二氟甲基鸟氨酸和3，3'-二吲哚基甲烷协同抑制食管癌增殖的机制研究

Esophageal squamous cell carcinoma（ESCC）is mostly found in the middle and late stage. The five-year survival rate of ESCC is 15-20% even with surgery, radiotherapy and chemotherapy. Recurrence and metastasis are the main reasons for the low five-year survival rate of ESCC. Investigating the molecular mechanism of esophageal cancer recurrence and discovering low toxic compounds or compounds combination which can prevent recurrence of ESCC have both important scientific significance and clinical value. Our previous studies have found that difluoromethylornithine (DMFO) and 3,3'-diindolylmethane(DIM) have synergistic anti-ESCC effect in vitro and in vivo with no obvious side effects. These results imply that the combination of these two compounds have potential applications in esophageal cancer recurrence chemoprevention. However, the molecular mechanism of synergistic anti-ESCC recurrence is not clear. We will adopt multidimensional omics, molecular experiment, animal experiment and clinical research to analysis the mechanism of synergistic inhibitory effect by DFMO and DIM, further clarify the molecular mechanism of esophageal cancer recurrence. This research will lay a foundation for the development of new esophageal cancer relapse prevention drugs.

食管鳞癌大多发现于中晚期，以手术、放疗和化疗治疗为主，其五年生存率约15-20%。食管鳞癌的复发是导致患者五年生存率低的主要原因之一。研究食管癌复发的分子机制，开展食管癌复发的化学预防研究具有重要的科学意义和临床价值。我们前期研究发现二氟甲基鸟氨酸（difluoromethylornithine DFMO）和3，3'-二吲哚基甲烷（3,3'-diindolylmethane DIM）在细胞和动物水平具有协同抑制食管癌增殖的作用，毒性研究显示没有显著的毒副作用，提示该化合物组合具有抑制食管癌复发的应用前景。但其协同抗食管癌增殖的机制并不清楚。我们将采用多维谱学技术,分析两种化合物的作用机制，并采用分子生物学技术，结合动物实验探索两种化合物协同作用的机制，并进一步阐明食管癌复发的分子机制，为开发新的食管癌复发预防药物奠定基础。

食管癌大多发现于中晚期，以手术、放疗和化疗治疗为主，其五年生存率约15-20%。研究食管癌发生发展的分子机制，开展食管癌的化学预防研究具有重要的科学意义和临床价值。研究发现二氟甲基鸟氨酸（difluoromethylornithine DFMO）和3，3'-二吲哚基甲烷（3,3'-diindolylmethane DIM）在细胞水平具有协同抑制食管癌增殖的作用；将临床食管癌肿瘤组织接种免疫缺陷小鼠，建立患者源性异种移植(PDX)模型，DIM+DFMO联合应用可显著抑制3例PDX模型肿瘤的生长且没有显著的毒副作用；接着采用蛋白质组学、生物信息学和分子生物学实验阐明其协同抗食管癌增殖的机制，证明DFMO和DIM联用通过抑制DNA复制和细胞周期调控信号通路抑制食管癌细胞增殖和肿瘤生长，涉及的差异表达基因MCM2、MCM3、MCM5、MCM6、MCM7、CDK1、LIG1均呈反向下调；利用2例食管癌病例的临床试验评价DIM+DFMO抗食管癌的疗效，结果良好，包括吞咽困难减轻，血液肿瘤标志物(CA19-9, CA15-3和AFP)降低，至少一个月无进展生存期无严重毒性。因此，DIM+DFMO是一种通过抑制DNA复制和细胞周期活性来治疗食管癌的有前景的潜在治疗组合。