Mononuclear
ruthenium-
dmso compounds showed interesting antimetastatic properties on experimental models of solid tumours. In line with the interesting results with multinuclear
platinum complexes, which proved to overcome
cisplatin resistance, we thought it worthwhile to test the pharmacological properties of some dinuclear
ruthenium complexes to ascertain the possible advantages due to the introduction of a second
metal centre over
NAMI-A and its mononuclear analogues. These compounds belong to the general formula X2[[RuCl4(
dmso-S)]2(mu-L)] or [X][[RuCl4(
dmso-S)](mu-L)[RuCl3(
dmso-S)(
dmso-O)]] where L is a
nitrogen donor
ligand (
pyrazine;
pyrimidine; 4,4'-bipyridine; 1,2-bis(4-pyridyl)
ethane; 1,2-bis(4-pyridyl)
ethylene; 1,3-bis(4-pyridyl)
propane) and X a counterion. We focused on parameters related to metastatic ability such as
gelatinase activity, detected by zymography, and invasive potential, measured by means of a transwell chamber. These activities were correlated to the ability to inhibit tumour
metastases in vivo. All dinuclear complexes, except compound D8 ([NH4]2[[RuCl4(
dmso-S)]2(mu-pyz]), decrease the number of tumour cells that cross a
matrigel barrier, and inhibit
MMP-9 gelatinolytic activity at concentrations lower than that of
NAMI-A and of other mononuclear
ruthenium complexes. In vivo compounds D5 (Na2[[RuCl4(
dmso-S)]2(mu-ethylbipy)]) and D7 ([NH4][[RuCl4(
dmso-S)](mu-pyz)[RuCl3(
dmso-S) (
dmso-O)]]) show anti-
metastasis activity, at two dose levels, with mild or null effect on primary tumour growth; compound D8 is the weakest active. All compounds tend to accumulate in liver and kidneys, rather than in tumour and lungs. However, compound D5, the most active in vitro on invasion and
gelatinases and active in vivo on
metastasis, is better concentrated in the lungs than compound D8 which is less active or inactive in vitro and in vivo. Histological analysis show liver, as well as kidney toxicities that limit in vivo activity. These data thus suggest dinuclear
ruthenium complexes as promising anti-invasive agents for
cancer treatment.