02 BOOK OF ABSTRACTS .indd

Antiprotease therapy in cancer: hot or not ?
María Beatriz Durán Alonso, Cornelis J.F. Van Noorden* and Tamara T. Lah
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ve~na
pot 111, 1000 Ljubljana, Slovenia; *Department of Cell Biology and Histology, Academic
Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam,
The Netherlands
There is clear evidence from experimental and clinical studies that proteases are
involved in the spread of cancer. Not only do they play important roles in invasion
and metastasis but also in other stages in cancer progression, namely upregulation
of cell proliferation, downregulation of apoptosis, escape from immune responses,
angiogenesis and the acquisition of multi-drug resistant phenotypes by the cancer
cells.
Despite their known participation in tumour progression, clinical trials using
protease inhibitors have been, to date, mostly disappointing. Several factors may
be accountable for this failure, among them the lack of specificity of many of these
compounds and the late stages of cancer of the patient populations undergoing
these treatments. In addition, the genetic instability of cancer cells allows them to
adapt quickly to new situations. Furthermore, regulation of the proteolytic systems
is highly complex, both in terms of their activation in cascade-like processes and the
effects the interactions between the tumour cells themselves and the surrounding
stroma exert on the expression and, ultimately, the activity of these enzymes. Another
clear obstacle to the development of antiprotease-based anti-cancer treatments is
the lack of an in-depth knowledge of the specific roles played by the individual
proteases and the interplay between them, in tissue- and stage-specific settings.
Further work will be required in order to answer these questions. This, together with
improvements on the specificity and other properties of the protease inhibitors, as
well as the availability of other methods to alter protease activity, such as antibodies
and genetic manipulation, are expected to aid the development of future anti-cancer
therapies where antiprotease approaches may be used in conjunction with cytotoxic
drugs. Promising data, already being obtained with antithrombotics, the urokinasetype
plasminogen activator system, the membrane-bound membrane-type 1-MMP,
cathepsin L, and the proteasome, will be discussed.
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