Department of Neurosurgery, University Medical Center Freiburg, Breisacher Strasse 64, D-79106 Freiburg, Germany.
Neuro Oncol. 2011 Feb;13(2):203-11. doi: 10.1093/neuonc/noq161. Epub 2010 Nov 1.
Nitric oxide (NO) signaling in tumors and endothelial cells regulates vascular permeability and blood flow and therefore influences tumor uptake and response to therapeutic compounds. As delivery and efficacy of chemotherapy is impaired in CNS neoplasms due to a partially intact blood-brain barrier (BBB), we studied the effects of NO released by the short-acting NO donor disodium 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate methanolate (PROLI/NO) on BBB integrity and blood flow in C6 gliomas using [¹⁴C]-aminoisobutyric acid (AIB) and [¹⁴C]-iodoantipyrine quantitative autoradiography. PROLI/NO selectively increased intratumoral uptake of [¹⁴C]AIB and [¹⁴C]sucrose when given as a 3-minute intracarotid infusion or a 15-minute i.v. infusion (AIB: tumor, K₁ = 68.7 ± 3.2 vs 24.9 ± 0.9 µL g⁻¹ min⁻¹, P < .0001; sucrose, K₁ = 16.9 ± 0.9 vs 11.5 ± 0.9 µL g⁻¹ min⁻¹, P = .0007). This effect was achieved without significant changes in cerebral and tumor blood flow or arterial blood pressure, which indicates that the effect on vascular permeability is independent of changes in vascular tone induced by NO. This effect was mediated by activation of the NO/3',5'-cyclic guanosine monophosphate (cGMP) pathway, as it was blocked by guanylate cyclase inhibition by LY83583 and reproduced by the delivery of 8-bromoguanosine 5'-monophosphate or inhibition of cGMP degradation by the phosphodiesterase inhibitor zaprinast. Inhibition of inducible NO synthase by aminoguanidine or cyclooxygenase inhibition by indometacin or dexamethasone did not reduce the blood-tumor barrier (BTB) response to PROLI/NO. PROLI/NO, and perhaps other NO-donating compounds, can be used to selectively increase BTB permeability in gliomas through the NO/cGMP pathway at doses that do not cause unwanted vasodilatory changes in blood flow and that do not affect the systemic circulation.
一氧化氮（NO）在肿瘤和内皮细胞中的信号转导调节血管通透性和血流，从而影响肿瘤摄取和对治疗化合物的反应。由于血脑屏障（BBB）部分完整，中枢神经系统肿瘤中的化疗药物的递送和疗效受损，我们使用 [¹⁴C]-氨基异丁酸（AIB）和 [¹⁴C]-碘安替比林定量放射自显影研究了短半衰期 NO 供体 disodium 1-[2-(羧基)吡咯烷-1-基]二氮烯-1-基-1,2-二醇甲醇化物（PROLI/NO）对 C6 神经胶质瘤 BBB 完整性和血流的影响。当 PROLI/NO 通过 3 分钟的颈动脉内输注或 15 分钟的静脉内输注给予时，它选择性地增加了肿瘤内 [¹⁴C]AIB 和 [¹⁴C]蔗糖的摄取（AIB：肿瘤，K₁ = 68.7 ± 3.2 与 24.9 ± 0.9 µL g⁻¹ min⁻¹，P <.0001；蔗糖，K₁ = 16.9 ± 0.9 与 11.5 ± 0.9 µL g⁻¹ min⁻¹，P =.0007）。这种作用是在脑和肿瘤血流或动脉血压没有明显变化的情况下实现的，这表明对血管通透性的影响独立于由 NO 诱导的血管张力变化。这种作用是通过激活 NO/3',5'-环鸟苷单磷酸（cGMP）途径介导的，因为它被鸟苷酸环化酶抑制剂 LY83583 阻断，并通过 8-溴鸟苷 5'-单磷酸的递送或磷酸二酯酶抑制剂扎普司特抑制 cGMP 降解来复制。氨基胍抑制诱导型一氧化氮合酶或吲哚美辛或地塞米松抑制环氧合酶并不能降低 PROLI/NO 对血脑屏障（BTB）的反应。PROLI/NO 以及其他可能的 NO 供体化合物，可以通过 NO/cGMP 途径选择性地增加神经胶质瘤中的 BTB 通透性，而不会引起血流中不需要的血管舒张变化，也不会影响全身循环。
