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

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

Author information

1
Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637, USA. finnocen@medicine.bsd.uchicago.edu

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.

PMID:
18677484
PMCID:
PMC2731557
DOI:
10.1007/s00280-008-0793-8
[Indexed for MEDLINE]
Free PMC Article

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