Reducing effects of recombinant human endostatin combined with paclitaxel under different delivery order on expressions of serum VEGF and HIF-1α in lung cancer xenografts in mice

Objective: To study the effects of recombinant human endostatin (rh-endostatin) combined with paclitaxel (PTX) under different delivery order on the expression levels of serum vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) in lung cancer xenografts in mice, and to investigate the optimal delivery order of rh-endostatin combined with PTX.Methods: Subcutaneous Lewis lung cancer xenograft model of C57/BL mice was established, then the mice were randomly divided into control group (intraperitoneal injection with 0.9% NaCl, d1-14), PTX group (intraperitoneal injection with PTX, d1), rh-endostatin group (intraperitoneal injection with rh-endostatin, d1-14), combination group 1 [intraperitoneal injection with rh-endostatin (d1-14) and PTX (d1)], combination group 2 [intraperitoneal injection with rh-endostatin (d1-14) and PTX (d4)], and combination group 3 [intraperitoneal injection with rh-endostatin (d1-14) and PTX (d7)]. After drug administration, the volume of xenograft tumor in different groups was measured dynamically, the microvascular density (MVD) and the expression level of α-smooth muscle actin (α-SMA) in xenograft tumor tissues were detected by immunohistochemistry, the serum VEGF and HIF-1α levels were detected by enzyme-linked immunosorbent assay (ELISA), as well as the concentration of PTX in xenograft tumor tissues was detected by high-performance liquid chromatography (HPLC).Results: Since the second day of drug administration, the serum VEGF levels in rh-endostatin group and three combination groups were significantly lower than that in the control group (all P < 0.05). Since the fifth day of drug administration, HIF-1α levels in rh-endostatin group and three combination groups were also decreased significantly (all P < 0.05). On the fifth and eighth days of drug administration, MVDs in rh-endostatin group and 3 combination groups were lower than that in the control group (all P < 0.05), while the expression level of α-SMA was significantly increased (all P < 0.05). As compared with the other two combination groups, the most significant differences in MVD and expressions of VEGF, HIF-1α and α-SMA were seen between combination group 2 and the control group (all P < 0.05). Furthermore, the concentration of PTX in xenograft tumor tissues in combination group 2 was significantly higher than those in the other two combination groups (both P < 0.05), and the size of xenograft tumor was significantly smaller than those of the other combination groups (both P < 0.05).Conclusion: The levels of serum HIF-1α and VEGF may be promising indicators to monitor the normalization of tumor microvessels. In the initial stage of decline of VEGF level, the combined use of rh-endostatin and PTX can increase the concentration of PTX in tumor tissues, therefore improve the antitumor efficacy of PTX. DOI:10.3781/j.issn.1000-7431.2016.11.914