Sharma Anup, Vatapalli Rajita, Abdelfatah Eihab, Wyatt McMahon K, Kerner Zachary, A Guzzetta Angela, Singh Jasvinder, Zahnow Cynthia, B Baylin Stephen, Yerram Sashidhar, Hu Yue, Azad Nilofer, Ahuja Nita
Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2017 Apr 26;12(4):e0176139. doi: 10.1371/journal.pone.0176139. eCollection 2017.
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. In the metastatic setting, the majority of patients respond to initial therapies but eventually develop resistance and progress. In this study, we test the hypothesis that priming with epigenetic therapy sensitizes CRC cell lines, which were previously resistant to subsequent chemotherapeutic agents. When multiple CRC cell lines are first exposed to 500 nM of the DNA demethylating agent, 5-aza-cytidine (AZA) in-vitro, and the cells then established as in-vivo xenografts in untreated NOD-SCID mice; there is an enhanced response to cytotoxic chemotherapy with agents commonly used in CRC treatment. For irinotecan (IRI), growth diminished by 16-62 fold as assessed, by both proliferation (IC50) and anchorage independent cell growth soft agar assays. Treatment of resistant HCT116 cell line along with in-vivo, for CRC line xenografts, AZA plus IRI again exhibits this synergistic response with significant improvement in survival and tumor regression in the mice. Genome-wide expression correlates changes in pathways for cell adhesion and DNA repair with the above responses. A Phase 1/2 clinical trial testing this concept is already underway testing the clinical efficacy of this concept in IRI resistant, metastatic CRC (NCT01896856).
结直肠癌（CRC）是美国癌症死亡的第二大主要原因。在转移性情况下，大多数患者对初始治疗有反应，但最终会产生耐药性并病情进展。在本研究中，我们检验了以下假设：用表观遗传疗法进行预处理可使先前对后续化疗药物耐药的CRC细胞系敏感化。当多个CRC细胞系首先在体外暴露于500 nM的DNA去甲基化剂5-氮杂胞苷（AZA），然后将这些细胞在未治疗的NOD-SCID小鼠体内建立异种移植瘤时；对CRC治疗中常用的细胞毒性化疗药物有增强的反应。对于伊立替康（IRI），通过增殖（IC50）和非锚定依赖性细胞生长软琼脂试验评估，生长减少了16至62倍。对于耐药的HCT116细胞系，在体内对CRC细胞系异种移植瘤进行治疗时，AZA加IRI再次表现出这种协同反应，小鼠的生存期和肿瘤消退有显著改善。全基因组表达将细胞黏附和DNA修复途径的变化与上述反应相关联。一项检验这一概念的1/2期临床试验已经在进行，测试这一概念在IRI耐药的转移性CRC中的临床疗效（NCT01896856）。
