Pharmacological Effects of the Ruthenium Complex NAMI-A Given Orally to CBA Mice With MCa Mammary Carcinoma.

NAMI-A, imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate, is a ruthenium based compounds capable of inhibiting the growth of lung metastases of solid tumours in a number of experimental conditions.The aim of this study was to investigate the potential use of NAMI-A by the oral route to treat lung metastases of MCa mammary carcinoma in the CBA mouse. treatment of mice, carrying intramuscular tumours in advanced stage of growth, for 11 consecutive days caused a significant reduction of the weight of lung metastases over the range of doses from 150 to 600 mg/kg/day. No sign of toxicity was observed at the histological analysis in the gut epithelium or in the kidney parenchyma, and NAMI-A concentration in the kidney was more than 10-fold lower than after intraperitoneal treatments. NAMI-A is thus active against metastases also by the oral route, suggesting the use of this way to treat tumour bearing hosts for long periods.

Lack of In vitro cytotoxicity, associated to increased G(2)-M cell fraction and inhibition of matrigel invasion, may predict In vivo-selective antimetastasis activity of ruthenium complexes.

The ruthenium complexes trans-dichlorotetrakisdimethylsulfoxide ruthenium(II) (trans-Ru), imidazolium trans-imidazoletetrachlororuthenate (ICR), sodium trans-tetramethylensulfoxideisoquinolinetetrachlororuthenate (TEQU), and imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate (NAMI-A) are tested in vitro by short exposure of MCF-7, LoVo, KB, and TS/A tumor cells to 10(-4) M concentration, and in vivo on Lewis lung carcinoma by a daily i.p. treatment for 6 consecutive days using equitoxic and maximum tolerated doses. NAMI-A 1) inhibited tumor cell invasion of matrigel, 2) induced a transient accumulation of cells in the G(2)-M phase, 3) did not modify in vitro cell growth, and 4) markedly reduced lung metastasis formation. TEQU showed significant cytotoxicity in vitro and was not antimetastatic in vivo. ICR and trans-Ru did not modify cell cycle distribution of in vitro tumor cells nor did they inhibit matrigel invasion; ICR was also devoid of antimetastasis effects in vivo. Ruthenium uptake by tumor cells did account for in vitro cytotoxicity but not for other in vitro actions or for in vivo antimetastasis activity. The contemporary absence of cytotoxicity, associated to inhibition of matrigel crossing and to transient block in the premitotic G(2)-M phase, appears to be prerequisites for a ruthenium compound to show in vivo-selective antimetastasis effect. The validation of this model for other classes of compounds will allow an understanding of the combined weight of the above-mentioned phenomena for tumor metastasis growth and control.

Effects of NAMI-A and some related ruthenium complexes on cell viability after short exposure of tumor cells.

A series of three ruthenium complexes, i.e. trans-dichlorote-trakisdimethyl-sulfoxide ruthenium(ll) (trans-Ru), imidazolium trans-imidazoletetra-chlororuthenate (ICR) and sodium trans-tetramethylensulfoxideisoquinoline-tetrachlororuthenate (TEQU), were studied in vitro in comparison to NAMI-A, a potent ruthenium-based antimetastasis agent. In vitro challenge of TS/A adenocarcinoma or KB oral carcinoma tumor cells with 10(-4) M concentration for 1 h evidenced the lack of cytotoxicity of NAMI-A, ICR and trans-Ru, the accumulation of cells in the G2/M pre-mitotic cell phase by NAMI-A and the attachment of tumor cells to the plastic substrate was significantly greater for NAMI-A than for ICR. These data stress that in vitro cytotoxicity is not necessary for in vivo activity of ruthenium antitumor complexes: NAMIA, ICR and trans-Ru, are in fact known to be active against murine tumors in the mouse system. Rather, TEQU, the compound free of in vivo activity, was the only one to reduce cell growth of in vitro cultured cells. In conclusion, the data on the effects of NAMI-A on in vitro cultured cells show that the increase of cell adhesion properties and the transient cell cycle arrest in the G2/M phase are much more relevant than the effects on cell properties relevant to cell growth (i.e. on CD44, CD54 or CD71 antigens) for determining in vivo antimetastasis activity.