Hardwick L J A, Velamakanni S, van Veen H W
Department of Pharmacology, University of Cambridge, Cambridge, UK.
Br J Pharmacol. 2007 May;151(2):163-74. doi: 10.1038/sj.bjp.0707218. Epub 2007 Mar 20.
The breast cancer resistance protein (also termed ABCG2) is an ATP-binding cassette transporter, which mediates the extrusion of toxic compounds from the cell, and which was originally identified in relation to the development of multidrug resistance of cancer cells. ABCG2 interacts with a range of substrates including clinical drugs but also substances such as sterols, porphyrins and a variety of dietary compounds. Physiological functions of ABCG2 at both cellular and systemic levels are reviewed. For example, ABCG2 expression in erythrocytes may function in porphyrin homeostasis. In addition, ABCG2 expression at apical membranes of cells such as hepatocytes, enterocytes, endothelial and syncytiotrophoblast cells may correlate to protective barrier or secretory functions against environmental or clinically administered substances. ABCG2 also appears influential in the inter-patient variation and generally poor oral bioavailability of certain chemotherapeutic drugs such as topotecan. As this often precludes an oral drug administration strategy, genotypic and environmental factors altering ABCG2 expression and activity are considered. Finally, clinical modulation of ABCG2 activity is discussed. Some of the more recent strategies include co-administered modulating agents, hammerhead ribozymes or antisense oligonucleotides, and with specificity in cell targeting, these may be used to reduce drug resistance and increase drug bioavailability to improve the profile of chemotherapeutic efficacy versus toxicity. While many such strategies remain in relative infancy at present, increased knowledge of modulators of ABCG2 could hold the key to novel approaches in medical treatment.
乳腺癌耐药蛋白(也称为ABCG2)是一种ATP结合盒转运蛋白,它介导细胞内有毒化合物的外排,最初是在癌细胞多药耐药性的发展过程中被发现的。ABCG2与一系列底物相互作用,包括临床药物以及固醇、卟啉和各种膳食化合物等物质。本文综述了ABCG2在细胞和全身水平的生理功能。例如,红细胞中ABCG2的表达可能在卟啉稳态中发挥作用。此外,肝细胞、肠上皮细胞、内皮细胞和合体滋养层细胞等细胞顶端膜上ABCG2的表达可能与针对环境或临床给药物质的保护屏障或分泌功能相关。ABCG2在某些化疗药物(如拓扑替康)的患者间差异和普遍较差的口服生物利用度方面似乎也有影响。由于这常常排除了口服给药策略,因此考虑了改变ABCG2表达和活性的基因和环境因素。最后,讨论了ABCG2活性的临床调节。一些最新的策略包括联合使用调节剂、锤头状核酶或反义寡核苷酸,并且通过细胞靶向的特异性,这些可用于降低耐药性并提高药物生物利用度,以改善化疗疗效与毒性的情况。虽然目前许多此类策略仍处于相对初期阶段,但对ABCG2调节剂的更多了解可能是医疗新方法的关键。