ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Imidazoles/pharmacology , Organometallic Compounds/pharmacology , Peptides/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Cell Adhesion/drug effects , Cell Membrane/drug effects , Cell Membrane/metabolism , Fibronectins/metabolism , Humans , Intercellular Signaling Peptides and Proteins , KB Cells , Kidney/cytology , Kidney/drug effects , Kidney/metabolism , Ligands , Neoplasm Metastasis , Rhodamines , Spectrophotometry, AtomicABSTRACT
The influence of chemical stability on the antimetastatic ruthenium(III) compound imidazolium trans-imidazoletetrachlorodimethylsulphoxideruthenium(III) (NAMI-A) in aqueous solution was studied both in vitro and in vivo. The loss of dimethyl-sulphoxide (DMSO) ligand from the compound was tested by using a NAMI-A solution acidified with HCl at pH 3.0 and aged for 0, 4, 8 and 24 h prior to intraperitoneal (i.p.) injection into CBA mice bearing advanced MCa mammary carcinoma. The activity of NAMI-A on lung metastases showed no change even after the loss of DMSO ligand from up to 50% of the molecules. The reduction of NAMI-A did not modify the number of KB cells blocked in the S+G2M phases, independent of whether the reduction occurred outside the cells or after loading the cells with the compound prior to treatment with the reductants (ascorbic acid, glutathione or cysteine). In vivo, the complete reduction of NAMI-A with equivalent amounts of ascorbic acid, glutathione or cysteine prior to administration to mice bearing advanced MCa mammary carcinoma was more active than NAMI-A alone. The data show that NAMI-A, although undergoing a series of chemical modifications, maintains its antimetastatic activity in a broad range of experimental conditions.
Subject(s)
Antineoplastic Agents/chemistry , Dimethyl Sulfoxide/analogs & derivatives , Dimethyl Sulfoxide/chemistry , Mammary Neoplasms, Experimental/drug therapy , Organometallic Compounds/chemistry , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Division , Dimethyl Sulfoxide/metabolism , Dimethyl Sulfoxide/pharmacokinetics , Dimethyl Sulfoxide/therapeutic use , Female , Lung Neoplasms/secondary , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred CBA , Neoplasm Transplantation , Organometallic Compounds/pharmacokinetics , Organometallic Compounds/therapeutic use , S Phase , Tumor Cells, CulturedABSTRACT
In this paper we report the stepwise preparation and the characterization of new unsymmetrical monoanionic Ru(III) dinuclear compounds, [NH(4)][{trans-RuCl(4)(Me(2)SO-S)}(mu-L){mer-RuCl(3)(Me(2)SO-S)(Me(2)SO-O)}] (L = pyz (1), pym (2)). By a similar synthetic approach we also prepared new mixed-valence Ru(III)/Ru(II) dinuclear compounds of formula [NH(4)][{trans-RuCl(4)(Me(2)SO-S)}(mu-pyz){cis,cis,cis-RuCl(2)(Me(2)SO-S)(2)(CO)}] (L = pyrazine (pyz, 3), pyrimidine (pym, 4)). Moreover, we describe the chemical behavior of compounds 1-4 in physiological solution, also after complete reduction (with ascorbic acid) to the corresponding Ru(II)/Ru(II) species. Overall, the chemical behavior of 1 and 2 after reduction resembles that of the corresponding dianionic and neutral dinuclear species, [{trans-RuCl(3)(Me(2)SO-S)}(2)(mu-L)](2-)and [{mer-RuCl(3)(Me(2)SO-S)(Me(2)SO-O)}(2) (mu-L)]. On the other hand, the mixed-valence dinuclear compounds 3 and 4, owing to the great inertness of the cis,cis,cis-RuCl(2)(Me(2)SO-S)(2)(CO)(1/2mu-L) fragment, behave substantially like the mononuclear species [trans-RuCl(4)(Me(2)SO-S)(L)](-) in which the terminally bonded L ligand can be considered as bearing a bulky substituent on the other N atom.
