The unique gene expression profile of the anti-tumour agent, cisplatin, compared with its clinically ineffective isomer, transplatin

Cisplatin is one of the most widely used cancer chemotherapeutic agents and is utilised to treat testicular and ovarian carcinomas as well as certain sarcomas and lymphomas. However, despite its clinical success, cisplatin treatment is still associated with a number of dose-limiting toxic side effects. The purpose of this study was to clarify the molecular events that are important in the anti-tumour activity of cisplatin, using gene expression profiling techniques. Cisplatin acts by forming covalent adducts with DNA. As well as inhibiting DNA replication and cell division, cisplatin DNA adducts also affect the level of transcription of human genes. In our study we found hundreds of human genes that were down-regulated in response to cisplatin as well genes that were up-regulated. We utilised a particularly powerful analysis technique to reveal the genes that were important in the anti-tumour activity of cisplatin. This involved the cisplatin analogue, transplatin, that although it produces DNA adducts, it does not have any anti-tumour activity. Hence by comparing the gene expression profiles of cisplatin and transplatin, the genes that are important in the anti-tumour activity of cisplatin can be revealed. Using this technique, we identified 27 genes that were up-regulated and 12 genes that were down-regulated, in response to cisplatin (but not transplatin) treatment of human cells. Ultimately, the identification of gene expression responses unique to cisplatin, could greatly benefit the design and development of improved cancer chemotherapeutics.