Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Bratislava, Slovakia.
Anticancer Drugs. 2010 Jul;21(6):565-77. doi: 10.1097/CAD.0b013e32833a4352.
Human cancer represents a heterogeneous group of diseases that are driven by progressive genetic and epigenetic abnormalities. The latter alterations involve hypermethylation and hypomethylation of DNA, and changed patterns of histone modification, with resultant remodeling of the chromatin structure that cause deregulation of the transcription activity of many genes. Unlike the remarkable progress in understanding the processes by which DNA methyltransferases can regulate gene expression and histone deacetylases can induce alteration of chromatin structure, the roles of epigenetic events in tumors remain insufficiently explained. In contrast to genetic changes, the epigenetic alterations in cancer cells can be reversed by the inhibition of DNA methylation and histone deacetylation. Therefore, many inhibition agents for re-expression, predominantly of tumor-suppressor genes, have been identified and tested in laboratory models and numerous clinical trials. Despite in-vitro evidence that a single drug can lead to reactivation of methylated genes, inhibitors of DNA methyltransferases and histone deacetylases have been investigated in combination, or together with cytotoxic chemotherapy, radiotherapy, immunotherapy, or hormonal therapy to improve the therapeutic effect. Ongoing trials are recognizing that the identification of a target group of patients who are more likely to respond to the epigenetic therapy, defining of an optimal dose and schedule of treatment, and the development of more specific inhibitors with minimal unwanted side effects are necessary. Thus, new combinations of anticancer agents, including epigenetic modulators, may lead to a more effective control of cancer.
人类癌症代表了一组异质性疾病，这些疾病是由渐进性的遗传和表观遗传异常所驱动的。后者的改变涉及 DNA 的超甲基化和低甲基化，以及组蛋白修饰模式的改变，导致染色质结构的重塑，从而导致许多基因的转录活性失调。与理解 DNA 甲基转移酶如何调节基因表达和组蛋白去乙酰化酶如何诱导染色质结构改变的过程取得的显著进展不同，表观遗传事件在肿瘤中的作用仍未得到充分解释。与遗传变化不同，癌细胞中的表观遗传改变可以通过抑制 DNA 甲基化和组蛋白去乙酰化来逆转。因此，已经鉴定并在实验室模型和许多临床试验中测试了许多用于重新表达的抑制剂，主要是肿瘤抑制基因的抑制剂。尽管体外证据表明，单一药物可以导致甲基化基因的重新激活，但 DNA 甲基转移酶和组蛋白去乙酰化酶的抑制剂已被联合研究，或与细胞毒性化疗、放疗、免疫治疗或激素治疗联合使用，以提高治疗效果。正在进行的试验认识到，有必要确定更有可能对表观遗传治疗有反应的目标患者群体，确定最佳剂量和治疗方案，并开发具有最小不良反应的更特异性抑制剂。因此，包括表观遗传调节剂在内的新型抗癌药物组合可能会更有效地控制癌症。
