Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain.
Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain.
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DOI：
10.1017/s1462399411001888
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发表时间：
2011-05-13
影响因子：
6.2
通讯作者：
Elmquist WF
中科院分区：
文献类型：
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作者：
Agarwal S;Sane R;Oberoi R;Ohlfest JR;Elmquist WF
多形性胶质母细胞瘤，由于其侵袭性，可以被认为是整个大脑的疾病。尽管最近在手术、放疗和化疗方面取得了进展，但目前的治疗方案对患者生存率的影响很小。癌症研究人员面临的一个关键挑战是有效地将药物递送到位于中枢神经系统内避难所的侵袭性胶质瘤细胞。血脑屏障（BBB）限制许多小分子和大分子进入大脑。药物向大脑的递送进一步受到BBB中存在的主动外排转运蛋白的限制，这些转运蛋白将药物从大脑中转运回血液。目前对药物递送的临床评估以及因此的功效是基于通常通过手术去除的大块肿瘤块中测量的药物水平。越来越多的证据表明，多形性胶质母细胞瘤不可避免的复发和致命性是由于未能有效治疗侵袭性胶质瘤细胞。这些侵入性细胞隐藏在被完整的BBB屏蔽的大脑区域中，在那里它们继续生长并引起复发性肿瘤。因此，将化疗剂有效递送至侵袭性神经胶质瘤细胞是至关重要的，并且长期功效将取决于分子靶向剂穿透整个脑中的完整和功能性BBB的能力。这篇综述强调了血脑屏障的各个方面，以及脑肿瘤细胞屏障，一种由于肿瘤细胞外排转运蛋白表达而形成的屏障，它们共同作用可以显著影响药物反应。然后，它讨论了胶质瘤作为一种全脑疾病的特殊挑战，特别强调需要有效地将药物递送穿过BBB以到达中央肿瘤和侵袭性胶质瘤细胞。
Glioblastoma multiforme, due to its invasive nature, can be considered a disease of the entire brain. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. A crucial challenge faced by cancer researchers is to effectively deliver drugs to invasive glioma cells residing in a sanctuary within the central nervous system. The blood–brain barrier (BBB) restricts delivery of many small and large molecules into the brain. Drug delivery to the brain is further restricted by active efflux transporters present at the BBB, which transport drugs out of the brain back into the blood. Current clinical assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumor mass that is usually removed by surgery. Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme is due to a failure to effectively treat invasive glioma cells. These invasive cells hide in areas of the brain that are shielded by an intact BBB where they continue to grow and give rise to the recurrent tumor. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore critical, and long-term efficacy will depend upon the ability of a molecularly targeted agent to penetrate an intact and functional BBB throughout the entire brain. This review highlights the various aspects of the BBB, and also the brain–tumor-cell barrier, a barrier due to expression of efflux transporters in tumor cells, that together can significantly influence drug response. It then discusses the special challenge of glioma as a disease of the whole brain, which lends particular emphasis to the need to effectively deliver drugs across the BBB to reach both the central tumor and the invasive glioma cells.