Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats.
Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats.
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DOI：
10.1093/neuonc/not149
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发表时间：
2014-01
期刊：
影响因子：
15.9
通讯作者：
Brown JM
中科院分区：
文献类型：
--
作者：
Liu SC;Alomran R;Chernikova SB;Lartey F;Stafford J;Jang T;Merchant M;Zboralski D;Zöllner S;Kruschinski A;Klussmann S;Recht L;Brown JM
肿瘤放疗阻断局部血管生成，迫使任何复发的肿瘤从循环细胞形成新的血管。我们以前已经证明，照射后复发的人胶质母细胞瘤在裸鼠的大脑中，可以通过抑制循环血管形成细胞通过阻断CXCR 4与其配体基质细胞衍生因子（SDF）-1（CXCL 12）的相互作用，延迟或预防。在本研究中，我们通过在免疫活性宿主中使用自体脑肿瘤的临床相关模型中直接中和SDF-1来测试这种策略。我们使用NOX-A12，一种以高亲和力结合并抑制SDF-1的l-对映体RNA寡核苷酸。本文研究了该抑制剂对N-乙基-N-亚硝基脲诱发的大鼠脑肿瘤放射反应的影响。在子宫内用N-乙基-N-亚硝基脲处理的大鼠从大约120天的年龄开始死于脑肿瘤。我们在115日龄时给予单剂量的全脑照射（20戈伊），在照射后立即开始用NOX-A12治疗，并以5或20 mg/kg持续4或8周，剂量和时间相当于良好耐受的人类暴露。我们发现一个显着的延长大鼠的寿命，这是依赖于药物剂量和治疗时间。此外，我们仅在肿瘤通过MRI可见时才治疗肿瘤，并证明肿瘤完全消退，这是单独照射或添加替莫唑胺无法实现的。肿瘤放射后抑制SDF-1是改善多形性胶质母细胞瘤肿瘤反应的有效方法。
Tumor irradiation blocks local angiogenesis, forcing any recurrent tumor to form new vessels from circulating cells. We have previously demonstrated that the post-irradiation recurrence of human glioblastomas in the brains of nude mice can be delayed or prevented by inhibiting circulating blood vessel–forming cells by blocking the interaction of CXCR4 with its ligand stromal cell-derived factor (SDF)–1 (CXCL12). In the present study we test this strategy by directly neutralizing SDF-1 in a clinically relevant model using autochthonous brain tumors in immune competent hosts. We used NOX-A12, an l-enantiomeric RNA oligonucleotide that binds and inhibits SDF-1 with high affinity. We tested the effect of this inhibitor on the response to irradiation of brain tumors in rat induced by n-ethyl-N-nitrosourea. Rats treated in utero with N-ethyl-N-nitrosourea began to die of brain tumors from approximately 120 days of age. We delivered a single dose of whole brain irradiation (20 Gy) on day 115 of age, began treatment with NOX-A12 immediately following irradiation, and continued with either 5 or 20 mg/kg for 4 or 8 weeks, doses and times equivalent to well-tolerated human exposures. We found a marked prolongation of rat life span that was dependent on both drug dose and duration of treatment. In addition we treated tumors only when they were visible by MRI and demonstrated complete regression of the tumors that was not achieved by irradiation alone or with the addition of temozolomide. Inhibition of SDF-1 following tumor irradiation is a powerful way of improving tumor response of glioblastoma multiforme.
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影响因子：
56.9
作者：
Asahara, T;Murohara, T;Isner, JM
通讯作者：
Isner, JM
影响因子：
7.4
作者：
Heinrich EL;Lee W;Lu J;Lowy AM;Kim J
通讯作者：
Kim J
影响因子：
50.3
作者：
Ahn, G-One;Brown, J. Martin
通讯作者：
Brown, J. Martin
影响因子：
20.1
作者：
Aicher, Alexandra;Rentsch, Markus;Heeschen, Christopher
通讯作者：
Heeschen, Christopher
影响因子：
4.1
作者：
LIANG, BC;THORNTON, AF;GREENBERG, HS
通讯作者：
GREENBERG, HS