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

Abstract

Background and Purpose 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. Materials and Methods 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 (8 Gy/1F) and then sacrificed to harvest tumor tissue for immunohistochemical test. Further 18F‐FMISO micro‐ PET in vivo explored the degree of hypoxia. Results 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 18F‐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. Conclusion 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.

Camptothecin enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma

“…Analyses were performed using GraphPad Prism software (version 8; GraphPad Software, Inc.). 32 mice with similar tumor size were randomly divided into 4 groups (group A) (saline), CPT group (group B) (3 mg/kg CPT), apatinib + PD-1 inhibitor group (group C) (60 mg/kg apatinib + 10 mg/kg PD-1 inhibitor), and apatinib + PD-1 inhibitor combined with CPT group (group D) (60 mg/kg apatinib + 10 mg/kg PD-1 inhibitor + 3 mg/kg CPT) 36 – 38 . CPT was injected intraperitoneally every 3 days, and apatinib was administered daily by gavage, while PD-1 inhibitor was injected intraperitoneally every 3 days.…”

The potential of vascular normalization for sensitization to radiotherapy

“…In addition, TKIs have been shown to contribute to vascular normalization and synergize with radiotherapy in situ models of glioblastoma, head and neck cancer, lung cancer, melanoma and colon cancer [ 8 ]. It has been shown that the low-dose tyrosine kinase inhibitor Apatinib promotes vascular normalization and hypoxia reduction in lung cancer and sensitizes radiation therapy [ 32 ]. The anti-vascular efficacy of different drugs also varies, such as in the treatment of hepatocellular carcinoma (HCC), the anti-angiogenic drugs lenvatinib and sorafenib are multi-targeted TKIs, and experimental comparisons have revealed that lenvatinib induces vascular normalization of hepatocellular carcinoma tumors earlier and more efficiently compared with sorafenib [ 33 ].…”

Recent advances progress of targeted drugs combined with radiotherapy for advanced non-small cell lung cancer: a review

“…Apatinib is a Tyrosine kinase inhibitor that can selectively inhibit VEGFR-2. A study found that low-dose Apatinib (60mg/kg) can promote the normalization of tumor blood vessels and significantly relieve intratumoral hypoxia, thereby enhancing the radiosensitivity of Lewis lung cancer xenograft mice ( 64 ). In addition, Apatinib can also enhance radiosensitivity by inhibiting DNA double strand break repair caused by radiation and downregulating AKT and ERK signaling in NSCLC cells ( 65 ).…”