Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, 305 ZhongShan Eastern Road, Nanjing, 210002, People's Republic of China.
J Cancer Res Clin Oncol. 2010 Aug;136(8):1201-11. doi: 10.1007/s00432-010-0770-6. Epub 2010 Feb 4.
Normalization of the tumor vasculature and microenvironment by several angiogenesis inhibitors has been reported. Given that recombinant human endostatin (rh-endostatin) is also an endogenous angiogenesis inhibitor, a comprehensive evaluation of the effects of rh-endostatin on tumor vasculature and microenvironment and chemotherapy sensitivity would be favorable.
Multiple treatment schedules of the combination of rh-endostatin and paclitaxel were tested in Lewis lung carcinoma. Further, we monitored microvascular density, tumor hypoxic fraction, and collagen covered tumor vessels at three different time points following the treatment of rh-endostatin, as well as the transcription of angiogenesis related factors (vascular endothelial growth factor-A and thrombospondin-1) and vasculature markers (regulator of G-protein signaling 5 and platelet/endothelial cell adhesion molecule-1).
The anti-tumor efficacy of paclitaxel was significantly improved 7 days after the treatment of rh-endostatin. Tumor microvascular density was decreased by rh-endostatin, although it became even higher 7 days after termination of rh-endostatin. Non-necrotic hypoxic fraction was significantly reduced 7 days after treatment of rh-endostatin, accompanied with increased collagen covered tumor vessels and coverage of pericytes around endothelial cells. Rh-endostatin could transiently upregulate the transcription of thrombospondin-1 and modulate the imbalance between vascular endothelial growth factor-A and thrombospondin-1.
Rh-endostatin could normalize the tumor vasculature and microenvironment in Lewis lung carcinoma probably via modulation of the balance between vascular endothelial growth factor-A and thrombospondin-1. During the time of vascular normalization, paclitaxel treatment was found to have maximal effect on tumor growth delay.
已有报道称，多种血管生成抑制剂可使肿瘤血管和微环境正常化。鉴于重组人血管内皮抑制素（rh-endostatin）也是一种内源性血管生成抑制剂，因此全面评估 rh-endostatin 对肿瘤血管和微环境及化疗敏感性的影响将是有利的。
在 Lewis 肺癌中测试了 rh-endostatin 与紫杉醇联合的多种治疗方案。此外，我们在 rh-endostatin 治疗后三个不同时间点监测微血管密度、肿瘤缺氧分数和胶原覆盖的肿瘤血管，并检测血管生成相关因子（血管内皮生长因子 A 和血小板/内皮细胞黏附分子 1）和血管标志物（G 蛋白信号调节因子 5 和血小板/内皮细胞黏附分子 1）的转录。
rh-endostatin 治疗后 7 天，紫杉醇的抗肿瘤疗效显著提高。rh-endostatin 降低了肿瘤微血管密度，但在 rh-endostatin 治疗结束后 7 天，其密度甚至更高。rh-endostatin 治疗后 7 天，非坏死性缺氧分数显著降低，同时胶原覆盖的肿瘤血管增加，内皮细胞周围周细胞覆盖增加。rh-endostatin 可短暂上调血栓素-1 的转录，并调节血管内皮生长因子 A 与血栓素-1 之间的失衡。
rh-endostatin 可能通过调节血管内皮生长因子 A 与血栓素-1 之间的平衡来使 Lewis 肺癌中的肿瘤血管和微环境正常化。在血管正常化期间，发现紫杉醇治疗对肿瘤生长延迟具有最大的效果。
