Effectiveness of ALK inhibitors in treatment of CNS metastases in NSCLC patients.

IF 4.9 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL
Michał Gil, Magdalena Knetki-Wróblewska, Przemysław Niziński, Maciej Strzemski, Paweł Krawczyk
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Abstract

Metastases to the central nervous system (CNS) in patients with non-small cell lung cancer constitute an extremely difficult clinical problem, and their occurrence is associated with a poor prognosis. Due to the existence of the blood-brain barrier (BBB) and the action of proteins responsible for the transport of drugs, e.g. P-glycoprotein (P-gp), the penetration of drugs into the CNS is insufficient. Until recently, the only method of CNS metastases treatment was radiotherapy and neurosurgery. The advancement of molecular biology allowed discover targets for molecularly targeted therapies. One of targets is abnormal anaplastic lymphoma kinase, which results from the rearrangement of the ALK gene in patients with non-small cell lung cancer (NSCLC). ALK rearrangement occurs in only about 4.5% of NSCLC patients, but its presence favors brain metastases. The ALK inhibitors (ALKi) were modified to obtain molecules with high ability to penetrate into the CNS. This was achieved by modifying the structure of individual molecules, which became, inter alia, less substrates for P-gp. These modifications caused that less than 10% of patients experience progression in CNS during new ALK inhibitors treatment. This review summarizes the knowledge about the action of BBB, the pharmacodynamics and pharmacokinetics of ALKi, with particular emphasis on their ability to penetrate the CNS and the intracranial activity of individual drugs from different generations of ALK inhibitors.

ALK抑制剂治疗非小细胞肺癌患者中枢神经系统转移的有效性。
癌症非小细胞肺癌患者中枢神经系统(CNS)转移是一个极其困难的临床问题,其发生与预后不良有关。由于血脑屏障(BBB)的存在和负责药物转运的蛋白质(如P-糖蛋白(P-gp))的作用,药物对中枢神经系统的渗透不足。直到最近,唯一的治疗中枢神经系统转移的方法是放射治疗和神经外科手术。分子生物学的进步使人们能够发现分子靶向治疗的靶点。靶点之一是异常间变性淋巴瘤激酶,它是由癌症(NSCLC)患者ALK基因重排引起的。ALK重排仅发生在约4.5%的NSCLC患者中,但其存在有利于脑转移。对ALK抑制剂(ALKi)进行修饰以获得具有高穿透中枢神经系统能力的分子。这是通过改变单个分子的结构来实现的,这些分子成为P-gp的较少底物。这些改变导致在新的ALK抑制剂治疗期间,只有不到10%的患者出现中枢神经系统进展。本文综述了血脑屏障的作用、ALKi的药效学和药代动力学,特别强调了它们穿透中枢神经系统的能力以及不同代ALK抑制剂的单个药物的颅内活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Annals of medicine
Annals of medicine 医学-医学:内科
CiteScore
4.90
自引率
0.00%
发文量
292
审稿时长
3 months
期刊介绍: Annals of Medicine is one of the world’s leading general medical review journals, boasting an impact factor of 5.435. It presents high-quality topical review articles, commissioned by the Editors and Editorial Committee, as well as original articles. The journal provides the current opinion on recent developments across the major medical specialties, with a particular focus on internal medicine. The peer-reviewed content of the journal keeps readers updated on the latest advances in the understanding of the pathogenesis of diseases, and in how molecular medicine and genetics can be applied in daily clinical practice.
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