In order to compare the mechanistic properties of the antitumour-active trans
platinum complex trans-[PtCl(2){Z-HN=C(OMe)Me}(NH(3))] (trans-Z) and of the antitumour-inactive isomer of
cisplatin trans-[PtCl(2)(NH(3))(2)] (
trans-DDP), the differential processing of the two compounds by SKOV-3
ovarian cancer cells has been investigated. trans-Z and
trans-DDP enter cells with the same efficacy, but trans-Z shows a two-fold higher affinity for cellular
DNA. The treatment with
trans-DDP IC(50) determines an initial and transient
cytostatic effect, paralleled by a moderate increase of apoptosis and by sequential and reversible arrests in S and G(2)/M phases of cell-cycle. In contrast, trans-Z IC(50) determines an initial cytotoxic effect, a more persistent and marked increase of apoptosis, and a more marked and prolonged arrest in S and G(2)/M phases of the cell-cycle. Treatment-induced gene expression modifications indicate that phenotypic effects of
trans-DDP are driven by an initial and transient up-regulation of some genes related to cell-cycle checkpoint and arrest networks, whereas the more dramatic phenotypic effects of trans-Z are driven by a persistent up-regulation of more numerous genes involved in cell-cycle checkpoint and arrest networks, and in
genome stability and DNA repair. Therefore, molecular and cellular events have been identified which are produced by trans-Z but not by
trans-DDP, and which likely represent the mechanistic basis of antitumour activity of trans-Z in the SKOV-3 system.