Abstract
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(-1) 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.