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A Synthetic Antagonist to Laminin Inhibits the Formation of Osteolytic Metastases by Human Melanoma Cells in Nude Mice¹

University of Texas Health Science Center at San Antonio, Department of Medicine, Division of Endocrinology/Metabolism [M. N., G. R. M., P. J. W., T. Y.], and Department of Pathology [B. B.], San Antonio, Texas 78284-7877

The mechanisms by which tumor cells metastasize to bone are not well understood. We have investigated the role of the basement membrane glycoprotein, laminin, in bone metastasis, since antagonists to laminin have been shown to inhibit the formation of lung metastases. We studied the formation of osteolytic metastases caused by a human tumor which is known to cause osteolysis and hypercalcemia in nude mice. We found that tumor-bearing nude mice developed hypercalcemia, cachexia, and characteristic osteolytic lesions throughout the skeleton after injection of this human melanoma cell line (A375) into the left ventricle. When we gave injections to nude mice with A375 cells which had been exposed to C(YIGSR)₃-NH₂, a laminin-derived synthetic peptide containing three linear sequences of YIGSR with an amino-terminal cysteine which competes with laminin for its receptor, we found a decrease in the formation of detectable osteolytic bone metastases. The tumor cells were incubated with the antagonist and then inoculated into nude mice which were administered the antagonist i.p. Hypercalcemia and cachexia were also decreased in tumor-bearing mice treated with the laminin antagonist. In contrast, laminin itself increased the number of osteolytic bone metastases, as has been shown for other tumor cells. These data suggest that laminin plays a role in the formation of osteolytic bone metastases in this model and that laminin antagonists may be useful in the prevention of bone metastases in some human tumors.

¹ Work reported here was supported by Grants CA40035, RR1346, and AR28149 from the NIH.

² To whom requests for reprints should be addressed, at the University of Texas Health Science Center, Department of Medicine, Division of Endocrinology/Metabolism, 7703 Floyd Curl Drive, San Antonio, TX 78284-7877.

Received 6/22/92. Accepted 8/18/92.

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