CHEMICALLY-MODIFIED TETRACYCLINES INHIBIT HUMAN-MELANOMA CELL INVASION AND METASTASIS

Recent work has shown that chemically modified tetracyclines (CMTs) ar e potent inhibitors of matrix metalloproteinase (MMP) activity, both i n vitro and in vivo, which is distinct from their antimicrobial activi ties (Golub et al, Crit Rev Oral Biol Med, 2, 297-321, 1991; Ryan et a l, Curr Opin Rheumatol, 8, 238-47, 1996), The process of tumor cell in vasion requires MMP-mediated degradation of extracellular matrix barri ers as a key step in the metastasic cascade. In this study, we examine d the effect(s) of doxycycline and CMTs on estracellular levels of gel atinase A and B activity from a highly invasive and metastatic human m elanoma cell line C8161, and correlated these observations with change s in the cells' biological behavior in an in vitro invasion assay and in an in vivo SCID mouse model, The results indicate that coincident w ith the ability of these compounds to differentially suppress extracel lular levels of gelatinase activity, C8161 cells treated with doxycycl ine, CMT-1, CMT-3, or CMT-6 were less invasive in vitro in a dose-depe ndent manner (3-50 mu g/ml). Furthermore, data derived from the in viv o model indicate that SCID mice dosed orally with CMT-1 or CMT-3 conta ined a reduced number of lung metastases following i.v. injection of C 8161 cells via tail vein inoculation. These observations suggest that careful screening of different CMTs could lead to the identification o f compounds which suppress the formation and magnitude of metastases a ssociated with certain cancers, and if used as an adjunct to other tre atment regimes, lead to greater efficacy in the treatment of metastati c cancers. (C) 1998 Lippincott-Raven Publishers.