T肽增强顺铂肿瘤杀伤作用的研究及机制探讨

T-peptide Enhances the Killing Effects of Cisplatinum on Lung Cancer

背景与目的 T肽是Tuftsin的衍生物,其基本功能是刺激巨噬细胞,提高巨噬细胞吞噬及分泌能力,通过增强效应细胞的细胞杀伤作用而被广泛用于多种恶性肿瘤术后抗肿瘤治疗。本研究旨在探讨T肽与化疗药物顺铂的联合能否提高铂类药物的抗肿瘤疗效及机制。方法应用酶联免疫吸附剂测定(enzyme-linked immunosorbent assay,ELISA)T肽和/或顺铂处理人巨噬细胞株U937后肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)和干扰素-γ(interferon-γ,IFN-γ)分泌水平的变化;应用裸鼠荷瘤动物模型,分析T肽和/或顺铂处理小鼠肿瘤变化情况以及小鼠用药期间外周血中巨噬细胞变化情况。结果 (1)应用ELISA检测发现在T肽组和T肽联合顺铂组中,U937细胞培养液中TNF-α水平明显高于对照组和顺铂组;T肽联合顺铂组中IFN-γ水平明显高于对照组、顺铂组和T肽组;(2)在小鼠荷瘤模型中,T肽联合顺铂组的肿瘤体积明显小于对照组、顺铂组和T肽组,并且小鼠没有明显的体重下降;(3)在小鼠外周血的检测分析中发现,T肽联合顺铂组中活化巨噬细胞数呈现增长趋势。免疫组化分析各组中肿瘤组织Ki67显示T肽联合顺铂组抑制肿瘤细胞增殖。结论 T肽能够促进巨噬细胞增殖和促进其分泌肿瘤细胞杀伤因子(TNF-α、IFN-γ);在体内动物模型中,T肽能够提高化疗药物如顺铂的疗效,使联合组具有更强的肿瘤抑制作用,同时能够减轻化疗药物的毒副作用。

Background and objective T peptide is extensively used in anti-tumor treatment. The aims of this study were to investigate whether T peptide enhances cisplatinum efficiency while reducing its side effects and to identify its effective mechanisms. Methods（1） Human macrophage U937 cells were treated with T peptide and/or cisplatinum. The levels of tumor necrosis factor-α（TNF-α） and interferon-γ（IFN-γ） of each group were detected by enzyme-linked immunosorbent assay（ELISA）;（2） Xenograft mouse models of human lung cancer were treated with T peptide and/or cisplatinum once every five days for three times. Tumor volumes were measured during treatment;（3） The percentages of macrophages in the peripheral blood of the xenograft mouse models were measured by FACS. Results（1） Compared with other groups, the level of TNF-α was significantly higher in the human macrophage U937 cells that were treated with T peptide combined with cisplatinum. The levels of IFN-γ were significantly higher in human macrophage U937 cells that were treated with T peptide alone or T peptide combined with cisplatinum;（2） In the xenograft mouse models, T peptide combined with cisplatinum treatment significantly inhibited tumor growth without weight loss compared with the other groups;（3） The percentages of macrophages in the peripheral blood were significantly higher in the xenograft mouse models that were treated with T peptide combined with cisplatinum compared with in the other groups. Conclusion T peptide promotes macrophage proliferation and increases tumor cellkilling factors（TNF-α, IFN-γ） in vitro. Moreover, T peptide enhances the efficacy of cisplatin and reduces its toxicity in vivo.