The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with anti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated, resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein overexpression, and multidrug resistance (MDR). Clearly however, additional mechanisms such as single nucleotide polymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and of other MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and the wealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vast knowledge from the bench to the bedside has proven to be unexpectedly difficult.

Many studies show that upon repeated treatment schedules of cell cultures or tumors with taxenes and anthracyclines as well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genes genomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins may contribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genes contained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed in many cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. This review describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possible connections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1 amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies to overcome cancer MDR.

耐药性的发展仍然是治愈性癌症治疗的主要障碍。广谱的ATP依赖性外排泵的过度表达，尤其是ABCB1（P-糖蛋白或MDR1）的过度表达是众所周知的对多种癌症化学治疗药物的耐药机制，包括紫杉烷类，蒽环类，长春花生物碱和表鬼臼毒素，已在肿瘤细胞系和各种肿瘤（包括各种实体瘤和血液系统恶性肿瘤）中发表的大量论文得到证实。在用抗肿瘤药（例如紫杉醇和阿霉素）对培养的肿瘤细胞或体内肿瘤进行重复甚至单次剂量治疗后，ABCB1升高已经证实拷贝数是由7q11.2-21位点处的染色体扩增事件导致的，导致明显的P-糖蛋白过表达和多药耐药性（MDR）。但是，显然，其他机制如单核苷酸多态性（SNP）和表观遗传修饰已显示出ABCB1和其他MDR外排泵过表达的作用。然而，尽管设计了4代ABCB1抑制剂，并且获得了有关ABC转运蛋白的生物化学和底物特异性的大量信息，但事实证明，将这些广博的知识从实验台转移到床边非常困难。

许多研究表明，使用紫杉类和蒽环类以及其他化学治疗药物对细胞培养物或肿瘤进行重复治疗后，可以观察到一系列基因组基因组周围ABCB1基因座的扩增和/或过表达。因此，其他蛋白质水平的改变可能有助于建立MDR表型，并导致不良的临床结果。因此，包含在该ABCB1扩增子中的基因包括ABCB4，SRI，DBF4，TMEM243和RUNDC3B在许多癌症中，尤其是在MDR肿瘤中过表达，而TP53TG1和DMTF1是真正的抑癌药。这篇综述描述了这些基因在癌症中的作用，尤其是在MDR的获得中，阐明了属于同一ABCB1扩增子区域的基因在转录调控（共扩增/抑制）中的可能联系，并描述了它们对肿瘤生物学的新的新兴贡献。以及克服癌症MDR的可能策略。