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

Federico Innocenti, Snezana Mirkov, Ramamoorthy Nagasubramanian, Jacqueline Ramírez, Wanqing Liu, Wasim K. Bleibel, Sunita J. Shukla, Kathleen Hennessy, Gary L. Rosner, Edwin Cook, M. Eileen Dolan, Mark J. Ratain

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)881-887
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume63
Issue number5
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

Keywords

  • Cytotoxicity
  • Pharmacogenetics
  • Polymorphism
  • Topoisomerase inhibitors
  • Werner's syndrome

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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  • Cite this

    Innocenti, F., Mirkov, S., Nagasubramanian, R., Ramírez, J., Liu, W., Bleibel, W. K., Shukla, S. J., Hennessy, K., Rosner, G. L., Cook, E., Eileen Dolan, M., & Ratain, M. J. (2009). The Werner's syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds. Cancer Chemotherapy and Pharmacology, 63(5), 881-887. https://doi.org/10.1007/s00280-008-0793-8