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(I I) (trans-Ru), imidazolium trans-imidazoletetrachlororuthenate (ICR), sodiu m 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 ce lls to 10(-4) M concentration, and in vivo on Lewis lung carcinoma by a dai ly i.p. treatment for 6 consecutive days using equitoxic and maximum tolera ted 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 viv o. ICR and trans- Ru did not modify cell cycle distribution of in vitro tum or cells nor did they inhibit matrigel invasion; ICR was also devoid of ant imetastasis effects in vivo. Ruthenium uptake by tumor cells did account fo r in vitro cytotoxicity but not for other in vitro actions or for in vivo a ntimetastasis activity. The contemporary absence of cytotoxicity, associate d to inhibition of matrigel crossing and to transient block in the premitot ic G(2)-M phase, appears to be prerequisites for a ruthenium compound to sh ow in vivo-selective antimetastasis effect. The validation of this model fo r other classes of compounds will allow an understanding of the combined we ight of the above-mentioned phenomena for tumor metastasis growth and contr ol.