Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province, China.
PLoS One. 2012;7(4):e34646. doi: 10.1371/journal.pone.0034646. Epub 2012 Apr 9.
Hypoxic tumor cells can reduce the efficacy of radiation. Antiangiogenic therapy may transiently "normalize" the tumor vasculature to make it more efficient for oxygen delivery. The aim of this study is to investigate whether the recombinant human endostatin (endostar) can create a "vascular normalization window" to alleviate hypoxia and enhance the inhibitory effects of radiation therapy in human nasopharyngeal carcinoma (NPC) in mice.
METHODOLOGY/PRINCIPAL FINDINGS: Transient changes in morphology of tumor vasculature and hypoxic tumor cell fraction in response to endostar were detected in mice bearing CNE-2 and 5-8F human NPC xenografts. Various treatment schedules were tested to assess the influence of endostar on the effect of radiation therapy. Several important factors relevant to the angiogenesis were identified through immunohistochemical staining. During endostar treatment, tumor vascularity decreased, while the basement membrane and pericyte coverage associated with endothelial cells increased, which supported the idea of vessel normalization. Hypoxic tumor cell fraction also decreased after the treatment. The transient modulation of tumor physiology caused by endostar improved the effect of radiation treatment compared with other treatment schedules. The expressions of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-14 decreased, while the level of pigment epithelium-derived factor (PEDF) increased.
Endostar normalized tumor vasculature, which alleviated hypoxia and significantly sensitized the function of radiation in anti-tumor in human NPC. The results provide an important experimental basis for combining endostar with radiation therapy in human NPC.
缺氧的肿瘤细胞会降低放射治疗的疗效。抗血管生成治疗可能会使肿瘤血管短暂地“正常化”，从而提高氧气输送效率。本研究旨在探讨重组人血管内皮抑制素（恩度）是否能产生一个“血管正常化窗口”，以减轻缺氧并增强放射治疗对小鼠人鼻咽癌（NPC）的抑制作用。
方法/主要发现：在携带 CNE-2 和 5-8F 人 NPC 异种移植物的小鼠中，检测到恩度对肿瘤血管形态和缺氧肿瘤细胞比例的短暂变化。测试了各种治疗方案，以评估恩度对放射治疗效果的影响。通过免疫组织化学染色鉴定了与血管生成相关的几个重要因素。在恩度治疗期间，肿瘤血管密度降低，而与内皮细胞相关的基底膜和周细胞覆盖增加，这支持了血管正常化的观点。治疗后，缺氧肿瘤细胞比例也降低。恩度对肿瘤生理学的短暂调节改善了放射治疗的效果，优于其他治疗方案。血管内皮生长因子（VEGF）、基质金属蛋白酶-2（MMP-2）、MMP-9 和 MMP-14 的表达降低，而色素上皮衍生因子（PEDF）的水平升高。
恩度使肿瘤血管正常化，减轻了缺氧，并显著增强了放射治疗在人 NPC 中的抗肿瘤作用。这些结果为在人 NPC 中结合恩度与放射治疗提供了重要的实验基础。
