The Werner's syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds

Cancer Chemother Pharmacol. 2009 Apr;63(5):881-7. doi: 10.1007/s00280-008-0793-8. Epub 2008 Aug 2.


Purpose: Werner's syndrome (WS) is a recessive disorder of premature onset of processes associated with aging. Defective DNA repair has been reported after exposure of cells isolated from WS patients to DNA-damaging agents. The germline 4330T>C (Cys1367Arg) variant in the WS gene (WRN) has been associated with protection from age-related diseases, suggesting it has a functional role. We studied whether the 4330T>C variant confers altered drug sensitivity in vitro.

Methods: 4330T>C was genotyped in 372 human lymphoblastoid cell lines (LCLs) from unrelated healthy Caucasian individuals using a TaqMan-based method. The study was powered to detect the effect of the 4330T>C genotypes after exposure to camptothecin (based upon preliminary data). The effect of the 4330T>C variant on the cytotoxicity of etoposide, carboplatin, cisplatin and daunorubicin was also tested. WRN expression in 57 LCLs was measured by microarray.

Results: No significant difference between the IC50 of the cells was observed among genotypes (P = 0.46) after exposure to camptothecin. No association was also observed for etoposide, carboplatin, cisplatin, and daunorubicin (ANOVA, P > 0.05). WRN expression also did not vary across genotypes (ANOVA, P = 0.37).

Conclusion: These results suggest that this nonsynonymous variant has relatively normal function at the cellular level.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology
  • B-Lymphocytes / drug effects*
  • Camptothecin / pharmacology
  • Carboplatin / pharmacology
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cisplatin / pharmacology
  • Daunorubicin / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • Etoposide / pharmacology
  • Exodeoxyribonucleases / genetics*
  • Genotype
  • Humans
  • Platinum Compounds / pharmacology*
  • Polymorphism, Single Nucleotide / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RecQ Helicases / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Topoisomerase Inhibitors*
  • Werner Syndrome / genetics*
  • Werner Syndrome Helicase


  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Enzyme Inhibitors
  • Platinum Compounds
  • RNA, Messenger
  • Topoisomerase Inhibitors
  • Etoposide
  • Carboplatin
  • Exodeoxyribonucleases
  • RecQ Helicases
  • WRN protein, human
  • Werner Syndrome Helicase
  • Cisplatin
  • Camptothecin
  • Daunorubicin