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Suppression by Cathepsin L Inhibitors of the Invasion of Amnion Membranes by Murine Cancer Cells¹

Department of Anatomy [S. Y., P. K. L.] and Cancer Research Laboratory [D. T. D.], University of Western Ontario, London, Ontario N6A 5B7, Canada; Abbott Laboratories, Abbott Park, Illinois [H. N. N.]; Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada [A. H. W.]; and Mt. Sinai Research Hospital Research Institute, Toronto, Ontario, Canada [C. W.]

Cysteine proteinases, particularly cathepsins B and L, have been strongly implicated in fostering metastasis in mice. In this work four different inhibitors of cysteine proteinases have been shown to inhibit the invasion of the human amnion by murine melanoma and mammary carcinoma cells in vitro. Two of the inhibitors are synthetic peptides {ZPhePheCHN₂ (benzyloxycarbonyl-L-phenylalanyl-L-phenylalanyldiazomethane) and ZPheAlaCH₂F [3-(N-benzyloxycarbonylphenylalanylamido)-DL-1-fluoro-2-butanone]} and two are thiol protease inhibitors (TPIn, TPId) isolated from the skeletal muscle of the hind limbs of normal and dystrophic mice, respectively. The inhibitors (ZPhePhe-CHN₂, TPId), with apparent selectivity for cathepsin L, blocked invasion as effectively as inhibitors (ZPheAlaCH₂F, TPIn) effective on both cathepsins. The data reveal that in these cell lines the cysteine proteinases contribute significantly to the invasive capacity of the cells, but to a lesser extent than do the metalloproteinases. We suggest that the cysteine proteinases facilitate the action of metalloproteinases (collagenase, gelatinase, and stromelysin), possibly by activating them, by inactivating the tissue inhibitor of metalloproteinases, and/or by making basement membrane matrix more accessible.

¹ This research was supported by the National Cancer Institute, Canada, the Medical Research Council of Canada, and The Cancer Research Society, Montreal, Canada.

² Present address: Department of Pathology, Dalhousie University, Halifax, Nova Scotia.

³ To whom requests for reprints should be addressed, at Nelson Biological Laboratories, Rutgers University, Piscataway, NJ 08855-1059.

Received 6/21/88. Revised 11/21/88. Revised 3/27/89. Accepted 4/ 4/89.

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