Enhanced suicide gene therapy using a tumor-specific promoter in combination with cisplatin

Human telomerase reverse transcriptase (hTERT) promoter has been proposed in cancer-targeted gene therapy. However, this promoter has not been strong enough to achieve therapeutic levels of transgene expression. We favor the hypothesis that telomerase may participate in the process of DNA repair and that the up-regulation of hTERT promoter activity may be a reaction to DNA damage. In previous investigations, we tested an 'indirected-activator' strategy that utilizes radiation to increase the activity of the hTERT promoter. The purpose of the present study was to implement a strategy using cisplatin to enhance hTERT promoter activity. The results indicate that, in human uterine cervical cancer (HeLa) cells exposed to 5 µg/ml cisplatin, the hTERT promoter had 3.1-fold increased activity compared to untreated cells. In addition, the combination of cisplatin and hTERT promoter-mediated horseradish peroxidase/indole-3-acetic acid gene-directed enzyme prodrug therapy induced cell cycle arrest at the S phase and apoptosis leading to a more significant reduction in cell viability. These findings suggest that hTERT promoter-mediated gene therapy is improved when combined with cisplatin.