Biol. Pharm. Bull. 30(10) 1958—1961 (2007)

causing symptoms of premature ageing. In 1996, the Werner syndrome gene (WRN) responsible for WS was identified. The gene product, WRN, acts as a DNA helicase (WRN helicase) with exonuclease activity. WRN greatly participates in DNA metabolism by facilitating cellular processes, including DNA replication, recombination, repair, and transcription in cooperation with other cellular proteins. WRN may participate in the retrovirus replication. WS patients lack functional WRN mainly because of mutations that cause premature termination in WRN synthesis, produce incomplete WRN molecules lacking C-terminal nuclear localization signals and so result in impaired nuclear transportation of WRN. The genotoxic clastogen 4-nitroquinoline-1-oxide (4NQO) induces a more distinct increase in both break and interchange aberrations in WS patient cells than in control cells from normal individuals or from patients with other diseases. WS patient lymphoblastoid cell lines (LCLs) transformed by Epstein-Barr virus are hypersensitive to 4NQO than LCLs from normal individuals without mutation. Previously we studied the effect of camptothecin (CPT), a DNA topoisomerase I-trapping agent, on several LCLs from non-WS individuals and WS patients, and showed that CPT had a stronger cytotoxic effect on LCLs from WS patients than LCLs from non-WS individuals. Poot et al. confirmed and extended our results by showing that CPT more strongly impairs S-phase transit in WS LCLs than in normal LCLs. Lebel and Leder made homozygous WS embryonic stem cells (ES) of mice that lacked normal WRN genes at both alleles. Such cells were more markedly sensitive to CPT than were wild-type ES cells. From these results, we investigated if silencing WRN gene expression by siRNA targeting the WRN gene (WRN-siRNA) increases the sensitivity of cells against CPT. We show here that specific down-regulation of WRN expression increases the cytotoxic effects of CPT in cancer cells, and we discuss the potential of using these findings for cancer therapy. MATERIALS AND METHODS