Michaelis Martin, Suhan Tatyana, Cinatl Jaroslav, Driever Pablo Hernáiz, Cinatl Jindrich
Institut für Medizinische Virologie, Klinikum der J.W. Goethe Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
Int J Oncol. 2004 Dec;25(6):1795-9.
Valproic acid (VPA) as a differentiation inducing anti-neoplastic substance is currently tested in solid tumour and leukaemia patients. Previously, we were able to show that the anti-cancer activity of VPA was synergistically increased by interferon-alpha (IFN-alpha) in Be(2)-C neuroblastoma (NB) cells. Now, we studied the effects of VPA in combination with IFN-alpha on two other NB cell lines. UKF-NB-2 and UKF-NB-3 cell growth was synergistically inhibited by VPA and IFN-alpha. Cell cycle investigations revealed massive accumulation of cells in G0/G1-phase after a combined treatment with VPA and IFN-alpha. The VPA-induced accumulation of acetylated histones in NB cell nuclei that indicates inhibition of histone deacetylases was not further enhanced by the combination treatment with IFN-alpha. Most strikingly, VPA plus IFN-alpha synergistically inhibited growth of UKF-NB-3 xenograft tumours in nude mice and induced complete cures in two out of six animals, while single treatment merely inhibited tumour growth. The results of this study together with our previous report strongly encourage the clinical evaluation of VPA and IFN-alpha for NB patients.
丙戊酸（VPA）作为一种诱导分化的抗肿瘤物质，目前正在实体瘤和白血病患者中进行试验。此前，我们已经证明，在Be(2)-C神经母细胞瘤（NB）细胞中，α-干扰素（IFN-α）可协同增强VPA的抗癌活性。现在，我们研究了VPA与IFN-α联合使用对另外两种NB细胞系的影响。VPA和IFN-α协同抑制UKF-NB-2和UKF-NB-3细胞的生长。细胞周期研究表明，VPA和IFN-α联合处理后，细胞大量积聚在G0/G1期。VPA诱导NB细胞核中乙酰化组蛋白的积累，这表明组蛋白脱乙酰酶受到抑制，而与IFN-α联合处理并未进一步增强这种抑制作用。最引人注目的是，VPA加IFN-α协同抑制裸鼠体内UKF-NB-3异种移植肿瘤的生长，并使六只动物中的两只完全治愈，而单一治疗仅抑制肿瘤生长。这项研究的结果与我们之前的报告一起，强烈鼓励对NB患者进行VPA和IFN-α的临床评估。
