P-glycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model.
P-glycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model.
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DOI：
10.3389/fphar.2013.00136
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发表时间：
2013
影响因子：
5.6
通讯作者：
Lockman PR
中科院分区：
文献类型：
--
作者：
Adkins CE;Mittapalli RK;Manda VK;Nounou MI;Mohammad AS;Terrell TB;Bohn KA;Yasemin C;Grothe TR;Lockman JA;Lockman PR
血脑屏障(BBB)是一种特殊的血管界面，限制许多化合物进入脑内。这是通过密封血管内皮细胞和紧密连接蛋白来防止细胞旁扩散来实现的。此外，血脑屏障高度表达大量的外排转运体，这些转运体积极地将化合物挤出回血液中。然而，当脑内发生转移性病变时，血管系统通常会随着被动通透性的增加而受损(血-肿瘤屏障；BTB)。尽管观察到被动通透性的变化，但主动外排在多大程度上仍能保持BTB的功能，这一点没有很好的文献记载。此外，已有文献报道P-糖蛋白(P-gp)在病变血管中的表达增加或减少。在此，我们同时将被动扩散标记物(14C-AIB)和受P-gp外流的示踪剂(罗丹明123)注入乳腺癌临床前小鼠模型中。我们观察到转移灶在血脑屏障和血脑屏障有相似的表达(p>；0.05；n=756-1214条血管评估)。此外，R123在正常脑和转移灶中的组织分布无显著差异(p>；0.05)。这可能与P-gp在BBB和BTB上的相似表达有关。此外，我们观察到P-gp在邻近血管的转移性癌细胞中的表达，这也可能有助于减少R123对病变的摄取。这些数据表明，尽管BTB的完整性被破坏，但外排机制似乎是完整的，在功能上可能与正常的BBB相当。BTB是向脑转移瘤输送药物的一个重大障碍。
The blood–brain barrier (BBB) is a specialized vascular interface that restricts the entry of many compounds into brain. This is accomplished through the sealing of vascular endothelial cells together with tight junction proteins to prevent paracellular diffusion. In addition, the BBB has a high degree of expression of numerous efflux transporters which actively extrude compounds back into blood. However, when a metastatic lesion develops in brain the vasculature is typically compromised with increases in passive permeability (blood-tumor barrier; BTB). What is not well documented is to what degree active efflux retains function at the BTB despite the changes observed in passive permeability. In addition, there have been previous reports documenting both increased and decreased expression of P-glycoprotein (P-gp) in lesion vasculature. Herein, we simultaneously administer a passive diffusion marker (14C-AIB) and a tracer subject to P-gp efflux (rhodamine 123) into a murine preclinical model of brain metastases of breast cancer. We observed that the metastatic lesions had similar expression (p > 0.05; n = 756–1214 vessels evaluated) at the BBB and the BTB. Moreover, tissue distribution of R123 was not significantly (p > 0.05) different between normal brain and the metastatic lesion. It is possible that the similar expression of P-gp on the BBB and the BTB contribute to this phenomenon. Additionally we observed P-gp expression at the metastatic cancer cells adjacent to the vasculature which may also contribute to reduced R123 uptake into the lesion. The data suggest that despite the disrupted integrity of the BTB, efflux mechanisms appear to be intact, and may be functionally comparable to the normal BBB. The BTB is a significant hurdle to delivering drugs to brain metastasis.
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DOI：
10.1186/1756-9966-29-122
发表时间：
2010-09-05
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Guo Z;Zhu J;Zhao L;Luo Q;Jin X
通讯作者：
Jin X
影响因子：
4.5
作者：
Lockman, PR;Koziara, JM;Allen, DD
通讯作者：
Allen, DD
影响因子：
6.4
作者：
Demeule, M;Shedid, D;Beliveau, R
通讯作者：
Beliveau, R
影响因子：
2.9
作者：
Jouan, Elodie;Le Vee, Marc;Fardel, Olivier
通讯作者：
Fardel, Olivier
影响因子：
4.5
作者：
Hagenbuch, B;Meier, PJ
通讯作者：
Meier, PJ