Division of Pharmacology, Department of Internal Medicine, University of Pisa, Pisa, Italy.
Drug Resist Updat. 2011 Dec;14(6):280-96. doi: 10.1016/j.drup.2011.08.001. Epub 2011 Sep 28.
Colorectal cancer is the second leading cause of cancer-related deaths in the world. Despite many therapeutic opportunities, prognosis remains dismal for patients with metastatic disease, and a significant portion of early-stage patients develop recurrence after chemotherapy. Epigenetic gene regulation is a major mechanism of cancer initiation and progression, through the inactivation of several tumor suppressor genes. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance. In the present review, we summarize epigenetic mechanisms triggering resistance to three commonly used agents in colorectal cancer: 5-fluorouracil, irinotecan and oxaliplatin. Those epigenetic biomarkers may help stratify colorectal cancer patients and develop a tailored therapeutic approach. In addition, epigenetic modifications are reversible through specific drugs: histone-deacetylase and DNA-methyl-transferase inhibitors. Preclinical studies suggest that these drugs may reverse chemoresistance in colorectal tumors. In conclusion, an epigenetic approach to colorectal cancer chemoresistance may pave the way to personalized treatment and to innovative therapeutic strategies.
结直肠癌是全球癌症相关死亡的第二大主要原因。尽管有许多治疗机会，但转移性疾病患者的预后仍然不佳，而且相当一部分早期患者在化疗后会复发。表观遗传基因调控是癌症发生和发展的主要机制，通过几个肿瘤抑制基因的失活。新出现的证据表明，表观遗传在化疗耐药性的发展中也可能发挥关键作用。在本综述中，我们总结了触发结直肠癌中三种常用药物（5-氟尿嘧啶、伊立替康和奥沙利铂）耐药性的表观遗传机制。这些表观遗传生物标志物可能有助于对结直肠癌患者进行分层，并制定针对性的治疗方法。此外，通过特定药物可以逆转表观遗传修饰：组蛋白去乙酰化酶和 DNA 甲基转移酶抑制剂。临床前研究表明，这些药物可能逆转结直肠肿瘤的化疗耐药性。总之，针对结直肠癌化疗耐药性的表观遗传方法可能为个性化治疗和创新治疗策略铺平道路。
