Effects of ruthenium complexes on experimental tumors: irrelevance of cytotoxicity for metastasis inhibition

A series of 18 ruthenium(III) complexes, structurally related to the selective antimetastatic drug Na[trans-RuCl4(DMSO)Im], and characterized by the presence of sulfoxide and nitrogen-donor ligands were tested on TLX5 lymphoma and some of them on MCa mammary carcinoma to evaluate the dependence of the degree of cytotoxicity and of antimetastatic activity on the chemical properties. In vitro cytotoxicity is present only at high concentrations (> 10(-4) M), depends upon lipophilicity and is markedly affected by the presence of 5% serum or plasma samples in the culture medium. The comparison of the effects on in vitro cytotoxicity with in vivo antitumor and antimetastatic action points out that these compounds reduce metastasis formation by a mechanism unrelated to a direct tumor cell cytotoxicity. If on one hand Na[trans-RuCl4(TMSO)Iq], the compound that shows the most potent in vitro cytotoxic effects, is the least effective against metastases, on the other Na[trans-RuCl4(DMSO)Im], the compound that better reduces metastasis formation, is rather devoid of cytotoxic effects on tumor cells kept in vitro. In particular, Na[trans-RuCl4(DMSO)Im] seems to distinguish between artificially induced metastases and spontaneous metastases and reduces only the former by a cytotoxic mechanism. Out of all the tested compounds, with the exception of Na[trans-RuCl4(DMSO)Ox], Na[trans-RuCl4(DMSO)Im] is confirmed to be the most selective antimetastatic agent of the group.