Experimental study of the vascular normalization window for tumors treated with apatinib and the efficacy of sequential chemotherapy with apatinib in lung cancer-bearing mice and patients.

Mingtao Liu,Xiuxiu Wang,Peng Jiang,Lijun Jing,Yu Li,Hui Li

doi:10.1002/cam4.2923

Abstract

In the tumor vascular system, the vascular structure is disordered, the morphology is abnormal, and the structure of the blood vessel walls is incomplete, leading to leakage of the blood vessel wall, elevated interstitial fluid pressure, and elevated blood flow resistance. These alterations lead to local microenvironmental changes, which mainly manifest as a lack of oxygen and acidosis, further affecting the efficacy of chemotherapy drugs. Antiangiogenic drugs can normalize the abnormalities caused by tumor angiogenesis, thereby transferring oxygen and drugs to tumor cells more efficiently through normalized blood vessels and enhancing the efficacy of chemotherapy drugs. Apatinib is a specific VEGFR‐2 inhibitor that blocks the transmission of the VEGF/VEGFR‐2 signaling pathway. In this study, we constructed a nude mouse xenograft model of lung cancer and administered apatinib at different doses and times to detect the normalization of reactive blood vessels through VEGF, α‐SMA, college‐IV, HIF‐1α, and MMP. The ultrastructure of tumor blood vessels was observed by electron microscopy, and the dose and timing of apatinib‐induced normalization of lung cancer in nude mice were confirmed. Then, we observed the inhibitory effect of apatinib combined with pemetrexed on transplanted tumors of lung cancer cells in nude mice at different time points and observed whether combination pemetrexed chemotherapy showed more significant effects in the time window of vascular normalization induced by apatinib. The inhibition of the growth of transplanted tumors was examined. Then 20 patients with advanced non–small cell lung cancer were enrolled, and apatinib sequential chemotherapy drugs were applied as a third‐line chemotherapy regimen to observe its clinical efficacy.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide, with approximately 1.2 million deaths annually.[1]
In recent years, many preclinical and clinical studies have shown that the short-term application of antiangiogenic drugs can have therapeutic effects, whereas long-term use can lead to vascular necrosis in the central area of the tumor, which results in hypoxia and an acidic microenvironment and decreases the sensitivity of solid tumor cells to chemotherapy.[10,11]
Since the first antiangiogenic drug bevacizumab was used clinically, antiangiogenic therapy has become an important means of treating tumors.[32]

Summary

| INTRODUCTION

Lung cancer is the leading cause of cancer-related death worldwide, with approximately 1.2 million deaths annually.[1]. Folkman proposed that tumor growth depends on the formation of tumor blood vessels and proposed that antiangiogenic strategies will be important for the treatment of tumors.[8] The traditional view was that antiangiogenic drugs can reduce the formation of tumor blood vessels, cause tumor necrosis, and "starve" tumors.[9] in recent years, many preclinical and clinical studies have shown that the short-term application of antiangiogenic drugs can have therapeutic effects, whereas long-term use can lead to vascular necrosis in the central area of the tumor, which results in hypoxia and an acidic microenvironment and decreases the sensitivity of solid tumor cells to chemotherapy.[10,11] In response to these clinical problems, Jain proposed the tumor vascular normalization theory, which suggests that tumor angiogenesis is a complex process in which the imbalance between proangiogenic factors and angiogenesis inhibitors is a key factor.[12,13] In tumor tissues, a variety of transcription factors, such as hypoxia-inducible factor (HIF), can trigger an increase in proangiogenic factors.[14] The most important proangiogenic factor is vascular endothelial growth factor (VEGF), which leads to an increase in neovascularization.[15] The neovascular morphology is distorted, swollen, and cystic. We examined whether combination chemotherapy in the normalization time window of blood vessels can effectively improve the therapeutic effect

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION