DNA Modifications by antitumor platinum and ruthenium compounds: Their recognition and repair

Abstract

The development of metal-based antitumor drugs has been stimulated by the clinical success of cis-diamminedichloroplatinum(II) (cisplatin) and its analogs and by the clinical trials of other platinum and ruthenium complexes with activity against resistant tumors and reduced toxicity including orally available platinum drugs. Broadening the spectrum of antitumor drugs depends on understanding existing agents with a view toward developing new modes of attack. It is therefore of great interest to understand the details of molecular and biochemical mechanisms underlying the biological efficacy of platinum and other transition-metal compounds. There is a large body of experimental evidence that the success of platinum complexes in killing tumor cells results from their ability to form various types of covalent adducts on DNA; thus, the research of DNA interactions of metal-based antitumor drugs has predominated. The present review summarizes current knowledge on DNA modifications by platinum and ruthenium complexes, their recognition by specific proteins, and repair. It also provides strong support for the view that either platinum or ruthenium drugs, which bind to DNA in a fundamentally different manner from that of 'classical' cisplatin, have altered pharmacological properties. The present article also demonstrates that this concept has already led to the synthesis of several new unconventional platinum or ruthenium antitumor compounds that violate the original structure-activity relationships.