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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Free Exchange across Cells, and Echistatin-Sensitive Membrane Target for the Metastasis Inhibitor NAMI-A (Imidazolium trans-Imidazole Dimethyl Sulfoxide Tetrachlororuthenate) on KB Tumor Cells

Department of Biomedical Sciences (F.F., V.S., A.F., G.S.) and Department of Chemical Sciences (B.S., E.A.), University of Trieste; and Callerio Foundation Onlus (M.C., G.S.), Trieste, Italy

The duration of cell proadhesive effects induced by imidazolium trans-imidazole dimethyl sulfoxide tetrachlororuthenate (NAMI-A), a compound endowed with in vivo antimetastatic properties, was tested in vitro on the human epithelial tumor cell line KB. The intensity of proadhesive effects continues to increase up to 48 to 72 h after NAMI-A withdrawal and declines only after 96 h. The proadhesive effect on cells seeded on fibronectin is greater than on plastic, since it already reaches its maximum after 24 h. This effect suggests a role for integrin activation, which is further stressed by the inhibitory activity of the disintegrin molecule echistatin. The intensity and duration of NAMI-A's proadhesive effects are correlated to cell exposure time and to the rapid release of NAMI-A metabolites in the culture medium in the first 5 min after drug withdrawal. These metabolites are probably neutral species with ruthenium-bound bioligands to allow for the rapid exchange between cells and extracellular medium. These data suggest a long-lasting effect of NAMI-A in biological systems, even at very low concentrations, and stress the low and reversible effects on kidney, where it naturally concentrates. These data on proadhesive effects are, further, relevant for in vivo antimetastatic effects, as this adhesion is associated to cell motility and invasion, which in turn are related to tumor malignancy and metastasis.

Address correspondence to: Gianni Sava, Callerio Foundation Onlus, Via A. Fleming 22-31, 34127 Trieste, Italy. E-mail: g.sava{at}callerio.org

This article has been cited by other articles:

				B. Gava, S. Zorzet, P. Spessotto, M. Cocchietto, and G. Sava Inhibition of B16 Melanoma Metastases with the Ruthenium Complex Imidazolium trans-Imidazoledimethylsulfoxide-tetrachlororuthenate and Down-Regulation of Tumor Cell Invasion J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 284 - 291. [Abstract] [Full Text] [PDF]