Karpf Adam R
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets; Buffalo, New York 14263, USA.
Epigenetics. 2006 Jul-Sep;1(3):116-20. doi: 10.4161/epi.1.3.2988.
The discovery of epigenetic silencing as a key mechanism of tumor suppressor gene inactivation in human cancer has led to great interest in utilizing epigenetic modulatory drugs as cancer therapeutics. It is less appreciated that medically important tumor-associated antigens, particularly the Cancer Testis or Cancer/Germ-line family of antigens (CG antigens), which are being actively tested as cancer vaccine targets, are epigenetically activated in many human cancers. However, a major limitation to the therapeutic value of CG antigen-directed vaccines is the limited and heterogeneous expression of CG antigens in tumors. Recent work has begun to dissect the specific epigenetic mechanisms controlling differential expression of CG antigen genes in human cancers. From a clinical perspective, convincing data indicate that epigenetic modulatory agents, including DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, robustly promote the expression of CG antigens, as well as class I major histocompatibility complex (MHC I) and other immune costimulatory molecules, in tumors. Importantly, the effects of these agents on CG antigen gene expression often show marked specificity for tumor cells as compared to normal cells. Taken together, these data encourage clinical evaluation of combination therapies involving epigenetic modulatory drugs and CG antigen-directed tumor vaccines for the treatment of human malignancies.
表观遗传沉默作为人类癌症中肿瘤抑制基因失活的关键机制被发现后，人们对利用表观遗传调节药物作为癌症治疗方法产生了浓厚兴趣。鲜为人知的是，医学上重要的肿瘤相关抗原，特别是正作为癌症疫苗靶点进行积极测试的癌胚抗原或癌/种系抗原家族（CG抗原），在许多人类癌症中是通过表观遗传方式被激活的。然而，CG抗原导向疫苗治疗价值的一个主要限制是CG抗原在肿瘤中的表达有限且异质性强。最近的研究开始剖析控制人类癌症中CG抗原基因差异表达的具体表观遗传机制。从临床角度来看，有说服力的数据表明，包括DNA甲基转移酶（DNMT）和组蛋白脱乙酰酶（HDAC）抑制剂在内的表观遗传调节剂能有力地促进肿瘤中CG抗原以及I类主要组织相容性复合体（MHC I）和其他免疫共刺激分子的表达。重要的是，与正常细胞相比，这些药物对CG抗原基因表达的影响通常对肿瘤细胞具有显著的特异性。综上所述，这些数据鼓励对涉及表观遗传调节药物和CG抗原导向肿瘤疫苗的联合疗法进行临床评估，以治疗人类恶性肿瘤。
