Carrier Ligand Effects in Platinum Resistant Cell Lines

Abstract

Cisplatin resistance is a major clinical problem. Studies performed in a number of laboratories have shown that cisplatin resistance is multifactorial and varies significantly from one cell line to another. Our laboratory has focused on the carrier ligand effects on resistance, particularly those effects involving the diaminocyclohexane (dach) carrier ligand. The dach carrier ligand is of both historical and clinical interest. In 1977 Burchenal and coworkers first showed that platinum complexes with the dach ligand were effective in L1210 and P388 cell lines which were resistant to cisplatin (1,2). Similar findings have subsequently been reported in a number of cisplatin-resistant human cell lines (3–5). While relatively little is known about the mechanism of these carrier ligand effects, one dach-Pt compound, tetrachloro(trans-d) 1,2-diaminocyclohexaneplatinum(IV) (also known as tetraplatin or ormaplatin), is currently in phase I clinical trials. We initiated studies into the mechanism of these dach ligand effects because we felt that this type of information might allow one to predict the clinical situations where ormaplatin and other dach-Pt complexes would be most effective. Such information might also help in the design and/or selection of more effective second generation platinum complexes, and might allow one to design assays which would predict the likely efficacy of these complexes in treating cisplatin-resistant tumors. Finally, we felt information on the mechanism of carrier ligand effects should contribute to our overall understanding of the resistance phenomenon.