文献简介

出版社:Cancer Chemother Pharmacol

作  者:Federico Innocenti Æ Snezana Mirkov Æ Ramamoorthy Nagasubramanian Æ Jacqueline Ramı´rez

编  号:10.1007/s00280-008-0793-8

关键字:Topoisomerase inhibitors  Werner’s syndrome  Pharmacogenetics  Polymorphism  Cytotoxicity

年  份:2009   点击量:511

文献摘要


Purpose

目的

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 agerelated diseases, suggesting it has a functional role. We studied whether the 4330T>C variant confers altered drug sensitivity in vitro.

Werner综合征(WS)是与衰老相关的过早发病的一种隐性遗传疾病。据报道,从WS患者中分离的细胞暴露在DNA损伤剂后有缺陷的DNA得到了修复。在WS基因(WRN)中的生殖系4330T>C(Cys1367Arg)变异已被证实与年龄相关性疾病的保护有关,暗示它具有一种功能性作用。我们研究4330T>C变异是否改变了体外药物的敏感性。

Methods

方法

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.

4330T>C是基于TaqMan方法从不相干的健康白种人中获得的372个人的类原始淋巴细胞系(LCLs)基因分型。本研究以检测接触喜树碱(根据原始数据)后的4330T>C基因型的影响为目的。4330T>C变异对依托泊苷、卡铂、顺铂和柔红霉素细胞毒性的影响也进行了测定。在57 LCLs中WRN的表达采用微阵列进行检测。

Results

结果

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).

接触喜树碱后在细胞在IC50细胞的基因型间(P = 0.46)没有观察到显著差异。没有观察到依托泊苷、卡铂、顺铂、柔红霉素(ANOVA,P﹥0.05 )之间有关联关系。WRN的表达在基因型上并没有变化(ANOVA,P = 0.37 )。

Conclusion

结论

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

这些结果表明这个非同义变异体在细胞水平上具有相对正常的功能。