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01-04-2009 | Original Article

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

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

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2009

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.

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Title: The Werner’s syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds
Authors: Federico Innocenti
Snezana Mirkov
Ramamoorthy Nagasubramanian
Jacqueline Ramírez
Wanqing Liu
Wasim K. Bleibel
Sunita J. Shukla
Kathleen Hennessy
Gary L. Rosner
Edwin Cook Jr
M. Eileen Dolan
Mark J. Ratain
Publication date: 01-04-2009
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0793-8

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Abstract

Purpose

Methods

Results

Conclusion

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