DNA Modifications by Novel Antitumor Platinum Drugs

Abstract

The development of metal-based antitumor drugs has been stimulated by the clinical success of cis-diamminedichloroplatinum(II) (cisplatin) and its analogues on one hand and by the clinical trials of other platinum 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 details of molecular and biochemical mechanisms underlying the biological efficacy of the 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 on DNA various types of covalent adducts so that the research of DNA interactions of metal-based antitumor drugs has predominated. The results so far obtained support the view that platinum compounds which bind to DNA in a fundamentally different manner to that of “classical” cisplatin will have altered pharmacological properties. This concept has already led to the synthesis of several new unconventional platinum antitumor compounds that violate the original structure- activity relationships.