The effect of antimetastatic sulfated chitin derivatives (SCM-chitin III) on angiogenesis induced by B16-BL6 cells was examined in syngeneic mice. SCM-chitin III caused a marked decrease of the number of vessels toward tumor mass (angiogenic response) without affecting the tumor cell growth when coinjected with tumor cells (on day 0), or injected into tumor site on day 1 or 3 after tumor inoculation. In contrast, carboxymethyl chitin as well as heparin had no effect. Invasion of endothelial cells through reconstituted basement membrane (Matrigel) toward tumor-conditioned media was significantly inhibited by SCM-chitin III in a Transwell chamber assay. SCM-chitin III also inhibited the haptotactic migration of endothelial cells to fibronectin-substrate, but did not inhibit the chemotactic activity in tumor conditioned media in vitro. SCM-chitin III did not directly affect the viability and the growth of tumor cells and endothelial cells in vitro. These results suggest that inhibition of lung tumor metastasis by SCM-chitin III may in part be due to the inhibition of tumor-associated angiogenesis.
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 (Grant 62870023) from the Japanese Ministry of Education, Science and Culture, as well as by Grants from the Osaka Foundation for Promotion of Clinical Immunology, the Ciba-Geigy Foundation for the Promotion of Science, and the Naito Foundation for Promotion of Science.