Abstract
Angiogenesis is essential for solid tumor progression, growth and metastasis. This process requires mitogenic signals from growth factors for endothelial cell proliferation (eg. bFGF), as well as hydrolases for extracellular matrix degradation to permit endothelial cell migration and tumor cell invasion (eg. matrix metalloproteases and heparanase). We have evaluated the antitumor and antimetastatic activity of a series of sulfated oligosaccharides in syngeneic murine and human tumor xenograft models. One of these compounds, GM1474 is a novel polysulfated oligosaccharide that has multiple biological activities, and binds tightly to bFGF as well as inhibiting tumor cellderived heparanase. GM1474 inhibited bFGF-dependent proliferation of endothelial cells in vitro and angiogenesis ex ovo in a chick chorioallantoic membrane (CAM) assay. GM1474 did not inhibit the in vitro proliferation of human or murine tumor cells. Systemic administration of GM1474 significantly inhibited subcutaneous tumor growth of human mammary (MDA-231), prostatic (PC-3) and hepatocellular (SKHep-1) carcinomas in nude mice. Administration of GM1474, on days 0–4 after iv. injection of B16-F10 melanoma cells into C57/BL6 mice, resulted in a dose-dependent increase in survival of treated animals. Treatment with GM1474 resulted in a >90% reduction in the number of spontaneous lung metastases that occurred in the SN12PM6 orthotopic model of human renal cell carcinoma. In the KM12L4a orthotopic human colorectal carcinoma model, GM1474 significantly inhibited the formation of spontaneous liver metastasis in nude mice. This compound also significantly inhibited the orthotopic growth of the human 253J-BV bladder cell carcinoma in nude mice. These data demonstrate that a sulfated oligosaccharide that binds bFGF and inhibits heparanase is angiostatic, and is a potent antitumor and antimetastatic agent in vivo.
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© 1996 Plenum Press, New York
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Tressler, R.J. et al. (1996). A Heparanase-Inhibitory, bFGF-Binding Sulfated Oligosaccharide that Inhibits Angiogenesis Ex Ovo has Potent Antitumor and Antimetastatic Activity in Vivo . In: Maragoudakis, M.E. (eds) Molecular, Cellular, and Clinical Aspects of Angiogenesis. NATO ASI Series, vol 285. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0389-3_19
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DOI: https://doi.org/10.1007/978-1-4613-0389-3_19
Publisher Name: Springer, Boston, MA
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