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Inhibition by Sulfated Chitin Derivatives of Invasion through Extracellular Matrix and Enzymatic Degradation by Metastatic Melanoma Cells¹

Institute of Immunological Science, Hokkaido University, Sapporo 060, Japan [I. S., J. M., I. A.]; Department of Tumor Biology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [M. N.]; and Department of Polymer Science, Faculty of Science, Hokkaido University, Sapporo 060, Japan [S. T.]

We have investigated the effects of sulfated chitin derivatives and heparin on the invasion of B16-BL6 melanoma cells through reconstituted basement membrane Matrigel which contains laminin, type IV collagen, heparan sulfate proteoglycan, and entactin. 6-O-sulfated chitin (S-chitin) and 6-O-sulfated and carboxymethyl chitin (SCM-chitin) significantly inhibited the penetration of tumor cells through Matrigel in parallel with the increased degree of sulfation. However, 6-O- and N-sulfated but partially N-deacetylated chitin derivative (SCM-chitosan) and CM-chitin had no effect. SCM-chitin with a high degree of sulfation (SCM-chitin III), which exhibited fairly low levels of anticoagulant activity, was more effective than intact heparin. SCM-chitin III and heparin were also shown to block the attachment and migration of tumor cells to laminin-coated substrates, which are considered to be involved in tumor invasion. The inhibition of cell attachment and migration by SCM-chitin III and heparin is likely to depend upon their specific binding to laminin molecules (possibly the heparin-binding domain). Degradation of heparan sulfate by heparanase was inhibited by SCM-chitin III and heparin in a dose-dependent manner. Surprisingly, SCM-chitin III could inhibit type IV collagenolytic activity of tumor cells more potently than heparin. Thus, nontoxic SCM-chitin III of low anticoagulant properties may provide a promising basis for the prevention of cancer metastasis.

¹ This work was supported in part by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, and Culture for the Comprehensive 10-Year Strategy for Cancer Control; from the Japanese Ministry of Health and Welfare and for Developmental Scientific Research (No. 62870023) from the Japanese Ministry of Education, Science, and Culture; and by Grant R01-CA41524 from the USPHS, National Cancer Institute, as well as by grants from the Osaka Foundation for the Promotion of Clinical Immunology, the Yamanouchi Foundation for Research on Metabolic Disorders, and the CIBA-Geigy Foundation for the Promotion of Science; and by Grants-in-Aid for Special Project Research from Hokkaido University, Japan.

² To whom requests for reprints should be addressed, at Institute of Immunological Science, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060, Japan.

Received 11/17/89. Revised 1/29/90.

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