检索历史 清除

目的 探讨新型肿瘤导向肽TMTP1与抗菌肽D(KLAKLAK)2偶联后对胃癌、前列腺癌生长与转移的抑制效应.方法 建立人前列腺癌裸鼠皮下移植瘤模型和胃癌裸鼠原位移植瘤模型,分别腹腔注射50 μmol/L磷酸盐缓冲液(对照组)、50 μmol/L TMTP1(TMTP1组)和50 μmoL/LTMTP1-GG-D(KLAKLAK)2[TMTP1-GG-D(KLAKLAK)2组],验证新型融合多肽TMTP1-GG-D(KLAKLAK)2对肿瘤组织的亲和能力,测量瘤体大小,行形态学观察,采用原位细胞凋亡法检测肿瘤组织的凋亡并绘制生存曲线.结果 在前列腺癌皮下移植瘤中,对照组、TMTP1组和TMTP1-GG-D(KLAKLAK)2组裸鼠的中位生存时间分别为50、55和70 d(P ＜0.05),肿瘤体积分别为(2.5±0.3)cm3、(1.8±0.2)cm3和(0.3 ±0.1)cm3(P ＜0.01).在胃癌皮下移植瘤中,对照组、TMTP1组和TMTP1-GG-D (KLAKLAK)2组裸鼠的中位生存时间分别为25、30和45 d(P ＜0.05),肿瘤体积分别为(3.8±0.4)cm3、(3.2 ±0.2)cm3和(0.4±0.1)cm3(p＜0.01).在胃癌原位肿瘤中,对照组和TMTP1组裸鼠的胃组织可见巨大的原位肿瘤,而TMTP1-GG-D(KLAKLAK)2组原位肿瘤体积明显缩小.对照组和TMTP1组裸鼠的肝脏、脾脏和腹壁均可见白色转移灶,TMTP1-GG-D(KLAKLAK)2组裸鼠无肉眼可见转移灶.对照组、TMTP1组和TMTP1-GG-D(KLAKLAK)2组细胞的凋亡率分别为(31.9±1.5)％、(37.2±2.3)％和(69.7±2.1)％(P＜0.01).结论 新型肿瘤导向肽TMTP1与抗菌肽融合后可有效抑制肿瘤的生长与转移,有望成为一种新型的抗肿瘤药物.

Objective Due to their lower risk for induction of resistance,antimicrobial peptides with selective anticancer effect could be developed into a new generation of anticancer drugs.We conjugated an antimicrobial peptide with tumor-targeting peptides (TMTP1) to explore whether it has inhibiting effect on the progression and metastasis of transplanted prostate cancer and gastric cancer in nude mice.Methods Subcutaneously transplanted human prostate cancer and orthotopically transplanted human gastric cancer in nude mice were prepared.50 μmol/L PBS (control group),50 μmol/L TMTP1 (TMTP1 group) or 50 μmol/L TMTP1-GG-D (KLAKLAK) 2 (treatment group) were injected i.p.to the three groups of nude mice,respectively.The binding ability of the novel fusion polypeptide TMTP1-GG-D (KLAKLAK) 2 to the tumors and its antitumor effect were assessed by measurement of tumor volume,histopathological examination of the tumor tissues,testing apoptosis index of tumor cells with TUNEL staining,and survival curve plotting of the mice.Results The median survival time of subcutaneous prostate cancer-bearing mice was 50 days in the control group,55 days in the TMTP1 group,and 70 days in the TMTP1-GG-D (KLAKLAK)2 group (P ＜0.05).The median survival time of the subcutaneous gastric cancer-beating mice was 25 days in the control group,30 days in the TMTP1 group,and 45 days in the TMTP1-GG-D (KLAKLAK)2 group (P ＜0.01).The tumor volume in the subcutaneous prostate cancer-bearing mice was (2.5 ± 0.3) cm3 in the control group,(1.8 ±0.2) cm3 in the TMTP1 group,and (0.3 ± 0.1) cm3 in the TMTP1-GG-D (KLAKLAK)2 group (P ＜ 0.01).The tumor volume of the subcutaneous gastric cancer-bearing mice was (3.8 ± 0.4) cm3 in the control group,(3.2 ± 0.2) cm3 in the TMTP1 group,and (0.4 ± 0.1) cm3 in the TMTP1-GG-D (KLAKLAK)2 group (P ＜ 0.01).Large tumors were observed in the stomach of the orthotopic gastric cancer-bearing mice of the control and TMTP1 groups.The tumor volume of the TMTP1-GG-D (KLAKLAK)2 group was obviously reduced.White metastases in the liver,spleen and abdominal wall were observed in the control and TMTP1 groups (P ＜ 0.01).TUNEL staining revealed that the apoptosis index of the control group was (31.9 ± 1.5) ％,TMTP1 group (37.2 ± 2.3) ％ and TMTP1-GG-D (KLAKLAK) 2 group (69.7 ±2.1) ％ (P ＜ 0.01).Conclusions The results of our study demonstrate that the novel fusion peptide of antimicriobial peptide conjugated with TMTP1 can effectively inhibit tumor progression and metastasis,therefore,is promising to be a novel effective anticancer drug.