Intravascular administration of tumor tropic neural progenitor cells permits targeted delivery of interferon-β and restricts tumor growth in a murine model of disseminated neuroblastoma
Intravascular administration of tumor tropic neural progenitor cells permits targeted delivery of interferon-β and restricts tumor growth in a murine model of disseminated neuroblastoma
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DOI：
10.1016/j.jpedsurg.2006.09.050
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发表时间：
2007-01-01
影响因子：
2.4
通讯作者：
Davidoff, Andrew M.
中科院分区：
文献类型：
--
作者：
Dickson, Paxton V.;Hamner, John B.;Davidoff, Andrew M.
背景：β干扰素具有较强的抗肿瘤活性，但全身毒性限制了其临床应用。我们研究了转导表达人干扰素-β(h干扰素-β)的亲肿瘤神经前体细胞(NC)进行靶向转移的可能性。方法：采用尾静脉注射肿瘤细胞的方法建立SCID小鼠播散性神经母细胞瘤模型。接种肿瘤细胞14天后，用生物发光成像(BLI)证实全身疾病。然后，静脉注射经复制缺陷型腺病毒转导的人F3.C1NPC以过表达h干扰素-β(F3-干扰素-β)。两次注射：第一次是在肿瘤细胞注射后14天，第二次是在肿瘤细胞注射后28天。对照组小鼠在相同时间点接受转导空载体腺病毒的鼻咽癌细胞。使用BLI监测疾病的进展。处死时，脏器重量和组织学进一步评估肿瘤负担。结果：在开始治疗后，BLI显示接受F3-干扰素-β的小鼠的疾病进展率显著降低。在尸检中，对照组小鼠有巨大的肿瘤取代了肝脏和肾脏，以及广泛的腹膜后和纵隔腺病。令人印象深刻的是，除了一些接受F3-干扰素-β治疗的小鼠肾脏内的小结节外，接受F3-干扰素-β治疗的小鼠体内的这些部位似乎大体正常。荧光成像证实F3.c1细胞在肿瘤生长部位积聚。结论：这些数据表明，在这种播散性神经母细胞瘤模型中，利用F3C1NPC的肿瘤亲和性，将干扰素-β靶向转移到播散性组织灶，导致肿瘤生长显著延迟。所描述的有效的干扰素-β治疗的新方法可能会绕过与干扰素-β的全身毒性相关的限制。(C)2007 Elsevier Inc.保留所有权利。
Background: Interferon-beta (IFN-beta) has potent antitumor activity; however, systemic toxicity has limited its clinical use. We investigated the potential of targeted delivery using tumor-tropic neural progenitor cells (NPCs) transduced to express human IFN-beta (hIFN-beta).Methods: Disseminated neuroblastoma was established in SCID mice by tail vein injection of tumor cells. Fourteen days after tumor cell inoculation, systemic disease was confirmed with bioluminescence imaging (BLI). Mice were then treated by intravenous injection of human F3.C1 NPCs that had been transduced with a replication deficient adenovirus to overexpress hIFN-beta (F3-IFN-beta). Two injections were given: the first at 14 days and the second at 28 days following tumor cell injection. Control mice received NPCs transduced with empty vector adenovirus at the same time points. Progression of disease was monitored using BLI. At sacrifice, organ weights and histology further evaluated tumor burden.Results: After initiation of therapy, BLI demonstrated a significant decrease in the rate of disease progression in mice receiving F3-IFN-beta. At necropsy, control mice had bulky tumor replacing the liver and kidneys, as well as extensive retroperitoneal and mediastinal adenopathy. Impressively, these sites within mice receiving F3-IFN-beta therapy appeared grossly normal with the exception of small nodules within the kidneys of some of the F3-IFN-beta-treated mice. The accumulation of F3.C1 cells within sites of tumor growth was confirmed by fluorescence imaging. Importantly, systemic levels of hIFN-beta in the treated mice remained below detectable levels.Conclusions: These data indicate that in this model of disseminated neuroblastoma, the tumor-tropic property of F3.C1 NPCs was exploited to target delivery of IFN-beta to disseminated tissue foci, resulting in significant tumor growth delay. The described novel approach for effective IFN-beta therapy may circumvent limitations associated with the systemic toxicity of IFN-beta. (c) 2007 Elsevier Inc. All rights reserved.