Elliott P J, Hayward N J, Dean R L, Blunt D G, Bartus R T
Alkermes, Inc., Cambridge, Massachusetts 02139, USA.
Cancer Res. 1996 Sep 1;56(17):3998-4005.
Rats implanted with RG-2 gliomas were administered i.v. RMP-7 and [14C]carboplatin. Changes in the permeability of the blood-brain barrier to carboplatin were determined using quantitative autoradiography. i.v. infusions of RMP-7 induced an increase in the permeability of the vascular barrier within the tumor to carboplatin. Additionally, permeability of brain tissue proximal to, but clearly outside the tumor mass, was also increased. Progressively less uptake of [14C]carboplatin was observed as distance from the tumor border increased. The increases in permeability induced by RMP-7 occurred in a dose-related fashion. No increase in carboplatin level was observed in several nonbrain tissues, including sciatic nerve, retina, heart, lung, liver, kidney, and spleen. Finally, the permeabilizing effects of RMP-7 were shown to occur independent of histaminergic or hypotensive mechanisms. These data provide additional insight into the permeabilizing effects and mechanism of RMP-7 and offer additional support for the therapeutic utility of this novel compound as an adjunctive treatment for human gliomas.
给植入RG-2神经胶质瘤的大鼠静脉注射RMP-7和[14C]卡铂。使用定量放射自显影法测定血脑屏障对卡铂通透性的变化。静脉输注RMP-7可使肿瘤内血管屏障对卡铂的通透性增加。此外，肿瘤块近端但明显在肿瘤块外的脑组织的通透性也增加。随着与肿瘤边界距离的增加，观察到[14C]卡铂的摄取逐渐减少。RMP-7诱导的通透性增加呈剂量相关方式。在包括坐骨神经、视网膜、心脏、肺、肝脏、肾脏和脾脏在内的几种非脑组织中未观察到卡铂水平升高。最后，研究表明RMP-7的通透作用独立于组胺能或降压机制发生。这些数据为RMP-7的通透作用和机制提供了更多见解，并为这种新型化合物作为人类神经胶质瘤辅助治疗的治疗效用提供了更多支持。
