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 language | English (US) |
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Pages (from-to) | 881-887 |
Number of pages | 7 |
Journal | Cancer Chemotherapy and Pharmacology |
Volume | 63 |
Issue number | 5 |
DOIs | |
State | Published - Apr 2009 |
Externally published | Yes |
Keywords
- Cytotoxicity
- Pharmacogenetics
- Polymorphism
- Topoisomerase inhibitors
- Werner's syndrome
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)