Investigating the chemotherapeutic mechanism of action of cisplatin

The DNA-damaging compound, cisplatin (cis-diammine-dichloridoplatinum (II)), is a highly successful anti-tumour agent widely used in the treatment of a range of human cancers. Despite the clinical efficacy of cisplatin, its curative potential is largely restricted by the occurrence of drug resistance and several dose-limiting toxic side effects. Attempts to ameliorate these deficiencies have met with limited success. However, it is ultimately hoped that such efforts will benefit from a more comprehensive understanding of the mechanism by which cisplatin elicits tumour-specific cytotoxicity. The overall aim of this project was to further elucidate the mechanism of action of cisplatin. For this purpose, different experimental approaches were employed to examine the interaction of cisplatin with DNA, and the drug's effect on human gene expression. Firstly, chromatin structures native to DNA in human cells were simulated in vitro via reconstitution techniques. Their effect on cisplatin-mediated DNA damage could then be evaluated. Secondly, the transcriptional response of human cells to cisplatin treatment was analysed using microarrays and gene expression profiling techniques.