Replacement of an NH3 by an Iminoether in Transplatin Makes an Antitumor Drug from an Inactive Compound

• Published in: Molecular pharmacology 2000-12, Vol.58 (6), p.1525-1535
• Main Authors: Leng, Marc, Locker, Daniel, Giraud-Panis, Marie-Josèphe, Schwartz, Annie, Intini, Francesco P., Natile, Giovanni, Pisano, Claudio, Boccarelli, Angelina, Giordano, Domenico, Coluccia, Mauro
• Format: Article
• Language: English
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1016/S0026-895X(24)12727-7

To investigate the modifications of antitumor activity and DNA binding mode of transplatin after replacement of one nonleaving group NH 3 by an iminoether group, trans -[PtCl 2 { Z -HN=C(OMe)Me}(NH 3 )] and trans -[PtCl 2 { E -HN=C(OMe)Me}(NH 3 )] complexes (differing in the Z or E configuration of iminoether, and abbreviated mixed Z and mixed E , respectively), have been synthesized. In a panel of human tumor cell lines, both mixed Z and mixed E show a cytotoxic potency higher than that of transplatin, the mean IC 50 values being 103, 37, and 215 μM, respectively. In vivo mixed Z is more active and less toxic than mixed E in murine P388 leukemia and retains its efficacy against SK-OV-3 human cancer cell xenograft in nude mice. In the reaction with naked DNA, mixed Z forms monofunctional adducts that do not evolve into intrastrand cross-links but close slowly into interstrand cross-links between complementary guanine and cytosine residues. The monofunctional mixed Z adducts are removed by thiourea and glutathione. The interstrand cross-links behave as hinge joints, increasing the flexibility of DNA double helix. The mixed Z , transplatin, and cisplatin interstrand cross-links, as well as mixed Z monofunctional adducts are not specifically recognized by HMG1 protein, which was confirmed to be able to specifically recognize cisplatin d(GpG) intrastrand cross-links. These data demonstrate that the DNA interaction properties of the antitumor-active mixed Z are very similar to those of transplatin, thus suggesting that clinical inactivity of transplatin could not depend upon its peculiar DNA binding mode.