Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Apoptose et Progression tumorale, Equipe labellisée Ligue Nationale Contre le Cancer, 8 quai moncousu, BP7021, 44007 Nantes, France.
Eur J Cancer. 2012 Oct;48(15):2431-41. doi: 10.1016/j.ejca.2012.01.002. Epub 2012 Feb 8.
A hallmark of cancer is the paradoxical co-presence, in the same tumour, of local and global DNA hypomethylation together with the regional hypermethylation of certain genes. Due to the oncogenic role of these different DNA methylation alterations, two therapeutic strategies are possible: the use of DNA methylating agents (DMA, such as folate) to inhibit global or local DNA hypomethylation or the use of DNA hypomethylating agents (DHA, such as 5-aza-2-deoxycytidine) to abrogate the accumulation of hypermethylated genes. Here we explored the use of folate to treat gliomas in a mouse model, using tumours induced by either PDGF-B or Ras/Akt overexpression, or by ethylnitrosourea (ENU) treatment. Under all conditions the volume of tumours were significantly less in folate treated mice than in untreated mice. Quantitative methylated DNA immunoprecipitation (qMeDIP) and quantitative methylated specific PCR (qMSP) analysis of methylation status showed that folate treatment, increased the methylation level of DNA repeat elements in tumour and in colorectal tissue and that of MGMT and specific oncogenes (PDGF-B or survivin) in tumours (but not in colorectal tissue), but had no effect on the expression of tumour suppressor genes (p53, PTENorbax) in tumours or in colorectal tissue. This suggests that folate has anti-neoplastic effects in gliomas and that no preneoplastic or neoplastic alterations were observed in unaffected colorectal tissue in response to the potential tumourigenic effects of folate. Collectively, our data support the proposal to include folate as a promising adjuvant in the design of anti-glioma therapeutic protocols in clinical studies.
癌症的一个标志是，在同一肿瘤中，局部和全局 DNA 低甲基化与某些基因的区域高甲基化同时存在。由于这些不同的 DNA 甲基化改变具有致癌作用，因此有两种治疗策略是可能的：使用 DNA 甲基化剂（DMA，如叶酸）抑制全局或局部 DNA 低甲基化，或使用 DNA 低甲基化剂（DHA，如 5-氮杂-2-脱氧胞苷）消除高甲基化基因的积累。在这里，我们使用 PDGF-B 或 Ras/Akt 过表达或乙基硝基亚硝脲（ENU）处理诱导的小鼠模型探索了叶酸治疗神经胶质瘤的用途。在所有情况下，叶酸治疗组的肿瘤体积明显小于未治疗组。甲基化 DNA 免疫沉淀（qMeDIP）和甲基化特异性定量 PCR（qMSP）分析甲基化状态表明，叶酸治疗增加了肿瘤和结直肠组织中 DNA 重复元件的甲基化水平，以及肿瘤中 MGMT 和特定癌基因（PDGF-B 或生存素）的甲基化水平（但在结直肠组织中没有），但对肿瘤中肿瘤抑制基因（p53、PTEN 或 bax）或结直肠组织中的表达没有影响。这表明叶酸对神经胶质瘤具有抗肿瘤作用，并且在不受影响的结直肠组织中未观察到叶酸对潜在致癌作用的反应的前肿瘤或肿瘤性改变。总之，我们的数据支持将叶酸纳入临床研究中抗神经胶质瘤治疗方案设计的有前途的辅助剂的建议。
