Apoptosis induction and inhibition of H-ras overexpression by novel trans-[PtCl2(isopropylamine)(amine ')] complexes

Hitherto, it has been generally accepted as a paradigm of the biochemical p harmacology of platinum antitumor drugs that a cis configuration of the lea ving groups is necessary for antitumor activity of platinum compounds. Howe ver, it has been recently observed that certain trans-platinum complexes ha ve both in vitro and in vivo antitumor activity. We previously reported the synthesis, characterization and cytotoxic activity against ms-transformed cells of several trans-[PtCl2LL'] complexes where L, and L' are asymmetric aliphatic amines (L=dimethylamine and butylamine, L'=isopropylamine). The r esults reported in this paper show that the compounds trans-[PtCl2(isopropy lamine) (dimethylamine)] and trans-[PtCl2(isopropylamine)(butylamine)] kill Pam 212-ras cisplatin resistant cells through apoptosis induction. Moreove r, Western blot data show that both compounds inhibit overexpression of H-r as oncogene in Pam 212-ras cells. Altogether, these data indicate that, in contrast with cis-DDP, the apoptotic activity of these novel trans-Pt(II) c ompounds in ras-transformed cells is associated with their ability to aboli sh ras-overexpression. (C) 1999 Elsevier Science Inc. All rights reserved.