Rogers Hazel Anne, Chapman Rebecca, Kings Holly, Allard Julie, Barron-Hastings Jodie, Pajtler Kristian W, Sill Martin, Pfister Stefan, Grundy Richard Guy
Children's Brain Tumour Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.
Hopp Children's Cancer Centre at the NCT (KiTZ), Heidelberg, Germany.
Oncotarget. 2018 Nov 23;9(92):36530-36541. doi: 10.18632/oncotarget.26370.
Epigenetic modifications have been shown to play an important role in the classification and pathogenesis of the pediatric brain tumor ependymoma, suggesting they are a potential therapeutic target.
Agents targeting epigenetic modifications inhibited the growth and induced the death of ependymoma cells with variable efficiency. However, this was often not at clinically achievable doses. Additionally, DNA methylation profiling revealed a lack of similarity to primary ependymomas suggesting alterations were induced during culture. Toxicity to fetal neural stem cells was also seen at similar drug concentrations.
Agents targeting epigenetic modifications were able to inhibit the growth and induced the death of ependymoma cells grown . However, many agents were only active at high doses, outside clinical ranges, and also resulted in toxicity to normal brain cells. The lack of similarity in DNA methylation profiles between cultured cells and primary ependymomas questions the validity of using cultured cells for pre-clinical analysis of agents targeting epigenetic mechanisms and suggests further investigation using models that are more appropriate should be undertaken before agents are taken forward for clinical testing.
The effects of agents targeting epigenetic modifications on the growth and death of a panel of ependymoma cell lines was investigated, as well as toxicity to normal fetal neural stem cells. The ependymoma cell lines were characterized using DNA methylation profiling.
表观遗传修饰已被证明在小儿脑肿瘤室管膜瘤的分类和发病机制中起重要作用，这表明它们是潜在的治疗靶点。
靶向表观遗传修饰的药物能以不同效率抑制室管膜瘤细胞生长并诱导其死亡。然而，这通常不是临床可达到的剂量。此外，DNA甲基化谱分析显示与原发性室管膜瘤缺乏相似性，提示在培养过程中发生了改变。在相似药物浓度下也观察到对胎儿神经干细胞的毒性。
靶向表观遗传修饰的药物能够抑制室管膜瘤细胞生长并诱导其死亡。然而，许多药物仅在超出临床范围的高剂量下才有活性，并且还会对正常脑细胞产生毒性。培养细胞与原发性室管膜瘤之间DNA甲基化谱缺乏相似性，这对使用培养细胞进行靶向表观遗传机制药物的临床前分析的有效性提出了质疑，并表明在将药物推进到临床试验之前，应使用更合适的模型进行进一步研究。
研究了靶向表观遗传修饰的药物对一组室管膜瘤细胞系生长和死亡的影响，以及对正常胎儿神经干细胞的毒性。使用DNA甲基化谱分析对室管膜瘤细胞系进行了表征。
