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

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.

Giant Fungated Locally Advanced Breast Carcinoma Responded to Hypofractionated Radiotherapy Combined with Apatinib: A Case Report and Literature Review

“…However, this type of vascular normalization effect of apatinib varies from person to person. 23 In our patient, the application of apatinib (250mg daily for 34 days) before RT might play a role in normalizing tumor blood vessels, which contributed to enhance the RT efficacy to a certain extent.…”

Case Report: Antiangiogenic Therapy Plus Immune Checkpoint Inhibitors Combined With Intratumoral Cryoablation for Hepatocellular Carcinoma

“…Anti-angiogenic therapy can downregulate the expression of VEGF, inhibit tumor angiogenesis, and therefore improve the inhibitory effect of cryoablation on tumors ( 26 , 27 ). It is well known that in the tumor vascular system, the vascular structure is disordered, the morphology is abnormal, and the structure of vascular walls is incomplete, leading to leakage of the vascular wall, elevated interstitial fluid pressure, and elevated blood flow resistance ( 28 ). We therefore hypothesized that new blood vessels formed after cryoablation will also have these characteristics and therefore antiangiogenic therapy combined with cryoablation may also have a synergistic effect.…”

“…In addition, the order of drug administration also plays a very important role. Experiments have shown that sequential immunotherapy or chemotherapy after antiangiogenic therapy generates a vascular normalization window and has a better therapeutic effect ( 28 , 30 ).…”

Marine Polysaccharides as a Versatile Biomass for the Construction of Nano Drug Delivery Systems

“…Self-assembled NPs are formed under the action of non-covalent bonds. The driving force mainly includes polyelectrolyte complexation, hydrophobic interaction, and ionic interactions [ 21 , 42 ]. There are many ways to achieve covalent crosslinking, such as chemical crosslinking and radiation crosslinking [ 43 , 44 ].…”