Cisplatin Analogues with an Increased Interaction with DNA: Prospects for Therapy

Cisplatin is widely used as a cancer chemotherapeutic agent and this review covers the mechanism of action of cisplatin, cellular resistance to cisplatin, the genomic location of cisplatin adducts and the properties of DNA-targeted Pt complexes. A particular focus of this review is the interaction of Pt compounds with DNA. The technology involved in determining Pt-drug/DNA interactions has advanced and permits clearer views of this process. In particular, molecular biological techniques permit a more accurate and precise determination of the sequence specific preference of Pt adduct formation. Prospects for the sequence specific genome-wide determination of Pt adduct formation using next-generation sequencing are also discussed. Cisplatin analogues that are targeted to DNA via an attached DNA-affinic moiety are potentially beneficial anti-tumour agents. In particular the 9-aminoacridine Pt complexes possess a number of important characteristics, including activity against cisplatin-resistant cells. Their ability to circumvent resistance due to increased DNA repair may allow these DNA-targeted analogues to avoid many of the drawbacks associated with current clinical oncology treatment. This ability is thought to be due to their altered DNA sequence specificity, compared with cisplatin, where Pt adduct formation for the 9- aminoacridine Pt complexes was shifted away from consecutive guanines towards 5'-CG and 5'-GA dinucleotide sequences. Evidence for this evasion of repair processes and avoidance of cellular cisplatin resistance was found for 9-aminoacridine Pt complexes in studies with cisplatin resistant cells. The prospects for clinical use of these DNA-targeted anti-tumour agents were evaluated.