Liao Wei-Hua, Yang Li-Fang, Liu Xiao-Yu, Zhou Gao-Feng, Jiang Wu-Zhong, Hou Bob-Lei, Sun Lun-Quan, Cao Ya, Wang Xiao-Yi
Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
BMC Cancer. 2014 Nov 18;14:835. doi: 10.1186/1471-2407-14-835.
EBV-encoded latent membrane protein 1 (EBV-LMP1) is an important oncogenic protein for nasopharyngeal carcinoma (NPC) and has been shown to engage a plethora of signaling pathways. Correspondingly, an LMP1-targeted DNAzyme was found to inhibit the growth of NPC cells both in vivo and in vitro by suppressing cell proliferation and inducing apoptosis. However, it remains unknown whether an LMP1-targeted DNAzyme would affect the vasculature of NPC. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been applied in the clinical trials of anti-angiogenic drugs for more than ten years, and Ktrans has been recommended as a primary endpoint. Therefore, the objective of the current study was to use DCE-MRI to longitudinally study the effect of an EBV-LMP1-targeted DNAzyme on the vasculature of patients with NPC.
Twenty-four patients were randomly divided into two groups: a combined treatment group (radiotherapy + LMP1-targeted DNAzyme) and a radiotherapy alone group (radiotherapy + normal saline). DCE-MRI scans were conducted 1 ~ 2 days before radiotherapy (Pre-RT), during radiotherapy (RT 50 Gy), upon completion of radiotherapy (RT 70 Gy), and three months after radiotherapy (3 months post-RT). Parameters of vascular permeability and intra- and extravascular volumes were subsequently obtained (e.g., Ktrans, kep, ve) using nordicICE software.
Both Ktrans and kep values for NPC tumor tissues decreased for both groups after treatment. Moreover, a statistically significant difference in Ktrans values at the pre-therapy and post-therapy timepoints emerged earlier for the combined treatment group (RT 50 Gy, P =0.045) compared to the radiotherapy alone group (3 months post-RT, P = 0.032). For the kep values, the downward trend observed for both the combined treatment group and the radiotherapy alone group were similar. In contrast, ve values for all of the tumor tissues increased following therapy.
The EBV-LMP1-targeted DNAzyme that was tested was found to accelerate the decline of Ktrans values for patients with NPC. Correspondingly, the LMP1-targeted DNAzyme treatments were found to affect the angiogenesis and microvascular permeability of NPC.
ClinicalTrials.gov: NCT01449942. Registered 6 October 2011.
EB病毒编码的潜伏膜蛋白1（EBV-LMP1）是鼻咽癌（NPC）的一种重要致癌蛋白，已被证明参与多种信号通路。相应地，一种靶向LMP1的脱氧核酶被发现可通过抑制细胞增殖和诱导凋亡来抑制NPC细胞在体内和体外的生长。然而，靶向LMP1的脱氧核酶是否会影响NPC的脉管系统仍不清楚。动态对比增强磁共振成像（DCE-MRI）已在抗血管生成药物的临床试验中应用了十多年，并且Ktrans已被推荐作为主要终点。因此，本研究的目的是使用DCE-MRI纵向研究靶向EBV-LMP1的脱氧核酶对NPC患者脉管系统的影响。
24例患者被随机分为两组：联合治疗组（放疗+靶向LMP1的脱氧核酶）和单纯放疗组（放疗+生理盐水）。在放疗前1至2天（放疗前）、放疗期间（50 Gy放疗时）、放疗结束时（70 Gy放疗时）以及放疗后三个月（放疗后3个月）进行DCE-MRI扫描。随后使用nordicICE软件获得血管通透性以及血管内和血管外容积的参数（例如，Ktrans、kep、ve）。
两组治疗后NPC肿瘤组织的Ktrans和kep值均降低。此外，联合治疗组（50 Gy放疗时，P = 0.045）与单纯放疗组（放疗后3个月，P = 0.032）相比，治疗前和治疗后时间点的Ktrans值出现统计学显著差异。对于kep值，联合治疗组和单纯放疗组观察到的下降趋势相似。相反，所有肿瘤组织的ve值在治疗后均升高。
经测试，靶向EBV-LMP1的脱氧核酶可加速NPC患者Ktrans值的下降。相应地，发现靶向LMP1的脱氧核酶治疗会影响NPC的血管生成和微血管通透性。
ClinicalTrials.gov：NCT01449942。2011年10月6日注册。
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