NON-ANTICOAGULANT HEPARIN-CARRYING POLYSTYRENE (NAC-HCPS) AFFECTS ANGIOGENESIS AND INHIBITS SUBCUTANEOUS INDUCED TUMOR GROWTH AND METASTASIS TO THE LUNG.

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Non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) consists of about ten periodate-oxidized (IO_4-), alkaline-degraded low molecular weight-hepann (LMW-Hep) chains linked to a polystyrene core and has a markedly lower anti-coagulant activity than Hep, but similar to IO_4- and IO_4-LMW-Hep. In this study, we evaluated the effect of NAC-HCPS on tumor progression and metastasis. NAC-HCPS has a higher activity to inhibit VEGF_<165>-, FGF-2- or HGF-induced human microvascular endothelial cell (HMVEC) growth than Hep, IO_4-Hep and IO_4-LMW-Hep, which is probably due to the Hep-clustering effect of NAC-HCPS.NAC-HCPS inhibited HMVEC, B16 melanoma (B16) and Lewis lung cancer (3LL) cell adhesion to Matrigel-coated plates. Furthermore, NAC-HCPS showed a strong inhibitory activity in the tubular formation of endothelial cells on Matrigel and B16 and 3LL cell invasion in a Matrigel-coated chamber assay. In vivo studies showed that growth of subcutaneous induced tumors and lung metastasis of B16 and 3LL cells were more effectively inhibited by NAC-HCPS than IO_4-Hep and IO_4-LMW-Hep. Furthermore, NAC-HCPS markedly reduced the number of CD34-positive cells in subcutaneous 3LL tumors, indicating a strong inhibition of angiogenesis. These results suggest that NAC-HCPS has an inhibitory activity on angiogenesis and tumor invasion and may be very useful in malignancy therapy.
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