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首页> 外文期刊>Biochemical Pharmacology >DNA repair mechanisms involved in gemcitabine cytotoxicity and in the interaction between gemcitabine and cisplatin.
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DNA repair mechanisms involved in gemcitabine cytotoxicity and in the interaction between gemcitabine and cisplatin.

机译：DNA修复机制涉及吉西他滨细胞毒性以及吉西他滨和顺铂之间的相互作用。

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摘要

The influence of DNA repair mechanisms on the interaction between gemcitabine and cisplatin was studied using a panel of Chinese hamster ovary (CHO) cell lines deficient in one of the following repair pathways: base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end joining (NHEJ). NER and HR are known to be involved in platinum-DNA adduct repair. Single agent experiments demonstrated that each of the repair deficient cell lines had a similar sensitivity towards gemcitabine as the parental cell lines, whereas the NER- and HR-deficient lines showed increased sensitivity towards cisplatin. Furthermore, in the parental cell lines, the administration sequence cisplatin followed by gemcitabine was synergistic, whereas the reversed schedule showed additivity and simultaneous administration revealed antagonistic cytotoxicity. In the repair deficient cell lines, using this synergistic schedule of cisplatin followed by gemcitabine, loss of synergy was observed in the NER- and HR-deficient cell lines. However, the magnitude of the effect in the NER-deficient cells was small. The sensitivity to the combination of cisplatin and gemcitabine shown by the BER- and NHEJ-deficient cell lines did not differ significantly from that of the parental cell line. Cellular accumulation of platinum as well as the formation of GG- and AG-intrastrand adducts in the parental line and in the HR-deficient line were not affected by gemcitabine.In conclusion, our results indicate that BER, NER, HR, and NHEJ are most likely incapable of modulating the cytotoxicity of gemcitabine, and that HR is involved in the synergistic interaction between cisplatin and gemcitabine in our cell system.
机译：利用一组缺乏以下修复途径之一的中国仓鼠卵巢（CHO）细胞系研究了DNA修复机制对吉西他滨与顺铂之间相互作用的影响：碱基切除修复（BER），核苷酸切除修复（NER），同源重组（HR）和非同源末端连接（NHEJ）。已知NER和HR参与铂DNA加合物的修复。单剂实验表明，每种修复缺陷细胞系对吉西他滨的敏感性与亲本细胞系相似，而NER和HR缺陷系显示出对顺铂的敏感性增加。此外，在亲本细胞系中，顺铂和吉西他滨的给药顺序是协同的，而相反的时间表显示出加和性，同时给药显示出拮抗的细胞毒性。在修复缺陷型细胞系中，使用顺铂和吉西他滨的协同增效方案，在NER和HR缺陷型细胞系中观察到协同作用丧失。但是，在NER缺陷细胞中的作用程度很小。缺乏BER和NHEJ的细胞系对顺铂和吉西他滨组合的敏感性与亲本细胞系的敏感性没有显着差异。吉西他滨不影响亲本系和HR缺乏系中铂的细胞积累以及GG和AG内链加合物的形成。结论，我们的结果表明BER，NER，HR和NHEJ是最有可能无法调节吉西他滨的细胞毒性，并且HR参与了我们细胞系统中顺铂和吉西他滨之间的协同相互作用。

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