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腺病毒介导的 TFF2-CTP-Flag 肽治疗结直肠癌的潜力。

Therapeutic potential of adenovirus-mediated TFF2-CTP-Flag peptide for treatment of colorectal cancer.

机构信息

Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.

Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461-1602, USA.

出版信息

Cancer Gene Ther. 2019 Feb;26(1-2):48-57. doi: 10.1038/s41417-018-0036-z. Epub 2018 Jul 25.

DOI:10.1038/s41417-018-0036-z
PMID:30042499
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6760534/
Abstract

TFF2 is a small, secreted protein with anti-inflammatory properties. We previously have shown that TFF2 gene delivery via adenovirus (Ad-Tff2) suppresses colon tumor growth in colitis associated cancer. Therefore, systemic administration of TFF2 peptide could potentially provide a similar benefit. Because TFF2 shows a poor pharmacokinetic, we sought to modify the TFF2 peptide in a manner that would lower its clearance rate but retain bioactivity. Given the absence of a sequence-based prediction of TFF2 functionality, we chose to genetically fuse the C-terminus of TFF2 with the carboxyl-terminal peptide of human chorionic gonadotropin β subunit, and inserted into adenoviral vector that expresses Flag. The resulting Ad-Tff2-CTP-Flag construct translates into a TFF2 fused with two CTP and three Flag motifs. Administered Ad-Tff2-CTP-Flag decreased tumorigenesis and suppressed the expansion of myeloid cells in vivo. The fusion peptide TFF2-CTP-Flag delivered by adenovirus Ad-Tff2-CTP-Flag as well purified recombinant fusion TFF2-CTP-Flag was retained in the blood longer compared with wild-type TFF2 delivered by Ad-Tff2 or recombinant TFF2. Consistently, purified recombinant fusion TFF2-CTP-Flag suppressed expansion of myeloid cells by down-regulating cyclin D1 mRNA in vitro. Here, we demonstrate for the very first time the retained bioactivity and possible pharmacokinetic advantages of TFF2 with a modified C-terminus.

摘要

TFF2 是一种具有抗炎特性的小分泌蛋白。我们之前的研究表明，通过腺病毒（Ad-Tff2）传递 TFF2 基因可抑制结肠炎相关癌症中的结肠肿瘤生长。因此，TFF2 肽的系统给药可能具有类似的益处。由于 TFF2 的药代动力学特性较差，我们试图通过修饰 TFF2 肽的方式降低其清除率，但保留其生物活性。由于缺乏 TFF2 功能的基于序列的预测，我们选择将 TFF2 的 C 末端与人类绒毛膜促性腺激素 β 亚基的羧基末端肽基因融合，并插入表达 Flag 的腺病毒载体中。由此产生的 Ad-Tff2-CTP-Flag 构建体翻译为与两个 CTP 和三个 Flag 基序融合的 TFF2。给予 Ad-Tff2-CTP-Flag 可减少肿瘤发生并抑制体内髓样细胞的扩张。与通过 Ad-Tff2 或重组 TFF2 传递的野生型 TFF2 相比，腺病毒 Ad-Tff2-CTP-Flag 传递的融合肽 TFF2-CTP-Flag 以及纯化的重组融合 TFF2-CTP-Flag 在血液中保留时间更长。一致地，纯化的重组融合 TFF2-CTP-Flag 通过下调体外髓样细胞的 cyclin D1 mRNA 来抑制其扩张。在这里，我们首次证明了具有修饰的 C 末端的 TFF2 的保留的生物活性和可能的药代动力学优势。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffe7/6760534/2c61b643d2b8/41417_2018_36_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffe7/6760534/fb609af5a6f9/41417_2018_36_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffe7/6760534/6f64e6e14bfe/41417_2018_36_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffe7/6760534/719a523e4655/41417_2018_36_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffe7/6760534/2c61b643d2b8/41417_2018_36_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffe7/6760534/fb609af5a6f9/41417_2018_36_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffe7/6760534/6f64e6e14bfe/41417_2018_36_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffe7/6760534/719a523e4655/41417_2018_36_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffe7/6760534/2c61b643d2b8/41417_2018_36_Fig4_HTML.jpg

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