Driever P H, Knüpfer M M, Cinatl J, Wolff J E
Department of Pediatric Neurology, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Klin Padiatr. 1999 Jul-Aug;211(4):323-8. doi: 10.1055/s-2008-1043809.
Despite surgery and adjuvant cytotoxic therapy anaplastic astrocytoma, glioblastoma and diffuse intrinsic brain stem glioma continue to have dismal prognosis. Differentiation induction is a new approach taking into account that malignant glioma cells share many features with immature glial progenitor cells that are capable of terminal differentiation. The concept of differentiation therapy is currently evaluated for several pediatric malignancies with or without multimodal standard therapy. Valproic acid (VPA) is a branched chain fatty acid that is able to inhibit proliferation of neuroectodermal cells and to induce these cells along neuronal or glial lineage. Preclinical studies have shown that VPA inhibits growth of human and rodent glial tumor cells in vitro and induces a distinct mature glial phenotype. In addition, growth of human neuroblastoma cells is inhibited in vitro and in vivo and exhibits marked evidence of differentiation. Treatment of neuroblastoma and glioma cells with VPA was accompanied by changes of surface molecule expression that enhance immunogenicity and reduce their capability to metastasize. The antitumoral effects observed in preclinical studies were reached at concentrations that are readily achieved in patients treated with VPA for epilepsy. Epilepsy patients receiving VPA have significantly enhanced hemoglobin F levels, supporting the hypothesis that nontoxic levels of VPA can induce cellular differentiation. Broad clinical experience with VPA and its low toxicity encourage the evaluation of VPA in patients that have been submitted to postoperative combined chemo- and radiotherapy for pediatric malignant glioma.
尽管进行了手术和辅助细胞毒性治疗，但间变性星形细胞瘤、胶质母细胞瘤和弥漫性固有脑干胶质瘤的预后仍然很差。诱导分化是一种新方法，它考虑到恶性胶质瘤细胞与能够终末分化的未成熟神经胶质祖细胞有许多共同特征。目前正在评估分化疗法对几种儿童恶性肿瘤单独或联合多模式标准疗法的疗效。丙戊酸（VPA）是一种支链脂肪酸，能够抑制神经外胚层细胞的增殖，并诱导这些细胞沿着神经元或神经胶质谱系分化。临床前研究表明，VPA在体外可抑制人和啮齿动物胶质肿瘤细胞的生长，并诱导出明显的成熟神经胶质表型。此外，VPA在体外和体内均可抑制人神经母细胞瘤细胞的生长，并显示出明显的分化迹象。用VPA处理神经母细胞瘤和胶质瘤细胞会伴随着表面分子表达的变化，增强免疫原性并降低其转移能力。临床前研究中观察到的抗肿瘤作用是在接受VPA治疗癫痫的患者中容易达到的浓度下实现的。接受VPA治疗的癫痫患者血红蛋白F水平显著升高，支持了VPA无毒水平可诱导细胞分化的假说。VPA广泛的临床经验及其低毒性促使人们对接受小儿恶性胶质瘤术后联合化疗和放疗的患者进行VPA评估。
