Key laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
Acta Pharmacol Sin. 2019 Apr;40(4):556-562. doi: 10.1038/s41401-018-0058-y. Epub 2018 Jul 5.
Tumor vascular normalization has been proposed as a therapeutic strategy for malignant neoplasms, which can also interpret the synergistic effect of anti-angiogenesis agents combined with chemotherapy. Apatinib (Apa), a highly selective VEGFR2 inhibitor, attracts much attentions due to its encouraging anticancer activity, especially in the clinical trials of combined treatment. In this study, we investigated whether Apa could promote vascular normalization in tumor in a certain time window. Mice bearing LoVo colon cancer xenograft were orally administrated Apa (150 mg kg per day) for 5, 7, 10, or 12 days. Apa significantly inhibited tumor growth and decreased the microvessel density. Using multi-photon microscopy and electron microscopy, we found that Apa improved tumor vessel morphology by pruning distorted vessel branches and decreased the gap between endothelial cells after a 7-day treatment. Furthermore, Apa decreased vessel leakage and increased pericyte coverage on vascular endothelial cells, suggesting that tumor vessels were more mature and integrated. The intratumoral distribution of adriamycin (ADR) in Apa group was improved from day 7 to 10 without change in plasma drug concentration. Tumor blood perfusion was also increased in this window, and the expression of hypoxia induced factor 1α was downregulated, suggesting the effect of Apa on alleviating tumor hypoxic micro-environment. In conclusion, Apa may improve the effective perfusion of tumor vessels and increase the intratumoral distribution of ADR in a certain time window via normalizing tumor vessels. This normalization window (7 to 10 days of treatment) may contribute to develop a regimen of combined medication in clinic use of Apa.
肿瘤血管正常化已被提出作为治疗恶性肿瘤的一种策略，这也可以解释抗血管生成药物与化疗联合使用的协同作用。阿帕替尼（Apa）是一种高选择性 VEGFR2 抑制剂，由于其令人鼓舞的抗癌活性，特别是在联合治疗的临床试验中，引起了广泛关注。在本研究中，我们研究了 Apa 是否可以在一定时间窗口内促进肿瘤中的血管正常化。携带 LoVo 结肠癌细胞异种移植的小鼠每天口服给予 Apa（150mg/kg）5、7、10 或 12 天。Apa 显著抑制肿瘤生长并降低微血管密度。通过多光子显微镜和电子显微镜，我们发现 Apa 在 7 天治疗后通过修剪扭曲的血管分支和减少内皮细胞之间的间隙改善肿瘤血管形态。此外，Apa 降低了血管通透性并增加了血管内皮细胞上的周细胞覆盖，表明肿瘤血管更加成熟和整合。在 Apa 组中，阿霉素（ADR）在肿瘤内的分布从第 7 天到第 10 天得到改善，而血浆药物浓度没有变化。在此窗口中，肿瘤血液灌注也增加，缺氧诱导因子 1α 的表达下调，表明 Apa 缓解肿瘤缺氧微环境的作用。总之，Apa 可能通过使肿瘤血管正常化，在一定时间窗口内改善肿瘤血管的有效灌注，并增加 ADR 在肿瘤内的分布。这种正常化窗口（治疗的 7 至 10 天）可能有助于开发 Apa 在临床联合用药方案。
