Low- dose Apatinib promotes vascular normalization and hypoxia reduction and sensitizes radiotherapy in lung cancer.

Abstract

Abnormal vascular network of tumor can create a hypoxic microenvironment, and reduce radiotherapy sensitivity. Normalization of tumor vasculature can be a new therapeutic strategy for sensitizing radiotherapy. This study aimed to explore the effect of apatinib on vascular normalization, as well as the syngeneic effect with radiotherapy on lung cancer. Lewis lung carcinoma (LLC) xenograft-bearing female C57BL/6 mice were treated with different doses of apatinib (30, 60, and 120 mg/kg per day) and/or radiation therapy (8Gy/1F) and then sacrificed to harvest tumor tissue for immunohistochemical test. Further 18 F-FMISO micro- PET in vivo explored the degree of hypoxia. Immunohistochemistry of CD31 and alpha-smooth muscle actin (α-SMA) proved that low-dose apatinib can normalize vasculature in tumor, especially on Day 10. Tissue staining of hypoxyprobe-1 and 18 F-FMISO micro- PET in vivo showed that 60 mg/kg/day of apatinib significantly alleviates hypoxia. Moreover, this study further proved that low-dose apatinib (60 mg/kg/day) can enhance the radio-response of LLC xenograft mice. Our data suggested that low- dose apatinib can successfully induce a vascular normalization window and function as a radio- sensitizer in the lung cancer xenografts model.