血红素氧合酶-1抑制剂锌原卟啉Ⅸ对裸鼠胃癌腹膜转移的抑制作用

Inhibitory Effect of Heme Oxygenase-1 Inhibitor Zinc Protoporphyrin Ⅸ on Peritoneal Metastasis of Gastric Cancer in Nude Mice

背景:前期研究证实血红素氧合酶-1(HO-1)是与人胃癌腹膜高转移细胞株GC9811-P具有亲和力的多肽序列PⅢ的天然配体,两者结合可能抑制胃癌的腹膜转移。目的:探讨HO-1抑制剂锌原卟啉Ⅸ(ZnPPⅨ)对裸鼠胃癌腹膜转移的抑制作用及其可能机制。方法:48只BALB/c裸鼠经GC9811-P胃癌组织块胃壁原位种植建立胃癌腹膜转移模型后随机分为3组,于术后1周起分别予ZnPPⅨ、钴原卟啉(CoPPⅨ,HO-1诱导剂)或铜原卟啉(CuPPⅨ,阴性对照)40μg隔日腹腔注射。术后第23d每组取6只裸鼠处死,测定腹膜转移结节数量、体积、质量和腹水量。其余裸鼠用于存活率实验,于出现明显生命衰竭体征时处死,以免疫组化方法检测腹膜转移瘤中CD31标记的肿瘤微血管密度(MVD),以酶联免疫吸附测定(ELISA)检测血管内皮生长因子(VEGF)含量。结果:与CoPPⅨ组和CuPPⅨ组相比,ZnPPⅨ组荷瘤裸鼠腹膜转移结节数量、体积、质量和腹水量均显著减低(P<0.05),生存期延长(P<0.01),腹膜转移瘤MVD和VEGF含量降低(P<0.05)。结论:HO-1参与了胃癌腹膜转移的调控,其抑制剂ZnPPⅨ可能通过抑制肿瘤血管发生而抑制裸鼠胃癌腹膜转移。

Background： Our previous study demonstrated that heine oxygenase-1 （HO-1） is the natural ligand of peptide sequence Pro, which has a specific binding capacity to human gastric cancer cell line GC9811-P, a gastric cancer cell line with high potential of peritoneal metastasis, and the two combination may have some effects on the peritoneal metastasis of gastric cancer. Aims： To appraise the inhibitory effect of HO-1 inhibitor zinc protoporphyrin Ⅸ （ZnPPⅨ） on peritoneal metastasis of gastric cancer in nude mice and its possible mechanism. Methods： Peritoneal metastasis model of gastric cancer was constructed by implantation of tumor mass derived from GC9811-P cells to the gastric wall of BALB/c nude mice. One week after implantation, 48 nude mice were randomly divided into 3 groups and injected intraperitoneally with ZnPPⅨ, CoPPⅨ （HO-1 inductor） or CuPPIX （negative control） 40 μg, respectively every other day. Six nude mice in each group were sacrificed 23 days after implantation, and the number, volume, weight of peritoneal metastatic nodules and the volume of ascites were measured. The rest of the mice in each group were used for evaluating the survival rate. The tumor-bearing nude mice were sacrificed when failures of vital signs occurred. CD31 labeled tumor microvessel density （MVD） in peritoneal metastatic nodules was measured by immunohistochemistry, and the content of vascular endothelial growth factor （VEGF） was determined by enzyme-linked immunosorbent assay （ELISA）. Results： ZnPP IX administration decreased remarkably the number, volume, weight of peritoneal metastatic nodules and the volume of aseites in tumor-bearing nude mice as compared with CoPPⅨ and CuPPIX treated groups （P〈0.05）. The MVD value and VEGF content in peritoneal metastatic nodules in ZnPPⅨ group also decreased significantly （P〈0.05）, while the survival rate was higher than that in the other two groups （P〈0.01）. Conclusions： HO-1 is involved in the modulating of peritoneal metastasis of gastric cancer. HO-1 inhibitor ZnPPⅨ may inhibit peritoneal metastasis of gastric cancer in nude mice via tumor angiogenesis suppression.