Kinetic aspects of platinum anticancer agents

Platinum(II) compounds, such as cis-[Pt(NH₃)₂Cl₂] (cisplatin) are well known for their use as anticancer drugs. The antitumor activity of platinum drugs is attributed to their ability to bind to DNA causing its damage and subsequently inducing apoptosis in cancer cells. The kinetics of ligand exchange around platinum plays a crucial role in the activity of platinum complexes. Aquation of cisplatin to cis-[Pt(NH₃)₂(H₂O)Cl]⁺ is usually the first step in cisplatin binding to DNA. The monohydrated complex then coordinates to the N7 positions of guanine and adenine to form mainly 1,2-intrastrand adducts. Aquated platinum(II) species are produced more slowly from carboplatin and oxaliplatin as the ring opening of carboxylate is a very slow process compared with the easy hydrolysis of cisplatin. Therefore, in these cases it is predicted that the reaction of the platinum drug with DNA would proceed by a direct attack of guanine on platinum. The kinetic and thermodynamic aspects of aquation of platinum drugs and Pt-DNA interaction have been widely studied. In particular, the use of NMR spectroscopy has facilitated in exploring the basic steps of these reactions. The hydrogen bond donating capacity of DNA bases to the platinum ligands stabilizes the transition state for monoadduct formation and thus enhances the rate of platination. Theoretical investigations suggest a trigonal bipyramidal transition state for the substitution reactions. The present review highlights some important findings obtained from the kinetic studies of platinum anticancer agents and describes various theoretical aspects of platinum binding to DNA.