The cytotoxicity of some ferrocenium salts and the lack of activity of the corresponding ferrocenes has been already demonstrated. The cytotoxic activity in different conditions of decamethylferrocenium tetrafluoroborate (DEMFc(+)) in comparison with four other ferrocenium derivatives on MCF-7 cell line is reported. The relative stability in aqueous solutions with different buffering agents is investigated by means of UV-vis spectroscopy and correlated to the cytotoxic properties of the compounds. DEMFc(+), the most stable compound, shows the highest efficiency in inhibiting cell growth (IC(50) 35 microM, for 48 h treatment). Relaxation time measurements point out the involvement of water molecules in the degradation process. ESR results confirm the ability of ferrocenium cations to produce oxygen radical species as a consequence of their degradation in water. Oxygen-dependent formation of both hydroxyl and superoxide radicals is established by the spin-trapping technique. A direct evidence of the DEMFc(+) radical production into the viable cells is obtained by means of fluorescence-activated cell sorter (FACS) analysis that reveals a dose-dependent growth of 8-oxoguanine, the initial product of the guanine oxidation. This DNA oxidative stress justifies the cytotoxic effect of DEMFc(+). Furthermore, the cytotoxic cooperative effect of bleomycin, an iron-dependent antitumor drug, and DEMFc(+) has been tested. We have demonstrated the synergic effect between the two drugs, that is explained by the complementary oxidative damage inflicted to DNA as well as by the increasing of bleomycin activation by the iron(II/III) species available in the cell compartment from ferrocenium degradation.

1 Macrophage Stimulating Protein (MSP), a serum factor related to Hepatocyte Growth Factor, was originally discovered to stimulate chemotaxis of murine resident peritoneal macrophages. MSP is the ligand for Ron, a member of the Met subfamily of tyrosine kinase receptors. The e ects of MSP on human macrophages and the role played in human pathophysiology have long been elusive. 2 We show here that human recombinant MSP (hrMSP) evokes a dose-dependent superoxide anion production in human alveolar and peritoneal macrophages as well as in monocyte-derived macrophages, but not in circulating human monocytes. Consistently, the mature Ron protein is expressed by the MSP responsive cells but not by the unresponsive monocytes. The respiratory burst evoked by hrMSP is quantitatively higher than the one induced by N-formylmethionyl-leucylphenylalanine and similar to phorbol myristate acetate-evoked one. 3 To investigate the mechanisms involved in NADPH oxidase activation, leading to superoxide anion production, di erent signal transduction inhibitors were used. By using the non selective tyrosine kinase inhibitor genistein, the selective c-Src inhibitor PP1, the tyrosine phosphatase inhibitor sodium orthovanadate, the phosphatidylinositol 3-kinase inhibitor wortmannin, the p38 inhibitor SB203580, the MEK inhibitor PD098059, we demonstrate that hrMSP-evoked superoxide production is mediated by tyrosine kinase activity, requires the activation of Src but not of PI 3-kinase. We also show that MAP kinase and p38 signalling pathways are involved. 4 These results clearly indicate that hrMSP induces the respiratory burst in human macrophages but not in monocytes, suggesting for the MSP/Ron complex a role of activator as well as of possible marker for human mature macrophages.

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