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2',3'-DIDEOXYCYTIDINE INDUCED DRUG RESISTANCE IN HUMAN CELLS

机译:2',3'-去氧代胞苷对人细胞的药物耐药性

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2',3'-Dideoxycytidine (ddC) is a nucleoside analogue that inhibits HIV-1 replication in vitro and is currently used in AIDS therapy. This compound exerts a delayed cytotoxicity due to inhibition of mitochondrial DNA (mDNA) synthesis. We have found that long term exposure of U937 human monoblastoid cells to ddC allowed the selection of a drug-resistant cell line (U937-R) with 66% mDNA normal ddC transport and altered deoxycytidine kinase kinetic properties. In this paper we show that U937-R cells contain an increased number of mitochondria per cell and a reduced copy number of mDNA/mitochondria. Furthermore, the intracellular concentrations of deoxycytidine 5'-triphosphate (dCTP) and 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) are also reduced although with a higher dCTP/ddCTP ratio in U937-R compared to the parental cells. This mechanism of drug resistance, with drug-resistance based on viral mutations, can provide an explanation for drug failure in antiviral therapy. [References: 15]
机译:2',3'-二脱氧胞苷(ddC)是一种核苷类似物,可在体外抑制HIV-1复制,目前用于AIDS治疗。由于抑制了线粒体DNA(mDNA)的合成,该化合物产生了延迟的细胞毒性。我们已经发现,U937人类单胚细胞长期暴露于ddC,可以选择具有66%mDNA正常ddC转运并改变了脱氧胞苷激酶动力学特性的耐药细胞系(U937-R)。在本文中,我们显示U937-R细胞每个细胞的线粒体数目增加,而mDNA /线粒体的拷贝数减少。此外,尽管与亲代细胞相比,U937-R中的dCTP / ddCTP比值更高,但脱氧胞苷5'-三磷酸(dCTP)和2',3'-二脱氧胞苷5'-三磷酸(ddCTP)的细胞内浓度也降低了。这种耐药性机制以及基于病毒突变的耐药性可以为抗病毒治疗中的药物失败提供解释。 [参考:15]

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