Nitric oxide synthase inhibition enhances the antitumor effect of radiation in the treatment of squamous carcinoma xenografts.
Nitric oxide synthase inhibition enhances the antitumor effect of radiation in the treatment of squamous carcinoma xenografts.
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DOI：
10.1371/journal.pone.0020147
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Mikkelsen RB
中科院分区：
文献类型：
--
作者：
Cardnell RJ;Mikkelsen RB
本研究旨在探讨一氧化氮合酶抑制剂L精氨酸与电离辐射(IR)联合应用对鳞癌生长的抑制作用。对荷FADU和A431异种移植瘤的动物，在饮水中加入L-NNA。用于肿瘤生长和存活研究的IR剂量为10GY，用于体外克隆形成实验的IR剂量为4GY。用免疫组织化学方法检测冰冻切片中细胞凋亡和缺氧的标志物。静脉注射后，用荧光显微镜观察冰冻切片的血流量。注射氟化球。口服L-硝酸甘油24小时可使肿瘤血流量减少80%(p<；0.01)。在24小时内，L-NNA治疗使肿瘤停止生长至少10天，然后肿瘤再次生长。生长受阻的部分原因是由于L-NNA和单次4GyIR联合使用后，体外克隆形成实验测得的肿瘤细胞杀伤率为82%，而L-NNA组为49%，IR组为29%。卡普兰-迈耶对动物存活的分析显示，联合治疗具有明显的生存优势。研究还发现，L-NNA与IR联合使用至少与单一ip一样有效。顺铂加IR的剂量。与体内研究相比，体外细胞暴露于L-NNA后，无论是否有IR，克隆形成能力都没有影响。Western和免疫化学分析表明，L-NNA治疗可增强精氨酸酶-2的表达，这可能代表了血管重塑和逃避一氧化氮合酶的抑制。对于像头颈部鳞状细胞癌这样对特定血管生成途径的抑制剂只有轻微反应的肿瘤，靶向肿瘤和支持基质细胞中的NO依赖的促生存和血管生成机制可能为肿瘤控制提供一种潜在的新策略。
This study tests whether the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine (L-NNA), combines favorably with ionizing radiation (IR) in controlling squamous carcinoma tumor growth. Animals bearing FaDu and A431 xenografts were treated with L-NNA in the drinking water. IR exposure was 10 Gy for tumor growth and survival studies and 4 Gy for ex vivo clonogenic assays. Cryosections were examined immunohistochemically for markers of apoptosis and hypoxia. Blood flow was assayed by fluorescent microscopy of tissue cryosections after i.v. injection of fluorospheres. Orally administered L-NNA for 24 hrs reduces tumor blood flow by 80% (p<0.01). Within 24 hrs L-NNA treatment stopped tumor growth for at least 10 days before tumor growth again ensued. The growth arrest was in part due to increased cell killing since a combination of L-NNA and a single 4 Gy IR caused 82% tumor cell killing measured by an ex vivo clonogenic assay compared to 49% by L-NNA or 29% by IR alone. A Kaplan-Meyer analysis of animal survival revealed a distinct survival advantage for the combined treatment. Combining L-NNA and IR was also found to be at least as effective as a single i.p. dose of cisplatin plus IR. In contrast to the in vivo studies, exposure of cells to L-NNA in vitro was without effect on clonogenicity with or without IR. Western and immunochemical analysis of expression of a number of proteins involved in NO signaling indicated that L-NNA treatment enhanced arginase-2 expression and that this may represent vasculature remodeling and escape from NOS inhibition. For tumors such as head and neck squamous carcinomas that show only modest responses to inhibitors of specific angiogenic pathways, targeting NO-dependent pro-survival and angiogenic mechanisms in both tumor and supporting stromal cells may present a potential new strategy for tumor control.
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影响因子：
6
作者：
Hlushchuk, Ruslan;Riesterer, Oliver;Djonov, Valentin
通讯作者：
Djonov, Valentin
DOI：
10.1093/jnci/93.12.921
发表时间：
2001-06-20
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Lammering, G;Hewit, TH;Schmidt-Ullrich, RK
通讯作者：
Schmidt-Ullrich, RK
影响因子：
11.2
作者：
Lahdenranta J;Hagendoorn J;Padera TP;Hoshida T;Nelson G;Kashiwagi S;Jain RK;Fukumura D
通讯作者：
Fukumura D
影响因子：
64.8
作者：
Lim, Kian-Huat;Ancrile, Brooke B.;Counter, Christopher M.
通讯作者：
Counter, Christopher M.
影响因子：
3
作者：
Maher, JC;Krishan, A;Lampidis, TJ
通讯作者：
Lampidis, TJ