一氧化氮供体对血脑肿瘤屏障的选择性开放及C6胶质瘤大鼠的长期存活

Selective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival in rats with C6 gliomas.

作者信息

Weyerbrock Astrid, Walbridge Stuart, Pluta Ryszard M, Saavedra Joseph E, Keefer Larry K, Oldfield Edward H

机构信息

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.

出版信息

J Neurosurg. 2003 Oct;99(4):728-37. doi: 10.3171/jns.2003.99.4.0728.

DOI:10.3171/jns.2003.99.4.0728

PMID:14567609

Abstract

OBJECT

The response of brain tumors to systemic chemotherapy is limited by the blood-tumor barrier (BTB). Nitric oxide (NO) has been implicated in the regulation of vascular permeability and blood flow. The authors evaluated the effects of exogenous NO, which was released from a short-acting NO donor (Proli/NO), and those of NO metabolites on the capillary permeability of tumors and normal brain tissue by using quantitative autoradiography in a C6 glioma model in rats.

METHODS

The Proli/NO was infused at a wide dose range (10(-2) to 10(-12) M) either intravenously or into the internal carotid artery (ICA) and demonstrated substantial tumor-selective increases in blood-brain barrier (BBB) permeability in response to various-sized tracers ([14C]aminoisobutyric acid, [14C]sucrose, [14C]dextran). Internal carotid artery or intravenous administration of sodium nitrite had a comparable effect on BTB permeability. The NO effect on microvascular permeability could be obtained without causing hemodynamic side effects. The effect of NO on the efficacy of carboplatin chemotherapy was investigated in intracerebral C6 gliomas. Simultaneous intravenous infusions of Proli/NO (10(-6) M) and carboplatin (20 mg/kg) led to long-term survival in 40% of rats harboring intracerebral C6 gliomas compared with control animals receiving ICA or intravenous infusions of carboplatin, Proli/NO, or vehicle alone. No residual tumor was demonstrated on histological or magnetic resonance imaging studies performed in rats treated with Proli/NO and carboplatin, and no toxicity was observed.

CONCLUSIONS

This new approach demonstrated the in vivo efficacy and safety of NO and nitrite in enhancing the delivery of systemically delivered radiolabeled tracers and carboplatin into rat gliomas. The NO-induced tumor-selective BBB disruption and intravenous carboplatin chemotherapy may be more efficacious than current chemotherapy strategies against brain tumors.

摘要

目的

脑肿瘤对全身化疗的反应受血肿瘤屏障（BTB）限制。一氧化氮（NO）与血管通透性和血流调节有关。作者通过在大鼠C6胶质瘤模型中使用定量放射自显影技术，评估了短效NO供体（Proli/NO）释放的外源性NO及其代谢产物对肿瘤和正常脑组织毛细血管通透性的影响。

方法

将Proli/NO以宽剂量范围（10⁻²至10⁻¹² M）静脉内或经颈内动脉（ICA）注入，并显示出对不同大小示踪剂（[¹⁴C]氨基异丁酸、[¹⁴C]蔗糖、[¹⁴C]葡聚糖）的血脑屏障（BBB）通透性有显著的肿瘤选择性增加。经颈内动脉或静脉内给予亚硝酸钠对BTB通透性有类似作用。NO对微血管通透性的作用可在不引起血流动力学副作用的情况下获得。在脑内C6胶质瘤中研究了NO对卡铂化疗疗效的影响。与单独接受ICA或静脉内注入卡铂、Proli/NO或赋形剂的对照动物相比，同时静脉内注入Proli/NO（10⁻⁶ M）和卡铂（20 mg/kg）可使40%患有脑内C6胶质瘤的大鼠长期存活。在用Proli/NO和卡铂治疗的大鼠中进行的组织学或磁共振成像研究未显示残留肿瘤，也未观察到毒性。