Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.

译文

神经胶质瘤是高度致命的肿瘤,目前可用的疗法无法治愈。替莫唑胺是最近引入的烷基化剂,在治疗高级别神经胶质瘤方面具有显着益处。然而,从头开始或获得的化学抗性经常发生,并且归因于O6-methylguanine-DNA甲基转移酶水平的升高或失配修复能力的丧失。然而,很少有神经胶质瘤过表达O6-methylguanine-DNA甲基转移酶或错配修复缺陷,这表明其他机制可能与替莫唑胺的耐药性有关。本研究的目的是从人神经胶质瘤细胞系 (SNB-19) 产生替莫唑胺抗性变体,并使用大规模基因组和转录分析来研究获得性替莫唑胺抗性的分子基础。两个独立获得的抗替莫唑胺的变体对其他烷基化剂 [1,3-双 (2-氯乙基)-1-亚硝基脲和卡铂] 没有交叉抗性,并且具有共同的遗传改变,例如2p区域的丢失和丢失染色体4和16q区域的扩增。核型改变与亲本SNB-19细胞系中先存的抗性细胞的克隆选择兼容。微阵列分析表明,17,000个基因中有78个在亲本细胞和替莫唑胺抗性变体之间差异表达。没有一个与已知的抗性机制 (例如DNA修复) 有关,而有趣的是,参与分化的几个基因被下调。数据表明,在该模型中获得对替莫唑胺的耐药性是由于在亲本肿瘤中选择了分化较少的耐药细胞。

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