De Schutter Harlinde, Nuyts Sandra
Lab of Experimental Radiotherapy, UH Leuven, campus Gasthuisberg, Leuvens Kanker Instituut, Herestraat 49, 3000 Leuven, Belgium.
Anticancer Agents Med Chem. 2009 Jan;9(1):99-108. doi: 10.2174/187152009787047707.
Over the last few decades, epigenetic tumor changes characterized by promoter hypermethylation and histone modifications have become a topic of intense research. Of particular interest is the potential reversibility of these processes that has led to the development of epigenetic anticancer drugs such as demethylating agents and histone deacetylase inhibitors (HDAC-I). Besides single agent clinical activity in both hematological and solid malignancies, combinations of both types of epigenetic drugs with classic chemotherapeutics have shown promising results. In addition, as demethylating agents and HDAC-I act synergistically to reverse gene silencing, treatment schedules combining both epigenetic strategies could theoretically enhance tumor response. This assumption has been validated in vitro and in vivo for several hematological and solid cancer types, and awaits further clinical investigation. Nowadays, the majority of patients with cancer are treated with radiotherapy. To optimize the results obtained with this treatment modality, efforts are being put in strategies enhancing tumor response selectively in favor of normal tissue response. The combination of epigenetic drugs with radiotherapy is particularly valuable since a drug- and dose-dependent radiosensitizing potential of several classes of HDAC-I has been proven in vitro and in vivo. The molecular mechanisms underlying this radiosensitization have not been fully clarified yet. In general, higher concentrations of HDAC-I are believed to exert cell cycle redistribution, induction of apoptosis, and downregulation of surviving signals. The radiosensitizing effect of lower, non-toxic doses of HDAC-I has been attributed to, at least in part, acetylation-induced changes leading to altered double strand break (DSB) formation and repair. Although promising so far, further research is needed before HDAC-I administered alone or in combination with demethylating agents will be implemented in the clinic to act as radiosensitizers.
在过去几十年中，以启动子高甲基化和组蛋白修饰为特征的表观遗传肿瘤变化已成为深入研究的课题。这些过程的潜在可逆性尤其令人感兴趣，这促使了表观遗传抗癌药物的开发，如去甲基化剂和组蛋白脱乙酰酶抑制剂（HDAC-I）。除了在血液系统恶性肿瘤和实体恶性肿瘤中的单药临床活性外，这两种表观遗传药物与传统化疗药物的联合使用已显示出有前景的结果。此外，由于去甲基化剂和HDAC-I协同作用以逆转基因沉默，结合这两种表观遗传策略的治疗方案理论上可以增强肿瘤反应。这一假设已在体外和体内针对几种血液系统和实体癌类型得到验证，有待进一步的临床研究。如今，大多数癌症患者接受放射治疗。为了优化通过这种治疗方式获得的结果，人们正在努力制定策略，以选择性地增强肿瘤反应，同时有利于正常组织反应。表观遗传药物与放射治疗的联合尤其有价值，因为几类HDAC-I在体外和体内已被证明具有药物和剂量依赖性的放射增敏潜力。这种放射增敏的分子机制尚未完全阐明。一般来说，较高浓度的HDAC-I被认为会导致细胞周期重新分布、诱导细胞凋亡以及下调存活信号。较低的、无毒剂量的HDAC-I的放射增敏作用至少部分归因于乙酰化诱导的变化，导致双链断裂（DSB）形成和修复改变。尽管目前前景乐观，但在HDAC-I单独或与去甲基化剂联合用于临床作为放射增敏剂之前，还需要进一步研究。
