Reversing Agents for ATP-Binding Cassette Drug Transporters
Reversing Agents for ATP-Binding Cassette Drug Transporters
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DOI：
10.1007/978-1-60761-416-6_14
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发表时间：
2010-01-01
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影响因子：
--
通讯作者：
Lee, Chow H.
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文献类型：
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作者：
Lee, Chow H.
肿瘤细胞所表现出的多药耐药（MDR）表型被认为是肿瘤患者成功化疗的主要障碍。MDR表型的主要形式是由一组ATP结合盒（ABC）药物转运蛋白，包括P-糖蛋白，多药耐药相关蛋白1和乳腺癌耐药蛋白。人们一直在积极寻找能够在培养细胞、动物模型以及最终在患者中逆转MDR表型的化合物。对MDR调节剂的持续研究，直接作用于ABC转运蛋白以阻断其活性的化合物，已经产生了三代药物。一些第三代MDR调节剂在临床试验中显示出与前几代MDR调节剂相比令人鼓舞的结果。这些调节剂毒性较低，并且不影响抗癌药物的药代动力学。大量的天然产物也已被鉴定为以类似于MDR调节剂的方式有效逆转MDR。本章还对其他已被广泛研究的MDR逆转策略进行了回顾和讨论。这些包括旨在破坏ABC药物转运蛋白mRNA的策略，抑制ABC转运蛋白基因转录的方法，使用抗体中等阻断ABC转运蛋白活性的方法。本文综述了ABC药物转运蛋白LIP的逆转剂的发展到2008年底，并提供了一个乐观的看法，我们已经取得了什么，我们可以从这里去。
The multidrug resistance (MDR) phenotype exhibited by cancer cells is believed to be the major barriers to successful chemotherapy in cancer patients. The major form of MDR phenotype is contributed by a group of ATP-binding cassette (ABC) drug transporters which include P-glycoprotein, multidrug resistance-associated protein 1, and breast cancer resistance protein. There has been intense search for compounds which can act to reverse MDR phenotype in cultured cells, in animal models, and ultimately in patients. The ongoing search for MDR modulators, Compounds that act directly on the ABC transporter proteins to block their activity, has led to three generations of drugs. Some of the third-generation MDR modulators have demonstrated encouraging results compared to earlier generation MDR modulators in clinical trials. These modulators are less toxic and they do not affect the pharmacokinetics of anticancer drugs. Significant numbers of natural products have also been identified for their effectiveness in reversing MDR in a manner similar to the MDR modulators. Other MDR reversing strategies that have been studied quite extensively are also reviewed and discussed in this chapter. These include strategies aimed at destroying mRNAs for ABC drug transporters, approaches in inhibiting transcription of ABC transporter genes, mid blocking of ABC transporter activity using antibodies. This review summarizes the development of reversing agents for ABC drug transporters LIP to the end of 2008, and provides an optimistic view of what we have achieved and where we could go from here.