Previous data have indicated that the proteoglycan (PG) pattern is different on tumor cells with different liver metastatic potential. We selected "conventional" glycosaminoglycan (GAG) biosynthesis inhibitors, beta-D-xyloside (BX), 2-deoxy-D-glucose (2-DG), ethane-l-hydroxy-l,l-diphosphonate (ETDP) and the newly discovered 5-hexyl-2-deoxyuridine (HUdR), to modulate PGs on highly metastatic/liver-specific 3LL-HH murine carcinoma and HT168 human melanoma cells and to influence their liver colonization potential. These compounds all induced remarkable changes in GAG biosynthesis, but to varying degrees: glucosamine labelling was affected mainly by 2-DG, and HUdR and sulphation by BX and HUdR. Furthermore, the ratio of heparan sulphate/chondroitin sulphate (HS/CS) of PGs was increased by ETDP and decreased after treatment by HUdR. In addition to changes in PG metabolism, tumor-cell proliferation and adhesion to fibronectin were affected; BX and 2-DG stimulated cell proliferation and adhesion, while HUdR inhibited both proliferation and adhesion. Most interestingly, HUdR, the most effective inhibitor of HS/HSPG, depressed the formation of liver colonies, while ETDP, the most effective inhibitor of CS/CSPG, stimulated the appearance of liver colonies. These observations indicated that, at least in these experimental systems, tumor cells with a high HS/CS ratio are more likely to form liver metastases; consequently, anti-HS agents could also be anti-metastatic.