重组内皮抑素对肿瘤血管结构和乏氧改善作用的实验观察

目的 观察重组内皮抑素作用下小鼠Lewis肺癌移植瘤在血管退化前是否存在血管正常化时间窗,在此时间窗内肿瘤乏氧是否改善.方法 激光共聚焦显微镜动态观察重组内皮抑素作用下肿瘤血管的形态学变化,免疫组化染色检测不同时间段肿瘤乏氧细胞比例,观测肿瘤生长情况并绘制肿瘤生长曲线.结果 重组内皮抑素处理后肿瘤血管密度逐渐下降,连续治疗9 d较对照组下降最为明显.重组内皮抑素处理后周细胞覆盖内皮细胞比例逐渐增加,第3天开始明显增加,第5天增加最明显,第7天后明显下降.对照组基底膜与内皮细胞连接松散,厚度增加,而重组内皮抑素处理后,基底膜与内皮细胞连接紧密,厚度下降.在重组内皮抑素处理后第5天肿瘤乏氧细胞比例下降最明显,连续5 d用重组内皮抑素,肿瘤生长未见加快.结论 重组内皮抑素能使肿瘤血管正常化,其时间窗为治疗后3～7 d;此时肿瘤氧供明显改善,为临床联合应用放疗和重组内皮抑素提供了实验依据.

Abstract：

Objective To investigate whether recombinant human endostatin can create a time window of vascular normalization prior to vascular pruning to alleviate hypoxia in Lewis lung carcinoma in mice. Methods Kinetic changes in morphology of tumor vasculature in response to recombinant human endostatin were detected under a confocal microscope with immunofluorescent staining in Lewis lung carcinomas in mice. The hypoxic cell fraction of different time was assessed with immunohistochemical staining . Effects on tumor growth were monitored as indicated in the growth curve of tumors . Results Compared with the control group vascularity of the tumors was reduced over time by recombinant human endostatin treatment and significantly regressed for 9 days. During the treatment, pericyte coverage increased at day 3, increased markedly at day 5, and fell again at day 7. The vascular basement membrane was thin and closely associated with endothelial cells after recombinant human endostatin treatment, but appeared thickened, loosely associated with endothelial cells in control tumors. The decrease in hypoxic cell fraction at day 5 after treatment was also found. Tumor growth was not accelerated 5 days after recombinant human endostatin treatment. Conclusions Recombinant human endostatin can normalize tumor vasculature within day 3 to 7, leading to improved tumor oxygenation. The results provide important experimental basis for combining recombinant human endostatin with radiation therapy in human tumors.

Recombinant human endostatin improves tumor vasculature and alleviates hypoxia in Lewis lung carcinoma

Objective To investigate whether recombinant human endostatin can create a time window of vascular normalization prior to vascular pruning to alleviate hypoxia in Lewis lung carcinoma in mice. Methods Kinetic changes in morphology of tumor vasculature in response to recombinant human endostatin were detected under a confocal microscope with immunofluorescent staining in Lewis lung carcinomas in mice. The hypoxic cell fraction of different time was assessed with immunohistochemical staining . Effects on tumor growth were monitored as indicated in the growth curve of tumors . Results Compared with the control group vascularity of the tumors was reduced over time by recombinant human endostatin treatment and significantly regressed for 9 days. During the treatment, pericyte coverage increased at day 3, increased markedly at day 5, and fell again at day 7. The vascular basement membrane was thin and closely associated with endothelial cells after recombinant human endostatin treatment, but appeared thickened, loosely associated with endothelial cells in control tumors. The decrease in hypoxic cell fraction at day 5 after treatment was also found. Tumor growth was not accelerated 5 days after recombinant human endostatin treatment. Conclusions Recombinant human endostatin can normalize tumor vasculature within day 3 to 7, leading to improved tumor oxygenation. The results provide important experimental basis for combining recombinant human endostatin with radiation therapy in human tumors.