DNA甲基转移酶作为癌症治疗的目标。

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Ghoshal K,白

DNA甲基转移酶作为癌症治疗的目标。

今天药物(巴克)。2007年6月,43 (6):395 - 422。

PubMed ID

17612710 (在PubMed

]

文摘

5-position DNA甲基化的胞嘧啶,由DNA甲基转移酶催化,是主要的表观遗传修饰在哺乳动物。畸变在甲基化起到关键作用的多种疾病,包括癌症。最近的研究证实,突变,methylation-mediated基因沉默常常会导致肿瘤发生。矛盾的是,全基因组DNA hypomethylation致癌作用也可能起到关键作用的诱导染色体不稳定和假基因的表达。由于甲基化不改变DNA碱基序列,最近很多注意力一直集中在发展中DNA甲基转移酶的小分子抑制剂,可以作为抗癌药物。由Pharmion Vidaza (5-azacytidine)、销售(美国博尔德有限公司),是第一个DNA甲基转移酶抑制剂通过美国食品和药物管理局(FDA)化疗对骨髓增生异常综合征(MDS),异构骨髓疾病。最近MGI制药有限公司(美国布鲁明顿、锰)得到FDA的批准市场Dacogen (5-aza-2脱氧胞苷或decitabine)治疗MDS患者。这些药物被用来反对某些贫血初胎球蛋白基因的诱导表达。兴趣这些药物作为抗癌药物的临床试验已更新直到最近因为methylation-mediated沉默逆转的关键基因在癌症。临床试验表明,这两种药物对白血病治疗潜力如MDS、急性髓系白血病、慢性粒细胞性白血病和慢性myelomonocytic白血病。 In contrast, their effectiveness with solid tumors appears to be less promising, which challenges researchers to develop inhibitors with more efficacy and less toxicity. The major hindrance of their usage as anticancer agents is their instability in vivo as well as the toxicity secondary to their excessive incorporation into DNA, which causes cell cycle arrest. Gene expression profiling in cancer cells revealed that antineoplastic property of these drugs is mediated through both methylation-dependent and -independent pathways. Recently, we have shown that treatment of cancer cells with these cytidine analogues also induces proteasomal degradation of DNA methyltransferase 1, the ubiquitously expressed enzyme upregulated in almost all cancer cells. Development of related stable drugs that can facilitate gene activation in cancer cells by enhancing degradation of DNA methyltransferases without being incorporated into DNA would be ideal for chemotherapy. In this monograph we review historical perspective and recent advances on the molecular mechanisms of action and clinical applications of these DNA hypomethylating agents.

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药物

阿扎胞苷

药物靶点

药物	目标	类	生物	药理作用	行动
阿扎胞苷	DNA甲基转移酶1 (cytosine-5)	蛋白质	人类	是的	抑制剂	细节