The antimetabolite Tiazofurin (TR) inhibits glycoconjugate biosynthesis and invasiveness of tumour cells.
We investigated the effect of Tiazofurin (TR-2-beta-D-furanosylthiazole-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 microM, caused inhibition 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 filters. 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 microM TR treatment of 3LL-HH cells inhibited glycosylation of a wide range of glycoproteins with the most pronounced effect on proteoglycans. TR pretreatment of 3LL-HH tumour cells resulted in the loss of lung colonisation potential in vivo. Furthermore, in vivo TR treatment inhibited the formation of liver metastases of 3LL-HH murine carcinoma. TR treatment 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 much lower for cell adhesion and lung colonisation than for cell proliferation, we suggest that the predominant effect of TR is the inhibition of metastasis in these model systems. We also suggest that both the effect of TR on tumour cell proliferation and on extracellular matrix interaction contribute to its remarkable antimetastatic potential in vivo.
Tímár
J
J
First Institute of Pathology & Experimental Cancer Research, Semmelweis University of Medicine, Budapest, Hungary.
Tóvári
J
J
Pogány
G
G
Ladányi
A
A
Paku
S
S
Rśó
E
E
Bocsi
J
J
Jeney
A
A
Lapis
K
K
D000595:Amino Acid Sequence; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006001:Glycoconjugates / Q000096:biosynthesis*; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D006001:Glycoconjugates; D012254:Ribavirin; C033706:tiazofurin