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目的探讨特异性溶瘤重组腺病毒KH901的抗肿瘤效果及表达人粒细胞-巨噬细胞集落刺激因子(GM-CSF)的水平。方法裸鼠皮下接种人肝细胞癌(Hep3B)细胞或人前列腺癌(LNcap)细胞,建立相应裸鼠移植瘤模型。KH901瘤体内注射给药,同时设阳性对照〔5-氟尿嘧啶(5-FU)或顺铂尾静脉注射〕和阴性对照〔生理盐水(NS)尾静脉注射〕,以相对肿瘤增殖率(T/C%)和抑瘤率观察抗肿瘤效果;建立人肺癌(A549)裸鼠移植瘤模型,瘤体内注射KH901,分别于首次给药后第2、7、11、14、18、36d各取3只动物眶静脉采血并摘取肿瘤,以ELISA法测定血清和肿瘤匀浆液上清中GM-CSF含量。结果1在Hep3B裸鼠抑瘤实验中,KH901高剂量(3×1010VP/鼠)组的T/C%和抑瘤率分别为7.31%、93.61%,与KH901低剂量(3×108VP/鼠)组(40.27%、68.76%)和5-FU组(37.33%、61.49%)相比显示出较强的抑瘤效果(P<0.05)。2在LNcap裸鼠抑瘤实验中,KH901多次给药(3×1010VP/鼠×3)组的T/C%和抑瘤率分别为5.47%、95.29%,其抑瘤效果强于顺铂组(25.47%、71.93%),但与KH901单次给药(3×1010VP/鼠×1)组(12.94%、87.94%)相比差异无统计学意义。3在A549裸鼠移植瘤模型中,肿瘤和血清中的GM-CSF分别在第7d〔(47.72±9.21)ng/mg〕和第11d〔(92.45±18.64)ng/mL〕出现高峰,随后,GM-CSF表达量逐渐降低。结论KH901有明显的抗肿瘤作用,在体内肿瘤中表达高水平的GM-CSF,并渗入血管到循环系统,形成血液GM-CSF的高峰。
Objective To investigate the antitumor effect and the level of human granulocyte-macrophage colony-stimulating factor (GM-CSF) expression of specific oncolytic adenovirus KH901. Methods Nude mice were inoculated subcutaneously with human hepatocellular carcinoma (Hep3B) cells or human prostate cancer (LNcap) cells to establish a corresponding nude mouse xenograft model. KH901 was injected intratumorally and the positive control (5-fluorouracil or cisplatin tail vein) and the negative control (NS tail vein) were injected at the same time, and the relative tumor growth rate (T / C %) And tumor inhibition rate; To establish human lung cancer (A549) xenografted model in nude mice, KH901 was injected into the tumor in vivo, and three mice were sacrificed on the 2nd, 7th, 11th, 14th, 18th and 36th day after the first administration Animal orbital venous blood and tumor removal, serum and tumor homogenate supernatant by ELISA assay of GM-CSF content. Results 1 In the anti-tumor experiment of Hep3B nude mice, the T / C% and tumor inhibition rates of KH901 high dose (3 × 1010VP / mouse) group were 7.31% and 93.61% (40.27%, 68.76%) compared with 5-FU group (37.33%, 61.49%) showed a strong anti-tumor effect (P <0.05). (2) In tumor inhibition experiment of LNcap nude mice, the T / C% and tumor inhibition rate of KH901 administered multiple times (3 × 1010VP / mouse × 3) were 5.47% and 95.29% (25.47%, 71.93%), but no significant difference compared with KH901 single administration (3 × 1010VP / mouse × 1) group (12.94%, 87.94%). 3 In the A549 nude mice xenograft model, GM-CSF in tumor and serum peaked on the 7th day [(47.72 ± 9.21) ng / mg] and the 11th day [(92.45 ± 18.64) ng / mL] GM-CSF expression decreased gradually. Conclusion KH901 has a significant anti-tumor effect. It expresses high levels of GM-CSF in tumors in vivo and penetrates blood vessels into the circulatory system to form the peak of blood GM-CSF.