UMC Utrecht, Utrecht, Netherlands.
Expert Opin Investig Drugs. 2012 Sep;21(9):1391-415. doi: 10.1517/13543784.2012.694425. Epub 2012 Jun 6.
Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to inhibit the proliferation of various cancers including glioblastoma multiforme.
We provide a comprehensive review of the mechanisms of action of valproate in gliomas, of its potential side effects and of the published clinical results obtained with this drug in glioblastomas. Valproate inhibits a subset of histone deacetylases and cellular kinases, and affects gene transcription through histone hyperacetylation, DNA hypomethylation and the modulation of several transcription factors. As a result, VPA induces differentiation of glioma cells, can prevent their invasion in surrounding tissues and may inhibit tumor angiogenesis. VPA can also inhibit DNA repair, thereby potentiating cytotoxic treatments such as chemotherapies or radiation therapy. Based on these mechanisms and case reports of glioblastoma remissions following VPA treatment, several clinical studies currently assess the therapeutic potential of VPA in glioma therapy.
The combination of VPA treatment with chemotherapy and radiotherapy in glioblastoma appears a rational option that deserves well-designed prospective clinical trials that assess the efficacy and the molecular characteristics of the responding tumors in these patients.
多形性胶质母细胞瘤是最常见和最具侵袭性的原发性脑肿瘤。丙戊酸已被用作抗癫痫药和情绪稳定剂数十年。最近，它被发现可抑制多种癌症的增殖，包括多形性胶质母细胞瘤。
我们全面回顾了丙戊酸在神经胶质瘤中的作用机制、其潜在的副作用以及该药物在胶质母细胞瘤中获得的已发表的临床结果。丙戊酸抑制了一组组蛋白去乙酰化酶和细胞激酶，并通过组蛋白乙酰化、DNA 低甲基化和几种转录因子的调节来影响基因转录。因此，VPA 诱导神经胶质瘤细胞分化，可防止其向周围组织浸润，并可能抑制肿瘤血管生成。VPA 还可以抑制 DNA 修复，从而增强化疗或放疗等细胞毒性治疗的效果。基于这些机制以及丙戊酸治疗后胶质母细胞瘤缓解的病例报告，目前有几项临床研究评估了 VPA 在神经胶质瘤治疗中的治疗潜力。
将 VPA 治疗与化疗和放疗联合用于胶质母细胞瘤似乎是一种合理的选择，值得进行精心设计的前瞻性临床试验，以评估该疗法对这些患者肿瘤的疗效和分子特征。
