Cancer Research Unit, The Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne, NE2 4HH, England.
CNS Drugs. 1997 Apr;7(4):257-63. doi: 10.2165/00023210-199707040-00001.
The chemotherapy of tumours located in the brain is far from satisfactory, with very poor response rates even with tumour types known to be sensitive when they occur extracranially. The brain is protected by the blood-brain barrier, which consists of tight capillary endothelial cell junctions. As a result, many drugs cannot penetrate into the tumour to achieve cytotoxic concentrations. Although the vasculature of some tumours may allow greater uptake of drugs than into normal brain tissue, the poor uptake of drugs into CNS tumours is still seen as a barrier to effective chemotherapy.The permeability of the blood-brain barrier may be affected by osmotic agents or mediators of inflammation. Notable among the latter is bradykinin, which induces a transient, specific increase in permeability that is more pronounced in tumour than in normal brain.The nonapeptide RMP-7 [H-Arg-Pro-Hyp-Gly-Thi-Ser-Pro-Tyr(Me)-ψ(CH2NH)-Arg-OH] was developed as a bradykinin analogue. This peptide displays greater stability in plasma than the parent compound. Preclinical investigations in animal tumour models showed that RMP-7 increased the uptake of a number of markers in RG2 gliomas implanted into rat brain. More importantly, RMP-7 also increased carboplatin uptake in the tumour and brain surrounding the tumour, without affecting uptake into normal brain. Animals treated with RMP-7 and carboplatin showed significantly prolonged survival compared with controls. The doses used in these animal studies were quite high, administered via the intracarotid artery.In studies in humans, lower doses of RMP-7 were used and the drug was usually administered intravenously. Adverse effects were mild and transient, mostly related to vasodilation. Phase I and II studies in patients with brain tumours confirmed the increased uptake of radiochemical markers into tumours that had been seen in animal models. Recently published data suggest that the combination of carboplatin with RMP-7 has activity in malignant brain tumours, both in terms of neurological improvement and overall survival, and was well tolerated. In particular, the neurotoxicity reported with other methods of increasing blood-brain barrier permeability has not been reported. Using a reliable method of individualised carboplatin administration, based on renal function, any effect of RMP-7 on the elimination of carboplatin may be determined.Overall, the use of RMP-7 as an adjunct to the treatment of tumours within the CNS may potentially be effective in terms of increasing tumour drug concentrations.
脑部肿瘤的化疗效果远不理想，即使是在颅外发生的对肿瘤类型敏感的肿瘤，反应率也很低。大脑受到血脑屏障的保护，血脑屏障由紧密的毛细血管内皮细胞连接组成。结果，许多药物无法穿透肿瘤达到细胞毒性浓度。尽管一些肿瘤的血管可能允许比正常脑组织更多地摄取药物，但中枢神经系统肿瘤摄取药物的能力仍然被认为是有效化疗的障碍。血脑屏障的通透性可能受到渗透剂或炎症介质的影响。在后者中，值得注意的是缓激肽，它诱导短暂的、特异性的通透性增加，在肿瘤中比在正常脑中更为明显。非肽 RMP-7 [H-Arg-Pro-Hyp-Gly-Thi-Ser-Pro-Tyr(Me)-ψ(CH2NH)-Arg-OH] 是作为缓激肽类似物开发的。这种肽在血浆中的稳定性比母体化合物更高。在动物肿瘤模型中的临床前研究表明，RMP-7 增加了植入大鼠脑内 RG2 神经胶质瘤的许多标记物的摄取。更重要的是，RMP-7 还增加了肿瘤和肿瘤周围脑的卡铂摄取，而不影响正常脑的摄取。与对照组相比，用 RMP-7 和卡铂治疗的动物存活时间明显延长。这些动物研究中使用的剂量相当高，通过颈内动脉给药。在人类研究中，使用较低剂量的 RMP-7，药物通常通过静脉给药。不良反应轻微且短暂，主要与血管扩张有关。在脑肿瘤患者的 I 期和 II 期研究中，证实了在动物模型中观察到的放射性化学标记物向肿瘤的摄取增加。最近发表的数据表明，卡铂与 RMP-7 联合应用于恶性脑肿瘤具有活性，无论是在神经改善还是总生存期方面，且耐受性良好。特别是，没有报道报道其他增加血脑屏障通透性的方法所报告的神经毒性。使用基于肾功能的个体化卡铂给药的可靠方法，可以确定 RMP-7 对卡铂消除的任何影响。总的来说，RMP-7 作为 CNS 内肿瘤治疗的辅助手段，在增加肿瘤药物浓度方面可能具有潜在的有效性。
