A cycloplatinated compound of p-isopropylbenzaldehyde thiosemicarbazone and its chloro-bridged derivative induce apoptosis in cis-DDP resistant cellswhich overexpress the H-ras oncogene

cis-Diamminedichloroplatinum(II) (cis-DDP) is a widely used antitumour drug which produces important damage on the DNA inducing apoptosis in several c ell lines. We have analysed the cytotoxic activity of novel cyclometallated complexes of p-isopropylbenzaldehyde thiosemicarbazone (p-is.TSCN) and the ir dimeric chloro-bridged derivatives in murine keratinocytes transformed b y the H-ras oncogene which are resistant to cis-DDP (Pam-ras cells). The da ta show that, in contrast with cis-DDP, the tetrameric cycloplatinated comp lex [Pt(p-is.TSCN)](4) and its dimeric chloro-bridged derivative [Pt( mu Cl ) (p-is.TSCN)], have a good in vitro therapeutic index when comparing the c ytotoxicity in Pam-ras cells to normal murine keratinocytes (Pam 212 cells) since they induce cell death in Pam-ras cells at drug concentrations signi ficantly lower than those needed to kill Pam 212 cells. At equitoxic doses (IC90), both complexes produce characteristic features of apoptosis in Pam- ras cells together with a drastic decrease in levels of H-ras protein. Thes e effects are not observed when the cells are treated with the IC90 of the cis-DDP drug nor the p-is.TSCN ligand. Altogether, these results suggest th at the platinum compounds [Pt(p-is.TSCN)](4) and [Pt(mu Cl) (p-is.TSCN)](2) might have potential as antitumour agents in view of their specific induct ion of apoptosis in cis-DDP resistant cells. (C) 1999 Elsevier Science Inc. All rights reserved.