We investigated the induction of a stress response gene by anticancer drugs that damage and covalently modify DNA and other cellular macromolecules. Two human colon adenocarcinoma cell lines (HT-29 and BE) which differ in sensitivity to chloroethylnitrosoureas were treated with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) or with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Both of these drugs can alkylate, crosslink and carbamoylate cellular macromolecules. Treated cells were compared to controls for cytoplasmic levels of HSP70 RNA and for synthesis of heat shock proteins. We also tested for induction of stress response gene expression by equitoxic or greater concentrations of other nitrosourea analogues which can alkylate only, alkylate and crosslink only or carbamoylate only, as well as other DNA crosslinking agents (chlorambucil and cis-platinum). Of these, only BCNU and CCNU, the chloroethylnitrosoureas having all three of the macromolecule-modifying activities, strongly induce HSP70 RNA levels in a dose-dependent and time-dependent manner. Induction of HSP70 by BCNU occurred in both cell lines at dose ranges that were cytocidal to the BCNU-resistant HT-29 cells. No induction was seen in BE cells at the lower BCNU concentrations that were equitoxic to that more sensitive cell line. These observations suggest that induction of HSP70 by BCNU and CCNU is neither a direct consequence of DNA crosslinks nor an invariable result of cytocidal drugs.

译文

我们研究了破坏和共价修饰DNA和其他细胞大分子的抗癌药物对应激反应基因的诱导。用1,3-双-(2-氯乙基)-1-亚硝基脲 (BCNU) 或用1-(2-氯乙基)-1-亚硝基脲 (CCNU) 处理对氯乙基亚硝基脲敏感性不同的两种人结肠腺癌细胞系 (HT-29和BE)。3-环己基-1-亚硝基脲 (CCNU)。这两种药物都可以烷基化,交联和氨基甲酸的细胞大分子。将处理过的细胞与HSP70 RNA的细胞质水平和热休克蛋白的合成对照进行比较。我们还测试了等氧或更高浓度的其他亚硝基脲类似物 (仅可烷基化,烷基化和交联或仅氨基甲酸酯) 以及其他DNA交联剂 (苯丁酸氮芥和顺铂) 诱导应激反应基因表达的方法。其中,只有BCNU和CCNU,具有所有三种大分子修饰活性的氯乙基亚硝基脲,以剂量依赖性和时间依赖性方式强烈诱导HSP70 RNA水平。BCNU诱导HSP70在对BCNU抗性HT-29细胞具有杀灭作用的剂量范围内发生。在较低的BCNU浓度下的BE细胞中未见诱导,该浓度与该更敏感的细胞系等分。这些观察结果表明,BCNU和CCNU诱导HSP70既不是DNA交联的直接结果,也不是杀细胞药物的不变结果。

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