Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines.
Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines.
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发表时间：
2003-03
期刊：
影响因子：
11.2
通讯作者：
M. Selvakumaran;Debra A Pisarcik;R. Bao;A. Yeung;T. C. Hamilton
中科院分区：
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作者：
M. Selvakumaran;Debra A Pisarcik;R. Bao;A. Yeung;T. C. Hamilton
在美国，卵巢癌是女性死于妇科恶性肿瘤的主要原因。对化疗药物顺铂的耐药性是成功治疗卵巢癌的主要限制因素。为了克服卵巢癌治疗中的顺铂耐药问题，我们试图通过干扰核苷酸切除修复(NER)途径来增强顺铂的细胞毒性。NER途径负责修复与DNA结合的顺铂。NER组分ERCC1的表达与顺铂耐药有关。因此，我们通过反义RNA方法来靶向ERCC1RNA，并且我们发现我们可以通过表达反义ERCC1RNA来使相对敏感的A2780细胞系和高耐药的OVCAR10细胞系对顺铂增敏，通过3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium溴化试验检测。表达反义ERCC1的A2780细胞对顺铂的敏感性提高1.9-8.1倍。OVCAR10反义ERCC1细胞株的IC(50)为2.28~2.7微米，而对照OVCAR10细胞的IC(50)为9.52微米。OVCAR10反义ERCC1细胞也表现出DNA损伤修复能力的降低，通过宿主细胞的重新激活来评估。此外，移植了反义细胞系的免疫受损小鼠在顺铂治疗后比携带对照细胞的小鼠存活时间更长。这些数据表明，有可能通过干扰顺铂耐药细胞系中的NER途径来显著增强顺铂的细胞毒性，并在卵巢癌异种移植模型中提高小鼠的生存能力。
Ovarian cancer is the leading cause of death among women from gynecological malignancies inthe United States. Resistance to the chemotherapeutic agent cisplatin isa major limitation for the successful treatment of ovarian cancer. In an effort to overcome the cisplatin resistance problem in ovarian cancer treatment, we have sought to enhance cisplatin cytotoxicity by perturbing the nucleotide excision repair (NER) pathway. The NER pathway is responsible for repairing cisplatin bound to DNA. Expression of one of the NER components, ERCC1, is correlated with cisplatin drug resistance. Hence, we targeted ERCC1 by antisense RNA methodologies, and we show that we could sensitize a relatively sensitive A2780 cell line and also the highly resistant OVCAR10 cell line to cisplatin by expressing antisense ERCC1 RNA in them as measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The A2780 cell lines expressing antisense ERCC1 had 1.9-8.1-fold enhancements in cisplatin sensitivity. The OVCAR10 antisense ERCC1 cell lines had IC(50) values ranging from 2.28 microM to 2.7 microM cisplatin as compared with 9.52 micro M for control OVCAR10 cells. The OVCAR10 antisense ERCC1 cells also show reduced DNA-damage repair capacity as assessed by host cell reactivation. Furthermore, immunocompromised mice transplanted with the antisense cell lines survived longer than the mice bearing control cells after response to cisplatin treatment. These data suggest that it is possible to substantially enhance the cisplatin cytotoxicity by disturbing the NER pathway in cisplatin-resistant cell lines and to enhance the survival capacity of mice in an ovarian cancer xenograft model.