Antitumor activity of Endostar combined with radiation against human nasopharyngeal carcinoma in mouse xenograft models

Abstract

Abstract. Radiation treatment for nasopharyngeal carcinoma (NPC) is common and effective. However, local recurrence occurs frequently. Endostar, a novel recombinant human endostatin, is an antiangiogenic drug with a potent antitumor effect. The present study aimed to observe and explore the radiosensitization effects of Endostar on NPC and its underlying mechanism. The NPC subcutaneous transplantation tumor animal model was established to evaluate the antitumor activity of Endostar combined with radiation (Endostar + radiation) treatment compared with monotherapy (Endostar or radiation). Tumor growth and tumor weight were measured to evaluate the antitumor effect. The level of vascular endothelial growth factor (VEGF) and microvessel density (MVD) were measured using immunohistochemical staining of the tumor tissues. Significant antitumor activity was found in the Endostar + radiation group. The tumor inhibition rates of Endostar, radiation and Endostar + radiation were 27.12, 60.45 and 86.11%, respectively. The VEGF levels in the tumor tissue in the Endostar + radiation group were lower than those in the radiation and control groups. The MVD in the tumor tissues in the Endostar + radiation group was 12.2±2.5, lower than that in the Endostar (29.3±3.4), radiation (23.5±3.6) and control (44.7±5.1) groups. These results suggest that Endostar increases the radiation sensitivity of NPC-transplanted tumors in nude mice by lowering VEGF expression. In this study, the NPC animal model was established, which reflects the efficacy of clinical combination therapies and the combination of Endostar and radiation. The mechanisms of the combination therapies should be further investigated using this model. IntroductionNasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in China. Presently, the main treatment for NPC is radiation therapy. Over the past 20 years, with the development of imaging, radiation techniques and equipment for NPC, the local control rate among patients in the early stage of the disease has risen to 70-90%. However, in patients in the late stages of the disease (stages III-IV), the local control rate is only 50%, with a five-year overall survival rate of 40-70% (1). The main causes of treatment failure are local recurrence and distant metastases, which are closely related to each other (2). The key factor that results in the local recurrence of tumors is the presence of tumor cells possessing a resistance to radiation. Therefore, decreasing radiation resistance and increasing radiation sensitivity of tumor cells are of significant clinical relevance.Previous studies (3,4) have indicated that radiation therapy results in the elevated expression of vascular endothelial growth factor (VEGF), which may contribute to the resistance to radiation in tumors. Therefore, radiation therapy combined with antiangiogenic therapy may be effective in decreasing radiation resistance.A number of studies have indicated that neovascularization is closely related to the progression and metastasis of tumo...

Association between VEGF–460T/C gene polymorphism and clinical outcomes of nasopharyngeal carcinoma treated with intensity-modulated radiation therapy

“…Therefore, radiotherapy combined with anti-VEGF therapy may effectively decrease radiation resistance. 22 Our study also showed no significant association between LRFS and VEGF –460T/C polymorphism. This finding mainly stems from the following factors: first, despite more than 80% of the patients being at the T3–4 stage, the application of IMRT and combined CRT greatly improved the local control of the patients, resulting in 3-year LRFS of more than 90%.…”

Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles

“…Endostar, a novel modified recombinant human endostatin, has showed strong antiangiogenic effect on various xenograft tumor model and cancer patients, including NPC. [32][33][34] The results of this study demonstrated that Endostar impeded tumor growth without evident tumor regression and that a significant tumor growth inhibition was not observed until day 8, because Endostar was principally cytostatic rather than cytotoxic. It was also shown that Endostar could reduce the tumor vessels, resulting in the decrease of microvessel density, and subsequently lowered the integrin avβ3 expression.…”

Metformin inhibits the growth of nasopharyngeal carcinoma cells and sensitizes the cells to radiation via inhibition of the DNA damage repair pathway

“…Cells in the early log phase were trypsinized and plated in a 96-well plate at a density of 1x10 4 cells per well. Twenty-four hours later, the medium was removed and replaced with fresh medium with metformin at the indicated concentrations (0, 4,8,16,25,32, 50 and 64 mM) for 24 or 48 h in the presence of 1% fBS. Cell density was measured using the CCK-8 (Dojindo Molecular Technologies, Japan) assay following the manufacturer's instructions.…”