Metallothioneins and platinum(II) anti-tumor compounds

The classical square planar transition metal complex cis-diamminodichlorido platinum(II) (cisplatin) ranks among the most successful and widely applied antitumor drugs for the treatment of a number of cancers. However, the risk of unforeseen resistance formation and the appearance of severe side effects in cancer patients constitutes a considerable need for the development of novel platinum based antitumor compounds. Since the introduction of cisplatin into the clinic, a few similar compounds, like cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin), were developed, which can partly overcome the problems. The ubiquitously occurring small zinc and copper binding proteins metallothioneins (MTs) constitute the most potent cytosolic sink for platinum drugs. It appeared that, besides the formation of the very strong platinum(II)-sulfur bond involving the twenty cysteine residues of MT, the incorporation of platinum(II) into the MT structure contributes effectively to the scavenging of the drug. However, recently it became evident that the extent, to which MT sequesters platinum drugs, depends not only on the type of cancer, but also on the interaction of MT with the ligand sphere of the platinum center. For example, in contrast to cis-platinum(II) compounds, trans-platinum(II) compounds retain their N-donor ligands upon reaction with MT. From these studies, guidelines may be derived for the development of N-donor carrier ligands leading to novel platinum(II) drugs. This review describes the role of metallothioneins for the platinum(II) drug sequestration in vivo. Furthermore, it summarizes the recent developments toward the understanding of the reaction between platinum(II) and MT thiols and the structural aspects of the platinum(II) incorporation into the MT domains, and comments about future perspectives are given.