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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Inhibition of B16 Melanoma Metastases with the Ruthenium Complex Imidazolium trans-Imidazoledimethylsulfoxide-tetrachlororuthenate and Down-Regulation of Tumor Cell Invasion

Department of Biomedical Science, University of Trieste (B.G., S.Z., G.S.), Trieste, Italy; Callerio Foundation-Onlus, Institute of Biological Research (M.C., G.S.), Trieste, Italy; and Reference Centre for Oncology (P.S.), Aviano, Italy

The antimetastatic ruthenium complex imidazolium trans-imidazoledimethylsulfoxide-tetrachlorouthenate (NAMI-A) is tested in the B16 melanoma model in vitro and in vivo. Treatment of B6D2F1 mice carrying intra-footpad B16 melanoma with 35 mg/kg/day NAMI-A for 6 days reduces metastasis weight independently of whether NAMI-A is given before or after surgical removal of the primary tumor. Metastasis reduction is unrelated to NAMI-A concentration, which is 10-fold lower than on primary site (1 versus 0.1 mM), and is correlated to the reduction of plasma gelatinolitic activity and to the decrease of cells expressing CD44, CD54, and integrin-₃ adhesion molecules. Metastatic cells also show the reduction of the S-phase cells with accumulation in the G₀/G₁ phase. In vitro, on the highly metastatic B16F10 cell line, NAMI-A reduces cell Matrigel invasion and its ability to cross a layer of endothelial cells after short exposure (1 h) to 1 to 100 µM concentrations. In these conditions, NAMI-A reduces the gelatinase activity of tumor cells, and it also increases cell adhesion to poly-L-lysine and, in particular, to fibronectin, and this effect is associated to the increase of F-actin condensation. This work shows the selective effectiveness of NAMI-A on the metastatic melanoma and suggests that metastasis inhibition is due to the negative modulation of tumor cell invasion processes, a mechanism in which the reduction of the gelatinolitic activity of tumor cells plays a crucial role.

Address correspondence to: Prof. G. Sava, Department of Biomedical Sciences, University of Trieste, via L. Giorgieri 7, 34127 Trieste, Italy. E-mail: g.sava{at}callerio.org