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Effects of Inhibitors of Plasminogen Activator, Serine Proteinases, and Collagenase IV on the Invasion of Basement Membranes by Metastatic Cells

Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, NIH, Bethesda, Maryland 20892 [R. R., E. W. T., Y. I., G. R. M.]; Department of Immunoinflammatory Diseases, G. D. Searle Co., Skokie, IL 60077 [J. R. D., G. C. F.]; and Department of Biochemistry, Weizmann Institute of Science, Rehovot, Israel 76100 [R. M.]

Using both human and murine cell lines, we show that malignant cells are able to invade through basement membrane and also secrete elevated amounts of collagenase IV, an enzyme implicated in the degradation of basement membranes. Using serine proteinase inhibitors and antibodies to plasminogen activators as well as a newly described collagenase inhibitor we demonstrate that a protease cascade leads to the activation of an enzyme(s) that cleaves collagen IV. Inhibition at each step reduces the invasion of the tumor cells through reconstituted basement membrane in vitro. Treatment with a collagenase inhibitor reduced the incidence of lung lesions in mice given i.v. injections of malignant melanoma cells.

¹ Supported in part by the Breast Cancer Study Group, Medical Breast Cancer Section, Medicine Branch, National Cancer Institute, NIH.

Received 7/ 2/87. Revised 11/17/87. Revised 3/10/88. Accepted 3/17/88.

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