ABC transporters: unvalidated therapeutic targets in cancer and the CNS.
ABC transporters: unvalidated therapeutic targets in cancer and the CNS.
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DOI：
10.2174/187152010794473957
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发表时间：
2010-10-01
影响因子：
2.8
通讯作者：
Bates SE
中科院分区：
文献类型：
--
作者：
Robey RW;Massey PR;Amiri-Kordestani L;Bates SE
35年前在耐药细胞中发现了多药转运蛋白P-糖蛋白(Pgp)，这促使人们进行了数十年的工作，试图通过抑制药物外排来克服耐药性。尽管令人信服的实验室数据表明药物的体外转运可以被抑制，但将这一发现转化为临床的努力并未成功。由于Pgp和包括ABCG2在内的相关转运体和ABCC家族成员的过度表达与不良预后有关，因此合理的假设是这种不良预后与外排药物暴露的减少有关，从而与耐药性有关。在这篇综述中，我们将讨论ABC转运蛋白是否通过减少肿瘤中的药物积累来调节癌症的耐药性，以及“Pgp抑制假说”是否错误。这一假说认为，通过抑制Pgp介导的药物外排可以提高化疗效果，这一假说仅在模型系统中得到验证。未能在临床上证实这一点的可能原因包括肿瘤中存在其他药物积累和摄取的调节因素。尽管有这些困难，药物转运体作为中枢神经系统(CNS)治疗靶点的潜在作用已经出现。这两条研究路线都指出，需要显像剂来促进研究药物在人类癌症中的积累。这是靶向治疗的迫切需要，在这种治疗中，可能存在重要的剂量-反应关系，并且耐药性导致许多新型靶向药物在部分患者中无效。
The discovery of the multidrug transporter P-glycoprotein (Pgp) over 35 years ago in drug resistant cells prompted several decades of work attempting to overcome drug resistance by inhibition of drug efflux. Despite convincing laboratory data showing that drug transport can be inhibited in vitro, efforts to translate this discovery to the clinic have not succeeded. Since overexpression of Pgp and related transporters including ABCG2 and members of the ABCC family have been linked with poor outcome, it remains a reasonable hypothesis that this poor outcome is linked to reduction of drug exposure by efflux, and thus to drug resistance. In this review, we will discuss the question of whether ABC transporters mediate drug resistance in cancer through a reduction in drug accumulation in tumors, and whether the “Pgp inhibition hypothesis” might be wrong. The hypothesis, which holds that increased chemotherapy effectiveness can be achieved by inhibiting Pgp-mediated drug efflux has only been validated in model systems. Possible explanations for the failure to validate this clinically include the existence of other modulators of drug accumulation and uptake in tumors. Despite these difficulties, a potential role has emerged for drug transporters as therapeutic targets in the central nervous system (CNS). Both lines of investigation point to the need for imaging agents to facilitate the study of drug accumulation in human cancer. This is a critical need for targeted therapies where an important dose-response relationship is likely to exist, and where drug resistance renders many of the novel targeted agents ineffective in a subset of patients.