Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, Room 13N240, Bethesda, MD 20892, U.S.A.
Essays Biochem. 2011 Sep 7;50(1):209-32. doi: 10.1042/bse0500209.
The phenomenon of multidrug resistance in cancer is often associated with the overexpression of the ABC (ATP-binding cassette) transporters Pgp (P-glycoprotein) (ABCB1), MRP1 (multidrug resistance-associated protein 1) (ABCC1) and ABCG2 [BCRP (breast cancer resistance protein)]. Since the discovery of Pgp over 35 years ago, studies have convincingly linked ABC transporter expression to poor outcome in several cancer types, leading to the development of transporter inhibitors. Three generations of inhibitors later, we are still no closer to validating the 'Pgp hypothesis', the idea that increased chemotherapy efficacy can be achieved by inhibition of transporter-mediated efflux. In this chapter, we highlight the difficulties and past failures encountered in the development of clinical inhibitors of ABC transporters. We discuss the challenges that remain in our effort to exploit decades of work on ABC transporters in oncology. In learning from past mistakes, it is hoped that ABC transporters can be developed as targets for clinical intervention.
癌症多药耐药现象通常与 ABC（ATP 结合盒）转运蛋白 Pgp（P-糖蛋白）（ABCB1）、MRP1（多药耐药相关蛋白 1）（ABCC1）和 ABCG2 [BCRP（乳腺癌耐药蛋白）] 的过度表达有关。自 35 年前发现 Pgp 以来，研究令人信服地将 ABC 转运蛋白的表达与几种癌症类型的不良预后联系起来，导致了转运蛋白抑制剂的开发。经过三代抑制剂的发展，我们仍然无法验证“Pgp 假说”，即通过抑制转运蛋白介导的外排可以提高化疗效果的观点。在本章中，我们强调了在开发 ABC 转运蛋白临床抑制剂方面遇到的困难和过去的失败。我们讨论了在利用肿瘤学中数十年的 ABC 转运蛋白工作方面仍然存在的挑战。在从过去的错误中吸取教训的同时，希望能够将 ABC 转运蛋白开发为临床干预的靶点。
