's
recommendations by using purified pancreatic proenzymes/enzymes, trypsinogen/trypsin (TG/TR), chymotrypsinogen/chymotrypsin
(CG/CH) and amylase (AM). The mixture of these enzymatic activities produces potent antimetastatic and antitumor effects in
cellular, animal and human systems. The treatment of cultured tumor cells with TR and CH at nanomolar concentrations, comparable
to those achieved in the blood of the patients, causes complete arrest of the directional movement of metastatic cells. Conversely,
the same treatment of normal cells results in enhanced motility and an accelerated closure of the gap created in cell monolayers.
Further, treatment of cells with serine proteases results in the formation of cellular 3-dimensional structures such as lamellae,
cell streams and aggregates. In some cell types, the aggregates are compacted via cadherin-based cell-cell communication systems
and form compact spheroids. In the highly metastatic cells with lower cadherin expression, the ability to form spheroids also
diminishes. Tumor cells unable to form spheroids when treated with proteases are subject to elimination by apoptosis. In contrast,
a large proportion of cells that form spheroids remain viable, although they are metabolically suppressed. Protease-treated
tumor cells contain a disrupted actin cytoskeleton and exhibit a loss of front-to-back polarity. We hypothesize that the provision
of zymogens, rather than the enzymes, was of crucial importance to the clinical effectiveness in the human trials conducted
by Beard and his co-workers. The precursor nature of the active enzymes may offer protection against numerous serpins present
in the tissues and blood. Experimental evidence supports the assertion that the conversion from proenzyme to enzyme occurs
selectively on the surface of the tumor cells, but not on normal cells. We believe that this selectivity of activation is
responsible for the antitumor/antimetastatic effect of proenzyme therapy and low toxicity to normal cells or tumor host. Elevated
levels of endostatin and angiostatin appear in the blood of TG/CG/AM-treated tumor-bearing mice, but not in tumor mice treated
with the vehicle alone or in proenzyme-treated tumor-free mice. These findings support the conclusion that proteolysis is
the active mechanism of the proenzyme treatment. Future studies will focus on the molecular mechanisms of the proenzyme therapy
including the identification of molecular target(s) on the tumor cells. In conclusion, we have discovered that proenzyme therapy,
mandated first by John Beard nearly one hundred years ago, shows remarkable selective effects that result in growth inhibition
of tumor cells with metastatic potential. |
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| ISSN: | 0250-7005 1791-7530 |