Lack of In Vitro Cytotoxicity, Associated to Increased G₂-M Cell Fraction and Inhibition of Matrigel Invasion, May Predict In Vivo-Selective Antimetastasis Activity of Ruthenium Complexes

Abstract

The ruthenium complexestrans-dichlorotetrakisdimethylsulfoxide ruthenium(II) (trans-Ru), imidazoliumtrans-imidazoletetrachlororuthenate (ICR), sodiumtrans-tetramethylensulfoxideisoquinolinetetrachlororuthenate (TEQU), and imidazoliumtrans-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 G₂-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 G₂-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.