THE ANTIMETABOLITE TIAZOFURIN (TR) INHIBITS GLYCOCONJUGATE BIOSYNTHESIS AND INVASIVENESS OF TUMOR-CELLS

We investigated the effect of Tiazofurin (TR-2-beta-D-furanosylthiazol e-4-carbamide) on tumour cell invasion using metastatic 3LL-HH murine lung carcinoma and HT168-M1 human melanoma as experimental models. TR pretreatment of 3LL-HH cells, in a dose range of 15-60 mu M, caused in hibition of cell proliferation, adhesion to plastic and extracellular matrix proteins. The TR-induced altered matrix interactions of 3LL-HH cells were reflected in decreased migration through matrix-covered fil ters. Analysis of the expression of certain invasion markers indicated that TR suppressed the expression of alpha v beta 3 integrin and MMP2 metalloproteinase. Biochemical studies indicated that 24 h 60 mu M TR treatment of 3LL-HH cells inhibited glycosylation of a wide range of glycoproteins with the most pronounced effect on proteoglycans. TR pre treatment of 3LL-HH tumour cells resulted in the loss of lung colonisa tion potential in vivo. Furthermore, in vivo TR treatment inhibited th e formation of liver metastases of 3LL-HH murine carcinoma. TR treatme nt also induced inhibition of integrin and MMP2 expression, migration and liver colonisation of the human melanoma HT168-M1 cell line. Since the TR concentration which inhibited various cellular functions was m uch lower for cell adhesion and inhibition of metastasis in these mode l systems. We also suggest that both the effect of TR on tumour cell p roliferation and on extracellular matrix interaction contribute to its remarkable antimetastatic potential in vivo.