Low-dose endostatin normalizes the structure and function of tumor vasculature and improves the delivery and anti-tumor efficacy of cytotoxic drugs in a lung cancer xenograft murine model.

Abstract

To some extent endostatin normalizes tumor vasculature. However, the optimum time window and optimum drug dose for tumor vascular normalization need to be explored. Here we investigate the effect of low-dose endostatin on the structure and function of tumor vasculature and the delivery and anti-tumor efficacy of cytotoxic drugs. A lung cancer xenograft murine model was treated with low-dose endostatin for 10 days. The structure and function of the tumor vasculature were evaluated using various techniques. Paclitaxel was added in different schedules. Endostatin caused a significant reduction in microvessel density. Tumor vascular walls after endostatin treatment were better structured. Tumor blood perfusion was increased on day six after endostatin administration. On days three, six, and 10, Evans blue extravasation into the parenchyma of tumors was decreased. On days three and six, endostatin-treated mice had greater paclitaxel delivery. The time window of vascular normalization was approximately three to six days. On days one to three, and days four to six, combined therapy with paclitaxel significantly inhibited tumor growth. Low-dose endostatin aids normalization of tumor vasculature. This resulted in improved delivery of cytotoxic drugs to the tumor, which closely correlates with synergistic efficacy when combined with paclitaxel during the normalization window.