Recent work has shown that chemically modified
tetracyclines (CMTs) are potent inhibitors of
matrix metalloproteinase (
MMP) activity, both in vitro and in vivo, which is distinct from their antimicrobial activities (Golub et al. Crit Rev Oral Biol Med, 2, 297-321, 1991; Ryan et al. Curr Opin Rheumatol, 8, 23847, 1996). The process of
tumor cell invasion requires
MMP-mediated degradation of extracellular matrix barriers as a key step in the metastasic cascade. In this study, we examined the effect(s) of
doxycycline and CMTs on extracellular levels of
gelatinase A and B activity from a highly invasive and metastatic human
melanoma cell line C8161, and correlated these observations with changes in the cells'
biological behavior in an in vitro invasion assay and in an in vivo SCID mouse model. The results indicate that coincident with the ability of these compounds to differentially suppress extracellular levels of
gelatinase activity, C8161 cells treated with
doxycycline,
CMT-1,
CMT-3, or CMT-6 were less invasive in vitro in a dose-dependent manner (3-50 microg/ml). Furthermore, data derived from the in vivo model indicate that SCID mice dosed orally with
CMT-1 or
CMT-3 contained a reduced number of lung
metastases following i.v. injection of C8161 cells via tail vein inoculation. These observations suggest that careful screening of different CMTs could lead to the identification of compounds which suppress the formation and magnitude of
metastases associated with certain
cancers, and if used as an adjunct to other treatment regimes, lead to greater efficacy in the treatment of metastatic
cancers.