The antitumor effect of Tiazofurin (TR) consists of anti-proliferative and anti-invasive elements

We have studied the effects of the antimetabolite, Tiazofurin (TR-2-beta-D-furanosylthiazole-4-carboxamide), on the metastatization of HT168-M1 human melanoma cell line compared to 3LL-HH murine lung carcinoma. TR pretreatment of 3LL-HH cells, in a dose range 15-60 mu M, caused inhibition of cell proliferation as well as adhesion to the EHS-matrix. TR inhibited the entry of adherent tumor cells to the S phase and accumulation in G1, however in non-adherent cells TR completely inhibited the entry of tumor cells to G2 phase. In contrast to these data TR treatment of HT168-M1 cells did not cause inhibition of cell proliferation, a change in cell cycle distribution or in the quantity of apoptotic cells. However, TR pretreatment did inhibit the adhesion to and migration through EHS-matrix of melanoma cells similar to 3LL-HH cells. Furthermore, in vivo TR treatment inhibited the formation of liver metastases of HT168-M1 melanoma cells without major effects on the spleen primary tumor. Since in vivo TR treatment of HT168-M1 and 3LL-HH tumor bearing mice significantly decreased the number and incidence of liver metastases though there was different effect on the in vitro/in vivo growth (lack of inhibitory effect in case of HT168-M1 cells), we suggest that the antiproliferative and anti-metastatic effects of TR could be separated. We also suggest that the antimetastatic effects of TR are due to inhibition of adhesion and migration of tumor cells.