The acidic tumor microenvironment promotes the reconversion of nitrite into nitric oxide:: Towards a new and safe Radiosensitizing strategy
The acidic tumor microenvironment promotes the reconversion of nitrite into nitric oxide:: Towards a new and safe Radiosensitizing strategy
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DOI：
10.1158/1078-0432.ccr-07-4001
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发表时间：
2008-05-01
影响因子：
11.5
通讯作者：
Feron, Olivier
中科院分区：
文献类型：
--
作者：
Frerart, Francoise;Sonveaux, Pierre;Feron, Olivier
目的：亚硝酸盐的生物学状态最近从一氧化氮分解代谢的无活性终产物演变为一氧化氮（NO）在血管内和组织内的最大储存。虽然低O-2分压有利于亚硝酸盐转化为NO的酶促再转化，但低pH支持非酶促途径。由于缺氧和酸性是肿瘤微环境的特征，我们研究了亚硝酸盐注射是否会优先导致肿瘤产生NO并影响对治疗的反应。实验设计：评估亚硝酸盐对小动脉血管松弛、肿瘤细胞呼吸和肿瘤血流、氧合和放疗反应的影响。结果：我们首先通过记录高环鸟苷3',5'-单磷酸依赖的小动脉血管松弛，证明了pH值的小幅下降（-0.6 pH单位）有利于亚硝酸盐产生生物活性NO。然后，我们记录了向荷瘤小鼠静脉注射亚硝酸盐导致肿瘤中部分O-2压力的短暂增加，但在健康组织中没有。血流测量未能揭示亚硝酸盐对肿瘤灌注的影响，但我们发现，在酸性ph下，亚硝酸盐暴露的肿瘤细胞对O-2的消耗减少。最后，我们发现，低剂量的亚硝酸盐可以使肿瘤对放疗敏感，导致显著的生长延迟和小鼠存活率的增加（与单独照射相比）。结论：本研究确定了低pH条件（在许多肿瘤中遇到）是一个精致的环境，有利于肿瘤选择性地产生NO，以响应亚硝酸盐全身注射。这项工作为使用亚硝酸盐作为一种安全和临床适用的放射增敏方式开辟了新的视角。
Purpose: The biological status of nitrite recently evolved from an inactive end product of nitric oxide catabolism to the largest intravascular and tissue storage of nitric oxide (NO). Although low partial O-2 pressure favors enzymatic reconversion of nitrite into NO, low pH supports a nonenzymatic pathway. Because hypoxia and acidity are characteristics of the tumor microenvironment, we examined whether nitrite injection could preferentially lead to NO production in tumors and influence response to treatments.Experimental Design: The effects of nitrite were evaluated on arteriole vasorelaxation, tumor cell respiration and tumor blood flow, oxygenation, and response to radiotherapy.Results: We first showed that a small drop in pH (-0.6 pH unit) favored the production of bioactive NO from nitrite by documenting a higher cyclic guanosine 3',5'-monophosphatedependent arteriole vasorelaxation. We then documented that an i.v. bolus injection of nitrite to tumor-bearing mice led to a transient increase in partial O-2 pressure in tumor but not in healthy tissues. Blood flow measurements failed to reveal an effect of nitrite on tumor perfusion, but we found that O-2 consumption by nitrite-exposed tumor cells was decreased at acidic pH. Finally, we showed that low dose of nitrite could sensitize tumors to radiotherapy, leading to a significant growth delay and an increase in mouse survival (versus irradiation alone).Conclusions: This study identified low pH condition (encountered in many tumors) as an exquisite environment that favors tumor-selective production of NO in response to nitrite systemic injection. This work opens new perspectives for the use of nitrite as a safe and clinically applicable radiosensitizing modality.