Division of Pharmacology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
Mouse Cancer Clinic, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
Cell Rep Med. 2021 Jan 19;2(1):100184. doi: 10.1016/j.xcrm.2020.100184.
The impact of a compromised blood-brain barrier (BBB) on the drug treatment of intracranial tumors remains controversial. We characterize the BBB integrity in several intracranial tumor models using magnetic resonance imaging, distribution and efficacy of docetaxel in brain tumors grafted in Abcb1-proficient and Abcb1-deficient mice. Leakiness of the tumor vasculature varies from extensive to absent. Regardless of the extent of leakiness, tumor blood vessels express ATP-binding cassette transporters (Abcb1 and Abcg2). A leaky vasculature results in higher docetaxel tumor levels compared to normal brain. Nevertheless, Abcb1 can reduce drug distribution and efficacy even in leaky models. Thus, BBB leakiness does not ensure the unimpeded access of ATP-binding cassette transporter substrate drugs. Therapeutic responses may be observed, but the full potential of such therapeutics may still be attenuated. Consequently, BBB-penetrable drugs with little to no affinity for efflux transporters are preferred for the treatment of intracranial tumors.
血脑屏障（BBB）受损对颅内肿瘤的药物治疗的影响仍存在争议。我们使用磁共振成像来描述几种颅内肿瘤模型中的 BBB 完整性，研究了多西紫杉醇在 Abcb1 功能正常和 Abcb1 缺失的小鼠脑内移植肿瘤中的分布和疗效。肿瘤血管的通透性从广泛到不存在不等。无论通透性的程度如何，肿瘤血管都表达 ATP 结合盒转运体（Abcb1 和 Abcg2）。渗漏的血管导致肿瘤内的多西紫杉醇水平高于正常大脑。然而，Abcb1 甚至在渗漏模型中也可以减少药物的分布和疗效。因此，BBB 渗漏并不能确保 ABC 转运体底物药物的无障碍进入。可能会观察到治疗反应，但此类治疗的全部潜力仍可能受到抑制。因此，对于颅内肿瘤的治疗，首选具有低亲和力或无亲和力的 BBB 穿透性药物。
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