A copper connection to the uptake of platinum anticancer drugs.

Abstract

Cisplatin [ cis -diamminedichloroplatinum (II)] is a highly active anticancer agent. This agent is curative against most testicular cancers and is highly active against a wide range of other tumor types, notably ovarian, bladder carcinoma, and non-small-cell lung cancer (1). Treatment failure is frequently caused by the development of resistance to cisplatin. Although the insensitive tumors generally exhibit only low-level resistance, the use of cisplatin at close to its maximally tolerated dose implies that the developed resistance eliminates cisplatin as an active compound. Resistance to cisplatin has been widely studied in a variety of models and in clinical samples, but it has been difficult to identify the molecular changes leading to drug resistance. Ishida et al. (2) report in this issue of PNAS the identification of an important pathway for uptake of cisplatin into yeast and mammalian cells, uptake mediated by a high-affinity copper transporter. The action of cisplatin in cell killing is now well established (3). In serum, the high concentration of chloride ions enhances cisplatin stability. The lower chloride concentration in cells favors rapid hydrolysis of the chloride ligands of cisplatin, leading to an activated molecule that is capable of reacting bifunctionally. Although cisplatin can react with a variety of cellular macromolecules, there is strong evidence that the most important target is DNA (3, 4). An important line of evidence that DNA is an essential target of cisplatin is the observation that bacterial and yeast mutants that are defective in various DNA-repair pathways are also hypersensitive to cisplatin. Cisplatin can form both intrastrand and interstrand DNA crosslinks, with intrastrand purine:purine representing the majority of the adducts. Figure a Cisplatin structure courtesy of Mitch Miller (NetGenics, Cleveland). As is the case with other anticancer agents, reduced accumulation of cisplatin is frequently observed in cisplatin-resistant cell lines. Although drug efflux has …